US009265.742B2

(12) United States Patent (10) Patent No.: US 9,265,742 B2 Bannister et al. (45) Date of Patent: *Feb. 23, 2016

(54) COMPOSITIONS AND METHODS FOR (56) References Cited TREATING INFLAMMATORY PAIN U.S. PATENT DOCUMENTS (71) Applicant: Infirst Healthcare Limited, London 3,228,831 A 1/1966 Nicholson et al. (GB) 3,800,038 A 3, 1974 Rudel 4,571.400 A 2f1986 Arnold 4,684.666 A 8, 1987 HaaS (72) Inventors: Robin M. Bannister, Essex (GB); John 4,918, 103 A 4, 1990 Park et al. Brew, Hertfordshire (GB) 5,011,852 A 4, 1991 Park et al. 5,059,626 A * 10/1991 Park et al...... 514,658 5,154,930 A 10/1992 Popescu (73) Assignee: Infirst Healthcare Limited (GB) 5,552,160 A 9/1996 Liversidge et al. 5,645,856 A 7/1997 Lacy et al. 5,955.451 A 9/1999 Lichtenberger et al. (*) Notice: Subject to any disclaimer, the term of this 6,267,985 B1 7/2001 Chen et al. patent is extended or adjusted under 35 6,294,192 B1 9, 2001 Patel et al. U.S.C. 154(b) by 0 days. 6,319,513 B1 1 1/2001 Dobrozsi 6,383,471 B1 5, 2002 Chen et al. This patent is Subject to a terminal dis 6,451,339 B2 9, 2002 Patel et al. claimer. 6,923,988 B2 8, 2005 Patel et al. 7,473.432 B2 1/2009 Cevc et al. 2003,0008003 A1 1/2003 Jamali (21) Appl. No.: 14/155,080 2003/0170279 A1 9, 2003 Lambert et al. 2003/0232097 A1 12/2003 Radhakrishnan et al. 2004.0024057 A1 2/2004 Earl et al. (22) Filed: Jan. 14, 2014 2004/O25.3276 A1 12/2004 Sato et al. 2005/O152968 A1 7/2005 Brophy et al. (65) Prior Publication Data 2006, OO6281.0 A1 3/2006 Woo et al. 2006,007861.6 A1 4/2006 Georgewill et al. US 2014/O128354 A1 May 8, 2014 2007, OO15834 A1 1/2007 Flashner-Barak et al. 2007.0036831 A1 2/2007 Baker 2007, 0104741 A1 5/2007 Murty et al. Related U.S. Application Data 2007. O19008O A1 8/2007 Friedman (63) Continuation-in-part of application No. 13/365,824, (Continued) filed on Feb. 3, 2012, now Pat. No. 8,895,536, which is FOREIGN PATENT DOCUMENTS a continuation-in-part of application No. PCT/GB2011/052115, filed on Oct. 31, 2011. CN 1736,369 2, 2006 CN 101.129335 A 2, 2008 (60) Provisional application No. 61/752.356, filed on Jan. (Continued) 14, 2013. OTHER PUBLICATIONS (30) Foreign Application Priority Data Csizmazia, E., et al., Penetration enhancer effect of Sucrose laurate and Transcutol on ibuprofen, Journal of Drug Delivery Science and Oct. 29, 2010 (GB) ...... 1018289.7 Technology, vol. 21, No. 5 Sep. 2011 XP009 168551. Feb. 4, 2011 (GB) ...... 11 O1937.9 Hesson Chung, et al., Oil Components Modulate Physical Charac Aug. 10, 2011 (GB) ...... 1113728.8 teristics and Function of the Natural Oil Emulsions as Drug or Gene Delivery System, Journal of Controlled Release 71:339-350 (2001). Aug. 10, 2011 (GB) ...... 1113729.6 List et al., Hydrogenation of Soybean Oil Triglycerides: Effect of Aug. 10, 2011 (GB) ...... 1113730.4 Pressure on Selectivity. JAOCS (2000), vol. 77, pp. 311-314. Nickitas-Etienne, PCT International Preliminary Report on Patent (51) Int. Cl. ability, PCT/GB2011/050 189, pp. 11 (Aug. 7, 2012). A6 IK3I/9 (2006.01) Nickitas-Etienne, PCT International Preliminary Report on Patent ability, PCT/GB2011/052115, pp. 8 (Apr. 30, 2013). A6 IK3I/92 (2006.01) PCT International Search Report and the Written Opinion of the A6 IK3I/96 (2006.01) Internation Searching Authority PCT/EP2014/050627. A6 IK3I/60 (2006.01) A6 IK9/08 (2006.01) (Continued) A6 IK 47/44 (2006.01) Primary Examiner — Kevin E Weddington A6 IK9/20 (2006.01) (74) Attorney, Agent, or Firm — One3 IP Management, P.C.; (52) U.S. Cl. Dean G. Stathakis; Peter D. Weinstein CPC ...... A61 K31/192 (2013.01); A61 K9/08 (2013.01); A61 K9/2013 (2013.01); A61 K (57) ABSTRACT 31/196 (2013.01); A61 K3I/60 (2013.01); The present specification discloses pharmaceutical composi A61K 47/44 (2013.01); A61 K31/19 (2013.01) tions, methods of preparing Such pharmaceutical composi (58) Field of Classification Search tions, and methods and uses of treating a chronic inflamma CPC ...... A61K 31/19: A61K 3 1/60; A61 K31/202 tion and/or an inflammatory disease in an individual using USPC ...... 514/570, 571 Such pharmaceutical compositions. See application file for complete search history. 26 Claims, No Drawings US 9,265,742 B2 Page 2

(56) References Cited WO 2006/099325 A2 9, 2006 WO 2008/070950 A1 6, 2008 U.S. PATENT DOCUMENTS WO WO 2008070950 A1 * 6, 2008 WO 2008.120207 A3 10, 2008 2007/0203173 A1 8, 2007 Mudumba et al. WO 2008, 134512 A1 11, 2008 2008. O153894 A1 6/2008 Britten et al. WO 2009/033131 A2 3, 2009 2008. O15421.0 A1 6/2008 Jordan et al. WO 2009/047785 A3 4, 2009 20090304782 A1 12, 2009 De Blas et al. WO 2009/067734 A1 6, 2009 2010.0099767 A1 4, 2010 Davis WO 2009/069139 A1 6, 2009 2010.0125060 A1 5, 2010 Razzak et al. WO 2010/059717 A2 5, 2010 2011/O142945 A1 6, 2011 Chen et al. WO 2010/087947 A2 8, 2010 2011/0195993 Al 8, 2011 Masson et al. WO 2010/0973.32 A1 9, 2010 2012fO270845 A1 10, 2012 Bannister et al. WO 2010/097334 A1 9, 2010 2012fO270899 A1 10, 2012 Bannister et al. WO 2010 103312 A1 9, 2010 2013, O156853 A1 6, 2013 Zh tal WO WO 2010 103312 A1 ck 9, 2010 ang et al. WO 2011/095814 A1 8, 2011 WO 2012/056251 A1 5, 2012 FOREIGN PATENT DOCUMENTS WO 2012, 104654 A1 8, 2012 WO 2012, 104655 A2 8, 2012 CN 102.793628 A 11, 2012 OTHER PUBLICATIONS EP 306060 A2 3, 1989 PCT International Search Report and the Written Opinion of the EP Q32: A2, 1993 Internation Searching Authority PCT/EP2014/050628. FR 2810243 A1 * 12/2001 PCT International Search Report and the Written Opinion of the GB 233.1458. A 5, 1999 Internation Searching Authority PCT/EP2014/050637. 36. A i.e. Schule, PCT International Search Report & Written Opinion, JP 2008143807 12/2006 PCTGB2012050241, pp. 24 (Jul 13, 2012). JP 2009 155282 T 2009 Schule, PCT International Search Report & Written Opinion, WO 92.09272 A1 6, 1992 PCTGB2012050242, pp. 12 (Jan. 22, 2013). WO 95/11039 A1 4f1995 Strickley, Solubilizing Excipients in Oral and Inkectable Formula WO 97.03655 A1 2, 1997 tions Pharaceutical (2004), yol. 21, pp. 21, pp. 201-230. WO 98.25595 A1 6, 1998 Wolfgang Grebe, et al., a Multicenter, Randomized, Double-Blind, WO OOf 27372 A1 5, 2000 Double-Dummy, Placebo- and Active-Controlled, Parallel-Group WO OO57859 A1 5, 2000 Comparison of Diclofenac-K and Ibuprofen for the Treatment of WO OOf 67728 A2 11/2000 Adults with Influenza-like Symptoms, Clinical Therapeutics 25(2): WO OOf 76478 A1 12/2000 444-459 (2003). WO 02/085414 A2 10/2002 Vane Jr et al., Mechanism of action of anti-inflammatory drugs, IntJ WO O3,O13566 A1 2, 2003 Tissue React. 1998:20(1):3-15, abstract. WO 2004/082.588 A2 9, 2004 WO 2005/OO9436 A1 2/2005 * cited by examiner US 9,265,742 B2 1. 2 COMPOSITIONS AND METHODS FOR ceptable adjuvant. In other aspects, the pharmaceutical com TREATING INFLAMMATORY PAN positions disclosed herein further comprise a pharmaceutically-acceptable stabilizing agent. This continuation-in-part application claims priority pur Other aspects of the present specification disclose a suant to 35 U.S.C. S 120 to patent application U.S. Ser. No. method of preparing a pharmaceutical composition, the 13/365.824, filed Feb. 3, 2012, a continuation-in-part appli method comprising the step of contacting a therapeutic com cation that claims priority to patent application PCT/ pound with a pharmaceutically-acceptable adjuvant under GB2011/052115, filed Oct. 31, 2011, an international patent conditions which allow the formation of the pharmaceutical application that claims priority to GB 1018289.7, filed Oct. composition. Other aspects of the present specification dis 29, 2010, and claims priority to patent application U.S. Ser. 10 close a method of preparing a pharmaceutical composition, No. 13/365,828, filed Feb. 3, 2012, and claims priority to GB the method comprising the steps: a) contacting a pharmaceu 1113730.4, filed Aug. 10, 2011, GB 11 13729.6, filed Aug. 10, tically-acceptable solvent with atherapeutic compound under 2011, GB 1113728.8, filed Aug. 10, 2011, and GB conditions which allow the therapeutic compound to dissolve 1101937.9, filed Feb. 4, 2011, and this continuation-in-part in the pharmaceutically-acceptable solvent, thereby forming application claims priority pursuant to 35 U.S.C. S 119(e) to 15 a solution, wherein the therapeutic compound has an anti U.S. Provisional Patent Application 61/752,309, filed Jan. 14, pain activity, and b) contacting the solution formed in Step (a) 2013, and U.S. Provisional Patent Application 61/752,356, with a pharmaceutically-acceptable adjuvant under condi filed Jan. 14, 2013, each of which is hereby incorporated by tions which allow the formation of the pharmaceutical com reference in its entirety. position. In other aspects, the method of preparing disclosed Pain is a subjective and very complex perception that sig herein further comprises c) removing the pharmaceutically nals to an individual that tissue damage has occurred or may acceptable solvent from the pharmaceutical composition. be occurring. Pain may be transitory, lasting only until the Other aspects of the present specification disclose a phar noxious stimulus causing the pain is removed or the underling maceutical composition, the pharmaceutical composition damage or pathology has healed or may lasts beyond the made according to a method comprising the step of contact healing of an injury, continuing for a period of several months 25 ing a therapeutic compound with a pharmaceutically-accept or longer. A pain response has both physiological as well as able adjuvant under conditions which allow the formation of psychological components. A pain response evokes a wide the pharmaceutical composition. Other aspects of the present range of sensations that may be described as a dull, aching specification disclose a pharmaceutical composition, the sensation, a sharp stabbing sensation, a hot, cold, or icy-hot pharmaceutical composition made according to a method sensation, a tingling or itchy sensation or a numbness. Pain 30 comprising the steps: a) contacting a pharmaceutically-ac can be felt in one area of the body, Such as your back, abdo ceptable solvent with a therapeutic compound under condi men or chest or throughout the body, such as when all the tions which allow the therapeutic compound to dissolve in the muscles in a body ache from the flu. pharmaceutically-acceptable solvent, thereby forming a solu Severe pain is the most common reason for an individual to tion, wherein the therapeutic compound has an anti-pain consult a healthcare provider in the United States. It is a major 35 activity, and b) contacting the Solution formed in step (a) with symptom in many medical conditions, and can significantly a pharmaceutically-acceptable adjuvant under conditions interfere with a person’s quality of life and general function which allow the formation of the pharmaceutical composi ing. As such, severe pain is a significant and costly healthcare tion. In other aspects, the method of making a pharmaceutical problem. composition disclosed herein further comprises c) removing Current therapies for treating severe pain are limited, often 40 the pharmaceutically-acceptable solvent from the pharma involving the administration of multiple medications with the ceutical composition. understanding that pain relief will not be complete and the Other aspects of the present specification disclose a quality of life may not be restored. These therapies may method of treating an individual with a severe pain condition, require frequent dosing, can be associated with undesirable the method comprising the step of administering to the indi systemic side effects, and typically provide unsatisfactory 45 vidual in need thereof a pharmaceutical composition dis relief. Therefore, there remains a need for a therapeutic option closed herein, whereinadministration results in a reduction in developed specifically for severe pain that provides sustained a symptom associated with the severe pain condition, thereby relief while minimizing the potential for systemic side effects treating the individual. and drug-drug interactions. Other aspects of the present specification disclose a use of The present specification discloses pharmaceutical com 50 a pharmaceutical composition disclosed herein in the manu positions and methods for treating an individual Suffering facture of a medicament for the treatment of a severe pain from a severe pain condition. The pharmaceutical composi condition. tions disclosed herein are essentially a lipid delivery system Other aspects of the present specification disclose a use of that enables atherapeutic compound having anti-pain activity a pharmaceutical composition disclosed herein for the treat to be delivered in a manner that more effectively inhibits a 55 ment of a severe pain condition. pain response. The end result is an improved treatment for a severe pain condition. DESCRIPTION SUMMARY Aspects of the present specification disclose, in part, a 60 composition. A composition disclosed herein is generally Aspects of the present specification disclose a pharmaceu administered as a pharmaceutical acceptable composition. As tical composition comprising a therapeutic compound and a used herein, the term “pharmaceutically acceptable” refers pharmaceutically-acceptable adjuvant. A therapeutic com any molecular entity or composition that does not produce an pound may have an anti-pain activity. Other aspects of the adverse, allergic or other untoward or unwanted reaction present specification disclose a pharmaceutical composition 65 when administered to an individual. As used herein, the term comprising a therapeutic compound disclosed herein, a phar “pharmaceutically acceptable composition' is synonymous maceutically-acceptable solvent, and a pharmaceutically-ac with “pharmaceutical composition' and means a therapeuti US 9,265,742 B2 3 4 cally effective concentration of an active ingredient, Such as, tation, benzalkonium chloride, chlorobutanol, thimerosal, e.g., any of the therapeutic compounds disclosed herein. A phenylmercuric acetate, phenylmercuric nitrate, a stabilized pharmaceutical composition disclosed herein is useful for oxychloro composition and chelants, such as, e.g., DTPA or medical and Veterinary applications. A pharmaceutical com DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. position may be administered to an individual alone, or in Tonicity adjustors useful in a pharmaceutical composition combination with other Supplementary active ingredients, include, without limitation, salts such as, e.g., Sodium chlo agents, drugs or hormones. ride, potassium chloride, mannitol or glycerin and other phar A pharmaceutical composition disclosed herein may maceutically acceptable tonicity adjustor. The pharmaceuti optionally include a pharmaceutically-acceptable carrier that cal composition may be provided as a salt and can be formed facilitates processing of an active ingredient into pharmaceu 10 with many acids, including but not limited to, hydrochloric, tically-acceptable compositions. As used herein, the term Sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend “pharmacologically-acceptable carrier is synonymous with to be more soluble in aqueous or other protonic solvents than “pharmacological carrier and means any carrier that has are the corresponding free base forms. It is understood that Substantially no long term or permanent detrimental effect these and other Substances known in the art of pharmacology when administered and encompasses terms such as “pharma 15 can be included in a pharmaceutical composition. cologically acceptable vehicle, stabilizer, diluent, additive, In one embodiment, a pharmaceutical composition dis auxiliary or excipient. Such a carrier generally is mixed with closed herein comprises a therapeutic compound having an a therapeutic compound or permitted to dilute or enclose the anti-pain activity and a pharmaceutically-acceptable adju active compound and can be a solid, semi-solid, or liquid vant. An anti-pain activity encompasses a deadening or agent. It is understood that a therapeutic compound or other absence of the sense of pain or nociception without loss of active ingredient can be soluble or can be delivered as a consciousness and includes, without limitation, an analgesic Suspension in the desired carrier or diluent. Any of a variety of activity, and/or a nociceptive activity. In another embodi pharmaceutically acceptable carriers can be used including, ment, a pharmaceutical composition disclosed herein com without limitation, aqueous media such as, e.g., water, Saline, prises a therapeutic compound having an anti-pain activity, a glycine, hyaluronic acid and the like; Solid carriers such as, 25 pharmaceutically-acceptable solvent, and a pharmaceuti e.g., mannitol, lactose, starch, magnesium Stearate, sodium cally-acceptable adjuvant. In aspects of this embodiment, a saccharin, talcum, cellulose, glucose, Sucrose, magnesium pharmaceutical composition disclosed herein may further carbonate, and the like; Solvents; dispersion media; coatings; comprise a pharmaceutically-acceptable stabilizing agent. In antibacterial and antifungal agents; isotonic and absorption other aspects of this embodiment, a pharmaceutical compo delaying agents; or any other inactive ingredient. Selection of 30 sition disclosed herein may further comprise a pharmaceuti a pharmacologically acceptable carrier can depend on the cally-acceptable carrier, a pharmaceutically-acceptable com mode of administration. Except insofar as any pharmacologi ponent, or both pharmaceutically-acceptable carrier and cally acceptable carrier is incompatible with the active ingre pharmaceutically-acceptable component. dient, its use in pharmaceutically acceptable compositions is Aspects of the present specification disclose, in part, a contemplated. Non-limiting examples of specific uses of such 35 therapeutic compound. A therapeutic compound is a com pharmaceutical carriers can be found in Pharmaceutical Dos pound that provides pharmacological activity or other direct age Forms and Drug Delivery Systems (Howard C. Ansel et effect in the diagnosis, cure, mitigation, treatment, or preven al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. tion of disease, or to affect the structure or any function of the 1999); REMINGTON: THE SCIENCE AND PRACTICE body of man or animals. A therapeutic compound disclosed OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Wil 40 herein may be used in the form of a pharmaceutically accept liams & Wilkins, 20th ed. 2000); Goodman & Gilman's The able salt, Solvate, or Solvate of a salt, e.g. the hydrochloride. Pharmacological Basis of Therapeutics (Joel G. Hardman et Additionally, therapeutic compound disclosed herein may be al., eds., McGraw-Hill Professional, 10th ed. 2001); and provided as racemates, or as individual enantiomers, includ Handbook of Pharmaceutical Excipients (Raymond C. Rowe ing the R- or S-enantiomer. Thus, the therapeutic compound et al., APhA Publications, 4th edition 2003). These protocols 45 disclosed herein may comprise a R-enantiomer only, a are routine procedures and any modifications are well within S-enantiomer only, or a combination of both a R-enantiomer the scope of one skilled in the art and from the teaching and a S-enantiomer of a therapeutic compound. A therapeutic herein. compound disclosed herein may have an anti-pain activity. A pharmaceutical composition disclosed herein can In an embodiment, a therapeutic compound disclosed optionally include, without limitation, other pharmaceuti 50 herein has an anti-pain activity capable of reducing a severe cally acceptable components (or pharmaceutical compo pain response. In aspects of this embodiment, a therapeutic nents), including, without limitation, buffers, preservatives, compound disclosed herein has an anti-pain activity capable tonicity adjusters, salts, antioxidants, osmolality adjusting of reducing a severe pain response by, e.g., at least 10%, at agents, physiological Substances, pharmacological Sub least 15%, at least 20%, at least 25%, at least 30%, at least stances, bulking agents, emulsifying agents, wetting agents, 55 35%, at least 40%, at least 45%, at least 50%, at least 55%, at Sweetening or flavoring agents, and the like. Various buffers least 60%, at least 65%, at least 70%, at least 75%, at least and means for adjusting pH can be used to prepare a pharma 80%, at least 85%, at least 90% or at least 95%. In other ceutical composition disclosed herein, provided that the aspects of this embodiment, a therapeutic compound dis resulting preparation is pharmaceutically acceptable. Such closed herein has an anti-pain activity capable of reducing a buffers include, without limitation, acetate buffers, citrate 60 severe pain response in a range from, e.g., about 10% to about buffers, phosphate buffers, neutral buffered saline, phosphate 100%, about 20% to about 100%, about 30% to about 100%, buffered saline and borate buffers. It is understood that acids about 40% to about 100%, about 50% to about 100%, about or bases can be used to adjust the pH of a composition as 60% to about 100%, about 70% to about 100%, about 80% to needed. Pharmaceutically acceptable antioxidants include, about 100%, about 10% to about 90%, about 20% to about without limitation, sodium metabisulfite, sodium thiosulfate, 65 90%, about 30% to about 90%, about 40% to about 90%, acetylcysteine, butylated hydroxyanisole and butylated about 50% to about 90%, about 60% to about 90%, about 70% hydroxytoluene. Useful preservatives include, without limi to about 90%, about 10% to about 80%, about 20% to about US 9,265,742 B2 5 6 80%, about 30% to about 80%, about 40% to about 80%, 100%, about 40% to about 100%, about 50% to about 100%, about 50% to about 80%, or about 60% to about 80%, about about 60% to about 100%, about 70% to about 100%, about 10% to about 70%, about 20% to about 70%, about 30% to 80% to about 100%, about 10% to about 90%, about 20% to about 70%, about 40% to about 70%, or about 50% to about about 90%, about 30% to about 90%, about 40% to about 70%. 5 90%, about 50% to about 90%, about 60% to about 90%, In an embodiment, a therapeutic compound disclosed about 70% to about 90%, about 10% to about 80%, about 20% herein has an anti-pain activity capable of reducing a nocice to about 80%, about 30% to about 80%, about 40% to about ptive pain response. In aspects of this embodiment, a thera 80%, about 50% to about 80%, or about 60% to about 80%, peutic compound disclosed herein has an anti-pain activity about 10% to about 70%, about 20% to about 70%, about 30% capable of reducing a nociceptive pain response by, e.g., at 10 to about 70%, about 40% to about 70%, or about 50% to about least 10%, at least 15%, at least 20%, at least 25%, at least 70%. 30%, at least 35%, at least 40%, at least 45%, at least 50%, at In an embodiment, a therapeutic compound disclosed least 55%, at least 60%, at least 65%, at least 70%, at least herein has an anti-pain activity capable of reducing a visceral 75%, at least 80%, at least 85%, at least 90% or at least 95%. pain response. In aspects of this embodiment, a therapeutic In other aspects of this embodiment, a therapeutic compound 15 compound disclosed herein has an anti-pain activity capable disclosed herein has an anti-pain activity capable of reducing of reducing a visceral pain response by, e.g., at least 10%, at a nociceptive pain response in a range from, e.g., about 10% least 15%, at least 20%, at least 25%, at least 30%, at least to about 100%, about 20% to about 100%, about 30% to about 35%, at least 40%, at least 45%, at least 50%, at least 55%, at 100%, about 40% to about 100%, about 50% to about 100%, least 60%, at least 65%, at least 70%, at least 75%, at least about 60% to about 100%, about 70% to about 100%, about 80%, at least 85%, at least 90% or at least 95%. In other 80% to about 100%, about 10% to about 90%, about 20% to aspects of this embodiment, a therapeutic compound dis about 90%, about 30% to about 90%, about 40% to about closed herein has an anti-pain activity capable of reducing a 90%, about 50% to about 90%, about 60% to about 90%, visceral pain response in a range from, e.g., about 10% to about 70% to about 90%, about 10% to about 80%, about 20% about 100%, about 20% to about 100%, about 30% to about to about 80%, about 30% to about 80%, about 40% to about 25 100%, about 40% to about 100%, about 50% to about 100%, 80%, about 50% to about 80%, or about 60% to about 80%, about 60% to about 100%, about 70% to about 100%, about about 10% to about 70%, about 20% to about 70%, about 30% 80% to about 100%, about 10% to about 90%, about 20% to to about 70%, about 40% to about 70%, or about 50% to about about 90%, about 30% to about 90%, about 40% to about 70%. 90%, about 50% to about 90%, about 60% to about 90%, In an embodiment, a therapeutic compound disclosed 30 about 70% to about 90%, about 10% to about 80%, about 20% herein has an anti-pain activity capable of reducing a pain to about 80%, about 30% to about 80%, about 40% to about response mediated by a nociceptive receptor. In aspects of this 80%, about 50% to about 80%, or about 60% to about 80%, embodiment, atherapeutic compound disclosed herein has an about 10% to about 70%, about 20% to about 70%, about 30% anti-pain activity capable of reducing a pain response medi to about 70%, about 40% to about 70%, or about 50% to about ated by a nociceptive receptor by, e.g., at least 10%, at least 35 70%. 15%, at least 20%, at least 25%, at least 30%, at least 35%, at In an embodiment, a therapeutic compound disclosed least 40%, at least 45%, at least 50%, at least 55%, at least herein has an anti-pain activity capable of reducing a patho 60%, at least 65%, at least 70%, at least 75%, at least 80%, at logical pain response. In aspects of this embodiment, a thera least 85%, at least 90% or at least 95%. In other aspects of this peutic compound disclosed herein has an anti-pain activity embodiment, atherapeutic compound disclosed herein has an 40 capable of reducing a pathological pain response by, e.g., at anti-pain activity capable of reducing a pain response medi least 10%, at least 15%, at least 20%, at least 25%, at least ated by a nociceptive receptorina range from, e.g., about 10% 30%, at least 35%, at least 40%, at least 45%, at least 50%, at to about 100%, about 20% to about 100%, about 30% to about least 55%, at least 60%, at least 65%, at least 70%, at least 100%, about 40% to about 100%, about 50% to about 100%, 75%, at least 80%, at least 85%, at least 90% or at least 95%. about 60% to about 100%, about 70% to about 100%, about 45 In other aspects of this embodiment, a therapeutic compound 80% to about 100%, about 10% to about 90%, about 20% to disclosed herein has an anti-pain activity capable of reducing about 90%, about 30% to about 90%, about 40% to about a pathological pain response in a range from, e.g., about 10% 90%, about 50% to about 90%, about 60% to about 90%, to about 100%, about 20% to about 100%, about 30% to about about 70% to about 90%, about 10% to about 80%, about 20% 100%, about 40% to about 100%, about 50% to about 100%, to about 80%, about 30% to about 80%, about 40% to about 50 about 60% to about 100%, about 70% to about 100%, about 80%, about 50% to about 80%, or about 60% to about 80%, 80% to about 100%, about 10% to about 90%, about 20% to about 10% to about 70%, about 20% to about 70%, about 30% about 90%, about 30% to about 90%, about 40% to about to about 70%, about 40% to about 70%, or about 50% to about 90%, about 50% to about 90%, about 60% to about 90%, 70%. about 70% to about 90%, about 10% to about 80%, about 20% In an embodiment, a therapeutic compound disclosed 55 to about 80%, about 30% to about 80%, about 40% to about herein has an anti-pain activity capable of reducing a Somatic 80%, about 50% to about 80%, or about 60% to about 80%, pain response. In aspects of this embodiment, a therapeutic about 10% to about 70%, about 20% to about 70%, about 30% compound disclosed herein has an anti-pain activity capable to about 70%, about 40% to about 70%, or about 50% to about of reducing a Somatic pain response by, e.g., at least 10%, at 70%. least 15%, at least 20%, at least 25%, at least 30%, at least 60 In an embodiment, a therapeutic compound disclosed 35%, at least 40%, at least 45%, at least 50%, at least 55%, at herein has an anti-pain activity capable of reducing a neuro least 60%, at least 65%, at least 70%, at least 75%, at least pathic pain response. In aspects of this embodiment, a thera 80%, at least 85%, at least 90% or at least 95%. In other peutic compound disclosed herein has an anti-pain activity aspects of this embodiment, a therapeutic compound dis capable of reducing a neuropathic pain response by, e.g., at closed herein has an anti-pain activity capable of reducing a 65 least 10%, at least 15%, at least 20%, at least 25%, at least Somatic pain response in a range from, e.g., about 10% to 30%, at least 35%, at least 40%, at least 45%, at least 50%, at about 100%, about 20% to about 100%, about 30% to about least 55%, at least 60%, at least 65%, at least 70%, at least US 9,265,742 B2 7 8 75%, at least 80%, at least 85%, at least 90% or at least 95%. therapeutic compound disclosed herein has an anti-pain In other aspects of this embodiment, a therapeutic compound activity capable of reducing a mononeuropathic pain disclosed herein has an anti-pain activity capable of reducing response by, e.g., at least 10%, at least 15%, at least 20%, at a neuropathic pain response in a range from, e.g., about 10% least 25%, at least 30%, at least 35%, at least 40%, at least to about 100%, about 20% to about 100%, about 30% to about 45%, at least 50%, at least 55%, at least 60%, at least 65%, at 100%, about 40% to about 100%, about 50% to about 100%, least 70%, at least 75%, at least 80%, at least 85%, at least about 60% to about 100%, about 70% to about 100%, about 90% or at least 95%. In other aspects of this embodiment, a 80% to about 100%, about 10% to about 90%, about 20% to therapeutic compound disclosed herein has an anti-pain about 90%, about 30% to about 90%, about 40% to about activity capable of reducing a mononeuropathic pain 90%, about 50% to about 90%, about 60% to about 90%, 10 response in a range from, e.g., about 10% to about 100%, about 70% to about 90%, about 10% to about 80%, about 20% about 20% to about 100%, about 30% to about 100%, about to about 80%, about 30% to about 80%, about 40% to about 40% to about 100%, about 50% to about 100%, about 60% to 80%, about 50% to about 80%, or about 60% to about 80%, about 100%, about 70% to about 100%, about 80% to about about 10% to about 70%, about 20% to about 70%, about 30% 100%, about 10% to about 90%, about 20% to about 90%, to about 70%, about 40% to about 70%, or about 50% to about 15 about 30% to about 90%, about 40% to about 90%, about 50% 70%. to about 90%, about 60% to about 90%, about 70% to about In an embodiment, a therapeutic compound disclosed 90%, about 10% to about 80%, about 20% to about 80%, herein has an anti-pain activity capable of reducing a central about 30% to about 80%, about 40% to about 80%, about 50% neuropathic pain response. In aspects of this embodiment, a to about 80%, or about 60% to about 80%, about 10% to about therapeutic compound disclosed herein has an anti-pain 70%, about 20% to about 70%, about 30% to about 70%, activity capable of reducing a central neuropathic pain about 40% to about 70%, or about 50% to about 70%. response by, e.g., at least 10%, at least 15%, at least 20%, at In an embodiment, a therapeutic compound disclosed least 25%, at least 30%, at least 35%, at least 40%, at least herein has an anti-pain activity capable of reducing a monon 45%, at least 50%, at least 55%, at least 60%, at least 65%, at europathic multiplex pain response. In aspects of this least 70%, at least 75%, at least 80%, at least 85%, at least 25 embodiment, atherapeutic compound disclosed herein has an 90% or at least 95%. In other aspects of this embodiment, a anti-pain activity capable of reducing a mononeuropathic therapeutic compound disclosed herein has an anti-pain multiplex pain response by, e.g., at least 10%, at least 15%, at activity capable of reducing a central neuropathic pain least 20%, at least 25%, at least 30%, at least 35%, at least response in a range from, e.g., about 10% to about 100%, 40%, at least 45%, at least 50%, at least 55%, at least 60%, at about 20% to about 100%, about 30% to about 100%, about 30 least 65%, at least 70%, at least 75%, at least 80%, at least 40% to about 100%, about 50% to about 100%, about 60% to 85%, at least 90% or at least 95%. In other aspects of this about 100%, about 70% to about 100%, about 80% to about embodiment, atherapeutic compound disclosed herein has an 100%, about 10% to about 90%, about 20% to about 90%, anti-pain activity capable of reducing a mononeuropathic about 30% to about 90%, about 40% to about 90%, about 50% multiplex pain response in a range from, e.g., about 10% to to about 90%, about 60% to about 90%, about 70% to about 35 about 100%, about 20% to about 100%, about 30% to about 90%, about 10% to about 80%, about 20% to about 80%, 100%, about 40% to about 100%, about 50% to about 100%, about 30% to about 80%, about 40% to about 80%, about 50% about 60% to about 100%, about 70% to about 100%, about to about 80%, or about 60% to about 80%, about 10% to about 80% to about 100%, about 10% to about 90%, about 20% to 70%, about 20% to about 70%, about 30% to about 70%, about 90%, about 30% to about 90%, about 40% to about about 40% to about 70%, or about 50% to about 70%. 40 90%, about 50% to about 90%, about 60% to about 90%, In an embodiment, a therapeutic compound disclosed about 70% to about 90%, about 10% to about 80%, about 20% herein has an anti-pain activity capable of reducing a periph to about 80%, about 30% to about 80%, about 40% to about eral neuropathic pain response. In aspects of this embodi 80%, about 50% to about 80%, or about 60% to about 80%, ment, a therapeutic compound disclosed herein has an anti about 10% to about 70%, about 20% to about 70%, about 30% pain activity capable of reducing a peripheral neuropathic 45 to about 70%, about 40% to about 70%, or about 50% to about pain response by, e.g., at least 10%, at least 15%, at least 20%, 70%. at least 25%, at least 30%, at least 35%, at least 40%, at least In an embodiment, a therapeutic compound disclosed 45%, at least 50%, at least 55%, at least 60%, at least 65%, at herein has an anti-pain activity capable of reducing a poly least 70%, at least 75%, at least 80%, at least 85%, at least neuropathic pain response. In aspects of this embodiment, a 90% or at least 95%. In other aspects of this embodiment, a 50 therapeutic compound disclosed herein has an anti-pain therapeutic compound disclosed herein has an anti-pain activity capable of reducing a polyneuropathic pain response activity capable of reducing a peripheral neuropathic pain by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, response in a range from, e.g., about 10% to about 100%, at least 30%, at least 35%, at least 40%, at least 45%, at least about 20% to about 100%, about 30% to about 100%, about 50%, at least 55%, at least 60%, at least 65%, at least 70%, at 40% to about 100%, about 50% to about 100%, about 60% to 55 least 75%, at least 80%, at least 85%, at least 90% or at least about 100%, about 70% to about 100%, about 80% to about 95%. In other aspects of this embodiment, a therapeutic com 100%, about 10% to about 90%, about 20% to about 90%, pound disclosed herein has an anti-pain activity capable of about 30% to about 90%, about 40% to about 90%, about 50% reducing a polyneuropathic pain response in a range from, to about 90%, about 60% to about 90%, about 70% to about e.g., about 10% to about 100%, about 20% to about 100%, 90%, about 10% to about 80%, about 20% to about 80%, 60 about 30% to about 100%, about 40% to about 100%, about about 30% to about 80%, about 40% to about 80%, about 50% 50% to about 100%, about 60% to about 100%, about 70% to to about 80%, or about 60% to about 80%, about 10% to about about 100%, about 80% to about 100%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 70%, or about 50% to about 70%. about 40% to about 90%, about 50% to about 90%, about 60% In an embodiment, a therapeutic compound disclosed 65 to about 90%, about 70% to about 90%, about 10% to about herein has an anti-pain activity capable of reducing a monon 80%, about 20% to about 80%, about 30% to about 80%, europathic pain response. In aspects of this embodiment, a about 40% to about 80%, about 50% to about 80%, or about US 9,265,742 B2 9 10 60% to about 80%, about 10% to about 70%, about 20% to 80% to about 100%, about 10% to about 90%, about 20% to about 70%, about 30% to about 70%, about 40% to about about 90%, about 30% to about 90%, about 40% to about 70%, or about 50% to about 70%. 90%, about 50% to about 90%, about 60% to about 90%, In an embodiment, a therapeutic compound disclosed about 70% to about 90%, about 10% to about 80%, about 20% herein has an anti-pain activity capable of reducing an auto to about 80%, about 30% to about 80%, about 40% to about nomic neuropathic pain response. In aspects of this embodi 80%, about 50% to about 80%, or about 60% to about 80%, ment, a therapeutic compound disclosed herein has an anti about 10% to about 70%, about 20% to about 70%, about 30% pain activity capable of reducing an autonomic neuropathic to about 70%, about 40% to about 70%, or about 50% to about pain response by, e.g., at least 10%, at least 15%, at least 20%, 70%. at least 25%, at least 30%, at least 35%, at least 40%, at least 10 In an embodiment, a therapeutic compound disclosed 45%, at least 50%, at least 55%, at least 60%, at least 65%, at herein has an anti-pain activity capable of reducing a referred least 70%, at least 75%, at least 80%, at least 85%, at least pain response. In aspects of this embodiment, a therapeutic 90% or at least 95%. In other aspects of this embodiment, a compound disclosed herein has an anti-pain activity capable therapeutic compound disclosed herein has an anti-pain of reducing a referred pain response by, e.g., at least 10%, at activity capable of reducing an autonomic neuropathic pain 15 least 15%, at least 20%, at least 25%, at least 30%, at least response in a range from, e.g., about 10% to about 100%, 35%, at least 40%, at least 45%, at least 50%, at least 55%, at about 20% to about 100%, about 30% to about 100%, about least 60%, at least 65%, at least 70%, at least 75%, at least 40% to about 100%, about 50% to about 100%, about 60% to 80%, at least 85%, at least 90% or at least 95%. In other about 100%, about 70% to about 100%, about 80% to about aspects of this embodiment, a therapeutic compound dis 100%, about 10% to about 90%, about 20% to about 90%, closed herein has an anti-pain activity capable of reducing a about 30% to about 90%, about 40% to about 90%, about 50% referred pain response in a range from, e.g., about 10% to to about 90%, about 60% to about 90%, about 70% to about about 100%, about 20% to about 100%, about 30% to about 90%, about 10% to about 80%, about 20% to about 80%, 100%, about 40% to about 100%, about 50% to about 100%, about 30% to about 80%, about 40% to about 80%, about 50% about 60% to about 100%, about 70% to about 100%, about to about 80%, or about 60% to about 80%, about 10% to about 25 80% to about 100%, about 10% to about 90%, about 20% to 70%, about 20% to about 70%, about 30% to about 70%, about 90%, about 30% to about 90%, about 40% to about about 40% to about 70%, or about 50% to about 70%. 