NZ613812B2 - Compositions and methods for treating chronic inflammation and inflammatory diseases - Google Patents

Abstract

Provided are pharmaceutical compositions comprising a therapeutic compound with anti-inflammatory activity, a pharmaceutically acceptable solvent and a pharmaceutically acceptable adjuvant. Exemplified therapeutic compounds include ibuprofen, gemfibrozil and naproxen. Further provided are methods of treating inflammatory diseases or conditions using the compositions. of treating inflammatory diseases or conditions using the compositions.

Description

Compositions and Methods for Treating Chronic mation and Inflammatory Diseases Inflammation involves the activation of the immune system in response to harmful stimuli, such as, e.g., a pathogen, infection, irritant, or damage to cells. As a stereotyped response, mation is a ism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen.

Inflammation can be classified as either acute or chronic. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is ed by mononuclear cells such as monocytes and lymphocytes.

Acute inflammation is an initial protective response of the body to remove an injurious stimulus by maintaining tissue integrity and contributing to tissue repair. It a part of the body’s natural defense system t injury and e, and in the absence of acute inflammation, wounds and infections would never heal and progressive ction of the tissue would compromise the survival of the organism.

The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, cytes, r cells, mastocytes, vascular endothelial cells, and vascular smooth muscle cells. At the onset of a harmful stimulus, these cells undergo activation and release inflammatory mediating and sensitizing molecules, such as, e.g., pro-inflammatory nes, pro- inflammatory prostaglandins, leukotrienes, histamine, serotonin, neutral proteases, inin and nitric oxide. These inflammatory molecules modulate a complex series of biological events ing cellular and acellular components of the local vascular system, the immune system, and the injured tissue site to propagate and mature the inflammatory response. These events are responsible for eliciting an acute inflammatory response, typically characterized by 1) vasodilatation which increases blood flow into the tissue thereby causing erythema (redness and warmth), which may extend beyond this site (the flare response); 2) blood vessel permeability which increases plasma leakage into the tissue thereby causing edema (swelling); 3) alter the excitability of certain sensory neurons causing hypersensitivity and pain; 4) ate the release of inflammation ng molecules such as, e.g., neuropeptides like nce P (SP) and calcitonin elated peptide (CGRP), prostaglandins, and amino acids like glutamate, from the peripheral nerve endings; and 5) increase migration of leukocytes, mainly granulocytes, from the blood vessels into the tissue. An acute inflammatory response requires constant ation to be sustained and must be actively terminated when no longer needed. Hence, acute inflammation ceases once the injurious stimulus has been removed.

However, severe or prolonged noxious stimulation results in a chronic inflammatory se that leads to a progressive shift in the type of cells present at the site of tissue injury. Chronic inflammation may be characterized as the simultaneous destruction and healing of tissue from the inflammatory process, with the net result of provoking injury rather than mediating repair. As such, c inflammation is a disease. As an inflammatory response can occur anywhere in the body, chronic inflammation has been implicated in the hysiology of a wide range of seemingly unrelated disorders which underlay a large and varied group of human diseases. For example, chronic inflammation is involved in diseases as diverse as cardiovascular diseases, cancers, allergies, obesity, diabetes, digestive system es, degenerative diseases, auto-immune disorders, and Alzheimer's ts to treat chronic inflammation have met with d success. This is due, in part, to the fact that the etiology of c inflammation is a complex response based in part on the various inflammation inducing molecules and the multitude of inflammation mediating and sensitizing molecules that appear to elicit inflammation via redundant mechanism. In addition, besides blocking pro- inflammatory molecules, many anti-inflammatory drugs, also inhibit regulatory loops that release endogenous anti-inflammatory molecules. For e, NSAle reduce mation by blocking the enzymatic activity of cyclooxygenase, a key enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and leukotrienes. Thus, NSAle reduce mation by preventing the synthesis of all prostaglandins. However, NSAle not only prevents the synthesis of proinflammatory prostaglandins, these compounds also prevent the synthesis of anti-inflammatory prostaglandins. Hence, NSAle have limited s as they block nous anti-inflammatory response, which in some instances may prolong chronic inflammation. Therefore, compounds, compositions, uses, and methods preferentially ting flammatory responses would be highly desirable for the treatment of chronic inflammation.

The present specification ses pharmaceutical compositions and methods for treating an individual suffering from a chronic mation. The pharmaceutical compositions disclosed herein are essentially a lipid delivery system that enables a therapeutic compound having anti-inflammatory activity to be delivered in a manner that more effectively inhibits a pro-inflammatory response. The end result is an ed treatment for chronic inflammation.

Aspects of the present specification disclose a pharmaceutical composition comprising a therapeutic compound and a pharmaceutically-acceptable adjuvant. A therapeutic compound may have an anti-inflammatory activity. Other aspects of the present ication disclose a pharmaceutical composition comprising a therapeutic nd disclosed , a pharmaceutically-acceptable solvent, and a pharmaceutically-acceptable adjuvant. In other aspects, the pharmaceutical compositions disclosed herein further comprise a pharmaceutically-acceptable stabilizing agent.

Other aspects of the present specification disclose a method of preparing a pharmaceutical composition, the method comprising the step of contacting a therapeutic compound with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition. Other s of the present specification se a method of preparing a pharmaceutical composition, the method comprising the steps: a) contacting a pharmaceutically-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the solution formed in step (a) with a pharmaceutically— acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition. In other aspects, the method of preparing disclosed herein further comprises c) ng the pharmaceuticaIIy-acceptable solvent from the pharmaceutical composition.

Other aspects of the present specification disclose a pharmaceutical ition, the pharmaceutical composition made according to a method comprising the step of contacting a therapeutic compound with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition. Other aspects of the present specification disclose a pharmaceutical composition, the pharmaceutical composition made according to a method comprising the steps: a) contacting a pharmaceutically-acceptable solvent with a therapeutic compound under conditions which allow the eutic compound to dissolve in the ceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic nd has anti-inflammatory activity, and b) contacting the on formed in step (a) with a ceuticalIy-acceptable adjuvant under conditions which allow the formation of the pharmaceutical ition. In other aspects, the method of making a pharmaceutical composition disclosed herein further comprises c) removing the pharmaceutically-acceptable solvent from the ceutical composition.

Other aspects of the present specification se a method of treating an individual with a chronic inflammation, the method comprising the step of administering to the individual in need thereof a pharmaceutical composition disclosed herein, wherein administration results in a reduction in a symptom associated with the chronic inflammation, y treating the individual.

Other aspects of the present specification disclose a use of a pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment of a chronic inflammation.

Other aspects of the present specification disclose a use of a pharmaceutical composition disclosed herein for the treatment of a chronic mation.

BREIF DESCRIPTION OF THE DRAWINGS shows the effects of a ceutical composition disclosed herein on survival against Influenza A/PR/8/34 lethal challenge. Ibuprofen 335 pg = Group A; Ctrol ORAL = Group B; and ibuprofen 335 pg o/e ORAL (BC1054) = Group C. shows the effects of a pharmaceutical composition disclosed herein on in vivo levels of Th2 cytokines in the lungs of surviving mice. shows a graph of the effects of a pharmaceutical ition sed herein on in vivo levels of IL-10, whereas shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of IL-4. BC1054 ORAL = Group A; Vehicle ORAL = Group B; and BC1054 Lipid ORAL = Group C. shows the effects of a pharmaceutical composition disclosed herein on in vivo levels of Th2 cytokines in the lungs of surviving mice. Figure 3A shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of lL-10; Figure 3B shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of TNF-or; and shows a graph of the effects of a ceutical composition sed herein on in vivo levels of lFN-y. BC1054 ORAL = Group A; Vehicle ORAL = Group B; and BC1054 Lipid ORAL = Group C. shows the effects of a pharmaceutical composition disclosed herein on arthritis using an or- collagen antibody induced arthritis (ACAIA) murine model. PBS = Group A; Enbrel = Group B; Vehicle methylcellulose = Group C; 40 mg/kg parent drug = Group D; BC1054 vehicle = Group E; BC1054 20 mg/kg = Group F; and BC1054 30 mg/kg = Group G.

DESCRIPTION Aspects of the present specification disclose, in part, a pharmaceutical composition. As used herein, the term "pharmaceutically acceptable" means any molecular entity or composition that does not produce an adverse, allergic or other rd or unwanted reaction when stered to an individual.

As used herein, the term aceutically acceptable composition” is synonymous with “pharmaceutical composition” and means a eutically effective concentration of an active ingredient, such as, e.g., any of the therapeutic compounds disclosed herein. A pharmaceutical composition disclosed herein is useful for l and veterinary applications. A pharmaceutical ition may be administered to an individual alone, or in combination with other supplementary active ingredients, agents, drugs or hormones.

A pharmaceutical composition disclosed herein may optionally include a ceutically- acceptable carrier that facilitates processing of an active ingredient into pharmaceutically-acceptable compositions. As used herein, the term “pharmacologically-acceptable carrier” is synonymous with “pharmacological carrier” and means any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle, stabilizer, diluent, additive, auxiliary or excipient.” Such a carrier generally is mixed with an active compound or permitted to dilute or e the active compound and can be a solid, olid, or liquid agent. It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired r or diluent. Any of a variety of pharmaceutically acceptable carriers can be used including, without limitation, aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like; solid carriers such as, e.g., mannitol, lactose, starch, magnesium te, sodium rin, talcum, cellulose, glucose, e, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption ng agents; or any other inactive ingredient. Selection of a pharmacologically able carrier can depend on the mode of administration. Except insofar as any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated. Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott ms & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & 's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw—Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). These protocols are routine procedures and any modifications are well within the scope of one skilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include, without limitation, other pharmaceutically able components (or pharmaceutical components), ing, without tion, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting , physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like. Various buffers and means for adjusting pH can be used to prepare a pharmaceutical composition disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such s include, without limitation, acetate buffers, citrate s, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate s. It is understood that acids or bases can be used to adjust the pH of a composition as needed. Pharmaceutically acceptable antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Useful vatives include, without limitation, benzalkonium chloride, butanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA—bisamide. ty adjustors useful in a pharmaceutical composition e, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other ceutically acceptable tonicity adjustor. The ceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, ic, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical ition.

In one embodiment, a pharmaceutical composition disclosed herein comprises a therapeutic compound having anti-inflammatory activity and a ceuticaIIy-acceptable adjuvant. In another embodiment, a pharmaceutical composition disclosed herein comprises a therapeutic nd having anti-inflammatory activity, a pharmaceutically-acceptable solvent, and a pharmaceuticalIy-acceptable adjuvant. In aspects of this embodiment, a pharmaceutical composition disclosed herein may further comprise a pharmaceutically-acceptable stabilizing agent. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may further comprise a pharmaceutically-acceptable carrier, a pharmaceuticalIy-acceptable component, or both ceuticalIy-acceptable carrier and ceuticaIIy-acceptable component.

Aspects of the present specification disclose, in part, a therapeutic compound. A therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals. A therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride. Additionally, therapeutic nd disclosed herein may be ed as racemates, or as individual enantiomers, including the R- or S-enantiomer. Thus, the therapeutic compound disclosed herein may comprise a R- enantiomer only, a S-enantiomer only, or a combination of both a R-enantiomer and a S-enantiomer of a therapeutic compound. A therapeutic compound disclosed herein may have nflammatory activity.

In an embodiment, a eutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of an inflammation inducing molecule. In an aspect of this embodiment, a therapeutic compound disclosed herein has an nflammatory activity capable of reducing the levels of substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof. In other aspects of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory ty capable of reducing the levels of SP, CGRP, glutamate, or a combination thereof released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory ty capable of reducing the levels of SP, CGRP, glutamate, or a combination thereof ed from a sensory neuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

Prostaglandins mediate a local matory response and are involved in all inflammatory functions through action on prostaglandin receptors and mediate inflammatory signaling including chemotaxis phages, neutrophils and eosinophils), vasodilation and algesia. However, the PG- mediated inflammatory response is self-limiting (resolving). The principle resolution factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxisome proliferator-activator receptor gamma y) signaling. PPARy signaling pathway 1) induces apoptosis of hage M1 cells, thereby reducing the levels of Th1 pro-inflammatory cytokines and 2) promotes differentiation of monocytes into hage M2 cells. Macrophage M2 cells produce and release Th2 anti-inflammatory nes.

In an embodiment, a therapeutic compound disclosed herein has an nflammatory activity capable of reducing the levels of an inflammation ng prostaglandin. In other aspects of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of a inflammation inducing prostaglandin released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of a inflammation inducing prostaglandin released from a sensory neuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity substantially similar to 15dPGJ2. ln aspects of this embodiment, a therapeutic compound disclosed herein an anti-inflammatory activity that is, e.g., at least 5%, at least 15%, at least 25%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the activity observed for 2. In other s of this embodiment, a therapeutic compound disclosed herein an anti-inflammatory activity that is in a range from, e.g., about % to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50% of the activity ed for 15dPGJ2.

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. All PPARs are known to heterodimerize with the id X receptor (RXR) and bind to specific regions on the DNA of target genes called peroxisome proliferator hormone response elements (PPREs). PPARs play essential roles in the regulation of cellular differentiation, development, and lism (carbohydrate, lipid, protein), and genesis of higher sms. The family comprises three members, PPAR-d, PPAR-y, and PPAR- 6 (also known as PPAR-B). PPAR-d is expressed in liver, kidney, heart, muscle, adipose tissue, as well as other tissues. PPAR-ES is expressed in many tissues but markedly in brain, e tissue, and skin.

PPAR-y comprises three alternatively-spliced forms, each with a different expression n. PPAR-y1 is expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and . PPAR-y2 is expressed mainly in adipose tissue. PPAR-y3 is expressed in hages, large intestine, and white adipose tissue. Endogenous ligands for the PPARs include free fatty acids and noids. PPAR-y is activated by PGJ2 (a prostaglandin), whereas PPAR-d is activated by leukotriene B4.

In an embodiment, a therapeutic compound sed herein has an anti-inflammatory ty capable of stimulating all PPAR signaling pathways. Such a therapeutic compound includes a PPAR pan-agonist. In other embodiments, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating one or two of the PPAR signaling pathways. Such a therapeutic compound includes a selective PPAR agonist.

In r embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating a PPAR-or signaling pathway. In aspects of this embodiment, a eutic compound sed herein ates a PPAR-or ing y by, e.g., at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of this embodiment, a therapeutic compound disclosed herein stimulates a PPAR-or signaling pathway in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50%.

In another embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of ating a PPAR-6 signaling pathway. In aspects of this embodiment, a therapeutic compound disclosed herein stimulates a PPAR-6 signaling pathway by, e.g., at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of this embodiment, a therapeutic compound sed herein stimulates a PPAR-6 signaling pathway in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50%.

In another ment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating a PPARy signaling pathway. A therapeutic compounds disclosed herein may be capable of binding to all isoforms of PPAR-y, or may be capable of selectively binding to either PPAR-y1, PPAR-y2, PPAR-y3, or any combination of two thereof. In s of this embodiment, a therapeutic compound disclosed herein stimulates a PPARy signaling pathway by, e.g., at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of this embodiment, a therapeutic compound disclosed herein stimulates a PPARy signaling pathway in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50%. hages are activated and polarized into distinct ypes expressing unique cell surface molecules and secreting discrete sets of cytokines and chemokines. The cal M1 phenotype supports pro-inflammatory Th1 responses driven by cytokines such as, e.g., Interleukin-6 (IL-6), lL-12 and lL-23, while the alternate M2 phenotype is generally supportive of anti-inflammatory processes driven by lL-10. M2 cells can be further classified into subsets, M2a, M2b, and M2c, based on the type of stimulation and the subsequent expression of surface molecules and nes.

In yet another embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of promoting the resolving phenotypic change of M1 to M2. In an aspect of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of inducing apoptosis of Macrophage M1 cells. In another aspect of this embodiment, a eutic compound disclosed herein has an anti-inflammatory activity capable of promoting differentiation of Macrophage M2 cells. In yet another aspect of this embodiment, a therapeutic nd sed herein has an anti-inflammatory activity capable of inducing apoptosis of Macrophage M1 cells and promoting differentiation of Macrophage M2 cells.

In still another embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of modulating Th1 and Th2 cytokines. In an aspect of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity e of reducing the levels of Interferon- gamma (lFNy), Tumor necrosis factor-alpha (TNF-d), Interleukin-12 (IL-12), or a combination thereof released from a Th1 cell. In other aspects of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory ty capable of reducing the levels of lFNy, TNF-or, lL-12, or a combination f released from a Th1 cell by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In yet other aspects of this ment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of lFNy, TNF-or, lL-12, or a combination thereof released from a Th1 cell in a range from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another aspect of this embodiment, a therapeutic compound disclosed herein has an anti- matory activity capable of increasing the levels of lL-10 released from a Th2 cell. In other aspects of this embodiment, a eutic compound disclosed herein has an anti-inflammatory activity capable of sing the levels of lL-10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.

W0 2012/104655 10 In yet other aspects of this ment, a therapeutic compound disclosed herein has an anti- inflammatory activity capable of increasing the levels of lL-10 released from a Th2 cell in a range from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about % to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another aspect of this embodiment, a eutic compound disclosed herein has an anti- inflammatory activity capable of reducing the levels of lFNy, TNF-or, lL-12, or a combination thereof released from a Th1 cell and increasing the levels of lL-10 released from a Th2 cell. In other aspects of this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of lFNy, TNF-or, lL-12, or a combination thereof released from a Th1 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%, and capable of increasing the levels of lL-10 ed from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, a therapeutic compound disclosed herein has an nflammatory activity capable of reducing the levels of lFNy, TNF-or, lL-12, or a combination thereof ed from a Th1 cell in a range from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%, and capable of increasing the levels of lL-10 released from a Th2 cell in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

A therapeutic compound disclosed herein may have a log P value indicating that the compound is soluble in an organic t. As used herein, the term “log P value” refers to the logarithm (base 10) of W0 2012/104655 11 the partition coefficient (P) for a compound and is a measure of lipophilicity. Typically, P is defined as the ratio of concentrations of a unionized compound in the two phases of a e of two immiscible solvents at equilibrium. Thus, log P = Log 10 (P), where P = [solute in immiscible t 1] / [solute in immiscible solvent 2]. With regard to organic and s phases, the log P value of a compound is constant for any given pair of aqueous and organic solvents, and its value can be determined empirically by one of several phase-partitioning methods known to one skilled in the art including, e.g., a shake flask assay, a HPLC assay, and an interface between two ible electrolyte solutions ) assay.

In aspects of this embodiment, a therapeutic compound disclosed herein may have a log P value indicating that the compound is substantially soluble in an organic t. ln aspects of this embodiment, a therapeutic compound sed herein may have a log P value indicating that the compound is, e.g., at least 50% soluble in an organic t, at least 60% soluble in an organic solvent, at least 70% soluble in an organic solvent, at least 80% soluble in an organic solvent, or at least 90% soluble in an organic solvent. ln aspects of this embodiment, a eutic compound disclosed herein may have a log P value indicating that the compound is between, e.g., about 50% to about 100% soluble in an organic solvent, about 60% to about 100% soluble in an organic solvent, about 70% to about 100% soluble in an organic solvent, about 80% to about 100% e in an c solvent, or about 90% to about 100% soluble in an organic solvent.

In aspects of this embodiment, a therapeutic compound disclosed herein may have a log P value of, e.g., more than 1.1, more than 1.2, more than 1.4, more than 1.6, more than 1.8, more than 2.0, more than 2.2, more than 2.4, more than 2.6, more than 2.8, more than 3.0, more than 3.2, more than 3.4, or more than 3.6. In other aspects of this embodiment, a eutic compound disclosed herein may have a log P value in the range of, e.g., n 1.8 and 4.0, between 2.0 and 4.0, between 2.1 and 4.0, between 2.2 and 4.0, or n 2.3 and 4.0, between 2.4 and 4.0, n 2.5 and 4.0, between 2.6 and 4.0, or between 2.8 and 4.0. In other aspects of this embodiment, a therapeutic compound disclosed herein may have a log P value in the range of, e.g., between 3.0 and 4.0, or between 3.1 and 4.0, between 3.2 and 4.0, n 3.3 and 4.0, between 3.4 and 4.0, between 3.5 and 4.0, or between 3.6 and 4.0. In still other aspects of this embodiment, a therapeutic compound disclosed herein may have a log P value in the range of, e.g., between 2.0 and 2.5, between 2.0 and 2.7, between 2.0 and 3.0, or between 2.2 and 2.5.

