NZ711187B2 - Compositions and methods for treating cardiovascular disease - Google Patents

Abstract

Provided are pharmaceutical compositions comprising a therapeutic compound that normalizes lipid levels, a pharmaceutically acceptable adjuvant, and optionally a pharmaceutically acceptable solvent. In an embodiment the composition comprises: - a therapeutic compound with a log P value of 2.0 or more which is a NSAID or a PPAR gamma agonist (provided that the PPAR gamma agonist is not a fibrate) - at least 50% by weight of a pharmaceutically-acceptable lipid-adjuvant, the pharmaceutically acceptable lipid-adjuvant including at least 25% by weight of the composition a first pharmaceutically-acceptable lipid adjuvant that is solid at a temperature of about 20°C, and at least 20% by weight of the composition a second pharmaceutically acceptable lipid-adjuvant that is liquid at a temperature of about 20°C, and is a fatty acid having at least 12 carbons, a glycerolipid, a sphingolipid, a sterol lipid, a prenol lipid, a saccharolipid, or a polyketide; wherein the composition is formulated to be solid at a temperature of about 15ºC or lower and have a melting point temperature of about 25°C or higher. Exemplified therapeutic compounds include ibuprofen and gemfibrozil. ore which is a NSAID or a PPAR gamma agonist (provided that the PPAR gamma agonist is not a fibrate) - at least 50% by weight of a pharmaceutically-acceptable lipid-adjuvant, the pharmaceutically acceptable lipid-adjuvant including at least 25% by weight of the composition a first pharmaceutically-acceptable lipid adjuvant that is solid at a temperature of about 20°C, and at least 20% by weight of the composition a second pharmaceutically acceptable lipid-adjuvant that is liquid at a temperature of about 20°C, and is a fatty acid having at least 12 carbons, a glycerolipid, a sphingolipid, a sterol lipid, a prenol lipid, a saccharolipid, or a polyketide; wherein the composition is formulated to be solid at a temperature of about 15ºC or lower and have a melting point temperature of about 25°C or higher. Exemplified therapeutic compounds include ibuprofen and gemfibrozil.

Description

Compositions and s for Treating Cardiovascular Diseases Lipids constitute a broad group of naturally occurring hydrophobic or amphiphilic molecules thate fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides,sterol lipids and prenol lipids. The main biological functions of lipids include energy storage, as structuralcomponents of cell membranes, and as ant signaling molecules. Given these ental roles,all cells use and rely on lipids. One process used to transport lipids to cells involves apolipoproteins.

Apolipoproteins are proteins that bind to lipids to form lipoproteins, which are the vehicles used fortransporting the lipids, including triglycerides and terol, through the lymphatic and circulatorys. The lipid components of lipoproteins are not themselves e in water. However, e oftheir amphipathic properties, oproteins and other amphipathic molecules (such as, e.g.,phospholipids) can surround the lipids, ng the lipoprotein le that is itself water-soluble, and canthus be carried through water-based circulation, i.e. blood and lymph, etc.

There five major groups of lipoprotein particles, and the lipoprotein density and type ofapolipoproteins it ns determines the fate of the particle and its nce on metabolism.

Chylomicrons are the largest lipoprotein particle and these particles carry triglycerides from the inesto the liver, skeletal muscle, and adipose tissue. Very low-density lipoprotein (VLDL) particles are large,triglyceride-rich lipoprotein secreted by the liver that transports triglycerides to adipose tissue and muscle.

The third group lipoprotein particles are intermediate-density lipoprotein (IDL) particles, an intermediatebetween VLDL and low-density lipoprotein (LDL). IDL particles are formed when lipoprotein lipaseremoves triglycerides from VLDL particles in the capillaries and the return these smaller particles to thecirculation. The IDL particles have lost most of their triglyceride, but they retain teryl esters. Someof the IDL particles are rapidly taken up by the liver; others remain in ation, where they undergor triglyceride hydrolysis and are converted to LDL. LDL particles carry cholesterol from the liver tocells of the body, where these particles bind to LDL receptors that are subsequently endocytosed invesicles form via in—coated pits. After the clathrin coat is shed, the vesicles ultimately deliver theLDL to lysosomes where the cholesterol esters are hydrolyzed. The last group of lipoprotein particles ishigh-density lipoprotein (HDL) particles, which collect cholesterol from the body's tissues and bring it backto the liver.

High levels of lipids, e.g., cholesterol, and/or lipoprotein particles, e.g., VLDL, IDL, and/or LDLcan have deleterious effects on the cardiovascular system. For example, as a major extracellular carrierof cholesterol, LDL plays important physiologic roles in cellular function and regulation of metabolicpathways. Cells have complex feedback mechanisms that ensure sufficient supply of cholesterol andprevent its excessive accumulation in the blood. r, under pathologic conditions of, e.g.,hyperlipidemia, oxidative stress and/or genetic disorders, specific components of LDL become oxidized orotherwise modified, with a consequence that cholesterol transport by such modified LDL is diverted fromits logic targets and accumulates in the blood. 2012/050241 One effect of this accumulation is the high amounts of cholesterol and/or LDL become embeddedin the walls of blood vessels, an in so doing invokes an inflammatory response. In response to thisinflammation, blood monocytes adhere to the endothelium, transmigrate into the subendothelial space,and differentiate toward macrophages. Macrophages, in turn, engulf the cholesterol deposits andmodified LDL by phagoocytosis via scavenger receptors, which are distinct from LDL receptors.r, the adaptive mechanisms mediated by macrophages are not sufficient to process theuncontrolled cholesterol and/or LDL deposition seen under pathologic conditions. As a result, the lipid-laden macrophages transform into “foam cells” or “foamy cells” having a M1 phenotype. Bothcholesterol/LDL deposition and the attendant foam cell-mediated pro-inflammatory reactions in the bloodwall lead to the development of atherosclerotic lesions. Left untreated, this lipid accumulation and pro-inflammatory response result in the ssion of the lesions, which eventually leads to a cardiovasculardisease.

Another effect of high cholesterol/LDL accumulation in the blood is the formation LDL aggregatesor LDL agglomerates. Being of high molecular weight, LDL agglomerates initiate an inflammatoryresponse in a manner similar to that invoked by pathogens like s or bacteria. The inflammatoryresponse triggers agglomerate uptake by macrophages which converts these cells into foam cells havinga M1 phenotype, and the e of inflammation inducing les. Once again, left untreated, thelipid accumulation and pro-inflammatory response can result in a cardiovascular disease.

Attempts to treat cardiovascular disease by controlling levels of lipids and/or lipoproteins in theblood have met with limited success. For example, although administration of statins reducescardiovascular risk in some individuals, these therapeutic compounds do not reduce triglyceride levels.

Thus, in individuals at cardiovascular risk who t deleteriously high levels of cerides, anotherclass of therapeutic compounds called fibrates may be stered. However, although loweringtriglyceride and LDL , fibrates do not affect the level of HDL, the lipoprotein particle known to beprotective against cardiovascular disease. , combination treatments involving statins and fibrates,while effective, cause a significant increase to the risk of myopathy and rhabdomyolysis, and thereforecan only be carried out under very close medical supervision. In view of these problems, there is,therefore, y a need for improved compounds and compositions for the use and treatment ofvascular es, including those associated with high lipid and/or lipoprotein levels.

The present specification discloses pharmaceutical compositions and methods for treating anindividual suffering from a cardiovascular disease. The pharmaceutical compositions disclosed hereinare ially a lipid delivery system that enables a eutic compound having an activity thatmodulates lipid and/or lipoprotein levels to be delivered in a manner that more ively treats acardiovascular disease. 2012/050241 Aspects of the present specification disclose a pharmaceutical composition comprising atherapeutic compound and a pharmaceutically—acceptable adjuvant. A therapeutic compound may havean activity that normalizes lipid levels. Other aspects of the present specification disclose apharmaceutical composition comprising a therapeutic compound disclosed herein, a pharmaceutically-acceptable solvent, and a ceuticalIy-acceptable adjuvant. In other aspects, the ceuticalcompositions sed herein further comprise a pharmaceuticalIy-acceptable stabilizing agent.

Other aspects of the present ication disclose a method of preparing a pharmaceuticalcomposition, the method comprising the step of contacting a therapeutic compound with apharmaceuticaIIy-acceptable adjuvant under ions which allow the formation of the pharmaceuticalcomposition. Other aspects of the present specification disclose a method of preparing a pharmaceuticalcomposition, the method comprising the steps: a) ting a pharmaceuticalIy-acceptable solvent with atherapeutic compound under conditions which allow the therapeutic compound to dissolve in thepharmaceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic compound hasan activity that normalizes lipid levels, and b) contacting the on formed in step (a) with apharmaceutically-acceptable adjuvant under conditions which allow the formation of the ceuticalcomposition. In other aspects, the method of preparing disclosed herein further comprises 0) removingthe pharmaceuticalIy-acceptable solvent from the pharmaceutical ition.

Other s of the present specification se a pharmaceutical ition, thepharmaceutical composition made according to a method comprising the step of contacting a therapeuticcompound with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of thepharmaceutical composition. Other aspects of the present specification disclose a pharmaceuticalcomposition, the ceutical composition made according to a method comprising the steps: a)contacting a pharmaceutically—acceptable solvent with a therapeutic compound under conditions whichallow the therapeutic compound to dissolve in the pharmaceutically—acceptable t, thereby forming asolution, wherein the therapeutic compound has an activity that normalizes lipid levels, and b) contactingthe solution formed in step (a) with a pharmaceutically—acceptable adjuvant under conditions which allowthe formation of the pharmaceutical composition. In other aspects, the method of making apharmaceutical composition sed herein further ses 0) removing the pharmaceutically-acceptable solvent from the pharmaceutical composition.