90%, about 50% to about 90%, about 60% to about 90%, In an embodiment, a therapeutic compound disclosed about 70% to about 90%, about 10% to about 80%, about 20% herein has an anti-pain activity capable of reducing a neural to about 80%, about 30% to about 80%, about 40% to about gia pain response. In aspects of this embodiment, a therapeu 30 80%, about 50% to about 80%, or about 60% to about 80%, tic compound disclosed herein has an anti-pain activity about 10% to about 70%, about 20% to about 70%, about 30% capable of reducing a neuralgia pain response by, e.g., at least to about 70%, about 40% to about 70%, or about 50% to about 10%, at least 15%, at least 20%, at least 25%, at least 30%, at 70%. least 35%, at least 40%, at least 45%, at least 50%, at least In an embodiment, a therapeutic compound disclosed 55%, at least 60%, at least 65%, at least 70%, at least 75%, at 35 herein has an anti-pain activity capable of reducing a deaffer least 80%, at least 85%, at least 90% or at least 95%. In other entation pain response. In aspects of this embodiment, a aspects of this embodiment, a therapeutic compound dis therapeutic compound disclosed herein has an anti-pain closed herein has an anti-pain activity capable of reducing a activity capable of reducing a deafferentation pain response neuralgia pain response in a range from, e.g., about 10% to by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, about 100%, about 20% to about 100%, about 30% to about 40 at least 30%, at least 35%, at least 40%, at least 45%, at least 100%, about 40% to about 100%, about 50% to about 100%, 50%, at least 55%, at least 60%, at least 65%, at least 70%, at about 60% to about 100%, about 70% to about 100%, about least 75%, at least 80%, at least 85%, at least 90% or at least 80% to about 100%, about 10% to about 90%, about 20% to 95%. In other aspects of this embodiment, a therapeutic com about 90%, about 30% to about 90%, about 40% to about pound disclosed herein has an anti-pain activity capable of 90%, about 50% to about 90%, about 60% to about 90%, 45 reducing a deafferentation pain response in a range from, e.g., about 70% to about 90%, about 10% to about 80%, about 20% about 10% to about 100%, about 20% to about 100%, about to about 80%, about 30% to about 80%, about 40% to about 30% to about 100%, about 40% to about 100%, about 50% to 80%, about 50% to about 80%, or about 60% to about 80%, about 100%, about 60% to about 100%, about 70% to about about 10% to about 70%, about 20% to about 70%, about 30% 100%, about 80% to about 100%, about 10% to about 90%, to about 70%, about 40% to about 70%, or about 50% to about 50 about 20% to about 90%, about 30% to about 90%, about 40% 70%. to about 90%, about 50% to about 90%, about 60% to about In an embodiment, a therapeutic compound disclosed 90%, about 70% to about 90%, about 10% to about 80%, herein has an anti-pain activity capable of reducing a complex about 20% to about 80%, about 30% to about 80%, about 40% regional pain syndrome pain response. In aspects of this to about 80%, about 50% to about 80%, or about 60% to about embodiment, atherapeutic compound disclosed herein has an 55 80%, about 10% to about 70%, about 20% to about 70%, anti-pain activity capable of reducing a complex regional pain about 30% to about 70%, about 40% to about 70%, or about syndrome pain response by, e.g., at least 10%, at least 15%, at 50% to about 70%. least 20%, at least 25%, at least 30%, at least 35%, at least In an embodiment, a therapeutic compound disclosed 40%, at least 45%, at least 50%, at least 55%, at least 60%, at herein has an anti-pain activity capable of reducing a dysfunc least 65%, at least 70%, at least 75%, at least 80%, at least 60 tional pain response. In aspects of this embodiment, a thera 85%, at least 90% or at least 95%. In other aspects of this peutic compound disclosed herein has an anti-pain activity embodiment, atherapeutic compound disclosed herein has an capable of reducing a dysfunctional pain response by, e.g., at anti-pain activity capable of reducing a complex regional pain least 10%, at least 15%, at least 20%, at least 25%, at least syndrome pain response in a range from, e.g., about 10% to 30%, at least 35%, at least 40%, at least 45%, at least 50%, at about 100%, about 20% to about 100%, about 30% to about 65 least 55%, at least 60%, at least 65%, at least 70%, at least 100%, about 40% to about 100%, about 50% to about 100%, 75%, at least 80%, at least 85%, at least 90% or at least 95%. about 60% to about 100%, about 70% to about 100%, about In other aspects of this embodiment, a therapeutic compound US 9,265,742 B2 11 12 disclosed herein has an anti-pain activity capable of reducing as the ratio of concentrations of a unionized compound in the a dysfunctional pain response in a range from, e.g., about 10% two phases of a mixture of two immiscible solvents at equi to about 100%, about 20% to about 100%, about 30% to about librium. Thus, log P=Log 10 (P), where P=solute in immis 100%, about 40% to about 100%, about 50% to about 100%, cible solvent 1/Isolute in immiscible solvent 2. With regard about 60% to about 100%, about 70% to about 100%, about to organic and aqueous phases, the log Pvalue of a compound 80% to about 100%, about 10% to about 90%, about 20% to is constant for any given pair of aqueous and organic Solvents, about 90%, about 30% to about 90%, about 40% to about and its value can be determined empirically by one of several 90%, about 50% to about 90%, about 60% to about 90%, phase-partitioning methods known to one skilled in the art about 70% to about 90%, about 10% to about 80%, about 20% including, e.g., a shake flask assay, a HPLC assay, and an to about 80%, about 30% to about 80%, about 40% to about 10 interface between two immiscible electrolyte solutions 80%, about 50% to about 80%, or about 60% to about 80%, (ITIES) assay. about 10% to about 70%, about 20% to about 70%, about 30% In aspects of this embodiment, a therapeutic compound to about 70%, about 40% to about 70%, or about 50% to about disclosed herein may have a log P value indicating that the 70%. compound is substantially soluble in an organic solvent. In In an embodiment, a therapeutic compound disclosed 15 aspects of this embodiment, a therapeutic compound dis herein has an anti-pain activity capable of reducing a head closed herein may have a log P value indicating that the ache pain response. In aspects of this embodiment, a thera compound is, e.g., at least 50% soluble in an organic solvent, peutic compound disclosed herein has an anti-pain activity at least 60% soluble in an organic solvent, at least 70% capable of reducing aheadache pain response by, e.g., at least soluble in an organic solvent, at least 80% soluble in an 10%, at least 15%, at least 20%, at least 25%, at least 30%, at organic Solvent, or at least 90% soluble in an organic solvent. least 35%, at least 40%, at least 45%, at least 50%, at least In aspects of this embodiment, a therapeutic compound dis 55%, at least 60%, at least 65%, at least 70%, at least 75%, at closed herein may have a log P value indicating that the least 80%, at least 85%, at least 90% or at least 95%. In other compound is between, e.g., about 50% to about 100% soluble aspects of this embodiment, a therapeutic compound dis in an organic solvent, about 60% to about 100% soluble in an closed herein has an anti-pain activity capable of reducing a 25 organic solvent, about 70% to about 100% soluble in an headache pain response in a range from, e.g., about 10% to organic solvent, about 80% to about 100% soluble in an about 100%, about 20% to about 100%, about 30% to about organic solvent, or about 90% to about 100% soluble in an 100%, about 40% to about 100%, about 50% to about 100%, organic solvent. about 60% to about 100%, about 70% to about 100%, about In aspects of this embodiment, a therapeutic compound 80% to about 100%, about 10% to about 90%, about 20% to 30 disclosed herein may have a log P value of e.g., more than about 90%, about 30% to about 90%, about 40% to about 1.1, more than 1.2, more than 1.4, more than 1.6, more than 90%, about 50% to about 90%, about 60% to about 90%, 1.8, more than 2.0, more than 2.2, more than 2.4, more than about 70% to about 90%, about 10% to about 80%, about 20% 2.6, more than 2.8, more than 3.0, more than 3.2, more than to about 80%, about 30% to about 80%, about 40% to about 3.4, or more than 3.6. In other aspects of this embodiment, a 80%, about 50% to about 80%, or about 60% to about 80%, 35 therapeutic compound disclosed herein may have a log P about 10% to about 70%, about 20% to about 70%, about 30% value in the range of, e.g., between 1.8 and 4.0, between 2.0 to about 70%, about 40% to about 70%, or about 50% to about and 4.0, between 2.1 and 4.0, between 2.2 and 4.0, or between 70%. 2.3 and 4.0, between 2.4 and 4.0, between 2.5 and 4.0, In an embodiment, a therapeutic compound disclosed between 2.6 and 4.0, or between 2.8 and 4.0. In other aspects herein has an anti-pain activity capable of reducing a 40 of this embodiment, atherapeutic compound disclosed herein migraine pain response. In aspects of this embodiment, a may have a log Pvalue in the range of, e.g., between 3.0 and therapeutic compound disclosed herein has an anti-pain 4.0, or between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 activity capable of reducing a migraine pain response by, e.g., and 4.0, between 3.4 and 4.0, between 3.5 and 4.0, or between at least 10%, at least 15%, at least 20%, at least 25%, at least 3.6 and 4.0. In still other aspects of this embodiment, a thera 30%, at least 35%, at least 40%, at least 45%, at least 50%, at 45 peutic compound disclosed herein may have a log Pvalue in least 55%, at least 60%, at least 65%, at least 70%, at least the range of, e.g., between 2.0 and 2.5, between 2.0 and 2.7, 75%, at least 80%, at least 85%, at least 90% or at least 95%. between 2.0 and 3.0, or between 2.2 and 2.5. In other aspects of this embodiment, a therapeutic compound Atherapeutic compound disclosed herein may have a polar disclosed herein has an anti-pain activity capable of reducing surface area that is hydrophobic. As used herein, the term a migraine pain response in a range from, e.g., about 10% to 50 “polar surface area” refers to the surface sum over all of the about 100%, about 20% to about 100%, about 30% to about polar atoms in the structure of a compound and is a measure 100%, about 40% to about 100%, about 50% to about 100%, of hydrophobicity. Typically, these polar atoms include, e.g., about 60% to about 100%, about 70% to about 100%, about oxygen, nitrogen, and their attached hydrogens. In aspects of 80% to about 100%, about 10% to about 90%, about 20% to this embodiment, a therapeutic compound disclosed herein about 90%, about 30% to about 90%, about 40% to about 55 may have a polar surface area of e.g., less than 8.0 nm, less 90%, about 50% to about 90%, about 60% to about 90%, than 7.0 nm, less than 6.0 nm, less than 5.0 nm, less than about 70% to about 90%, about 10% to about 80%, about 20% 4.0 nm, or less than 3.0 nm. In other aspects of this embodi to about 80%, about 30% to about 80%, about 40% to about ment, a therapeutic compound disclosed herein may have a 80%, about 50% to about 80%, or about 60% to about 80%, polar surface area in the range of e.g., between 3.0 nm and about 10% to about 70%, about 20% to about 70%, about 30% 60 6.5 nm, between 3.0 nm and 6.0 nm, between 3.0 nm and to about 70%, about 40% to about 70%, or about 50% to about 5.5 nm, between 3.0 nm and 5.0 nm, between 3.0 nm and 70%. 4.5 nm, between 3.5 nm and 6.5 nm, between 3.5 nm and Atherapeutic compound disclosed herein may have a log P 6.0 nm, between 3.5 nm and 5.5 nm, between 3.5 nm and value indicating that the compound is soluble in an organic 5.0 nm, between 3.5 nm and 4.5 nm, between 4.0 nm and solvent. As used herein, the term “log value' refers to the 65 6.5 nm, between 4.0 nm and 6.0 nm, between 4.0 nm and logarithm (base 10) of the partition coefficient (P) for a com 5.5 nm, or between 4.0 nm and 5.0 nm, between 4.0 nm. pound and is a measure of lipophilicity. Typically, P is defined and 4.5 nm, or between 4.5 nm and 5.5 nm. In yet other US 9,265,742 B2 13 14 aspects of this embodiment, a therapeutic compound dis NSAID, and a fibrate. Other suitable PPARY agonists are closed herein may have a polar Surface area in the range of described in Masson and Caumont-Bertrand, PPAR Agonist e.g., between 2.0 nm and 6.5 nm, between 2.0 nm and 6.0 Compounds, Preparation and Uses, US 2011/0195993, nm, between 2.0 nm and 5.5 nm, between 2.0 nm and 5.0 which is hereby incorporated by reference in its entirety. nm, between 2.0 nm and 4.5 nm, between 2.5 nm and 6.5 Atherapeutic compound disclosed herein may be a nuclear nm, between 2.5 nm and 6.0 nm, between 2.5 nm and 5.5 receptor binding agent. Examples of a suitable nuclear recep nm, between 2.5 nm 2 and 5.0 nm, or between 2.5 nm and tor binding agent include, without limitation, a Retinoic Acid 4.5 nm. Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) A therapeutic compound disclosed herein may be a non binding agent, a Liver X Receptor (LXR) binding agent and a steroidal anti-inflammatory drug (NSAID). NSAIDs are a 10 Vitamin D binding agent. large group of therapeutic compounds with analgesic, anti A therapeutic compound disclosed herein may be an anti pain, and anti-pyretic properties. NSAIDs include, without hyperlipidemic agent. There are several classes of anti-hyper limitation, Aceclofenac, Acemetacin, Actarit, Alcofenac, lipidemic agents (also known as hypolipidemic agents). They Alminoprofen, Amfenac, Aloxipirin, AminophenaZone, may differ in both their impact on the cholesterol profile and Antraphenine, Aspirin, AZapropaZone, Benorilate, Benox 15 adverse effects. For example, some may lower low density aprofen, Benzydamine. Butibufen, Celecoxib, Chlorthenoxa lipoprotein (LDL), while others may preferentially increase cin, Choline Salicylate, Clometacin, Dexketoprofen, high density lipoprotein (HDL). Clinically, the choice of an Diclofenac, Diflunisal, EmorfaZone, Epirizole; Etodolac, agent will depend on the cholesterol profile of an individual, Etoricoxib, Feclobuzone, Felbinac, Fenbufen, Fenclofenac, cardiovascular risk of an individual, and/or the liver and kid Flurbiprofen, Glafenine, Hydroxylethyl salicylate, Ibupro ney functions of an individual. Examples of a suitable anti fen, Indometacin, Indoprofen, Ketoprofen, Ketorolac, Lactyl hyperlipidemic agent include, without limitation, a fibrate, a phenetidin, Loxoprofen, Lumiracoxib, Mefenamic acid, statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), Meloxicam, Metamizole, Metiazinic acid, Mofebutazone, a cholesterol absorption inhibitor, a pancreatic lipase inhibi Mofezolac, Nabumetone, Naproxen, Nifenazone, Niflumic tor, and a sympathomimetic amine. acid, Oxametacin, Phenacetin, Pipebuzone, Pranoprofen, 25 Atherapeutic compound disclosed herein may be a fibrate. Propyphenazone, ProquaZone, Protizinic acid, Rofecoxib, Fibrates area class of amphipathic carboxylic acids with lipid Salicylamide, Salsalate, Sulindac, Suprofen, Tiaramide, level modifying properties. These therapeutic compounds are Tinoridine, Tolfenamic acid, Valdecoxib, and Zomepirac. used for a range of metabolic disorders. One non-limiting use NSAIDs may be classified based on their chemical struc is as an anti-hyperlipidemic agent where it may lower levels ture or mechanism of action. Non-limiting examples of 30 of e.g., triglycerides and LDL as well as increase levels of NSAIDs include a salicylate derivative NSAID, a p-amino HDL. Examples of a suitable fibrate include, without limita phenol derivative NSAID, a propionic acid derivative tion, Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, and NSAID, an acetic acid derivative NSAID, an enolic acid Fenofibrate. derivative NSAID, a fenamic acid derivative NSAID, a non A therapeutic compound disclosed herein may be a statin. selective cyclo-oxygenase (COX) inhibitor, a selective 35 Statins (or HMG-CoA reductase inhibitors) are a class of cyclooxygenase 1 (COX 1) inhibitor, and a selective therapeutic compounds used to lower LDL and/or cholesterol cyclooxygenase 2 (COX 2) inhibitor. A NSAID may be a levels by inhibiting the enzyme HMG-CoA reductase, which profen. Examples of a suitable salicylate derivative NSAID plays a central role in the production of cholesterol in the include, without limitation, Acetylsalicylic acid (asprin), liver. To compensate for the decreased cholesterol availabil Diflunisal, and Salsalate. Examples of a suitable p-amino 40 ity, synthesis of hepatic LDL receptors is increased, resulting phenol derivative NSAID include, without limitation, Parac in an increased clearance of LDL particles from the blood. etamol and Phenacetin. Examples of a suitable propionic acid Examples of a suitable statin include, without limitation, derivative NSAID include, without limitation, Alminoprofen, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravasta Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, tin, Rosuvastatin, and Simvastatin. Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, 45 A therapeutic compound disclosed herein may be a tocot Oxaprozin, Pranoprofen, and Suprofen. Examples of a suit rienol. Tocotrienols are another class of HMG-CoA reductase able acetic acid derivative NSAID include, without limita inhibitors and may be used to lower LDL and/or cholesterol tion, Aceclofenac, Acemetacin, Actarit, Alcofenac, Amfenac, levels by inducing hepatic LDL receptor up-regulation and/or Clometacin, Diclofenac, Etodolac, Felbinac, Fenclofenac, decreasing plasma LDL levels. Examples of a suitable tocot Indometacin, Ketorolac, Metiazinic acid, Mofezolac, Nabu 50 rienol include, without limitation, a Y-tocotrienol and a 6-to metone, Naproxen, Oxametacin, Sulindac, and Zomepirac. cotrienol. Examples of a suitable enolic acid (Oxicam) derivative A therapeutic compound disclosed herein may be a niacin. NSAID include, without limitation, Droxicam, Isoxicam, Niacins are a class of therapeutic compounds with lipid level Lornoxicam, Meloxicam, Piroxicam, and Tenoxicam. modifying properties. For example, a niacin may lower LDL Examples of a suitable fenamic acid derivative NSAID 55 by selectively inhibiting hepatic diacy glycerol acyltrans include, without limitation, Flufenamic acid, Mefenamic ferase 2, reduce triglyceride synthesis, and VLDL secretion acid, Meclofenamic acid, and Tolfenamic acid. Examples of through a receptor HM74 and HM74A or GPR109A. These a suitable selective COX-2 inhibitors include, without limi therapeutic compounds are used for a range of metabolic tation, Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, disorders. One non-limiting use is as an anti-hyperlipidemic Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib. 60 agent where it may inhibit the breakdown of fats in adipose Atherapeutic compound disclosed herein may be a PPARY tissue. Because a niacin blocks the breakdown of fats, it agonist. Examples of a suitable PPARYagonist include, with causes a decrease in free fatty acids in the blood and, as a out limitation, BenZbromarone, a cannabidiol, CilostaZol. consequence, decreases the secretion of very-low-density Curcumin, Delta(9)-tetrahydrocannabinol, glycyrrhetinic lipoproteins (VLDL) and cholesterol by the liver. By lower acid, Indomethacin, Irbesartan, Monascin, mycophenolic 65 ing VLDL levels, a niacin may also increase the level of HDL acid, Resveratrol, 6-shogaol, Telmisartan, a thiazolidinedi in blood. Examples of a suitable niacin include, without limi one like RosiglitaZone, PioglitaZone, and TroglitaZone, a tation, acipimox, niacin, nicotinamide, and vitamin B3. US 9,265,742 B2 15 16 A therapeutic compound disclosed herein may be a bile compound is combined with an adjuvant disclosed herein. In acid sequestrant. Bile acid sequestrants (also known as resins) one embodiment, a therapeutic compound may be reacted are a class of therapeutic compounds used to bind certain with ethyl ester in order to form an ethyl ester of the thera components of bile in the gastrointestinal tract. They disrupt peutic compound. the enterohepatic circulation of bile acids by sequestering 5 In another embodiment, a pharmaceutical composition dis them and preventing their reabsorption from the gut. Bile acid closed herein does not comprise a pharmaceutically-accept sequestrants are particularly effective for lowering LDL and able solvent disclosed herein. In an aspect of this embodi cholesterol by sequestering the cholesterol-containing bile ment, a pharmaceutical composition comprises a therapeutic acids released into the intestine and preventing their reabsorp compound and a pharmaceutically-acceptable adjuvant, but tion from the intestine. In addition, a bile acid sequestrant 10 does not comprise a pharmaceutically-acceptable solvent dis may also raise HDL levels. Examples of a suitable bile acid closed herein. sequestrant include, without limitation, Cholestyramine, A pharmaceutical composition disclosed herein may com Colesevelam, and Colestipol. prise atherapeutic compound in an amount Sufficient to allow A therapeutic compound disclosed herein may be a cho customary administration to an individual. In aspects of this lesterol absorption inhibitor. Cholesterol absorption inhibi 15 embodiment, a pharmaceutical composition disclosed herein tors are a class of therapeutic compounds that inhibits the may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at absorption of cholesterol from the intestine. Decreased cho least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at lesterol absorption leads to an upregulation of LDL-receptors least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at on the surface of cells and an increased LDL-cholesterol least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at uptake into these cells, thus decreasing levels of LDL in the least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or blood plasma. Examples of a suitable cholesterol absorption at least 100 mg. ofatherapeutic compound. In other aspects of inhibitor include, without limitation, Ezetimibe, a phy this embodiment, a pharmaceutical composition disclosed tosterol, a sterol and a stanol. herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 A therapeutic compound disclosed herein may be a fat mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 absorption inhibitor. Fat absorption inhibitors are a class of 25 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least therapeutic compounds that inhibits the absorption of fat 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at from the intestine. Decreased fat absorption reduces caloric least 900 mg, at least 1,000 mg, at least 1,100 mg, at least intake. In one aspect, a fat absorption inhibitor inhibits pan 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least creatic lipase, an enzyme that breaks down triglycerides in the 1,500 mg of a therapeutic compound. In yet other aspects of intestine. Examples of a suitable fat absorption inhibitor 30 this embodiment, a pharmaceutical composition disclosed include, without limitation, Orlistat. herein may be in the range of, e.g., about 5 mg to about 100 A therapeutic compound disclosed herein may be a sym mg, about 10 mg to about 100 mg, about 50 mg to about 150 pathomimetic amine. Sympathomimetic amines area class of mg, about 100 mg to about 250 mg, about 150 mg to about therapeutic compounds that mimic the effects of transmitter 350 mg, about 250 mg to about 500 mg, about 350 mg to Substances of the sympathetic nervous system Such as cat 35 about 600 mg, about 500 mg to about 750 mg, about 600 mg echolamines, epinephrine (adrenaline), norepinephrine (no to about 900 mg, about 750 mg to about 1,000 mg, about 850 radrenaline), and/or dopamine. A sympathomimetic amine mg to about 1,200 mg. or about 1,000 mg to about 1,500 mg. may act as an O-adrenergic agonist, a f-adrenergic agonist, a In still other aspects of this embodiment, a pharmaceutical dopaminergic agonist, a monoamine oxidase (MAO) inhibi composition disclosed herein may be in the range of e.g., tor, and a COMT inhibitor. Such therapeutic compounds, 40 about 10 mg to about 250 mg, about 10 mg to about 500 mg. among other things, are used to treat cardiac arrest, low blood about 10 mg to about 750 mg, about 10 mg to about 1,000 mg. pressure, or even delay premature labor. Examples of a Suit about 10 mg to about 1,500 mg, about 50 mg to about 250 mg. able sympathomimetic amine include, without limitation, about 50 mg to about 500 mg, about 50 mg to about 750 mg. Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, meth about 50 mg to about 1,000 mg, about 50 mg to about 1,500 amphetamine, amphetamine, phenylephrine, isoproterenol, 45 mg, about 100 mg to about 250 mg, about 100 mg to about dobutamine, methylphenidate, lisdexamfetamine, cathine, 500 mg, about 100 mg to about 750 mg, about 100 mg to cathinone, methcathinone, cocaine, benzylpiperazine (BZP), about 1,000 mg, about 100 mg to about 1,500 mg, about 200 methylenedioxypyrovalerone (MDPV), 4-methylaminorex, mg to about 500 mg, about 200 mg to about 750 mg, about pemoline, phenmetrazine, and propylhexedrine. 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg. A therapeutic compound disclosed herein may be an ester 50 about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg. of a therapeutic compound. An ester of a therapeutic com or about 5 mg to about 250 mg. pound increases the log Pvalue relative to the same therapeu Aspects of the present specification disclose, in part, a tic compound, but without the ester modification. An ester pharmaceutically-acceptable solvent. A solvent is a liquid, group may be attached to a therapeutic compoundby, e.g., a Solid, or gas that dissolves another Solid, liquid, or gaseous carboxylic acid or hydroxyl functional group present of the 55 (the solute), resulting in a solution. Solvents useful in the therapeutic compound. An ester of a therapeutic compound pharmaceutical compositions disclosed herein include, with may have an increased hydrophobicity, and as such, may be out limitation, a pharmaceutically-acceptable polar aprotic dissolved in a reduced volume of solvent disclosed herein. In Solvent, a pharmaceutically-acceptable polar protic solvent Some instances, an ester of a therapeutic compound may be and a pharmaceutically-acceptable non-polar solvent. A phar combined directly with an adjuvant disclosed herein, thereby 60 maceutically-acceptable polar aprotic solvent includes, with eliminating the need of a solvent. An ester of a therapeutic out limitation, dichloromethane (DCM), tetrahydrofuran compound may enable the making of a pharmaceutical com (THF), ethyl acetate, acetone, dimethylformamide (DMF), position disclosed herein, in situations where a non-esterified acetonitrile (MeCN), dimethyl sulfoxide (DMSO). A phar form of the same therapeutic compound is otherwise immis maceutically-acceptable polar protic solvent includes, with cible in a solvent disclosed herein. An ester of a therapeutic 65 out limitation, acetic acid, formic acid, ethanol, n-butanol, compound may still be delivered in a manner that more effec 1-butanol, 2-butanol, isobutanol, Sec-butanol, tert-butanol, tively inhibits a pro-inflammatory response as long as the n-propanol, isopropanol, 1.2 propan-diol, methanol, glyc US 9,265,742 B2 17 18 erol, and water. A pharmaceutically-acceptable non-polar acetate, isobutylbuterate, isobutyl formate, penty1 acetate, Solvent includes, without limitation, pentane, cyclopentane, pentyl buterate, pentyl formate, and 1-hexadecyl acetate, hexane, cyclohexane, benzene, toluene, 1,4-Dioxane, chloro 1-hexadecyl buterate, and 1-hexadecyl formate. form, n-methyl-pyrrilidone (NMP), and diethyl ether. In another embodiment, a solvent may comprise a pharma A pharmaceutical composition disclosed herein may com ceutically-acceptable glycol ether. Glycol ethers are a group prise a solvent in an amount Sufficient to dissolve a therapeu of solvents based on alkyl ethers of ethylene glycol. Non tic compound disclosed herein. In other aspects of this limiting examples include diethylene glycol monomethyl embodiment, a pharmaceutical composition disclosed herein ether (2-(2-methoxyethoxy)ethanol), diethylene glycol may comprise a solvent in an amount of, e.g., less than about monoethyl ether (2-(2-ethoxyethoxy)ethanol), diethylene 90% (v/v), less than about 80% (v/v), less than about 70% 10 glycol monopropyl ether (2-(2-propoxyethoxy)ethanol), (v/v), less than about 65% (v/v), less than about 60% (v/v), diethylene glycol monoisopropyl ether (2-(2-isopropoxy less than about 55% (v/v), less than about 50% (v/v), less than ethoxy)ethanol), and diethylene glycol mono-n-butyl ether about 45% (v/v), less than about 40% (v/v), less than about (2-(2-butoxyethoxy)ethanol). Diethylene glycol monoethyl 35% (v/v), less than about 30% (v/v), less than about 25% ether (2-(2-ethoxyethoxy)ethanol) is commercially available (v/v), less than about 20% (v/v), less than about 15% (v/v), 15 as TRANSCUTOLOR). less than about 10% (v/v), less than about 5% (v/v), or less In another embodiment, a solvent may comprise a pharma than about 1% (v/v). In other aspects of this embodiment, a ceutically-acceptable diol. A diol or double alcohol is a pharmaceutical composition disclosed herein may comprise a chemical compound containing two hydroxyl groups (-OH solvent in an amount in a range of, e.g., about 1% (v/v) to 90% groups). (v/v), about 1% (v/v) to 70% (v/v), about 1% (v/v) to 60% In another embodiment, a solvent may comprise a pharma (v/v), about 1% (v/v) to 50% (v/v), about 1% (v/v) to 40% ceutically-acceptable propylene glycol. Propylene glycol, (v/v), about 1% (v/v) to 30% (v/v), about 1% (v/v) to 20% also called 1,2-propanediolor propane-1,2-diol, is an organic (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v) to 50% compound with formula CHO, or HO CH, CHOH (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% CH. (v/v), about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% 25 In another embodiment, a solvent may comprise a pharma (v/v), about 4% (v/v) to 50% (v/v), about 4% (v/v) to 40% ceutically-acceptable dipropylene glycol. Dipropylene gly (v/v), about 4% (v/v) to 30% (v/v), about 4% (v/v) to 20% col is a mixture of three isomeric chemical compounds, (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v) to 50% 4-oxa-2,6-heptandiol. 2-(2-Hydroxy-propoxy)-propan-1-ol. (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% and 2-(2-Hydroxy-1-methyl-ethoxy)-propan-1-ol. (v/v), about 6% (v/v) to 20% (v/v), about 6% (v/v) to 10% 30 In another embodiment, a solvent may comprise a pharma (v/v), about 8% (v/v) to 50% (v/v), about 8% (v/v) to 40% ceutically-acceptable polypropylene glycol (PPG) polymer. (v/v), about 8% (v/v) to 30% (v/v), about 8% (v/v) to 20% PPG polymers polymers, also known as polypropylene oxide (v/v), about 8% (v/v) to 15% (v/v), or about 8% (v/v) to 12% (PPO) polymers or polyoxypropylene (POP) polymers, are (v/v). prepared by polymerization of propylene oxide and are com In one embodiment, a solvent may comprise a pharmaceu 35 mercially available over a wide range of molecular weights tically-acceptable alcohol. As used herein, the term “alcohol from 100 g/mol to 10,000,000 g/mol. PPG polymers with a refers to an organic molecule comprising a hydroxyl func low molecular mass are liquids or low-melting solids, tional group (-OH) bond to a carbonatom, where the carbon whereas PPG polymers of a higher molecular mass are solids. atom is saturated. In aspects of this embodiment, the alcohol A PPG polymer include, without limitation, PPG 100, PPG may be, e.g., a C alcohol, a C alcohol, a C-salcohol, a 40 200, PPG 300, PPG 400, PPG 500, PPG 600, PPG 700, PPG C-7 alcohol, a Co alcohol, a C-1s alcohol, or a C-2 alco 800, PPG 900, PPG 1000, PPG 1100, PPG 1200, PPG 1300, hol. In other aspects of this embodiment, an alcohol may be, PPG 1400, PPG 1500, PPG 1600, PPG 1700, PPG 1800, PPG e.g., a primary alcohol, a secondary alcohol, or a tertiary 1900, PPG 2000, PPG 2100, PPG 2200, PPG 2300, PPG alcohol. In other aspects of this embodiment, an alcohol may 2400, PPG 2500, PPG 2600, PPG 2700, PPG 2800, PPG be, e.g., an acyclic alcohol, a monohydric alcohol, a polyhy 45 2900, PPG 3000, PPG 3250, PPG 3350, PPG 3500, PPG dric alcohol (also known as a polyol or Sugar alcohol), an 3750, PPG 4000, PPG 4250, PPG 4500, PPG 4750, PPG unsaturated aliphatic alcohol, an alicyclic alcohol, or a com 5000, PPG 5500, PPG 6000, PPG 6500, PPG 7000, PPG bination thereof. Examples of a monohydric alcohol include, 7500, PPG 8000, PPG 8500, PPG 9000, PPG 9500, PPG without limitation, methanol, ethanol, propanol, butanol, 10,000, PPG 11,000, PPG 12,000, PPG 13,000, PPG 14,000, pentanol, and 1-hexadecanol. Examples of a polyhydric alco 50 PPG 15,000, PPG 16,000, PPG 17,000, PPG 18,000, PPG 19,000, or PPG 20,000. erythritol,hol style, Xylitol, St. maltitol, ision Sorbitol S. (gluct1ol), ity mannitol,this In another embodiment, a solvent may comprise a pharma inositol, lactitol, galactitol (iditol), and isomalt. Examples of ceutically-acceptable polyethylene glycol (PEG) polymer. an unsaturated aliphatic alcohol include, without limitation, PEG polymers, also known as polyethylene oxide (PEO) prop-2-ene-1-ol. 3,7-dimethylocta-2,6-dien-1-ol, and prop 55 polymers or polyoxyethylene (POE) polymers, are prepared 2-in-1-ol. Examples of an alicyclic alcohol include, without by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 100 5-methyl-cyclohexane-1-ol.it. the 34.56-hexyl and 2-(2-propyl)- g/mol to 10,000,000 g/mol. PEG polymers with a low In another embodiment, a solvent may comprise an ester of molecular mass are liquids or low-melting Solids, whereas pharmaceutically-acceptable alcohol and an acid. Suitable 60 PEG polymers of a higher molecular mass are solids. A PEG pharmaceutically-acceptable alcohols include the ones dis polymer include, without limitation, PEG 100, PEG 200, closed herein. Suitable acids include, without limitation, ace PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, tic acid, butaric acid, and formic acid. An ester of an alcohol PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG and an acid include, without limitation, methyl acetate, 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG methylbuterate, methyl formate, ethyl acetate, ethylbuterate, 65 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG ethyl formate, propyl acetate, propyl buterate, propyl for 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG mate, butyl acetate, butyl buterate, butyl formate, isobutyl 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG US 9,265,742 B2 19 20 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 90% (v/v) to about 96% (v/v), about 75% (v/v) to about 93% 5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG (v/v), about 80% (v/v) to about 93% (v/v), about 85% (v/v) to 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG about 93% (v/v), about 88% (v/v) to about 93% (v/v), about 10,000, PEG 11,000, PEG 12,000, PEG 13,000, PEG 14,000, 89% (v/v) to about 93% (v/v), or about 90% (v/v) to about PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, PEG 93% (v/v). 19,000, or PEG 20,000. In one embodiment, an adjuvant may be a pharmaceuti In another embodiment, a solvent may comprise a pharma cally-acceptable lipid. A lipid may be broadly defined as a ceutically-acceptable glyceride. Glycerides comprise a Sub hydrophobic or amphiphilic small molecule. The amphiphilic stituted glycerol, where one, two, or all three hydroxyl groups nature of some lipids allows them to form structures such as of the glycerol are eachesterified using a fatty acid to produce 10 vesicles, liposomes, or membranes in an aqueous environ monoglycerides, diglycerides, and triglycerides, respec ment. Non-limiting examples, of lipids include fatty acids, tively. In these compounds, each hydroxyl groups of glycerol glycerolipids (like monoglycerides, diglycerides, and triglyc may be esterified by different fatty acids. Additionally, glyc erides), phospholipids, sphingolipids, sterol lipids, prenol erides may be acetylated to produce acetylated monoglycer lipids, saccharolipids, and polyketides. A pharmaceutical ides, acetylated diglycerides, and acetylated triglycerides. 15 composition disclosed herein may comprise a lipid such as, In one embodiment, a solvent may comprise a pharmaceu e.g. an oil, an oil-based liquid, a fat, a fatty acid, a wax, a fatty tically-acceptable solid solvent. Solid solvents may be useful acid ester, a fatty acid salt, a fatty alcohol, a glyceride (mono-, in the manufacture of a solid dose formulation of a pharma di- or triglyceride), a partially hydrolyzed glycerolipid, a ceutical composition disclosed herein. Typically, a solid sol phospholipids, a glycol ester, a Sucrose ester, a glycerol oleate vent is melted in order to dissolve a therapeutic compound. A derivative, a medium chain triglyceride, or a mixture thereof. pharmaceutically-acceptable Solid solvent includes, without Other examples of pharmaceutically-acceptable lipids useful limitation, menthol and PEG polymers above about 20,000 as adjuvants are described in, e.g., U.S. Pat. No. 6,923.988, g/mol. U.S. Pat. No. 6,451,339, U.S. Pat. No. 6,383,471, U.S. Pat. Aspects of the present specification disclose, in part, a No. 6,294,192, and U.S. Pat. No. 6,267,985, each of which is pharmaceutically-acceptable adjuvant. An adjuvant is a phar 25 hereby incorporated by reference in its entirety. macological agent that modifies the effect of other agents, A lipid useful in the pharmaceutical compositions dis Such as, e.g., a therapeutic compound disclosed herein. In closed herein may be a pharmaceutically-acceptable fatty addition, an adjuvant disclosed herein may be used as a sol acid. A fatty acid comprises a carboxylic acid with a long vent that dissolves a therapeutic compound disclosed herein, unbranched hydrocarbon chain which may be either saturated forming a adjuvant Solution. An adjuvant disclosed herein 30 or unsaturated. Thus arrangement confers a fatty acid with a facilitates delivery of a therapeutic compound in a manner polar, hydrophilic end, and a nonpolar, hydrophobic end that that more effectively inhibits a pro-inflammatory response. In is insoluble in water. Most naturally occurring fatty acids one embodiment, an adjuvant disclosed herein facilitates the have a hydrocarbon chain of an even number of carbonatoms, delivery of a therapeutic compound disclosed herein into typically between 4 and 24 carbons, and may be attached to macrophages. 35 functional groups containing oxygen, halogens, nitrogen, and A pharmaceutical composition disclosed herein may com Sulfur. Synthetic or non-natural fatty acids may have a hydro prise a pharmaceutically-acceptable adjuvant in an amount carbon chain of any number of carbon atoms from between 3 sufficient to mix with a solution disclosed herein or an emul and 40 carbons. Where a double bond exists, there is the sion disclosed herein. In other aspects of this embodiment, a possibility of either a cis or a trans geometric isomerism, pharmaceutical composition disclosed herein may comprise 40 which significantly affects the molecule's molecular configu an adjuvant in an amount of e.g., at least 10% (v/v), at least ration. Cis-double bonds cause the fatty acid chain to bend, an 20% (v/v), at least 30% (v/v), at least 35% (v/v), at least 40% effect that is more pronounced the more double bonds there (v/v), at least 45%(v/v), at least 50%(v/v), at least 55%(v/v), are in a chain. Most naturally occurring fatty acids are of the at least 60% (v/v), at least 65% (v/v), at least 70% (v/v), at cis configuration, although the trans form does exist in some least 75% (v/v), at least 80% (v/v), at least 85% (v/v), at least 45 natural and partially hydrogenated fats and oils. Examples of 90% (v/v), at least 95% (v/v), or at least 99% (v/v). In other fatty acids include, without limitation, Capryllic acid (8:0), aspects of this embodiment, a pharmaceutical composition pelargonic acid (9:0), Capric acid (10:0), Undecylic acid (11: disclosed herein may comprise an adjuvant in an amount in a O), Lauric acid (12:0), Tridecylic acid (13:0), Myristic acid range of, e.g., about 30% (v/v) to about 99% (v/v), about 35% (14:0). Myristoleic acid (14:1), Pentadecyclic acid (15:0), (v/v) to about 99% (v/v), about 40% (v/v) to about 99% (v/v), 50 Palmitic acid (16:0), Palmitoleic acid (16:1), Sapienic acid about 45% (v/v) to about 99% (v/v), about 50% (v/v) to about (16:1), Margaric acid (17:0), Stearic acid (18:0), Oleic acid 99% (v/v), about 30% (v/v) to about 98% (v/v), about 35% (18:1), Elaidic acid (18:1), Vaccenic acid (18:1), Linoleic acid (v/v) to about 98% (v/v), about 40% (v/v) to about 98% (v/v), (18:2), Linoelaidic acid (18:2), C-Linolenic acid (18:3), Y-Li about 45% (v/v) to about 98% (v/v), about 50% (v/v) to about nolenic acid (18:3), Stearidonic acid (18:4). Nonadecylic acid 98% (v/v), about 30% (v/v) to about 95% (v/v), about 35% 55 (19:0), Arachidic acid (20:0), Eicosenoic acid (20:1), (v/v) to about 95% (v/v), about 40% (v/v) to about 95% (v/v), Dihomo-y-linolenic acid (20:3), Mead acid (20:3), Arachi about 45% (v/v) to about 95% (v/v), or about 50% (v/v) to donic acid (20:4), Eicosapentaenoic acid (20:5), Heneico about 95% (v/v). In yet other aspects of this embodiment, a sylic acid (21:0), Behenic acid (22:0), Erucic acid (22:1). pharmaceutical composition disclosed herein may comprise Docosahexaenoic acid (22:6), Tricosylic acid (23:0), Ligno an adjuvant in an amount in a range of e.g., about 70% (v/v) 60 ceric acid (24:0), Nervonic acid (24:1), Pentacosylic acid to about 97%(v/v), about 75%(v/v) to about 97%(v/v), about (25:0), Cerotic acid (26:0), Heptacosylic acid (27:0), Mon 80% (v/v) to about 97% (v/v), about 85% (v/v) to about 97% tanic acid (28:0). Nonacosylic acid (29:0), Melissic acid (30: (v/v), about 88% (v/v) to about 97% (v/v), about 89% (v/v) to O), Henatriacontylic acid (31:0), Lacceroic acid (32:0), Psyl about 97% (v/v), about 90% (v/v) to about 97% (v/v), about lic acid (33:0), Geddic acid (34:0). Ceroplastic acid (35:0), 75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96% 65 and Hexatriacontylic acid (36:0). (v/v), about 85% (v/v) to about 96% (v/v), about 88% (v/v) to A lipid useful in the pharmaceutical compositions dis about 96% (v/v), about 89% (v/v) to about 96% (v/v), about closed herein may be a pharmaceutically-acceptable partially US 9,265,742 B2 21 22 hydrogenated lipid. The process of hydrogenation adds In other aspects of this embodiment, an adjuvant may com hydrogen atoms to unsaturated lipid, eliminating double prise two or more different pharmaceutically-acceptable fatty bonds and making them into partially or completely saturated acids including at least palmitic acid, Stearic acid, oleic acid, lipid. Partial hydrogenation is a chemical rather than enzy linoleic acid and/or linolenic acid, and any combination matic, that converts a part of cis-isomers into trans-unsatur thereof. In other aspects of this embodiment, an adjuvant may ated lipids instead of hydrogenating them completely. In the comprise a ratio of palmitic acid and/or Stearic acid and/or first reaction step, one hydrogen is added, with the other, oleic acid:linolenic acid and/or linoleic acid of, e.g., at least coordinatively unsaturated, carbon being attached to the cata 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least lyst. The second step is the addition of hydrogen to the 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, or at remaining carbon, producing a saturated fatty acid. The first 10 step is reversible, such that the hydrogen is readsorbed on the least 20:1. In yet other aspects of this embodiment, an adju catalyst and the double bond is re-formed. The intermediate vant may comprise a ratio of palmitic acid and/or Stearic acid with only one hydrogen added contains no double bond and and/or oleic acid:linolenic acid and/or linoleic acid in a range can freely rotate. Thus, the double bond can re-form as either of, e.g., about 1:1 to about 20:1, about 2:1 to about 15:1, about cis or trans, of which trans is favored, regardless the starting 15 4:1 to about 12:1, or about 6:1 to about 10:1. material. In other aspects of this embodiment, an adjuvant may com In an embodiment, an adjuvant may be a pharmaceutically prise four or more different pharmaceutically-acceptable acceptable Saturated or unsaturated fatty acid. In aspects of fatty acids including at least palmitic acid, Stearic acid, oleic this embodiment, a saturated or unsaturated fatty acid com acid, linoleic acid and/or linolenic acid, and any combination prises, e.g., at least 8, at least 10, at least 12, at least 14, at least thereof. In other aspects of this embodiment, an adjuvant may 16, at least 18, at least 20, at least 22, at least 24, at least 26, comprise a ratio of palmitic acid; Stearic acid:linolenic acid: at least 28, or at least 30 carbon atoms. In other aspects of this linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, 8:8:1:1, 7:7:1:1, 6:6: embodiment, a saturated or unsaturated fatty acid comprises, 1:1, 5:5:1:1, 4:4:1:1, 3:3:1:1, 2:2:1:1, or 1:1:1:1. In other e.g., between 4 and 24 carbonatoms, between 6 and 24 carbon aspects of this embodiment, an adjuvant may comprise a ratio atoms, between 8 and 24 carbon atoms, between 10 and 24 25 of palmitic acid; Stearic acid:linolenic acid:linoleic acid in a carbon atoms, between 12 and 24 carbon atoms, between 14 range of, e.g., about 10:10:1:1 to about 6:6:1:1, about 8:8:1:1 and 24 carbon atoms, or between 16 and 24 carbon atoms, to about 4:4:1:1, or about 5:5:1:1 to about 1:1:1:1. between 4 and 22 carbon atoms, between 6 and 22 carbon A lipid useful in the pharmaceutical compositions dis atoms, between 8 and 22 carbon atoms, between 10 and 22 closed herein may be a pharmaceutically-acceptable omega carbon atoms, between 12 and 22 carbonatoms, between 14 30 fatty acid. Non-limiting examples of an omega fatty acid and 22 carbon atoms, or between 16 and 22 carbon atoms, include omega-3, omega-6, omega-7, and omega-9. Omega-3 between 4 and 20 carbon atoms, between 6 and 20 carbon fatty acids (also known as n-3 fatty acids or c)-3 fatty acids) atoms, between 8 and 20 carbon atoms, between 10 and 20 are a family of essential unsaturated fatty acids that have in carbon atoms, between 12 and 20 carbonatoms, between 14 common a final carbon-carbon double bond in the n-3 posi and 20 carbon atoms, or between 16 and 20 carbon atoms. If 35 tion, that is, the third bond, counting from the methyl end of unsaturated, the fatty acid may have, e.g., 1 or more, 2 or the fatty acid. The omega-3 fatty acids are “essential fatty more, 3 or more, 4 or more, 5 or more, or 6 or more double acids because they are vital for normal metabolism and can bonds. not be synthesized by the human body. An omega-3 fatty acid In aspects of this embodiment, a pharmaceutically-accept includes, without limitation, Hexadecatrienoic acid (16:3). able Saturated or unsaturated fatty acid is liquid at room 40 C-Linolenic acid (18:3), Stearidonic acid (18:4). Eicosa temperature. The melting point of a fatty acid is largely deter trienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosapen mined by the degree of saturation/unsaturation of the hydro taenoic acid (20:5), Heneicosapentaenoic acid (21:5), carbon chain. In aspects of this embodiment, a Saturated or Docosapentaenoic acid (Clupanodonic acid) (22:5), Docosa unsaturated fatty acid has a melting point temperature of, e.g., hexaenoic acid (22:6), Tetracosapentaenoic acid (24:5), Tet 20° C. or below, 15° C. or below, 10° C. or below, 5° C. or 45 racosahexaenoic acid (Nisinic acid) (24:6). below, 0°C. or below, -5°C. or below, -10°C. or below, -15° Omega-6 fatty acids (also known as n-6 fatty acids or (O-6 C. or below, or -20° C. or below. In other aspects of this fatty acids) area family of unsaturated fatty acids that have in embodiment, a saturated or unsaturated fatty acid has a melt common a final carbon-carbon double bond in the n-6 posi ing point temperature in the range of, e.g., about -20°C. to tion, that is, the sixth bond, counting from the methyl end of about 20°C., about -20°C. to about 18°C., about -20°C. to 50 the fatty acid. An omega-6 fatty acid includes, without limi about 16°C., about -20°C. to about 12°C., about -20°C. to tation, Linoleic acid (18:2), Y-linolenic acid (18:3), Calendic about 8° C., about -20° C. to about 4°C., about -20°C. to acid (18:3), Eicosadienoic acid (20:2), Dihomo-y-linolenic about 0°C., about -15° C. to about 20° C., about -15° C. to acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22: about 18°C., about -15°C. to about 16°C., about -15°C. to 2), Adrenic acid (22:4), Docosapentaenoic acid (22:5), Tet about 12°C., about -15°C. to about 8°C., about -15° C. to 55 racosatetraenoic acid (24:4), and Tetracosapentaenoic acid about 4°C., about -15°C. to about 0°C. (24:5). In another embodiment, an adjuvant may comprise one Omega-7 fatty acids (also known as n-7 fatty acids or (D-7 kind of pharmaceutically-acceptable fatty acid. In aspects of fatty acids) area family of unsaturated fatty acids that have in this embodiment, an adjuvant may comprise only palmitic common a final carbon-carbon double bond in the n-7 posi acid, only Stearic acid, only oleic acid, only linoleic acid, or 60 tion, that is, the seventh bond, counting from the methyl end only linolenic acid. of the fatty acid. An omega-7 fatty acid includes, without In another embodiment, an adjuvant may comprise a plu limitation, 5-Dodecenoic acid (12:1), 7-Tetradecenoic acid rality of different pharmaceutically-acceptable fatty acids. In (14:1), 9-Hexadecenoic acid (Palmitoleic acid) (16:1), aspects of this embodiment, an adjuvant may comprise, e.g., 11-Decenoic acid (Vaccenic acid) (18:1), 9Z,11E conjugated two or more different fatty acids, three or more different fatty 65 Linoleic acid (Rumenic acid) (18:2), 13-Eicosenoic acid acids, four or more different fatty acids, five or more different (Paullinic acid) (20:1), 15-Docosenoic acid (22:1), and fatty acids, or six or more different fatty acids. 