A therapeutic compound disclosed herein may have a polar e area that is hydrophobic. As used herein, the term “polar surface area” refers to the surface sum over all of the polar atoms in the structure of a compound and is a measure of hydrophobicity. Typically, these polar atoms include, e.g., oxygen, nitrogen, and their attached hydrogens. ln aspects of this embodiment, a therapeutic compound disclosed herein may have a polar surface area of, e.g., less than 8.0 nm2, less than 7.0 nm2, less than 6.0 nm2, less than 5.0 nm2, less than 4.0 nm2, or less than 3.0 nm2. In other aspects of this embodiment, a therapeutic compound disclosed herein may have a polar surface area in the range of, e.g., between 3.0 nm2 and 6.5 nm2, between 3.0 nm2 and 6.0 nm2, between 3.0 nm2 and 5.5 nm2, between 3.0 nm2 and .0 nm2, between 3.0 nm2 and 4.5 nm2, between 3.5 nm2 and 6.5 nm2, between 3.5 nm2 and 6.0 nm2, W0 2012/104655 12 between 3.5 nm2 and 5.5 nm2, between 3.5 nm2 and 5.0 nm2, between 3.5 nm2 and 4.5 nm2, between 4.0 nm2 and 6.5 nm2, between 4.0 nm2 and 6.0 nm2, between 4.0 nm2 and 5.5 nm2, or between 4.0 nm2 and .0 nm2, n 4.0 nm2 and 4.5 nm2, or between 4.5 nm2 and 5.5 nm2. In yet other aspects of this embodiment, a eutic compound sed herein may have a polar surface area in the range of, e.g., between 2.0 nm2 and 6.5 nm2, between 2.0 nm2 and 6.0 nm2, between 2.0 nm2 and 5.5 nm2, between 2.0 nm2 and 5.0 nm2, between 2.0 nm2 and 4.5 nm2, between 2.5 nm2 and 6.5 nm2, between 2.5 nm2 and 6.0 nm2, between 2.5 nm2 and 5.5 nm2, between 2.5 nm2 and 5.0 nm2, or n 2.5 nm2 and 4.5 nm2.

A therapeutic compound disclosed herein may be a non-steroidal anti-inflammatory drug (NSAID). NSAle are a large group of therapeutic compounds with analgesic, anti-inflammatory, and anti-pyretic properties. NSAle reduce inflammation by blocking cyclooxygenase. NSAle include, without limitation, Aceclofenac, Acemetacin, Actarit, Alcofenac, Alminoprofen, Amfenac, Aloxipirin, Aminophenazone, Antraphenine, Aspirin, Azapropazone, Benorilate, profen, Benzydamine, Butibufen, Celecoxib, Chlorthenoxacin, Choline late, Clometacin, Dexketoprofen, Diclofenac, Diflunisal, Emorfazone, Epirizole; Etodolac, Etoricoxib, uzone, Felbinac, Fenbufen, Fenclofenac, Flurbiprofen, Glafenine, Hydroxylethyl salicylate, Ibuprofen, lndometacin, lndoprofen, ofen, lac, Lactyl phenetidin, Loxoprofen, Lumiracoxib, Mefenamic acid, Meloxicam, Metamizole, Metiazinic acid, Mofebutazone, lac, Nabumetone, Naproxen, Nifenazone, Niflumic acid, Oxametacin, Phenacetin, Pipebuzone, Pranoprofen, Propyphenazone, Proquazone, Protizinic acid, Rofecoxib, Salicylamide, Salsalate, Sulindac, Suprofen, Tiaramide, Tinoridine, amic acid, Valdecoxib, and Zomepirac.

NSAle may be classified based on their chemical structure or mechanism of action. Non- limiting examples of NSAIDs include a salicylate derivative NSAID, a p-amino phenol tive NSAID, a nic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) tor, and a selective cyclooxygenase 2 (COX 2) inhibitor. A NSAID may be a profen. Examples of a suitable salicylate derivative NSAID include, without tion, Acetylsalicylic acid (asprin), Diflunisal, and Salsalate. Examples of a suitable p-amino phenol derivative NSAID include, without limitation, Paracetamol and Phenacetin. Examples of a suitable propionic acid derivative NSAID e, without tion, profen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, lndoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen, and Suprofen. es of a suitable acetic acid derivative NSAID include, without limitation, fenac, Acemetacin, Actarit, Alcofenac, Amfenac, Clometacin, Diclofenac, Etodolac, Felbinac, Fenclofenac, lndometacin, Ketorolac, Metiazinic acid, Mofezolac, Nabumetone, Naproxen, acin, Sulindac, and Zomepirac.

Examples of a suitable enolic acid (Oxicam) derivative NSAID include, without limitation, Droxicam, lsoxicam, Lornoxicam, Meloxicam, cam, and Tenoxicam. Examples of a suitable fenamic acid derivative NSAID include, without limitation, Flufenamic acid, Mefenamic acid, Meclofenamic acid, and Tolfenamic acid. Examples of a suitable selective COX-2 inhibitors include, without limitation, Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, cam, Parecoxib, Rofecoxib, and Valdecoxib.

W0 2012/104655 13 A therapeutic compound disclosed herein may be a PPARy agonist. Examples of a suitable PPARy agonist include, without limitation, Benzbromarone, a cannabidiol, azol, in, Delta(9)— ydrocannabinol, glycyrrhetinic acid, lndomethacin, lrbesartan, Monascin, mycophenolic acid, Resveratrol, 6-shogaol, Telmisartan, a lidinedione like Rosiglitazone, Pioglitazone, and Troglitazone, a NSAID, and a fibrate. Other suitable PPARy agonists are described in Masson and t-Bertrand, PPAR Agonist Compounds, Preparation and Uses, US 2011/0195993, which is hereby incorporated by reference in its entirety.

A therapeutic compound disclosed herein may be a nuclear receptor binding agent. Examples of a le nuclear or g agent include, without limitation, a Retinoic Acid Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor (LXR) binding agent and a Vitamin D binding agent.

A therapeutic compound disclosed herein may be an anti-hyperlipidemic agent. There are several classes of anti-hyperlipidemic agents (also known as hypolipidemic agents). They may differ in both their impact on the terol profile and adverse effects. For example, some may lower low density otein (LDL), while others may entially increase high density lipoprotein (HDL). Clinically, the choice of an agent will depend on the cholesterol profile of an individual, cardiovascular risk of an individual, and/or the liver and kidney functions of an dual. Examples of a suitable anti- hyperlipidemic agent include, without limitation, a fibrate, a , a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, and a sympathomimetic amine.

A therapeutic compound disclosed herein may be a fibrate. Fibrates are a class of amphipathic carboxylic acids with lipid level modifying properties. These therapeutic compounds are used for a range of metabolic disorders. One non-limiting use is as an anti-hyperlipidemic agent where it may lower levels of, e.g., triglycerides and LDL as well as increase levels of HDL. Examples of a suitable fibrate include, without limitation, Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, and Fenofibrate.

A therapeutic compound disclosed herein may be a statin. Statins (or HMG-CoA reductase inhibitors) are a class of therapeutic compounds used to lower LDL and/or cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver.

To sate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased, resulting in an increased nce of LDL particles from the blood. Examples of a suitable statin include, t limitation, Atorvastatin, Fluvastatin, Lovastatin, statin, Pravastatin, Rosuvastatin, and Simvastatin.

A therapeutic compound disclosed herein may be a tocotrienol. Tocotrienols are anotehr class of HMG-CoA reductase inhibitors and may be used to lower LDL and/or cholesterol levels by inducing W0 2012/104655 14 c LDL receptor up-regulation and/or decreasing plasma LDL levels. Examples of a suitable tocotrienol include, without limitation, a y-tocotrienol and a 6- tocotrienol.

A therapeutic compound disclosed herein may be a niacin. Niacins are a class of therapeutic compounds with lipid level ing properties. For example, a niacin may lower LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reduce triglyceride synthesis, and VLDL secretion through a receptor HM74 and HM74A or GPR109A. These therapeutic compounds are used for a range of metabolic disorders. One non-limiting use is as an anti-hyperlipidemic agent where it may inhibit the breakdown of fats in adipose tissue. Because a niacin blocks the breakdown of fats, it causes a decrease in free fatty acids in the blood and, as a consequence, decreases the secretion of very-low-density lipoproteins (VLDL) and cholesterol by the liver. By lowering VLDL levels, a niacin may also increase the level of HDL in blood. Examples of a suitable niacin e, without limitation, ox, niacin, nicotinamide, and vitamin B3.

A therapeutic compound disclosed herein may be a bile acid sequestrant. Bile acid sequestrants (also known as resins) are a class of therapeutic compounds used to bind certain components of bile in the gastrointestinal tract. They disrupt the hepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. Bile acid sequestrants are particularly effective for lowering LDL and cholesterol by sequestering the cholesterol-containing bile acids released into the intestine and preventing their reabsorption from the intestine. In addition, a bile acid sequestrant may also raise HDL levels. Examples of a suitable bile acid sequestrant include, t limitation, Cholestyramine, velam, and ipol.

A therapeutic compound disclosed herein may be a cholesterol absorption inhibitor. Cholesterol absorption inhibitors are a class of therapeutic compounds that inhibits the absorption of cholesterol from the intestine. Decreased cholesterol absorption leads to an upregulation of ceptors on the surface of cells and an increased LDL-cholesterol uptake into these cells, thus decreasing levels of LDL in the blood . Examples of a suitable cholesterol absorption inhibitor include, without tion, Ezetimibe, a phytosterol, a sterol and a .

A therapeutic compound sed herein may be a fat absorption inhibitor. Fat absorption inhibitors are a class of therapeutic compounds that inhibits the absorption of fat from the intestine.

Decreased fat absorption reduces caloric intake. In one aspect, a fat absorption inhibitor inhibits pancreatic lipase, an enzyme that breaks down cerides in the intestine. Examples of a suitable fat absorption inhibitor include, t limitation, Orlistat.

A therapeutic compound disclosed herein may be a homimetic amine. homimetic amines are a class of therapeutic compounds that mimic the effects of transmitter substances of the sympathetic nervous system such as catecholamines, hrine (adrenaline), norepinephrine (noradrenaline), and/or dopamine. A sympathomimetic amine may act as an q-adrenergic agonist, a [3- adrenergic agonist, a dopaminergic agonist, a monoamine oxidase (MAO) inhibitor, and a COMT W0 2012/104655 15 inhibitor. Such therapeutic compounds, among other things, are used to treat cardiac arrest, low blood pressure, or even delay premature labor. Examples of a suitable sympathomimetic amine include, without limitation, Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamfetamine, cathine, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), enedioxypyrovalerone (MDPV), 4- methylaminorex, pemoline, phenmetrazine, and propylhexedrine.

A therapeutic compound disclosed herein may be an ester of a therapeutic compound. An ester of a therapeutic compound increases the logP value relative to the same therapeutic compound, but t the ester modification. An ester group may be attached to a therapeutic compound by, e.g., a carboxylic acid or hydroxyl functional group present of the therapeutic compound. An ester of a eutic compound may have an increased hobicity, and as such, may be dissolved in a reduced volume of solvent disclosed herein. In some instances, an ester of a therapeutic compound may be combined ly with an adjuvant disclosed herein, y eliminating the need of a solvent. An ester of a therapeutic compound may enable the making of a pharmaceutical composition disclosed herein, in situations where a non-esterified form of the same eutic compound is othenNise immiscible in a solvent sed herein. An ester of a therapeutic compound may still be delivered in a manner that more effectively inhibits a pro-inflammatory response as long as the compound is combined with an adjuvant disclosed herein. In one ment, a therapeutic compound may be reacted with ethyl ester in order to form an ethyl ester of the eutic compound.

In another embodiment, a pharmaceutical composition disclosed herein does not comprise a pharmaceutically-acceptable solvent disclosed . In an aspect of this embodiment, a pharmaceutical ition comprises a therapeutic compound and a pharmaceutically-acceptable adjuvant, but does not se a pharmaceutically-acceptable solvent sed herein.

A pharmaceutical composition disclosed herein may comprise a therapeutic compound in an amount sufficient to allow customary administration to an individual. In aspects of this ment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound. In other aspects of this ment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a therapeutic compound. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or W0 2012/104655 16 about 1,000 mg to about 1,500 mg. In still other s of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

Aspects of the present specification disclose, in part, a pharmaceutically-acceptable solvent. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous (the solute), resulting in a solution. Solvents useful in the pharmaceutical compositions disclosed herein include, without limitation, a pharmaceutically-acceptable polar aprotic solvent, a pharmaceutically-acceptable polar protic solvent and a pharmaceutically-acceptable non-polar solvent. A pharmaceutically-acceptable polar c solvent includes, t tion, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO). A pharmaceutically-acceptable polar protic solvent includes, without limitation, acetic acid, formic acid, ethanol, n-butanol, 1-butanol, nol, anol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water. A pharmaceutically-acceptable non-polar solvent includes, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-Dioxane, chloroform, n-methyl-pyrrilidone (NMP), and diethyl ether.

A pharmaceutical composition disclosed herein may comprise a solvent in an amount sufficient to ve a therapeutic compound disclosed . In other aspects of this embodiment, a pharmaceutical composition disclosed herein may se a solvent in an amount of, e.g., less than about 90% (v/v), less than about 80% (v/v), less than about 70% (v/v), less than about 65% (v/v), less than about 60% (v/v), less than about 55% (v/v), less than about 50% (v/v), less than about 45% (v/v), less than about 40% (v/v), less than about 35% (v/v), less than about 30% (v/v), less than about 25% (v/v), less than about 20% (v/v), less than about 15% (v/v), less than about 10% (v/v), less than about 5% (v/v), or less than about 1% (v/v). In other aspects of this embodiment, a pharmaceutical ition disclosed herein may comprise a solvent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v), about 1% (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about 1% (v/v) to 50% (v/v), about 1% (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v), about 1% (v/v) to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v) to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v), about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v) to 50% (v/v), about 4% (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v), about 4% (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v) to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v), about 6% (v/v) to 20% (v/v), about 6% (v/v) to % (v/v), about 8% (v/v) to 50% (v/v), about 8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v), about 8% (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8% (v/v) to 12% (v/v).

In one embodiment, a t may comprise a pharmaceutically-acceptable alcohol. As used herein, the term “alcohol” refers to an organic molecule comprising a hydroxyl functional group (—OH) bond to a carbon atom, where the carbon atom is saturated. ln aspects of this ment, the alcohol may be, e.g., a C24 alcohol, a C1_4 alcohol, a C15 alcohol, a C14 alcohol, a C140 alcohol, a C145 l, or a C140 alcohol. In other aspects of this embodiment, an alcohol may be, e.g., a primary alcohol, a secondary alcohol, or a tertiary alcohol. In other aspects of this embodiment, an alcohol may be, e.g., an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol (also known as a polyol or sugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol, or a ation thereof. Examples of a monohydric l include, without limitation, methanol, ethanol, propanol, butanol, pentanol, and 1-hexadecanol. es of a polyhydric alcohol include, without limitation, glycol, glycerol, arabitol, erythritol, xylitol, maltitol, sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol), and isomalt. es of an unsaturated aliphatic alcohol include, without limitation, -eneol, 3,7-dimethylocta-2,6-dieno|, and propinol. Examples of an alicyclic alcohol include, without tion, cyclohexane-1,2,3,4,5,6- hexol and 2 - (2-propyl)methyl-cyclohexaneo|.

In another embodiment, a solvent may comprise an ester of ceutically-acceptable l and an acid. Suitable pharmaceutically-acceptable alcohols include the ones disclosed herein. Suitable acids include, without limitation, acetic acid, butaric acid, and formic acid. An ester of an alcohol and an acid include, without limitation, methyl acetate, methyl buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate, and 1-hexadecyl formate.

In another ment, a solvent may se a pharmaceutically-acceptable polyethylene glycol (PEG) polymer. PEG polymers, also known as polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers, are ed by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 100 g/mol to 10,000,000 g/mol. PEG polymers with a low molecular mass are s or low-melting solids, whereas PEG polymers of a higher molecular mass are solids. A PEG polymer include, without limitation, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG 13,000, PEG , PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, PEG 19,000, or PEG 20,000.

In another embodiment, a solvent may comprise a pharmaceutically-acceptable glyceride.

Glycerides comprise a tuted ol, where one, two, or all three hydroxyl groups of the glycerol are each esterified using a fatty acid to produce monoglycerides, diglycerides, and triglycerides, respectively. In these compounds, each hydroxyl groups of glycerol may be fied by different fatty W0 2012/104655 18 acids. Additionally, glycerides may be acetylated to produce acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides.

In one embodiment, a t may comprise a ceutically-acceptable solid solvent. Solid solvents may be useful in the manufacture of a solid dose formulation of a pharmaceutical composition disclosed herein. Typically, a solid solvent is melted in order to dissolve a therapeutic compound. A pharmaceutically-acceptable solid solvent includes, without limitation, Menthol and PEG polymers above about 20,000 g/mol.

Aspects of the present specification disclose, in part, a pharmaceutically-acceptable adjuvant. An adjuvant is a pharmacological agent that modifies the effect of other agents, such as, e.g., a therapeutic compound sed herein. In addition, an adjuvant disclosed herein may be used as a solvent that dissolves a therapeutic compound disclosed herein, forming a adjuvant solution. An adjuvant sed herein facilitates delivery of a therapeutic compound in a manner that more effectively inhibits a pro- inflammatory response. In one embodiment, an adjuvant disclosed herein tates the delivery of a therapeutic compound sed herein into macrophages.

A pharmaceutical composition disclosed herein may se a ceutically-acceptable adjuvant in an amount sufficient to mix with a solution disclosed herein or an emulsion disclosed herein.

In other aspects of this ment, a pharmaceutical composition disclosed herein may comprise an nt in an amount of, e.g., at least 10% (v/v), at least 20% (v/v), at least 30% (v/v), at least 35% (v/v), at least 40% (v/v), at least 45% (v/v), at least 50% (v/v), at least 55% (v/v), at least 60% (v/v), at least 65% (v/v), at least 70% (v/v), at least 75% (v/v), at least 80% (v/v), at least 85% (v/v), at least 90% (v/v), at least 95% (v/v), or at least 99% (v/v). In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise an adjuvant in an amount in a range of, e.g., about 30% (v/v) to about 99% (v/v), about 35% (v/v) to about 99% (v/v), about 40% (v/v) to about 99% (v/v), about 45% (v/v) to about 99% (v/v), about 50% (v/v) to about 99% (v/v), about 30% (v/v) to about 98% (v/v), about % (v/v) to about 98% (v/v), about 40% (v/v) to about 98% (v/v), about 45% (v/v) to about 98% (v/v), about 50% (v/v) to about 98% (v/v), about 30% (v/v) to about 95% (v/v), about 35% (v/v) to about 95% (v/v), about 40% (v/v) to about 95% (v/v), about 45% (v/v) to about 95% (v/v), or about 50% (v/v) to about 95% (v/v). In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise an adjuvant in an amount in a range of, e.g., about 70% (v/v) to about 97% (v/v), about 75% (v/v) to about 97% (v/v), about 80% (v/v) to about 97% (v/v), about 85% (v/v) to about 97% (v/v), about 88% (v/v) to about 97% (v/v), about 89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97% (v/v), about 75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96% (v/v), about 85% (v/v) to about 96% (v/v), about 88% (v/v) to about 96% (v/v), about 89% (v/v) to about 96% (v/v), about 90% (v/v) to about 96% (v/v), about 75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93% (v/v), about 85% (v/v) to about 93% (v/v), about 88% (v/v) to about 93% (v/v), about 89% (v/v) to about 93% (v/v), or about 90% (v/v) to about 93% (v/v).

W0 2012/104655 19 In one embodiment, an adjuvant may be a pharmaceutically-acceptable lipid. A lipid may be broadly defined as a hydrophobic or amphiphilic small molecule. The amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous nment.

Non-limiting examples, of lipids include fatty acids, glycerolipids (like monoglycerides, diglycerides, and triglycerides), olipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides. A pharmaceutical composition disclosed herein may comprise a lipid such as, e.g. an oil, an oil-based liquid, a fat, a fatty acid, a wax, a fatty acid ester, a fatty acid salt, a fatty alcohol, a glyceride (mono-, di- or tri-glyceride), a phospholipids, a glycol ester, a sucrose ester, a glycerol oleate derivative, a medium chain triglyceride, or a mixture thereof.

A lipid useful in the pharmaceutical compositions disclosed herein may be a ceutically- able fatty acid. A fatty acid comprises a ylic acid with a long unbranched hydrocarbon chain which may be either saturated or unsaturated. Thus arrangement confers a fatty acid with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water. Most naturally occurring fatty acids have a hydrocarbon chain of an even number of carbon atoms, typically between 4 and 24 carbons, and may be ed to functional groups containing oxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fatty acids may have a hydrocarbon chain of any number of carbon atoms from between 3 and 40 carbons. Where a double bond exists, there is the possibility of either a cis or a trans geometric isomerism, which significantly affects the molecule's molecular uration. Cis-double bonds cause the fatty acid chain to bend, an effect that is more pronounced the more double bonds there are in a chain.