Other aspects of the t specification disclose a method of treating an individual with acardiovascular disease, the method comprising the step of administering to the individual in need thereofa pharmaceutical composition disclosed herein, wherein administration results in a reduction in asymptom associated with the cardiovascular disease, thereby treating the individual.

Other aspects of the present specification se a use of a pharmaceutical compositionsed herein in the manufacture of a medicament for the treatment of a cardiovascular disease.

Other aspects of the present specification disclose a use of a pharmaceutical compositiondisclosed herein for the treatment of a cardiovascular disease.

BREIF DESCRIPTION OF THE DRAWINGS shows the s of a pharmaceutical ition disclosed herein on survival againstInfluenza A/PR/8/34 lethal challenge. Ibuprofen 335 ug = Group A; Ctrol ORAL = Group B; and ibuprofen335 pg o/e ORAL (BC1054) = Group C. shows the s of a ceutical composition disclosed herein on in vivo levels ofTh2 cytokines in the lungs of surviving mice. shows a graph of the effects of a pharmaceuticalcomposition disclosed herein on in vivo levels of IL-10, whereas shows a graph of the effects of apharmaceutical composition sed herein on in vivo levels of IL-4. BC1054 ORAL = Group A; VehicleORAL = Group B; and BC1054 Lipid ORAL = Group C. shows the s of a pharmaceutical composition sed herein on in vivo levels ofTh2 cytokines in the lungs of surviving mice. Figure 3A shows a graph of the effects of a pharmaceuticalcomposition disclosed herein on in vivo levels of lL-10; Figure 3B shows a graph of the effects of apharmaceutical composition disclosed herein on in vivo levels of TNF-or; and shows a graph ofthe effects of a pharmaceutical composition disclosed herein on in vivo levels of lFN-y. BC1054 ORAL =Group A; Vehicle ORAL = Group B; and BC1054 Lipid ORAL = Group C.

DESCRIPTION Aspects of the present specification disclose, in part, a pharmaceutical composition. As usedherein, the term "pharmaceutically acceptable" means any molecular entity or composition that does notproduce an adverse, allergic or other untoward or unwanted reaction when administered to an individual.

As used herein, the term “pharmaceutically acceptable composition” is synonymous with “pharmaceuticalcomposition” and means a therapeutically effective tration of an active ient, such as, e.g.,any of the therapeutic nds disclosed herein. A pharmaceutical composition disclosed herein isuseful for medical and veterinary applications. A pharmaceutical ition may be administered to anindividual alone, or in combination with other supplementary active ingredients, agents, drugs or A pharmaceutical composition disclosed herein may optionally include a pharmaceuticallyacceptablecarrier that facilitates sing of an active ingredient into pharmaceutically-acceptablecompositions. As used herein, the term “pharmacologically-acceptable carrier” is synonymous with“pharmacological carrier” and means any carrier that has substantially no long term or permanentdetrimental effect when administered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary or excipient.” Such a r generally is mixed with an activecompound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquidagent. It is understood that the active ingredients can be soluble or can be delivered as a suspension inthe desired carrier or t. Any of a variety of pharmaceutically acceptable carriers can be usedincluding, without limitation, aqueous media such as, e.g., water, saline, e, hyaluronic acid and thelike; solid carriers such as, e.g., mannitol, lactose, , magnesium te, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium ate, and the like; solvents; dispersion media; coatings;antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactiveingredient. Selection of a pharmacologically acceptable carrier can depend on the mode ofadministration. Except insofar as any pharmacologically acceptable carrier is incompatible with the activeingredient, its use in pharmaceutically acceptable itions is contemplated. Non-limiting examplesof specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and DrugDelivery s (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999);REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott,Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of eutics(Joel G. Hardman et al., eds., McGraw—Hill Professional, 10th ed. 2001); and Handbook ofPharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). Theseprotocols are routine procedures and any modifications are well within the scope of one skilled in the artand from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include, without limitation, otherpharmaceutically acceptable components (or pharmaceutical components), including, without tion,buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiologicalsubstances, cological substances, bulking agents, emulsifying agents, g agents, ningor flavoring agents, and the like. Various buffers and means for adjusting pH can be used to prepare apharmaceutical composition disclosed herein, ed that the ing ation is pharmaceuticallyacceptable. Such buffers include, without tion, acetate buffers, citrate buffers, phosphate buffers,neutral buffered saline, phosphate ed saline and borate buffers. It is understood that acids or basescan be used to adjust the pH of a composition as needed. Pharmaceutically acceptable antioxidantsinclude, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservatives include, without limitation,benzalkonium chloride, chlorobutanol, thimerosal, mercuric acetate, mercuric nitrate, astabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA—bisamide, calcium DTPA,and CaNaDTPA—bisamide. Tonicity adjustors useful in a pharmaceutical composition include, withoutlimitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and otherpharmaceutically acceptable tonicity adjustor. The ceutical ition may be provided as a saltand can be formed with many acids, including but not limited to, hydrochloric, sulfuric, , lactic,tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than arethe ponding free base forms. It is tood that these and other substances known in the art ofpharmacology can be included in a pharmaceutical composition.

In one embodiment, a pharmaceutical composition disclosed herein ses a therapeuticcompound having an ty that izes lipid levels and a pharmaceutically-acceptable adjuvant. Inanother embodiment, a pharmaceutical composition disclosed herein ses a therapeutic compoundhaving an activity that normalizes lipid levels, a ceutically—acceptable t, and apharmaceutically-acceptable nt. ln aspects of this embodiment, a pharmaceutical compositiondisclosed herein may further comprise a pharmaceutically-acceptable stabilizing agent. In other aspectsof this embodiment, a pharmaceutical composition disclosed herein may further comprise apharmaceutically-acceptable carrier, a pharmaceutically-acceptable component, or bothpharmaceutically-acceptable carrier and pharmaceutically-acceptable component.

Aspects of the present specification disclose, in part, a therapeutic compound. A therapeuticcompound 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 bodyof man or animals. A therapeutic compound disclosed herein may be used in the form of apharmaceutically acceptable salt, solvate, or solvate of a salt, eg. the hloride. Additionally,therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers,including the R— or S—enantiomer. Thus, the therapeutic compound disclosed herein may se a R-enantiomer only, a S—enantiomer only, or a ation of both a tiomer and a S-enantiomer of aeutic compound. A therapeutic compound disclosed herein may have an activity that normalizeslipid levels. As used herein, the term “normalizes lipid levels" refers to an activity that reduces a level of alipid or lipoprotein that is deleteriously high to a normal or non-harmful level, increases a level of a lipid orlipoprotein to a level that is beneficial to an individual, or both. For example, a therapeutic compoundhaving an activity that normalizes lipid levels may reduce cholesterol and/or LDL that is deleteriously highto a normal or non-harmful level, increase HDL to a level that is beneficial to an individual, or both.

Lipid and lipoprotein abnormalities are common in the general tion, and are regarded as amodifiable risk factor for cardiovascular disease due to their influence on atherosclerosis. Becausestudies have shown that higher levels of LDL particles promote health problems and cardiovasculardisease, they are often ally called the “bad cholesterol” particles. This is in contrast to HDLparticles, which are frequently referred to as “good cholesterol” or “healthy cholesterol” particles, ehigher HDL levels are correlated with cardiovascular health. High levels of HDL are thought to reduceLDL levels by acting as a sink for excess triglycerides levels in LDL.

In an embodiment, a therapeutic compound disclosed herein has an anti-hyperlipidemia activity.

In an aspect of this embodiment, a therapeutic nd disclosed herein has yperlipidemiaactivity capable of reducing the levels of VLDL, IDL, LDL, or a combination thereof. In other aspects ofthis embodiment, a therapeutic compound disclosed herein has anti—hyperlipidemia activity capable ofreducing the levels of VLDL, IDL, LDL, or a combination thereof by, e.g., at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or atleast 95%. In yet other aspects of this ment, a therapeutic compound disclosed herein has anti-ipidemia ty capable of reducing the levels of VLDL, IDL, LDL, or a ation thereof in arange from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about40% 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 about70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein increases the level of HDL. Inan aspect of this embodiment, a therapeutic compound disclosed herein increases the level of HDL by,e.g., at least 2%, at least 3%, at least 10%, at least 12%, at least 15%, at least 17%, at least 20%, at least22%, at least 25%, at least 27%, at least 30%, at least 32%, at least 35%, at least 37%, at least 40%, atleast 42%, at least 45% or at least 47%. In yet other s of this ment, a therapeuticcompound disclosed herein increases the level of HDL in a range from, e.g., about 2% to about 100%,about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%,about 30% to about 50%, about 35% to about 50%, about 40% to about 50%, about 2% to about 45%,about 10% to about 45%, about 15% to about 45%, about 20% to about 45%, about 25% to about 45%,about 30% to about 45%, about 35% to about 45%, about 2% to about 40%, about 10% to about 40%,about 15% to about 40%, about 20% to about 40%, about 25% to about 40%, or about 30% to about40%, about 2% to about 35%, about 10% to about 35%, about 15% to about 35%, about 20% to about%, or about 25% to about 35%.