17-Tetracosenoic acid (24:1). US 9,265,742 B2 23 24 Omega-9 fatty acids (also known as n-9 fatty acids or ()-9 A lipid useful in the pharmaceutical compositions dis fatty acids) are a family of unsaturated fatty acids that have in closed herein may be a pharmaceutically-acceptable partially common a final carbon-carbon double bond in the n-9 posi hydrolyzed glycerolipid. In an aspect of this embodiment, a tion, that is, the ninth bond, counting from the methyl end of pharmaceutically-acceptable partially hydrolyzed glycero the fatty acid. An omega-9 fatty acid includes, without limi 5 lipid is a triglyceride partially hydrolyzed into a mixture of tation, Oleic acid (18:1), Elaidic acid (18:1), Eicosenoic acid mono-, di-, and triglycerides. (20:1), Mead acid (20:3), Erucic acid (22:1), Nervonic acid A lipid useful in the pharmaceutical compositions dis (24:1), and Ricinoleic acid. closed herein may be a pharmaceutically-acceptable glycol A lipid useful in the pharmaceutical compositions dis fatty acid ester. A pharmaceutically-acceptable glycol fatty 10 acid ester can be a monoester of a glycol, a diester of a glycol, closed herein may be a pharmaceutically-acceptable fat. Also or a triester of a glycol. A glycol fatty acid ester include, known as a hard fat or Solid fat, a fat includes any fatty acid without limitation, a ethylene glycol fatty acid ester, a dieth that is solid at normal room temperature. Such as, e.g. about ylene glycol fatty acid ester, a propylene glycol fatty acid 20° C. Fats consist of a wide group of compounds that are ester, and a dipropylene fatty acid ester. Non-limiting generally soluble in organic solvents and generally insoluble 15 examples of glycol fatty acid esters include, e.g., ethelene in water. A fat suitable as a lipid useful in the pharmaceutical glycol caprylate, ethelene glycol pelargonate, ethelene glycol compositions disclosed herein, may be a triglyceride, a tri caprate, ethelene glycol undecylate, ethelene glycol laurate, ester of glycerol or any of several fatty acids. ethelene glycol tridecylate, ethelene glycol myristate, A lipid useful in the pharmaceutical compositions dis ethelene glycol myristolate, ethelene glycol pentadecyclate, closed herein may be a pharmaceutically-acceptable oil. An ethelene glycol palmitate, ethelene glycol palmitoleate, oil, also known as a liquid fat, includes any fatty acid that is ethelene glycol sapienate, ethelene glycol margarate, liquid at normal room temperature, such as, e.g. about 20°C. ethelene glycol Stearate, ethelene glycol palmitostearate, An oil suitable as a lipid useful in the pharmaceutical com ethelene glycol oleate, ethelene glycol elaidate, ethelene gly positions disclosed herein, may be a natural oil, a vegetable col vaccinate, ethelene glycollinoleate, ethelene glycollino oil or any Substance that does not mix with water and has a 25 elaidate, ethelene glycol O-linolenate, ethelene glycoly-lino greasy feel. Examples of suitable natural oils include, without lenate, ethelene glycol Stearidonate, ethelene glycol limitation, mineral oil, triacetin, ethyl oleate, a hydrogenated capprylocaprate, ethelene glycol dicapprylocaprate, natural oil, or a mixture thereof. Examples of Suitable veg diethelene glycol caprylate, diethelene glycol pelargonate, etable oils include, without limitation, almond oil, arachis oil, diethelene glycol caprate, diethelene glycol undecylate, avocado oil, canola oil, castor oil, coconut oil, corn oil, cot 30 diethelene glycol laurate, diethelene glycol tridecylate, tonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil diethelene glycol myristate, diethelene glycol myristolate, (flaxseed oil), olive oil, palm oil, peanut oil, rapeseed oil, rice diethelene glycol pentadecyclate, diethelene glycol palmi bran oil, safflower oil, sesame oil, soybean oil, Soya oil, Sun tate, diethelene glycol palmitoleate, diethelene glycol sapi flower oil, theobroma oil (cocoa butter), walnut oil, wheat enate, diethelene glycol margarate, diethelene glycol Stear germ oil, or a mixture thereof. Each of these oils is commer 35 ate, diethelene glycol palmitostearate, diethelene glycol cially available from a number of sources well recognized by oleate, diethelene glycol elaidate, diethelene glycol vacci those skilled in the art. nate, diethelene glycollinoleate, diethelene glycollinoelaid An oil is typically a mixture of various fatty acids. For ate, diethelene glycol O-linolenate, diethelene glycoly-lino example, Rapeseed oil, obtained from the seeds of Brassica lenate, diethelene glycol Stearidonate, diethelene glycol napus, includes both omega-6 and omega-3 fatty acids in a 40 capprylocaprate, diethelene glycol dicapprylocaprate, propy ratio of about 2:1. As another example, linseed oil, obtained lene glycol caprylate, propylene glycol pelargonate, propy from the seeds of Linum usitatissimum, includes abut 7% lene glycol caprate, propylene glycol undecylate, propylene palmitic acid, about 3.4–4.6% stearic acid, about 18.5-22.6% glycol laurate, propylene glycol tridecylate, propylene glycol oleic acid, about 14.2-17% linoleic acid, and about 51.9- myristate, propylene glycol myristolate, propylene glycol 55.2% C-linolenic acid. As another example, theobroma oil, 45 pentadecyclate, propylene glycol palmitate, propylene glycol obtained from the seeds of Theobroma cacao, includes glyc palmitoleate, propylene glycol sapienate, propylene glycol erides derived from palmitic acid, Stearic acid, oleic acid, margarate, propylene glycol Stearate, propylene glycol linoleic acid, and arichidic acid, with melting point of 34-38° palmitostearate, propylene glycol oleate, propylene glycol C. In aspects of this embodiment, a pharmaceutical compo elaidate, propylene glycol vaccinate, propylene glycol sition comprises an oil including at least two different fatty 50 linoleate, propylene glycol linoelaidate, propylene glycol acids, at least three different fatty acids, at least four different O-linolenate, propylene glycoly-linolenate, propylene glycol fatty acids, at least five different fatty acids, or at least six Stearidonate, propylene glycol capprylocaprate, propylene different fatty acids. glycol dicapprylocaprate, dipropylene glycol caprylate, A lipid useful in the pharmaceutical compositions dis dipropylene glycol pelargonate, dipropylene glycol caprate, closed herein may be a pharmaceutically-acceptable glycero 55 dipropylene glycol undecylate, dipropylene glycol laurate, lipid. Glycerolipids are composed mainly of mono-, di-, and dipropylene glycol tridecylate, dipropylene glycol myristate, tri-Substituted glycerols. One group of glycerolipids is the dipropylene glycol myristolate, dipropylene glycol pentade glycerides, where one, two, or all three hydroxyl groups of cyclate, dipropylene glycol palmitate, dipropylene glycol glycerol are eachesterified using a fatty acid disclosed herein palmitoleate, dipropylene glycol sapienate, dipropylene gly to produce monoglycerides, diglycerides, and triglycerides, 60 col margarate, dipropylene glycol Stearate, dipropylene gly respectively. In these compounds, each hydroxyl groups of col palmitostearate, dipropylene glycol oleate, dipropylene glycerol may be esterified by different fatty acids. Addition glycol elaidate, dipropylene glycol vaccinate, dipropylene ally, glycerides may be acetylated to produce acetylated glycollinoleate, dipropylene glycollinoelaidate, dipropylene monoglycerides, acetylated diglycerides, and acetylated trig glycol O-linolenate, dipropylene glycol Y-linolenate, dipro lycerides. One group of glycerolipids is the glycerides, where 65 pylene glycol Stearidonate, dipropylene glycol cappryloca one, two, or all three hydroxyl groups of glycerol have Sugar prate, dipropylene glycol dicapprylocaprate, or any combi residues attached via a glycosidic linkage. nation thereof. US 9,265,742 B2 25 26 A lipid useful in the pharmaceutical compositions dis glyceride, a palmitoyl PPG glyceride, a palmitoleoyl PPG closed herein may be a pharmaceutically-acceptable poly glyceride, a sapienoyl PPG glyceride, a margaroyl PPG glyc ether fatty acid ester. A pharmaceutically-acceptable poly eride, a stearoyl PPG glyceride, a palmitostearoyl PPG glyc ether fatty acid ester can be a mono-fatty acid ester of a eride, an oleoyl PPG glyceride, an elaidoyl PPG glyceride, a polyether, a di-fatty acid ester of a polyether, or a tri-fatty acid vaccinoyl PPG glyceride, a linoleoyl PPG glyceride, a lino ester of a polyether. A polyether fatty acid ester includes, elaidoyl PPG glyceride, an O-linolenoyl PPG glyceride, a without limitation, a PEG fatty acid ester, a PEG glyceryl Y-linolenoyl PPG glyceride, a stearidonoyl PPG glyceride, a fatty acid, a PEG fatty acid ester glyceride, a PPG fatty acid capprylocaproyl PPG glyceride, a dicapprylocaproyl PPG ester, a PPG glyceryl fatty acid, and a PPG fatty acid ester glyceride, or any combination thereof. glyceride. A PEG or PPG may be a molecular mass of, e.g., 10 Commercially available pharmaceutically-acceptable 5-20,000. Non-limiting examples of polyether fatty acid polyether fatty acid esters include, without limitation, capry esters include, e.g., a PEG caprylate, a PEG pelargonate, a locaproyl macrogol-8 glycerides (LABRASOL(R), propy PEG caprate, a PEG undecylate, a PEG laurate, a PEG tride lene glycol monopalmitostearate (MONOSTEOL(R), glyc cylate, a PEG myristate, a PEG myristolate, a PEG pentade eryl dibelhenate (COMPRITOL.R. 888), glycerol behenate cyclate, a PEG palmitate, a PEG palmitoleate, a PEG sapi 15 (COMPRITOL(R) EATO), behenoyl pollyoxyl-8 glycerides enate, a PEG margarate, a PEG stearate, a PEG (COMPRITOL(R) HD5 ATO), triglycerol disostearate palmitostearate, PEG oleate, PEG elaidate, PEG vaccinate, (PLUROL(R) Diisostearique), PEG-8 beeswax (APIFIL(R), PEG linoleate, PEG linoelaidate, PEG O-linolenate, PEG lauroyl macrogol-32 glycerides (GELUCIRE 44/14), Y-linolenate, PEG stearidonate, PEG capprylocaprate, PEG stearoyl macrogol-32 glycerides (GELUCIRE 50.13), propy dicapprylocaprate, a PEG glyceryl caprylate, a PEG glyceryl lene glycol dicaprylocaprate (LABRAFAC(R) PG), polyglyc pelargonate, a PEG glyceryl caprate, a PEG glyceryl unde erol-3 dioleate (PLUROL(R) Oleigue CC 497), propylene gly cylate, a PEG glyceryl laurate, a PEG glyceryl tridecylate, a col monolaurate (type I) (LAUROGLYCOLR) FCC), PEG glyceryl myristate, a PEG glyceryl myristolate, a PEG propylene glycol monolaurate (type II) (LAUROGLYCOLOR glyceryl pentadecyclate, a PEG glyceryl palmitate, a PEG 90), propylene glycol monocaprylate (type I) (CAPRYOLOR glyceryl palmitoleate, a PEG glyceryl Sapienate, a PEG glyc 25 PGMC), propylene glycol monocaprylate (type II) (CA eryl margarate, a PEG glyceryl Stearate, a PEG glyceryl PRYOLR 90), linoleoyl macrogol-6 glycerides (LABRA palmitostearate, PEG glyceryl oleate, PEG glyceryl elaidate, FIL(R) M2125CS), oleoyl macrogol-6 glycerides (LABRA PEG glyceryl vaccinate, PEG glyceryllinoleate, PEG glyc FIL(R) M1944CS), lauroyl macrogol-6 glycerides eryl linoelaidate, PEG glyceryl C-linolenate, PEG glyceryl (LABRAFIL(R) M2130CS), glycerol dipalmitostearate Y-linolenate, PEG glyceryl Stearidonate, PEG glyceryl cap 30 (Biogapress Vegetal BM297ATO), glycerol distearate (type I) prylocaprate, PEG glyceryl dicapprylocaprate, a capryloyl (PRECIROL(R) ATO 5), and glycerol monolinoleate PEG glyceride, a pelargonoyl PEG glyceride, a caproyl PEG (MAISINETM35-1). glyceride, an undecyloyl PEG glyceride, a lauroyl PEG glyc A lipid useful in the pharmaceutical compositions dis eride, a tridecyloyl PEG glyceride, a myristoyl PEG glycer closed herein may be a mixture of pharmaceutically-accept ide, a myristoloyl PEG glyceride, a pentadecycloyl PEG glyc 35 able lipids. Examples of mixtures of pharmaceutically-ac eride, a palmitoyl PEG glyceride, a palmitoleoyl PEG ceptable lipids include, without limitation, a mixture of one or glyceride, a sapienoyl PEG glyceride, a margaroyl PEG glyc more glycerolipids disclosed herein, a mixture of one or more eride, a stearoyl PEG glyceride, a palmitostearoyl PEG glyc glycol fatty acid esters disclosed herein, a mixture of more eride, an oleoyl PEG glyceride, an elaidoyl PEG glyceride, a polyether fatty acid esters disclosed herein, a mixture of more vaccinoyl PEG glyceride, a linoleoyl PEG glyceride, a lino 40 glycerides disclosed herein. elaidoyl PEG glyceride, an O-linolenoyl PEG glyceride, a In aspects of this embodiment, a mixture of pharmaceuti Y-linolenoyl PEG glyceride, a stearidonoyl PEG glyceride, a cally-acceptable lipids includes a mixture of mono-, di-, and/ capprylocaproyl PEG glyceride, a dicapprylocaproyl PEG or triglycerides having a melting point of e.g., about 33°C., glyceride, a PPG caprylate, a PPG pelargonate, a PPG about 34°C., about 35° C., about 36°C., about 37°C., about caprate, a PPG undecylate, a PPG laurate, a PPG tridecylate, 45 38°C., about 39°C., about 40°C., about 41° C., about 43°C., a PPG myristate, a PPG myristolate, a PPG pentadecyclate, a about 43°C., about 44°C., about 45° C., about 45° C., about PPG palmitate, a PPG palmitoleate, a PPG sapienate, a PPG 47°C., about 48°C., about 49°C., about 50° C. In aspects of margarate, a PPG stearate, a PPG palmitostearate, a PPG this embodiment, a mixture of pharmaceutically-acceptable oleate, a PPG elaidate, a PPG vaccinate, a PPG linoleate, a lipids includes a mixture of mono-, di-, and/or triglycerides PPG linoelaidate, a PPG C-linolenate, a PPG Y-linolenate, a 50 having a melting point of, e.g., about 30° C. to about 44°C., PPG stearidonate, a PPG capprylocaprate, a PPG dicappry about 30° C. to about 45° C., about 30° C. to about 46°C., locaprate, a PPG glyceryl caprylate, a PPG glyceryl pelargo about 30° C. to about 47°C., about 30° C. to about 48°C., nate, a PPG glyceryl caprate, a PPG glyceryl undecylate, a about 30° C. to about 49° C., about 30° C. to about 50° C., PPG glyceryl laurate, a PPG glyceryl tridecylate, a PPG glyc about 32° C. to about 44° C., about 32° C. to about 45° C., eryl myristate, a PPG glyceryl myristolate, a PPG glyceryl 55 about 32° C. to about 46° C., about 32° C. to about 47°C., pentadecyclate, a PPG glyceryl palmitate, a PPG glyceryl about 32° C. to about 48°C., about 32° C. to about 49°C., palmitoleate, a PPG glyceryl sapienate, a PPG glyceryl mar about 32° C. to about 50° C., about 34° C. to about 44°C., garate, a PPG glyceryl Stearate, a PPG glyceryl palmitostear about 34° C. to about 45° C., about 34° C. to about 46°C., ate, a PPG glyceryl oleate, a PPG glyceryl elaidate, a PPG about 34° C. to about 47°C., about 34° C. to about 48°C., glyceryl vaccinate, a PPG glyceryllinoleate, a PPG glyceryl 60 about 34° C. to about 49° C., about 34° C. to about 50° C., linoelaidate, a PPG glyceryl C-linolenate, a PPG glyceryl about 36° C. to about 44° C., about 36° C. to about 45° C., Y-linolenate, a PPG glyceryl Stearidonate, a PPG glyceryl about 36° C. to about 46° C., about 36° C. to about 47°C., capprylocaprate, a PPG glyceryl dicapprylocaprate, a capry about 36° C. to about 48°C., about 36° C. to about 49°C., loyl PPG glyceride, a pelargonoyl PPG glyceride, a caproyl about 36° C. to about 50° C., about 38°C. to about 44°C., PPG glyceride, an undecyloyl PPG glyceride, a lauroyl PPG 65 about 38°C. to about 45° C., about 38°C. to about 46°C., glyceride, a tridecyloyl PPG glyceride, a myristoyl PPG glyc about 38°C. to about 47°C., about 38°C. to about 48°C., eride, a myristoloyl PPG glyceride, a pentadecycloyl PPG about 38°C. to about 49° C., about 38°C. to about 50° C., US 9,265,742 B2 27 28 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., 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° 10 Commercially available mixtures of pharmaceutically-ac C., about 35° C., about 36° C., about 37° C., about 38°C., ceptable lipids include, without limitation, mixtures of about 39°C., about 40°C., about 41° C., about 43°C., about PEG-6 sterate and ethylene glycol palmitostearate and PEG 43°C., about 44°C., about 45° C., about 45° C., about 47°C., 32 stearate (TEFOSE(R) 1500; TEFOSE(R) 63), mixtures of about 48°C., about 49° C., about 50° C. In aspects of this triceteareth-4 phosphate and ethylene glycol palmitostearate embodiment, a mixture of pharmaceutically-acceptable lip 15 and diethylene glycol palmitostearate (SEDEFOSR 75), ids includes a mixture PEG fatty acid esters having a melting mixtures of glycerol monostearate and PEG-75 stearate point of, e.g., about 30° C. to about 44°C., about 30° C. tO (GELOTR), mixtures of cetyl alcohol and ethoxylated fatty about 45° C., about 30° C. to about 46° C., about 30° C. tO alcohols (seteth-2-, steareth-20) (EMULCIRE(R), mixtures about 47°C., about 30° C. to about 48°C., about 30° C. tO of Saturated Co-Cs triglycerides having a melting point about 49°C., about 30° C. to about 50° C., about 32° C. tO around 33°C. (GELUCIRE(R) 33/01), mixtures of saturated about 44°C., about 32° C. to about 45° C., about 32° C. tO Co-Cs triglycerides having a melting point around 39° C. about 46°C., about 32° C. to about 47°C., about 32° C. tO (GELUCIRE(R)39/01), mixtures of saturated Co-Cs triglyc about 48°C., about 32° C. to about 49° C., about 32° C. tO erides having a melting point around 43° C. (GELUCIRER) about 50° C., about 34° C. to about 44° C., about 34° C. tO 43/01), mixtures of glycerol monostearate 40-55 (type I) and about 45° C., about 34° C. to about 46° C., about 34° C. tO 25 diglycerides (GELEOL(R) Mono and Diglycerides), and mix about 47°C., about 34° C. to about 48°C., about 34° C. tO tures of medium-chain triglycerides (LABRAFAC(R) Lipo about 49°C., about 34° C. to about 50° C., about 36° C. tO phile WL 1349). about 44°C., about 36° C. to about 45° C., about 36° C. tO Aspects of the present specification disclose, in part, a about 46°C., about 36° C. to about 47°C., about 36° C. tO pharmaceutically-acceptable stabilizing agent. A stabilizing about 48°C., about 36° C. to about 49° C., about 36° C. tO 30 agent reduces or eliminates formation of esters of a therapeu about 50° C., about 38° C. to about 44° C., about 38°C. tO tic compound that may result as a unwanted reaction with the about 45° C., about 38° C. to about 46° C., about 38° C. to particular solvent used. A stabilizing agent include, without about 47°C., about 38° C. to about 48°C., about 38°C. tO limitation, water, a sacrificial acid comprising a fatty acid about 49°C., about 38° C. to about 50° C., about 40° C. tO component and acetic acid, ethyl acetate, a sodium acetate/ about 44°C., about 40° C. to about 45° C., about 40° C. tO 35 acetic acid (E262), a monoglyceride, an acetylated about 46°C., about 40° C. to about 47°C., about 40° C. tO monoglyceride, a diglyceride, an acetylated monoglyceride, about 48°C., about 40° C. to about 49° C., about 40° C. tO an acetylated diglyceride, a fatty acid, and a fatty acid salt. about 50° C., about 42° C. to about 44° C., about 42° C. tO In one embodiment, a pharmaceutically-acceptable stabi about 45° C., about 42° C. to about 46° C., about 42°C. tO lizing agent may comprise a pharmaceutically-acceptable about 47°C., about 42° C. to about 48°C., about 42°C. tO 40 emulsifying agent. An emulsifying agent (also known as an about 49°C., or about 42°C. to about 50° C. emulgent) is a Substance that stabilizes an emulsion compris In other aspects of this embodiment, a mixture of pharma ing a liquid dispersed phase and a liquid continuous phase by ceutically-acceptable lipids includes a mixture of mono-, di-, increasing its kinetic stability. Thus, in situations where the and/or triglycerides and PEG fatty acid esters having a melt Solvent and adjuvant used to make a pharmaceutical compo ing point of, e.g., about 33°C., about 34°C., about 35°C., 45 sition disclosed herein are normally immiscible, an emulsi about 36°C., about 37°C., about 38°C., about 39°C., about fying agent disclosed herein is used to create a homogenous 40°C., about 41° C., about 43°C., about 43°C., about 44°C., and stable emulsion. An emulsifying agent includes, without about 45° C., about 45° C., about 47°C., about 48°C., about limitation, a surfactant, a polysaccharide, a lectin, and a phos 49°C., about 50°C. In aspects of this embodiment, a mixture pholipid. of pharmaceutically-acceptable lipids includes a mixture of 50 In an aspect of this embodiment, an emulsifying agent may mono-, di-, and/or triglycerides and PEG fatty acid esters comprise a surfactant. As used hereon, the term 'surfactant having a melting point of, e.g., about 30° C. to about 44°C., refers to a natural or synthetic amphiphilic compound. A about 30° C. to about 45° C., about 30° C. to about 46° C., Surfactant can be non-ionic, Zwitterionic, or ionic. Non-lim about 30° C. to about 47°C., about 30° C. to about 48°C., iting examples of Surfactants include polysorbates like about 30° C. to about 49° C., about 30° C. to about 50° C., 55 polysorbate 20 (TWEENR 20), polysorbate 40 (TWEENR) about 32° C. to about 44° C., about 32° C. to about 45° C., 40), polysorbate 60 (TWEENR 60), polysorbate 61 about 32° C. to about 46° C., about 32° C. to about 47°C., (TWEENR 61), polysorbate 65 (TWEENR 65), polysorbate about 32° C. to about 48°C., about 32° C. to about 49° C., 80 (TWEENR 80), and polysorbate 81 (TWEENR 81); about 32° C. to about 50° C., about 34° C. to about 44°C., poloxamers (polyethylene-polypropylene copolymers), like about 34° C. to about 45° C., about 34° C. to about 46° C., 60 Poloxamer 124 (PLURONICR) L44), Poloxamer 181 (PLU about 34° C. to about 47°C., about 34° C. to about 48°C., RONICR) L61), Poloxamer 182 (PLURONICR) L62), Polox about 34° C. to about 49° C., about 34° C. to about 50° C., amer 184 (PLURONICR) L64), Poloxamer 188 (PLU about 36° C. to about 44° C., about 36° C. to about 45° C., RONIC(R) F68), Poloxamer 237 (PLURONIC(R) F87), about 36° C. to about 46° C., about 36° C. to about 47°C., Poloxamer 338 (PLURONICRL108), Poloxamer 407 (PLU about 36° C. to about 48°C., about 36° C. to about 49° C., 65 RONIC(R) F127), polyoxyethyleneglycol dodecyl ethers, like about 36° C. to about 50° C., about 38°C. to about 44°C., BRIJR 30, and BRIJR 35:2-dodecoxyethanol (LUBROL(R)- about 38°C. to about 45° C., about 38°C. to about 46° C., PX); polyoxyethylene octyl phenyl ether (TRITONR) US 9,265,742 B2 29 30 X-100); sodium dodecyl sulfate (SDS);3-(3-Cholamidopro The pharmaceutical compositions disclosed hereinact as a pyl)dimethylammonio-1-propanesulfonate (CHAPS): delivery system that enable atherapeutic compound disclosed 3-(3-Cholamidopropyl)dimethylammonio-2-hydroxy-1- herein to be more effectively delivered or targeted to a cell propanesulfonate (CHAPSO); Sucrose monolaurate; and type, tissue, organ, or region of the body in a manner that Sodium cholate. Other non-limiting examples of Surfactant more effectively inhibits a pain response. This inhibition excipients can be found in, e.g., Ansel, Supra, (1999); results in an improved treatment of a severe pain. For Gennaro, supra, (2000); Hardman, supra, (2001); and Rowe, example, a pharmaceutical composition disclosed herein may supra, (2003), each of which is hereby incorporated by refer facilitate the delivery of a therapeutic compound disclosed ence in its entirety. herein into macrophages. One possible mechanism that In an aspect of this embodiment, an emulsifying agent may 10 achieves this selective biodistribution is that the pharmaceu comprise a polysaccharide. Non-limiting examples of tical compositions disclosed herein may be designed to take polysaccharides include guar gum, agar, alginate, calgene, a advantage of the activity of chylomicrons. Chylomicrons are dextran (like dextran 1 K, dextran 4K, dextran 40K, dextran relatively large lipoprotein particles having a diameter of 75 60K, and dextran 70K), dextrin, glycogen, inulin, starch, a nm to 1,200 nm. Comprising triglycerides (85-92%), phos starch derivative (like hydroxymethyl starch, hydroxyethyl 15 pholipids (6-12%), cholesterol (1-3%) and apolipoproteins starch, hydroxypropyl Starch, hydroxybutyl starch, and (1-2%), chylomicrons transport dietary lipids from the intes hydroxypentyl starch), hetastarch, cellulose, FICOLL, tines to other locations in the body. Chylomicrons are one of methyl cellulose (MC), carboxymethyl cellulose (CMC), the five major groups of lipoproteins, the others being VLDL, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose IDL, low-density lipoproteins (LDL), high-density lipopro (HPC), hydroxyethyl methyl cellulose (NEMC), hydrox teins (HDL), that enable fats and cholesterol to move within ypropyl methylcellulose (HPMC); polyvinyl acetates (PVA): the water-based solution of the bloodstream. polyvinyl pyrrolidones (PVP), also known as povidones, hav During digestion, fatty acids and cholesterol undergo pro ing a K-value of less than or equal to 18, a K-value greater cessing in the gastrointestinal tract by the action of pancreatic than 18 or less than or equal to 95, or a K-value greater than juices including lipases and emulsification with bile salts to 95, like PVP 12 (KOLLIDONR 12), PVP 17 (KOLLIDONR 25 generate micelles. These micelles allow the absorption of 17), PVP 25 (KOLLIDONR 25), PVP 30 (KOLLIDONR) lipid as free fatty acids by the absorptive cells of the small 30), PVP 90 (KOLLIDONR 90); and polyethylene imines intestine, known as enterocytes. Once in the enterocytes, (PEI). triglycerides and cholesterol are assembled into nascent chy In an aspect of this embodiment, an emulsifying agent may lomicrons. Nascent chylomicrons are primarily composed of comprise a lectin. Lectins are Sugar-binding proteins that are 30 triglycerides (85%) and contain some cholesterol and choles highly specific for their Sugar moieties. Lectins may be clas teryl esters. The main apolipoprotein component is apolipo sified according to the sugar moiety that they bind to, and protein B-48 (APOB48). These nascent chylomicrons are include, without limitation, mannose-binding lectins, galac released by exocytosis from enterocytes into lacteals, lym tose/N-acetylgalactosamine-binding lectins, N-acetylgluX phatic vessels originating in the villi of the Small intestine, osamine-binding lectins, N-acetylneuramine-binding lectins, 35 and are then secreted into the bloodstream at the thoracic N-acetylneuraminic acid-binding lectins, and fucose-binding ducts connection with the left subclavian vein. lectins. Non-limiting examples of Surfactants include con While circulating in lymph and blood, chylomicrons canavain A, lentil lectin, Snowdrop lectin, Roin, peanut agglu exchange components with HDL. The HDL donates apolipo tinin, jacain, hairy vetch lectin, wheat germ agglutinin, elder protein C-II (APOC2) and apolipoprotein E (APOE) to the berry lectin, Maackia anurensis leukoagglutinin, Maackia 40 nascent chylomicron and thus converts it to a mature chylo anurensis hemoagglutinin, Ulex europaeus agglutinin, and micron (often referred to simply as “chylomicron'). APOC2 Aleuria aurantia lectin. is the cofactor for lipoprotein lipase (LPL) activity. Once In an aspect of this embodiment, an emulsifying agent may triglyceride stores are distributed, the chylomicron returns comprise a phospholipid. The structure of the phospholipid APOC2 to the HDL (but keeps APOE), and, thus, becomes a generally comprises a hydrophobic tail and a hydrophilic 45 chylomicron remnant, now only 30-50 nm. APOB48 and head and is amphipathic in nature. Most phospholipids con APOE are important to identify the chylomicron remnant in tain a diglyceride, a phosphate group, and a simple organic the liver for endocytosis and breakdown into lipoproteins molecule Such as choline; one exception to this rule is sphin (VLDL, LDL and HDL). These lipoproteins are processed gomyelin, which is derived from sphingosine instead of glyc and stored by competent cells, including, e.g., hepatocytes, erol. Phospholipids include, without limitation, diacylglycer 50 adipocytes and macrophages. Thus, without wishing to be ides and phosphosphingolipids. Non-limiting examples of limited by any theory, upon oral administration, a pharma diacylglycerides include a phosphatidic acid (phosphatidate) ceutical composition disclosed herein can be processed into (PA), a phosphatidylethanolamine (cephalin) (PE), a phos micelles while in the gastrointestinal tract, absorbed by phatidylcholine (lecithin) (PC), a phosphatidylserine (PS), enterocytes and assembled into nascent chylomicrons, and a phosphoinositide including phosphatidylinositol (PI), 55 remain associated with chylomicron remnants taken up by the phosphatidylinositol phosphate (PIP), phosphatidylinositol liver, and ultimately loaded into macrophages which are bisphosphate (PIP2), and phosphatidylinositol triphosphate present in tissues experiencing pain. (PIP3). Non-limiting examples of phosphosphingolipids As another example, a pharmaceutical composition dis include a ceramide phosphorylcholine (sphingomyelin) closed herein may facilitate the delivery of a therapeutic (SPH), ceramide phosphorylethanolamine (sphingomyelin) 60 compound disclosed herein into dentritic cells. One possible (Cer-PE), and ceramide phosphorylglycerol. mechanism to achieve selective biodistribution of the phar In one embodiment, a pharmaceutically-acceptable stabi maceutical compositions disclosed herein may be to take lizing agent does not comprise a pharmaceutically-acceptable advantage of the endocytotic/phagocytotic activity of den emulsifying agent. tritic cells. Dendritic cells are immune cells forming part of In another embodiment, a pharmaceutical composition 65 the mammalian immune system. The main function of den does not comprise a pharmaceutically-acceptable emulsify dritic cells is to process antigen material and present it on the ing agent. surface to other cells of the immune system. Thus, dendritic US 9,265,742 B2 31 32 cells function as antigen-presenting cells that act as messen 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least gers between innate and adaptive immunity. Dendritic cells 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at are present in tissues in contact with the external environ least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 ment, such as, e.g., the skin (where there is a specialized mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at dendritic cell type called Langerhans cells) and the inner 5 least 1,400 mg. or at least 1,500 mg. In other aspects of this lining of the nose, lungs, stomach and intestines. These cells embodiment, the amount of a therapeutic compound that is can also be found in an immature state in the blood. Once contacted with the solvent in step (a) may be in the range of activated, they migrate to the lymph nodes where they interact e.g., about 10 mg to about 100 mg, about 50 mg to about 150 with T cells and B cells to initiate and shape the adaptive mg, about 100 mg to about 250 mg, about 150 mg to about immune response. Dendritic cells are known to endocytose 10 350 mg, about 250 mg to about 500 mg, about 350 mg to and phagocytose lipid particles as part of their environmental about 600 mg, about 500 mg to about 750 mg, about 600 mg monitoring and antigen presentation processes. Without to about 900 mg, about 750 mg to about 1,000 mg, about 850 wishing to be limited by any theory, upon topical or inhalatory mg to about 1,200 mg. or about 1,000 mg to about 1,500 mg. administration, a pharmaceutical composition disclosed In other aspects of this embodiment, the amount of a thera herein can penetrate into the skin or inner lining of the nose, 15 peutic compound that is dissolved in the solvent in step (a) lungs, stomach and intestines, be endocytosed/phagocytosed may be in the range of, e.g., about 10 mg to about 250 mg. by dentritic cells, and ultimately loaded into T cells and/or B about 10 mg to about 500 mg, about 10 mg to about 750 mg. cells which are present in tissues experiencing pain. about 10 mg to about 1,000 mg, about 10 mg to about 1,500 Aspects of the present specification disclose, in part, a mg, about 50 mg to about 250 mg, about 50 mg to about 500 method of preparing a pharmaceutical composition disclosed 20 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 herein. A method disclosed herein comprises the step of con mg, about 50 mg to about 1,500 mg, about 100 mg to about tacting a pharmaceutically-acceptable adjuvant disclosed 250 mg, about 100 mg to about 500 mg, about 100 mg to herein with a therapeutic compound disclosed herein under about 750 mg, about 100 mg to about 1,000 mg, about 100 mg conditions which allow the therapeutic compound to dissolve to about 1,500 mg, about 200 mg to about 500 mg, about 200 in the pharmaceutically-acceptable adjuvant, thereby form- 25 mg to about 750 mg, about 200 mg to about 1,000 mg. or ing a pharmaceutical composition disclosed herein. about 200 mg to about 1,500 mg. Aspects of the present specification disclose, in part, a Step (a) may be carried out at room temperature, in order to method of preparing a pharmaceutical composition disclosed allow a therapeutic compound to dissolve fully in the phar herein. A method disclosed herein comprises the steps of a) maceutically-acceptable solvent. However, in other embodi contacting a pharmaceutically-acceptable solvent disclosed 30 ments of the method, Step (a) may be carried out at a tem herein with a therapeutic compound disclosed herein under perature that is greater than room temperature. In aspects of conditions which allow the therapeutic compound to dissolve this embodiment, Step (a) may be carried out at a temperature in the pharmaceutically-acceptable solvent, thereby forming that is, e.g., greater than 21°C., greater than 25°C., greater a solution; and b) contacting the solution formed in step (a) than 30°C., greater than 35° C. or greater than 37°C., greater with a pharmaceutically-acceptable adjuvant disclosed 35 than 40°C., greater than 42°C., greater than 45° C., greater herein under conditions which allow the formation of a phar than 50° C., greater than 55° C., or greater than 60° C. In maceutical composition. The methods of preparing disclosed aspects of this embodiment, Step (a) may be carried out at a herein may further comprise a step (c) of removing the phar temperature that is between, e.g., about 20°C. to about 30°C., maceutically-acceptable solvent from the pharmaceutical about 25° C. to about 35° C., about 30° C. to about 40°C., composition. 40 about 35° C. to about 45° C., about 40° C. to about 50° C., The amount of a therapeutic compound that is contacted about 45° C. to about 55° C., or about 50° C. to about 60° C. with the pharmaceutically-acceptable solvent in step (a) of In certain cases, Step (a) may be carried out at temperatures the method may be in any amount desired. Factors used to below room temperature, in order to allow atherapeutic com determine the amount of a therapeutic compound used pound to dissolve fully in solvent. However, in other embodi include, without limitation, the final amount the therapeutic 45 ments of the method, step (a) may be carried out at a tempera compound desired in the pharmaceutical composition, the ture that is less than room temperature, e.g., less than 10°C., desired concentration of a therapeutic compound in the solu greater than 5°C., greater than 0°C., greater than -10°C. or tion, the hydrophobicity of the therapeutic compound, the greater than -20°C. The contacting in Step (a) may comprise lipophobicity of the therapeutic compound, the temperature mixing the therapeutic compound and the pharmaceutically under which the contacting step (a) is performed, and the time 50 acceptable solvent, e.g., by Stirring, inversion, Sonication, or under which the contacting step (a) is performed, the particu Vortexing. The mixing may be carried out for, e.g., at least 1 lar formulation desired, and the particular route of delivery of second, at least 5 seconds, at least 10 seconds, at least 20 the pharmaceutical compound. seconds, at least 30 seconds, at least 45 seconds, at least 60 The Volume of a pharmaceutically-acceptable solvent used seconds, or more, until the therapeutic compound is fully in step (a) of the method may be any volume desired. Factors 55 dissolved in the solvent. used to determine the Volume of a pharmaceutically-accept After contacting, the concentration of a therapeutic com able solvent used include, without limitation, the final amount pound disclosed herein in the Solution may be in any concen of a pharmaceutical composition desired, the desired concen tration desired. In aspects of this embodiment, the concentra tration of a therapeutic compound in the Solution, the hydro tion of a therapeutic compound disclosed herein in the phobicity of the therapeutic compound, and the lipophobicity 60 solution may be, e.g., at least 0.00001 mg/mL, at least 0.0001 of the therapeutic compound, the particular formulation mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least desired, and the particular route of delivery of the pharma 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 ceutical compound. mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 In aspects of this embodiment, the amount of a therapeutic mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least compound that is contacted with the solvent in step (a) may 65 1,000 mg/mL, or at least 1,200 mg/mL. In other aspects of this be, e.g., at least 10 mg, at least 20 mg, at least 30 mg, at least embodiment, the concentration of a therapeutic compound 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least disclosed herein in the solution may be, e.g., at most 1,000 US 9,265,742 B2 33 34 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most 1:12, about 0:1 to about 1:12, about 1:1 to about 1:12, about 1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at 1:2 to about 1:12, about 1:3 to about 1:12, about 1:4 to about most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 1:12, about 1:5 to about 1:12, about 1:6 to about 1:12, about mg/mL. In other aspects of this embodiment, the concentra 1:7 to about 1:12, about 1:8 to about 1:12, about 5:1 to about tion of a therapeutic compound disclosed herein in the solu 1:10, about 4:1 to about 1:10, about 3:1 to about 1:10, about tion may be in a range of, e.g., about 0.00001 mg/mL to about 2:1 to about 1:10, about 0:1 to about 1:10, about 1:1 to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, 1:10, about 1:2 to about 1:10, about 1:3 to about 1:10, about about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL 1:4 to about 1:10, about 1:5 to about 1:10, about 1:6 to about to about 3,000 mg/mL, about 1 mg/mL to about 3,000 1:10, about 1:7 to about 1:10, or about 1:8 to about 1:10. mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 10 Step (b) may be carried out at room temperature, in order to mg/mL to about 3,000 mg/mL, about 750 mg/mL to about allow the solution comprising the therapeutic compound to 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, form the pharmaceutical composition. However, in other about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL embodiments of the method, Step (b) may be carried out at a to about 2,000 mg/mL, about 500 mg/mL to about 2,000 temperature that is greater than room temperature. In aspects mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 15 of this embodiment, Step (b) may be carried out at a tempera 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to ture that is, e.g., greater than 21°C., greater than 25°C., about 1,500 mg/mL, about 250 mg/mL to about 1,500 greater than 30°C., greater than 35°C. or greater than 37°C., mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750 greater than 40°C., greater than 42°C., greater than 45°C., mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about greater than 50°C., greater than 55°C., or greater than 60° C. 