Most naturally occurring fatty acids are of the cis configuration, gh the trans form does exist in some natural and partially hydrogenated fats and oils. Examples of fatty acids e, without limitation, Capryllic acid (8:0), pelargonic acid (9:0), Capric acid , lic acid (11:0), Lauric acid (12:0), Tridecylic acid (13:0), Myristic acid (14:0), Myristoleic acid (14:1), Pentadecyclic acid (15:0), ic acid (16:0), Palmitoleic acid (16:1), Sapienic acid (16:1), Margaric acid (17:0), Stearic acid (18:0), Oleic acid (18:1), Elaidic acid (18:1), Vaccenic acid (18:1), Linoleic acid (18:2), aidic acid (18:2), d-Linolenic acid (18:3), y-Linolenic acid (18:3), Stearidonic acid (18:4), cylic acid (19:0), Arachidic acid , Eicosenoic acid (20:1), Dihomo-y-linolenic acid (20:3), Mead acid (20:3), Arachidonic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosylic acid , Behenic acid (22:0), Erucic acid (22:1), Docosahexaenoic acid (22:6), Tricosylic acid , Lignoceric acid (24:0), Nervonic acid (24:1), Pentacosylic acid (25:0), Cerotic acid (26:0), Heptacosylic acid (27:0), Montanic acid (28:0), Nonacosylic acid (29:0), Melissic acid (30:0), Henatriacontylic acid (31:0), Lacceroic acid (32:0), Psyllic acid , Geddic acid (34:0), Ceroplastic acid (35:0), and Hexatriacontylic acid (36:0).

In an embodiment, an adjuvant may be a ceutically-acceptable saturated or unsaturated fatty acid. In aspects of this ment, a saturated or unsaturated fatty acid comprises, e.g., at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24, at least 26, at least 28, or at least 30 carbon atoms, In other aspects of this embodiment, a saturated or unsaturated fatty acid comprises, e.g., between 4 and 24 carbon atoms, n 6 and 24 carbon atoms, between 8 and 24 carbon atoms, between 10 and 24 carbon atoms, between 12 and 24 carbon atoms, between 14 and 24 carbon atoms, or between 16 and 24 carbon atoms, between 4 and 22 carbon atoms, between 6 W0 2012/104655 20 and 22 carbon atoms, between 8 and 22 carbon atoms, n 10 and 22 carbon atoms, between 12 and 22 carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22 carbon atoms, between 4 and 20 carbon atoms, between 6 and 20 carbon atoms, between 8 and 20 carbon atoms, n 10 and carbon atoms, between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, or between 16 and 20 carbon atoms. lf unsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more double bonds.

In aspects of this embodiment, a pharmaceutically-acceptable saturated or unsaturated fatty acid is liquid at room temperature. The melting point of a fatty acid is largely determined by the degree of saturation/unsaturation of the hydrocarbon chain. In s of this embodiment, a saturated or rated fatty acid has a melting point temperature of, e.g., 20°C or below, 15°C or below, 10°C or below, 5°C or below, 0°C or below, -5°C or below, -10°C or below, -15°C or below, or -20°C or below. In other aspects of this embodiment, a saturated or unsaturated fatty acid has a melting point ature in the range of, e.g., about -20°C to about 20°C, about -20°C to about 18°C, about -20°C to about 16°C, about -20°C to about 12°C, about -20°C to about 8°C, about -20°C to about 4°C, about -20°C to about 0°C, about -15°C to about 20°C, about -15°C to about 18°C, about -15°C to about 16°C, about -15°C to about 12°C, about -15°C to about 8°C, about -15°C to about 4°C, about -15°C to about 0°C.

In another embodiment, an adjuvant may comprise one kind of pharmaceutically-acceptable fatty acid. In aspects of this embodiment, an adjuvant may comprise only palmitic acid, only stearic acid, only oleic acid, only linoleic acid, or only linolenic acid.

In another ment, an adjuvant may comprise a ity of different pharmaceutically- acceptable fatty acids. In aspects of this embodiment, an nt may comprise, e.g., two or more different fatty acids, three or more different fatty acids, four or more different fatty acids, five or more different fatty acids, or six or more different fatty acids.

In other aspects of this embodiment, an adjuvant may se two or more different pharmaceutically-acceptable fatty acids including at least palmitic acid, stearic acid, oleic acid, linoleic acid and/or linolenic acid, and any combination thereof. In other aspects of this embodiment, an adjuvant may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/or linoleic acid of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, or at least 20:1. In yet other aspects of this ment, an adjuvant may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/or linoleic acid in a range of, e.g., about 1:1 to about 20:1, about 2:1 to about 15:1, about 4:1 to about 12:1, or about 6:1 to about 10:1.

In other aspects of this embodiment, an adjuvant may comprise four or more different pharmaceutically-acceptable fatty acids including at least palmitic acid, c acid, oleic acid, linoleic acid and/or linolenic acid, and any combination thereof. In other aspects of this embodiment, an adjuvant may comprise a ratio of palmitic acid;stearic acid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, W0 04655 21 8:8:1:1, 7:7:1:1, 6:6:1:1, 5:5:1:1, 4:4:1:1, 3:3:1:1, 2:2:1:1, or 1:1:1:1. In other aspects of this embodiment, an adjuvant may comprise a ratio of palmitic acid;stearic acid:linolenic acid:linoleic acid in a range of, e.g., about 10:10:1:1 to about 6:6:1:1, about 8:8:1:1 to about 1, or about 5:5:1:1 to about 1:1:1:1.

A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable omega fatty acid. Non-limiting examples of an omega fatty acid include omega-3, 6, and omega-9. Omega-3 fatty acids (also known as n-3 fatty acids or (U—3 fatty acids) are a family of essential unsaturated fatty acids that have in common a final carbon—carbon double bond in the n—3 position, that is, the third bond, counting from the methyl end of the fatty acid. The omega-3 fatty acids are "essential" fatty acids because they are vital for normal metabolism and cannot be sized by the human body. An omega-3 fatty acid includes, without limitation, catrienoic acid (16:3), or-Linolenic acid , Stearidonic acid (18:4), Eicosatrienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), Docosapentaenoic acid (22:5), odonic acid (22:5), Docosahexaenoic acid (22:6), Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid (Nisinic acid) (24:6).

Omega-6 fatty acids (also known as n-6 fatty acids or (U—6 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n—6 position, that is, the sixth bond, counting from the methyl end of the fatty acid. An omega-6 fatty acid includes, without limitation, Linoleic acid (18:2), Gamma-linolenic acid , Calendic acid (18:3), Eicosadienoic acid (20:2), Dihomo-gamma-linolenic acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22:2), Adrenic acid (22:4), Docosapentaenoic acid (22:5), Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid . Omega-9 fatty acids (also known as n-9 fatty acids or (U—9 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon—carbon double bond in the n—9 position, that is, the ninth bond, counting from the methyl end of the fatty acid. An omega-9 fatty acid includes, without limitation, oleic acid (18:1), Elaidic acid , Eicosenoic acid (20:1), Mead acid , Erucic acid (22:1), and Nervonic acid (24:1 ).

A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable oil. An oil includes any fatty acid that is liquid at normal room temperature, such as, e.g. about 20°C. In st, a fat includes any fatty acid that is solid at normal room temperature, such as, e.g. about 20°C. An oil suitable as a lipid useful in the pharmaceutical compositions disclosed herein, may be a natural oil or a vegetable oil. Examples of le natural oils e, without limitation, mineral oil, tin, ethyl oleate, a hydrogenated natural oil, or a mixture f. Examples of suitable vegetable oils include, t limitation, almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seed oil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or a mixture thereof. Each of these oils is commercially available from a number of sources well recognized by those skilled in the art.

W0 2012/104655 22 An oil is typically a mixture of various fatty acids. For example, Rapeseed oil, obtained from the seeds of Brassica napus, includes both omega-6 and omega-3 fatty acids in a ratio of about 2:1. As another example, d oil, obtained from the seeds of Linum usitatissimum, includes abut 7% ic acid, about 3.4-4.6% stearic acid, about 18.5-22.6% oleic acid, about 14.2-17% linoleic acid, and about 51.9-55.2% or-linolenic acid. In aspects of this embodiment, a pharmaceutical composition comprises an oil including at least two different fatty acids, at least three different fatty acids, at least four different fatty acids, at least five different fatty acids, or at least six different fatty acids.

A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable olipid. Glycerolipids are composed mainly of mono-, di-, and tri-substituted glycerols.

One group of glycerolipids is the glycerides, where one, two, or all three hydroxyl groups of glycerol are each esterified using a fatty acid to produce monoglycerides, diglycerides, and triglycerides, respectively.

In these compounds, each hydroxyl groups of glycerol may be esterified by different fatty acids.

Additionally, glycerides may be acetylated to produce ated monoglycerides, acetylated diglycerides, and acetylated triglycerides. One group of olipids is the glycerides, where one, two, or all three hydroxyl groups of glycerol have sugar residues attached via a glycosidic linkage.

Aspects of the present specification disclose, in part, a pharmaceutically-acceptable stabilizing agent. A stabilizing agent reduces or eliminates formation of esters of a therapeutic compound that may result as a unwanted reaction with the ular solvent used. A stabilizing agent include, without limitation, water, a sacrificial acid sing a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid (E262), a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated monoglyceride, an acetylated diglyceride, a fatty acid, and a fatty acid salt.

In one embodiment, a pharmaceutically-acceptable stabilizing agent may comprise a ceutically-acceptable emulsifying agent. An fying agent (also known as an emulgent) is a substance that stabilizes an emulsion comprising a liquid dispersed phase and a liquid continuous phase by increasing its kinetic stability. Thus, in situations where the solvent and adjuvant used to make a pharmaceutical composition disclosed herein are ly immiscible, an emulsifying agent disclosed herein is used to create a homogenous and stable emulsion. An emulsifying agent includes, t limitation, a surfactant, a polysaccharide, a lectin, and a phospholipid.

In an aspect of this embodiment, an fying agent may comprise a surfactant. As used hereon, the term “surfactant” refers to a l or synthetic amphiphilic compound. A surfactant can be nic, zwitterionic, or ionic. Non-limiting examples of tants include polysorbates like polysorbate 20 (TWEEN® 20), polysorbate 40 (TWEEN® 40), polysorbate 60 (TWEEN® 60), polysorbate 61 (TWEEN® 61), polysorbate 65 (TWEEN® 65), polysorbate 80 (TWEEN® 80), and polysorbate 81 (TWEEN® 81); mers (polyethylene-polypropylene copolymers), like Poloxamer 124 (PLURON|C® L44), Poloxamer 181 N|C® L61), Poloxamer 182 (PLURON|C® L62), Poloxamer 184 N|C® L64), mer 188 (PLURON|C® F68), Poloxamer 237 (PLURON|C® F87), Poloxamer 338 (PLURON|C® L108), Poloxamer 407 (PLURON|C® F127), polyoxyethyleneglycol dodecyl ethers, like W0 2012/104655 23 BRIJ® 30, and BRIJ® 35; 2-dodecoxyethanol (LUBROL®-PX); polyoxyethylene octyl phenyl ether (TRITON® X—100); sodium dodecyl sulfate (SDS); 3-[(3-Cholamidopropyl)dimethylammonio] propanesulfonate (CHAPS); Cholamidopropyl)dimethylammonio]hydroxypropanesulfonate (CHAPSO); sucrose monolaurate; and sodium cholate. Other non-limiting examples of surfactant excipients can be found in, e.g., Ansel, supra, (1999); o, supra, (2000); Hardman, supra, (2001); and Rowe, supra, (2003), each of which is hereby incorporated by reference in its entirety.

In an aspect of this embodiment, an fying agent may comprise a polysaccharide. Non- limiting examples of polysaccharides include guar gum, agar, alginate, e, a dextran (like dextran 1K, dextran 4K, dextran 40K, dextran 60K, and n 70K), dextrin, glycogen, inulin, starch, a starch derivative (like hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, ybutyl starch, and ypentyl starch), hetastarch, cellulose, FICOLL, methyl cellulose (MC), ymethyl cellulose (CMC), yethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (HPMC); polyvinyl acetates (PVA); polyvinyl pyrrolidones (PVP), also known as povidones, having a K-value of less than or equal to 18, a e greater than 18 or less than or equal to 95, or a e greater than 95, like PVP 12 (KOLLIDON® 12), PVP 17 DON ® 17), PVP 25 (KOLLIDON ® 25), PVP 30 (KOLLIDON ® 30), PVP 90 (KOLLIDON ® 90); and polyethylene imines (PEI).

In an aspect of this embodiment, an emulsifying agent may comprise a lectin. s are sugar- binding proteins that are highly specific for their sugar moieties. Lectins may be classified according to the sugar moiety that they bind to, and include, without limitation, mannose-binding lectins, galactose/N- acetylgalactosamine-binding lectins, N-acetylgluxosamine-binding lectins, N-acetylneuramine-binding lectins, N-acetylneuraminic acid-binding lectins, and fucose-binding lectins. Non-limiting examples of surfactants include concanavain A, lentil lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairy vetch lectin, wheat germ agglutinin, elderberry lectin, Maackia anurensis leukoagglutinin, Maackia anurensis hemoagglutinin, Ulex europaeus agglutinin, and Aleuria aurantia lectin.

In an aspect of this embodiment, an emulsifying agent may comprise a phospholipid. The structure of the phospholipid generally comprises a hydrophobic tail and a hilic head and is amphipathic in nature. Most phospholipids contain a eride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from sphingosine instead of glycerol. Phospholipids include, t tion, diacylglycerides and osphingolipids. Non-limiting es of diacylglycerides include a phosphatidic acid (phosphatidate) (PA), a phosphatidylethanolamine (cephalin) (PE), a phosphatidylcholine (lecithin) (PC), a phosphatidylserine (PS), and a phosphoinositide including phosphatidylinositol (Pl), phosphatidylinositol phosphate (PlP), phosphatidylinositol bisphosphate (PlP2), and phosphatidylinositol triphosphate (PlP3).

Non-limiting examples of phosphosphingolipids include a de phosphorylcholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer—PE), and ceramide phosphorylglycerol.

W0 2012/104655 24 In one embodiment, a pharmaceutically-acceptable stabilizing agent does not comprise a pharmaceutically-acceptable emulsifying agent.

In r ment, a pharmaceutical ition does not comprise a pharmaceutically- acceptable emulsifying agent.

The ceutical compositions disclosed herein act as a delivery system that enable a therapeutic compound disclosed herein to be more effectively delivered or targeted to a cell type, tissue, organ, or region of the body in a manner that more effectively ts a pro-inflammatory response. This inhibition results in an improved treatment of a chronic inflammation. For example, a pharmaceutical composition disclosed herein may facilitate the delivery of a therapeutic compound disclosed herein into macrophages. One possible mechanism that achieves this selective biodistribution is that the pharmaceutical compositions disclosed herein may be designed to take advantage of the activity of chylomicrons. icrons are relatively large lipoprotein particles having a diameter of 75 nm to 1,200 nm. Comprising triglycerides (85-92%), phospholipids (6-12%), cholesterol (1-3%) and apolipoproteins , chylomicrons ort dietary lipids from the intestines to other locations in the body.

Chylomicrons are one of the five major groups of lipoproteins, the others being VLDL, lDL, low-density lipoproteins (LDL), high-density lipoproteins (HDL), that enable fats and cholesterol to move within the water-based solution of the bloodstream.

During digestion, fatty acids and cholesterol undergo processing in the gastrointestinal tract by the action of pancreatic juices including lipases and emulsification with bile salts to generate micelles.

These micelles allow the absorption of lipid as free fatty acids by the absorptive cells of the small intestine, known as enterocytes. Once in the enterocytes, triglycerides and cholesterol are assembled into nascent chylomicrons. Nascent chylomicrons are primarily composed of triglycerides (85%) and contain some cholesterol and cholesteryl esters. The main apolipoprotein ent is apolipoprotein B- 48 8). These nascent chylomicrons are released by exocytosis from enterocytes into ls, lymphatic vessels originating in the villi of the small intestine, and are then secreted into the bloodstream at the thoracic duct's connection with the left subclavian vein.

While circulating in lymph and blood, icrons exchange ents with HDL. The HDL donates apolipoprotein C-ll (APOCZ) and apolipoprotein E (APOE) to the nascent chylomicron and thus converts it to a mature chylomicron (often referred to simply as "chylomicron"). APOCZ is the or for otein lipase (LPL) activity. Once triglyceride stores are distributed, the chylomicron returns APOCZ to the HDL (but keeps APOE), and, thus, becomes a chylomicron remnant, now only 30—50 nm. APOB48 and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdown into lipoproteins (VLDL, LDL and HDL). These lipoproteins are sed and stored by competent cells, including, e.g., hepatocytes, adipocytes and macrophages. Thus, without wishing to be limited by any theory, upon oral administration of the ceutical itions disclosed herein are processed into micelles while in the gastrointestinal tract, absorbed by enterocytes and assembled into nascent W0 2012/104655 25 chylomicrons, remain ated with chylomicron remnants taken up by the liver, and ultimately loaded into macrophages.

Aspects of the present specification disclose, in part, a method of preparing a pharmaceutical composition disclosed herein. A method sed herein comprises the step of contacting a pharmaceutically-acceptable adjuvant disclosed herein with a therapeutic compound disclosed herein under conditions which allow the therapeutic nd to dissolve in the pharmaceutically-acceptable adjuvant, thereby forming a pharmaceutical composition disclosed herein.

Aspects of the present specification disclose, in part, a method of preparing a pharmaceutical composition disclosed herein. A method sed herein comprises the steps of a) contacting a pharmaceutically-acceptable solvent disclosed herein with a therapeutic compound disclosed herein under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution; and b) contacting the solution formed in step (a) with a pharmaceutically-acceptable adjuvant sed herein under conditions which allow the formation of a pharmaceutical composition. The methods of preparing disclosed herein may further comprise a step (c) of removing the pharmaceutically-acceptable solvent from the pharmaceutical composition.

The amount of a therapeutic nd that is contacted with the pharmaceutically-acceptable solvent in step (a) of the method may be in any amount desired. Factors used to determine the amount of a therapeutic compound used include, without limitation, the final amount the therapeutic compound desired in the pharmaceutical composition, the desired concentration of a therapeutic compound in the solution, the hydrophobicity of the therapeutic compound, the lipophobicity of the therapeutic nd, the temperature under which the contacting step (a) is performed, and the time under which the contacting step (a) is med The volume of a ceutically-acceptable solvent used in step (a) of the method may be any volume desired. Factors used to determine the volume of a pharmaceutically-acceptable solvent used include, without limitation, the final amount of a pharmaceutical ition desired, the desired concentration of a eutic compound in the solution, the hydrophobicity of the eutic compound, and the lipophobicity of the therapeutic compound.

In aspects of this embodiment, the amount of a eutic compound that is contacted with the solvent in step (a) may be, e.g., at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg. In other aspects of this embodiment, the amount of a eutic compound that is contacted with the solvent in step (a) may be in the range of, e.g., about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about W0 2012/104655 26 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg. In other aspects of this embodiment, the amount of a eutic compound that is dissolved in the t in step (a) may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, or about 200 mg to about 1,500 mg.

Step (a) may be d out at room temperature, in order to allow a therapeutic nd to dissolve fully in the pharmaceutically-acceptable solvent. However, in other embodiments of the method, step (a) may be carried out at a temperature that is greater than room temperature, e.g., greater than 21°C, greater than 25°C, greater than 30°C, greater than 35°C or greater than 37°C. In certain cases, Step (a) may be carried out at atures below room temperature, in order to allow a therapeutic compound to dissolve fully in t. However, in other embodiments of the method, step (a) may be carried out at a temperature that is less than room temperature, e.g., less than 10°C, greater than 5°C, r than 0°C, greater than -10°C or r than -20°C. The contacting in Step (a) may comprise mixing the therapeutic compound and the pharmaceutically-acceptable solvent, e.g., by stirring, inversion, sonication, or vortexing. The mixing may be carried out for, e.g., at least 1 second, at least 5 s, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds, or more, until the therapeutic compound is fully dissolved in the solvent.

After contacting, the concentration of a therapeutic compound disclosed herein in the solution may be in any concentration desired. In aspects of this embodiment, the concentration of a therapeutic compound disclosed herein in the solution may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In other aspects of this embodiment, the concentration of a therapeutic compound disclosed herein in the solution may be, e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects of this embodiment, the concentration of a therapeutic compound disclosed herein in the solution may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about 100 WO 04655 27 mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750 mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 1 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

The volume of a pharmaceutically-acceptable adjuvant used in step (b) of the method may be any volume desired. Factors used to determine the volume of a pharmaceutically-acceptable nt used include, without limitation, the final amount of a pharmaceutical ition desired, the desired concentration of a eutic compound in the pharmaceutical composition, the ratio of solvent:adjuvant used and the miscibility of solvent and adjuvant.

In aspects of this embodiment, the ratio of solution:adjuvant may be, e.g., at least 5:1, at least 4:1, at least 3:1, at least 2:1, at least 0:1, at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, at least 1:20, or at least 1:25.