When cholesterol and/or oteins like LDL become embedded in the walls of blood vessels,an immune response can be invoked that subsequently s in a chronic inflammatory response. Suchchronic inflammation can that ally can weaken and damage the blood vessels, causing them toburst. Thus, one consequence of modulating the levels of a lipid or lipoprotein is the reduction orelimination of a chronic inflammation. Prostaglandins mediate a local inflammatory response and areinvolved in all inflammatory functions through action on prostaglandin receptors and mediateinflammatory signaling including chemotaxis (macrophages, neutrophils and eosinophils), vasodilationand algesia. However, the PG-mediated inflammatory response is self-limiting (resolving). The principleresolution factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxidaseproliferator—activator receptor gamma (PPAR-y) signaling. PPARy signaling pathway 1) inducesapoptosis of Macrophage M1 cells, thereby reducing the levels of Th1 pro-inflammatory cytokines and 2)promotes differentiation of monocytes into Macrophage M2 cells. Macrophage M2 cells produce andrelease Th2 anti-inflammatory cytokines.

In an embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activitye of reducing the levels of an inflammation inducing prostaglandin. In other aspects of thisembodiment, a therapeutic compound sed herein has an anti-inflammatory activity capable ofreducing the levels of a inflammation inducing glandin released from a sensory neuron by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In yet other aspects of this ment, a therapeuticcompound disclosed herein has an anti-inflammatory activity e of reducing the levels of ainflammation inducing prostaglandin released from a sensory neuron in a range from, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about50% 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 about70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein has an anti-inflammatoryactivity substantially similar to 15dPGJ2. In aspects of this embodiment, a therapeutic compounddisclosed herein an anti-inflammatory activity that is, e.g., at least 5%, at least 15%, at least 25%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90% or at least 95% of the activity observed for 15dPGJ2. In other aspects of this embodiment, atherapeutic 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 ty observedfor 15dPGJ2.

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear or nsthat function as transcription factors regulating the expression of genes. All PPARs are known toheterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genescalled peroxisome proliferator hormone response ts (PPREs). PPARs play essential roles in theregulation of cellular differentiation, pment, and metabolism (carbohydrate, lipid, protein), andtumorigenesis of higher sms. The family comprises three members, PPAR—or, PPAR-y, and PPAR-6 (also known as PPAR-B). PPAR-d is expressed in liver, kidney, heart, muscle, adipose tissue, as wellas other s. PPAR-ES is sed in many tissues but markedly in brain, adipose tissue, and skin.

PPAR-v comprises three alternatively-spliced forms, each with a different expression pattern. PPAR-v1 isexpressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen. PPAR-v2is expressed mainly in e tissue. PPAR—y3 is expressed in macrophages, large intestine, and whiteadipose tissue. Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPAR-y isactivated by PGJ2 (a prostaglandin), whereas PPAR-d is activated by leukotriene B4.

The de novo tion of HDL particles by the liver is thought to be triggered by activation of thePPAR signaling pathways. 80 PPAR agonists that are targeted to cell types involved in lipid sing(macrophage, adipocytes and hepatocytes) through the normal lipid absorption mechanism willselectively increase cial HDL levels and so normalize blood lipid profiles and treat a cardiovasculardisease.

In an embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activitycapable of stimulating all PPAR signaling ys. Such a therapeutic compound includes a PPARpan—agonist. In other embodiments, a therapeutic nd disclosed herein has an anti-inflammatoryactivity capable of stimulating one or two of the PPAR ing pathways. Such a eutic ndincludes a selective PPAR agonist.

In another embodiment, a therapeutic compound disclosed herein has an anti-inflammatoryactivity capable of stimulating a r signaling pathway. In aspects of this embodiment, a euticnd disclosed herein stimulates a PPAR-or signaling pathway by, e.g., at least 5%, at least 15%, atleast 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of thisment, a therapeutic compound disclosed herein stimulates a PPAR-a signaling y in a rangefrom, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 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-inflammatoryactivity capable of stimulating a PPAR-6 signaling pathway. In aspects of this embodiment, a therapeuticcompound disclosed herein stimulates a PPAR-6 signaling pathway by, e.g., at least 5%, at least 15%, atleast 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of thisment, a therapeutic compound disclosed herein stimulates a PPAR-6 signaling pathway in a rangefrom, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 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-inflammatoryactivity capable of stimulating a PPARV signaling pathway. A therapeutic compounds disclosed hereinmay be capable of binding to all isoforms of PPAR-y, or may be capable of selectively binding to eitherPPAR-yl, PPAR-y2, PPAR-y3, or any combination of two thereof. In aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPARy signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In otheraspects of this embodiment, a therapeutic compound disclosed herein stimulates a PPARV signalingpathway in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% toabout 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% toabout 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25%to about 50%.

Macrophages are activated and polarized into distinct ypes expressing unique cell surfacemolecules and secreting discrete sets of nes and chemokines. The classical M1 phenotypesupports pro-inflammatory Th1 responses driven by cytokines such as, e.g., Interleukin-6 (IL-6), |L-12 and|L-23, while the alternate M2 phenotype is generally supportive of anti-inflammatory processes driven by|L-10. M2 cells can be further classified into subsets, M2a, M2b, and M2c, based on the type ofstimulation and the subsequent expression of e molecules and cytokines.

In yet another ment, a therapeutic compound disclosed herein has an anti-inflammatoryactivity capable of promoting the ing phenotypic change of M1 to M2. In an aspect of thisembodiment, a therapeutic compound disclosed herein has an nflammatory activity capable ofinducing apoptosis of Macrophage M1 cells. In another aspect of this embodiment, a euticcompound disclosed herein has an anti-inflammatory activity capable of ing differentiation ofMacrophage M2 cells. In yet another aspect of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of inducing apoptosis of Macrophage M1 cells andpromoting entiation of Macrophage M2 cells.

In still another embodiment, a therapeutic compound disclosed herein has an anti-inflammatoryactivity capable of modulating Th1 and Th2 cytokines. In an aspect of this embodiment, a therapeuticcompound disclosed herein has an anti-inflammatory ty capable of reducing the levels of Interferon-gamma (lFNy), Tumor necrosis factor-alpha (TNF-or), |L—12, or a combination thereof released from a Th1cell. In other aspects of this embodiment, a eutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of lFNv, TNF-cx, |L-12, or a ation thereofreleased from a Th1 cell by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, or at least 90%. In yet other aspects of this embodiment, atherapeutic compound disclosed herein has an anti—inflammatory activity capable of reducing the levels ofIFNy, TNF-or, |L-12, or a combination thereof released from a Th1 cell in a range from, e.g., about 5% toabout 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about40% 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 about70%, 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 increasing the levels of lL-10 released from a Th2 cell. In other aspectsof this embodiment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable ofincreasing the levels of lL-1O 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 least60%, 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 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 about100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 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 ment, a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of lFNv, TNF-or, lL-12, or a combination thereofreleased from a Th1 cell and increasing the levels of lL-1O released from a Th2 cell. In other aspects ofthis embodiment, a eutic compound sed herein has an anti-inflammatory activity capable ofng the levels of lFNv, TNF-cr, lL-12, or a combination thereof released from a Th1 cell by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%, and capable of increasing the levels of lL-10 released from a Th2cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activity e of ng the levels oflFNv, TNF-d, lL-12, or a combination thereof released from a Th1 cell in a range from, e.g., about 5% toabout 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about40% 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 about70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%, and capable ofincreasing the levels of lL-1O 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 about100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% toabout 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 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 sed herein has an anti-inflammatoryactivity capable of reducing the levels of an inflammation inducing molecule. In an aspect of thisembodiment, a therapeutic compound sed herein has an anti-inflammatory activity capable ofreducing the levels of substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or acombination thereof. In other aspects of this embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of reducing the levels of SP, CGRP, ate, or a combinationthereof released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet otheraspects of this ment, a therapeutic compound disclosed herein has an anti-inflammatory activitycapable of reducing the levels of SP, CGRP, glutamate, or a combination thereof ed from a sensoryneuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 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%.

A therapeutic compound disclosed herein may have a log P value indicating that the compound issoluble in an organic solvent. As used herein, the term “log P value” refers to the logarithm (base 10) ofthe partition cient (P) for a compound and is a measure of lipophilicity. lly, P is defined as theratio of concentrations of a unionized compound in the two phases of a e of two immiscible solventsat equilibrium. Thus, log P = Log 10 (P), where P = [solute in immiscible solvent 1] / [solute in immisciblesolvent 2]. With regard to c and aqueous phases, the log P value of a compound is constant forany given pair of aqueous and organic solvents, and its value can be determined empirically by one ofseveral phase-partitioning s known to one skilled in the art including, e.g., a shake flask assay, aHPLC assay, and an interface n two immiscible electrolyte solutions (ITIES) assay.

In aspects of this ment, a therapeutic compound disclosed herein may have a log P valueindicating that the compound is substantially soluble in an organic solvent. ln aspects of thisembodiment, a therapeutic compound disclosed herein may have a log P value indicating that thecompound is, e.g., at least 50% soluble in an organic solvent, 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 therapeutic nd disclosed hereinmay have a log P value indicating that the compound is between, e.g., about 50% to about 100% solublein 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% soluble in an organic solvent, or about 90% toabout 100% soluble in an organic solvent.

In s of this embodiment, a therapeutic compound disclosed herein may have a log P valueof, 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, morethan 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, ormore than 3.6. In other aspects of this embodiment, a eutic compound disclosed herein may havea log P value in the range of, e.g., between 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, between 2.5 and 4.0, between 2.6and 4.0, or between 2.8 and 4.0. In other aspects of this embodiment, a therapeutic compound disclosedherein 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, between 3.3 and 4.0, between 3.4 and 4.0, between 3.5 and 4.0, or between 3.6and 4.0. In still other aspects of this embodiment, a therapeutic compound sed herein may have alog 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, orbetween 2.2 and 2.5.