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, In aspects of this embodiment, Step (a) may be carried out at about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL a temperature that is between, e.g., about 20°C. to about 30° to about 1,200 mg/mL, about 750 mg/mL to about 1,200 C., about 25°C. to about 35°C., about 30° C. to about 40°C., mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about about 35° C. to about 45° C., about 40° C. to about 50° C., 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 45° C. to about 55° C., or about 50° C. to about 60° C. about 1,000 mg/mL, about 500 mg/mL to about 1,000 25 In certain cases, Step (b) may be carried out at temperatures mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 below room temperature, in order to allow atherapeutic com mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 pound to dissolve fully in a pharmaceutically-acceptable sol mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 vent. However, in other embodiments of the method, step (b) mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 may be carried out at a temperature that is less than room mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about 30 temperature, e.g., less than 10°C., greater than 5°C., greater 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 than 0°C., greater than -10°C. or greater than -20°C. The mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about contacting in Step (b) may comprise mixing the solution and 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about the pharmaceutically-acceptable adjuvant, e.g., by stirring, 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to inversion, Sonication, or Vortexing. The mixing may be car about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, 35 ried out for, e.g., at least 1 second, at least 5 seconds, at least about 0.001 mg/mL to about 10 mg/mL, or about 0.001 10 seconds, at least 20 seconds, at least 30 seconds, at least 45 mg/mL to about 100 mg/mL. seconds, at least 60 seconds, or more, until the pharmaceuti The Volume of a pharmaceutically-acceptable adjuvant cal composition is formed. used in step (b) of the method may be any volume desired. In certain embodiments, a rapid cooling step may be used Factors used to determine the volume of a pharmaceutically 40 to reduce the temperature of a pharmaceutical composition acceptable adjuvant used include, without limitation, the final disclosed herein after its formation. For example, a rapid amount of a pharmaceutical composition desired, the desired cooling step may be used in procedures were temperatures concentration of a therapeutic compound in the pharmaceu greater than room temperature are used to allow a therapeutic tical composition, the ratio of solvent:adjuvant used, and the compound to dissolve fully in the pharmaceutically-accept miscibility of solvent and adjuvant, the particular formulation 45 able solvent and/or to allow the solution comprising the thera desired, and the particular route of delivery of the pharma peutic compound to form the pharmaceutical composition. In ceutical compound. aspects of this embodiment, a rapid cooling step results in a In aspects of this embodiment, the ratio of solution:adju temperature decrease of, e.g., about 30° C. in 20 minutes, vant may be, e.g., at least 5:1, at least 4:1, at least 3:1, at least about 25°C. in 20 minutes, about 20°C. in 20 minutes, about 2:1, at least 0:1, at least 1:1, at least 1:2, at least 1:3, at least 50 15° C. in 20 minutes, about 30°C. in 15 minutes, about 25°C. 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least in 15 minutes, about 20°C. in 15 minutes, about 15° C. in 15 1:9, at least 1:10, at least 1:15, at least 1:20, or at least 1:25. In minutes, about 30° C. in 10 minutes, about 25° C. in 10 other aspects of this embodiment, the ratio of Solution:adju minutes, about 20° C. in 10 minutes, about 15° C. in 10 vant may be in a range of, e.g., about 5:1 to about 1:25, about minutes, about 30°C. in 5 minutes, about 25°C. in 5 minutes, 4:1 to about 1:25, about 3:1 to about 1:25, about 2:1 to about 55 about 20°C. in 5 minutes, about 15° C. in 5 minutes. In other 1:25, about 0:1 to about 1:25, about 1:1 to about 1:25, about aspects of this embodiment, a rapid cooling step results in a 1:2 to about 1:25, about 1:3 to about 1:25, about 1:4 to about temperature decrease of, e.g., about 20°C. to about 30°C. in 1:25, about 1:5 to about 1:25, about 5:1 to about 1:20, about 20 minutes, about 20° C. to about 30°C. in 15 minutes, about 4:1 to about 1:20, about 3:1 to about 1:20, about 2:1 to about 20°C. to about 30°C. in 10 minutes, about 20°C. to about 30° 1:20, about 0:1 to about 1:20, about 1:1 to about 1:20, about 60 C. in 5 minutes, about 15° C. to about 25°C. in 20 minutes, 1:2 to about 1:20, about 1:3 to about 1:20, about 1:4 to about about 15° C. to about 25°C. in 15 minutes, about 15° C. to 1:20, about 1:5 to about 1:20, about 5:1 to about 1:15, about about 25°C. in 10 minutes, about 15° C. to about 25°C. in 5 4:1 to about 1:15, about 3:1 to about 1:15, about 0:1 to about minutes, about 10°C. to about 20°C. in 20 minutes, about 10° 1:15, about 2:1 to about 1:15, about 1:1 to about 1:15, about C. to about 20°C. in 15 minutes, about 10°C. to about 20° C. 1:2 to about 1:15, about 1:3 to about 1:15, about 1:4 to about 65 in 10 minutes, or about 10° C. to about 20° C. in 5 minutes. 1:15, about 1:5 to about 1:15, about 5:1 to about 1:12, about In yet aspects of this embodiment, a rapid cooling step 4:1 to about 1:12, about 3:1 to about 1:12, about 2:1 to about results in a temperature decrease of e.g., about 2.0° US 9,265,742 B2 35 36 C./minute, about 1.9°C/minute, about 1.8° C./minute, about more than 50° C., more than 55° C., more than 60° C., more 1.7°C./minute, about 1.6°C./minute, about 1.5° C./minute, than 65°C., more than 70° C., more than 80°C., or more than about 1.4° C./minute, about 1.3° C./minute, about 1.2 25°C. In other aspects of this embodiment, removal of sol C./minute, about 1.1° C./minute, about 1.0°C./minute, about vent from the pharmaceutical composition disclosed herein 0.9°C./minute, about 0.8° C./minute, about 0.7°C./minute, may be carried out at ambient atmospheric pressure and at a about 0.6° C./minute, about 0.5° C./minute, about 0.4° temperature in a range of, e.g., about 25°C. to about 100°C., C./minute, about 0.3° C./minute, about 0.2° C./minute, or about 25° C. to about 95°C., about 25° C. to about 90° C., about 0.1° C./minute. In still aspects of this embodiment, a about 25° C. to about 85°C., about 25° C. to about 80°C., rapid cooling step results in a temperature decrease of, e.g., about 25° C. to about 75° C., about 25° C. to about 70° C., about 0.1° C. to about 0.4° C./minute, about 0.2°C. to about 10 about 25°C. to about 65° C., or about 25°C. to about 60° C. 0.6°C./minute, about 0.4°C. to about 0.8°C/minute, about In another embodiment, removal of solvent from the phar 0.6°C. to about 1.0°C./minute, about 0.8° C. to about 1.2 maceutical composition disclosed herein may be carried out C./minute, about 1.0°C. to about 1.4° C./minute, about 1.2 under vacuum and at a temperature below ambient tempera C. to about 1.6° C./minute, about 1.4° C. to about 1.8° ture. In aspects of this embodiment, removal of solvent from C./minute, about 1.6°C. to about 2.0° C./minute, about 0.1° 15 the pharmaceutical composition disclosed herein may be car C. to about 0.5° C./minute, about 0.5° C. to about 1.0° ried out under vacuum and at a temperature of, e.g., less than C./minute, about 1.0°C. to about 1.5°C/minute, about 1.5° 20°C., less than 18°C., less than 16°C., less than 14°C., less C. to about 2.0° C./minute, about 0.5° C. to about 1.5° than 12°C., less than 10°C., less than 8°C., less than 6°C., C./minute, or about 1.0° C. to about 2.0° C./minute. less than 4°C., less than 2° C., or less than 0° C. In other In some embodiments, temperatures greater than room aspects of this embodiment, removal of solvent from the temperature employed in either Step (a) or Step (b) or both pharmaceutical composition disclosed herein may be carried may be used to remove the solvent from a pharmaceutical out under vacuum and at a temperature in a range of, e.g., composition. In other embodiment, removal of solvent from a about -20°C. to about 20°C., about -20°C. to about 18°C., pharmaceutical composition requires a separate Step (c). In about -20°C. to about 16°C., about -20°C. to about 14°C., Step (c), the solvent removal from a pharmaceutical compo 25 about -20°C. to about 12°C., about -20°C. to about 10°C., sition may be accomplished using one of a variety of proce about -20° C. to about 8° C., about -20° C. to about 6°C., dures known in the art, including, without limitation, evapo about -20° C. to about 4°C., about -20° C. to about 2°C., ration, dialyzation, distillation, lypholization, and filtration. about -20°C. to about 0°C., about -15°C. to about 20°C., These removal procedures may be done under conditions of about -10°C. to about 20° C., about -5°C. to about 20°C., ambient atmosphere, under low pressure, or under a vacuum 30 about 0°C. to about 20° C., about -10°C. to about 20°C., and either at ambient temperature or at temperatures requir about -10°C. to about 18°C., about -10°C. to about 16°C., ing heating. about -10°C. to about 14°C., about -10°C. to about 12°C., In one embodiment, Step (c) may result in the complete about -10°C. to about 10°C., about -10°C. to about 8°C., removal of a pharmaceutically-acceptable solvent from the about -10° C. to about 6° C., about -10° C. to about 4°C., pharmaceutical composition disclosed herein. In aspects of 35 about -10°C. to about 2°C., or about -10°C. to about 0°C. this embodiment, Step (c) may result in, e.g., at least 5%, at The final concentration of a therapeutic compound dis least 10%, at least 15%, at least 20%, at least 25%, at least closed herein in a pharmaceutical composition disclosed 30%, at least 35%, at least 40%, at least 45%, at least 50%, at herein may be of any concentration desired. In an aspect of least 55%, at least 60%, at least 65%, at least 70%, at least this embodiment, the final concentration of a therapeutic 75%, at least 80%, at least 85%, at least 90%, at least 93%, at 40 compound in a pharmaceutical composition may be a thera least 95%, at least 97%, or at least 99% removal of a phar peutically effective amount. In other aspects of this embodi maceutically-acceptable solvent from the pharmaceutical ment, the final concentration of a therapeutic compound in a composition disclosed herein. pharmaceutical composition may be, e.g., at least 0.00001 Step (c) is conducted at a temperature that allows for the mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least evaporation of a pharmaceutically-acceptable solvent dis 45 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 closed herein, and as such, an evaporation temperature is mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 Solvent dependant. Factors which influence an evaporation mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 temperature of a solvent disclosed herein include, without mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In limitation, the particular solvent used, the amount of Solvent other aspects of this embodiment, the concentration of a present, the particular therapeutic compound present, the par 50 therapeutic compound disclosed herein in the Solution may ticular adjuvant present, the stability of the therapeutic com be, e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most pound present, the reactivity of the therapeutic compound 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, at present, the particular atmospheric pressure used, the time most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 desired for complete evaporation. Generally, a pharmaceuti mg/mL, or at most 3,000 mg/mL. In other aspects of this cal composition will require heating if the evaporation step is 55 embodiment, the final concentration of a therapeutic com conducted at ambient pressure, e.g., 1 atm. However, under pound in a pharmaceutical composition may be in a range of high vacuum conditions, the evaporation step may be con e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about ducted attemperatures below ambient temperature, e.g., less 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to than 22° C. about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, In one embodiment, removal of solvent from the pharma 60 about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to ceutical composition disclosed herein may be carried out at about 3,000 mg/mL, about 500 mg/mL to about 3,000 ambient atmospheric pressure and at a temperature above mg/mL, about 750 mg/mL to about 3,000 mg/mL, about ambient temperature. In aspects of this embodiment, removal 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to of solvent from the pharmaceutical composition disclosed about 2,000 mg/mL, about 250 mg/mL to about 2,000 herein may be carried out at ambient atmospheric pressure 65 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 and at a temperature of, e.g., more than 25°C., more than 30° mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about C., more than 35° C., more than 40° C., more than 45° C., 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, US 9,265,742 B2 37 38 about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL about 100 mg/mL to about 700 mg/mL, about 100 mg/mL to to about 1,500 mg/mL, about 750 mg/mL to about 1,500 about 800 mg/mL, about 100 mg/mL to about 900 mg/mL, mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about about 100 mg/mL to about 1,000 mg/mL, about 200 mg/mL 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to to about 300 mg/mL, about 200 mg/mL to about 400 mg/mL, about 1,200 mg/mL, about 500 mg/mL to about 1,200 about 200 mg/mL to about 500 mg/mL, about 200 mg/mL to mg/mL, about 750 mg/mL to about 1,200 mg/mL, about about 600 mg/mL, about 200 mg/mL to about 700 mg/mL, 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to about 200 mg/mL to about 800 mg/mL, about 200 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 about 900 mg/mL, about 200 mg/mL to about 1,000 mg/mL, mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 about 300 mg/mL to about 400 mg/mL, about 300 mg/mL to mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 10 about 500 mg/mL, about 300 mg/mL to about 600 mg/mL, 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about about 300 mg/mL to about 700 mg/mL, about 300 mg/mL to 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about about 800 mg/mL, about 300 mg/mL to about 900 mg/mL, 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about about 300 mg/mL to about 1,000 mg/mL, about 400 mg/mL 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 to about 500 mg/mL, about 400 mg/mL to about 600 mg/mL, mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to 15 about 400 mg/mL to about 700 mg/mL, about 400 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 about 800 mg/mL, about 400 mg/mL to about 900 mg/mL, mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about about 400 mg/mL to about 1,000 mg/mL, about 500 mg/mL 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to to about 600 mg/mL, about 500 mg/mL to about 700 mg/mL, about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 500 mg/mL to about 800 mg/mL, about 500 mg/mL to about 0.001 mg/mL to about 10 mg/mL, or about 0.001 about 900 mg/mL, about 500 mg/mL to about 1,000 mg/mL, mg/mL to about 100 mg/mL. about 600 mg/mL to about 700 mg/mL, about 600 mg/mL to A pharmaceutical composition produced using the meth about 800 mg/mL, about 600 mg/mL to about 900 mg/mL, or ods disclosed herein may be formulated for either local or about 600 mg/mL to about 1,000 mg/mL. systemic delivery using topical, enteral or parenteral routes of In semi-solid and Solid formulations, an amount of a thera administration. Additionally, a therapeutic compound dis 25 peutic compound disclosed herein typically may be between closed herein may beformulated by itself in a pharmaceutical about 0.01% to about 45% by weight. In aspects of this composition, or may beformulated together with one or more embodiment, an amount ofatherapeutic compound disclosed other therapeutic compounds disclosed herein in a single herein may be from, e.g., about 0.1% to about 45% by weight, pharmaceutical composition. about 0.1% to about 40% by weight, about 0.1% to about 35% A pharmaceutical composition produced using the meth 30 by weight, about 0.1% to about 30% by weight, about 0.1% to ods disclosed herein may be a liquid formulation, semi-solid about 25% by weight, about 0.1% to about 20% by weight, formulation, or a solid formulation. A formulation disclosed about 0.1% to about 15% by weight, about 0.1% to about 10% herein can be produced in a manner to form one phase. Such by weight, about 0.1% to about 5% by weight, about 1% to as, e.g., an oil or a solid. Alternatively, a formulation disclosed about 45% by weight, about 1% to about 40% by weight, herein can be produced in a manner to form two phase. Such 35 about 1% to about 35% by weight, about 1% to about 30% by as, e.g., an emulsion. A pharmaceutical composition dis weight, about 1% to about 25% by weight, about 1% to about closed herein intended for Such administration may be pre 20% by weight, about 1% to about 15% by weight, about 1% pared according to any method known to the art for the to about 10% by weight, about 1% to about 5% by weight, manufacture of pharmaceutical compositions. Semi-solid about 5% to about 45% by weight, about 5% to about 40% by formulations suitable for topical administration include, 40 weight, about 5% to about 35% by weight, about 5% to about without limitation, ointments, creams, salves, and gels. 30% by weight, about 5% to about 25% by weight, about 5% A liquid formulation can be formed by using various lipids to about 20% by weight, about 5% to about 15% by weight, like oils of other fatty acids that remain as liquids in the about 5% to about 10% by weight, about 10% to about 45% temperature range desired. In an embodiment, a pharmaceu by weight, about 10% to about 40% by weight, about 10% to tical composition disclosed herein is liquid at room tempera 45 about 35% by weight, about 10% to about 30% by weight, ture. In aspects of this embodiment, a pharmaceutical com about 10% to about 25% by weight, about 10% to about 20% position disclosed herein may be formulated to be a liquid at by weight, about 10% to about 15% by weight, about 15% to a temperature of, e.g., about 25°C. or higher, about 23°C. or about 45% by weight, about 15% to about 40% by weight, higher, about 21°C. or higher, about 19°C. or higher, about about 15% to about 35% by weight, about 15% to about 30% 17° C. or higher, about 15° C. or higher, about 12° C. or 50 by weight, about 15% to about 25% by weight, about 15% to higher, about 10°C. or higher, about 8°C. or higher, about 6° about 20% by weight, about 20% to about 45% by weight, C. or higher, about 4°C. or higher, or about 0°C. or higher. about 20% to about 40% by weight, about 20% to about 35% In liquid and semi-solid formulations, a concentration of a by weight, about 20% to about 30% by weight, about 20% to therapeutic compound disclosed herein typically may be about 25% by weight, about 25% to about 45% by weight, between about 50 mg/mL to about 1,000 mg/mL. In aspects of 55 about 25% to about 40% by weight, about 25% to about 35% this embodiment, a therapeutically effective amount of a by weight, or about 25% to about 30% by weight. therapeutic compound disclosed herein may be from, e.g., In one embodiment, a liquid formulation comprises a about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to therapeutic compound, a glycol ether, a partially-hydroge about 200 mg/mL, about 50 mg/mL to about 300 mg/mL, nated fat, an oil, and an alcohol. In an aspect of this embodi about 50 mg/mL to about 400 mg/mL, about 50 mg/mL to 60 ment, a liquid formulation comprises about 15% to about about 500 mg/mL, about 50 mg/mL to about 600 mg/mL, 35% by weight of therapeutic compound, about 5% to about about 50 mg/mL to about 700 mg/mL, about 50 mg/mL to 25% by weight of glycol ether, about 15% to about 40% by about 800 mg/mL, about 50 mg/mL to about 900 mg/mL, weight of partially-hydrogenated fat, about 15% to about about 50 mg/mL to about 1,000 mg/mL, about 100 mg/mL to 40% of an oil, and about 1% to about 15% of an alcohol. In about 200 mg/mL, about 100 mg/mL to about 300 mg/mL, 65 another aspect of this embodiment, a liquid formulation com about 100 mg/mL to about 400 mg/mL, about 100 mg/mL to prises about 20% to about 30% by weight of therapeutic about 500 mg/mL, about 100 mg/mL to about 600 mg/mL, compound, about 10% to about 20% by weight of glycol US 9,265,742 B2 39 40 ether, about 20% to about 35% by weight of partially-hydro may be a free acid of a salt of ibuprofen. In other aspects of genated fat, about 20% to about 35% of an oil, and about 2% this embodiment, an oil is rapeseed oil or theobroma oil. to about 10% of an alcohol. In yet another aspect of this In one embodiment, a liquid formulation comprises a embodiment, a liquid formulation comprises about 23% to therapeutic compound, an ester of an alcohol, and an oil. In an about 27% by weight of therapeutic compound, about 13% to aspect of this embodiment, a liquid formulation comprises about 17% by weight of glycol ether, about 25% to about 30% about 1% to about 10% by weight of therapeutic compound, by weight of partially-hydrogenated fat, about 25% to about about 1% to about 10% by weight of an ester of an alcohol, 30% of an oil, and about 4% to about 8% of an alcohol. Instill and about 80% to about 98% of an oil. In another aspect of this another aspect of this embodiment, a liquid formulation com embodiment, a liquid formulation comprises about 2% to prises about 24% to about 26% by weight of therapeutic 10 compound, about 14% to about 16% by weight of glycol about 8% by weight of therapeutic compound, about 1% to ether, about 26% to about 28% by weight of partially-hydro about 7% by weight of an ester of an alcohol, and about 85% genated fat, about 26% to about 28% of an oil, and about 5% to about 97% of an oil. In yet another aspect of this embodi to about 7% of an alcohol. In other aspects of this embodi ment, a liquid formulation comprises about 3% to about 7% ment, an oil is rapeseed oil or theobroma oil. 15 by weight of therapeutic compound, about 2% to about 6% by In another embodiment, a liquid formulation comprises a weight of an ester of an alcohol, and about 87% to about 95% therapeutic compound, a glycol ether, a glyceryl monoli of an oil. In still another aspect of this embodiment, a liquid noleate, an oil, and an alcohol. In an aspect of this embodi formulation comprises about 4% to about 6% by weight of ment, a liquid formulation comprises about 15% to about therapeutic compound, about 3% to about 5% by weight of an 35% by weight of therapeutic compound, about 5% to about ester of an alcohol, and about 90% to about 92% of an oil. In 25% by weight of glycol ether, about 15% to about 40% by other aspects of this embodiment, an oil is rapeseed oil or weight of glyceryl monolinoleate, about 15% to about 40% of theobroma oil. an oil, and about 1% to about 15% of an alcohol. In another In another embodiment, a liquid formulation comprises a aspect of this embodiment, a liquid formulation comprises therapeutic compound, an ethyl acetate, and an oil. In an about 20% to about 30% by weight of therapeutic compound, 25 aspect of this embodiment, a liquid formulation comprises about 10% to about 20% by weight of glycol ether, about 20% about 1% to about 10% by weight of therapeutic compound, to about 35% by weight of glyceryl monolinoleate, about about 1% to about 10% by weight of an ethyl acetate, and 20% to about 35% of an oil, and about 2% to about 10% of an about 80% to about 98% of an oil. In another aspect of this alcohol. In yet another aspect of this embodiment, a liquid embodiment, a liquid formulation comprises about 2% to formulation comprises about 23% to about 27% by weight of 30 about 8% by weight of therapeutic compound, about 1% to therapeutic compound, about 13% to about 17% by weight of about 7% by weight of an ethyl acetate, and about 85% to glycol ether, about 25% to about 30% by weight of glyceryl about 97% of an oil. In yet another aspect of this embodiment, monolinoleate, about 25% to about 30% of an oil, and about a liquid formulation comprises about 3% to about 7% by 4% to about 8% of an alcohol. In still another aspect of this weight of therapeutic compound, about 2% to about 6% by embodiment, a liquid formulation comprises about 24% to 35 weight of an ethyl acetate, and about 87% to about 95% of an about 26% by weight of therapeutic compound, about 14% to oil. In still another aspect of this embodiment, a liquid for about 16% by weight of glycol ether, about 26% to about 28% mulation comprises about 4% to about 6% by weight of by weight of glyceryl monolinoleate, about 26% to about therapeutic compound, about 3% to about 5% by weight of an 28% of an oil, and about 5% to about 7% of an alcohol. In ethyl acetate, and about 90% to about 92% of an oil. In other other aspects of this embodiment, an oil is rapeseed oil or 40 aspects of this embodiment, an oil is rapeseed oil or theo theobroma oil. broma oil. In another embodiment, a liquid formulation comprises an In another embodiment, a liquid formulation comprises an ibuprofen, a diethylene glycol monoethyl ether, a glyceryl ibuprofen, an ethyl acetate, and an oil. In an aspect of this monolinoleate, an oil, and an alcohol. In an aspect of this embodiment, a liquid formulation comprises about 1% to embodiment, a liquid formulation comprises about 15% to 45 about 10% by weight of an ibuprofen, about 1% to about 10% about 35% by weight of an ibuprofen, about 5% to about 25% by weight of an ethyl acetate, and about 80% to about 98% of by weight of diethylene glycol monoethyl ether, about 15% to an oil. In another aspect of this embodiment, a liquid formu about 40% by weight of glyceryl monolinoleate, about 15% lation comprises about 2% to about 8% by weight of an to about 40% of an oil, and about 1% to about 15% of an ibuprofen, about 1% to about 7% by weight of an ethyl alcohol. In another aspect of this embodiment, a liquid for 50 acetate, and about 85% to about 97% of an oil. In yet another mulation comprises about 20% to about 30% by weight of an aspect of this embodiment, a liquid formulation comprises ibuprofen, about 10% to about 20% by weight of diethylene about 3% to about 7% by weight of an ibuprofen, about 2% to glycol monoethyl ether, about 20% to about 35% by weight of about 6% by weight of an ethyl acetate, and about 87% to glyceryl monolinoleate, about 20% to about 35% of an oil, about 95% of an oil. In still another aspect of this embodi and about 2% to about 10% of an alcohol. In yet another 55 ment, a liquid formulation comprises about 4% to about 6% aspect of this embodiment, a liquid formulation comprises by weight of an ibuprofen, about 3% to about 5% by weight of about 23% to about 27% by weight of an ibuprofen, about an ethyl acetate, and about 90% to about 92% of an oil. In 13% to about 17% by weight of diethylene glycol monoethyl other aspects of this embodiment, an ibuprofen may be a free ether, about 25% to about 30% by weight of glyceryl mono acid of a salt of ibuprofen. In other aspects of this embodi linoleate, about 25% to about 30% of an oil, and about 4% to 60 ment, an oil is rapeseed oil or theobroma oil. about 8% of an alcohol. In still another aspect of this embodi In one embodiment, a Solid or semi-solid formulation dis ment, a liquid formulation comprises about 24% to about closed herein is formulated without a hydrophilic solvent like 26% by weight of an ibuprofen, about 14% to about 16% by water. Such formulations result in the formation of co-crys weight of diethylene glycol monoethyl ether, about 26% to tals of the lipids and therapeutic compound. Stated another about 28% by weight of glyceryl monolinoleate, about 26% 65 way, Such formulations do not form liposomal emulsions to about 28% of an oil, and about 5% to about 7% of an and/or micellular particles, which require hydrophilic Sol alcohol. In other aspects of this embodiment, an ibuprofen Vent. US 9,265,742 B2 41 42 In one embodiment, a Solid formulation comprises a thera In another embodiment, a Solid formulation comprises an peutic compound, a hard fat, a partially-hydrogenated fat, and ibuprofen, a mixture of mono-, di-, and triglycerides and PEG a polyethylene glycol. In an aspect of this embodiment, a fatty acid esters, a glyceryl monolinoleate, and a polyethylene solid formulation comprises about 1% to about 30% by glycol. In an aspect of this embodiment, a solid formulation weight of therapeutic compound, about 8% to about 70% by 5 comprises about 1% to about 30% by weight of an ibuprofen, weight of hard fat, about 2% to about 65% by weight of about 8% to about 70% by weight of a mixture of mono-, di-, partially-hydrogenated fat, and about 1% to about 15% of and triglycerides and PEG fatty acid esters, about 2% to about polyethylene glycol. In another aspect of this embodiment, a 65% by weight of a glyceryl monolinoleate, and about 1% to solid formulation comprises about 10% to about 30% by about 15% of polyethylene glycol. In another aspect of this 10 embodiment, a solid formulation comprises about 10% to weight of therapeutic compound, about 20% to about 50% by about 30% by weight of an ibuprofen, about 20% to about weight of hard fat, about 10% to about 30% by weight of 50% by weight of a mixture of mono-, di-, and triglycerides partially-hydrogenated fat, and about 5% to about 15% of and PEG fatty acid esters, about 10% to about 30% by weight polyethylene glycol. In yet another aspect of this embodi of a glyceryl monolinoleate, and about 5% to about 15% of ment, a solid formulation comprises about 20% to about 30% 15 polyethylene glycol. In yet another aspect of this embodi by weight of therapeutic compound, about 30% to about 50% ment, a solid formulation comprises about 20% to about 30% by weight of hard fat, about 10% to about 30% by weight of by weight of an ibuprofen, about 30% to about 50% by weight partially-hydrogenated fat, and about 7% to about 13% of of a mixture of mono-, di-, and triglycerides and PEG fatty polyethylene glycol. In still another aspect of this embodi acid esters, about 10% to about 30% by weight of a glyceryl ment, a solid formulation comprises about 20% to about 30% monolinoleate, and about 7% to about 13% of polyethylene by weight of therapeutic compound, about 35% to about 50% glycol. In still another aspect of this embodiment, a solid by weight of hard fat, about 15% to about 25% by weight of formulation comprises about 20% to about 30% by weight of partially-hydrogenated fat, and about 7% to about 13% of an ibuprofen, about 35% to about 50% by weight of a mixture polyethylene glycol. In a further aspect of this embodiment, a of mono-, di-, and triglycerides and PEG fatty acid esters, solid formulation comprises about 23% to about 27% by 25 about 15% to about 25% by weight of a glyceryl monoli weight of therapeutic compound, about 41% to about 47% by noleate, and about 7% to about 13% of polyethylene glycol. weight of hard fat, about 18% to about 22% by weight of In a further aspect of this embodiment, a solid formulation partially-hydrogenated fat, and about 9% to about 11% of comprises about 23% to about 27% by weight of an ibupro polyethylene glycol. In other aspects of this embodiment, a fen, about 41% to about 47% by weight of a mixture of polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 30 mono-, di-, and triglycerides and PEG fatty acid esters, about 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700. 18% to about 22% by weight of a glyceryl monolinoleate, and In another embodiment, a solid formulation comprises a about 9% to about 11% of polyethylene glycol. In other therapeutic compound, a mixture of mono-, di-, and triglyc aspects of this embodiment, a polyethylene glycol is, e.g., a erides and PEG fatty acid esters, a glyceryl monolinoleate, PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a and a polyethylene glycol. In an aspect of this embodiment, a 35 PEG 600, or a PEG 700. solid formulation comprises about 1% to about 30% by In another embodiment, a solid formulation comprises a weight of therapeutic compound, about 8% to about 70% by therapeutic compound, a hard fat, a partially-hydrogenated weight of a mixture of mono-, di-, and triglycerides and PEG fat, a polyethylene glycol, and a propylene glycol. In an fatty acid esters, about 2% to about 65% by weight of a aspect of this embodiment, a Solid formulation comprises glyceryl monolinoleate, and about 1% to about 15% of poly 40 about 1% to about 30% by weight of therapeutic compound, ethylene glycol. In another aspect of this embodiment, a Solid about 8% to about 70% by weight of hard fat, about 2% to formulation comprises about 10% to about 30% by weight of about 65% by weight of partially-hydrogenated fat, about 1% therapeutic compound, about 20% to about 50% by weight of to about 15% of polyethylene glycol, and about 1% to about a mixture of mono-, di-, and triglycerides and PEG fatty acid 15% of propylene glycol. In another aspect of this embodi esters, about 10% to about 30% by weight of a glyceryl 45 ment, a solid formulation comprises about 10% to about 30% monolinoleate, and about 5% to about 15% of polyethylene by weight of therapeutic compound, about 20% to about 50% glycol. In yet another aspect of this embodiment, a solid by weight of hard fat, about 10% to about 30% by weight of formulation comprises about 20% to about 30% by weight of partially-hydrogenated fat, about 5% to about 15% of poly therapeutic compound, about 30% to about 50% by weight of ethylene glycol, and about 5% to about 15% of propylene a mixture of mono-, di-, and triglycerides and PEG fatty acid 50 glycol. In yet another aspect of this embodiment, a solid esters, about 10% to about 30% by weight of a glyceryl formulation comprises about 20% to about 30% by weight of monolinoleate, and about 7% to about 13% of polyethylene therapeutic compound, about 30% to about 50% by weight of glycol. In still another aspect of this embodiment, a Solid hard fat, about 10% to about 30% by weight of partially formulation comprises about 20% to about 30% by weight of hydrogenated fat, about 7% to about 13% of polyethylene therapeutic compound, about 35% to about 50% by weight of 55 glycol, and about 7% to about 13% of propylene glycol. In a mixture of mono-, di-, and triglycerides and PEG fatty acid still another aspect of this embodiment, a solid formulation esters, about 15% to about 25% by weight of a glyceryl comprises about 20% to about 30% by weight of therapeutic monolinoleate, and about 7% to about 13% of polyethylene compound, about 35% to about 50% by weight of hard fat, glycol. In a further aspect of this embodiment, a Solid formu about 15% to about 25% by weight of partially-hydrogenated lation comprises about 23% to about 27% by weight of thera- 60 fat, about 7% to about 13% of polyethylene glycol, and about peutic compound, about 41% to about 47% by weight of a 7% to about 13% of propylene glycol. In a further aspect of mixture of mono-, di-, and triglycerides and PEG fatty acid this embodiment, a solid formulation comprises about 23% to esters, about 18% to about 22% by weight of a glyceryl about 27% by weight of therapeutic compound, about 41% to monolinoleate, and about 9% to about 11% of polyethylene about 47% by weight of hard fat, about 18% to about 22% by glycol. In other aspects of this embodiment, a polyethylene 65 weight of partially-hydrogenated fat, about 9% to about 11% glycolis, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, of polyethylene glycol, and about 9% to about 11% of pro a PEG 500, a PEG 600, or a PEG 700. pylene glycol. In other aspects of this embodiment, a poly US 9,265,742 B2 43 44 ethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a an ibuprofen, about 35% to about 50% by weight of a mixture PEG 400, a PEG 500, a PEG 600, or a PEG 700. of mono-, di-, and triglycerides and PEG fatty acid esters, In another embodiment, a solid formulation comprises a about 15% to about 25% by weight of a glyceryl monoli therapeutic compound, a mixture of mono-, di-, and triglyc noleate, about 7% to about 13% of polyethylene glycol, and erides and PEG fatty acid esters, a glyceryl monolinoleate, a 5 about 7% to about 13% of propylene glycol. In a further polyethylene glycol, and a propylene glycol. In an aspect of aspect of this embodiment, a Solid formulation comprises this embodiment, a solid formulation comprises about 1% to about 23% to about 27% by weight of an ibuprofen, about about 30% by weight of therapeutic compound, about 8% to 41% to about 47% by weight of a mixture of mono-, di-, and about 70% by weight of a mixture of mono-, di-, and triglyc triglycerides and PEG fatty acid esters, about 18% to about erides and PEG fatty acid esters, about 2% to about 65% by 10 22% by weight of a glyceryl monolinoleate, about 9% to weight of a glyceryl monolinoleate, about 1% to about 15% of about 11% of polyethylene glycol, and about 9% to about polyethylene glycol, and about 1% to about 15% of propylene 11% of propylene glycol. In other aspects of this embodi glycol. In another aspect of this embodiment, a solid formu ment, a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a lation comprises about 10% to about 30% by weight of thera PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700. peutic compound, about 20% to about 50% by weight of a 15 In another embodiment, a semi-solid formulation com mixture of mono-, di-, and triglycerides and PEG fatty acid prises a therapeutic compound, a hard fat, a partially-hydro esters, about 10% to about 30% by weight of a glyceryl genated fat, a polyethylene glycol, and a propylene glycol. In monolinoleate, about 5% to about 15% of polyethylene gly an aspect of this embodiment, a semi-solid formulation com col, and about 5% to about 15% of propylene glycol. In yet prises about 15% to about 55% by weight of therapeutic another aspect of this embodiment, a solid formulation com- 20 compound, about 7% to about 20% by weight of hard fat, prises about 20% to about 30% by weight of therapeutic about 20% to about 50% by weight of partially-hydrogenated compound, about 30% to about 50% by weight of a mixture of fat, about 7% to about 20% of polyethylene glycol, and about mono-, di-, and triglycerides and PEG fatty acid esters, about 1% to about 8% of propylene glycol. In another aspect of this 10% to about 30% by weight of a glyceryl monolinoleate, and embodiment, a semi-solid formulation comprises about 20% about 7% to about 13% of polyethylene glycol, and about 7%. 