In other aspects of this embodiment, the ratio of solution:adjuvant may be in a range of, e.g., about 5:1 to about 1:25, about 4:1 to about 1:25, about 3:1 to about 1:25, about 2:1 to about 1:25, about 0:1 to about 1:25, about 1:1 to about 1:25, about 1:2 to about 1:25, about 1:3 to about 1:25, about 1:4 to about 1:25, about 1:5 to about 1:25, about 5:1 to about 1:20, about 4:1 to about 1:20, about 3:1 to about 1:20, about 2:1 to about 1:20, about 0:1 to about 1:20, about 1:1 to about 1:20, about 1:2 to about 1:20, about 1:3 to about 1:20, about 1:4 to about 1:20, about 1:5 to about 1:20, about 5:1 to about 1:15, about 4:1 to about 1:15, about 3:1 to about 1:15, about 0:1 to about 1:15, about 2:1 to about 1:15, about 1:1 to about 1:15, about 1:2 to about 1:15, about 1:3 to about 1:15, about 1:4 to about 1:15, about 1:5 to about 1:15, about :1 to about 1:12, about 4:1 to about 1:12, about 3:1 to about 1:12, about 2:1 to about 1:12, about 0:1 to about 1:12, about 1:1 to about 1:12, about 1:2 to about 1:12, about 1:3 to about 1:12, about 1:4 to about 1:12, about 1:5 to about 1:12, about 1:6 to about 1:12, about 1:7 to about 1:12, about 1:8 to about 1:12, about 5:1 to about 1:10, about 4:1 to about 1:10, about 3:1 to about 1:10, about 2:1 to about 1:10, about 0:1 to about 1:10, about 1:1 to about 1:10, about 1:2 to about 1:10, about 1:3 to about 1:10, about 1:4 to about 1:10, about 1:5 to about 1:10, about 1:6 to about 1:10, about 1:7 to about 1:10, or about 1:8 to about 1:10.

Step (b) may be carried out at room temperature, in order to allow the solution comprising the therapeutic compound to form the pharmaceutical composition. However, in other embodiments of the method, step (b) may be carried out at a temperature that is r than room temperature, e.g., greater than 21°C, greater than 25°C, greater than 30°C, greater than 35°C or greater than 37°C. In certain cases, Step (b) may be carried out at temperatures below room temperature, in order to allow a W0 2012/104655 28 therapeutic compound to dissolve fully in a pharmaceutically-acceptable solvent. However, in other embodiments of the method, step (b) may be d out at a temperature that is less than room temperature, e.g., less than 10°C, greater than 5°C, greater than 0°C, greater than -10°C or greater than - °C. The contacting in Step (b) may comprise mixing the solution and the pharmaceutically-acceptable adjuvant, e.g., by stirring, inversion, sonication, or vortexing. The mixing may be carried out for, e.g., at least 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 s, at least 45 seconds, at least 60 seconds, or more, until the pharmaceutical composition is formed.

In Step (c), the solvent removal from a ceutical composition may be accomplished using one of a variety of procedures known in the art, including, without limitation, evaporation, dialyzation, distillation, lypholization, and filtration. These removal procedures may be done under ions of ambient atmosphere, under low pressure, or under a vacuum.

In one embodiment, Step (c) may result in the complete removal of a pharmaceutically- acceptable solvent from the pharmaceutical composition disclosed herein. In aspects of this embodiment, Step (c) may result in, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least %, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, or at least 99% removal of a pharmaceutically-acceptable solvent from the pharmaceutical composition sed herein.

Step (c) is conducted at a temperature that allows for the evaporation of a pharmaceutically- acceptable solvent sed herein, and as such, an ation temperature is solvent dependant.

Factors which influence an evaporation temperature of a solvent disclosed herein include, without limitation, the particular solvent used, the amount of t present, the particular therapeutic compound present, the particular adjuvant present, the stability of the therapeutic compound present, the reactivity of the therapeutic compound present, the particular atmospheric pressure used, the time d for complete evaporation. lly, a pharmaceutical composition will e heating if the evaporation step is conducted at ambient pressure, e.g., 1 atm. However, under high vacuum conditions, the evaporation step may be ted at temperatures below ambient temperature, e.g., less than 22 °C.

In one embodiment, removal of solvent from the pharmaceutical composition disclosed herein may be carried out at ambient atmospheric pressure and at a temperature above ambient ature.

In aspects of this embodiment, removal of solvent from the ceutical composition disclosed herein may be carried out at ambient atmospheric pressure and at a temperature of, e.g., more than 25°C, more than 30°C, more than 35°C, more than 40°C, more than 45°C, more than 50°C, more than 55°C, more than 60°C, more than 65°C, more than 70°C, more than 80°C, or more than 25°C. In other aspects of this embodiment, removal of solvent from the pharmaceutical composition sed herein may be carried out at t atmospheric pressure and at a temperature in a range of, e.g., about 25°C to about 100°C, about 25°C to about 95°C, about 25°C to about 90°C, about 25°C to about 85°C, about 25°C to W0 2012/104655 29 2012/050242 about 80°C, about 25°C to about 75°C, about 25°C to about 70°C, about 25°C to about 65°C, or about °C to about 60°C.

In another embodiment, removal of solvent from the pharmaceutical composition disclosed herein may be carried out under vacuum and at a temperature below ambient ature. In aspects of this embodiment, l of solvent from the pharmaceutical composition disclosed herein may be carried out under vacuum and at a temperature of, e.g., less than 20°C, less than 18°C, less than 16°C, less than 14°C, less than 12°C, less than 10°C, less than 8°C, less than 6°C, less than 4°C, less than 2°C, or less than 0°C. In other aspects of this embodiment, removal of solvent from the pharmaceutical composition disclosed herein may be carried out under vacuum and at a temperature in a range of, e.g., about -20°C to about 20°C, about -20°C to about 18°C, about -20°C to about 16°C, about -20°C to about 14°C, about - °C to about 12°C, about -20°C to about 10°C, about -20°C to about 8°C, about -20°C to about 6°C, about -20°C to about 4°C, about -20°C to about 2°C, about -20°C to about 0°C, about -15°C to about °C, about -10°C to about 20°C, about -5°C to about 20°C, about 0°C to about 20°C, about -10°C to about 20°C, about -10°C to about 18°C, about -10°C to about 16°C, about -10°C to about 14°C, about - °C to about 12°C, about -10°C to about 10°C, about -10°C to about 8°C, about -10°C to about 6°C, about -10°C to about 4°C, about -10°C to about 2°C, or about -10°C to about 0°C.

The final concentration of a therapeutic compound disclosed herein in a pharmaceutical composition disclosed herein may be of any concentration desired. In an aspect of this ment, the final concentration of a therapeutic compound in a pharmaceutical composition may be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of a therapeutic compound in a pharmaceutical ition may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In other aspects of this embodiment, the tration of a therapeutic compound disclosed herein in the solution may be, e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other s of this embodiment, the final concentration of a therapeutic compound in a pharmaceutical composition may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750 mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about 1,000 W0 2012/104655 30 mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 1 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

A ceutical composition produced using the methods disclosed herein may be a liquid formulation or a solid or semi-solid formulation. A liquid formulation can be formed by using various lipids like oils of other fatty acids that remain as liquids in the ature range desired. In an embodiment, a pharmaceutical composition sed herein is liquid at room temperature. In aspects of this embodiment, a pharmaceutical composition disclosed herein may be formulated to be a liquid at a temperature of, e.g., about 25°C or higher, about 23°C or , about 21°C or higher, about 19°C or higher, about 17°C or higher, about 15°C or higher, about 12°C or higher, about 10°C or higher, about 8°C or higher, about 6°C or higher, about 4°C or higher, or about 0°C or higher.

A solid or semi-solid formulation sed herein takes advantage of the different melting point temperatures of the various adjuvants like fatty acids. Formation of a solid or semi-solid dosage form can be by modifying the respective trations of the fatty acids comprising a pharmaceutical composition disclosed herein. For example, linolenic acid has a melting point temperature (Tm) of about -11°C, linoleic acid has a Tm of about -5°C, oleic acid has a Tm of about 16°C, palmitic acid has a Tm of about 61-62°C, and Stearic acid has a Tm of about 67-72°C. Increasing the proportion(s) of ic, stearic or oleic acid would increase the overall melting temperature of a composition, while, conversely, increasing the proportion(s) of linoleic and linolenic acid would decrease the melting temperature of a composition.

Thus, by controlling the types and s of the adjuvant components added, a pharmaceutical composition disclosed herein can be made that is substantially solid or semi-solid at room temperature, but melts when it is ingested, and reaches body temperature. The resulting melted composition readily forms micelles which are absorbed by the ine, assembled into chylomicrons, and ultimately absorbed by macrophages. The solid dosage form may be a powder, granule, tablet, capsule or suppository.

In an embodiment, a pharmaceutical composition disclosed herein is solid at room ature.

In aspects of this embodiment, a pharmaceutical composition disclosed herein may be formulated to be a solid at a temperature of, e.g., about 35°C or lower, about 33°C or lower, about 31°C or lower, about 29°C or lower, about 27°C or lower, about 25°C or lower, about 23°C or lower, about 21 °C or lower, about 19°C or lower, about 17°C or lower, about 15°C or lower, about 12°C or lower, about 10°C or lower, about 8°C or lower, about 6°C or lower, about 4°C or lower, or about 0°C or lower.

In other s of this ment, a pharmaceutical ition disclosed has a melting point temperature of, e.g., 5 °C or higher, 10 °C or higher, 15 °C or higher, 22°C or higher, 23°C or higher, 24°C W0 04655 31 or higher, 25°C or higher, 26°C or higher, 27°C or higher, 28°C or , 29°C or higher, 30°C or higher, 31°C or higher, 32°C or higher, 33°C or higher, 34°C or higher, or 35°C or . In other aspects of this embodiment, a ceutical composition disclosed has a melting point temperature in the range of, e.g., about 5°C to about 24°C, about 10°C to about 24°C. about 22°C to about 24°C, about 23°C to about °C, about 24°C to about 26°C, about 25°C to about 27°C, about 26°C to about 28°C, about 27°C to about 29°C, about 28°C to about 30°C, about 29°C to about 31°C, about 30°C to about 32°C, about 31°C to about 33°C, about 32°C to about 34°C, or about 33°C to about 35°C. In other aspects of this embodiment, a pharmaceutical composition sed has a melting point temperature in the range of, e.g., about 22°C to about 26°C, about 24°C to about 28°C, about 26°C to about 30°C, about 28°C to about 32°C, or about 30°C to about 34°C.

Aspects of the present specification disclose, in part, a method of ng an dual with a chronic inflammation. In one embodiment, the method comprises the step of administering to an individual in need thereof a ceutical composition disclosed herein, wherein administration reduces a symptom associated with the chronic inflammation, thereby treating the individual.

Aspects of the t ication disclose, in part, treating an individual ing from a chronic inflammation. As used herein, the term “treating,” refers to reducing or eliminating in an individual a clinical symptom of a c inflammation; or delaying or preventing in an individual the onset of a clinical symptom of a chronic inflammation. For example, the term “treating” can mean reducing a symptom of a condition characterized by a c inflammation by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%.

The actual symptoms associated with chronic inflammation are well known and can be determined by a person of ordinary skill in the art by taking into account factors, including, without tion, the location of the chronic inflammation, the cause of the chronic inflammation, the severity of the chronic inflammation, and/or the tissue or organ affected by the chronic inflammation. Those of skill in the art will know the appropriate symptoms or indicators associated with a specific type of chronic inflammation and will know how to determine if an individual is a candidate for treatment as disclosed herein.

Chronic inflammation symptoms include, without limitation, edema, hyperemia, erythema, ng, tenderness, stiffness, swollenness, fever, chills, stuffy nose, stuffy head, breathing problems, fluid retention, blood clots, loss of te, increased heart rate, formation of granulomas, fibrinous, pus, non-viscous serous fluid, or ulcer and pain. The actual symptoms associated with a chronic inflammation are well known and can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the location of the inflammation, the cause of the inflammation, the severity of the inflammation, the tissue or organ affected, and the associated disorder. ic patterns of chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved. For example, granulomatous inflammation is an inflammation resulting from the formation of granulomas W0 2012/104655 32 2012/050242 arising from a limited but diverse number of diseases, include, without limitation, tuberculosis, leprosy, sarcoidosis, and syphilis. Purulent inflammation is an inflammation resulting in large amount of pus, which ts of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as lococci is characteristic of this kind of inflammation. Serous inflammation is an inflammation resulting from copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.

Ulcerative mation is an mation resulting from the necrotic loss of tissue from the epithelial surface, ng lower layers and forming an ulcer.

A chronic inflammation symptom can be associated with a large, unrelated group of disorders which underlay a variety of diseases and disorders. The immune system is often involved with chronic inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with etiological origins in chronic inflammatory processes include cancer, atherosclerosis, and ischaemic heart disease. miting examples of disorders exhibiting chronic inflammation as a symptom e, without limitation, acne, acid reflux/heartburn, age related macular degeneration (AMD), allergy, allergic rhinitis, Alzheimer’s disease, amyotrophic l sclerosis, anemia, icitis, arteritis, arthritis, asthma. atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, omyositis, diabetes, diabetic athy, diabetic retinopathy, diabetic pathy, diabetic ulcer, digestive system e, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, tis, gastroenteritis, gingivitis, glomerulonephritis, tis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, matory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), a migraine, le sclerosis, myelitis, ditis, is, nephritis, non-alcoholic steatohepatitis, y, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, is, , pancreatitis, Parkinson’s disease, parotitis, pelvic inflammatory disease, pemphigus vularis, pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, nitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, is, stomatitis, stroke, surgical cation, synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, tic brain injury, lant rejection, trigonitis, tuberculosis, tumor, urethritis, s, uveitis, vaginitis, vasculitis, and vulvitis. See also, Eric R. First, Application of Botu/inum Toxin to the Management of Neurogenic Inflammatory Disorders, US. Patent 6,063,768, which is hereby incorporated by reference in its entirety.

W0 2012/104655 33 In one embodiment, a chronic inflammation comprises a tissue inflammation. Tissue inflammation is a chronic inflammation that is confined to a particular tissue or organ. ln aspect of this embodiment, a tissue inflammation comprises, e.g., a skin inflammation, a muscle inflammation, a tendon inflammation, a ligament inflammation, a bone inflammation, a cartilage inflammation, a lung inflammation, a heart inflammation, a liver inflammation, a pancreatic inflammation, a kidney inflammation, a r inflammation, a stomach inflammation, an intestinal inflammation, a neuron inflammation, and a brain inflammation.

In another embodiment, a chronic inflammation comprises a systemic inflammation. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but in fact ovenNhelms the body, ing the endothelium and other organ systems.

When it is due to infection, the term sepsis is applied, with the terms bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.

In another embodiment, a chronic inflammation comprises an arthritis. Arthritis includes a group of conditions involving damage to the joints of the body due to the inflammation of the synovium including, without limitation osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies like ankylosing spondylitis, reactive arthritis r's syndrome), psoriatic tis, enteropathic tis associated with inflammatory bowel disease, Whipple disease and Behcet disease, septic arthritis, gout (also known as gouty arthritis, crystal synovitis, metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease. Arthritis can affect a single joint (monoarthritis), two to four joints arthritis) or five or more joints (polyarthritis) and can be either an auto-immune disease or a non- autoimmune disease.

In another embodiment, a chronic inflammation comprises an autoimmune disorder. mune diseases can be broadly divided into systemic and organ-specific autoimmune disorders, depending on the principal clinico-pathologic features of each disease. Systemic autoimmune diseases e, without limitation, ic lupus erythematosus (SLE), Sjogren's syndrome, Scleroderma, toid arthritis and polymyositis. Local mune diseases may be endocrinologic (Diabetes Mellitus Type 1, oto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus is), hematologic (autoimmune ytic anemia), neural (multiple sis) or can involve virtually any circumscribed mass of body tissue. Types of autoimmune disorders include, without limitation, acute disseminated encephalomyelitis (ADEM), Addison's disease, an allergy or ivity, ophic lateral sclerosis, hospholipid antibody me (APS), arthritis, autoimmune hemolytic , autoimmune hepatitis, autoimmune inner ear disease, autoimmune pancreatitis, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease (COPD), es mellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's thyroiditis, hidradenitis suppurativa, thic thrombocytopenic purpura, inflammatory bowel disease, interstitial cystitis, lupus (including d lupus erythematosus, drug- induced lupus erythematosus. lupus nephritis, neonatal lupus, subacute cutaneous lupus erythematosus W0 2012/104655 34 and systemic lupus erythematosus), morphea, multiple sclerosis (MS), myasthenia gravis, myopathies, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, primary biliary cirrhosis, recurrent disseminated encephalomyelitis (multiphasic disseminated encephalomyelitis), rheumatic fever, schizophrenia, scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis, and vitiligo. See Pamela D.

Van Schaack & Kenneth L. Tong, Treatment of Autoimmune Disorder With a oxin, US. Patent Publication 2006/138059, which is hereby incorporated by reference in its entirety.

In another ment, a chronic inflammation comprises a myopathy. Myopathies are caused when the immune system inappropriately attacks components of the muscle, leading to inflammation in the muscle. A myopathy includes an inflammatory myopathy and an auto-immune myopathy.

Myopathies include, without limitation, dermatomyositis, inclusion body myositis, and polymyositis.

In another embodiment, a chronic mation comprises a vasculitis. Vasculitis is a varied group of disorders featuring inflammation of a vessel wall ing tic s and blood vessels like veins (phlebitis), arteries (arteritis) and aries due to leukocyte migration and resultant .

The inflammation may affect any size blood vessel, anywhere in the body. It may affect either arteries and/or veins. The inflammation may be focal, meaning that it affects a single location within a vessel; or it may be widespread, with areas of inflammation scattered throughout a particular organ or tissue, or even affecting more than one organ system in the body. itis include, without limitation, Buerger's disease (thromboangiitis obliterans), cerebral vasculitis (central nervous system vasculitis), Churg- Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell (temporal) tis, Golfer's vasculitis, Henoch-Schonlein purpura, hypersensitivity vasculitis (allergic vasculitis), Kawasaki disease, microscopic polyarteritis/polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid itis, Takayasu arteritis, Wegener's granulomatosis, and vasculitis secondary to connective tissue disorders like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), relapsing polychondritis, Behcet's disease, or other tive tissue disorders, vasculitis secondary to viral infection.

In another ment, a chronic inflammation comprises a skin disorder. Skin disorders e, without limitation, an acne, including acne vulgaris, a bullous phemigoid, a itis, including atopic dermatitis and chronic actinic dermatitis, an eczema like atopic eczema, contact , xerotic eczema, seborrhoeic dermatitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis, neurodermatitis, and autoeczematization, and statis dermatitis, hidradenitis suppurativa, lichen planus, psoriasis ing e psoriasis, nail psoriasis, guttate psoriasis, scalp sis, inverse psoriasis, pustular psoriasis, erythrodermis psoriasis, and psoriatic tis, rosacea and scleroderma including morphea.

In another embodiment, a chronic inflammation comprises a gastrointestinal disorder. A intestinal disorder includes, without limitation, irritable bowel disease, an matory bowel disease including s disease and an ulcerative colitis like ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis.

W0 2012/104655 35 In another embodiment, a chronic inflammation comprises a cardiovascular disease. When LDL cholesterol s embedded in arterial walls, it can invoke an immune response. Chronic inflammation eventually can damage the arteries, which can cause them to burst. Cardiovascular disease is any of a number of specific diseases that affect the heart itself and/or the blood vessel system, especially the veins and arteries leading to and from the heart. There are more than 60 types of cardiovascular disorders including, without limitation, a hypertension, endocarditis, myocarditis, heart valve ction, congestive heart failure, myocardial infarction, a ic cardiac conditions, blood vessel inflammation like arteritis, phlebitis, vasculitis; arterial occlusive disease like arteriosclerosis and stenosis, matory cardiomegaly, a peripheral arterial disease; an aneurysm; an embolism; a tion; a pseudoaneurysm; a vascular malformation; a vascular nevus; a thrombosis; a thrombphlebitis; a varicose veins; a stroke. Symptoms of a cardiovascular disorder affecting the heart include, t limitation, chest pain or chest discomfort (angina), pain in one or both arms, the left shoulder, neck, jaw, or back, shortness of breath, dizziness, faster heartbeats, nausea, abnormal heartbeats, feeling ed. Symptoms of a cardiovascular disorder affecting the brain include, without limitation, sudden numbness or weakness of the face, arm, or leg, especially on one side of the body, sudden confusion or trouble speaking or understanding speech, sudden trouble seeing in one or both eyes, sudden dizziness, difficulty walking, or loss of balance or coordination, sudden severe he with no known cause. Symptoms of a vascular disorder affecting the legs, pelvis and/or arm include, without tion, claudication, which is a pain, ache, or cramp in the s, and cold or numb feeling in the feet or toes, especially at night.

In another ment, a chronic inflammation comprises a cancer. Inflammation orchestrates the microenvironment around tumors, contributing to proliferation, survival and ion. For example, fibrinous inflammation results from a large increase in vascular permeability which allows fibrin to pass h the blood s. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited. This is ly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function. In another example, a cancer is an inflammatory cancer like a NF-KB-driven inflammatory cancer.

In another embodiment, a chronic inflammation comprises a pharmacologically-induced inflammation. Certain drugs or exogenic chemical compounds are known to affect inflammation. For example, Vitamin A deficiency causes an increase in an inflammatory response. Certain illicit drugs such as cocaine and ecstasy may exert some of their detrimental effects by ting transcription factors tely involved with inflammation (e.g. NF-KB).

In r embodiment, a chronic inflammation comprises an infection. An infectious sm can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not ned by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. A W0 2012/104655 36 pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system. lnfections include, without limitation, bacterial cystitis, bacterial encephalitis, pandemic influenza, viral encephalitis, and viral hepatitis (A, B and C).

In another embodiment, a c inflammation comprises a tissue or organ injury. Tissue or organ injuries include, without limitation, a burn, a laceration, a wound, a puncture, or a trauma.