A therapeutic compound disclosed herein may have a polar surface area that is hydrophobic. Asused herein, the term “polar surface area” refers to the e sum over all of the polar atoms in thestructure of a compound and is a measure of hydrophobicity. Typically, these polar atoms include, e.g.,oxygen, nitrogen, and their ed hydrogens. In aspects of this embodiment, a therapeutic nddisclosed herein may have a polar surface area of, e.g., less than 8.0 an, less than 7.0 nmz, less than6.0 nm2, less than 5.0 nmz, less than 4.0 nm2, or less than 3.0 nm2. In other aspects of this embodiment,a eutic compound disclosed herein may have a polar surface area in the range of, e.g., between3.0 an and 6.5 nmz, between 3.0 an and 6.0 nmz, between 3.0 nm2 and 5.5 nm2, n 3.0 nm2 and.0 nm2, between 3.0 nm2 and 4.5 nm2, between 3.5 an and 6.5 nm2, n 3.5 nm2 and 6.0 nm2,n 3.5 nm2 and 5.5 nmz, between 3.5 nm2 and 5.0 an, n 3.5 an and 4.5 an, between 4.0nm2 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, between 4.0 nm2 and 4.5 nmz, or between 4.5 nm2 and 5.5 an. In yet other aspects of thisembodiment, a therapeutic compound disclosed herein may have a polar surface area in the range of,e.g., between 2.0 nm2 and 6.5 an, between 2.0 nm2 and 6.0 nm2, between 2.0 nm2 and 5.5 nm2,between 2.0 nm2 and 5.0 nmz, between 2.0 nm2 and 4.5 an, between 2.5 an and 6.5 an, between 2.5nm2 and 6.0 nm2, between 2.5 nm2 and 5.5 nm2, between 2.5 nm2 and 5.0 nm2, or between 2.5 nm2 and4.5 nm2.

A therapeutic compound disclosed herein may be a non-steroidal anti-inflammatory drug(NSAID). NSAIDs are a large group of therapeutic compounds with analgesic, anti-inflammatory, andanti—pyretic properties. NSAIDs reduce mation by blocking cyclooxygenase. NSAIDs include,without limitation, Aceclofenac, Acemetacin, Actarit, Alcofenac, Alminoprofen, Amfenac, Aloxipirin,Aminophenazone, Antraphenine, Aspirin, Azapropazone, Benorilate, Benoxaprofen, Benzydamine,Butibufen, Celecoxib, henoxacin, Choline Salicylate, Clometacin, Dexketoprofen, Diclofenac,Diflunisal, Emorfazone, Epirizole; Etodolac, oxib, uzone, Felbinac, Fenbufen, Fenclofenac,Flurbiprofen, Glafenine, ylethyl salicylate, Ibuprofen, Indometacin, Indoprofen, Ketoprofen,Ketorolac, Lactyl phenetidin, ofen, Lumiracoxib, Mefenamic acid, Meloxicam, Metamizole,Metiazinic acid, Mofebutazone, Mofezolac, Nabumetone, Naproxen, Nifenazone, Niflumic acid,Oxametacin, Phenacetin, Pipebuzone, Pranoprofen, Propyphenazone, Proquazone, Protizinic acid,Rofecoxib, Salicylamide, Salsalate, Sulindac, Suprofen, Tiaramide, Tinoridine, Tolfenamic acid,Valdecoxib, and rac.

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 derivative NSAID, apropionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, afenamic acid derivative NSAID, a non-selective cyclo—oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, and a selective cyclooxygenase 2 (COX 2) inhibitor. A NSAID maybe a profen. Examples of a suitable salicylate derivative NSAID include, without limitation, Acetylsalicylicacid (asprin), isal, and Salsalate. es of a suitable o phenol derivative NSAID include,without limitation, Paracetamol and Phenacetin. es of a suitable propionic acid derivative NSAIDinclude, without limitation, Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen,Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen, and Suprofen.

Examples of a suitable acetic acid derivative NSAID include, without limitation, Aceclofenac, acin,Actarit, nac, Amfenac, acin, Diclofenac, Etodolac, ac, Fenclofenac, Indometacin,Ketorolac, Metiazinic acid, Mofezolac, Nabumetone, Naproxen, Oxametacin, Sulindac, and Zomepirac.es of a suitable enolic acid (Oxicam) derivative NSAID include, t limitation, Droxicam,Isoxicam, icam, Meloxicam, cam, and Tenoxicam. Examples of a suitable fenamic acidderivative NSAID include, without limitation, Flufenamic acid, Mefenamic acid, enamic acid, andTolfenamic acid. Examples of a suitable selective COX-2 inhibitors include, without limitation, Celecoxib,Etoricoxib, Firocoxib, coxib, Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib.

A therapeutic compound disclosed herein may be a PPARy agonist. Examples of a suitablePPARv agonist include, without limitation, Benzbromarone, a cannabidiol, Cilostazol, Curcumin, Delta(9)—ydrocannabinol, glycyrrhetinic acid, lndomethacin, lrbesartan, Monascin, mycophenolic acid,Resveratrol, 6-shogaol, Telmisartan, a thiazolidinedione like Rosiglitazone, Pioglitazone, andTroglitazone, a NSAID, and a fibrate. Other suitable PPARy agonists are described in Masson andCaumont-Bertrand, PPAR Agonist Compounds, Preparation and Uses, US 2011/0195993, which ishereby incorporated by reference in its entirety.

A therapeutic compound disclosed herein may be a r receptor binding agent. Examples ofa suitable nuclear receptor binding agent e, without limitation, a Retinoic Acid or (RAR)binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor (LXR) g agent and aVitamin D g agent.

A therapeutic compound disclosed herein may be an anti-hyperlipidemic agent. There areseveral classes of anti-hyperlipidemic agents (also known as hypolipidemic agents). They may differ inboth their impact on the cholesterol profile and adverse effects. For example, some may lower LDL, whileothers may preferentially increase HDL. Clinically, the choice of an agent will depend on the cholesterolprofile of an individual, cardiovascular risk of an individual, and/or the liver and kidney functions of andual. Examples of a suitable anti-hyperlipidemic agent include, without limitation, a fibrate, a statin,a tocotrienol, a , a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreaticlipase inhibitor, and a sympathomimetic amine.

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

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

To compensate 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,without limitation, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, tatin, Rosuvastatin, andSimvastatin.

A therapeutic compound disclosed herein may be a tocotrienol. Tocotrienols are another class ofA reductase inhibitors and may be used to lower LDL and/or terol levels by inducinghepatic LDL receptor up-regulation and/or decreasing plasma LDL . Examples of a letocotrienol include, without limitation, a y-tocotrienol and a 6- tocotrienol.

A therapeutic compound disclosed herein may be a niacin. Niacins are a class of therapeuticcompounds with lipid level modifying properties. For example, a niacin may lower LDL by selectivelyting hepatic diacyglycerol acyltransferase 2, reduce ceride synthesis, and VLDL secretionthrough a receptor HM74 and HM74A or GPR109A. These therapeutic compounds are used for a rangeof lic disorders. One non-limiting use is as an anti-hyperlipidemic agent where it may inhibit thebreakdown of fats in adipose tissue. Because a niacin blocks the breakdown of fats, it causes a decreasein free fatty acids in the blood and, as a consequence, decreases the secretion of VLDL and cholesterolby the liver. By lowering VLDL levels, a niacin may also se the level of HDL in blood. es ofa suitable niacin include, without limitation, acipimox, 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 inthe gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering themand preventing their reabsorption from the gut. Bile acid sequestrants are particularly effective forlowering LDL and cholesterol by sequestering the cholesterol-containing bile acids released into theine and ting their rption from the intestine. In addition, a bile acid sequestrant may alsoraise HDL levels. es of a suitable bile acid sequestrant include, without limitation,Cholestyramine, Colesevelam, and Colestipol.

A therapeutic compound disclosed herein may be a cholesterol absorption inhibitor. Cholesterolabsorption inhibitors are a class of therapeutic compounds that inhibits the absorption of terol fromthe intestine. Decreased cholesterol absorption leads to an lation of LDL-receptors on the surfaceof cells and an increased LDL-cholesterol uptake into these cells, thus decreasing levels of LDL in theblood plasma. Examples of a suitable cholesterol absorption inhibitor include, without limitation,Ezetimibe, a phytosterol, a sterol and a stanol.

A therapeutic compound disclosed herein may be a fat absorption inhibitor. Fat absorptioninhibitors 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 inhibitspancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Examples of a suitable fatabsorption inhibitor include, without limitation, at.

A therapeutic compound disclosed herein may be a sympathomimetic amine. Sympathomimeticamines are a class of therapeutic compounds that mimic the effects of transmitter substances of thehetic nervous system such as olamines, epinephrine (adrenaline), norepinephrine(noradrenaline), and/or dopamine. A sympathomimetic amine may act as an d-adrenergic agonist, a B-adrenergic agonist, a dopaminergic agonist, a monoamine oxidase (MAO) inhibitor, and a COMTinhibitor. Such therapeutic compounds, among other things, are used to treat cardiac arrest, low bloodpressure, or even delay premature labor. Examples of a suitable sympathomimetic amine include,without limitation, Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, phetamine,amphetamine, ephrine, isoproterenol, dobutamine, phenidate, lisdexamfetamine, cathine,cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone , 4-methylaminorex, ne, phenmetrazine, and propylhexedrine.