25 to about 50% by weight of therapeutic compound, about 8% to about 13% of propylene glycol. In still another aspect of to about 18% by weight of hard fat, about 25% to about 45% this embodiment, a solid formulation comprises about 20% to by weight of partially-hydrogenated fat, about 8% to about about 30% by weight of therapeutic compound, about 35% to 18% of polyethylene glycol, and about 2% to about 6% of about 50% by weight of a mixture of mono-, di-, and triglyc propylene glycol. In another aspect of this embodiment, a erides and PEG fatty acid esters, about 15% to about 25% by 30 semi-solid formulation comprises about 20% to about 50% weight of a glyceryl monolinoleate, about 7% to about 13% of by weight of therapeutic compound, about 10% to about 16% polyethylene glycol, and about 7% to about 13% of propylene by weight of hard fat, about 25% to about 45% by weight of glycol. In a further aspect of this embodiment, a Solid formu partially-hydrogenated fat, about 10% to about 16% of poly lation comprises about 23% to about 27% by weight of thera ethylene glycol, and about 2% to about 6% of propylene peutic compound, about 41% to about 47% by weight of a 35 glycol. In yet another aspect of this embodiment, a semi-solid mixture of mono-, di-, and triglycerides and PEG fatty acid formulation comprises about 20% to about 50% by weight of esters, about 18% to about 22% by weight of a glyceryl therapeutic compound, about 11% to about 15% by weight of monolinoleate, about 9% to about 11% of polyethylene gly hard fat, about 30% to about 40% by weight of partially col, and about 9% to about 11% of propylene glycol. In other hydrogenated fat, about 11% to about 15% of polyethylene aspects of this embodiment, a polyethylene glycol is, e.g., a 40 glycol, and about 3% to about 5% of propylene glycol. In still PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a another aspect of this embodiment, a semi-solid formulation PEG 600, or a PEG 700. comprises about 25% to about 44% by weight of therapeutic In another embodiment, a Solid formulation comprises an compound, about 12% to about 14% by weight of hard fat, ibuprofen, a mixture of mono-, di-, and triglycerides and PEG about 32% to about 39% by weight of partially-hydrogenated fatty acid esters, a glyceryl monolinoleate, a polyethylene 45 fat, about 12% to about 14% of polyethylene glycol, and glycol, and a propylene glycol. In an aspect of this embodi about 4% of propylene glycol. In other aspects of this ment, a solid formulation comprises about 1% to about 30% embodiment, a polyethylene glycol is, e.g., a PEG 100, a PEG by weight of an ibuprofen, about 8% to about 70% by weight 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG of a mixture of mono-, di-, and triglycerides and PEG fatty 700. acid esters, about 2% to about 65% by weight of a glyceryl 50 In another embodiment, a semi-solid formulation com monolinoleate, about 1% to about 15% of polyethylene gly prises a therapeutic compound, a mixture of mono-, di-, and col, and about 1% to about 15% of propylene glycol. In triglycerides and PEG fatty acid esters, a glyceryl monoli another aspect of this embodiment, a solid formulation com noleate, a polyethylene glycol, and a propylene glycol. In an prises about 10% to about 30% by weight of an ibuprofen, aspect of this embodiment, a semi-solid formulation com about 20% to about 50% by weight of a mixture of mono-, di-, 55 prises about 15% to about 55% by weight of therapeutic and triglycerides and PEG fatty acid esters, about 10% to compound, about 7% to about 20% by weight of a mixture of about 30% by weight of a glyceryl monolinoleate, about 5% mono-, di-, and triglycerides and PEG fatty acid esters, about to about 15% of polyethylene glycol, and about 5% to about 20% to about 50% by weight of a glyceryl monolinoleate, 15% of propylene glycol. In yet another aspect of this about 7% to about 20% of polyethylene glycol, and about 1% embodiment, a solid formulation comprises about 20% to 60 to about 8% of propylene glycol. In another aspect of this about 30% by weight of an ibuprofen, about 30% to about embodiment, a semi-solid formulation comprises about 20% 50% by weight of a mixture of mono-, di-, and triglycerides to about 50% by weight of therapeutic compound, about 8% and PEG fatty acid esters, about 10% to about 30% by weight to about 18% by weight of a mixture of mono-, di-, and of a glyceryl monolinoleate, and about 7% to about 13% of triglycerides and PEG fatty acid esters, about 25% to about polyethylene glycol, and about 7% to about 13% of propylene 65 45% by weight of a glyceryl monolinoleate, about 8% to glycol. In still another aspect of this embodiment, a Solid about 18% of polyethylene glycol, and about 2% to about 6% formulation comprises about 20% to about 30% by weight of of propylene glycol. In another aspect of this embodiment, a US 9,265,742 B2 45 46 semi-solid formulation comprises about 20% to about 50% a salt of a therapeutic compound, about 7% to about 20% by by weight of therapeutic compound, about 10% to about 16% weight of hard fat, about 20% to about 50% by weight of by weight of a mixture of mono-, di-, and triglycerides and partially-hydrogenated fat, about 7% to about 20% of poly PEG fatty acid esters, about 25% to about 45% by weight of ethylene glycol, and about 1% to about 8% of propylene a glyceryl monolinoleate, about 10% to about 16% of poly glycol. In another aspect of this embodiment, a semi-solid ethylene glycol, and about 2% to about 6% of propylene formulation comprises about 15% to about 30% by weight of glycol. In yet another aspect of this embodiment, a semi-solid a free acid ofatherapeutic compound, about 1% to about 25% formulation comprises about 20% to about 50% by weight of by weight of a salt of a therapeutic compound, about 10% to therapeutic compound, about 11% to about 15% by weight of about 16% by weight of hard fat, about 25% to about 45% by a mixture of mono-, di-, and triglycerides and PEG fatty acid 10 esters, about 30% to about 40% by weight of a glyceryl weight of partially-hydrogenated fat, about 10% to about monolinoleate, and about 11% to about 15% of polyethylene 16% of polyethylene glycol, and about 2% to about 6% of glycol, and about 3% to about 5% of propylene glycol. In still propylene glycol. In yet another aspect of this embodiment, a another aspect of this embodiment, a semi-solid formulation semi-solid formulation comprises about 15% to about 30% comprises about 25% to about 44% by weight of therapeutic 15 by weight of a free acid ofatherapeutic compound, about 1% compound, about 12% to about 14% by weight of a mixture of to about 25% by weight of a salt of a therapeutic compound, mono-, di-, and triglycerides and PEG fatty acid esters, about about 11% to about 15% by weight of hard fat, about 30% to 32% to about 39% by weight of a glyceryl monolinoleate, about 40% by weight of partially-hydrogenated fat, about about 12% to about 14% of polyethylene glycol, and about 11% to about 15% of polyethylene glycol, and about 3% to 4% of propylene glycol. In other aspects of this embodiment, about 5% of propylene glycol. In still another aspect of this a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG embodiment, a semi-solid formulation comprises about 20% 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700. to about 24% by weight of a free acid of a therapeutic com In another embodiment, a semi-solid formulation com pound, about 5% to about 20% by weight of a salt of a prises an ibuprofen, a mixture of mono-, di-, and triglycerides therapeutic compound, about 12% to about 14% by weight of and PEG fatty acid esters, a glyceryl monolinoleate, a poly 25 hard fat, about 32% to about 39% by weight of partially ethylene glycol, and a propylene glycol. In an aspect of this hydrogenated fat, about 12% to about 14% of polyethylene embodiment, a semi-solid formulation comprises about 15% glycol, and about 4% of propylene glycol. In other aspects of to about 55% by weight of an ibuprofen, about 7% to about this embodiment, a polyethylene glycol is, e.g., a PEG 100, a 20% by weight of a mixture of mono-, di-, and triglycerides PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or and PEG fatty acid esters, about 20% to about 50% by weight 30 a PEG 7OO. of a glyceryl monolinoleate, about 7% to about 20% of poly In another embodiment, a semi-solid formulation com ethylene glycol, and about 1% to about 8% of propylene prises a therapeutic compound, a mixture of mono-, di-, and glycol. In another aspect of this embodiment, a semi-solid triglycerides and PEG fatty acid esters, a glyceryl monoli formulation comprises about 20% to about 50% by weight of noleate, a polyethylene glycol, and a propylene glycol. In an an ibuprofen, about 8% to about 18% by weight of a mixture 35 aspect of this embodiment, a semi-solid formulation com of mono-, di-, and triglycerides and PEG fatty acid esters, prises about 10% to about 35% by weight of a free acid of a about 25% to about 45% by weight of a glyceryl monoli therapeutic compound, about 1% to about 30% by weight of noleate, about 8% to about 18% of polyethylene glycol, and a salt of a therapeutic compound, about 7% to about 20% by about 2% to about 6% of propylene glycol. In another aspect weight of a mixture of mono-, di-, and triglycerides and PEG of this embodiment, a semi-solid formulation comprises 40 fatty acid esters, about 20% to about 50% by weight of a about 20% to about 50% by weight of an ibuprofen, about glyceryl monolinoleate, about 7% to about 20% of polyeth 10% to about 16% by weight of a mixture of mono-, di-, and ylene glycol, and about 1% to about 8% of propylene glycol. triglycerides and PEG fatty acid esters, about 25% to about In another aspect of this embodiment, a semi-solid formula 45% by weight of a glyceryl monolinoleate, about 10% to tion comprises about 15% to about 30% by weight of a free about 16% of polyethylene glycol, and about 2% to about 6% 45 acid of a therapeutic compound, about 1% to about 25% by of propylene glycol. In yet another aspect of this embodiment, weight of a salt of a therapeutic compound, about 10% to a semi-solid formulation comprises about 20% to about 50% about 16% by weight of a mixture of mono-, di-, and triglyc by weight of an ibuprofen, about 11% to about 15% by weight erides and PEG fatty acid esters, about 25% to about 45% by of a mixture of mono-, di-, and triglycerides and PEG fatty weight of a glyceryl monolinoleate, about 10% to about 16% acid esters, about 30% to about 40% by weight of a glyceryl 50 of polyethylene glycol, and about 2% to about 6% of propy monolinoleate, and about 11% to about 15% of polyethylene lene glycol. In yet another aspect of this embodiment, a semi glycol, and about 3% to about 5% of propylene glycol. In still solid formulation comprises about 15% to about 30% by another aspect of this embodiment, a semi-solid formulation weight of a free acid ofatherapeutic compound, about 1% to comprises about 25% to about 44% by weight of an ibupro about 25% by weight of a salt of a therapeutic compound, fen, about 12% to about 14% by weight of a mixture of 55 about 11% to about 15% by weight of a mixture of mono-, di-, mono-, di-, and triglycerides and PEG fatty acid esters, about and triglycerides and PEG fatty acid esters, about 30% to 32% to about 39% by weight of a glyceryl monolinoleate, about 40% by weight of a glyceryl monolinoleate, and about about 12% to about 14% of polyethylene glycol, and about 11% to about 15% of polyethylene glycol, and about 3% to 4% of propylene glycol. In other aspects of this embodiment, about 5% of propylene glycol. In still another aspect of this a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 60 embodiment, a semi-solid formulation comprises about 20% 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700. to about 24% by weight of a free acid of a therapeutic com In another embodiment, a semi-solid formulation com pound, about 5% to about 20% by weight of a salt of a prises a therapeutic compound, a hard fat, a partially-hydro therapeutic compound, about 12% to about 14% by weight of genated fat, a polyethylene glycol, and a propylene glycol. In a mixture of mono-, di-, and triglycerides and PEG fatty acid an aspect of this embodiment, a semi-solid formulation com 65 esters, about 32% to about 39% by weight of a glyceryl prises about 10% to about 35% by weight of a free acid of a monolinoleate, about 12% to about 14% of polyethylene gly therapeutic compound, about 1% to about 30% by weight of col, and about 4% of propylene glycol. In other aspects of this US 9,265,742 B2 47 48 embodiment, a polyethylene glycolis, e.g., a PEG 100, a PEG 35° C. or lower, about 33°C. or lower, about 31° C. or lower, 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG about 29° C. or lower, about 27°C. or lower, about 25°C. or 700. lower, about 23°C. or lower, about 21°C. or lower, about 19° In another embodiment, a semi-solid formulation com C. or lower, about 17° C. or lower, about 15° C. or lower, prises an ibuprofen, a mixture of mono-, di-, and triglycerides about 12° C. or lower, about 10° C. or lower, about 8° C. or and PEG fatty acid esters, a glyceryl monolinoleate, a poly lower, about 6°C. or lower, about 4°C. or lower, or about 0° ethylene glycol, and a propylene glycol. In an aspect of this C. or lower. embodiment, a semi-solid formulation comprises about 10% In other aspects of this embodiment, a pharmaceutical to about 35% by weight of a free acid of an ibuprofen, about composition disclosed has a melting point temperature of 1% to about 30% by weight of a salt of an ibuprofen, about 7% 10 e.g., 5°C. or higher, 10°C. or higher, 15° C. or higher, 22°C. to about 20% by weight of a mixture of mono-, di-, and or higher, 23°C. or higher, 24°C. or higher, 25°C. or higher, triglycerides and PEG fatty acid esters, about 20% to about 26°C. or higher, 27°C. or higher, 28°C. or higher, 29° C. or 50% by weight of a glyceryl monolinoleate, about 7% to higher,30° C. or higher, 31° C. or higher, 32° C. or higher, 33° about 20% of polyethylene glycol, and about 1% to about 8% C. or higher, 34° C. or higher, or 35° C. or higher. In other of propylene glycol. In another aspect of this embodiment, a 15 aspects of this embodiment, a pharmaceutical composition semi-solid formulation comprises about 15% to about 30% disclosed has a melting point temperature in the range of, e.g., by weight of a free acid of an ibuprofen, about 1% to about about 5°C. to about 24°C., about 10°C. to about 24°C. about 25% by weight of a salt of an ibuprofen, about 10% to about 22°C. to about 24°C., about 23°C. to about 25°C., about 24° 16% by weight of a mixture of mono-, di-, and triglycerides C. to about 26°C., about 25°C. to about 27°C., about 26°C. and PEG fatty acid esters, about 25% to about 45% by weight to about 28°C., about 27°C. to about 29°C., about 28°C. to of a glyceryl monolinoleate, about 10% to about 16% of about 30° C., about 29° C. to about 31° C., about 30° C. to polyethylene glycol, and about 2% to about 6% of propylene about 32° C., about 31° C. to about 33°C., about 32° C. to glycol. In yet another aspect of this embodiment, a semi-solid about 34°C., or about 33° C. to about 35°C. In other aspects formulation comprises about 15% to about 30% by weight of of this embodiment, a pharmaceutical composition disclosed a free acid of an ibuprofen, about 1% to about 25% by weight 25 has a melting point temperature in the range of, e.g., about 22° of a salt of an ibuprofen, about 11% to about 15% by weight C. to about 26°C., about 24°C. to about 28°C., about 26°C. of a mixture of mono-, di-, and triglycerides and PEG fatty to about 30° C., about 28°C. to about 32°C., or about 30° C. acid esters, about 30% to about 40% by weight of a glyceryl to about 34° C. monolinoleate, and about 11% to about 15% of polyethylene Aspects of the present specification disclose, in part, a glycol, and about 3% to about 5% of propylene glycol. In still 30 method of treating an individual with a severe pain condition. another aspect of this embodiment, a semi-solid formulation In one embodiment, the method comprises the step of admin comprises about 20% to about 24% by weight of a free acid of istering to an individual in need thereof a pharmaceutical an ibuprofen, about 5% to about 20% by weight of a salt of an composition disclosed herein, wherein administration ibuprofen, about 12% to about 14% by weight of a mixture of reduces a symptom associated with the severe pain, thereby mono-, di-, and triglycerides and PEG fatty acid esters, about 35 treating the individual. 32% to about 39% by weight of a glyceryl monolinoleate, Aspects of the present specification disclose, in part, treat about 12% to about 14% of polyethylene glycol, and about ing an individual Suffering from a severe pain condition. As 4% of propylene glycol. In other aspects of this embodiment, used herein, the term “treating refers to reducing or elimi a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG nating in an individual a clinical symptom of a severe pain 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700. 40 condition; or delaying or preventing in an individual the onset A solid or semi-solid formulation disclosed herein takes ofa clinical symptom of a severe pain condition. For example, advantage of the different melting point temperatures of the the term “treating can mean reducing a symptom of a con various adjuvants like fatty acids. Formation of a solid or dition characterized by a severe pain condition by, e.g., at semi-solid dosage form can be by modifying the respective least 20%, at least 25%, at least 30%, at least 35%, at least concentrations of the fatty acids comprising a pharmaceutical 45 40%, at least 45%, at least 50%, at least 55%, at least 60%, at composition disclosed herein. For example, linolenic acid has least 65%, at least 70%, at least 75%, at least 80%, at least a melting point temperature (T) of about -11° C., linoleic 85%, at least 90% at least 95%, or at least 100%. The actual acid has a T of about -5°C., oleic acid has a T of about 16° symptoms associated with a severe pain condition are well C. palmitic acid has a T of about 61-62°C., and Stearic acid known and can be determined by a person of ordinary skill in has a T of about 67-72°C. Increasing the proportion(s) of 50 the art by taking into account factors, including, without palmitic, Stearic or oleic acid would increase the overall melt limitation, the location of the severe pain condition, the cause ing temperature of a composition, while, conversely, increas of the severe pain condition, the severity of the severe pain ing the proportion(s) of linoleic and linolenic acid would condition, and/or the tissue or organ affected by the severe decrease the melting temperature of a composition. Thus, by pain condition. Those of skill in the art will know the appro controlling the types and amounts of the adjuvant compo 55 priate symptoms or indicators associated with a specific type nents added, a pharmaceutical composition disclosed herein of severe pain condition and will know how to determine if an can be made that is substantially solid or semi-solid at room individual is a candidate for treatment as disclosed herein. temperature, but melts when it is ingested, and reaches body Pain may be measured using one or more pain thresholds. temperature. The resulting melted composition readily forms Pain thresholds are measured by gradually increasing the micelles which are absorbed by the intestine, assembled into 60 intensity of a stimulus Such as electric current or heat applied chylomicrons, and ultimately absorbed by macrophages. The to the body. The pain perception threshold is the point at Solid dosage form may be a powder, granule, tablet, capsule which the stimulus begins to hurt, and the pain tolerance or Suppository. threshold is reached when the individual acts to stop the pain. In an embodiment, a pharmaceutical composition dis Pain may be measured using one or more pain scale ques closed herein is solid at room temperature. In aspects of this 65 tionnaires. Although a self-reported questionnaire by an indi embodiment, a pharmaceutical composition disclosed herein vidual suffering from a severe pain condition tend to be the may beformulated to be a solidata temperature of, e.g., about most reliable measure of pain, reports from health care pro US 9,265,742 B2 49 50 fessionals may also be used. A number of pain measurement mobility, financial management, health management and scales have been developed including, without limitation, maintenance, meal preparation and cleanup, and safety pro Alder Hey Triage Pain Score, Behavioral Pain Scale (BPS), cedures and emergency responses. Brief Pain Inventory (BPI), Checklist of Nonverbal Pain Indi As used herein, the term "severe pain' comprises any cators (CNPI), Critical-Care Pain Observation Tool (CPOT), acute, Subacute, chronic nociceptive, pathological pain, or COMFORT scale, Dallas Pain Questionnaire, Descriptor dif psychological pain. In aspects of this embodiment, a severe ferential scale (DDS), Disease-Specific Pain Scale (DSPI), pain is not an inflammatory pain or a pain whose primary Dolorimeter Pain Index (DPI), Faces Pain Scale Revised origin is due to an inflammatory response. (FPS-R), Face Legs Activity Cry Consolability scale, A severe pain condition may be classified according to Lequesne algofunctional index, Original index, McGill Pain 10 duration and pattern of occurrence. Such as, e.g., acute pain, Questionnaire (MPQ), Multidimensional Pain Inventory Subacute pain, and chronic pain. Acute pain is an organic pain (MPI), Neck Pain and Disability Scale NPAD, Numerical state that is typically transitory and of Sudden onset, lasting 11 point box (BS-11), Numeric Rating Scale (NRS-11), Pedi only until the noxious stimulus is removed and/or the under atric Pain Questionnaire (PPO), Roland-Morris Back Pain lying damage or pathology has healed. Chronic pain is an Questionnaire, Visual analog scale (VAS), and Wong-Baker 15 organic pain state that is persistent and extends beyond the FACES Pain Rating Scale. As one example, a NRS-11 scale is expected period of healing and may be present continuously an 11-point Scale for patient self-reporting that ranks the pain or intermediately. Subacute pain is an organic pain state that being experienced on a scale of 0 to 10, with 0 being no pain refers to a pain that is somewhere in between acute pain and at all, 1-3 being mild pain that interferes little with activities chronic pain. Although somewhat arbitrary, the distinction of daily life, 4-6 being moderate pain that interferes signifi between acute, Subacute, and chronic pain may be defined cantly with activities of daily life, and 7-10 being severe pain based on the interval of time from onset. Thus, an acute pain that completely interferes with activities of daily life. Quality is one that lasts less then one month, a Subacute pain is one can be established by having the individual complete the that lasts from one to six months, and a chronic pain is one that McGill Pain Questionnaire indicating which words best lasts six months or more. describe their pain. 25 A severe pain condition may also be classified as 1) a Severe pain condition symptoms include, without limita nociceptive pain; 2) a pathological pain; and 3) an inflamma tion, a coldness, a numbness, an itching, a paresthesias, an tory pain. electric shock sensation, a burning sensation, an ice-burn In one embodiment, a severe pain condition comprises a sensation, dysesthesia, allodynia, hyperalgesia, hyperpathia, nociceptive pain. Nociceptive pain is a severe pain condition a somatic pain sensation, and a visceral pain sensation. The 30 where an organic pain state is caused by a noxious insult or actual symptoms associated with a severe pain condition are injury of peripheral nerve fibers that respond only to stimuli well known and can be determined by a person of ordinary approaching or exceeding harmful intensity (nociceptors), skill in the art by taking into account factors, including, with and is commonly described as an aching pain. This type of out limitation, the location of the severe pain, the cause of the pain is associated with damage to non-neural tissue. Such as severe pain, the severity of the severe pain, the tissue or organ 35 skin, muscles, visceral organs, joints, tendons, or bones, and affected, and the associated disorder. is represented by a normally functioning somatosensory ner A pharmaceutical composition disclosed herein are useful Vous system. Nociceptive pain may be classified according to to treat severe pain. Pain is any unpleasant sensory and/or the mode of noxious stimulation, such as, e.g., thermal pain, emotional experience associated with actual or potential tis mechanical pain, and chemical pain, or according to the loca Sue damage, or described in terms of Such damage. Pain may 40 tion of the pain, such as, e.g., Somatic pain or visceral pain. occur in varying degrees of severity and is usually a conse In one embodiment, a severe pain condition comprises a quence of an injury, a disease, or an emotional disorder, Somatic pain. Somatic pain is a nociceptive pain that origi although the underlying cause may or may not be apparent to nates from ligaments, tendons, bones, blood vessels, and even a healthcare provider. A severe pain is one where the severity nerves themselves. It is detected with Somatic nociceptors. of the pain response significantly interferes or prevents an 45 The scarcity of pain receptors in these areas produces a dull, individual from performing one or more activities of daily poorly-localized pain of longer duration than cutaneous pain. life. An activity of daily life (ADL) is an activity an individual Non-limiting examples of Somatic pain include 1) excessive normally does such as feeding, bathing, dressing, grooming, muscle tension can be caused, for example, by a sprain or a work, homemaking, and leisure. ADLS may be categorized strain; 2) repetitive motion disorders can result from overuse based on whether the activity is a basic, an instrumental, oran 50 of the hands, wrists, elbows, shoulders, neck, back, hips, occupational one. Basic ADLs (BADLs) comprise self-care knees, feet, legs, or ankles; 3) muscle disorders causing tasks, including, e.g., personal hygiene and grooming, dress Somatic pain include, for example, a polymyositis, a dermato ing and undressing, self feeding, functional transfers (getting myositis, a lupus, a fibromyalgia, a polymyalgia rheumatica, into and out of bed or wheelchair, getting onto or off toilet, and a rhabdomyolysis; 4) myalgia including, e.g., muscle etc.), bowel and bladder management, and ambulation (walk 55 pain caused by overuse, over-stretching, viral infection, meta ing with or without use of an assistive device (walker, cane, or bolic myopathy, a nutritional deficiency, or chronic fatigue crutches) or using a wheelchair). Instrumental ADLS syndrome; 5) infections including, e.g., an abscess, a trichi (IADLs) are not necessary for fundamental functioning, but nosis, an influenza, a Lyme disease, a malaria, a Rocky Moun let an individual live independently in a community. IADLs tain spotted fever, Avian influenza, the common cold, com include, e.g., performing housework, taking medications as 60 munity-acquired pneumonia, meningitis, monkeypox, Severe prescribed, managing money, shopping for groceries or cloth Acute Respiratory Syndrome, toxic shock syndrome, trichi ing, using communication devices, using technology, using nosis, typhoid fever, and upper respiratory tract infection; and transportation within the community. Occupational ADLS 6) drugs including, e.g., cocaine, a statin for lowering choles (OADLS) are generally optional in nature and may be del terol (Suchasatorvastatin, simvastatin, and lovastatin), and an egated to others. OADLS include, e.g., caring of others (in 65 ACE inhibitor for lowering blood pressure (such as enalapril cluding selecting and Supervising caregivers), caring of pets, and captopril). Somatic pain may be classified as a Superficial child rearing, using of communication devices, community Somatic pain or a deep Somatic pain. Superficial Somatic pain US 9,265,742 B2 51 52 is initiated by activation of nociceptors in the skin or other neuropathic pain include central neuropathic pain, peripheral Superficial tissue, and is sharp, well-defined and clearly neuropathic pain, and deafferentation pain. located. Examples of injuries that produce Superficial Somatic In one embodiment, a severe pain condition comprises a pain include minor wounds and minor (first degree) burns. central neuropathic pain. Damage or disease affecting nerves Deep Somatic pain is initiated by Stimulation of nociceptors in of the central nervous system is referred to as a central neu ligaments, tendons, bones, blood vessels, fasciae and ropathic pain. Typically, the damage or disease occurs as muscles, and is dull, aching, poorly localized pain. Examples cerebral lesions, predominantly thalamic but may involve include sprains and broken bones. Suprathalamic and infrathalamic regions. Generally, the onset In one embodiment, a severe pain condition comprises a of central neuropathic pain is usually delayed after the occur visceral pain. Visceral pain is a nociceptive pain that is initi 10 rence of the initial episode that results in damage to the central ated by stimulation of nociceptors in the body's organs and nervous system; onset of pain may occur during the phase of internal cavities typically caused by stretching or ischemia. recovery from neurologic deficits. Central neuropathic pain Visceral pain is a diffuse, poorly localized pain and may be may be present in post-stroke conditions including, e.g., tha described as aching pain, sickening pain, dull pain, Squeezing 15 lamic infarction, brainstem infarction, or Subarachnoid hem pain, and/or deep pain, and it may be accompanied by nausea orrhage, cerebral venous thrombosis, cerebral tumors com and Vomiting. Visceral pain is extremely difficult to localize, pressing the thalamus or brainstem, cerebral abscesses and several injuries to visceral tissue may exhibit “referred compressing the thalamus or brainstem, traumatic brain pain, where the sensation is localized to an area completely injury, post-Surgical pain following brain or spine Surgery, unrelated to the site of injury. The even greater scarcity of complications following brain Surgery including thalamo nociceptors in these areas produces pain that is usually more tomy for movement disorders, multiple Sclerosis, and Parkin aching and of a longer duration than Somatic pain. Non son disease, spinal cord injury, complications following spi limiting examples of Somatic pain include 1) functional vis nal Surgery including anterolateral cordotomy and ceral pain including, e.g., an irritable bowel syndrome and a commissural myelotomy, ischemic lesions including anterior chronic functional abdominal pain (CFAP), a functional con 25 spinal artery syndrome and Wallenberg syndrome, Syringo stipation and a functional dyspepsia, a non-cardiac chest pain myelia, radiation myelopathy, HIV myelopathy. (NCCP) and a chronic abdominal pain; 2) chronic gas In one embodiment, a severe pain condition comprises a trointestinal inflammation including, e.g., a gastritis, an peripheral neuropathic pain. Damage or disease affecting inflammatory bowel disease, like, e.g., a Crohn's disease, an sensory, motor, and/or autonomic nerves of the peripheral ulcerative colitis, a microscopic colitis, a diverticulitis and a 30 nervous system is referred to as a peripheral neuropathic pain. gastroenteritis; an interstitial cystitis; an intestinal ischemia; a Peripheral neuropathic pain occurs when peripheral nerves cholecystitis; an appendicitis; a gastroesophageal reflux: an fail to carry information to and from the brain and spinal cord, ulcer, a nephrolithiasis, an urinary tract infection, a pancre resulting in pain, loss of sensation, or inability to control atitis and a hernia; 3) autoimmune pain including, e.g., a muscles. In some cases, the failure of nerves that control sarcoidosis and a vasculitis; 4) organic visceral pain includ 35 blood vessels, intestines, and other organs results in abnormal ing, e.g., pain resulting from a traumatic, inflammatory or blood pressure, digestion problems, and loss of other basic degenerative lesion of the gut or produced by a tumor imping body processes. Symptoms also depend on whether the con ing on sensory innervation; and 5) treatment-induced visceral dition affects the whole body or just one nerve. Risk factors pain including, e.g., a pain attendant to chemotherapy therapy for neuropathy include diabetes, heavy alcohol use, exposure or a pain attendant to radiation therapy. 40 to certain chemicals and drugs, prolonged pressure on a In one embodiment, a severe pain condition comprises a nerve. Some people have a hereditary predisposition for pathological pain. Damage A pathological pain is a severe peripheral neuropathy. The four cardinal patterns of periph pain condition where an organic pain state caused by disease eral neuropathic pain are mononeuropathy, mononeuropathic or damage to any part of the nervous system or by caused by multiplex, polyneuropathy, and autonomic neuropathy. an abnormal functioning of the nervous system. This type of 45 In one embodiment, a severe pain condition comprises a pain is associated with damage to neural tissue and an abnor mononeuropathic. A mononeuropathy is a peripheral neur mally functioning Somatosensory nervous system, rather than opathy involving functional loss or pathological change stimulation of pain receptors. Non-limiting examples of a affecting a single nerve or nerve group. Mononeuropathy is pathological pain include neuropathic pain and dysfunctional most often caused by damage to a local area resulting from pain. 50 injury or trauma, although occasionally systemic disorders In one embodiment, a severe pain condition comprises a may cause isolated nerve damage. The usual causes are direct neuropathic pain. Damage Neuropathic pain is a pathological trauma, prolonged pressure on the nerve, and compression of pain where an organic pain state is caused by damage or the nerve by swelling or injury to nearby body structures. The disease of the Somatosensory nervous system, resulting in damage includes destruction of the myelin sheath (covering) abnormal sensory firing from the peripheral nervous system, 55 of the nerve or of part of the nerve cell (the axon). This central nervous systems, or both. Neuropathic pain may damage slows or prevents conduction of impulses through the involve spontaneous or evoked pain, and may have continu nerve. Mononeuropathy may involve any part of the body. ous and/or episodic (paroxysmal) components. Neuropathic Mononeuropathic pain is associated with, e.g., a sciatic nerve pain may be associated with dysesthesia (abnormal pain dysfunction, a common peroneal nerve dysfunction. a radial responses). Such as, e.g., allodynia (a painful response to a 60 nerve dysfunction, an ulnar nerve dysfunction, a cranial stimulus that normally is not painful), hyperalgesia (an accen mononeuropathy VI, a cranial mononeuropathy VII, a cranial tuated response to a painful stimulus that usually causes only mononeuropathy III (compression type), a cranial mononeur a mild discomfort), and hyperpathia (where a short discom opathy III (diabetic type), an axillary nerve dysfunction, a fort becomes a prolonged severe pain). Painful sensations can carpal tunnel syndrome, a femoral nerve dysfunction, a tibial be described as a coldness, numbness, itching, paresthesias 65 nerve dysfunction, a Bell’s palsy, a thoracic outlet syndrome, (tingling or “pins and needles' sensation), an electric shock, a carpal tunnel syndrome or other focal entrapment neuropa and a burning or ice-burn pain. Non-limiting examples of a thy, and a sixth (abducent) nerve palsy US 9,265,742 B2 53 54 In one embodiment, a severe pain condition comprises a tory demyelinating polyneuropathy (CIDP), genetic meta mononeuropathic multiplex. A mononeuropathic multiplex is bolic disorders (e.g., leukodystrophy), and toxins. a peripheral neuropathy involving functional loss or patho In one embodiment, a severe pain condition comprises a logical change that sequentially or simultaneously affects neuronopathy. Neuronopathy is the result of destruction of several non-contiguous nerves in an asymmetric manner. A peripheral nervous system neurons. They may be caused by neuropathic pain based on mononeuropathy multiplex may motor neuron diseases, sensory neuronopathies (e.g., Herpes develop over days to years and typically presents with acute Zoster), toxins or autonomic dysfunction. Neurotoxins may or Subacute loss of sensory and motor function of individual cause neuronopathies, such as the chemotherapy agent Vinc nerves. The pattern of involvement is asymmetric; however, ristine. A person with neuronopathy may present in different as the disease progresses deficit(s) becomes more confluent 10 ways, depending on the cause, the way it affects the nerve and symmetrical, making it difficult to differentiate from cells, and the type of nerve cell that is most affected. polyneuropathy. Mononeuropathic multiplex may also cause There are numerous conditions that can cause polyneur pain characterized as deep, aching pain that is worse at night, opathy. Peripheral neuropathic pain include, without limita and frequently present in the lower back, hip, or leg. Monon tion, neuropathies associated with systemic disease like dia europathic multiplex may also cause pain characterized as 15 betic neuropathy, neuropathies associated with metabolic acute, unilateral, severe limb pain followed by anterior conditions like alcoholic neuropathy and burning feet Syn muscle weakness and loss of knee reflex. Mononeuropathic drome, neuropathies associated with viral infections like her multiplex pain is associated with, e.g., diabetes mellitus, pes Zoster and HIV, neuropathies associated with nutritional infections, such as, e.g., leprosy, lyme disease, HIV, and deficiencies, neuropathies associated with toxins, neuropa toxicity. thies associated with tumor compression, neuropathies asso In one embodiment, a severe pain condition comprises a ciated with remote manifestations of malignancies, neuropa polyneuropathy. A polyneuropathy is a peripheral neuropathy thies associated with drugs like chemotherapy, neuropathies involving functional loss or pathological change affecting associated with radiation, neuropathies associated with multiple nerves throughout the body in a symmetric manner. immune mediated disorders, and neuropathies associated A polyneuropathy may be acute and appear without warning, 25 with physical trauma to a nerve trunk. Polyneuropathic pain, or chronic and develop gradually over alonger period of time. includes, without limitation, post-polio syndrome, postmas Many polyneuropathies have both motor and sensory tectomy syndrome, diabetic neuropathy, alcohol neuropathy, involvement, and Some also involve dysfunction of the auto amyloid, toxins, AIDS, hypothyroidism, uremia, Vitamin nomic nervous system. These disorders are often symmetri deficiencies, chemotherapy-induced pain, 2',3'-dideXoycyti cal, and usually due to various systematic illnesses and dis 30 dine (ddC) treatment, Guillain-Barre syndrome or Fabrys ease processes that affect the peripheral nervous system in its disease. entirety. A polyneuropathy frequently affect the feet and In one embodiment, a severe pain condition comprises an hands, causing weakness, loss of sensation, pins-and-needle autonomic neuropathy. An autonomic neuropathy is a periph sensations or burning pain. Polyneuropathies can be classi eral neuropathy involving functional loss or pathological fied in different ways, such as by cause, by speed of progres 35 change affecting the non-voluntary, non-sensory nervous sys sion, or by the parts of the body involved. Classes of poly tem (i.e., the autonomic nervous system). Autonomic neur neuropathy are also distinguished by which part of the nerve opathy is a form of polyneuropathy which affects mostly the cell is mainly affected: the axon, the myelin sheath, or the cell internal organs Such as the bladder, muscles, the cardiovas body. cular system, the digestive tract, and the genital organs. In one embodiment, a severe pain condition comprises a 40 Peripheral neuropathic pain may be present in systemic distal axonopathy. Distal axonopathy, or “dying-back neur diseases, metabolic disorders, nutrient disorders, drug-in opathy', is the result of some metabolic or toxic derangement duced disorders, traumatic injury, traumatic and entrapment of a neuron. They may be caused by metabolic diseases Such syndromes, post-Surgical pain Surgery, complications follow as diabetes, renal failure, deficiency syndromes such as mal ing Surgery, HIV sensory neuropathy, demyelinating polyra nutrition and alcoholism, or the effects of toxins or drugs such 45 diculoneuropathy, postherpetic neuralgia, nerve root avul as chemotherapy. The most common cause of distal axonopa sions, cranial neuralgias like trigeminal neuralgia, thy is diabetes, and the most common distal axonopathy is neuropathic cancer pain, compression of peripheral nerves, diabetic neuropathy. They can be divided according to the nerve plexuses, and nerve roots, paraneoplastic peripheral type of axon affected: large-fiber, small-fiber, or both. The neuropathy, ganglionopathy, complication of cancer thera most distal portions of axons are usually the first to degener 50 pies like chemotherapy, radiation, and Surgery, and complex ate, and axonal atrophy advances slowly towards the nerve's regional pain syndrome like Type 1 and Type 2. cell body. If the cause is removed, regeneration is possible, In one embodiment, a severe pain condition comprises a though the prognosis depends on the duration and severity of neuralgia. A neuralgia is a peripheral neuropathic pain that the stimulus. People with distal axonopathies usually present radiates along the course of one or more specific nerves with sensorimotor disturbances that have a symmetrical 55 usually without any demonstrable pathological change in the “stocking and glove' distribution. Deep tendon reflexes and nerve structure. The affected nerves are responsible for sens autonomic nervous system functions are also lost or dimin ing touch, temperature and pressure. Simple stimuli such as ished in affected areas. eating, talking, washing the face, or any light touch or sensa In one embodiment, a severe pain condition comprises a tion can trigger an attack (even the sensation of a gentle myelinopathy. Myelinopathy, or “demyelinating polyneur 60 breeze). The attacks can occur in clusters or as an isolated opathy', is due to a loss of myelin (or of the Schwann cells attack. Generally, a neuralgia causes short episodes of excru that make and contain it). This demyelination leaves the axon ciating pain, usually for less than two minutes. However, in intact, but slows down or completely blocks the conduction of the atypical forms of neuralgia, the pain can also present as action potentials through the axon of the nerve cell. The most merely aching to severe pain and last for extended periods. common cause is acute inflammatory demyelinating poly 65 Symptoms include sharp, stabbing pain or constant, burning neuropathy (AIDP, the most common form of Guillain-Barré pain located anywhere, usually on or near the Surface of the syndrome), though other causes include chronic inflamma body, in the same location for each episode; pain along the US 9,265,742 B2 55 56 path of a specific nerve; impaired function of affected body commonly described as a burning pain, a coldness, an electric part due to pain, or muscle weakness due to concomitant shock, a “pins and needles' sensation, numbness and itching. motor nerve damage; increased sensitivity of the skin or In one embodiment, a severe pain condition comprises a numbness of the affected skin area; and any touch or pressure headache. A severe pain condition may be a headache (medi is interpreted as pain. Movement may also be painful. A 5 cally known as cephalgia) is a condition of mild to severe pain neuralgia, includes, without limitation, a trigeminal neural in the head; sometimes neck or upper back pain may also be gia, a glossopharyngeal neuralgia, a post-herpetic neuralgia interpreted as a headache. It may indicate an underlying local (caused by, e.g., herpesvirus, syphilis and Lyme disease), a or systemic disease or be a disorder in itself. A headache carpal tunnel syndrome, a meralgia paresthetica, a sciatica includes, without limitation, a muscular/myogenic headache, and an atypical facial pain. 10 a vascular headache, a traction headache, inflammatory head In one embodiment, a severe pain condition comprises a ache, a chronic sinusitis headache, a hormone headache, a Complex Regional Pain Syndrome (CRPS). A CRPS is a rebound headache, an organic headache, and an ictal head neuropathy resulting from Sympathetically-maintained pain. ache. Although unknown, mechanisms probably involve abnormal In one embodiment, a severe pain condition comprises a sympathetic-Somatic nerve connections (ephapses), local muscular/myogenic headache. Muscular/myogenic head inflammatory changes, and changes in the spinal cord. CRPS aches appear to involve the tightening or tensing of facial and presents in two forms. CRPS 1 (reflex sympathetic dystrophy neck muscles; they may radiate to the forehead. Tension syndrome) is a chronic nerve disorder