In another embodiment, a chronic inflammation comprises a transplant ion. Transplant rejection occurs when a transplanted organ or tissue is not accepted by the body of the transplant recipient e the immune system of the recipient s the transplanted organ or tissue. An ve immune se, transplant rejection is mediated through both T cell ed and humoral immune (antibodies) mechanisms. A transplant rejection can be classified as a hyperacute rejection, an acute rejection, or a chronic rejection. Chronic rejection of a transplanted organ or tissue is where the rejection is due to a poorly understood chronic inflammatory and immune response t the transplanted tissue. Also included in the term “transplant rejection” is a graft-versus-host disease (GVHD). GVHD is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack. It can also take place in a blood transfusion under certain circumstances. GVHD is divided into acute and chronic forms. Acute and chronic GVHD appear to involve different immune cell subsets, different cytokine profiles, at different host targets, and respond differently to treatment.

In another embodiment, a c inflammation comprises a Th1-mediated inflammatory disease.

In a well-functioning immune system, an immune response should result in a well balanced pro- inflammatory Th1 response and anti-inflammatory Th2 response that is suited to address the immune challenge. Generally speaking, once a pro-inflammatory Th1 response is initiated, the body relies on the anti-inflammatory response d by a Th2 response to ract this Th1 se. This counteractive response includes the release of Th2 type cytokines such as, e.g., lL-4, lL-5, and lL-13 which are associated with the promotion of lgE and eosinophilic responses in atopy, and also lL-10, which has an anti-inflammatory response. A Th1-mediated inflammatory disease es an excessive pro-inflammatory response produced by Th1 cells that leads to chronic inflammation. The Th1-mediated disease may be virally, bacterially or chemically (e.g. nmentally) induced. For example, a virus causing the Th1-mediated disease may cause a c or acute infection, which may cause a respiratory disorder or influenza.

In another embodiment, a c inflammation ses a chronic enic inflammation.

Chronic neurogenic Inflammation refers to an matory response initiated and/or maintained through the release of inflammatory molecules like SP or CGRP which released from peripheral sensory nerve terminals (i.e., an efferent function, in contrast to the normal afferent signaling to the spinal cord in these nerves). c neurogenic inflammation includes both primary inflammation and secondary neurogenic inflammation. As used herein, the term "primary" neurogenic inflammation refers to tissue inflammation (inflammatory symptoms) that is initiated by, or results from, the release of substances from primary sensory nerve terminals (such as C and A-delta fibers). As used herein, the term "secondary" neurogenic inflammation” refers to tissue inflammation initiated by non-neuronal sources (e.g., extravasation from vascular bed or tissue interstitium-derived, such as from mast cells or immune cells) of inflammatory ors, such as peptides or cytokines, stimulating sensory nerve terminals and g a release of inflammatory mediators from the nerves. The net effect of both forms (primary and secondary) of chronic neurogenic inflammation is to have an inflammatory state that is maintained by the sensitization of the eral sensory nerve fibers. The physiological consequence of the resulting chronic neurogenic inflammation depends on the tissue in question, producing, such as, e.g., ous pain (allodynia, hyperalgesia), joint pain and/or arthritis, visceral pain and dysfunction, pulmonary ction (asthma, COPD), and bladder dysfunction (pain, overactive bladder).

A composition or compound is stered to an individual. An individual is typically a human being. Typically, any individual who is a ate for a conventional chronic inflammation treatment is a candidate for a chronic inflammation treatment disclosed . Pre-operative evaluation typically includes routine history and physical examination in addition to thorough informed consent disclosing all relevant risks and benefits of the procedure.

A ceutical composition disclosed herein may comprise a therapeutic compound in a eutically effective amount. As used herein, the term “effective amount” is synonymous with peutically effective amount”, “effective dose”, or “therapeutically ive dose” and when used in reference to treating a chronic inflammation refers to the minimum dose of a therapeutic compound sed herein necessary to achieve the desired therapeutic effect and includes a dose ient to reduce a symptom associated with a chronic inflammation. The iveness of a therapeutic compound disclosed herein in treating a chronic inflammation can be determined by observing an improvement in an individual based upon one or more al symptoms, and/or physiological indicators associated with the condition. An improvement in a chronic inflammation also can be indicated by a reduced need for a concurrent y.

The appropriate effective amount of a therapeutic compound disclosed herein to be administered to an dual for a particular chronic mation can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the type of chronic inflammation, the location of the chronic inflammation, the cause of the chronic mation, the ty of the chronic mation, the degree of relief desired, the duration of relief desired, the particular therapeutic compound used, the rate of excretion of the therapeutic compound used, the pharmacodynamics of the therapeutic compound used, the nature of the other compounds to be included in the composition, the particular route of administration, the particular characteristics, history and risk factors of the patient, such as, e.g., age, weight, general health and the like, or any combination thereof. Additionally, where repeated administration of a therapeutic compound is used, an effective amount of a therapeutic compound will further depend upon factors, including, without limitation, the frequency of administration, the half-life of the therapeutic compound, or any combination thereof. In is known by a person of ordinary skill in the art that an effective amount of a therapeutic nd disclosed herein can be extrapolated W0 2012/104655 38 from in vitro assays and in vivo administration studies using animal models prior to stration to humans.

In aspects of this embodiment, a therapeutically effective amount of a therapeutic compound disclosed herein reduces a symptom associated with a chronic inflammation by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeutically ive amount of a therapeutic nd disclosed herein reduces a symptom associated with a chronic mation by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a therapeutic compound disclosed herein reduces a symptom associated with a chronic mation by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

In yet other aspects of this embodiment, a therapeutically effective amount of a therapeutic compound sed herein generally is in the range of about 0. 001 mg/kg/day to about 100 mg/kg/day. ln aspects of this embodiment, an ive amount of a therapeutic compound disclosed herein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 day, or at least 50 mg/kg/day. In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35 day, about 0.001 mg/kg/day to about 40 day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.01 day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day. In still other s of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 W0 2012/104655 39 mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 1 day to about 10 day, about 1 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to about 20 day, about 1 mg/kg/day to about 25 mg/kg/day, about 1 mg/kg/day to about 30 day, about 1 mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to about 100 mg/kg/day.

In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 day to about 25 mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 day to about 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.

Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For instance, treatment of a chronic inflammation may se a one-time administration of an effective dose of a pharmaceutical composition sed herein. Alternatively, treatment of a chronic inflammation may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once . The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a ceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer es therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a ceutical composition disclosed herein that is administered can be adjusted accordingly.

In one embodiment, upon administration to an dual, a ceutical composition comprising a therapeutic compound sed herein results in a bio-distribution of the therapeutic compound different than a bio-distribution of the therapeutic compound included in the same pharmaceutical composition, except without an adjuvant disclosed herein.

In another embodiment, upon administration to an individual, a therapeutic compound of the ceutical composition disclosed herein is delivered to a macrophage. Macrophages are one of the key cell types believed to be involved in the control of the inflammation response. The resultant high level of a therapeutic compound having anti-inflammatory activity present in the macrophages results in a W0 2012/104655 40 clinically effective treatment of chronic inflammation. In an aspect of this embodiment, upon administration to an dual, a therapeutically effective amount of a therapeutic compound of the pharmaceutical composition disclosed herein is preferentially delivered to a hage. In other aspect of this embodiment, upon administration to an dual, a therapeutic nd of the pharmaceutical composition disclosed herein is substantially delivered to a macrophage. In yet other aspect of this embodiment, upon administration to an dual, the amount of a therapeutic compound of the pharmaceutical ition disclosed herein delivered to a hage is, e.g., at least 5%, at least %, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition. In still other aspects of this embodiment, upon administration to an individual, the amount of a therapeutic nd of the pharmaceutical composition disclosed herein delivered to a macrophage is in a range of, e.g., about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, or about 50% to about 70% of the total amount of the therapeutic compound ned in the administered pharmaceutical composition.

In another embodiment, upon stration to an dual, a pharmaceutical composition disclosed herein reduces gastric irritation. In an aspect of this embodiment, a ceutical composition disclosed herein substantially reduces gastric irritation. In yet another embodiment, upon administration to an individual, a pharmaceutical composition disclosed herein reduces gastric irritation when compared to the same ceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In an aspect of this embodiment, a pharmaceutical composition disclosed herein substantially reduces gastric irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces gastric irritation by, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces gastric irritation in a range of, e.g., about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about % to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, W0 2012/104655 41 about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, or about 50% to about 70%.

In another embodiment, upon administration to an individual, a pharmaceutical composition disclosed herein reduces intestinal irritation. In an aspect of this embodiment, a pharmaceutical ition sed herein substantially reduces intestinal irritation. In yet another embodiment, upon administration to an individual, a pharmaceutical composition sed herein reduces intestinal irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In an aspect of this embodiment, a pharmaceutical composition disclosed herein substantially reduces intestinal irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In other aspects of this embodiment, a pharmaceutical composition sed herein reduces intestinal irritation by, e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable nt. In yet other aspects of this embodiment, a ceutical composition disclosed herein reduces intestinal irritation by, e.g., about % to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, or about 50% to about 70% when compared to the same ceutical composition disclosed herein, except without the ceutically-acceptable adjuvant.

A pharmaceutical composition sed herein can also be administered to an individual in combination with other eutic compounds to increase the l therapeutic effect of the treatment.

The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.

Aspects of the present invention can also be described as follows: W0 2012/104655 42 1. A pharmaceutical ition comprising: a) a therapeutic nd, wherein the therapeutic compound has an anti-inflammatory activity; and b) a pharmaceutically-acceptable adjuvant.

The pharmaceutical composition according to embodiment 1, wherein the composition further comprises a pharmaceutically-acceptable solvent.

A pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeutic compound has an anti-inflammatory activity; b) a pharmaceutically-acceptable solvent; and c) a ceutically-acceptable nt.

A pharmaceutical composition sing: a) a therapeutic compound, wherein the therapeutic compound has an anti-inflammatory activity; b) a pharmaceutically-acceptable solvent; and c) a pharmaceutically-acceptable adjuvant, wherein the ratio of the pharmaceutically-acceptable solvent to pharmaceutically-acceptable nt is in a range from about 0:1 to about 1:25.

The pharmaceutical composition according to embodiment 2 or 3, wherein the ratio of the pharmaceutically-acceptable solvent to pharmaceutically-acceptable adjuvant is in a range from about 0:1 to about 1:25.

The pharmaceutical composition according to embodiments 1-5, n the nflammatory activity reduces the level of an inflammation inducing molecule.

The pharmaceutical composition according to ment 6, wherein the inflammation inducing molecule comprises substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or a ation thereof.

The pharmaceutical composition according to embodiment 7, wherein the anti-inflammatory activity reduces the level of SP, CGRP, glutamate, or a combination thereof by at least 10%.

The pharmaceutical composition according to embodiments 1-8, wherein the anti-inflammatory ty s the level of an inflammation inducing prostaglandin.

. The pharmaceutical composition according to embodiment 9, wherein the level of the inflammation inducing prostaglandin is reduced by at least 10%. 11. The pharmaceutical composition according to embodiments 1-10, wherein the nflammatory activity stimulates a PPAR signaling pathway. 12. The pharmaceutical composition according to ment 11, wherein the PPAR signaling pathway is stimulated by at least 10%.

W0 2012/104655 43 13. The pharmaceutical ition according to embodiments 1-12, wherein the anti-inflammatory ty induces apoptosis of Macrophage M1 cells, promotes differentiation of hage M2 cells, or both. 14. The pharmaceutical composition according to ments 1-13, wherein the anti-inflammatory activity reducing the levels of eron-gamma (lFNy), Tumor necrosis factor-alpha (TNF-d), Interleukin-12 (IL-12), or a combination thereof released from Th1 cells, increases the levels of lL-10 released from a Th2 cell, or both.

. The pharmaceutical composition ing to embodiment 14, wherein the levels of lFNy, TNF-or, IL- 12, or a combination thereof released from a Th1 cell are reduced by at least 10%. 16. The pharmaceutical composition according to embodiment 14, wherein the levels of lL-10 released from a Th2 cell are increased by at least 10%. 17. The pharmaceutical ition according to embodiments 1-16, wherein the therapeutic compound has a logP value indicating that the compound is soluble in an organic solvent. 18. The pharmaceutical composition according to embodiments 1-17, wherein the therapeutic compound has a logP value of more than 1.0. 19. The pharmaceutical composition according to embodiments 1-17, wherein the therapeutic compound has a logP value of more than 2.0.

. The pharmaceutical ition ing to embodiments 1-19, wherein the therapeutic compound has a polar surface area that is hydrophobic. 21. The pharmaceutical composition according to embodiments 1-20, wherein the therapeutic compound has a polar surface area that is less than 8.0 nm2. 22. The pharmaceutical ition according to embodiments 1-20, wherein the therapeutic compound has a polar surface area that is less than 6.0 nm2. 23. The pharmaceutical composition according to embodiments 1-22, wherein the therapeutic compound ses a eroidal anti-inflammatory drug (NSAID). 24. The pharmaceutical composition according to embodiment 23, wherein the NSAID comprises a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a W0 04655 44 non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor or a combination thereof.

. The pharmaceutical composition according to embodiments 1-24, wherein the therapeutic compound ses a PPARV agonist. 26. The pharmaceutical composition according to embodiment 25, wherein the PPARV agonist comprises Monascin, lrbesartan, Telmisartan, mycophenolic acid, Resveratrol, Delta(9)—tetrahydrocannabinol, a cannabidiol, Curcumin, Cilostazol, Benzbromarone, 6-shogaol, rhetinic acid, a thiazolidinedione, a NSAID, a fibrate, or a combination thereof. 27. The pharmaceutical composition ing to embodiments 1-26, wherein the therapeutic compound comprises a nuclear or binding agent. 28. The pharmaceutical composition according to embodiment 27, wherein the nuclear receptor binding agent comprises a ic Acid Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor (LXR) g agent, a Vitamin D binding agent, or a combination thereof. 29. The pharmaceutical composition according to embodiments 1-28, wherein the therapeutic nd comprises an anti-hyperlipidemic agent.

. The pharmaceutical composition according to embodiment 29, wherein the anti-hyperlipidemic agent comprises a fibrate, a statin, a ienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption tor, a pancreatic lipase inhibitor, a sympathomimetic amine, or a combination thereof. 31. The pharmaceutical ition according to embodiment 29, wherein the fibrate ses brate, Ciprofibrate, rate, Gemfibrozil, Fenofibrate, or a combination thereof. 32. The pharmaceutical composition according to ment 29, wherein the statin comprises Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof. 33. The pharmaceutical composition according to embodiment 29, n the niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof. 34. The pharmaceutical composition according to embodiment 29, wherein the bile acid sequestrant comprises Cholestyramine, Colesevelam, ipol, or a combination thereof.

. The pharmaceutical composition according to embodiment 29, wherein the cholesterol absorption inhibitor comprises Ezetimibe, a phytosterol, a sterol, a stanol, or a combination thereof.

W0 2012/104655 45 36. The ceutical composition according to ment 29, wherein the fat tion tor comprises Orlistat 37. The pharmaceutical composition according to embodiment 29, wherein the sympathomimetic amine comprises Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, |isdexamfetamine, cathine, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4- methylaminorex, pemo|ine, phenmetrazine, propylhexedrine, or a combination thereof. 38. The pharmaceutical composition according to ments 1-37, wherein the therapeutic compound comprises an ester of a therapeutic compound. 39. The pharmaceutical composition ing to embodiments 1-38, wherein the therapeutic compound ses an ester of a therapeutic compound according to embodiments 23-37. 40. The pharmaceutical composition according to embodiments 1-39, n the pharmaceutically- acceptable solvent is less than about 20% (v/v). 41. The ceutical composition according to embodiments 1-40, wherein the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable polar aprotic solvent, a pharmaceutically-acceptable polar protic solvent, a pharmaceutically-acceptable non-polar solvent, or a combination thereof. 42. The pharmaceutical composition according to embodiments 1-41, wherein the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable alcohol. 43. The pharmaceutical composition according to embodiment 42, wherein the pharmaceutically- acceptable alcohol comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof. 44. The pharmaceutical composition according to ment 42, wherein the pharmaceutically- acceptable alcohol comprises a C140 l. 45. The pharmaceutical composition according to embodiment 42, wherein the pharmaceutically- acceptable l comprises methanol, ethanol, propanol, butanol, ol, 1-hexadecanol, or a combination f. 46. The pharmaceutical ition according to embodiments 1-45, wherein the ceutically- acceptable solvent comprises a pharmaceutically-acceptable ester of pharmaceutically-acceptable alcohol and an acid.

W0 2012/104655 46 47. The pharmaceutical composition according to embodiment 46, wherein the pharmaceutically- able ester comprises methyl e, methyl buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl e, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, yl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl te, and 1-hexadecyl formate, or a combination thereof. 48. The pharmaceutical composition according to embodiments 1-47, wherein the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable polyethylene glycol (PEG) polymer. 49. The pharmaceutical composition according to embodiment 48, wherein the pharmaceutically- acceptable hylene glycol (PEG) polymer is less than about 2,000 g/mol. 50. The pharmaceutical composition according to embodiment 48, wherein the pharmaceutically- acceptable polyethylene glycol (PEG) polymer is more than about 2,000 g/mol. 51. The pharmaceutical composition according to ments 1-50, wherein the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable glyceride. 52. The pharmaceutical composition according to embodiment 51, wherein the pharmaceutically- acceptable glyceride comprises a monoglyceride, a diglyceride, a triglyceride, an acetylated monoglyceride, an acetylated diglyceride, an acetylated ceride, or a combination thereof. 53. The pharmaceutical ition according to embodiments 1-52, wherein the pharmaceutically- acceptable t is a liquid at 20°C. 54. The pharmaceutical composition according to embodiments 1-52, wherein the pharmaceutically- acceptable t is a solid at 20°C. 55. The pharmaceutical composition according to ment 54, wherein the pharmaceutically- acceptable solid solvent comprises menthol. 56. The pharmaceutical composition according to embodiments 1-55, wherein the adjuvant is at least 80% (v/v). 57. The pharmaceutical composition according to embodiments 1-56, wherein the pharmaceutically- acceptable adjuvant is a liquid at 20°C. 58. The pharmaceutical composition according to embodiments 1-56, wherein the pharmaceutically- able adjuvant is a solid at 20°C.

WO 04655 47 59. The pharmaceutical composition according to embodiments 1-58, n the pharmaceutically- acceptable adjuvant comprises a pharmaceutically-acceptable lipid. 60. The ceutical composition according to embodiment 59, n the pharmaceutically- acceptable lipid comprises a saturated fatty acid, an unsaturated fatty acid, or a combination thereof. 61. The ceutical composition according to embodiment 59 or 60, wherein the pharmaceutically- acceptable lipid comprises two or more saturated or unsaturated fatty acids. 62. The pharmaceutical composition according to embodiment 61, wherein the two or more saturated or unsaturated fatty acids includes palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof. 63. The pharmaceutical composition according to embodiments 60-62, wherein the unsaturated fatty acid has a melting point temperature of 20°C or below. 64. The pharmaceutical composition according to ments 60-62, wherein the unsaturated fatty acid is a solid at 20°C. 65. The pharmaceutical composition according to embodiments 60-62, wherein the unsaturated fatty acid comprises an omega fatty acid. 66. The pharmaceutical composition according to embodiment 59, wherein the pharmaceutically- able lipid comprises a pharmaceutically-acceptable oil. 67. The pharmaceutical composition according to ment 66, wherein the pharmaceutically- acceptable oil comprises almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or a combination thereof. 68. The pharmaceutical composition according to embodiments 1-67, wherein the pharmaceutical composition further ses a pharmaceutically-acceptable stabilizing agent. 69. The pharmaceutical composition according to embodiment 68, wherein the ceutically- acceptable stabilizing agent comprises water, a sacrificial acid comprising a fatty acid ent and acetic acid, ethyl e, a sodium acetate/acetic acid, a monoglyceride, an acetylated yceride, a diglyceride, an acetylated diglyceride, a fatty acid, a fatty acid salt, or a combination thereof.

W0 2012/104655 48 70. The pharmaceutical composition according to embodiment 68, wherein the pharmaceutically- acceptable stabilizing agent comprises a pharmaceutically-acceptable emulsifying agent. 71. The pharmaceutical composition according to embodiment 70, wherein the pharmaceutically- acceptable fying agent comprises a surfactant, a polysaccharide, a lectin, a phospholipid, or a combination thereof. 72. The pharmaceutical composition ing to embodiments 1-69, wherein the ceutical composition does not comprise a pharmaceutically-acceptable emulsifying agent. 73. A method of preparing a pharmaceutical ition, the method comprising the step of contacting a therapeutic compound with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition. 74. A method of preparing a pharmaceutical composition, the method sing the steps: a) contacting a pharmaceutically-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the solution formed in step (a) with a pharmaceutically-acceptable adjuvant under conditions which allow the ion of the pharmaceutical composition. 75. A method of preparing a ceutical composition, the method comprising the steps: a) contacting a pharmaceutically-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the on formed in step (a) with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition, wherein the ratio of the pharmaceutically-acceptable solvent to pharmaceutically-acceptable adjuvant is in a range from about 0:1 to about 1:25. 76. The method according to embodiments 73-75, wherein the eutic compound has a logP value indicating that the compound is soluble in an organic t. 77. The method according to embodiment 73-76, wherein the therapeutic nd has a logP value of more than 1.0. 78. The method according to embodiment 73-76, wherein the therapeutic compound has a logP value of more than 2.0. 79. The method according to embodiments 73-78, wherein the therapeutic nd has a polar surface area that is hydrophobic.