A therapeutic compound disclosed herein may be an ester of a therapeutic compound. An esterof a therapeutic compound increases the logP value relative to the same therapeutic compound, butwithout the ester modification. An ester group may be attached to a eutic compound by, 9.9., aylic acid or yl functional group present of the therapeutic compound. An ester of atherapeutic compound may have an increased hydrophobicity, and as such, may be dissolved in areduced volume of solvent disclosed . In some instances, an ester of a therapeutic compound maybe combined directly with an adjuvant disclosed herein, thereby eliminating the need of a solvent. Anester of a therapeutic compound may enable the making of a pharmaceutical ition disclosedherein, in situations where a non-esterified form of the same therapeutic compound is otherwiseimmiscible in a solvent disclosed herein. An ester of a therapeutic compound may still be delivered in amanner that more effectively normalizes lipid levels and/or inhibits a pro-inflammatory response as longWO 04654 as the compound is combined with an adjuvant disclosed herein. In one ment, a therapeuticcompound 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 apharmaceutically-acceptable solvent disclosed herein. In an aspect of this embodiment, apharmaceutical composition comprises a therapeutic compound and a pharmaceutically-acceptableadjuvant, but does not comprise a ceutically-acceptable t disclosed herein.

A pharmaceutical composition disclosed herein may se a therapeutic compound in anamount sufficient to allow customary stration to an individual. In aspects of this embodiment, apharmaceutical 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 50mg, 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 least85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound. In other aspects ofthis embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, atleast 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least900 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, orat least 1,500 mg of a therapeutic compound. In yet other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg toabout 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350mg, 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, orabout 1,000 mg to about 1,500 mg. In still other aspects of this ment, a pharmaceuticalcomposition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg toabout 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about1,500 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, about100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mgto about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg toabout 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about1,000 mg, or about 5 mg to about 250 mg.

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

A pharmaceutical composition disclosed herein may comprise a t in an amount sufficient todissolve a therapeutic compound disclosed herein. In other aspects of this embodiment, apharmaceutical composition sed herein may comprise a solvent in an amount of, e.g., less thanabout 90% (v/v), less than about 80% (v/v), less than about 70% (v/v), less than about 65% (v/v), lessthan 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 compositiondisclosed 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) to40% (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), about2% (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), about8% (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8% (v/v) to 12% (WV).

In one embodiment, a solvent may comprise a ceutically—acceptable l. As usedherein, the term “alcohol” refers to an organic le sing a hydroxyl functional group (—OH)bond to a carbon atom, where the carbon atom is saturated. In aspects of this embodiment, the alcoholmay be, e.g., a C24 alcohol, a CM alcohol, a C15 alcohol, a CH alcohol, a C140 alcohol, a 01.15 alcohol, ora C140 alcohol. In other aspects of this embodiment, an alcohol may be, e.g., a primary alcohol, asecondary alcohol, or a ry alcohol. In other aspects of this embodiment, an alcohol may be, e.g., anacyclic alcohol, a monohydric alcohol, a polyhydric alcohol (also known as a polyol or sugar l), anunsaturated aliphatic alcohol, an lic alcohol, or a combination thereof. Examples of a monohydricl include, without limitation, methanol, ethanol, ol, butanol, pentanol, and 1—hexadecanol.

Examples of a polyhydric alcohol include, t limitation, glycol, glycerol, arabitol, erythritol, xylitol,maltitol, sorbitol iol), mannitol, inositol, lactitol, galactitol (iditol), and isomalt. Examples of anunsaturated aliphatic alcohol include, without limitation, propeneol, 3,7-dimethylocta-2,6-dienol,and prop-2—inol. Examples of an alicyclic alcohol include, without limitation, cyclohexane-1,2,3,4,5,6-hexol and 2 — pyl)—5—methyl—cyclohexane—1—ol.

In another embodiment, a solvent may comprise an ester of pharmaceutically-acceptable alcoholand an acid. Suitable pharmaceutically—acceptable alcohols include the ones disclosed herein. Suitableacids include, without limitation, acetic acid, butaric acid, and formic acid. An ester of an alcohol and anacid include, without limitation, methyl acetate, methyl buterate, methyl formate, ethyl e, ethylbuterate, ethyl formate, propyl e, propyl buterate, propyl formate, butyl acetate, butyl te, butylformate, isobutyl acetate, isobutyl buterate, yl formate, pentyl acetate, pentyl buterate, pentylformate, and 1—hexadecyl e, 1—hexadecyl buterate, and 1-hexadecyl formate.

In another embodiment, a solvent may comprise a pharmaceutically—acceptable hyleneglycol (PEG) polymer. PEG polymers, also known as polyethylene oxide (PEO) polymers orpolyoxyethylene (POE) polymers, are prepared by polymerization of ethylene oxide and are commerciallyavailable over a wide range of molecular weights from 100 g/mol to 10,000,000 g/mol. PEG polymers witha low molecular mass are liquids or low-melting , whereas PEG polymers of a higher molecularmass are solids. A PEG polymer e, 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, PEG1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG ,PEG 11,000, PEG 12,000, PEG 13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG18,000, PEG , or PEG 20,000.

In another embodiment, a solvent may comprise a pharmaceutically-acceptable glyceride.ides comprise a substituted glycerol, where one, two, or all three hydroxyl groups of the glycerolare each esterified using a fatty acid to produce monoglycerides, diglycerides, and triglycerides,respectively. In these compounds, each hydroxyl groups of ol may be esterified by different fattyacids. Additionally, glycerides may be ated to produce acetylated monoglycerides, acetylateddiglycerides, and acetylated triglycerides.

In one ment, a solvent may comprise a pharmaceutically-acceptable solid solvent. Solidsolvents may be useful in the manufacture of a solid dose formulation of a pharmaceutical compositiondisclosed herein. Typically, a solid solvent is melted in order to dissolve a therapeutic nd. Apharmaceutically-acceptable solid solvent includes, without limitation, Menthol and PEG polymers aboveabout 20,000 g/mol.

Aspects of the present ication disclose, in part, a pharmaceutically-acceptable adjuvant. Anadjuvant is a pharmacological agent that modifies the effect of other agents, such as, 6.9., a therapeuticcompound disclosed herein. In addition, an adjuvant disclosed herein may be used as a solvent thatdissolves a therapeutic compound disclosed herein, forming a adjuvant solution. An adjuvant disclosedherein facilitates delivery of a therapeutic compound in a manner that more effectively normalizes lipidlevels and/or inhibits a pro-inflammatory response. In one embodiment, an adjuvant disclosed hereinfacilitates the delivery of a therapeutic compound disclosed herein into macrophages.

A pharmaceutical composition disclosed herein may comprise a pharmaceutically-acceptableadjuvant in an amount sufficient to mix with a solution disclosed herein or an emulsion disclosed herein.

In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise anadjuvant 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 least65% (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 pharmaceuticalcomposition disclosed herein may comprise an adjuvant in an amount in a range of, 6.9., 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 about95% (v/v). In yet other aspects of this embodiment, a ceutical composition disclosed herein maycomprise an adjuvant in an amount in a range of, 6.9., 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), about88% (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 about96% (v/v), about 75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93% (v/v), about 85% (v/v) toabout 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% (WV).

In one embodiment, an adjuvant may be a ceutically-acceptable lipid. A lipid may bebroadly defined as a hydrophobic or amphiphilic small molecule. The amphiphilic nature of some lipidsallows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment.

Non-limiting examples, of lipids include fatty acids, olipids (like monoglycerides, diglycerides, andtriglycerides), phospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides. Aceutical composition disclosed herein may comprise a lipid such as, 9.9. an oil, an oil-basedliquid, a fat, a fatty acid, a wax, a fatty acid ester, a fatty acid salt, a fatty alcohol, a glyceride , di-or tri-glyceride), a phospholipids, a glycol ester, a sucrose ester, a glycerol oleate derivative, a mediumchain triglyceride, or a e thereof.

A lipid useful in the pharmaceutical compositions disclosed herein may be a ceutically-acceptable fatty acid. A fatty acid comprises a ylic acid with a long unbranched hydrocarbon chainwhich may be either saturated or unsaturated. Thus arrangement confers a fatty acid with a polar,hydrophilic end, and a nonpolar, hobic end that is insoluble in water. Most naturally occurring fattyacids have a hydrocarbon chain of an even number of carbon atoms, typically between 4 and 24 carbons,and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur. Synthetic ornon-natural fatty acids may have a hydrocarbon chain of any number of carbon atoms from between 3and 40 carbons. Where a double bond exists, there is the possibility of either a cis or a trans geometric 2012/050241isomerism, which significantly affects the molecule's molecular configuration. uble bonds cause thefatty 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, although the trans form does exist insome natural and partially hydrogenated fats and oils. Examples of fatty acids include, without limitation,Capryllic acid (8:0), pelargonic acid (9:0), Capric acid (10:0), Undecylic acid (11:0), Lauric acid (12:0),ylic acid (13:0), Myristic acid (14:0), Myristoleic acid (14:1), Pentadecyclic acid , Palmitic acid, Palmitoleic acid (16:1), ic 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), Linoelaidic acid (18:2), cr-Linolenicacid , y-Linolenic acid (18:3), Stearidonic acid (18:4), Nonadecylic acid (19:0), Arachidic acid (20:0),Eicosenoic acid (20:1), Dihomo-y-linolenic acid (20:3), Mead acid (20:3), Arachidonic acid (20:4),Eicosapentaenoic acid (20:5), Heneicosylic acid (21:0), Behenic acid (22:0), Erucic acid ,Docosahexaenoic acid (22:6), Tricosylic acid (23:0), Lignoceric acid (24:0), Nervonic acid (24:1),Pentacosylic acid (25:0), Cerotic acid (26:0), Heptacosylic acid (27:0), Montanic acid (28:0), Nonacosylicacid (29:0), Melissic acid (30:0), Henatriacontylic acid (31:0), Lacceroic acid (32:0), Psyllic acid (33:0),Geddic acid (34:0), Ceroplastic acid (35:0), and Hexatriacontylic acid .