that occurs most often headache is the most common form of myogenic headache. A in the arms or legs after a minor or major injury. CRPS 1 is tension headache is a condition involving pain or discomfort associated with severe pain; changes in the nails, bone, and in the head, Scalp, or neck, usually associated with muscle skin; and an increased sensitivity to touch in the affected limb. tightness in these areas. Tension headaches result from the CRPS 2 (causalgia) is caused by an identified injury to the contraction of neck and Scalp muscles. One cause of this nerve and results in a syndrome of Sustained burning pain, muscle contraction is a response to stress, depression or anxi allodynia, and hyperpathia after a traumatic nerve lesion, 25 ety. Any activity that causes the head to be held in one position often combined with vasomotor and Sudomotor dysfunction for a long time without moving can cause a headache. Such and later trophic changes. activities include typing or use of computers, fine work with In one embodiment, a severe pain condition comprises a the hands, and use of a microscope. Sleeping in a cold room referred pain. Referred pain arises from pain localized to an or sleeping with the neck in an abnormal position may also area separate from the site of pain stimulation. Often, referred 30 trigger this type of headache. A tension-type headache, pain arises when a nerve is compressed or damaged at or near includes, without limitation, an episodic tension headache its origin. In this circumstance, the sensation of pain will and a chronic tension headache. generally be felt in the territory that the nerve serves, even In one embodiment, a severe pain condition comprises a though the damage originates elsewhere. A common example vascular headache. The most common type of vascular head occurs in intervertebral discherniation, in which a nerve root 35 ache is migraine. Other kinds of vascular headaches include arising from the spinal cord is compressed by adjacent disc cluster headaches, which cause repeated episodes of intense material. Although pain may arise from the damaged disc pain, and headaches resulting from high blood pressure. itself, pain will also be felt in the region served by the com In one embodiment, a severe pain condition comprises a pressed nerve (for example, the thigh, knee, or foot). Reliev migraine headache. A migraine is a heterogeneous disorder ing the pressure on the nerve root may ameliorate the referred 40 that generally involves recurring headaches. Migraines are pain, provided that permanent nerve damage has not different from other headaches because they occur with other occurred. Myocardial ischaemia (the loss of blood flow to a symptoms, such as, e.g., nausea, vomiting, or sensitivity to part of the heart muscle tissue) is possibly the best known light. In most people, a throbbing pain is felt only on one side example of referred pain; the sensation can occur in the upper of the head. Clinical features such as type of aura symptoms, chest as a restricted feeling, or as an ache in the left shoulder, 45 presence of prodromes, or associated symptoms such as Ver arm or even hand. tigo, may be seen in Subgroups of patients with different In one embodiment, a severe pain condition comprises a underlying pathophysiological and genetic mechanisms. A deafferentation pain. Damage or disease affecting peripheral migraine headache, includes, without limitation, a migraine or central afferent neural activity is referred to as a deaffer without aura (common migraine), a migraine with aura (clas entation pain. Deafferentation pain is due to partial or com 50 sic migraine), a menstrual migraine, a migraine equivalent plete loss of the sensory input from a portion of the body, and (acephalic headache), a complicated migraine, an abdominal can be caused by interruption of either peripheral sensory migraine and a mixed tension migraine. fibres or nerves from the central nervous system. The mecha In one embodiment, a severe pain condition comprises a nism underlying this type of pain is unknown but may involve cluster headache. Cluster headaches affect one side of the sensitization of central neurons, with lower activation thresh 55 head (unilateral) and may be associated with tearing of the olds and expansion of receptive fields. A deafferentation pain eyes and nasal congestion. They occurs inclusters, happening syndrome, includes, without limitation, a phantom pain, a repeatedly every day at the same time for several weeks and brain injury, a spinal cord injury, a lumbar radiculopathy, a then remitting. post-stroke pain, a paraplegia, avulsion of the brachial plexus In one embodiment, a severe pain condition comprises a or other types of lesions of peripheral nerves, a pathology of 60 sinusitis headache. Sinusitis is inflammation, either bacterial, the central nervous system. fungal, viral, allergic or autoimmune, of the paranasal In one embodiment, a severe pain condition comprises a sinuses. Chronic sinusitis is one of the most common com dysfunctional pain. Dysfunctional pain is a pathological pain plications of the common cold. Symptoms include: Nasal where an organic pain state is caused by abnormal function of congestion; facial pain; headache; fever, general malaise; the Somatosensory nervous system, but which are not initi 65 thick green or yellow discharge; feeling of facial fullness ated by an identifiable lesion of any part of the nervous worsening on bending over. In a small number of cases, system. Similar to neuropathic pain, dysfunctional pain is chronic maxillary sinusitis can also be brought on by the US 9,265,742 B2 57 58 spreading of bacteria from a dental infection. Chronic hyper factors, including, without limitation, the type of the severe plastic eosinophilic sinusitis is a noninfective form of chronic pain condition, the location of the severe pain condition, the sinusitis. cause of the severe pain condition, the severity of the severe In one embodiment, a severe pain condition comprises a pain condition, the degree of relief desired, the duration of traction headache. Traction and inflammatory headaches are relief desired, the particular therapeutic compound used, the usually symptoms of other disorders, ranging from stroke to rate of excretion of the therapeutic compound used, the phar sinus infection. macodynamics of the therapeutic compound used, the nature In one embodiment, a severe pain condition comprises a of the other compounds to be included in the composition, the rebound headache. Rebound headaches, also known as medi particular formulation, the particular route of administration, cation overuse headaches, occur when medication is taken 10 the particular characteristics, history and risk factors of the too frequently to relieve headache. Rebound headaches fre patient, such as, e.g., age, weight, general health and the like, quently occur daily and can be very painful. or any combination thereof. Additionally, where repeated In one embodiment, a severe pain condition comprises a administration of a therapeutic compound is used, an effec ictal headache. Ictal headaches are headaches associated with tive amount of a therapeutic compound will further depend seizure activity. 15 upon factors, including, without limitation, the frequency of In one embodiment, a severe pain condition comprises a administration, the half-life of the therapeutic compound, or psychogenic pain. Psychogenic pain, also called psychalgia any combination thereof. In is known by a person of ordinary or somatoform pain, is pain caused, increased, or prolonged skill in the art that an effective amount of a therapeutic com by mental, emotional, or behavioral factors. Headache, back pound disclosed herein can be extrapolated from in vitro pain, and stomach pain are sometimes diagnosed as psy assays and in Vivo administration studies using animal mod chogenic. Sufferers are often Stigmatized, because both medi els prior to administration to humans. cal professionals and the general public tend to think that pain In aspects of this embodiment, a therapeutically effective from a psychological source is not “real'. However, special amount ofatherapeutic compound disclosed herein reduces a ists consider that it is no less actual or hurtful than pain from symptom associated with a severe pain condition by, e.g., at any other source. Individuals with long term pain frequently 25 least 10%, at least 15%, at least 20%, at least 25%, at least display psychological disturbance. 30%, at least 35%, at least 40%, at least 45%, at least 50%, at In one embodiment, a severe pain condition comprises an least 55%, at least 60%, at least 65%, at least 70%, at least inflammatory pain. An inflammatory pain is a severe pain 75%, at least 80%, at least 85%, at least 90%, at least 95% or condition where an organic pain state is caused by the release at least 100%. In other aspects of this embodiment, a thera of mediators at a site of tissue inflammation which activate 30 peutically effective amount of a therapeutic compound dis and sensitize the nociceptive pain pathway. This type of pain closed herein reduces a symptom associated with a severe is associated with any tissue damage caused by a chronic pain condition by, e.g., at most 10%, at most 15%, at most inflammatory response. Inflammatory pain may be associate 20%, at most 25%, at most 30%, at most 35%, at most 40%, with an arthritic disorder, an autoimmune disease, a connec at most 45%, at most 50%, at most 55%, at most 60%, at most tive tissue disorder, an injury, an infection, and a neuritis. 35 65%, at most 70%, at most 75%, at most 80%, at most 85%, In one embodiment, a severe pain condition does not com at most 90%, at most 95% or at most 100%. In yet other prise an inflammatory pain. aspects of this embodiment, a therapeutically effective In one embodiment, a severe pain condition is not caused amount ofatherapeutic compound disclosed herein reduces a by an inflammatory response. symptom associated with a severe pain condition by, e.g., A pharmaceutical composition disclosed herein is admin 40 about 10% to about 100%, about 10% to about 90%, about istered to an individual. An individual is typically a human 10% to about 80%, about 10% to about 70%, about 10% to being. Typically, any individual who is a candidate for a about 60%, about 10% to about 50%, about 10% to about conventional severe pain treatment is a candidate for a severe 40%, about 20% to about 100%, about 20% to about 90%, pain 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 45 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 50 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 severe pain condition 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 55 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 severe pain condition. 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 severe pain con least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/ dition 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 60 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 severe pain condition 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 65 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to a particular severe pain condition 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, US 9,265,742 B2 59 60 about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 to a method of treating a severe pain condition disclosed mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day herein. A pharmaceutical composition may be administered to about 100 mg/kg/day. In yet other aspects of this embodi to an individual by any of a variety of means depending, e.g., ment, an effective amount of a therapeutic compound dis on the type of the severe pain condition to be treated, the closed herein may be in the range of, e.g., about 0.01 mg/kg/ 5 location of the severe pain condition to be treated, the specific day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 therapeutic compound or composition used, or other com mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, pound to be included in the composition, and the history, risk about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 factors and symptoms of the individual. As such, topical, mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to enteral or parenteral routes of administration may be suitable about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 10 for of treating a severe pain condition disclosed herein and mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, such routes include both local and systemic delivery of a about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 therapeutic compound or composition disclosed herein. mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to Compositions comprising either a single therapeutic com about 100 mg/kg/day. In still other aspects of this embodi pound disclosed herein, or two or more therapeutic com ment, an effective amount of a therapeutic compound dis 15 pounds disclosed herein are intended for inhaled, topical, closed herein may be in the range of, e.g., about 0.1 mg/kg/ intranasal, Sublingual, injection, infusion, instillation, rectal day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 and/or vaginal use may be prepared according to any method mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, known to the art for the manufacture of pharmaceutical com about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/ positions. day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 In one embodiment, upon administration to an individual, mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, a pharmaceutical composition comprising atherapeutic com about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/ pound disclosed herein results in a bio-distribution of the day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 therapeutic compound different than a bio-distribution of the mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day. therapeutic compound included in the same pharmaceutical In other aspects of this embodiment, an effective amount of 25 composition, except without an adjuvant disclosed herein. atherapeutic compound disclosed herein may be in the range In another embodiment, upon administration to an indi of e.g., about 1 mg/kg/day to about 10 mg/kg/day, about 1 vidual, a therapeutic compound of the pharmaceutical com mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to position disclosed herein is delivered to a macrophage. Mac about 20 mg/kg/day, about 1 mg/kg/day to about 25 mg/kg/ rophages are one of the key cell types believed to be involved day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 30 in the control of the inflammation response. The resultant mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to high level of a therapeutic compound having anti-pain activ about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/ ity present in the macrophages results in a clinically effective day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 treatment of a severe pain condition. In an aspect of this mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to embodiment, upon administration to an individual, a thera about 100 mg/kg/day. In yet other aspects of this embodi 35 peutically effective amount of a therapeutic compound of the ment, an effective amount of a therapeutic compound dis pharmaceutical composition disclosed herein is preferen closed herein may be in the range of, e.g., about 5 mg/kg/day tially 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 40 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. 45 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 severe pain condition may comprise a 85%, at least 90%, at least 95%, or at least 100% of the total one-time administration of an effective dose of a pharmaceu amount of the therapeutic compound contained in the admin tical composition disclosed herein. Alternatively, treatment 50 istered pharmaceutical composition. In still other aspects of of a severe pain condition may comprise multiple adminis this embodiment, upon administration to an individual, the trations of an effective dose of a pharmaceutical composition amount of a therapeutic compound of the pharmaceutical carried out over a range of time periods, such as, e.g., once composition disclosed herein delivered to a macrophage is in daily, twice daily, trice daily, once every few days, or once a range of, e.g., about 5% to about 100%, about 10% to about weekly. The timing of administration can vary from indi 55 100%, about 15% to about 100%, about 20% to about 100%, vidual 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 60 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. 65 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 US 9,265,742 B2 61 62 70%, about 15% to about 70%, about 20% to about 70%, ceptable adjuvant. In other aspects of this embodiment, a about 25% to about 70%, about 30% to about 70%, about 35% pharmaceutical composition disclosed herein reduces gastric to about 70%, about 40% to about 70%, about 45% to about irritation by, e.g., at least 5%, at least 10%, at least 15%, at 70%, or about 50% to about 70% of the total amount of the least 20%, at least 25%, at least 30%, at least 35%, at least therapeutic compound contained in the administered pharma 40%, at least 45%, at least 50%, at least 55%, at least 60%, at ceutical composition. least 65%, at least 70%, at least 75%, at least 80%, at least In another embodiment, upon administration to an indi 85%, at least 90%, at least 95%, or at least 100%. In yet other vidual, a therapeutic compound of the pharmaceutical com aspects of this embodiment, a pharmaceutical composition position disclosed herein is delivered to a dentritic cell. Den disclosed herein reduces gastric irritation in a range of, e.g., dritic cells are one of the key cell types believed to coordinate 10 about 5% to about 100%, about 10% to about 100%, about the interplay between innate and adaptive immunity. The 15% to about 100%, about 20% to about 100%, about 25% to resultant high level of a therapeutic compound having anti about 100%, about 30% to about 100%, about 35% to about pain activity present in the dentritic cells results in a clinically 100%, about 40% to about 100%, about 45% to about 100%, effective treatment of a severe pain condition. In an aspect of about 50% to about 100%, about 5% to about 90%, about 10% this embodiment, upon administration to an individual, a 15 to about 90%, about 15% to about 90%, about 20% to about therapeutically effective amount of a therapeutic compound 90%, about 25% to about 90%, about 30% to about 90%, of the pharmaceutical composition disclosed herein is pref about 35% to about 90%, about 40% to about 90%, about 45% erentially delivered to a dentritic cell. In other aspect of this to about 90%, about 50% to about 90%, about 5% to about embodiment, upon administration to an individual, a thera 80%, about 10% to about 80%, about 15% to about 80%, peutic compound of the pharmaceutical composition dis about 20% to about 80%, about 25% to about 80%, about 30% closed herein is substantially delivered to a dentritic cell. In to about 80%, about 35% to about 80%, about 40% to about yet other aspect of this embodiment, upon administration to 80%, about 45% to about 80%, about 50% to about 80%, an individual, the amount of a therapeutic compound of the about 5% to about 70%, about 10% to about 70%, about 15% pharmaceutical composition disclosed herein delivered to a to about 70%, about 20% to about 70%, about 25% to about dentritic cell is, e.g., at least 5%, at least 10%, at least 15%, at 25 70%, about 30% to about 70%, about 35% to about 70%, least 20%, at least 25%, at least 30%, at least 35%, at least about 40% to about 70%, about 45% to about 70%, or about 40%, at least 45%, at least 50%, at least 55%, at least 60%, at 50% to about 70%. least 65%, at least 70%, at least 75%, at least 80%, at least In another embodiment, upon administration to an indi 85%, at least 90%, at least 95%, or at least 100% of the total vidual, a pharmaceutical composition disclosed herein amount of the therapeutic compound contained in the admin 30 reduces intestinal irritation. In an aspect of this embodiment, istered pharmaceutical composition. In still other aspects of a pharmaceutical composition disclosed herein Substantially this embodiment, upon administration to an individual, the reduces intestinal irritation. In yet another embodiment, upon amount of a therapeutic compound of the pharmaceutical administration to an individual, a pharmaceutical composi composition disclosed herein delivered to a dentritic cell is in tion disclosed herein reduces intestinal irritation when com a range of, e.g., about 5% to about 100%, about 10% to about 35 pared to the same pharmaceutical composition disclosed 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%, 40 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 45 least 70%, at least 80%, at least 90%, or at least 100% when 80%, about 30% to about 80%, about 35% to about 80%, compared to the same pharmaceutical composition disclosed about 40% to about 80%, about 45% to about 80%, about 50% herein, except without the pharmaceutically-acceptable adju to about 80%, about 5% to about 70%, about 10% to about vant. In yet other aspects of this embodiment, a pharmaceu 70%, about 15% to about 70%, about 20% to about 70%, tical composition disclosed herein reduces intestinal irritation about 25% to about 70%, about 30% to about 70%, about 35% 50 by, e.g., about 5% to about 100%, about 10% to about 100%, to about 70%, about 40% to about 70%, about 45% to about about 15% to about 100%, about 20% to about 100%, about 70%, or about 50% to about 70% of the total amount of the 25% to about 100%, about 30% to about 100%, about 35% to therapeutic compound contained in the administered pharma about 100%, about 40% to about 100%, about 45% to about ceutical composition. 100%, about 50% to about 100%, about 5% to about 90%, In another embodiment, upon administration to an indi 55 about 10% to about 90%, about 15% to about 90%, about 20% vidual, a pharmaceutical composition disclosed herein to about 90%, about 25% to about 90%, about 30% to about reduces gastric irritation. In an aspect of this embodiment, a 90%, about 35% to about 90%, about 40% to about 90%, pharmaceutical composition disclosed herein Substantially about 45% to about 90%, about 50% to about 90%, about 5% reduces gastric irritation. In yet another embodiment, upon to about 80%, about 10% to about 80%, about 15% to about administration to an individual, a pharmaceutical composi 60 80%, about 20% to about 80%, about 25% to about 80%, tion disclosed herein reduces gastric irritation when com about 30% to about 80%, about 35% to about 80%, about 40% pared to the same pharmaceutical composition disclosed to about 80%, about 45% to about 80%, about 50% to about herein, except without the pharmaceutically-acceptable adju 80%, about 5% to about 70%, about 10% to about 70%, about vant. In an aspect of this embodiment, a pharmaceutical com 15% to about 70%, about 20% to about 70%, about 25% to position disclosed herein Substantially reduces gastric irrita 65 about 70%, about 30% to about 70%, about 35% to about tion when compared to the same pharmaceutical composition 70%, about 40% to about 70%, about 45% to about 70%, or disclosed herein, except without the pharmaceutically-ac about 50% to about 70% when compared to the same phar US 9,265,742 B2 63 64 maceutical composition disclosed herein, except without the 17. The pharmaceutical composition according to embodi pharmaceutically-acceptable adjuvant. ment 16, wherein the anti-pain activity reduces a patho A pharmaceutical composition disclosed hereincan also be logical pain response by at least 10%. administered to an individual in combination with other 18. The pharmaceutical composition according to embodi therapeutic compounds to increase the overall therapeutic 5 ments 1-7, wherein the anti-pain activity reduces a neuro effect of the treatment. The use of multiple compounds to pathic pain response. treat an indication can increase the beneficial effects while 19. The pharmaceutical composition according to embodi reducing the presence of side effects. ment 18, wherein the anti-pain activity reduces a neuro Aspects of the present invention can also be described as pathic pain response by at least 10%. follows: 10 20. The pharmaceutical composition according to embodi 1. A pharmaceutical composition comprising: a) atherapeutic ments 1-7, wherein the anti-pain activity reduces a central compound, wherein the therapeutic compound has an anti neuropathic pain response. pain activity; and b) a pharmaceutically-acceptable adju 21. The pharmaceutical composition according to embodi Vant. ment 20, wherein the anti-pain activity reduces a central 2. The pharmaceutical composition according to embodiment 15 neuropathic pain response by at least 10%. 1, wherein the composition further comprises a pharma 22. The pharmaceutical composition according to embodi ceutically-acceptable solvent. ments 1-7, wherein the anti-pain activity reduces a periph 3. A pharmaceutical composition comprising: a) atherapeutic eral neuropathic pain response. compound, wherein the therapeutic compound has an anti 23. The pharmaceutical composition according to embodi pain activity; b) a pharmaceutically-acceptable solvent; ment 22, wherein the anti-pain activity reduces a peripheral and c) a pharmaceutically-acceptable adjuvant. neuropathic pain response by at least 10%. 4. A pharmaceutical composition comprising: a) atherapeutic 24. The pharmaceutical composition according to embodi compound, wherein the therapeutic compound has an anti ments 1-7, wherein the anti-pain activity reduces a monon pain activity; b) a pharmaceutically-acceptable solvent; 25 europathic pain response. and c) a pharmaceutically-acceptable adjuvant, wherein 25. The pharmaceutical composition according to embodi the ratio of the pharmaceutically-acceptable solvent to ment 24, wherein the anti-pain activity reduces a monon pharmaceutically-acceptable adjuvant is in a range from europathic pain response by at least 10%. about 0:1 to about 1:25. 26. The pharmaceutical composition according to embodi 5. The pharmaceutical composition according to embodiment 30 ments 1-7, wherein the anti-pain activity reduces a monon 2 or 3, wherein the ratio of the pharmaceutically-accept europathic multiplex pain response. able solvent to pharmaceutically-acceptable adjuvant is in 27. The pharmaceutical composition according to embodi a range from about 0:1 to about 1:25. ment 26, wherein the anti-pain activity reduces a monon 6. The pharmaceutical composition according to embodi europathic multiplex pain response by at least 10%. ments 1-5, wherein the anti-pain activity reduces a severe 35 28. The pharmaceutical composition according to embodi pain response. ments 1-7, wherein the anti-pain activity reduces a poly 7. The pharmaceutical composition according to embodiment neuropathic pain response. 6, wherein the anti-pain activity reduces a severe pain 29. The pharmaceutical composition according to embodi response by at least 10%. ment 28, wherein the anti-pain activity reduces a poly 8. The pharmaceutical composition according to embodi 40 neuropathic pain response by at least 10%. ments 1-7, wherein the anti-pain activity reduces a nocice 30. The pharmaceutical composition according to embodi ptive pain response. ments 1-7, wherein the anti-pain activity reduces an auto 9. The pharmaceutical composition according to embodiment nomic neuropathic pain response. 8, wherein the anti-pain activity reduces a nociceptive pain 31. The pharmaceutical composition according to embodi response by at least 10%. 45 ment 30, wherein the anti-pain activity reduces an auto 10. The pharmaceutical composition according to embodi nomic neuropathic pain response by at least 10%. ments 1-7, wherein the anti-pain activity reduces a pain 32. The pharmaceutical composition according to embodi response mediated by a nociceptive receptor. ments 1-7, wherein the anti-pain activity reduces a neural 11. The pharmaceutical composition according to embodi gia pain response. ment 10, wherein the anti-pain activity reduces a pain 50 33. The pharmaceutical composition according to embodi response mediated by a nociceptive receptor by at least ment 32, wherein the anti-pain activity reduces a neuralgia 10%. pain response by at least 10%. 12. The pharmaceutical composition according to embodi 34. The pharmaceutical composition according to embodi ments 1-7, wherein the anti-pain activity reduces a Somatic ments 1-7, wherein the anti-pain activity reduces a com pain response. 55 plex regional pain syndrome pain response. 13. The pharmaceutical composition according to embodi 35. The pharmaceutical composition according to embodi ment 12, wherein the anti-pain activity reduces a Somatic ment 34, wherein the anti-pain activity reduces a complex pain response by at least 10%. regional pain syndrome pain response by at least 10%. 14. The pharmaceutical composition according to embodi 36. The pharmaceutical composition according to embodi ments 1-7, wherein the anti-pain activity reduces a visceral 60 ments 1-7, wherein the anti-pain activity reduces a referred pain response. pain response. 15. The pharmaceutical composition according to embodi 37. The pharmaceutical composition according to embodi ment 14, wherein the anti-pain activity reduces a visceral ment 36, wherein the anti-pain activity reduces a referred pain response by at least 10%. pain response by at least 10%. 16. The pharmaceutical composition according to embodi 65 38. The pharmaceutical composition according to embodi ments 1-7, wherein the anti-pain activity reduces a patho ments 1-7, wherein the anti-pain activity reduces a deaf logical pain response. ferentation pain response. US 9,265,742 B2 65 66 39. The pharmaceutical composition according to embodi prises a Retinoic Acid Receptor (RAR) binding agent, a ment 38, wherein the anti-pain activity reduces a deaffer Retinoid X Receptor (RXR) binding agent, a Liver X entation pain response by at least 10%. Receptor (LXR) binding agent, a Vitamin D binding agent, 40. The pharmaceutical composition according to embodi or a combination thereof. ments 1-7, wherein the anti-pain activity reduces a dys 5 58. The pharmaceutical composition according to embodi functional pain response. ments 1-57, wherein the therapeutic compound comprises 41. The pharmaceutical composition according to embodi an anti-hyperlipidemic agent. ment 38, wherein the anti-pain activity reduces a dysfunc 59. The pharmaceutical composition according to embodi tional pain response by at least 10%. ment 58, wherein the anti-hyperlipidemic agent comprises 42. The pharmaceutical composition according to embodi 10 ments 1-7, wherein the anti-pain activity reduces a head a fibrate, a statin, a tocotrienol, a niacin, a bile acid seques ache pain response. trants (resin), a cholesterol absorption inhibitor, a pancre 43. The pharmaceutical composition according to embodi atic lipase inhibitor, a sympathomimetic amine, or a com ment 42, wherein the anti-pain activity reduces aheadache bination thereof. pain response by at least 10%. 15 60. The pharmaceutical composition according to embodi 44. The pharmaceutical composition according to embodi ment 59, wherein the fibrate comprises Bezafibrate, ments 1-7, wherein the anti-pain activity reduces a Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a migraine pain response. combination thereof. 45. The pharmaceutical composition according to embodi 61. The pharmaceutical composition according to embodi ment 44, wherein the anti-pain activity reduces a migraine ment 59, wherein the statin comprises Atorvastatin, Fluv pain response by at least 10%. astatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, 46. The pharmaceutical composition according to embodi Simvastatin, or a combination thereof. ments 1-45, wherein the therapeutic compound has a log P 62. The pharmaceutical composition according to embodi value indicating that the compound is soluble in an organic ment 59, wherein the niacin comprises acipimox, niacin, solvent. 25 nicotinamide, vitamin B3, or a combination thereof. 47. The pharmaceutical composition according to embodi 63. The pharmaceutical composition according to embodi ments 1-46, wherein the therapeutic compound has a log P ment 59, wherein the bile acid sequestrant comprises value of more than 1.0. Cholestyramine, Colesevelam, Colestipol, or a combina 48. The pharmaceutical composition according to embodi tion thereof. ments 1-46, wherein the therapeutic compound has a log P 30 64. The pharmaceutical composition according to embodi value of more than 2.0. ment 59, wherein the cholesterol absorption inhibitor com 49. The pharmaceutical composition according to embodi prises Ezetimibe, a phytosterol, a sterol, a stanol, or a ments 1-48, wherein the therapeutic compound has a polar combination thereof. Surface area that is hydrophobic. 65. The pharmaceutical composition according to embodi 50. The pharmaceutical composition according to embodi 35 ment 59, wherein the fat absorption inhibitor comprises ments 1-49, wherein the therapeutic compound has a polar Orlistat surface area that is less than 8.0 nm. 66. The pharmaceutical composition according to embodi 51. The pharmaceutical composition according to embodi ment 59, wherein the sympathomimetic amine comprises ments 1-49, wherein the therapeutic compound has a polar Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, surface area that is less than 6.0 nm. 40 methamphetamine, amphetamine, phenylephrine, isoprot 52. The pharmaceutical composition according to embodi erenol, dobutamine, methylphenidate, lisdexamfetamine, ments 1-51, wherein the therapeutic compound comprises cathine, cathinone, methcathinone, cocaine, benzylpipera a non-steroidal anti-pain drug (NSAID). zine (BZP), methylenedioxypyrovalerone (MDPV), 4-me 53. The pharmaceutical composition according to embodi thylaminorex, pemoline, phenmetrazine, propylhexedrine, ment 52, wherein the NSAID comprises a salicylate deriva 45 or a combination thereof. tive NSAID, a p-amino phenol derivative NSAID, a propi 67. The pharmaceutical composition according to embodi onic acid derivative NSAID, an acetic acid derivative ments 1-66, wherein the therapeutic compound comprises NSAID, an enolic acid derivative NSAID, a fenamic acid an ester of a therapeutic compound. derivative NSAID, a non-selective cyclo-oxygenase 68. The pharmaceutical composition according to embodi (COX) inhibitor, a selective cyclooxygenase 1 (COX1) 50 ments 1-67, wherein the therapeutic compound comprises inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor an ester of a therapeutic compound according to embodi or a combination thereof. ments 52-66. 54. The pharmaceutical composition according to embodi 69. The pharmaceutical composition according to embodi ments 1-53, wherein the therapeutic compound comprises ments 1-68, wherein the pharmaceutically-acceptable sol a PPARY agonist. 55 vent is less than about 20% (v/v). 55. The pharmaceutical composition according to embodi 70. The pharmaceutical composition according to embodi ment 54, wherein the PPARYagonist comprises Monascin, ments 1-69, wherein the pharmaceutically-acceptable sol Irbesartan, Telmisartan, mycophenolic acid, Resveratrol, vent comprises a pharmaceutically-acceptable polar apro Delta(9)-tetrahydrocannabinol, a cannabidiol, Curcumin, tic solvent, a pharmaceutically-acceptable polar protic Cilostazol, BenZbromarone, 6-shogaol, glycyrrhetinic 60 Solvent, a pharmaceutically-acceptable non-polar solvent, acid, a thiazolidinedione, a NSAID, a fibrate, or a combi or a combination thereof. nation thereof. 71. The pharmaceutical composition according to embodi 56. The pharmaceutical composition according to embodi ments 1-70, wherein the pharmaceutically-acceptable sol ments 1-55, wherein the therapeutic compound comprises vent comprises a pharmaceutically-acceptable alcohol. a nuclear receptor binding agent. 65 72. The pharmaceutical composition according to embodi 57. The pharmaceutical composition according to embodi ment 71, wherein the pharmaceutically-acceptable alcohol ment 56, wherein the nuclear receptor binding agent com comprises an acyclic alcohol, a monohydric alcohol, a US 9,265,742 B2 67 68 polyhydric alcohol, an unsaturated aliphatic alcohol, an 85. The pharmaceutical composition according to embodi alicyclic alcohol, or a combination thereof. ments 1-84, wherein the adjuvant is at least 80% (v/v). 73. The pharmaceutical composition according to embodi 86. The pharmaceutical composition according to embodi ment 71, wherein the pharmaceutically-acceptable alcohol ments 1-85, wherein the pharmaceutically-acceptable comprises a C-2 alcohol. adjuvant is a liquid at 20° C. 74. The pharmaceutical composition according to embodi 87. The pharmaceutical composition according to embodi ment 71, wherein the pharmaceutically-acceptable alcohol ments 1-86, wherein the pharmaceutically-acceptable comprises methanol, ethanol, propanol, butanol, pentanol, adjuvant is a solid at 20° C. 1-hexadecanol, or a combination thereof. 88. The pharmaceutical composition according to embodi 75. The pharmaceutical composition according to embodi 10 ments 1-87, wherein the pharmaceutically-acceptable ments 1-74, wherein the pharmaceutically-acceptable sol adjuvant comprises a pharmaceutically-acceptable lipid. vent comprises a pharmaceutically-acceptable ester of 89. The pharmaceutical composition according to embodi pharmaceutically-acceptable alcohol and an acid. ment 88, wherein the pharmaceutically-acceptable lipid 76. The pharmaceutical composition according to embodi comprises a saturated fatty acid, an unsaturated fatty acid, ment 75, wherein the pharmaceutically-acceptable ester 15 or a combination thereof. comprises methyl acetate, methyl buterate, methyl for 90. The pharmaceutical composition according to embodi mate, ethyl acetate, ethylbuterate, ethyl formate, propyl ment 88 or 89, wherein the pharmaceutically-acceptable acetate, propyl buterate, propyl formate, butyl acetate, lipid comprises two or more Saturated or unsaturated fatty butyl buterate, butyl formate, isobutyl acetate, isobutyl acids. buterate, isobutyl formate, penty1 acetate, pentylbuterate, 91. The pharmaceutical composition according to embodi pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl ment 90, wherein the two or more saturated or unsaturated buterate, and 1-hexadecyl formate, or a combination fatty acids includes palmitic acid, Stearic acid, oleic acid, thereof. linoleic acid, linolenic acid, or a combination thereof. 77. The pharmaceutical composition according to embodi 92. The pharmaceutical composition according to embodi ments 1-76, wherein the pharmaceutically-acceptable sol 25 ments 89-91, wherein the unsaturated fatty acid has a melt vent comprises a pharmaceutically-acceptable glycol ing point temperature of 20° C. or below or wherein the ether, a pharmaceutically-acceptable diol, a pharmaceuti unsaturated fatty acid is a solid at 20° C. cally-acceptable propylene glycol, a pharmaceutically-ac 93. The pharmaceutical composition according to embodi ceptable dipropylene glycol, a pharmaceutically-accept ments 89-91, wherein the unsaturated fatty acid comprises able polypropylene glycol (PPG) polymer, a 30 an omega fatty acid. pharmaceutically-acceptable polyethylene glycol (PEG) 94. The pharmaceutical composition according to embodi polymer, or any combination thereof. ment 88, wherein the pharmaceutically-acceptable lipid 78. The pharmaceutical composition according to embodi comprises a pharmaceutically-acceptable oil. ment 77, wherein the pharmaceutically-acceptable glycol 95. The pharmaceutical composition according to embodi ether comprises diethylene glycol monomethyl ether (2- 35 ment 94, wherein the pharmaceutically-acceptable oil (2-methoxyethoxy)ethanol), diethylene glycol monoethyl comprises almond oil, arachis oil, avocado oil, canola oil, ether (2-(2-ethoxyethoxy)ethanol), diethylene glycol castor oil, coconut oil, corn oil, cottonseed oil, grape seed monopropyl ether (2-(2-propoxyethoxy)ethanol), diethyl oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, ene glycol monoisopropyl ether (2-(2-isopropoxyethoxy) peanut oil, rapeseed oil, rice bran oil, safflower oil, Sesame ethanol), diethylene glycol mono-n-butyl ether (2-(2-bu 40 oil, soybean oil, Soya oil, Sunflower oil, theobroma oil, toxyethoxy)ethanol), or any combination thereof. walnut oil, wheat germ oil, or a combination thereof. 79. The pharmaceutical composition according to embodi 96. The pharmaceutical composition according to embodi ment 77, wherein the pharmaceutically-acceptable ment 88, wherein the pharmaceutically-acceptable lipid polypropylene glycol (PPG) polymer or the pharmaceuti comprises a pharmaceutically-acceptable glycerolipid, a cally-acceptable polyethylene glycol (PEG) polymer is 45 pharmaceutically-acceptable glycol fatty acid ester, a phar less than about 2,000 g/mol. maceutically-acceptable polyether fatty acid ester, a mix 80. The pharmaceutical composition according to embodi ture of pharmaceutically-acceptable lipids, or any combi ment 77, wherein the pharmaceutically-acceptable nation thereof. polypropylene glycol (PPG) polymer or the pharmaceuti 97. The pharmaceutical composition according to embodi cally-acceptable polyethylene glycol (PEG) polymer is 50 ments 1-96, wherein the pharmaceutical composition fur more than about 2,000 g/mol. ther comprises a pharmaceutically-acceptable stabilizing 81. The pharmaceutical composition according to embodi agent. ments 1-51, wherein the pharmaceutically-acceptable sol 98. The pharmaceutical composition according to embodi vent comprises a pharmaceutically-acceptable glyceride. ment 97, wherein the pharmaceutically-acceptable stabi 82. The pharmaceutical composition according to embodi 55 lizing agent comprises water, a sacrificial acid comprising ment 81, wherein the pharmaceutically-acceptable glycer a fatty acid component and acetic acid, ethyl acetate, a ide comprises a monoglyceride, a diglyceride, a triglycer Sodium acetate/acetic acid, a monoglyceride, an acetylated ide, an acetylated monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated diglyceride, a diglyceride, an acetylated triglyceride, or a combination fatty acid, a fatty acid salt, or a combination thereof. thereof. 