W0 2012/104655 49 80. The method according to embodiments 73-79, wherein the therapeutic compound has a polar surface area that is less than 8.0 nm2. 81. The method according to embodiments 73-79, wherein the therapeutic compound has a polar e area that is less than 6.0 nm2. 82. The method according to embodiments 73-81, n the therapeutic compound comprises a non- steroidal anti-inflammatory drug (NSAID). 83. The method according to embodiment 82, wherein the NSAID comprises a sa|icy|ate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an eno|ic acid tive NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) tor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a combination thereof. 84. The method according to ments 73-83, wherein the therapeutic compound comprises a PPARV agonist. 85. The method according to embodiment 84, wherein the PPARV agonist comprises Monascin, rtan, Telmisartan, mycophenolic acid, Resveratrol, 9)—tetrahydrocannabinol, a cannabidiol, Curcumin, Cilostazol, Benzbromarone, 6-shogaol, glycyrrhetinic acid, a thiazolidinedione, a NSAID, a fibrate, or a ation thereof. 86. The method according to embodiments 73-85, wherein the therapeutic compound comprises a nuclear receptor binding agent. 87. The method according to ment 86, wherein the nuclear receptor binding agent comprises a Retinoic Acid Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor (LXR) binding agent, a Vitamin D binding agent, or a combination thereof. 88. The method according to embodiments 73-87, wherein the therapeutic compound comprises an anti- hyperlipidemic agent. 89. The method according to embodiment 88, n the anti-hyperlipidemic agent comprises a fibrate, a statin, a tocotrienol, a , a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, a sympathomimetic amine, or a combination thereof. 90. The method according to embodiment 89, wherein the fibrate ses Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a combination thereof.

W0 2012/104655 50 91. The method according to embodiment 89, wherein the statin comprises statin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof. 92. The method according to embodiment 89, wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof. 93. The method according to embodiment 89, wherein the bile acid sequestrant comprises Cholestyramine, Colesevelam, Colestipol, or a combination thereof. 94. The method according to embodiment 89, wherein the terol absorption inhibitor ses Ezetimibe, a phytosterol, a , a , or a combination thereof. 95. The method according to embodiment 89, wherein the fat absorption inhibitor comprises Orlistat 96. The method according to embodiment 89, wherein the sympathomimetic amine comprises Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amine, phenylephrine, terenol, dobutamine, methylphenidate, |isdexamfetamine, cathine, one, methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4- aminorex, pemo|ine, phenmetrazine, propylhexedrine, or a combination thereof. 97. The method according to embodiments 73-96, wherein the therapeutic compound comprises an ester of a therapeutic compound. 98. The method according to embodiments 73-97, wherein the therapeutic compound comprises an ester of a therapeutic compound according to embodiments 76-97. 99. The method according to embodiments 74-98, wherein the ceutically-acceptable solvent is less than about 20% (WV). 100. The method according to embodiments 74-99, wherein the pharmaceutically—acceptable solvent comprises a ceutically-acceptable polar aprotic solvent, a pharmaceutically—acceptable polar protic solvent, a pharmaceutically-acceptable non-polar solvent, or a combination thereof. 101. The method according to embodiments 74-100, wherein the pharmaceutically—acceptable solvent comprises a pharmaceutically-acceptable alcohol. 102. The method according to embodiment 101, wherein the pharmaceutically-acceptable l comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic l, an lic alcohol, or a combination thereof.

W0 2012/104655 51 2012/050242 103. The method ing to embodiment 101, wherein the ceutically-acceptable alcohol comprises a C140 alcohol. 104. The method according to embodiment 101, n the pharmaceutically-acceptable alcohol comprises methanol, l, propanol, butanol, pentanol, 1-hexadecanol, or a combination thereof. 105. The method according to embodiment 101, wherein the pharmaceutically-acceptable solvent comprises a pharmaceutically-acceptable ester of pharmaceutically-acceptable alcohol and an acid. 106. The method according to embodiment 105, wherein the pharmaceutically-acceptable ester comprises methyl acetate, methyl buterate, methyl e, ethyl acetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, yl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate, and 1-hexadecyl formate, or a combination thereof. 107. The method according to embodiments 74-106, wherein the pharmaceutically-acceptable solvent is a pharmaceutically-acceptable polyethylene glycol (PEG) polymer. 108. The method ing to embodiment 107, wherein the pharmaceutically-acceptable polyethylene glycol (PEG) polymer is less than about 2,000 g/mol. 109. The method according to embodiment 107, wherein the pharmaceutically-acceptable polyethylene glycol (PEG) polymer is more than about 2,000 g/mol. 110. The method ing to embodiments 74-109, wherein the pharmaceutically-acceptable solvent comprises a pharmaceutically-acceptable glyceride. 111. The method according to embodiments 110, wherein the ceutically-acceptable glyceride is a monoglyceride, a diglyceride, a triglyceride, an acetylated monoglyceride, an acetylated diglyceride, an acetylated triglyceride, or a combination f. 112. The method according to ments 74-111, wherein the pharmaceutically-acceptable solvent is a liquid at 20°C. 113. The method according to embodiments 74-111, wherein the pharmaceutically-acceptable solvent is a solid at 20°C. 114. The method according to embodiment 113, wherein the pharmaceutically-acceptable solid t is menthol.

W0 2012/104655 52 2012/050242 115. The method according to embodiments 73-114, wherein the pharmaceutically-acceptable nt is at least 80% (v/v). 116 . The method according to embodiments 73-115, wherein the pharmaceutically-acceptable adjuvant is a liquid at 20°C. 117 . The method ing to embodiments 73-115, wherein the pharmaceutically-acceptable adjuvant is a solid at 20°C. 118. The method according to embodiments 73-117, wherein the pharmaceutically-acceptable adjuvant ses a pharmaceutically-acceptable lipid. 119 . The method according to embodiment 118, wherein the pharmaceutically-acceptable lipid comprises a pharmaceutically-acceptable saturated fatty acid, an unsaturated fatty acid, or a combination 120. The method according to embodiment 118 or 119, wherein the pharmaceutically-acceptable lipid comprises two or more pharmaceutically-acceptable saturated or unsaturated fatty acids. 121 . The method according to embodiments 120, wherein the two or more pharmaceutically-acceptable saturated or unsaturated fatty acids include palmitic acid, c acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof. 122. The method according to embodiments 119-121, wherein the pharmaceutically-acceptable rated fatty acid has a melting point temperature of 20°C or below. 123. The method according to embodiments 119-121, wherein the pharmaceutically-acceptable unsaturated fatty acid is a solid at 20°C. 124. The method according to embodiments 119-123, wherein the pharmaceutically-acceptable unsaturated fatty acid comprises an omega fatty acid. 125. The method according to embodiments 118-124, wherein the pharmaceutically-acceptable lipid comprises a pharmaceutically-acceptable oil. 126 . The method according to embodiment 125, wherein the pharmaceutically-acceptable oil comprises almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, seed oil, grape seed oil, hazelnut oil, hemp oil, d oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, wer oil, walnut oil, wheat germ oil, or a combination thereof.

W0 2012/104655 53 127. The method according to embodiments 74 or , wherein in step(b) the ratio of the pharmaceutically-acceptable solvent to ceutically-acceptable adjuvant is in a range from about 0:1 to about 1:25. 128. The method according to embodiments 73-127, wherein the step (a) further comprising contacting a pharmaceutically-acceptable stabilizing agent with the pharmaceutically-acceptable solvent and the therapeutic nd. 129.The method according to embodiment 128, n the pharmaceutically-acceptable stabilizing agent comprises water, a sacrificial acid comprising a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid, a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated diglyceride, a fatty acid, a fatty acid salt, or a combination thereof. 130. The method according to embodiment 128 or 129, wherein the pharmaceutically-acceptable stabilizing agent comprises a pharmaceutically-acceptable emulsifying agent. 131. The method according to embodiment 130, wherein the pharmaceutically-acceptable emulsifying agent comprises a surfactant, a polysaccharide, a lectin, a phospholipid, or a combination thereof. 132. The method according to embodiments 73-129, wherein the pharmaceutical ition does not comprise a ceutically-acceptable emulsifying agent. 133. The method according to embodiments 74-132, wherein the method r comprises ng the pharmaceutically-acceptable solvent from the pharmaceutical composition. 134. The method according to embodiment 133, wherein at least 5% the pharmaceutically-acceptable solvent is removed from the pharmaceutical composition. 135. The method according to embodiment 133 or 134, wherein at, removal of solvent from the pharmaceutical composition disclosed herein is carried out at a temperature of less than 20°C. 136. The method ing to embodiments 73-135, wherein the pharmaceutical composition made is according to embodiments 1-72. 137 A method of treating an individual with a c inflammation, the method comprising the step of: administering to the individual in need thereof a ceutical composition according to embodiments 1-72, wherein administration results in a reduction in a symptom associated with the c inflammation, thereby treating the dual. 138. Use of a pharmaceutical composition according to embodiments 1-72 in the manufacture of a medicament for the treatment of a chronic inflammation.

W0 2012/104655 54 139. Use of a ceutical composition according to embodiments 1-72 for the treatment of a c inflammation. 140. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with acne, acid /heartburn, age related macular degeneration (AMD), allergy, allergic rhinitis, Alzheimer’s disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma. atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac e, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, ic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, ive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve ction, hepatitis, hidradenitis suppurativa, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, conjunctivitis, laryngitis, lupus nephritis, mastitis, ditis, meningitis, metabolic syndrome (syndrome X), a migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, itis, orchitis, osteochondritis, osteopenia, yelitis, osteoporosis, is, otitis, pancreatitis, son’s disease, parotitis, pelvic inflammatory e, pemphigus vularis, pericarditis, peritonitis, gitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, sis, pulpitis, pyelonephritis, pylephlebitis, renal e, reperfusion injury, tis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complication, synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, ulosis, tumor, urethritis, s, uveitis, vaginitis, vasculitis, or vulvitis. 141. The method according to embodiment 137 or the use according to embodiment 138 or 139, n the chronic inflammation is a tissue inflammation. 142. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is a ic mation. 143. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is an arthritis.

W0 04655 55 2012/050242 144. The method or use according to embodiment 140 or 143, wherein the arthritis is a monoarthritis, an oligoarthritis, or a polyarthritis. 145. The method or use according to ment 140 or 143, wherein the arthritis is an auto-immune disease or a non-autoimmune disease. 146. The method or use according to ment 140 or 143, n the arthritis is an osteoarthritis, a rheumatoid arthritis, a juvenile idiopathic arthritis, a septic arthritis, a spondyloarthropathy, a gout, a pseudogout, or s disease. 147. The method or use according to embodiment 146, wherein the spondyloarthropathy is an ankylosing spondylitis, a reactive arthritis (Reiter's syndrome), a psoriatic arthritis, an pathic arthritis associated with inflammatory bowel disease, a Whipple disease or a Behcet disease. 148. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is an autoimmune disorder. 149. The method or use according to embodiment 140 or 148, wherein the autoimmune disorder is a systemic autoimmune disorder or an organ-specific mune disorder. 150. The method or use according to embodiment 140 or 148, wherein the autoimmune disorder is an acute disseminated alomyelitis (ADEM), an Addison's disease, an allergy, an anti- olipid antibody syndrome (APS), an autoimmune hemolytic anemia, an mune hepatitis, an autoimmune inner ear disease, a bullous pemphigoid, a celiac disease, a Chagas disease, a chronic ctive pulmonary disease (COPD), a diabetes mellitus type 1 (IDDM), an endometriosis, a Goodpasture's syndrome, a Graves' disease, a Guillain-Barré syndrome (GBS), a Hashimoto's ditis, a hidradenitis suppurativa, an idiopathic thrombocytopenic purpura, an inflammatory bowel disease, an interstitial cystitis, a lupus (including a discoid lupus erythematosus, a drug-induced lupus erythematosus. a lupus nephritis, a neonatal lupus, a subacute cutaneous lupus matosus, a systemic lupus erythematosus, a morphea, a multiple sclerosis (MS), a enia gravis, a myopathy, a narcolepsy, a neuromyotonia, a pemphigus vulgaris, a pernicious anaemia, a primary y cirrhosis, a recurrent disseminated encephalomyelitis, a rheumatic fever, a schizophrenia, a scleroderma, a Sjogren's me, a tenosynovitis, a vasculitis, or a vitiligo. 151. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is a myopathy. 152. The method or use according to embodiment 137 or 148, wherein the myopathy is a dermatomyositis, an inclusion body myositis, or a polymyositis.

W0 2012/104655 56 2012/050242 153. The method according to embodiment 137 or the use ing to embodiment 138 or 139, wherein the chronic inflammation is a vasculitis. 154. The method or use ing to embodiment 140 or 153, wherein the vasculitis is itis is a Buerger's disease, an arteritis, a cerebral vasculitis, a Churg-Strauss tis, a cryoglobulinemia, an ial cryoglobulinemic vasculitis, a giant cell arteritis, a Golfer's vasculitis, a Henoch- Schonlein purpura, a hypersensitivity itis, a ki disease, a phlebitis, a microscopic polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, a thrombophlebitis, a Wegener's granulomatosis, or a vasculitis secondary to connective tissue disorder, or vasculitis secondary to viral infection. 155. The method according to embodiment 137 or the use according to embodiment 138 or 139, n the chronic inflammation is associated with a skin disorder. 156. The method or use according to embodiment 140 or 155, wherein the skin disorder is a dermatitis, an eczema, a statis dermatitis, a hidradenitis suppurativa, a psoriasis, a rosacea or a scleroderma. 157. The method or use according to embodiment 156, wherein the eczema is an atopic eczema, a contact eczema, a xerotic eczema, a seborrhoeic dermatitis, a dyshidrosis, a discoid eczema, a venous eczema, a dermatitis herpetiformis, a neurodermatitis, or an autoeczematization. 158. The method or use according to embodiment 156, wherein the psoriasis is a plaqure psoriasis, a nail psoriasis, a guttate psoriasis, a scalp psoriasis, an inverse sis, a pustular psoriasis, or an erythrodermis psoriasis. 159. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with a gastrointestinal disorder. 160. The method or use according to embodiment 140 or 159, wherein the gastrointestinal disorder is an irritable bowel disease or an inflammatory bowel. 161. The method or use according to embodiment 160, n the matory bowel is a Crohn's disease or an ulcerative colitis. 162. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with a cardiovascular disease. 163. The method or use according to embodiment 140 or 162, wherein the vascular disease is a hypertension, heart valve dysfunction, congestive heart failure, myocardial infarction, a diabetic cardiac conditions, a blood vessel inflammation, arterial occlusive e, a peripheral arterial WO 04655 57 disease, an aneurysm, an embolism, a dissection, a pseudoaneurysm, a vascular malformation, a vascular nevus, a thrombosis, a phlebitis, a varicose veins, or a stroke. 164. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with a cancer. 165. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is ated with a pharmacologically-induced inflammation. 166. The method according to embodiment 137 or the use ing to embodiment 138 or 139, n the chronic mation is associated with an infection. 167. The method or use according to embodiment 140 or 166, wherein the infection is a bacterial cystitis, a bacterial encephalitis, a pandemic influenza, a viral encephalitis, a viral hepatitis A, a viral hepatitis B, or a viral hepatitis C. 168. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with a tissue or organ . 169. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with a transplant rejection or a graft-versus-host disease. 170. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic mation is associated with a Th1-mediated matory disease. 171. The method according to embodiment 137 or the use according to embodiment 138 or 139, wherein the chronic inflammation is associated with chronic neurogenic inflammation. 172. The method ing to embodiments 137 or 140-171 or the use according to embodiments 138- 171, wherein upon administration to an individual, the pharmaceutical ition comprising the therapeutic compound according to embodiments 1-72 results in a bio-distribution of the therapeutic nd different than a bio-distribution of the therapeutic compound included in the same pharmaceutical composition, except without the ceutically-acceptable adjuvant. 173. The method according to embodiments 137 or 140-172 or the use according to embodiments 138- 172, wherein upon administration to an individual, the amount of the eutic compound of the pharmaceutical composition according to embodiments 1-72 delivered to a macrophage is at least % of the total amount of the therapeutic compound ned in the administered pharmaceutical composition.

W0 2012/104655 58 174. The method ing to embodiments 137 or 140-173 or the use according to embodiments 138- 173, wherein upon administration to an individual, the pharmaceutical composition according to embodiments 1-72 reduces inal tion by at least 5% when compared to the pharmaceutical composition according to embodiments 1-72, except without the pharmaceutically-acceptable adjuvant. 175. The method according to embodiments 137 or 140-171 or the use according to embodiments 138- 174, wherein upon administration to an individual, the pharmaceutical composition according to embodiments 1-72 reduces gastric tion by at least 5% when compared to the pharmaceutical composition ing to embodiments 1-72, except without the pharmaceutically-acceptable EXAMPLES The ing non-limiting es are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples should not be construed to limit any of the embodiments bed in the present ication, including those pertaining to the compounds, alcohols, lipids, pharmaceutical compositions, methods of preparing pharmaceutical compositions, or methods or uses of treating a chronic inflammation or disease associated with chronic inflammation.

Example 1 Liquid Formulations of Pharmaceutical Composition This example illustrates how to make a pharmaceutical composition as disclosed herein as a liquid formulation.

Initially, 2,400 mg of ibuprofen was contacted directly with 2.0 mL of rapeseed oil in an attempt to dissolve a therapeutic compound directly into an adjuvant at a concentration of 1,200 mg/mL. However, ibuprofen remained insoluble in the oil and did not ve to ntially measureable degree.

Ibuprofen remained insolubility even if the mixture was mixed by vortexing for 20 s, the contacting was done at 20°C or 37°C, and/or the mixture was allowed to incubate for 24 hours at 20°C or 37°C. The insolubility of ibuprofen in rapeseed oil was surprising given that ibuprofen has a logP value of 3.6; such a high logP value is indicative of a compound that would readily soluble in an adjuvant like oil.

Since, it was not possible to dissolve ibuprofen directly into oil, despite its high logP value, it was next tried to dissolve a therapeutic drug in a solvent to first create a solution comprising the nd.

As a first step, experiments were conducted to the miscibility of a solvent in an adjuvant like oil in the absence of a therapeutic compound. In these experiments 0.5 mL ethanol was contacted with ten ent volumes of ed oil (Table 1). Each mixture was tested at 22°C and at 37°C in which the ethanol and oil were initially heated in a water bath before being mixed together. Mixing was attempted by W0 04655 59 vortex mixing for 20 seconds, and the containers were allowed to settle before visual assessment, either immediately, or after 24 hours. Each mixture was evaluated to determine whether or not the ethanol and rapeseed oil form immiscible layers, or a homogeneous mixture. The s are summarized in Table 1.

Mixtures comprising solvent:adjuvant ratios of 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6 formed immiscible layers at either 22°C or at 37°C, either immediately or after 24 hours of incubation, indicating that the ethanol and oil did not mix well at these ratios. However, in t:adjuvant ratios above 1:7 a homogeneous mixture was formed under all conditions tested.

Table 1. Liquid Formulations without Therapeutic compound Components Temperature Solvent Adjuvant 22°C 37°C ("‘L) ("‘L) m— 24 hours Immediate 24 hours 0.5 0.5 -— IL IL IL 0.5 1.0 -— IL IL IL 0.5 1.5 IL IL IL 0.5 2.0 IL IL IL 0.5 2.5 IL IL IL 0.5 3.0 IL IL IL 0.5 3.5 HM HM HM 0.5 4.0 HM HM HM 0.5 4.5 HM HM HM 0.5 5.0 HM HM HM lL, lmmiscible layers.

HM, Homogeneous mixture.

Once the appropriate ratios of alcohol and lipid necessary to form a homogenous e were determined, it was next determined whether ting a therapeutic compound first in a solvent before contacting with an adjuvant would result in the compound dissolving in the solvents. To conduct these experiments, either 1,000 mg or 1,200 mg of ibuprofen was ved into 0.5 mL of ethanol. The resulting alcohol solution was then contacted with rapeseed oil at two different solvent:adjuvant ratios (1 :2 and 1:9). Each e was tested at 20°C and at 37°C in which the ethanol solution and oil were initially heated in a water bath before being mixed together. Mixing was attempted by vortex mixing for 20 seconds, and the containers were allowed to settle before visual assessment, either immediately, or after 24 hours. Each mixture was evaluated to ine whether or not the ethanol solution and rapeseed oil form immiscible layers, or a homogeneous mixture. The results are summarized in Table 2. In contrast to the situation in the e of a therapeutic nd, when ibuprofen is present in the ethanol, it caused the ethanol and oil to form a homogeneous mixture under all conditions tested in solvent:adjuvant ratios above 1:2. This observation was very sing because, although not wish to be bound by any theory, it appears that a therapeutic nd may be having some effect on the manner in which an adjuvant and solvent interact with each other, such that a homogeneous mixture is formed in a way that does not occur when the eutic compound is absent. In on, the results indicate that a therapeutic compound can be formulated at clinically useful concentrations.