In an embodiment, an adjuvant may be a pharmaceutically-acceptable saturated or unsaturatedfatty acid. In aspects of this embodiment, 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 unsaturatedfatty acid comprises, e.g., n 4 and 24 carbon atoms, n 6 and 24 carbon atoms, between 8and 24 carbon atoms, n 10 and 24 carbon atoms, between 12 and 24 carbon atoms, between 14and 24 carbon atoms, or between 16 and 24 carbon atoms, n 4 and 22 carbon atoms, between 6and 22 carbon atoms, between 8 and 22 carbon atoms, between 10 and 22 carbon atoms, between 12and 22 carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22 carbon atoms, between 4and 20 carbon atoms, between 6 and 20 carbon atoms, between 8 and 20 carbon atoms, between 10 andcarbon atoms, between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, or between 16and 20 carbon atoms. If unsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 or more, 4 ormore, 5 or more, or 6 or more double bonds.

In aspects of this embodiment, a pharmaceutically-acceptable saturated or unsaturated fatty acidis liquid at room temperature. The melting point of a fatty acid is largely ined by the degree ofsaturation/unsaturation of the hydrocarbon chain. In s of this embodiment, a saturated orunsaturated fatty acid has a melting point temperature of, e.g., 20°C or below, 15°C or below, 10°C orbelow, 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. Inother aspects of this ment, a saturated or unsaturated fatty acid has a melting point temperature inthe 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 about0°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 toabout 12°C, about -15°C to about 8°C, about -15°C to about 4°C, about -15°C to about 0°C.

In r embodiment, an adjuvant may se one kind of pharmaceutically-acceptable fattyacid. In aspects of this embodiment, an adjuvant may comprise only palmitic acid, only stearic acid, onlyoleic acid, only linoleic acid, or only linolenic acid.

In another embodiment, an adjuvant may comprise a plurality of different pharmaceutically-able fatty acids. In aspects of this embodiment, an adjuvant may comprise, e.g., two or moredifferent fatty acids, three or more different fatty acids, four or more different fatty acids, five or moredifferent fatty acids, or six or more different fatty acids.

In other s of this embodiment, an adjuvant may comprise two or more differentpharmaceutically-acceptable fatty acids including at least palmitic acid, stearic acid, oleic acid, linoleicacid and/or linolenic acid, and any combination thereof. In other aspects of this embodiment, annt may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/orlinoleic 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 least8:1, at least 9:1, at least 10:1, at least 15:1, or at least 20:1. In yet other aspects of this embodiment, annt may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/orlinoleic 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 s of this embodiment, an adjuvant may comprise four or more differentpharmaceutically-acceptable fatty acids including at least ic acid, stearic acid, oleic acid, linoleicacid and/or linolenic acid, and any combination thereof. In other aspects of this embodiment, an adjuvantmay comprise a ratio of palmitic acid:stearic acid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1,8:8:1:1, 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 s 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 4:4:1:1, 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. 3 fatty acids (also known as n-3 fatty acids or 00—3 fatty acids) are a family ofessential unsaturated fatty acids that have in common a final carbon—carbon double bond in the n-3position, that is, the third bond, counting from the methyl end of the fatty acid. The omega—3 fatty acidsare "essential" fatty acids because they are vital for normal lism and cannot be synthesized by thehuman body. An omega-3 fatty acid includes, without limitation, Hexadecatrienoic acid (16:3), cr-Linolenicacid (18:3), donic acid (18:4), Eicosatrienoic acid (20:3), tetraenoic acid ,Eicosapentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), pentaenoic acid (22:5),Clupanodonic 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 (Jo—6 fatty acids) are a family of unsaturatedfatty acids that have in common a final carbon-carbon double bond in the n-6 position, that is, the sixthbond, counting from the methyl end of the fatty acid. An omega-6 fatty acid includes, without limitation,Linoleic acid (18:2), Gamma-linolenic acid (18:3), Calendic acid , Eicosadienoic acid (20:2),Dihomo—gamma-linolenic acid (20:3), Arachidonic acid (20:4), dienoic acid (22:2), Adrenic acid(22:4), Docosapentaenoic acid (22:5), Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid(24:5). Omega-9 fatty acids (also known as n-9 fatty acids or 03—9 fatty acids) are a family of unsaturatedfatty acids that have in common a final carbon—carbon double bond in the n-9 position, that is, the ninthbond, counting from the methyl end of the fatty acid. An omega-9 fatty acid includes, without limitation,oleic acid (18:1), Elaidic acid (18:1), Eicosenoic acid (20:1), Mead acid (20:3), Erucic acid (22:1), andNervonic acid (24:1 ).

A lipid useful in the pharmaceutical compositions disclosed herein may be a ceutically-acceptable oil. An oil includes any fatty acid that is liquid at normal room temperature, such as, e.g.about 20°C. In contrast, 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 suitable natural oils include, without limitation, mineraloil, tin, ethyl oleate, a hydrogenated natural oil, or a mixture thereof. Examples of suitable vegetableoils include, without limitation, almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, cornoil, 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, walnutoil, wheat germ oil, or a mixture thereof. Each of these oils is commercially available from a number ofsources well recognized by those skilled in the art.

An oil is lly a mixture of various fatty acids. For example, Rapeseed oil, obtained from theseeds of Brassica napus, includes both omega-6 and omega-3 fatty acids in a ratio of about 2:1. Asr example, linseed oil, obtained from the seeds of Linum issimum, includes abut 7% palmiticacid, about 3.4-4.6% stearic acid, about 2.6% oleic acid, about 14.2-17% linoleic acid, and about51.9-55.2% d—linolenic acid. In aspects of this embodiment, a pharmaceutical composition ses anoil including at least two different fatty acids, at least three different fatty acids, at least four different fattyacids, 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 glycerolipid. 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 areeach fied using a fatty acid to produce monoglycerides, diglycerides, and triglycerides, tively.

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

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

Aspects of the present specification disclose, in part, a pharmaceutically-acceptable stabilizingagent. A stabilizing agent s or eliminates formation of esters of a eutic compound that mayresult as a unwanted reaction with the particular solvent used. A stabilizing agent include, withoutlimitation, water, a sacrificial acid comprising a fatty acid ent and acetic acid, ethyl acetate, asodium acetate/acetic acid (E262), a monoglyceride, an ated monoglyceride, a diglyceride, anacetylated monoglyceride, an acetylated diglyceride, a fatty acid, and a fatty acid salt.

In one embodiment, a pharmaceutically-acceptable stabilizing agent may comprise apharmaceutically-acceptable emulsifying agent. An emulsifying agent (also known as an emulgent) is asubstance that stabilizes an emulsion comprising a liquid dispersed phase and a liquid continuous phaseby increasing its kinetic stability. Thus, in ions where the solvent and adjuvant used to make apharmaceutical composition disclosed herein are ly immiscible, an fying agent disclosedherein is used to create a homogenous and stable emulsion. An emulsifying agent includes, withoutlimitation, a surfactant, a polysaccharide, a lectin, and a olipid.

In an aspect of this embodiment, an emulsifying agent may comprise a surfactant. As used, the term “surfactant” refers to a natural or synthetic amphiphilic compound. A surfactant can benon-ionic, zwitterionic, or ionic. Non-limiting es of surfactants include polysorbates likerbate 20 (TWEEN® 20), polysorbate 40 (TWEEN® 40), polysorbate 60 (TWEEN® 60), polysorbate61 (TWEEN® 61), polysorbate 65 (TWEEN® 65), polysorbate 8O (TWEEN® 80), and polysorbate 81® 81); poloxamers (polyethylene-p0lypropylene copolymers), like Poloxamer 124 (PLURON|C®L44), Poloxamer 181 (PLURONIC® L61), Poloxamer 182 (PLURONIC® L62), Poloxamer 184(PLURONIC® L64), Poloxamer 188 NIC® F68), Poloxamer 237 (PLURONIC® F87), Poloxamer338 (PLURONIC® L108), Poloxamer 407 (PLURONIC® F127), polyoxyethyleneglycol l ethers, likeBRIJ® 30, and BRIJ® 35; coxyethanol (LUBROL®-PX); polyoxyethylene octyl phenyl ether(TRITON® X—100); sodium dodecyl e (SDS); 3-[(3-Cholamidopropyl)dimethylammonio]propanesulfonate (CHAPS); 3-[(3-Cholamidopropyl)dimethylammonio]hydroxypropanesulfonate(CHAPSO); sucrose monolaurate; and sodium cholate. Other non-limiting examples of surfactantexcipients can be found in, e.g., Ansel, supra, (1999); Gennaro, 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 emulsifying agent may comprise a ccharide. Non-limiting examples of polysaccharides include guar gum, agar, alginate, calgene, a dextran (like n1K, dextran 4K, dextran 40K, dextran 60K, and dextran 70K), dextrin, glycogen, inulin, starch, a starchderivative (like hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxybutyl starch, andhydroxypentyl starch), hetastarch, cellulose, FICOLL, methyl cellulose (MC), carboxymethyl cellulose(CMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose, ypropyl methyl cellulose (HPMC); polyvinyl acetates (PVA); polyvinyl pyrrolidones (PVP),also known as povidones, having a e of less than or equal to 18, a K-value greater than 18 or lessthan or equal to 95, or a K-value greater than 95, like PVP 12 (KOLLIDON® 12), PVP 17 (KOLLIDON ®17), PVP 25 (KOLLIDON ® 25), PVP 30 (KOLLIDON ® 30), PVP 9O (KOLLIDON ® 90); and polyethyleneimines (PEI).