60 99. The pharmaceutical composition according to embodi 83. The pharmaceutical composition according to embodi ment 97, wherein the pharmaceutically-acceptable stabi ments 1-82, wherein the pharmaceutically-acceptable sol lizing agent comprises a pharmaceutically-acceptable vent is a liquid at 20°C. or wherein the pharmaceutically emulsifying agent. acceptable solvent is a solid at 20° C. 100. The pharmaceutical composition according to embodi 84. The pharmaceutical composition according to embodi 65 ment 99, wherein the pharmaceutically-acceptable emul ment 83, wherein the pharmaceutically-acceptable solid Sifying agent comprises a Surfactant, a polysaccharide, a Solvent comprises menthol. lectin, a phospholipid, or a combination thereof. US 9,265,742 B2 69 70 101. The pharmaceutical composition according to embodi cannabinol, a cannabidiol, Curcumin, Cilostazol, Ben ments 1-100, wherein the pharmaceutical composition Zbromarone, 6-shogaol, glycyrrhetinic acid, a does not comprise a pharmaceutically-acceptable emulsi thiazolidinedione, a NSAID, a fibrate, or a combination fying agent. thereof. 102. A method of preparing a pharmaceutical composition, 5 115. The method according to embodiments 102-114, the method comprising the step of contacting a therapeutic wherein the therapeutic compound comprises a nuclear compound with a pharmaceutically-acceptable adjuvant receptor binding agent. under conditions which allow the formation of the phar 116. The method according to embodiment 115, wherein the maceutical composition. nuclear receptor binding agent comprises a Retinoic Acid 103. A method of preparing a pharmaceutical composition, 10 the method comprising the steps: a) contacting a pharma Receptor (RAR) binding agent, a Retinoid X Receptor ceutically-acceptable solvent with a therapeutic compound (RXR) binding agent, a Liver X Receptor (LXR) binding under conditions which allow the therapeutic compound to agent, a Vitamin D binding agent, or a combination thereof. dissolve in the pharmaceutically-acceptable solvent, 117. The method according to embodiments 102-116, thereby forming a solution, wherein the therapeutic com 15 wherein the therapeutic compound comprises an anti-hy pound has anti-pain activity, and b) contacting the Solution perlipidemic agent. formed in step (a) with a pharmaceutically-acceptable 118. The method according to embodiment 117, wherein the adjuvant under conditions which allow the formation of the anti-hyperlipidemic agent comprises a fibrate, a statin, a pharmaceutical composition. tocotrienol, a niacin, a bile acid sequestrants (resin), a 104. A method of preparing a pharmaceutical composition, cholesterol absorption inhibitor, a pancreatic lipase inhibi the method comprising the steps: a) contacting a pharma tor, a sympathomimetic amine, or a combination thereof. ceutically-acceptable solvent with a therapeutic compound 119. The method according to embodiment 118, wherein the under conditions which allow the therapeutic compound to fibrate comprises Bezafibrate, Ciprofibrate, Clofibrate, dissolve in the pharmaceutically-acceptable solvent, Gemfibrozil, Fenofibrate, or a combination thereof. thereby forming a solution, wherein the therapeutic com 25 120. The method according to embodiment 118, wherein the pound has anti-pain activity, and b) contacting the Solution statin comprises Atorvastatin, Fluvastatin, Lovastatin, formed in step (a) with a pharmaceutically-acceptable Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a adjuvant under conditions which allow the formation of the combination thereof. pharmaceutical composition, wherein the ratio of the phar 121. The method according to embodiment 118, wherein the maceutically-acceptable solvent to pharmaceutically-ac 30 niacin comprises acipimox, niacin, nicotinamide, Vitamin ceptable adjuvant is in a range from about 0:1 to about 1:25. B3, or a combination thereof. 105. The method according to embodiments 102-104, 122. The method according to embodiment 118, wherein the wherein the therapeutic compound has a log P value indi bile acid sequestrant comprises Cholestyramine, cating that the compound is soluble in an organic solvent. Colesevelam, Colestipol, or a combination thereof. 106. The method according to embodiment 102-105, wherein 35 123. The method according to embodiment 118, wherein the the therapeutic compound has a log P value of more than cholesterol absorption inhibitor comprises EZetimibe, a 1.O. phytosterol, a sterol, a stanol, or a combination thereof. 107. The method according to embodiment 102-105, wherein 124. The method according to embodiment 118, wherein the the therapeutic compound has a log P value of more than fat absorption inhibitor comprises Orlistat 2.O. 40 125. The method according to embodiment 118, wherein the 108. The method according to embodiments 102-107, sympathomimetic amine comprises Clenbuterol, Salbuta wherein the therapeutic compound has a polar surface area mol, ephedrine, pseudoephedrine, methamphetamine, that is hydrophobic. amphetamine, phenylephrine, isoproterenol, dobutamine, 109. The method according to embodiments 102-108, methylphenidate, lisdexamfetamine, cathine, cathinone, wherein the therapeutic compound has a polar surface area 45 methcathinone, cocaine, benzylpiperazine (BZP), methyl that is less than 8.0 nm. enedioxypyrovalerone (MDPV), 4-methylaminorex, 110. The method according to embodiments 102-108, pemoline, phenmetrazine, propylhexedrine, or a combina wherein the therapeutic compound has a polar surface area tion thereof. that is less than 6.0 nm. 126. The method according to embodiments 102-125, 111. The method according to embodiments 102-110, 50 wherein the therapeutic compound comprises an ester of a wherein the therapeutic compound comprises a non-steroi therapeutic compound. dal anti-pain drug (NSAID). 127. The method according to embodiments 102-126, 112. The method according to embodiment 111, wherein the wherein the therapeutic compound comprises an ester of a NSAID comprises a salicylate derivative NSAID, a therapeutic compound according to embodiments p-amino phenol derivative NSAID, a propionic acid 55 111-126. derivative NSAID, an acetic acid derivative NSAID, an 128. The method according to embodiments 103-127, enolic acid derivative NSAID, a fenamic acid derivative wherein the pharmaceutically-acceptable solvent is less NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, than about 20% (v/v). a selective cyclooxygenase 1 (COX1) inhibitor, a selective 129. The method according to embodiments 103-128, cyclooxygenase 2 (COX 2) inhibitor, or a combination 60 wherein the pharmaceutically-acceptable solvent com thereof. prises a pharmaceutically-acceptable polar aprotic solvent, 113. The method according to embodiments 102-112, a pharmaceutically-acceptable polar protic solvent, a phar wherein the therapeutic compound comprises a PPARY maceutically-acceptable non-polar solvent, or a combina agonist. tion thereof. 114. The method according to embodiment 113, wherein the 65 130. The method according to embodiments 103-129, PPARYagonist comprises Monascin, Irbesartan, Telmisar wherein the pharmaceutically-acceptable solvent com tan, mycophenolic acid, Resveratrol, Delta(9)-tetrahydro prises a pharmaceutically-acceptable alcohol. US 9,265,742 B2 71 72 131. The method according to embodiment 130, wherein the 149. The method according to embodiment 147 or 148, pharmaceutically-acceptable alcohol comprises an acyclic wherein the pharmaceutically-acceptable lipid comprises alcohol, a monohydric alcohol, a polyhydric alcohol, an two or more pharmaceutically-acceptable saturated or unsaturated aliphatic alcohol, an alicyclic alcohol, or a unsaturated fatty acids. combination thereof. 5 150. The method according to embodiments 149, wherein the 132. The method according to embodiment 130, wherein the two or more pharmaceutically-acceptable saturated or pharmaceutically-acceptable alcohol comprises a Co unsaturated fatty acids include palmitic acid, Stearic acid, alcohol. oleic acid, linoleic acid, linolenic acid, or a combination 133. The method according to embodiment 130, wherein the thereof. pharmaceutically-acceptable alcohol comprises methanol, 10 151. The method according to embodiments 148-150, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a wherein the pharmaceutically-acceptable unsaturated fatty combination thereof. acid has a melting point temperature of 20°C. or below. 134. The method according to embodiment 130, wherein the 152. The method according to embodiments 148-150, pharmaceutically-acceptable solvent comprises a pharma wherein the pharmaceutically-acceptable unsaturated fatty ceutically-acceptable ester of pharmaceutically-accept 15 acid is a solid at 20° C. able alcohol and an acid. 153. The method according to embodiments 148-152, 135. The method according to embodiment 134, wherein the wherein the pharmaceutically-acceptable unsaturated fatty pharmaceutically-acceptable ester comprises methyl acid comprises an omega fatty acid. acetate, methyl buterate, methyl formate, ethyl acetate, 154. The method according to embodiments 147-153, ethylbuterate, ethyl formate, propyl acetate, propylbuter wherein the pharmaceutically-acceptable lipid comprises a ate, propyl formate, butyl acetate, butyl buterate, butyl pharmaceutically-acceptable oil. formate, isobutyl acetate, isobutylbuterate, isobutyl for 155. The method according to embodiment 154, wherein the mate, penty1 acetate, pentylbuterate, pentyl formate, and pharmaceutically-acceptable oil comprises almond oil, 1-hexadecyl acetate, 1-hexadecylbuterate, and 1-hexade arachis oil, avocado oil, canola oil, castor oil, coconut oil, cyl formate, or a combination thereof. 25 corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp 136. The method according to embodiments 103-135, oil, linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, wherein the pharmaceutically-acceptable solvent is a phar rice bran oil, safflower oil, Sesame oil, soybean oil, soya oil, maceutically-acceptable polyethylene glycol (PEG) poly Sunflower oil, walnut oil, wheat germ oil, or a combination C. thereof. 137. The method according to embodiment 136, wherein the 30 156. The method according to embodiments 103 or 105-155, pharmaceutically-acceptable polyethylene glycol (PEG) wherein in step (b) the ratio of the pharmaceutically-ac polymer is less than about 2,000 g/mol. ceptable solvent to pharmaceutically-acceptable adjuvant 138. The method according to embodiment 136, wherein the is in a range from about 0:1 to about 1:25. pharmaceutically-acceptable polyethylene glycol (PEG) 157. The method according to embodiments 102-156, polymer is more than about 2,000 g/mol. 35 wherein the step (a) further comprising contacting a phar 139. The method according to embodiments 103-138, maceutically-acceptable stabilizing agent with the phar wherein the pharmaceutically-acceptable solvent com maceutically-acceptable solvent and the therapeutic com prises a pharmaceutically-acceptable glyceride. pound. 140. The method according to embodiments 139, wherein the 158. The method according to embodiment 157, wherein the pharmaceutically-acceptable glyceride is a monoglycer 40 pharmaceutically-acceptable stabilizing agent comprises ide, a diglyceride, a triglyceride, an acetylated monoglyc water, a sacrificial acid comprising a fatty acid component eride, an acetylated diglyceride, an acetylated triglyceride, and acetic acid, ethyl acetate, a sodium acetate/acetic acid, or a combination thereof. a monoglyceride, an acetylated monoglyceride, a diglyc 141. The method according to embodiments 103-140, eride, an acetylated diglyceride, a fatty acid, a fatty acid wherein the pharmaceutically-acceptable solvent is a liq 45 salt, or a combination thereof. uid at 20° C. 159. The method according to embodiment 157 or 158, 142. The method according to embodiments 103-141, wherein the pharmaceutically-acceptable stabilizing agent wherein the pharmaceutically-acceptable solvent is a solid comprises a pharmaceutically-acceptable emulsifying at 20° C. agent. 143. The method according to embodiment 142, wherein the 50 160. The method according to embodiment 159, wherein the pharmaceutically-acceptable solid solvent is menthol. pharmaceutically-acceptable emulsifying agent comprises 144. The method according to embodiments 102-143, a Surfactant, a polysaccharide, a lectin, a phospholipid, or a wherein the pharmaceutically-acceptable adjuvant is at combination thereof. least 80% (v/v). 161. The method according to embodiments 102-158, 145. The method according to embodiments 102-144, 55 wherein the pharmaceutical composition does not com wherein the pharmaceutically-acceptable adjuvant is a liq prise a pharmaceutically-acceptable emulsifying agent. uid at 20° C. 162. The method according to embodiments 103-161, 146. The method according to embodiments 102-144, wherein the method further comprises removing the phar wherein the pharmaceutically-acceptable adjuvant is a maceutically-acceptable solvent from the pharmaceutical Solid at 20° C. 60 composition. 147. The method according to embodiments 102-146, 163. The method according to embodiment 162, wherein at wherein the pharmaceutically-acceptable adjuvant com least 5% the pharmaceutically-acceptable solvent is prises a pharmaceutically-acceptable lipid. removed from the pharmaceutical composition. 148. The method according to embodiment 147, wherein the 164. The method according to embodiment 162 or 163, pharmaceutically-acceptable lipid comprises a pharma 65 wherein at, removal of solvent from the pharmaceutical ceutically-acceptable Saturated fatty acid, an unsaturated composition disclosed herein is carried out at a tempera fatty acid, or a combination thereof. ture of less than 20° C. US 9,265,742 B2 73 74 165. The method according to embodiments 102-164, tion of the therapeutic compound different than a bio wherein the pharmaceutical composition made is accord distribution of the therapeutic compound included in the ing to embodiments 1-101. same pharmaceutical composition, except without the 166 A method of treating an individual with a severe pain pharmaceutically-acceptable adjuvant. condition, the method comprising the step of administer 5 183. The method according to embodiments 166 or 169-182 ing to the individual in need thereof a pharmaceutical com or the use according to embodiments 167-182, wherein position according to embodiments 1-101, wherein admin upon administration to an individual, the amount of the istration results in a reduction in a symptom associated therapeutic compound of the pharmaceutical composition with the severe pain condition, thereby treating the indi according to embodiments 1-101 delivered to a macroph vidual. 10 age is at least 5% of the total amount of the therapeutic 167. Use of a pharmaceutical composition according to compound contained in the administered pharmaceutical embodiments 1-101 in the manufacture of a medicament composition. for the treatment of a chronic inflammation. 184. The method according to embodiments 166 or 169-183 168. Use of a pharmaceutical composition according to or the use according to embodiments 167-183, wherein embodiments 1-101 for the treatment of a severe pain con 15 upon administration to an individual, the pharmaceutical dition. composition according to embodiments 1-101 reduces 169. The method according to embodiment 166 or the use intestinal irritation by at least 5% when compared to the according to embodiment 167 or 168, wherein the severe pharmaceutical composition according to embodiments pain condition is an acute pain, a Subacute pain, or a 1-101, except without the pharmaceutically-acceptable chronic pain. adjuvant. 170. The method according to embodiment 166 or the use 185. The method according to embodiments 166 or 169-184 according to embodiment 167 or 168, wherein the severe or the use according to embodiments 167-184, wherein pain condition is a nociceptive pain. upon administration to an individual, the pharmaceutical 171. The method or use according to embodiment 170, composition according to embodiments 1-101 reduces gas wherein the nociceptive pain is a visceral pain, a deep 25 tric irritation by at least 5% when compared to the phar Somatic pain, a Superficial Somatic pain, or any combina maceutical composition according to embodiments 1-101, tion thereof. except without the pharmaceutically-acceptable adjuvant. 172. The method according to embodiment 166 or the use according to embodiment 167 or 168, wherein the severe EXAMPLES pain condition is a pathological pain. 30 173. The method or use according to embodiment 172, The following non-limiting examples are provided for wherein the pathological pain is a neuropathic pain, a dys illustrative purposes only in order to facilitate a more com functional pain, or any combination thereof. plete understanding of representative embodiments now con 174. The method or use according to embodiment 173, templated. These examples should not be construed to limit wherein the neuropathic pain is a central neuropathic pain, 35 any of the embodiments described in the present specifica a peripheral neuropathic pain, a deafferentation pain, or tion, including those pertaining to the compounds, alcohols, any combination thereof. lipids, pharmaceutical compositions, methods of preparing 175. The method or use according to embodiment 174, pharmaceutical compositions, or methods or uses of treating wherein the peripheral neuropathic pain is a mononeuropa a severe pain condition. thy, a mononeuropathic multiplex, a polyneuropathy, oran 40 autonomic neuropathy. Example 1 176. The method or use according to embodiment 175, wherein the polyneuropathy is a distal axonopathy, a Liquid Formulations of Pharmaceutical Composition myelinopathy, or a neuronopathy. 177. The method or use according to embodiment 174, 45 This example illustrates how to make a pharmaceutical wherein the peripheral neuropathic pain is a neuralgia or a composition as disclosed herein as a liquid formulation. complex regional pain syndrome. Initially, 2,400 mg of ibuprofen was contacted directly with 178. The method according to embodiment 166 or the use 2.0 mL of rapeseed oil in an attempt to dissolve a therapeutic according to embodiment 167 or 168, wherein the severe compound directly into an adjuvant at a concentration of pain condition is a referred pain. 50 1,200 mg/mL. However, ibuprofen remained insoluble in the 179. The method according to embodiment 166 or the use oil and did not dissolve to Substantially measurable degree. according to embodiment 167 or 168, wherein the severe Ibuprofen remained insolubility even if the mixture was pain condition is a headache. mixed by Vortexing for 20 seconds, the contacting was done at 180. The method or use according to embodiment 179, 20° C. or 37°C., and/or the mixture was allowed to incubate wherein the headache is a muscular/myogenic headache, a 55 for 24 hours at 20° C. or 37°C. The insolubility of ibuprofen vascular headache, a traction headache, inflammatory in rapeseed oil was surprising given that ibuprofen has a log P headache, a chronic sinusitis headache, a hormone head value of 3.6; such a high log P value is indicative of a com ache, a rebound headache, an organic headache, or an ictal pound that would readily soluble in an adjuvant like oil. headache. Since, it was not possible to dissolve ibuprofen directly into 181. The method according to embodiment 166 or the use 60 oil, despite its high log P value, it was next tried to dissolve a according to embodiment 167 or 168, wherein the severe therapeutic drug in a solvent to first create a solution com pain condition is a migraine. prising the compound. As a first step, experiments were con 182. The method according to embodiments 166 or 169-181 ducted to the miscibility of a solvent in an adjuvant like oil in or the use according to embodiments 167-181, wherein the absence of a therapeutic compound. In these experiments upon administration to an individual, the pharmaceutical 65 0.5 mL ethanol was contacted with ten different volumes of composition comprising the therapeutic compound rapeseed oil (Table 1). Each mixture was tested at 22°C. and according to embodiments 1-101 results in a bio-distribu at 37°C. in which the ethanol and oil were initially heated in US 9,265,742 B2 75 76 a water bath before being mixed together. Mixing was TABLE 2 attempted by Vortex mixing for 20 seconds, and the containers were allowed to settle before visual assessment, either imme Liquid Formulations with Therapeutic Compound diately, or after 24 hours. Each mixture was evaluated to Components Temperature determine whether or not the ethanol and rapeseed oil form 5 immiscible layers, or a homogeneous mixture. The results are Com- Ad- 22° C. 37o C. Summarized in Table 1. Mixtures comprising solvent:adju pound Solvent juvant 24 24 vant ratios of 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6 formed immis (mg) (mL) (mL) Ratio Immediate hours Immediate hours cible layers at either 22°C. or at 37°C., either immediately or 10 500 O.S 1.O 1:2 HM HM HM HM after 24 hours of incubation, indicating that the ethanol and 600 O.S 1.O 1:2 HM HM HM HM oil did not mix well at these ratios. However, in solvent: 500 O.S 4.5 1:9 HM HM HM HM adjuvant ratios above 1:7 a homogeneous mixture was 600 O.S 4.5 1:9 HM HM HM HM formed under all conditions tested. IL, Immiscible layers, 15 HM, Homogeneous mixture. TABLE 1. Liquid Formulations without Therapeutic Compound Example 2 Components Temperature Liquid Formulations of Pharmaceutical Composition Solvent Adjuvant 22° C. 37o C. This example illustrates how to make a pharmaceutical (mL) (mL) Ratio Immediate 24 hours Immediate 24 hours composition as disclosed herein as a liquid formulation. O.S O.S 1:1 IL IL IL IL 25 To prepare a pharmaceutical composition disclosed herein O.S 1.O 1:2 IL IL IL IL using gemfibrozil, the following formulations were exam O.S 1.5 1:3 IL IL IL IL ined. In these experiments, 600 mg gemfibrozil was contacted O.S 2.0 1:4 IL IL IL IL with different volumes of ethanol, as the solvent, warmed to O.S 2.5 1:5 IL IL IL IL O.S 3.0 1:6 IL IL IL IL 37° C., and the resulting solution was then contacted with O.S 3.5 1:7 HM HM HM HM 30 different volumes of linseed oil, as the adjuvant, warmed to O.S 4.0 1:8 HM HM HM HM 37° C. (Table 3). Each formulation was evaluated to deter 0.5 4.5 1:9 HM HM HM HM mine whether or not the ethanol and linseed oil form immis O.S S.O 1:10 HM HM HM HM cible layers, a clear homogeneous mixture, as well as whether or not the gemfibrozil crystallized out of solution. The results are summarized in Table 3. IL, Immiscible layers, 35 HM, Homogeneous mixture. Like ibuprofen in Example 1 above, gemfibrozil remained insoluble in the oil alone and did not dissolve to substantially Once the appropriate ratios of alcohol and lipid necessary measureable degree. The formulation comprising 0.2 mL to form a homogenous mixture were determined, it was next ethanol was unable to completely dissolve gemfibrozil. In determined whether contacting a therapeutic compound first 40 addition, although the formulation comprising 0.3 mL etha in a solvent before contacting with an adjuvant would result in nol was capable of dissolving gemfibrozil, the therapeutic the compound dissolving in the Solvents. To conduct these compound began to crystallizing out of Solution within 3 experiments, either 1,000 mg or 1,200 mg of ibuprofen was hours and complete crystallization occurred within 48 hours. dissolved into 0.5 mL of ethanol. The resulting alcohol solu All otherformulations tested were capable of dissolving gem tion was then contacted with rapeseed oil at two different 45 fibrozil and forming a pharmaceutical composition disclosed solvent:adjuvant ratios (1:2 and 1:9). Each mixture was tested herein. However, only the formulation comprising 0.5 mL at 20° C. and at 37°C. in which the ethanol solution and oil ethanol appeared to for a stable pharmaceutical composition were initially heated in a water bath before being mixed in that gemfibrozil remained completely dissolved after three together. Mixing was attempted by vortex mixing for 20 weeks. seconds, and the containers were allowed to settle before 50 visual assessment, either immediately, or after 24 hours. Each TABLE 3 mixture was evaluated to determine whether or not the etha Liquid Formulations with Therapeutic Compound nol solution and rapeseed oil form immiscible layers, or a homogeneous mixture. The results are Summarized in Table Components Temperature 55 2. In contrast to the situation in the absence of a therapeutic Compound Solvent Adjuvant 22° C. compound, when ibuprofen is present in the ethanol, it caused the ethanol and oil to form a homogeneous mixture under all (mg) (mL) (mL) Ratio Immediate 3 weeks conditions tested in solvent:adjuvant ratios above 1:2. This 600 O 1.O IM NA observation was very Surprising because, although not wish 600 O.2 IM NA 60 600 O.3 O.6 1:2 CR CR to be bound by any theory, it appears that a therapeutic com 600 0.4 0.4 1:1 HM CR pound may behaving some effect on the manner in which an 600 0.4 O.8 1:2 HM CR adjuvant and solvent interact with each other, Such that a 600 O.S 1.O 1:2 HM HM homogeneous mixture is formed in a way that does not occur HM, Clear homogeneous mixture. when the therapeutic compound is absent. In addition, the 65 CR, Crystallization. results indicate that a therapeutic compound can be formu DM, Immiscible. lated at clinically useful concentrations. US 9,265,742 B2 77 78 Example 3 fen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg of palmitic acid (T of about 61-62 Liquid Formulations of Pharmaceutical C.) and heated at 60° C. for 30 minutes to form a homoge Compositions neous solution. Formulation 2 solidified about 1 hour after cooling to 22°C. Incubating at 37° C. overnight cause For This example illustrates how to make a pharmaceutical mulation 2 to completely melt into a clear homogenous liq uid. However, Formulation 2 once again solidified about 1 composition as disclosed herein as a liquid formulation. hour after cooling to 22°C. Formulation 3 was prepared by To prepare a liquid pharmaceutical composition disclosed dissolving 200 mg of Ibuprofen into 400 mg of menthol, and herein using ibuprofen, the following method was performed. the resulting solution was then mixed with 200 mg of linoleic About 4 g ibuprofen was contacted with 3.6 mL of ethyl 10 acid (T, of about -5°C.) and heated at 37° C. for 2 hours to acetate, as the solvent, and the resulting solution was then form a homogeneous solution. Formulation 3 remained a contacted with 76.4 mL of rapeseed oil, as the adjuvant. The liquid, even after cooling to 22°C. for 72 hours. Formulation resulting pharmaceutical composition had a solvent:adjuvant 4 was prepared by dissolving 200 mg of Ibuprofen into 400 ratio of about 1:21. This pharmaceutical composition was mg of menthol, and the resulting solution was then mixed then placed in a round bottom flask and subjected to low 15 with 200 mg of linolenic acid (T of about -11° C.) and pressure on a rotary evaporator. The temperature was kept low heated at 37°C. for 2 hours to form a homogeneous solution. and evaporation continued to constant weight. The total Vol Formulation 4 remained a liquid, even after cooling to 22°C. ume lost was 3.65% of the total weight. The resulting liquid for 72 hours. no longer retained the characteristic ethyl acetate odor/taste, indicating that there was a Substantial removal of ethyl acetate form the pharmaceutical composition. TABLE 4 To prepare a liquid pharmaceutical composition disclosed Solid Formulations with Therapeutic Compound herein using ibuprofen, the following method was performed. About 2 g ibuprofen was contacted with 1.2 mL of diethylene Components Temperature glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), as the 25 Com- 22° C. 37o C. solvent, 2.2 mL MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate, and 2.2 mL rapeseed oil, as the adjuvants, and pound Solvent Adjuvant Upon 24 72 the resulting mixture was then contacted with 0.46 mL iso (mg) (mg) (mg) Ratio Cooling hours hours propanol. The mixture was added to a vessel heated to about 2OO 400 200 (stearic acid) 2:1 Solid Solid 40° C. to about 50° C. and stirred until all components of the 30 2OO 400 200 (palmitic acid) 2:1 Solid Liquid mixture dissolved and then cooled to about 30°C. The result 2OO 400 200 (linoleic acid) 2:1 Liquid Liquid Liquid ing pharmaceutical composition had a solvent:adjuvant ratio 2OO 400 200 (linolenic acid) 2:1 Liquid Liquid Liquid of about 1:3.67. This pharmaceutical composition was then aliquoted to produce 10 liquid capsules each containing about Based on these data, a Solid dosage form of a pharmaceu 200 mg ibuprofen. 35 tical composition disclosed hereincan be made. For example, a pharmaceutical composition will be formulated to be solid Example 4 or semi-solid at 22°C., but melt into a proper clear solution (and not a suspension) at 37°C. (Table 5). Solid Formulation of Pharmaceutical Composition 40 TABLE 5 This example illustrates how to make a pharmaceutical composition as disclosed herein as a solid formulation. Solid Formulations of Pharmaceutical Compositions Since certain fatty acids are liquid at room temperature, Compound 600 mg Ibuprofen while others are solid, an examination of the different fatty Solvent 500 mg Methanol acids was undertaken in an effort to evaluate the potential of 45 Adjuvant 2000 mg Palmitic acid 2000 mg Stearic acid each fatty acid in the manufacture of a solid formulation. This 250 mg Linolenic acid understanding would enable the development of a wide array 250 mg Linoleic acid of solid formulation by adjusting the relative ratios of each Ratio 1:9 Volume 5 mL. fatty acid. As an initial experiment, linolenic acid, linoleic Concentration 120 mg/mL acid, palmitic acid and Stearic acid were evaluated to assess 50 whether it was possible to prepare a pharmaceutical compo sition disclosed herein that could be formulated using only To prepare a solid pharmaceutical composition disclosed one of these fatty acids to be a solid or semi-solid at 22°C. herein using ibuprofen, the following method was performed. (simulating room temperature conditions), but melt into a About 15 g ibuprofen was contacted with about 9.0 mL of liquid at 37°C. (simulating internal body temperature condi 55 diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)etha tions after ingestion). nol), as the solvent, about 33 g GELUCIRE(R) 39/01 (Gatte Four different test formulations were prepared and evalu fosse), a waxy solid having a melting point of between 37°C. ated on their ability to form a solid dose formulation at 22°C. to 41° C. and comprising a mixture of Saturated Co-Cs and melt into a homogeneous solution at 37° C. without triglycerides, as the adjuvant, and about 3.6 mL isopropanol. forming a Suspension (Table 4). Formulation 1 was prepared 60 The mixture was added to a vessel heated to about 40°C. to by dissolving 200 mg of Ibuprofen into 400 mg of menthol, about 50° C. and stirred until all components of the mixture and the resulting solution was then mixed with 200 mg of dissolved, cooled to about 30° C., and then aliquoted by stearic acid (T of about 67-72°C.) and heated at 60° C. for poring into molds and cooled to room temperature. The 30 minutes to form a homogeneous solution. Formulation 1 resulting pharmaceutical composition had a solvent:adjuvant solidified immediately upon cooling to 22°C. Formulation 1 65 ratio of about 1:3.67. This pharmaceutical composition pro remained a solid even after incubating at 37° C. overnight. duced 75 solid tablets each containing about 200 mg ibupro Formulation 2 was prepared by dissolving 200 mg of Ibupro fen. US 9,265,742 B2 79 80 To prepare a solid pharmaceutical composition disclosed To prepare a semi-solid pharmaceutical composition dis herein using ibuprofen, the following method was performed. closed herein using ibuprofen, the following method was About 20 g ibuprofen was contacted with about 12.0 mL of performed. About 1 g ibuprofen free acid, about 0.2 g ibupro diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)etha fen sodium salt, about 0.6 g GELUCIRE(R)43/01 (Gattefosse), nol), as the solvent, about 16 g GELUCIRE(R) 43/01 (Gatte a waxy solid having a melting point of between 41° C. to 45° fosse), a waxy Solid having a melting point of between 41° C. C. and comprising a mixture of Saturated Co-Cs triglycer to 45° C. and comprising a mixture of saturated Co-Cs ides, and about 1.6 mL MAISINE(R) 35-1 (Gattefosse), a triglycerides, and about 16 g MAISINE(R) 35-1 (Gattefosse), glyceryl monolinoleate, about 0.6 mL PEG 400, and about a glyceryl monolinoleate, as the adjuvant, and about 3.6 mL 0.15 mL propylene glycol were added to a vessel heated to isopropanol. The mixture was added to a vessel heated to 10 about 50° C. to about 60° C. and stirred until all components about 40°C. to about 50° C. and stirred until all components of the mixture dissolved. The heated mixture is cooled to of the mixture dissolved, cooled to about 30° C., and then room temperature and aliquoited into an appropriate con aliquoted by poring into molds and cooled to room tempera tainer. This pharmaceutical composition produced a semi ture. The resulting pharmaceutical composition had a solvent: Solid ointment having a concentration of ibuprofen that is adjuvant ratio of about 1:2.67. This pharmaceutical compo 15 about 400 mg/mL. sition produced 100 solid tablets each containing about 200 To prepare a semi-solid pharmaceutical composition dis mg ibuprofen. closed herein using ibuprofen, the following method was To prepare a solid pharmaceutical composition disclosed performed. About 5 g ibuprofen free acid, about 5 g ibuprofen herein using ibuprofen, the following method was performed. sodium salt, about 3 g GELUCIRE(R)43/01 (Gattefosse), a About 80 g ibuprofen, about 152g GELUCIRE(R) 43/01 (Gat waxy solid having a melting point of between 41° C. to 45° C. tefosse), a waxy Solid having a melting point of between 41 and comprising a mixture of saturated Co-Cs triglycerides, C. to 45° C. and comprising a mixture of Saturated Co-Cs and about 8 mL MAISINE(R) 35-1 (Gattefosse), a glyceryl triglycerides, and about 72 mL MAISINE(R) 35-1 (Gatte monolinoleate, about 3 mL PEG 400, and about 1 mL propy fosse), a glyceryl monolinoleate, and about 32 mL PEG 400 lene glycol were added to a vessel heated to about 50° C. to were added to a vessel heated to about 50° C. to about 60° C. 25 about 60° C. and stirred until all components of the mixture and stirred until all components of the mixture dissolved. The dissolved. The heated mixture is cooled to room temperature heated mixture is cooled to about 40°C., and then aliquoted and aliquoited into an appropriate container. This pharmaceu by poring into molds and cooled to room temperature. This tical composition produced a semisolid ointment having a pharmaceutical composition produced 400 solid tablets each concentration of ibuprofen that is about 650 mg/mL. containing about 200 mg ibuprofen. 30 To prepare a solid pharmaceutical composition disclosed Example 6 herein using ibuprofen, the following method was performed. About 1.1 g ibuprofen sodium salt, about 1.9 g GELUCIRE(R) Animal Model for Intestinal Erosion 43/01 (Gattefosse), a waxy Solid having a melting point of between 41° C. to 45° C. and comprising a mixture of satu 35 To assess whether a pharmaceutical composition disclosed rated Co-Cs triglycerides, and about 0.9 mL MAISINE(R) herein reduced gastric irritation, experiments were conducted 35-1 (Gattefosse), a glyceryl monolinoleate, about 0.4 mL using an intestinal erosion murine model. PEG 400, and about 0.3 mL propylene glycol were added to Sprague-Dawley rats were divided into seven experimental a vessel heated to about 50° C. to about 60° C. and stirred until groups containing five animals each. After fasting overnight, all components of the mixture dissolved. The heated mixture 40 the animals were challenged with one with one of seven is cooled to about 40°C., and then aliquoted by poring into different treatments. Group A was a control in which each molds and cooled to room temperature. This pharmaceutical mouse was orally administered 1% methylcellulose/0.5% composition produced 5 solid tablets each containing about polysorbate 80 vehicle only. Group B was a control in which 200 mg ibuprofen. each mouse was orally administered solvent/adjuvant vehicle To prepare a solid pharmaceutical composition disclosed 45 only (gavage of 10% ethanol and 90% linseed oil). Group C herein using ibuprofen, the following method was performed. was a control in which each mouse was orally administered About 5 g ibuprofen free acid, about 5 g ibuprofen sodium 150 mg/kg aspirin. Group D was a control in which each salt, about 3 g GELUCIRE(R43/01 (Gattefosse), a waxy solid mouse was orally administered 100 mg/kg ibuprofen Sus having a melting point of between 41° C. to 45° C. and pended in 1% methylcellulose/0.5% polysorbate 80. Group E comprising a mixture of Saturated Co-Cs triglycerides, and 50 was the experimental group in which each mouse was admin about 8 mL MAISINE(R) 35-1 (Gattefosse), a glyceryl mono istered a pharmaceutical composition disclosed herein linoleate, about 3 mL PEG 400, and about 1 mL propylene (BC 1054-100) comprising 100 mg/kg of ibuprofen, 10% glycol were added to a vessel heated to about 50° C. to about ethanol, and 90% linseed oil. Group F was a control in which 60° C. and stirred until all components of the mixture dis each mouse was orally administered 100 mg/kg ibuprofen solved. The heated mixture is cooled to about 40°C., and then 55 suspended in 1% methylcellulose/0.5% polysorbate 80. aliquoted by poring into molds and cooled to room tempera Group G was the experimental group in which each mouse ture. This pharmaceutical composition produced 50 solid tab was administered a pharmaceutical composition disclosed lets each containing about 200 mg ibuprofen. herein (BC 1054-200) comprising 200 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Animals were sacrificed 4 Example 5 60 hours after treatment and the stomachs were examined for degree of hemorrhage and severity of mucosal erosive Semi-Solid Formulation of Pharmaceutical lesions. Gastric irritation was scored as follows: 0, no lesions; Composition 1, hyperemia; 2, one or two slight lesions; 3, more than two slight lesions or severe lesions; and 4, very severe lesions. A This example illustrates how to make a pharmaceutical 65 score of 50% or more relative to Group C (aspirin-treated composition as disclosed herein as a semi-solid formulation control group), which was set to 100%, was considered a useful for topical administration. positive score for gastric irritation. US 9,265,742 B2 81 82 Results are shown in Table 6. Group D (100 mg/kg of mines that the lower pain is due to an acute pain. The woman ibuprofen-treated control group) and Group F (200 mg/kg of is treated by oral administration a pharmaceutical composi ibuprofen-treated control group) produced gastric lesions that tion comprising ibuprofen as disclosed herein taken twice were 75% and 95%, respectively, severe as those induced by daily. Alternatively, the woman is treated by oral administra Group C (aspirin-treated control group). However, Group E tion a pharmaceutical composition comprising aspirinas dis (BC1054-100-treated experimental group) and Group G closed herein taken thrice daily. Alternatively, the woman is (BC1054-200-treated experimental group) produced gastric treated by oral administration a pharmaceutical composition lesions that were 20% and 40%, respectively, as severe as comprising naproxen as disclosed herein taken twice daily. those associated with Group C (aspirin-treated control The woman’s condition is monitored and after about 3 days of 10 treatment the woman indicates there is reduced pain. At one group). These results demonstrate that that a pharmaceutical and three week check-ups, the woman indicates that she con composition disclosed herein reduced the extent to which a tinues to have reduced pain. This reduction in acute pain therapeutic compound may cause mucosal lesions and cause symptoms indicates Successful treatment with the pharma gastric irritation. ceutical composition disclosed herein. In a similar manner, 15 any of the therapeutic compounds such as, e.g., a salicylate TABLE 6 derivative NSAID, a p-amino phenol derivative NSAID, a Results from Intestinal Erosion Assay propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid Mean % derivative NSAID, a non-selective cyclo-oxygenase (COX) Group Ulceration Score Aspirin Erosion inhibitor, a selective cyclooxygenase 1 (COX1) inhibitor, a A. O O selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, B O O will be formulated into a pharmaceutical composition and C 4 (100) D 3 751 administered to the patient as described above. E O.8 2O A 22 year old male complains of severe pain in his right F 3.8 951 25 shoulder that occurred while he was lifting weighs in the gym G 1.6 40 one month ago. A physician determines that the severe pain is a Subacute pain. The man is treated by oral administration a "Positive score for gastric erosion, pharmaceutical composition comprising ibuprofen as dis closed herein taken twice daily. Alternatively, the man is Example 7 30 treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Case Studies for the Treatment of Severe Pain Alternatively, the man is treated by oral administration a pharmaceutical composition comprising naproxen as dis A 51 year old male experienced severe dental pain due to closed herein taken twice daily. The man's condition is moni the exposure of a nerve after a tooth filling disintegrated. The 35 tored and after about 3 days of treatment the man indicates pain was perceived to be too severe to be controlled by ibu there is improvement in his ability to move his arm without profen or diclofenac, but the patient was reluctant to use pain in his shoulder. At one week and one and three month codeine (30 mg) with paracetamol (500mg) which was avail check-ups, the man indicates that he continues to have able to him. Prior to the patient coming into to see the dentist improved shoulder mobility and no pain. This reduction in for remedial dental work, he took 7 day course of a pharma 40 Subacute pain symptoms indicates successful treatment with ceutical composition disclosed herein (BC 1054) comprising the pharmaceutical composition disclosed herein. In a similar 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil manner, any of the therapeutic compounds such as, e.g., a (800 mgb.id), which effectively controlled the pain. Relief of salicylate derivative NSAID, a p-amino phenol derivative pain occurred within 30 minutes of taking each dose and NSAID, a propionic acid derivative NSAID, an acetic acid lasted for approximately 12 hours before redosing. The pain 45 derivative NSAID, an enolic acid derivative NSAID, a control was so good that he was no longer aware of pain in the fenamic