Table 2. Liquid Formulations with Therapeutic Compound W0 2012/104655 60 C0mponents Compound Solvent Adjuvant _— (mg) <mL> (mm "mm ——-———— IL, Immiscible layers.

HM, Homogeneous mixture.

Example 2 Liquid ations of ceutical Composition This example illustrates how to make a pharmaceutical composition as disclosed herein as a liquid formulation.

To prepare a pharmaceutical composition disclosed herein using gemfibrozil, the following formulations were examined. In these experiments, 600 mg gemfibrozil was ted with different volumes of ethanol, as the solvent, warmed to 37°C, and the resulting solution was then contacted with different volumes of linseed oil, as the adjuvant, warmed to 37°C (Table 3). Each formulation was evaluated to determine whether or not the ethanol and linseed oil form ible layers, a clear homogeneous mixture, as well as whether or not the gemfibrozil crystallized out of solution. The results are ized in Table 3.

Like ibuprofen in Example 1 above, gemfibrozil remained insoluble in the oil alone and did not dissolve to substantially measureable degree. The formulation comprising 0.2 mL ethanol was unable to completely dissolve gemfibrozil. In addition, although the ation comprising 0.3 mL ethanol was capable of dissolving gemfibrozil, the therapeutic nd began to crystallizing out of solution within 3 hours and complete crystallization occurred within 48 hours. All other formulations tested were e of dissolving gemfibrozil and forming a pharmaceutical composition disclosed herein. r, only the formulation comprising 0.5 mL l appeared to for a stable pharmaceutical composition in that gemfibrozil remained completely ved after three weeks.

Table 3. Liquid Formulations with Therapeutic Compound Compound Solvent Adiuvant _— (mgl ("‘L) ("‘L) —m “_H—— _———H —m-—— —m-—— HM, Clear homogeneous mixture.

W0 2012/104655 61 CR, Crystallization.

IM, Immiscible.

Example 3 Liquid Formulations of Pharmaceutical Composition This e illustrates how to make a pharmaceutical composition as disclosed herein as a liquid ation.

To prepare a pharmaceutical composition disclosed herein using ibuprofen, the following formulation was performed. In these experiments, 4 g ibuprofen was contacted with 3.6 mL of ethyl acetate, as the solvent, and the resulting solution was then contacted with 76.4 mL of rapeseed oil, as the adjuvant. The resulting pharmaceutical composition had a solvent:adjuvant ratio of about 1:21. This pharmaceutical composition was then placed in a round bottom flask and subjected to low re on a rotary evaporator. The temperature was kept low and evaporation continued to nt weight. The total volume lost was 3.65% of the total . The resulting liquid no longer retained the characteristic ethyl acetate odor/taste, indicating that there was a substantial removal of ethyl acetate form the pharmaceutical composition.

Example 4 Solid Formulation of Pharmaceutical Composition This example illustrates how to make a pharmaceutical composition as disclosed herein as a solid formulation.

Since n fatty acids are liquid at room temperature, while others are solid, an examination of the different fatty acids was undertaken in an effort to evaluate the potential of each fatty acid in the manufacture of a solid formulation. This understanding would enable the development of a wide array of solid formulation by adjusting the relative ratios of each fatty acid. As an initial experiment, linolenic acid, linoleic acid, palmitic acid and stearic acid were evaluated to assess whether it was le to prepare a pharmaceutical composition disclosed herein that could be formulated using only one of these fatty acids to be a solid or semi-solid at 22°C (simulating room temperature ions), but melt into a liquid at 37°C (simulating internal body ature conditions after ingestion).

Four different test formulations were prepared and evaluated on their y to form a solid dose formulation at 22°C and melt into a homogeneous solution at 37°C without g a suspension (Table 4). Formulation 1 was prepared by ving 200 mg of fen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg of stearic acid (Tm of about 67-72°C) and heated at 60°C for 30 minutes to form a neous solution. Formulation 1 solidified immediately upon cooling to 22°C. Formulation 1 remained a solid even after incubating at 37°C overnight. Formulation 2 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg of palmitic acid (Tm of about 61-62°C) and heated at 60°C for 30 minutes to form a W0 2012/104655 62 homogeneous on. Formulation 2 fied about 1 hour after cooling to 22°C. lncubating at 37°C overnight cause Formulation 2 to completely melt into a clear homogenous liquid. However, Formulation 2 once again solidified about 1 hour after cooling to 22°C. Formulation 3 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of l, and the resulting solution was then mixed with 200 mg of linoleic acid (Tm of about -5°C) and heated at 37°C for 2 hours to form a homogeneous solution. ation 3 remained a liquid, even after cooling to 22°C for 72 hours. Formulation 4 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of l, and the resulting solution was then mixed with 200 mg of linolenic acid (Tm of about -11°C) and heated at 37°C for 2 hours to form a homogeneous solution.

Formulation 4 ed a liquid, even after cooling to 22°C for 72 hours.

Table 4. Solid Formulations with Therapeutic Compound Compound Solvent Adjuvant (mg) (mg) (mg) 200 (stearicacid) 200 (palmitic acid 2:1 200 (Iinoleicacid) 400 200 enic acid) 2 1 Based on these data, a solid dosage form of a pharmaceutical composition disclosed herein can be made. For example, a pharmaceutical composition will be formulated to be solid or semi-solid at 22°C, but melt into a proper clear solution (and not a suspension) at 37°C (Table 5).

Table 5. Solid Formulations of Pharmaceutical Compositions nd 600 mg Ibuprofen Solvent 500mg ol Adjuvant 000mg Palmitic acid 000mg Stearic acid 50mg Linolenic acid 250mg Linoleic acid Ratio Volume Concentration 120 mg/mL Example 5 Animal Model for Intestinal Erosion To assess whether a pharmaceutical composition disclosed herein reduced gastric irritation, experiments were conducted using an intestinal erosion murine model.

Sprague-Dawley rats were divided into seven experimental groups containing five animals each.

After fasting overnight, the s were challenged with one with one of seven different treatments.

Group A was a control in which each mouse was orally administered 1% methylcellulose/0.5% polysorbate 80 vehicle only. Group B was a control in which each mouse was orally administered W0 2012/104655 63 solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil). Group C was a control in which each mouse was orally administered 150 mg/kg aspirin. Group D was a control in which each mouse was orally stered 100 mg/kg ibuprofen suspended in 1% cellulose/0.5% polysorbate 80. Group E was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054-100) comprising 100 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Group F was a control in which each mouse was orally stered 100 mg/kg fen suspended in 1% methylcellulose/0.5% polysorbate 80. Group G was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054-200) comprising 200 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Animals were sacrificed 4 hours after treatment and the stomachs were examined for degree of hemorrhage and severity of mucosal erosive s. Gastric irritation was scored as follows: 0, no lesions; 1, hyperemia; 2, one or two slight lesions; 3, more than two slight lesions or severe lesions; and 4, very severe lesions. A score of 50% or more relative to Group C (aspirin-treated control group), which was set to 100%, was considered a ve score for gastric irritation.

Results are shown in Table 6. Group D (100 mg/kg of ibuprofen-treated control group) and Group F (200 mg/kg of ibuprofen-treated l group) produced gastric lesions that were 75% and 95%, respectively, severe as those induced by Group C (aspirin-treated control group). However, Group E 4treated experimental group) and Group G (BC1054treated experimental group) produced gastric lesions that were 20% and 40%, respectively, as severe as those associated with Group C (aspirin-treated control . These results demonstrate that that a pharmaceutical composition disclosed herein reduced the extent to which a therapeutic compound may cause mucosal s and cause gastric irritation.

Table 6. Results from Intestinal Erosion Assay Group % Aspirin Erosion Ulceration Score Positive score for gastric erosion.

W0 2012/104655 64 Example 6 Animal Model for a Respiratory Inflammation To assess the effectiveness of a pharmaceutical composition sed herein in treating a respiratory inflammation, experiments were ted using a viral-induce influenza murine model.

C57BLK/6 female mice (6-7 weeks old) were divided into three experimental groups containing ten animals each. On day 1, animals received an intranasal lethal dose (50 uL total, 25 uL/nostril) of Influenza A/PR/8/34 under halothane-induced anaesthesia. On day 3, post-challenge with the virus, the animals received one of three treatments. Group A was a control in which each mouse was orally administered 335.6 ug of ibuprofen dissolved in 10 uL DMSO (no adjuvant). Group B was a control in which each mouse was orally stered solvent/adjuvant e only (gavage of 10% ethanol and 90% linseed oil). Group C was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054) sing 335.6 ug of ibuprofen, 10% ethanol, and 90% linseed oil. A dose of 335.6 ug of ibuprofen in the mouse is equivalent to 20mg/kg/day, or 1200 mg/day for a human (the maximum rd dose for ibuprofen). Animals were weighed, and monitored for signs of infection daily for up to day 6 when all animals were culled. Figure 1 clearly shows that oral administration of the solvent/adjuvant vehicle only (Group B) had an 80% mortality rate and that oral administration of ibuprofen only (Group A) exhibited a mortality rate of 60%. However, a single oral administration of BC1054 reduced the mortality rate to only 20%.

To determination of levels of lL-10 and lL-4, an ELISA was performed using a 96-well plate coated with a capture antibody for lL-10 or lL-4. Lungs ted from the culled mice were homogenized at 4°C, and the supernatant collected and stored at -70°C until needed. Thawed samples were vortexed for 30 seconds immediately before adding to the ELISA plate. Serial ons were performed within the plate with both the sample and the standards by pipetting 60 uL of assay diluent into each well. The plate was sealed and ted for 2 hours at room temperature. For lL-4, 60 uL of working detector was added (Detection Antibody + SAv-HRP reagent) to each well. The plate was sealed and incubated for 1 hour at room temperature. For lL-10, 60 uL of detection antibody was diluted in assay diluent to each well. Plates were washed and 60uL of SAv-HRP enzyme was d in assay diluent and added to the plate. The plate was sealed and incubated for 20 minutes at room temperature. Plates were then washed ten times. 60 uL of substrate on were added to each well and the plate was incubated for 30 minutes at room temperature in the dark. 60 uL of stop on was added to each well and absorbance was read at 450 nm. lL-10 and lL-4 concentrations were expressed as pg/mg of lung tissue. These results indicate that a pharmaceutical composition disclosed herein was effective in treating a atory inflammation.

Results show that animals from the Group A ofen-treated control group) and Group B (solvent/adjuvant vehicle-treated control group) controls exhibited 2600 pg/mg and 2000 pg/mg of lL-10, respectively (). However, Group C (BC1054-treated experimental group) revealed an lL-10 concentration of 6000 pg/mg, 3-fold higher than that seen in the control animals. These result also shows that animals from the Group A (ibuprofen-treated control group) and Group B (solvent/adjuvant vehicle- W0 04655 65 d control group) controls exhibited 6900 pg/mg and 5400 pg/mg of IL-4, respectively, while Group C (BC1054-treated mental group) exhibited an IL-4 concentration of 8300 pg/mg (FIG. ZB). Taken together, synergistic increase in IL-10 levels and/or the increase in IL-4 levels suggest that at least part of the cy observed for BC1054 was by inducing a switch from a Th1 to a Th2 response.

Further experiments were done to further determine which cell types were ated to release cytokines upon administration of a BC1054. C57BLK/6 female mice (6-7 weeks old) were divided into three experimental groups containing ten animals each. On day 1, animals received an intranasal lethal dose (50 uL total, 25 uL/nostril) of Influenza H1N1 under halothane-induced anaesthesia. On day 3, post- challenge with the virus, the animals received one of three treatments. Group A was a control in which each mouse was orally administered 335.6 pg of fen ved in 10 uL DMSO (no adjuvant).

Group B was a l in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil) (no ibuprofen). Group C was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054) sing 335.6 pg of ibuprofen, 10% ethanol, and 90% linseed oil. Lungs collected from fatally- ed mice were nized at 4°C, and the supernatant collected, , and IL-10, TNFd and IFNy levels measured using an ELISA.

The results show that Group A (ibuprofen-treated control group) and Group C 4-treated mental group) animals exhibited an increased IL-10 levels (). However, these IL-10 increases were associated with very different pharmacodynamic effects, and the pattern of pro- inflammatory cytokine reduction highlights the source of the IL-10 and its relevance to the effect on survival. For example, TNFd (which is macrophage-related cytokine) was not as markedly ted (FIG 3B) in Group A (ibuprofen-treated control group) animals, whereas the levels of IFNy (which is a lymphocyte-derived cytokine) were markedly lowered in this group when compared to Group C (BC1054- treated experimental group) animals (). This cytokine release pattern was associated with a poor outcome. r, in Group C (BC1054-treated experimental group) animals, TNFd levels were markedly lowered (FIG 38), while IFNy levels were largely unaffected (FIG 3C). This demonstrates that a pharmaceutical composition disclosed herein shows a protective effect on the H1N1-induced lethality through, in part, a macrophage-derived IL-10 levels rather than lymphocyte-derived IL10.

Example 7 Animal Model for Inflammatory Bowel Disease To assess the effectiveness of a pharmaceutical composition disclosed herein in treating an inflammatory bowel disease, experiments were conducted using a TBS-induced colitis murine model.

C57BI/6 male mice (6-7 weeks old) were divided into seven experimental groups containing at least ten animals each. On day 0, colitis was induced in mice from Groups B-G by intrarectal administration of 100 uL of TNBS (4 mg) in 50% ethanol under isoflurane anesthesia. Animals were dosed either once or three times a day from day -1 to day 5 with one of seven different treatments.

W0 2012/104655 66 Group A was a control in which each mouse was orally administered ethanol vehicle only. Group B was a control in which each mouse was orally administered 1% methylcellulose vehicle only. Group C was a control in which each mouse was orally administered solvent/adjuvant vehicle only e of 10% ethanol and 90% linseed oil). Group D was a control in which each mouse was orally administered 3 mg/kg of Prednisolone. Group E was a control in which each mouse was orally administered 20 mg/kg of ibuprofen suspended in 1% methylcellulose (1 mL/kg) (no adjuvant). Group F was the mental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054- ) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Group G was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054- ) comprising 30 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. All animals were weighed daily and assessed visually for the presence of diarrhea and/or bloody stool. On day 3 and on day 5 colitis severity was assessed in all animals using video endoscopy, where images were taken and colitis ty scored visually by a blinded observer on a scale from 0 to 4 as follows: 0, normal; 1, loss of vascularity; 2, loss of vascularity and lity; 3, friability and ns; and 4, ulcerations and bleeding.

Following endoscopy on day 5, animals were sacrificed and the colon removed and its length and weight measured. Serum samples were obtained and the colon was fixed in 10% formalin. An additional piece of colon tissue was collected, weighed, and snap frozen in liquid nitrogen.

Results from these experiments are shown in Table 7. Group B (TNBS—treated control group) showed a tically icant difference in mean weight change when compared to Group A (untreated ethanol control group), all other group comparisons showed no difference in mean weight . Group B (TNBS—treated control group) showed a statistically significant decrease in mean colon length when compared to Group A (untreated ethanol control group). Additionally, Group D (Prednisolone-treated control group), Group F (BC1054treated experimental group), and Group G (BC1054treated experimental group) all showed a statistically significant increase in mean colon length when ed to Group B treated control group). Although Group B (TNBS—treated control group) showed a tically significant increase in mean colon weight when compared to Group A (untreated ethanol control group), all other group comparisons showed no difference in mean colon weight. With regards to the endoscopy colitis score, Group D (Prednisolone-treated control group) showed a statistically significant reduced mean colitis scores on both day 3 and day 5 when ed to Group B (TNBS- treated control group). In a similar manner, both Group F (BC1054treated experimental group) and Group G (BC1054treated mental group) showed a tically significant reduced mean colitis scores on day 5 when compared to Group B (TNBS—treated control group). These results indicate that a pharmaceutical composition disclosed herein was effective in treating an inflammatory bowel disease.

Table 7. Results from Inflammatory Bowel e Mean Mean Mean Endoscopy Colitis Severity Score Animal Weight Colon Length Colon Weight 23.939 215mg —-_ 23699 258mg 1-99 24259 284mg 1-4‘0 1 Statistically significance difference compared to Group A (p= 0. 029). 2 Statistically significance ence compared to Group A (p= 0. 001 ). 48tatistica|ly3 significance difference compared to Group B (p= 0. 001). :8tatistically significance difference compared to Group B (p= 0. 001). :8tatistically significance difference ed to Group B (p= 0. 034). :8tatistically significance difference compared to Group A (p= 0. 009). stically significance difference compared to Group B (p= 0. 005). :8tatistically significance difference compared to Group B (p= 0. 002). 908tatistically significance difference compared to Group B (p= 0. 045).

O8tatistica|ly significance difference compared to Group B (p= 0. 002).

Animal Model for a Systemic Arthritis To assess the effectiveness of a pharmaceutical composition disclosed herein in treating tis, ments were conducted using an OI-collagen antibody induced arthritis (ACAIA) murine model that mimics a systemic arthritis like rheumatoid arthritis.

BALB/c mice, on day 0, were intravenously injected with a single inoculation with 2 mg/200 uL of an lagen ll monoclonal antibody, followed by an eritoneal injection of 50 ug/200 uL of lipopolysaccaride (LP8) at day 3. From day 3 and daily until day 8 and then on days 10 and 12, paw volumes (plethysmography) and arthritis scores were taken. The same animals were also treated daily from days 0 to day 11, the animals received one of six treatments. Group A was a l in which each mouse was orally administered phosphor-buffered saline (PBS) vehicle only. Group B was a control in which each mouse was eritoneally administered 10 mg/kg of Enbrel in PBS. Group C was a control in which each mouse was orally administered 1% methylcellulose vehicle only. Group D was a control in which each mouse was orally administered 40 mg/kg of ibuprofen suspended in 1% methylcellulose (1 mL/kg) (no adjuvant). Group E was a control in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil). Group F was the experimental group in which each mouse was orally administered a pharmaceutical composition disclosed herein 4-20) sing 20 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil.

Group G was the experimental group in which each mouse was orally administered a ceutical composition disclosed herein (BC1054-30) comprising 30 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Through the entire experiment (12 days), animals were checked daily for clinical signs al observations of the health of the animal) and body s. Total arthritis scores are determined by summing the arthritis scores of individual paws using the following grades: 0 = no signs of arthritis, 1 = mild but definite redness and swelling of the ankle/wrist or apparent redness or swelling limited to individual digits, regardless of the number of affected digits, 2 = moderate to severe redness and ng of the ankle/wrist, 3 = redness and swelling of the entire paw ing digits, 4 = maximally inflamed limb with involvement of multiplejoints.

The results of this experiment are shown in As expected, Group B (Enbrel-treated control group) animals showed the best results, with the lowest paw thicknesses at about 1.6 mm on day 12. The W0 2012/104655 68 two pharmaceutical compositions, Group F (BC1054treated mental group) and Group G (BC1054treated mental group) animals displayed the next best results, with Group G mice producing a paw thickness of only 1.7 mm, and Group F mice producing a paw thickness of about 1.73 mm. The negative control Group A (PBS vehicle-treated control group), Group C (methoxycellulose vehicle-treated control group), and Group E (solvent/adjuvant vehicle-treated control group) animals, as well as Group D (ibuprofen-treated control group) performed icantly worse with paw thicknesses of 1.9 mm and over when compared to Group F and Group G animals. These results indicate that a ceutical composition disclosed herein was effective in treating an arthritis.

Example 9 Case Studies for the Treatment of Chronic Inflammation A 47 year old female was diagnosed with reactive arthritis in one knee was treated with a pharmaceutical composition disclosed herein (BC1054) sing 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (1200 mg uid) over a 3 day period and found that the ng and pain started to go away after 1 day and was completely better after 3 days. ctive standard ibuprofen treatment was subsequently ceased. At a 3 month follow up, no signs of the reactive arthritis have been observed.

A 50 year old male was diagnosed with a chronically inflamed ankle after a maison neuve fracture in the ankle. The patient was taking 30 mg e with 500 mg paracetamol bid, along with 10 mg diclofenac tid for 8 months to control pain. He took a 5 day course of a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% ed oil (600 mg bid) and after 2 days reported a significant improvement in his pain, and then after 3 days he reported that the pain was completely controlled. He has subsequently ceased the codeine, paracetamol and diclofenac, and after a 2 month follow the patient is still pain free.

A 33 year old female diagnosed with stress related eczema, had an acute flare of moderate eczema on arms and chest. A pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (1200 mg uid) was administered for 7 days. After a couple of hours the lesion ceased g, after 1 day a noticeable ement in lesion swelling was reported. 2-3 days later the eczema lesions erythema had resolved and after 7 days the lesions had completely disappeared. In the past the patient had used emollients and ortisone , which made the lesions worse and would often lead to a course of antibiotics. The patient ted that her response to the BC1054 treatment was quick and complete, and was a marked improvement on previously pharmacological therapies.