In an aspect of this embodiment, an fying agent may se a . s are sugar-binding proteins that are highly specific for their sugar moieties. Lectins may be classified according tothe sugar moiety that they bind to, and include, without limitation, mannose-binding lectins, galactose/N-acetylgalactosamine-binding lectins, N—acetylgquosamine—binding lectins, N-acetylneuramine-bindinglectins, N-acetylneuraminic acid-binding lectins, and fucose-binding lectins. Non-limiting es oftants include concanavain A, lentil lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairyvetch , wheat germ agglutinin, elderberry lectin, Maackia anurensis leukoagglutinin, Maackiaanurensis hemoagglutinin, U/ex europaeus agglutinin, and Aleuria aurantia lectin.

In an aspect of this embodiment, an emulsifying agent may comprise a phospholipid. Thestructure of the phospholipid generally comprises a hydrophobic tail and a hydrophilic head and isamphipathic in nature. Most phospholipids contain a diglyceride, a phosphate group, and a simpleorganic molecule such as choline; one exception to this rule is sphingomyelin, which is derived fromsphingosine instead of glycerol. Phospholipids include, t limitation, diacylglycerides andphosphosphingolipids. Non-limiting examples of diacylglycerides include a phosphatidic acid(phosphatidate) (PA), a phosphatidylethanolamine (cephalin) (PE), a phosphatidylcholine (lecithin) (PC),a phosphatidylserine (PS), and a oinositide including phosphatidylinositol (Pl), atidylinositolphosphate (PIP), phosphatidylinositol bisphosphate (PIP2), and phosphatidylinositol triphosphate (PIP3).

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

In one embodiment, a pharmaceutically-acceptable stabilizing agent does not comprise apharmaceutically-acceptable emulsifying agent.

In another embodiment, a pharmaceutical composition does not comprise a ceutically-acceptable emulsifying agent.

The pharmaceutical compositions disclosed herein act as a delivery system that enable atherapeutic nd 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 normalizes lipid levels and/or inhibits a pro-inflammatory response. This modulation and/or inhibition results in an improved treatment of avascular disease. For example, a pharmaceutical composition sed herein may facilitate thery of a therapeutic compound disclosed herein into macrophages. One le mechanism thatachieves this selective biodistribution is that the pharmaceutical itions disclosed herein may beed to take advantage of the activity of chylomicrons. Chylomicrons are relatively large lipoproteinparticles having a diameter of 75 nm to 1,200 nm. Comprising triglycerides (85-92%), phospholipids (6-12%), cholesterol (1-3%) and oproteins (1-2%), Chylomicrons transport dietary lipids from theintestines to other locations in the body.

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

These micelles allow the tion of lipid as free fatty acids by the absorptive cells of the smallintestine, known as enterocytes. Once in the enterocytes, triglycerides and cholesterol are assembledinto nascent icrons. Nascent chylomicrons are primarily composed of triglycerides (85%) andcontain some cholesterol and cholesteryl esters. The main oprotein component is oprotein B-48 (APOB48). These t icrons are released by osis from enterocytes into ls,lymphatic vessels originating in the villi of the small intestine, and are then secreted into the bloodstreamat the thoracic duct's connection with the left subclavian vein.

While circulating in lymph and blood, chylomicrons exchange components with HDL. The HDLdonates apolipoprotein C-ll (APOCZ) and apolipoprotein E (APOE) to the nascent chylomicron and thusconverts it to a mature icron (often referred to simply as micron"). APOCZ is the cofactor forotein lipase (LPL) activity. Once ceride stores are distributed, the chylomicron returns APOC2to the HDL (but keeps APOE), and, thus, becomes a chylomicron remnant, now only 30—50 nm. APOB48and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdowninto lipoproteins (VLDL, LDL and HDL). These lipoproteins are processed and stored by competent cells,including, 6.9., hepatocytes, adipocytes and macrophages. Thus, without wishing to be limited by anytheory, upon oral administration of the pharmaceutical compositions disclosed herein are processed intomicelles while in the gastrointestinal tract, absorbed by enterocytes and assembled into nascentchylomicrons, remain associated with icron remnants taken up by the liver, and ultimately loadedinto macrophages.

Aspects of the present ication disclose, in part, a method of ing a pharmaceuticalcomposition disclosed herein. A method disclosed herein comprises the step of contacting apharmaceutically-acceptable adjuvant disclosed herein with a therapeutic compound disclosed hereinunder conditions which allow the therapeutic compound to dissolve in the pharmaceutically—acceptableadjuvant, thereby forming a pharmaceutical composition disclosed herein.

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

The amount of a therapeutic compound that is contacted with the pharmaceutically-acceptablesolvent in step (a) of the method may be in any amount desired. Factors used to determine the amountof a therapeutic compound used include, without limitation, the final amount the therapeutic compounddesired in the pharmaceutical composition, the desired concentration of a therapeutic compound in thesolution, the hobicity of the therapeutic compound, the lipophobicity of the therapeutic compound,the temperature under which the contacting step (a) is performed, and the time under which thecontacting step (a) is performed The volume of a pharmaceutically-acceptable solvent used in step (a) of the method may be anyvolume desired. s used to determine the volume of a pharmaceutically-acceptable solvent usede, without limitation, the final amount of a pharmaceutical composition desired, the desiredconcentration of a therapeutic 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 therapeutic compound that is ted with thesolvent 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 50mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, atleast 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least900 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, orat least 1,500 mg. In other s of this embodiment, the amount of a therapeutic compound that isted with the solvent in step (a) may be in the range of, e.g., about 10 mg to about 100 mg, about 50mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg toabout 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about1,500 mg. In other aspects of this embodiment, the amount of a therapeutic compound that is dissolvedin the solvent in step (a) may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about500 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 mgto about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg toabout 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000mg, or about 200 mg to about 1,500 mg.

Step (a) may be carried out at room temperature, in order to allow a therapeutic compound todissolve fully in the pharmaceutically-acceptable solvent. However, in other ments of the method,step (a) may be carried out at a temperature that is greater than room temperature, e.g., greater than21°C, greater than 25°C, greater than 30°C, greater than 35°C or greater than 37°C. In n cases,Step (a) may be carried out at temperatures below room temperature, in order to allow a therapeuticcompound to dissolve fully in solvent. However, in other embodiments of the method, step (a) may becarried out at a temperature that is less than room temperature, e.g., less than 10°C, r than 5°C,greater than 0°C, greater than -10°C or greater than -20°C. The contacting in Step (a) may comprisemixing 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 seconds, atleast 10 seconds, at least 20 seconds, at least 30 s, at least 45 seconds, at least 60 seconds, ormore, until the therapeutic compound is fully dissolved in the solvent.

After contacting, the concentration of a therapeutic compound sed herein in the solutionmay be in any concentration desired. In s of this embodiment, the concentration of a therapeuticcompound 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, atleast 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least700 mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In other aspects of this embodiment, theconcentration of a therapeutic compound sed herein in the solution may be, e.g., at most 1,000mg/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 most1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects ofthis embodiment, the concentration of a therapeutic compound sed herein in the solution may be ina range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about 2,000 mg/mL, about 100mg/mL to about 1,500 mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about 1,500mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about 100mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL to about 1,200mg/mL, about 750 mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about 1,000mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01 mg/mL, about 0.00001mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001mg/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 beany volume desired. Factors used to determine the volume of a pharmaceutically-acceptable adjuvantused include, without limitation, the final amount of a pharmaceutical composition d, the desiredconcentration of a therapeutic compound in the pharmaceutical composition, the ratio of solvent:adjuvantused, and the miscibility of solvent and adjuvant.

In aspects of this ment, the ratio of solution:adjuvant may be, e.g., at least 5:1, at least4:1, 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, atleast 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 toabout 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 about1:25, 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, 2012/050241about 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, about2:1 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 toabout 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 about1:15, 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 toabout 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 about1:12, 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, about0:1 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 toabout 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 toabout 1:10.

Step (b) may be d out at room temperature, in order to allow the solution comprising thetherapeutic compound to form the pharmaceutical composition. However, in other embodiments of themethod, step (b) may be carried out at a temperature that is greater than room temperature, e.g., greaterthan 21°C, greater than 25°C, greater than 30°C, greater than 35°C or greater than 37°C. In certaincases, Step (b) may be carried out at temperatures below room ature, in order to allow atherapeutic compound to dissolve fully in a pharmaceutically-acceptable solvent. However, in otherembodiments of the method, step (b) may be d out at a temperature that is less than roomtemperature, 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 ceutically-acceptableadjuvant, e.g., by ng, inversion, sonication, or vortexing. The mixing may be carried out for, e.g., atleast 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least45 seconds, at least 60 seconds, or more, until the pharmaceutical composition is formed.

In Step (0), the solvent removal from a pharmaceutical ition may be accomplished usingone 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 conditions ofambient atmosphere, under low pressure, or under a vacuum.

In one embodiment, Step (0) may result in the complete removal of a pharmaceutically-able solvent from the pharmaceutical composition sed herein. In aspects of thisment, Step (0) 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%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least95%, at least 97%, or at least 99% removal of a pharmaceutically-acceptable solvent from thepharmaceutical ition disclosed herein.

Step (0) is conducted at a temperature that allows for the evaporation of a pharmaceutically-acceptable solvent disclosed herein, and as such, an evaporation temperature is solvent dependant.

Factors which influence an evaporation temperature of a t disclosed herein include, withoutlimitation, the particular solvent used, the amount of solvent present, the particular therapeutic compoundt, the particular adjuvant present, the stability of the therapeutic compound present, the reactivity ofthe therapeutic compound present, the particular heric pressure used, the time desired forcomplete ation. Generally, a pharmaceutical composition will require heating if the ationstep is conducted at ambient pressure, e.g., 1 atm. However, under high vacuum conditions, theevaporation step may be conducted at temperatures below t temperature, e.g., less than 22 °C.