acid derivative NSAID, a non-selective cyclo-oxy affected tooth. genase (COX) inhibitor, a selective cyclooxygenase 1 (COX A 50 year old male was diagnosed with a maison neuve 1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, fracture in the ankle after a sport injury. The patient was or a fibrate, will be formulated into a pharmaceutical compo initially administered 30 mg codeine with 500 mg paraceta 50 sition and administered to the patient as described above. mol bid, along with 10 mg diclofenac tid for 8 months to A 67 year old male complains of severe pain in his ankle control his severe pain. After experiencing unacceptable side from a fall he took two months before. A physician deter effects he ceased opiate paracetamol and diclofenac therapy mines that the pain is a chronic pain. The man is treated by and commenced a 5 day course of a pharmaceutical compo oral administration a pharmaceutical composition compris sition disclosed herein (BC 1054) comprising 20 mg/kg of 55 ing ibuprofen as disclosed herein taken twice daily. Alterna ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid). tively, the man is treated by oral administration a pharmaceu After 2 days reported a significant improvement in his pain, tical composition comprising aspirin as disclosed herein and then after 3 days he reported that the pain was completely taken thrice daily. Alternatively, the man is treated by oral controlled. After a 2 month follow the patient is still free of administration a pharmaceutical composition comprising severe pain and he has since resumed an active sporting life. 60 naproxen as disclosed herein taken twice daily. The man’s condition is monitored and after about 3 days of treatment the Example 8 man indicates there is reduced pain in his ankle and mobility in his ankle is better. At one and three month check-ups, the Treatment of a Severe Pain Condition man indicates that he continues to have improved ankle 65 mobility and no pain. This reduction in chronic pain Symp A 62 year old female complains of severe lower back pain toms indicates Successful treatment with the pharmaceutical after lifting a heavy box the day before. A physician deter composition disclosed herein. In a similar manner, any of the US 9,265,742 B2 83 84 therapeutic compounds such as, e.g., a salicylate derivative fenamic acid derivative NSAID, a non-selective cyclo-oxy NSAID, a p-amino phenol derivative NSAID, a propionic genase (COX) inhibitor, a selective cyclooxygenase 1 (COX acid derivative NSAID, an acetic acid derivative NSAID, an 1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, enolic acid derivative NSAID, a fenamic acid derivative or a fibrate, will be formulated into a pharmaceutical compo NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a sition and administered to the patient as described above. selective cyclooxygenase 1 (COX1) inhibitor, a selective A33 year old female complains of chronic abdominal pain. cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be A physician determines that the pain is due to deep visceral formulated into a pharmaceutical composition and adminis noceceptive pain. The woman is treated by oral administra tered to the patient as described above. tion a pharmaceutical composition comprising ibuprofen as A 73 year old female complains of severe pain after burn 10 disclosed herein taken twice daily. Alternatively, the woman ing her forearm on a hot oven. A physician determines that the is treated by oral administration a pharmaceutical composi pain is due to Superficial Somatic noceceptive pain. The tion comprising aspirinas disclosed herein taken thrice daily. woman is treated by oral administration a pharmaceutical Alternatively, the woman is treated by oral administration a composition comprising ibuprofen as disclosed herein taken pharmaceutical composition comprising naproxen as dis twice daily. Alternatively, the womanistreated by oral admin 15 closed herein taken twice daily. The woman’s condition is istration a pharmaceutical composition comprising aspirin as monitored and after about 3 days of treatment the woman disclosed herein taken thrice daily. Alternatively, the woman indicates that there is a reduction in abdominal pain. At one is treated by oral administration a pharmaceutical composi and three month check-ups, the woman indicates that she tion comprising naproxen as disclosed herein taken twice continues to have reduced abdominal pain. This reduction in daily. The woman's condition is monitored and after about 3 deep visceral noceceptive pain symptoms indicates Success days of treatment the woman indicates that she no longer feels ful treatment with the pharmaceutical composition disclosed pain in her forearm. At one and three week check-ups, the herein. A similar type of oral administration of a pharmaceu woman indicates that she still feels no pain. This reduction in tical composition disclosed herein will be used to treat a Superficial Somatic noceceptive pain symptoms indicates suc patient Suffering from severe pain associated with any other cessful treatment with the pharmaceutical composition dis 25 deep visceral noceceptive pain, including, without limitation, closed herein. A similar type of oral administration of a phar a functional visceral pain, a chronic gastrointestinal inflam maceutical composition disclosed herein will be used to treat mation, an autoimmune pain, an organic Visceral pain, and a a patient Suffering from severe pain associated with any other treatment-induced visceral pain. In a similar manner, any of deep somatic noceceptive pain, including, without limitation, the therapeutic compounds such as, e.g., a salicylate deriva an excessive muscle tension, a repetitive motion disorder, a 30 tive NSAID, a p-amino phenol derivative NSAID, a propionic muscle disorder, a myalgia, an infection, and a drug-induced acid derivative NSAID, an acetic acid derivative NSAID, an pain. In a similar manner, any of the therapeutic compounds enolic acid derivative NSAID, a fenamic acid derivative Such as, e.g., a salicylate derivative NSAID, a p-amino phenol NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a derivative NSAID, a propionic acid derivative NSAID, an selective cyclooxygenase 1 (COX1) inhibitor, a selective acetic acid derivative NSAID, an enolic acid derivative 35 cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be NSAID, a fenamic acid derivative NSAID, a non-selective formulated into a pharmaceutical composition and adminis cyclo-oxygenase (COX) inhibitor, a selective cyclooxyge tered to the patient as described above. nase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX A 66 year old male complains of severe pain after Suffering 2) inhibitor, or a fibrate, will beformulated into a pharmaceu a stroke. A physician determines that the pain is due to central tical composition and administered to the patient as described 40 neuropathic pain. The man is treated by oral administration a above. pharmaceutical composition comprising ibuprofen as dis A37 year old male complains of severe pain due to a lower closed herein taken twice daily. Alternatively, the man is leg bone fracture while skiing. A physician determines that treated by oral administration a pharmaceutical composition the pain is due to deep Somatic noceceptive pain. The man is comprising aspirin as disclosed herein taken thrice daily. treated by oral administration a pharmaceutical composition 45 Alternatively, the man is treated by oral administration a comprising ibuprofen as disclosed herein taken twice daily. pharmaceutical composition comprising naproxen as dis Alternatively, the man is treated by oral administration a closed herein taken twice daily. The man's condition is moni pharmaceutical composition comprising aspirin as disclosed tored and after about 3 days of treatment the man indicates herein taken thrice daily. Alternatively, the man is treated by that there is a reduction in abdominal pain. At one and three oral administration a pharmaceutical composition compris 50 month check-ups, the man indicates that he continues to have ing naproxen as disclosed hereintaken twice daily. The man’s reduced pain. This reduction in central neuropathic pain condition is monitored and after about 3 days of treatment the symptoms indicates Successful treatment with the pharma man indicates there is reduced pain in his leg. At one and two ceutical composition disclosed herein. A similar type of oral month check-ups, the man indicates that he continues to have administration of a pharmaceutical composition disclosed reduced pain. This reduction in deep Somatic noceceptive 55 herein will be used to treat a patient suffering from severe pain pain symptoms indicates Successful treatment with the phar associated with any other central neuropathic or dysfunc maceutical composition disclosed herein. A similar type of tional pain, including, without limitation, cerebral venous oral administration of a pharmaceutical composition dis thrombosis, cerebral tumors or abscesses compressing a brain closed herein will be used to treat a patient suffering from portion, traumatic brain or spinal cord injury, complications severe pain associated with any other deep Somatic nocecep 60 following brain or spinal Surgery, multiple Sclerosis, and Par tive pain, including, without limitation, an excessive muscle kinson disease, ischemic lesions, Syringomyelia, radiation tension, a repetitive motion disorder, a muscle disorder, a myelopathy, and HIV myelopathy. In a similar manner, any of myalgia, an infection, and a drug-induced pain. In a similar the therapeutic compounds such as, e.g., a salicylate deriva manner, any of the therapeutic compounds such as, e.g., a tive NSAID, a p-amino phenol derivative NSAID, a propionic salicylate derivative NSAID, a p-amino phenol derivative 65 acid derivative NSAID, an acetic acid derivative NSAID, an NSAID, a propionic acid derivative NSAID, an acetic acid enolic acid derivative NSAID, a fenamic acid derivative derivative NSAID, an enolic acid derivative NSAID, a NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a US 9,265,742 B2 85 86 selective cyclooxygenase 1 (COX1) inhibitor, a selective NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be selective cyclooxygenase 1 (COX1) inhibitor, a selective formulated into a pharmaceutical composition and adminis cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be tered to the patient as described above. formulated into a pharmaceutical composition and adminis A 58 year old male, who is a diabetic, complains of severe tered to the patient as described above. pain. A physician determines that the pain is due to peripheral A 47 year old female complains of severe pain down her neuropathic pain from diabetic neuropathy. The man is left leg when she leans over to do the dishes. A physician treated by oral administration a pharmaceutical composition determines that the leg pain is due to a sciatic nerve dysfunc comprising ibuprofen as disclosed herein taken twice daily. tion. The woman is treated by oral administration a pharma Alternatively, the man is treated by oral administration a 10 ceutical composition comprising ibuprofen as disclosed pharmaceutical composition comprising aspirin as disclosed herein taken twice daily. Alternatively, the woman is treated herein taken thrice daily. Alternatively, the man is treated by by oral administration a pharmaceutical composition com oral administration a pharmaceutical composition compris prising aspirin as disclosed herein taken thrice daily. Alterna ing naproxen as disclosed hereintaken twice daily. The man’s tively, the woman is treated by oral administration a pharma condition is monitored and after about 3 days of treatment the 15 ceutical composition comprising naproxen as disclosed man indicates there is reduction in the pain. At one and three hereintaken twice daily. The woman's condition is monitored month check-ups, the man indicates that he still experiences and after about 3 days of treatment the woman indicates there reduced pain. This reduction in a peripheral neuropathic pain is reduced pain. At one and three month check-ups, the indicates Successful treatment with the pharmaceutical com woman indicates that she continues to have reduced pain in position disclosed herein. A similar type of oral administra her leg. This reduction in Sciatic nerve dysfunction symptoms tion of a pharmaceutical composition disclosed herein will be indicates Successful treatment with the pharmaceutical com used to treat a patient Suffering from severe pain associated position disclosed herein. A similar type of topical adminis with any other peripheral neuropathic or dysfunctional pain, tration of a pharmaceutical composition disclosed herein will including, without limitation, systemic diseases, metabolic be used to treat a patient Suffering from severe pain associated disorders, nutrient disorders, drug-induced disorders, trau 25 with any mononeuropathy, such as, e.g., a common peroneal matic and entrapment syndromes, complications following nerve dysfunction. a radial nerve dysfunction, an ulnar nerve Surgery, distal axonopathy, HIV sensory neuropathy, demy dysfunction, a cranial mononeuropathy VI, a cranial monon elinating polyradiculoneuropathy, postherpetic neuralgia, europathy VII, a cranial mononeuropathy III (compression nerve root avulsions, cranial neuralgias like trigeminal neu type), a cranial mononeuropathy III (diabetic type), an axil ralgia, neuropathic cancer pain, compression of peripheral 30 lary nerve dysfunction, a carpal tunnel syndrome, a femoral nerves, nerve plexuses, and nerve roots, paraneoplastic nerve dysfunction, a tibial nerve dysfunction, a Bell's palsy, a peripheral neuropathy, ganglionopathy, complication of can thoracic outlet syndrome, a carpal tunnel syndrome or other cer therapies like chemotherapy, radiation, and Surgery, and focal entrapment neuropathy, and a sixth (abducent) nerve complex regional pain syndrome like Type 1 and Type 2. In a palsy. In a similar manner, any of the therapeutic compounds similar manner, any of the therapeutic compounds such as, 35 Such as, e.g., a salicylate derivative NSAID, ap-amino phenol e.g., a salicylate derivative NSAID, a p-amino phenol deriva derivative NSAID, a propionic acid derivative NSAID, an tive NSAID, a propionic acid derivative NSAID, an acetic acetic acid derivative NSAID, an enolic acid derivative acid derivative NSAID, an enolic acid derivative NSAID, a NSAID, a fenamic acid derivative NSAID, a non-selective fenamic acid derivative NSAID, a non-selective cyclo-oxy cyclo-oxygenase (COX) inhibitor, a selective cyclooxyge genase (COX) inhibitor, a selective cyclooxygenase 1 (COX 40 nase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, 2) inhibitor, or a fibrate, will beformulated into a pharmaceu or a fibrate, will be formulated into a pharmaceutical compo tical composition and administered to the patient as described sition and administered to the patient as described above. above. A 59 year old female complains of severe pain by even the A 22 year old male complains of severe pain in his right leg faintest amount of pressure is applied to her forearm. A phy 45 that began after a hike in the woods. A physician determines sician determines that the pain is due to allodynia. The woman that the severe pain is Sue to a Lyme disease. The man is is treated by topical administration a pharmaceutical compo treated by intravenous injection administration of a pharma sition comprising ibuprofen as disclosed herein taken twice ceutical composition comprising ibuprofen as disclosed daily. Alternatively, the woman is treated by topical adminis herein taken twice daily. Alternatively, the man is treated by tration a pharmaceutical composition comprising aspirin as 50 intravenous injection administration of a pharmaceutical disclosed herein taken thrice daily. Alternatively, the woman composition comprising aspirin as disclosed herein taken is treated by topical administration a pharmaceutical compo thrice daily. Alternatively, the man is treated by intravenous sition comprising naproxen as disclosed herein taken twice injection administration of a pharmaceutical composition daily. The woman's condition is monitored and after about 3 comprising naproxen as disclosed herein taken twice daily. days of treatment the woman indicates there is reduced pain. 55 The man’s condition is monitored and after about 3 days of At one and three month check-ups, the woman indicates that treatment the man indicates there is reduced pain. At one she continues to have reduced pain. This reduction in allo week and one and three month check-ups, the man indicates dynia symptoms indicates successful treatment with the phar that he continues to no pain. This reduction in Lyme disease maceutical composition disclosed herein. A similar type of symptoms indicates Successful treatment with the pharma topical administration of a pharmaceutical composition dis 60 ceutical composition disclosed herein. A similar type of intra closed herein will be used to treat a patient suffering from venous injection administration of a pharmaceutical compo severe pain associated with any dysesthesia, Such as, e.g., sition disclosed herein will be used to treat a patient suffering hyperalgesia or hyperpathia. In a similar manner, any of the from severe pain associated with any mononeuropathic mul therapeutic compounds such as, e.g., a salicylate derivative tiplex. Such as, e.g., systemic diseases, metabolic disorders, NSAID, a p-amino phenol derivative NSAID, a propionic 65 nutrient disorders, drug-induced disorders, traumatic and acid derivative NSAID, an acetic acid derivative NSAID, an entrapment syndromes, toxicity, and infections. In a similar enolic acid derivative NSAID, a fenamic acid derivative manner, any of the therapeutic compounds such as, e.g., a US 9,265,742 B2 87 88 salicylate derivative NSAID, a p-amino phenol derivative formulated into a pharmaceutical composition and adminis NSAID, a propionic acid derivative NSAID, an acetic acid tered to the patient as described above. derivative NSAID, an enolic acid derivative NSAID, a A 42 year old male complains of severe pain whenever any fenamic acid derivative NSAID, a non-selective cyclo-oxy pressure is applied to his left side of his face. A physician genase (COX) inhibitor, a selective cyclooxygenase 1 (COX determines that the pain is due to a trigeminal neuralgia. The 1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, man is treated by topical administration of a pharmaceutical or a fibrate, will be formulated into a pharmaceutical compo composition comprising ibuprofen as disclosed herein taken sition and administered to the patient as described above. twice daily. Alternatively, the man is treated by topical admin A 67 year old male, a chronic alcoholic, complains of istration a pharmaceutical composition comprising aspirin as 10 disclosed herein taken thrice daily. Alternatively, the man is severe pain. A physician determines that the pain is a poly treated by topical administration a pharmaceutical composi neuropathy. The man is treated by oral administration a phar tion comprising naproxen as disclosed herein taken twice maceutical composition comprising ibuprofen as disclosed daily. The man’s condition is monitored and after about 3 herein taken twice daily. Alternatively, the man is treated by days of treatment the man indicates there is reduced pain in oral administration a pharmaceutical composition compris his face. At one and two month check-ups, the man indicates ing aspirin as disclosed herein taken thrice daily. Alterna that he continues to have reduced pain. This reduction in tively, the man is treated by oral administration a pharmaceu trigeminal neuralgia pain symptoms indicates Successful tical composition comprising naproxen as disclosed herein treatment with the pharmaceutical composition disclosed taken twice daily. The man’s condition is monitored and after herein. A similar type of topical administration of a pharma about 3 days of treatment the man indicates there is reduced ceutical composition disclosed herein will be used to treat a pain. At one and three month check-ups, the man indicates patient Suffering from severe pain associated with any other that he continues to have no pain. This reduction in poly neuralgia, including, without limitation, a glossopharyngeal neuropathic pain symptoms indicates successful treatment neuralgia, a post-herpetic neuralgia, a carpal tunnel Syn with the pharmaceutical composition disclosed herein. A drome, a meralgia paresthetica, a sciatica and an atypical similar type of oral administration of a pharmaceutical com 25 facial pain. In a similar manner, any of the therapeutic com position disclosed herein will be used to treat a patient suf pounds such as, e.g., a salicylate derivative NSAID, a fering from severe pain associated with any other polyneur p-amino phenol derivative NSAID, a propionic acid deriva opathy, including, without limitation, acute inflammatory tive NSAID, an acetic acid derivative NSAID, an enolic acid demyelinating polyneuropathy, chronic inflammatory demy derivative NSAID, a fenamic acid derivative NSAID, a non elinating polyneuropathy, and a genetic metabolic disorder. 30 selective cyclo-oxygenase (COX) inhibitor, a selective In a similar manner, any of the therapeutic compounds Such cyclooxygenase 1 (COX1) inhibitor, a selective cyclooxyge as, e.g., a salicylate derivative NSAID, a p-amino phenol nase 2 (COX2) inhibitor, or a fibrate, will beformulated into derivative NSAID, a propionic acid derivative NSAID, an a pharmaceutical composition and administered to the patient acetic acid derivative NSAID, an enolic acid derivative as described above. NSAID, a fenamic acid derivative NSAID, a non-selective 35 A 54 year old female complains of pain in her left shoulder cyclo-oxygenase (COX) inhibitor, a selective cyclooxyge after Suffering a heart-attack. A physician determines that the nase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX pain is due to referred pain from a myocardial ischaemia. The 2) inhibitor, or a fibrate, will beformulated into a pharmaceu woman is treated by oral administration a pharmaceutical tical composition and administered to the patient as described composition comprising ibuprofen as disclosed herein taken above. 40 twice daily. Alternatively, the womanistreated by oral admin A 73 year old female complains of severe pain in her istration a pharmaceutical composition comprising aspirin as bladder. A physician determines that the pain is due to an disclosed herein taken thrice daily. Alternatively, the woman autonomic neuropathy. The woman is treated by instillation is treated by oral administration a pharmaceutical composi administration of a pharmaceutical composition comprising tion comprising naproxen as disclosed herein taken twice ibuprofenas disclosed herein taken twice daily. Alternatively, 45 daily. The woman's condition is monitored and after about 3 the woman is treated by oral administration of a pharmaceu days of treatment the woman indicates that there is a reduc tical composition comprising aspirin as disclosed herein tion in shoulder pain. At one and three month check-ups, the taken thrice daily. Alternatively, the woman is treated by oral woman indicates that she continues to have reduced shoulder administration of a pharmaceutical composition comprising pain. This reduction in referred pain symptoms indicates Suc naproxen as disclosed herein taken twice daily. The woman’s 50 cessful treatment with the pharmaceutical composition dis condition is monitored and after about 3 days of treatment the closed herein. A similar type of oral administration of a phar woman indicates that she no longer feels pain in her bladder. maceutical composition disclosed herein will be used to treat At one and three month check-ups, the woman indicates that a patient Suffering from severe pain associated with any other she still feels no pain. This reduction in autonomic neuropa referred pain, including, without limitation, an intervertebral thy symptoms indicates successful treatment with the phar 55 disc herniation. In a similar manner, any of the therapeutic maceutical composition disclosed herein. A similar type of compounds such as, e.g., a salicylate derivative NSAID, a oral administration of a pharmaceutical composition dis p-amino phenol derivative NSAID, a propionic acid deriva closed herein will be used to treat a patient suffering from tive NSAID, an acetic acid derivative NSAID, an enolic acid severe pain associated with any other autonomic neuropathy derivative NSAID, a fenamic acid derivative NSAID, a non affecting any other internal organ. In a similar manner, any of 60 selective cyclo-oxygenase (COX) inhibitor, a selective the therapeutic compounds such as, e.g., a salicylate deriva cyclooxygenase 1 (COX1) inhibitor, a selective cyclooxyge tive NSAID, a p-amino phenol derivative NSAID, a propionic nase 2 (COX2) inhibitor, or a fibrate, will be formulated into acid derivative NSAID, an acetic acid derivative NSAID, an a pharmaceutical composition and administered to the patient enolic acid derivative NSAID, a fenamic acid derivative as described above. NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a 65 A 26 year old male complains of severe pain in the location selective cyclooxygenase 1 (COX1) inhibitor, a selective where is amputated arm once was. A physician determines cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be that the pain is due to phantom pain. The man is treated by oral US 9,265,742 B2 89 90 administration a pharmaceutical composition comprising and after about 3 days of treatment the woman indicates there ibuprofenas disclosed herein taken twice daily. Alternatively, is no migraine pain reoccurrence. At one and three month the man is treated by oral administration a pharmaceutical check-ups, the woman indicates that she continues to have composition comprising aspirin as disclosed herein taken reduced frequency and intensity of migraine headache pain. thrice daily. Alternatively, the man is treated by oral admin This reduction in migraine symptoms indicates Successful istration a pharmaceutical composition comprising naproxen treatment with the pharmaceutical composition disclosed as disclosed herein taken twice daily. The man's condition is herein. A similar type of oral administration of a pharmaceu monitored and after about 3 days of treatment the man indi tical composition disclosed herein will be used to treat a cates that there is a reduction in pain. At one and three month patient Suffering from severe pain associated with any other check-ups, the man indicates that he continues to have 10 migraine headache pain, including, without limitation, a reduced pain. This reduction in phantom pain symptoms indi migraine without aura (common migraine), a migraine with cates Successful treatment with the pharmaceutical composi aura (classic migraine), a menstrual migraine, a migraine tion disclosed herein. A similar type of oral administration of equivalent (acephalic headache), a complicated migraine, an a pharmaceutical composition disclosed herein will be used abdominal migraine and a mixed tension migraine. In a simi to treat a patient Suffering from severe pain associated with 15 lar manner, any of the therapeutic compounds such as, e.g., a any other deafferentation pain syndrome, including, without salicylate derivative NSAID, a p-amino phenol derivative limitation, a braininjury, a spinal cord injury, a lumbarradicu NSAID, a propionic acid derivative NSAID, an acetic acid lopathy, a post-stroke pain, a paraplegia, avulsion of the bra derivative NSAID, an enolic acid derivative NSAID, a chial plexus or other types of lesions of peripheral nerves, a fenamic acid derivative NSAID, a non-selective cyclo-oxy pathology of the central nervous system. In a similar manner, genase (COX) inhibitor, a selective cyclooxygenase 1 (COX any of the therapeutic compounds such as, e.g., a salicylate 1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, derivative NSAID, a p-amino phenol derivative NSAID, a or a fibrate, will be formulated into a pharmaceutical compo propionic acid derivative NSAID, an acetic acid derivative sition and administered to the patient as described above. NSAID, an enolic acid derivative NSAID, a fenamic acid In closing, it is to be understood that although aspects of the derivative NSAID, a non-selective cyclo-oxygenase (COX) 25 present specification are highlighted by referring to specific inhibitor, a selective cyclooxygenase 1 (COX1) inhibitor, a embodiments, one skilled in the art will readily appreciate selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, that these disclosed embodiments are only illustrative of the will be formulated into a pharmaceutical composition and principles of the subject matter disclosed herein. Therefore, it administered to the patient as described above. should be understood that the disclosed subject matter is in no A 58 year old male complains of a headache. The man is 30 way limited to a particular methodology, protocol, and/or treated by oral administration of a pharmaceutical composi reagent, etc., described herein. As such, various modifications tion comprising ibuprofen as disclosed herein taken twice or changes to or alternative configurations of the disclosed daily. Alternatively, the man is treated by oral administration Subject matter can be made in accordance with the teachings of a pharmaceutical composition comprising aspirin as dis herein without departing from the spirit of the present speci closed herein taken thrice daily. Alternatively, the man is 35 fication. Lastly, the terminology used herein is for the purpose treated by oral administration of a pharmaceutical composi of describing particular embodiments only, and is not tion comprising naproxen as disclosed herein taken twice intended to limit the scope of the present invention, which is daily. The man’s condition is monitored and after about 3 defined solely by the claims. Accordingly, the present inven hours the headache pain is gone. This elimination in headache tion is not limited to that precisely as shown and described. pain indicates successful treatment with the pharmaceutical 40 Certain embodiments of the present invention are composition disclosed herein. A similar type of oral admin described herein, including the best mode knownto the inven istration of a pharmaceutical composition disclosed herein tors for carrying out the invention. Of course, variations on will be used to treat a patient suffering from severe pain these described embodiments will become apparent to those associated with any other headache pain, including, without ofordinary skill in the art upon reading the foregoing descrip limitation, a muscular/myogenic headache, a vascular head 45 tion. The inventor expects skilled artisans to employ Such ache, a traction headache, inflammatory headache, a chronic variations as appropriate, and the inventors intend for the sinusitis headache, a hormone headache, a rebound headache, present invention to be practiced otherwise than specifically an organic headache, and an ictal headache. In a similar described herein. Accordingly, this invention includes all manner, any of the therapeutic compounds such as, e.g., a modifications and equivalents of the Subject matter recited in salicylate derivative NSAID, a p-amino phenol derivative 50 the claims appended hereto as permitted by applicable law. NSAID, a propionic acid derivative NSAID, an acetic acid Moreover, any combination of the above-described embodi derivative NSAID, an enolic acid derivative NSAID, a ments in all possible variations thereof is encompassed by the fenamic acid derivative NSAID, a non-selective cyclo-oxy invention unless otherwise indicated herein or otherwise genase (COX) inhibitor, a selective cyclooxygenase 1 (COX clearly contradicted by context. 1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, 55 Groupings of alternative embodiments, elements, or steps or a fibrate, will be formulated into a pharmaceutical compo of the present invention are not to be construed as limitations. sition and administered to the patient as described above. Each group member may be referred to and claimed individu A 59 year old female complains of severe headache pain. A ally or in any combination with other group members dis physician determines that the pain is due to migraine. The closed herein. It is anticipated that one or more members of a woman is treated by oral administration of a pharmaceutical 60 group may be included in, or deleted from, a group for reasons composition comprising ibuprofen as disclosed herein taken of convenience and/or patentability. When any such inclusion twice daily. Alternatively, the woman is treated by topical or deletion occurs, the specification is deemed to contain the administration of a pharmaceutical composition comprising group as modified thus fulfilling the written description of all aspirin as disclosed herein taken thrice daily. Alternatively, Markush groups used in the appended claims. the woman is treated by topical administration of a pharma 65 Unless otherwise indicated, all numbers expressing a char ceutical composition comprising naproxen as disclosed acteristic, item, quantity, parameter, property, term, and so hereintaken twice daily. The woman's condition is monitored forth used in the present specification and claims are to be US 9,265,742 B2 91 92 understood as being modified in all instances by the term The invention claimed is: “about.” As used herein, the term “about” means that the 1. A method of treating an individual with an inflammatory characteristic, item, quantity, parameter, property, or term so pain, the method comprising the step of administering to the qualified encompasses a range of plus or minus ten percent individual in need thereof a pharmaceutical composition, above and below the value of the stated characteristic, item, wherein administration results in a reduction in a symptom quantity, parameter, property, or term. Accordingly, unless associated with the inflammatory pain, thereby treating the indicated to the contrary, the numerical parameters set forthin individual, and wherein the pharmaceutical composition the specification and attached claims are approximations that comprises: may vary. At the very least, and not as an attempt to limit the a) about 10% to about 30% by weight of a non-steroidal 10 anti-pain drug (NSAID): application of the doctrine of equivalents to the scope of the b) a pharmaceutically-acceptable polyethylene glycol claims, each numerical indication should at least be construed (PEG) polymer in an amountless than about 15% of the in light of the number of reported significant digits and by total weight of the composition; and applying ordinary rounding techniques. Notwithstanding that c) a pharmaceutically-acceptable lipid in an amount of at the numerical ranges and values setting forth the broad scope 15 least 50% of the total weight of the composition, the of the invention are approximations, the numerical ranges and pharmaceutically-acceptable lipid comprising a phar values set forth in the specific examples are reported as pre maceutically-acceptable fat in an amount of at least 30% cisely as possible. Any numerical range or value, however, of the total weight of the composition and a pharmaceu inherently contains certain errors necessarily resulting from tically-acceptable monoglyceride or an acetylated the standard deviation found in their respective testing mea monoglyceride in an amount of at least 20% of the total Surements. Recitation of numerical ranges of values herein is weight of the composition, merely intended to serve as a shorthand method of referring wherein the pharmaceutical composition is formulated to individually to each separate numerical value falling within be a solid at a temperature of about 15° C. or lower and the range. Unless otherwise indicated herein, each individual have a melting point temperature in the range of about value of a numerical range is incorporated into the present 25 25°C. or higher. specification as if it were individually recited herein. 2. The method according to claim 1, wherein the inflam The terms “a,” “an,” “the' and similar referents used in the matory pain is an acute pain, a Subacute pain, or a chronic context of describing the present invention (especially in the pain. context of the following claims) are to be construed to cover 3. The method according to claim 1, wherein the inflam 30 matory pain is a nociceptive pain. both the singular and the plural, unless otherwise indicated 4. The method according to claim 3, wherein the nocicep herein or clearly contradicted by context. All methods tive pain is a visceral pain, a deep somatic pain, a superficial described herein can be performed in any suitable order Somatic pain, or any combination thereof. unless otherwise indicated herein or otherwise clearly con 5. The method according to claim 1, wherein the inflam tradicted by context. The use of any and all examples, or 35 matory pain is a pathological pain. exemplary language (e.g., “such as') provided herein is 6. The method according to claim 5, wherein the patho intended merely to better illuminate the present invention and logical pain is a neuropathic pain, a dysfunctional pain, or any does not pose a limitation on the Scope of the invention combination thereof. otherwise claimed. No language in the present specification 7. The method according to claim 6, wherein the neuro should be construed as indicating any non-claimed element 40 pathic pain is a central neuropathic pain, a peripheral neuro essential to the practice of the invention. pathic pain, a deafferentation pain, or any combination Specific embodiments disclosed herein may be further lim thereof. ited in the claims using consisting of or consisting essentially 8. The method or use according to claim 7, wherein the of language. When used in the claims, whether as filed or peripheral neuropathic pain is a mononeuropathy, a monon added per amendment, the transition term "consisting of 45 europathic multiplex, a polyneuropathy, or an autonomic excludes any element, step, or ingredient not specified in the neuropathy. claims. The transition term “consisting essentially of limits 9. The method or use according to claim 8, wherein the the scope of a claim to the specified materials or steps and polyneuropathy is a distal axonopathy, a myelinopathy, or a those that do not materially affect the basic and novel char neuronopathy. acteristic(s). Embodiments of the present invention so 50 10. The method or use according to claim 7, wherein the claimed are inherently or expressly described and enabled peripheral neuropathic pain is a neuralgia or a complex herein. regional pain syndrome. All patents, patent publications, and other publications 11. The method according to claim 1, wherein the inflam referenced and identified in the present specification are indi matory pain is a referred pain. vidually and expressly incorporated herein by reference in 55 12. The method according to claim 1, wherein the inflam their entirety for the purpose of describing and disclosing, for matory pain is a headache. example, the compositions and methodologies described in 13. The method or use according to claim 12, wherein the Such publications that might be used in connection with the headache is a muscular/myogenic headache, a vascular head present invention. These publications are provided solely for ache, a traction headache, inflammatory headache, a chronic their disclosure prior to the filing date of the present applica 60 sinusitis headache, a hormone headache, a rebound headache, tion. Nothing in this regard should be construed as an admis an organic headache, or an ictal headache. sion that the inventors are not entitled to antedate such dis 14. The method according to claim 1, wherein the severe closure by virtue of prior invention or for any other reason. All pain condition is a migraine. statements as to the date or representation as to the contents of 15. The method according to claim 1, wherein upon admin these documents is based on the information available to the 65 istration to an individual, the pharmaceutical composition applicants and does not constitute any admission as to the comprising the therapeutic compound results in a bio-distri correctness of the dates or contents of these documents. bution of the therapeutic compound different than a bio US 9,265,742 B2 93 94 distribution of the therapeutic compound included in the 20. The method according to claim 1, wherein the pharma same pharmaceutical composition, except without the phar ceutically-acceptable monoglyceride is glyceryl monoli maceutically-acceptable adjuvant. noleate. 21. The method according to claim 1, wherein the pharma 16. The method according to claim 1, wherein upon admin ceutically-acceptable fat comprises a triglyceride, an acety istration to an individual, the amount of the therapeutic com lated triglyceride, a triester of glycerol or a fatty acid. pound of the pharmaceutical composition delivered to a mac 22. The method according to claim 21, wherein the trig rophage is at least 5% of the total amount of the therapeutic lyceride is a mixtures of saturated Co-Cs triglycerides hav compound contained in the administered pharmaceutical ing a melting point around 43°C. composition. 23. The method according to claim 1, wherein the pharma 17. The method according to claim 1, wherein upon admin 10 ceutically-acceptable lipid in an amount of at least 60% of the istration to an individual, the pharmaceutical composition total weight of the composition. reduces intestinal irritation by at least 5% when compared to 24. The method according to claim 23, wherein the phar the pharmaceutical composition, except without the pharma maceutically-acceptable fat is in an amount of at least 35% of ceutically-acceptable adjuvant. 15 the total weight of the composition. 18. The method according to claim 1, wherein upon admin 25. The method according to claim 1, wherein the NSAID istration to an individual, the pharmaceutical composition is a propionic acid derivative NSAID. reduces gastric irritation by at least 5% when compared to the 26. The method according to claim 25, wherein the propi pharmaceutical composition, except without the pharmaceu onic acid derivative NSAID is alminoprofen, benoxaprofen, tically-acceptable adjuvant. dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indopro 19. The method according to claim 1, wherein the pharma fen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranopro ceutically-acceptable PEG polymer is about 8% (v/v) to 15% fen, or Suprofen. of the total weight of the composition.