An 85 year old male diagnosed with ve osteoarthritis, with marked swelling and severe pain in both knee. For 1 year, the patient had been prescribed prednisolone and NSAIDS to control arthritis, with no effect. In addition the patient had taken daily amine. Despite considerable pharmacological intervention, the patient regularly flared resulting in considerable restriction of mobility. The patient was given a 10 day course of a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg W0 04655 69 of ibuprofen, 10% ethanol, and 90% rapeseed oil (400 mg tid) and ence an appreciable improvement by day 3 and a complete resolution after the completion of the . The patient reported that his mobility was returned to normal and he has remained in remission at is 1 month examination.

A 38 years old male with ve osteoarthritis in 1 knee, for 6 months (pain and swelling). Over that period, the patient had tried a comprehensive spectrum of pharmacological therapies: prednisolone, Humira and sulfasalazine, alongside NSAle to control pain. Only the sulfasalazine had any iable effect, however the patient disliked its side effects, so requested to come off the sulfasalazine. After 2 weeks of being sulfsalazine free, the t experienced a flare of the reactive arthritis and ced a 4 day course of a pharmaceutical composition disclosed herein (BC1054) sing 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid), experiencing complete remission of the arthritis. After 2weeks of being drug free, the arthritis began to flare again and the patient was put on r 4 day treatment of BC1054, again experiencing complete remission. This time the arthritis flared again 1 week later. To account for this, the patient was given a final 10 day course of BC1054.

Subsequently, the arthritis remained in remission for 11 months, as per the last examination.

A 49 year old male diagnosed with hypercholesterolemia (LDL of 4.35 mmol/L) was placed on a pharmaceutical ition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid) for 7 days. After 5 days of ent the patient’s LDL levels had normalized to 3.89 mmol/L. The normalization of LDL level ted for 2 months after cessation of BC1054 dosing, as determined at the last examination.

A 60 year old male newly diagnosed with hypercholesterolemia (LDL of 4.31 mmol/L) was given a course of a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, % ethanol, and 90% rapeseed oil (1200 mg uid) to lower LDL levels to within the normal range. After 5 days of treatment the patients LDL levels were lowered to 3.36 mmol/L. The patient was followed up for 1 month and his LDL remained within the normal range, despite there being no further BC1054 dosing.

Example 10 Treatment of Chronic Inflammation A 62 year old female complains of joint ess and swelling and is diagnosed with rheumatoid arthritis. A physician determines that the joint stiffness and swelling is due to chronic inflammation. The woman is treated by oral administration a ceutical composition comprising ibuprofen as disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Alternatively, the woman is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily. The woman’s condition is monitored and after about 3 days of treatment the woman indicates there is reduced joint stiffness and ng. At one and three month check-ups, the woman indicates that she continues to have reduced joint stiffness and swelling in the area treated. This reduction in c inflammation symptoms indicates successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a pharmaceutical composition sed herein will be used to treat a patient suffering from chronic inflammation associated with any monoarthritis, rthritis, or thritis, such as, e.g., osteoarthritis, juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy (including ankylosing litis, reactive tis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple disease or Behcet disease), a synovitis, gout, pseudogout, or Still's disease, as well as, a bursitis, a rheumatic fever, or a tenosynovitis. In a similar manner, any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo- oxygenase (COX) tor, a selective cyclooxygenase 1 (COX 1) tor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a e, will be formulated into a pharmaceutical composition and stered to the patient as described above.

A 58 year old male complains of breathing difficulty and is diagnosed with chronic obstructive pulmonary disease (COPD). A ian determines that the ing difficulty is due to chronic inflammation. The man is treated by oral administration a ceutical composition comprising ibuprofen as disclosed herein taken twice daily. Alternatively, the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Alternatively, the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily. The man’s ion is monitored and after about 3 days of treatment the man indicates there is improvement in his ability to breath. At one and three month check-ups, the man indicates that he continues to have improved breathing. This reduction in a chronic inflammation symptom indicates successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a ceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with an asthma, a bronchiolitis, a itis, an emphysema, a laryngitis, a pharyngitis, a pleuritis, a pneumonitis, a rhinitis, a sinusitis, or any other type of chronic respiratory disorder. In a similar manner, any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a c acid derivative NSAID, a non- selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.

A 67 year old male ins of muscle soreness and is diagnosed with omyositis. A physician determines that the soreness is due to chronic inflammation. The man is treated by oral administration a pharmaceutical ition comprising ibuprofen as sed herein taken twice daily.

Alternatively, the man is treated by oral stration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. atively, the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily. The man’s condition is monitored and after about 3 days of treatment the man indicates there is reduced soreness.

At one and three month check-ups, the man indicates that he continues to have improved muscle 71 2012/050242 movement and reduced soreness This reduction in a chronic inflammation symptom indicates successful treatment with the pharmaceutical composition sed herein. A similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with an inclusion body myositis, a myasthenia gravis, a polymyositis or any other type of matory myopathy, as well as, a fasciitis, a fibrositis, a myositis, a neuromyotonia, a osis, or a itis. In a similar manner, any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selective xygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.

A 73 year old female complains of wheezing when she breathes and is diagnosed with Churg- Strauss arteritis. A physician determines that the wheezing is due to chronic inflammation. The woman is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Alternatively, the woman is treated by oral stration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.

The woman’s condition is red and after about 3 days of treatment the woman tes that she no longer is wheezing. At one and three month check-ups, the woman indicates that she still does not wheeze when she breathes. This ion in a chronic inflammation symptom tes successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic mation ated with any vasculitis, such as, e.g., a Buerger's disease, a cerebral vasculitis, a cryoglobulinemia, an essential cryoglobulinemic vasculitis, a giant cell arteritis, a Golfer's itis, a Henoch-Schonlein purpura, a hypersensitivity vasculitis, a Kawasaki disease, a microscopic polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, or a Wegener's granulomatosis, as well as, an arteritis, a carditis, an endocarditis, a heart e, high blood pressure, inflammatory megaly, an ischemic heart disease, a ditis, a pericarditis, a phlebitis, a lebitis, or a thrombophlebitis. In a similar manner, any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical ition and administered to the patient as described above.

A 37 year old male ins of skin redness and is diagnosed with rosacea. A physician determines that the redness is due to chronic inflammation. The man is treated by oral administration a ceutical composition comprising ibuprofen as sed herein taken twice daily. Alternatively, the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Alternatively, the man is treated by oral administration a pharmaceutical composition sing en as disclosed herein taken twice daily. The man’s condition is monitored and after about 3 days of treatment the man indicates there is reduced skin redness. At one and three month check-ups, the man indicates that he continues to have improved skin tone and reduced redness This reduction in a chronic inflammation symptom indicates successful treatment with the pharmaceutical ition disclosed herein. A similar type of oral administration of a pharmaceutical ition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with an acne, a cervicitis, a dermatitis, an eczema (including an atopic eczema, a contact eczema, a xerotic eczema, a seborrhoeic dermatitis, a dyshidrosis, a discoid eczema, a venous eczema, a dermatitis herpetiformis, a neurodermatitis, or an autoeczematization), an tritis, a gingivitis, a glossitis, a hidradenitis ativa, a keratitis, a keratoconjunctivitis, a mastitis, a psoriasis (including a plaqure sis, a nail psoriasis, a guttate psoriasis, a scalp psoriasis, an inverse psoriasis, a pustular psoriasis, or an erythrodermis psoriasis), a scleroderma, a statis dermatitis, a stomatitis, a litis, a vaginitis, a vitiligo, or a vulvitis. In a similar manner, any of the therapeutic compounds such as, e.g., a salicylate tive NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) tor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.

A 33 year old female ins of abdominal pain and diarrhea and is diagnosed with Crohn's disease. A physician determines that the abdominal pain and diarrhea is due to chronic mation.

The woman is d by oral administration a pharmaceutical ition comprising fen as sed herein taken twice daily. Alternatively, the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Alternatively, the woman is treated by oral administration a pharmaceutical ition comprising naproxen as sed herein taken twice daily. The woman’s condition is monitored and after about 3 days of treatment the woman indicates that there is a reduction in abdominal pain and she no longer has diarrhea. At one and three month check-ups, the woman indicates that she continues to have reduced abdominal pain and ea. This ion in a chronic inflammation symptom indicates successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from neurogenic mation associated with any inflammatory bowel disease, such as, e.g., an ulcerative colitis (including ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis), any irritable bowel disease, as well as, a colitis, an enteritis, an enterocolitis, a gastritis, a gastroenteritis, a metabolic syndrome (syndrome X), a spastic colon, or any other gastrointestinal disorder. In a similar manner, any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) tor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the t as described above.

A 46 year old male complains of fever, joint pains, and fatigue and is diagnosed with systemic lupus erythematosus. A physician determines that these symptoms are due to chronic inflammation. The man is d by oral administration a ceutical composition comprising ibuprofen as disclosed herein taken twice daily. Alternatively, the man is treated by oral administration a pharmaceutical composition sing aspirin as disclosed herein taken thrice daily. Alternatively, the man is treated by oral stration a ceutical composition comprising naproxen as disclosed herein taken twice daily. The man’s condition is monitored and after about 3 days of treatment the man indicates there is improvement in his health, his fever is gone, the pain in his joints is reduced and his is not as tired. At one and three month check-ups, the man indicates that he ues to have reduced joint pain and does not suffer from fevers or e. This reduction in a chronic mation symptom indicates successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any other systemic autoimmune disorder, including, t limitation, an hospholipid antibody syndrome (APS), a bullous pemphigoid, a Chagas e, a discoid lupus erythematosus, a drug-induced lupus erythematosus, a Goodpasture's syndrome, a Guillain-Barre syndrome, an idiopathic thrombocytopenic purpura, a myasthenia gravis, a neonatal lupus, a pernicious anemia, a polymyalgia rheumatica, a toid arthritis, a scleroderma, a Sjogren's syndrome, a subacute cutaneous lupus erythematosus, or a Wegener's granulomatosis. In a similar , any of the eutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a ive cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.

A 58 year old male complains of depression, sensitivity to cold, weight gain, forgetfulness, and constipation and is diagnosed with Hashimoto's thyroiditis. A physician ines that these symptoms are due to chronic inflammation. The man is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily. Alternatively, the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.

Alternatively, the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily. The man’s condition is monitored and after about 3 days of treatment the man indicates there is ion in all the symptoms complained of. At one and three month check-ups, the man indicates that he still does not experience depression, sensitivity to cold, weight gain, forgetfulness, and constipation. This ion in a chronic inflammation symptom tes successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a ceutical ition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any other local autoimmune disorder, including, without limitation, an acute disseminated alomyelitis (ADEM), an Addison's disease, an autoimmune hemolytic anemia, an autoimmune hepatitis (including primary biliary cirrhosis), an autoimmune inner ear disease, a celiac disease, a Crohn's e, a diabetes mellitus type 1, an endometriosis, a giant cell arteritis, a Graves' disease, an interstitial cystitis, a lupus nephritis, a multiple sclerosis, a morphea, a gus vulgaris, a recurrent disseminated encephalomyelitis, a sclerosing cholangitis, an ulcerative colitis, or a vitiligo. In a similar , any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol tive NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an eno|ic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selective xygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.

A 59 year old female ins of joint stiffness and swelling and is diagnosed with reactive arthritis. A physician determines that the joint stiffness and swelling is due to chronic inflammation. The woman is treated by oral stration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily. Alternatively, the woman is d by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily. Alternatively, the woman is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily. The woman’s condition is monitored and after about 3 days of treatment the woman indicates there is reduced joint stiffness and swelling. At one and three month check-ups, the woman indicates that she continues to have reduced joint stiffness and swelling in the area d. This reduction in a c inflammation symptom indicates successful treatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any monoarthritis, oligoarthritis, or polyarthritis, such as, e.g., osteoarthritis, juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy (including ankylosing litis, reactive arthritis (Reiter's syndrome), tic tis, enteropathic arthritis associated with inflammatory bowel disease, e e or Behcet disease), a synovitis, gout, pseudogout, or Still's e, as well as, a bursitis, a rheumatic fever, or a tenosynovitis. In a similar manner, any of the eutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol tive NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an eno|ic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo- ase (COX) inhibitor, a ive cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.

In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific ments, one skilled in the art will readily iate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and/or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing ular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the ing description. The inventor expects skilled ns to employ such variations as appropriate, and the inventors intend for the present invention to be practiced othenNise than specifically described .

Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by able law. Moreover, any combination of the above- described embodiments in all possible variations thereof is encompassed by the ion unless othenNise indicated herein or othenNise clearly dicted by context.

Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and d individually or in any combination with other group members disclosed . It is anticipated that one or more s of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability.

When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all h groups used in the appended claims.

Unless othenNise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being ed in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, ter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding ques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the ic examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each te cal value falling within the range.

Unless othenNise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context of bing the present invention ially in the context of the following claims) are to be construed to cover both the singular and the plural, unless othenNise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless othenNise indicated herein or ise clearly contradicted by context. The use of any and all es, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention ise claimed. No language in the present specification should be construed as indicating any non-claimed t essential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in the claims using consisting of or ting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” es any element, step, or ingredient not specified in the claims.

The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are ntly or expressly described and enabled herein.

All patents, patent publications, and other publications referenced and identified in the present ication are individually and expressly incorporated herein by reference in their ty for the purpose of describing and disclosing, for example, the compositions and methodologies bed in such publications that might be used in connection with the present invention. These publications are provided solely for their sure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the ants and does not constitute any admission as to the correctness of the dates or contents of these documents.

Claims (34)

1. A ceutical composition comprising: a) a therapeutic compound having an anti-inflammatory activity, wherein the therapeutic compound has a log P value of greater than 2.0; b) less than 20% of a pharmaceutically-acceptable solvent, wherein the solvent comprises a pharmaceutically-acceptable polyethelene glycol polymer, a pharmaceutically-acceptable alcohol, or a pharmaceutically-acceptable ester of pharmaceutically-acceptable alcohol and an acid; and c) at least 50% of a pharmaceutically-acceptable lipid-adjuvant, wherein the pharmaceutically-acceptable lipid-adjuvant is a fatty acid having at least 12 carbons, a olipid, a olipid, a sterol lipid, a prenol lipid, a saccharolipid, or a polyketide, wherein the pharmaceutical composition is formulated to have a melting point temperature of about 25°C or higher.

2. The pharmaceutical ition according to Claim 1, wherein the anti-inflammatory activity reduces the level of an inflammation inducing molecule, reduces the level of an mation inducing prostaglandin, stimulates a PPAR ing pathway, induces apoptosis of Macrophage M1 cells, promotes differentiation of Macrophage M2 cells, or both, reduces the levels of Interferon-gamma (IFNγ), Tumor necrosis factor-alpha (TNF- α), Interleukin-12 (IL-12), or a combination thereof released from Th1 cells, increases the levels of IL-10 released from a Th2 cell, or both.

3. The pharmaceutical composition ing to Claim 1 or Claim 2, wherein the therapeutic compound comprises a non-steroidal anti-inflammatory drug (NSAID), a PPARγ agonist, and/or an ester thereof.

4. The pharmaceutical composition according to Claim 3, wherein the NSAID comprises a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) tor, a selective cyclooxygenase 2 (COX 2) tor or a combination thereof.

5. The pharmaceutical composition according to Claim 4, wherein the salicylate derivative NSAID is Acetylsalicylic acid, isal or Salsalate.

6. The pharmaceutical composition according to Claim 4, wherein the p-amino phenol derivative NSAID is Paracetamol or Phenacetin.

7. The ceutical composition according to Claim 4, wherein the propionic acid derivative NSAID is Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, en, Oxaprozin, Pranoprofen or Suprofen.

8. The ceutical ition according to Claim 4, wherein the acetic acid derivative NSAID is Aceclofenac, Acemetacin, Actarit, Alcofenac, Amfenac, Clometacin, Diclofenac, Etodolac, ac, Fenclofenac, Indometacin, Ketorolac, Metiazinic acid, Mofezolac, Nabumetone, Naproxen, Oxametacin, ac or Zomepirac.

9. The pharmaceutical ition ing to Claim 4, wherein the enolic acid derivative NSAID is Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam or Tenoxicam.

10. The pharmaceutical composition according to Claim 4, wherein the fenamic acid derivative NSAID is Flufenamic acid, Mefenamic acid, Meclofenamic acid or Tolfenamic acid.

11. The pharmaceutical ition according to Claim 4, wherein the selective COX-2 inhibitors is Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, Meloxicam, Parecoxib, xib or Valdecoxib.

12. The pharmaceutical composition ing to Claim 3, wherein the PPARγ agonist comprises Monascin, Irbesartan, artan, mycophenolic acid, Resveratrol, Delta(9)- tetrahydrocannabinol, a cannabidiol, Curcumin, Cilostazol, Benzbromarone, 6-shogaol, glycyrrhetinic acid, a thiazolidinedione, a fibrate, or a combination thereof.

13. The pharmaceutical composition according to Claim 12, wherein the fibrate ses Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a combination thereof.

14. The pharmaceutical composition according to any one of Claims 1-13, wherein the t comprises a pharmaceutically-acceptable liquid polyethylene glycol polymer.

15. The pharmaceutical composition according to any one of Claims 1-14, wherein the pharmaceutically-acceptable solvent is less than about 15% (v/v).

16. The pharmaceutical composition according to Claim 15, wherein the pharmaceuticallyacceptable solvent is from about 8% (v/v) to about 15% (v/v).

17. The pharmaceutical ition according to Claim 16, wherein the pharmaceuticallyacceptable solvent is from about 8% (v/v) to about 12% (v/v).

18. The pharmaceutical composition according to any one of Claims 1-17, wherein the pharmaceutically-acceptable hylene glycol polymer is a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, a PEG 700, a PEG 800, a PEG 900, a PEG 1000, or any combination thereof.

19. The pharmaceutical composition ing to Claim 1-18, wherein the pharmaceuticallyacceptable lipid-adjuvant is in an amount of at least 60% (v/v).

20. The pharmaceutical composition according to any one of Claims 1-19, wherein the pharmaceutically-acceptable lipid-adjuvant includes at least 30% of a first glycerolipid consisting of a triglyceride or an acetylated triglyceride and at least 20% of a second glycerolipid consisting of a monoglyceride or an acetylated monoglyceride.

21. The pharmaceutical composition according to Claim 20, wherein the glycerolipid comprises at least 30% of a pharmaceutically-acceptable triglyceride and at least 20% of a pharmaceutically-acceptable monoglyceride.

22. The pharmaceutical composition according to any one of Claims 1-21, n the ceutically-acceptable lipid comprises a saturated fatty acid, an unsaturated fatty acid, or a ation thereof.

23. The pharmaceutical composition according to any one of Claims 1-22, wherein the pharmaceutical ition further comprises a pharmaceutically-acceptable stabilizing agent, wherein the pharmaceutically-acceptable stabilizing agent is not an emulsifying agent.

24. A method of preparing a pharmaceutical composition as defined in claims 1-22, the method comprising the steps: a) contacting the pharmaceutically-acceptable solvent with the therapeutic compound under conditions which allow the eutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a on, and b) ting the solution formed in step (a) with the pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.

25. The method ing to Claim 24, wherein step (a) further comprises ting a pharmaceutically-acceptable stabilizing agent with the pharmaceutically-acceptable solvent and the therapeutic compound, n the pharmaceutically-acceptable stabilizing agent is not an emulsifying agent.

26. Use of a pharmaceutical composition as d in Claims 1-23 in the manufacture of a medicament for the treatment of a chronic inflammation.

27. Use of a ceutical composition as d in Claims 1-23 for the treatment of a chronic inflammation in a non-human individual.

28. The use according to Claim 26 or Claim 27, wherein the chronic inflammation is associated with acne, acid reflux/heartburn, age related macular degeneration (AMD), allergy, allergic rhinitis, Alzheimer’s disease, ophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma. atherosclerosis, autoimmune disorders, tis, blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, is, cancer, cardiac arrest, is, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, s, congestive heart e, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, , emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, insulin ance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), a migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson’s disease, parotitis, pelvic inflammatory disease, pemphigus vularis, pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, enitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, al complication, synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, , traumatic brain , transplant rejection, trigonitis, ulosis, tumor, urethritis, s, uveitis, vaginitis, itis, or vulvitis.

29. The use according to Claim 26 or Claim 27, wherein the chronic inflammation is a tissue inflammation or a systemic inflammation.

30. The use according to Claim 26 or Claim 27, wherein the chronic inflammation is an autoimmune disease or a non-autoimmune disease.

31. The use according to Claim 26 or Claim 27, wherein the chronic inflammation is associated with an arthritis, a myopathy, a itis, a skin disorder, a gastrointestinal disorder, a cardiovascular disease, a cancer, a pharmacologically-induced inflammation, an infection, a tissue or organ injury, a transplant rejection, a graft-versus-host disease, a Th1-mediated inflammatory disease, a chronic neurogenic mation.

32. The pharmaceutical composition according to any one of claims 1-23, substantially as hereinbefore bed with reference to the examples and accompanying figures.

33. The method according to claim 24 or claim 25, substantially as hereinbefore described with reference to the examples and accompanying s.

34. The use according to any one of claims 26-31, substantially as hereinbefore described with reference to the examples and accompanying figures. W0