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

In aspects of this embodiment, removal of solvent from the pharmaceutical composition disclosed hereinmay be carried out at ambient atmospheric pressure and at a temperature of, e.g., more than 25°C, morethan 30°C, more than 35°C, more than 40°C, more than 45°C, more than 50°C, more than 55°C, morethan 60°C, more than 65°C, more than 70°C, more than 80°C, or more than 25°C. In other aspects ofthis embodiment, removal of solvent from the pharmaceutical composition disclosed herein may becarried out at t atmospheric pressure and at a temperature in a range of, e.g., about 25°C to about100°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 toabout 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 ment, removal of solvent from the ceutical composition disclosed hereinmay be carried out under vacuum and at a temperature below ambient temperature. In aspects of thisembodiment, removal of solvent from the pharmaceutical composition sed herein may be dout under vacuum and at a temperature of, e.g., less than 20°C, less than 18°C, less than 16°C, less than14°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 lessthan 0°C. In other aspects of this embodiment, removal of solvent from the pharmaceutical compositiondisclosed herein may be carried out under vacuum and at a temperature in a range of, e.g., about -20°Cto 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 toabout 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 pharmaceuticalcomposition disclosed herein may be of any concentration desired. In an aspect of this embodiment, thefinal concentration of a therapeutic compound in a pharmaceutical composition may be a euticallyeffective amount. In other aspects of this embodiment, the final concentration of a therapeutic compoundin a pharmaceutical composition may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least0.001 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 25mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In other aspects of this embodiment, thetration of a therapeutic compound disclosed herein in the solution may be, e.g., at most 1,000mg/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 most1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects ofthis embodiment, the final concentration of a therapeutic compound in a pharmaceutical composition maybe in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about 2,000 mg/mL, about 100mg/mL to about 1,500 mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about 1,500mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about 100mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL to about 1,200mg/mL, about 750 mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about 1,000mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01 mg/mL, about 1mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

A pharmaceutical composition produced using the methods sed herein may be a liquidformulation or a solid or semi-solid formulation. A liquid formulation can be formed by using s lipidslike oils of other fatty acids that remain as liquids in the temperature range desired. In an embodiment, apharmaceutical composition disclosed herein is liquid at room temperature. In aspects of thisembodiment, a pharmaceutical composition disclosed herein may be formulated to be a liquid at aature of, e.g., about 25°C or higher, about 23°C or higher, about 21°C or higher, about 19°C orhigher, about 17°C or higher, about 15°C or higher, about 12°C or higher, about 10°C or higher, about8°C or higher, about 6°C or higher, about 4°C or higher, or about 0°C or higher. In other aspects of thisembodiment, a ceutical composition disclosed herein may be formulated to be a liquid at atemperature of, e.g., A solid or semi-solid formulation sed herein takes advantage of the different melting pointatures of the various adjuvants like fatty acids. Formation of a solid or semi-solid dosage form canbe by modifying the respective trations of the fatty acids comprising a pharmaceutical compositiondisclosed herein. For example, linolenic acid has a melting point temperature (Tm) of about -11°C, linoleicacid 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 tion(s) of ic, stearic or oleic acidwould increase the overall melting temperature of a composition, while, conversely, increasing theproportion(s) of linoleic and nic acid would decrease the melting temperature of a composition.

Thus, by controlling the types and amounts of the adjuvant components added, a pharmaceuticalcomposition 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 readilyforms micelles which are absorbed by the intestine, assembled into chylomicrons, and ultimatelyabsorbed by hages. The solid dosage form may be a powder, granule, tablet, capsule orsuppository.

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

In aspects of this ment, a pharmaceutical composition disclosed herein may be formulated to be asolid at a temperature of, e.g., about 35°C or lower, about 33°C or lower, about 31°C or lower, about29°C or lower, about 27°C or lower, about 25°C or lower, about 23°C or lower, about 21°C or lower, about19°C or lower, about 17°C or lower, about 15°C or lower, about 12°C or lower, about 10°C or lower, about8°C or lower, about 6°C or lower, v 4°C or lower, or about 0°C or lower.

In other s of this embodiment, a pharmaceutical composition sed has a melting pointtemperature of, e.g., 5 °C or higher, 10 °C or higher, 15 °C or higher, 22°C or higher, 23°C or higher, 24°Cor higher, 25°C or higher, 26°C or higher, 27°C or higher, 28°C or higher, 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 higher. In other aspects of thisembodiment, 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 toabout 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°Cto about 33°C, about 32°C to about 34°C, or about 33°C to about 35°C. In other aspects of thisembodiment, a pharmaceutical composition disclosed 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 toabout 32°C, or about 30°C to about 34°C.

Aspects of the present specification disclose, in part, a method of treating an individual with acardiovascular disease. In one embodiment, the method comprises the step of stering to anindividual in need thereof a pharmaceutical composition disclosed , wherein administration sa symptom associated with the cardiovascular disease, thereby treating the individual.

Aspects of the present specification disclose, in part, treating an individual suffering from acardiovascular e. As used herein, the term “treating,” refers to reducing or eliminating in anindividual a clinical m of a cardiovascular disease; or delaying or preventing in an individual theonset of a clinical symptom of a cardiovascular e. For example, the term “treating” can meanreducing a symptom of a condition characterized by a cardiovascular disease by, e.g., at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at leastWO 04654 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or atleast 100%. The actual symptoms associated with a cardiovascular disease are well known and can bedetermined by a person of ry skill in the art by taking into account factors, including, withoutlimitation, the location of the cardiovascular disease, the cause of the cardiovascular disease, the severityof the cardiovascular disease, and/or the tissue or organ affected by the vascular disease. Thoseof skill in the art will know the appropriate symptoms or indicators associated with a specific type ofcardiovascular disease and will know how to determine if an individual is a ate for treatment asdisclosed herein.

Cardiovascular disease is any of a number of ic diseases that affect the heart itself and/orthe blood vessel system, especially the veins and arteries leading to and from the heart. Known and/orassociated causes of a cardiovascular disease include, without limitation, thy ratios of the twosmallest lipoproteins LDL and HDL, ipidemia, elevated blood glucose levels, upper normal and highblood pressure, Lp-PLA2, lipoprotein(a) and hyperhomocysteinemia. Symptoms of a cardiovasculardisorder affecting the heart include, without limitation, chest pain, chest discomfort, and pain in one orboth arms, one or both shoulders, neck, jaw, or back, shortness of breath, dizziness, faster heartbeats,, abnormal heartbeats, e, and/or myocardial tion. Symptoms of a cardiovasculardisorder affecting the brain include, without limitation, sudden numbness or weakness of the face, one orboth arms, or one or both legs, sudden confusion or trouble speaking or tanding speech, suddentrouble seeing in one or both eyes, sudden dizziness, difficulty walking, or loss of balance or coordination,and/or sudden severe headache with no known cause. Symptoms of a cardiovascular disorder affectingone or both leg, pelvis, one or both arms, and/or shoulder e, without limitation, muscle pain, musclecramp, cold ion in one or both feet and/or toes, one or both hands and/or fingers, and/or numbnessor weakness in one or both feet and/or toes, one or both hands and/or fingers.

There are more than 60 types of cardiovascular disease including, without limitation, ahyperlipidemia, a coronary heart disease, an atherosclerosis, a peripheral vascular disease, acardiomyopathy, a vasculitis, an inflammatory heart e, an ischemic heart disease, a congestiveheart failure, a hypertensive heart disease, a valvular heart disease, a hypertension, myocardialinfarction, a diabetic cardiac conditions, an aneurysm; an embolism, a dissection, a pseudoaneurysm, avascular malformation, a vascular nevus, a thrombosis, a varicose vein, and a stroke.

In one ment, a cardiovascular disease comprises a ipidemia. A hyperlipidemia (orhyperlipoproteinemia) refers to a condition characterized by abnormally elevated levels of lipids and/orlipoproteins in the blood. ipidemias may be fied as familial (or primary) when caused byspecific genetic abnormalities, acquired (or secondary) when resulting from another underlying er,or idiopathic, when of unknown cause. Hyperlipidemias may also be classified based on which types oflipids and/or oteins are elevated. Non-limiting examples of a hyperlipidemia include dyslipidemia,hypercholesterolemia, hyperglyceridemia, hypertriglyceridemia, hyperlipoproteinemia, andhyperchylomicronemia, and combined hyperlipidemia. Hyperlipoproteinemia include, 9.9.,hyperlipoproteinemia type la, hyperlipoproteinemia type lb, hyperlipoproteinemia type lc,hyperlipoproteinemia type Ila, hyperlipoproteinemia type Ilb, hyperlipoproteinemia type III,hyperlipoproteinemia type IV, and hyperlipoproteinemia type V.

In another embodiment, a cardiovascular e comprises a coronary heart disease. Acoronary heart disease refers to a condition characterized by failure of the coronary circulation to supplyadequate blood flow to cardiac muscle and nding tissue. Typically caused by the narrowing orblockage of the coronary artery, such as, e.g., an atherosclerotic coronary artery disease, a coronaryvasospasm, and/or a coronary stenosis. Chest pain and myocardial infarction are common symptoms ofand conditions caused by coronary heart disease.

In another embodiment, a cardiovascular disease ses a vascular occlusive disease (VOD).

A VOD refers to a condition characterized by an obstruction of a blood vessel. A VOD includes, withoutlimitation, an atherosclerosis, a peripheral vascular disease, and a stenosis.

In an aspect of this embodiment, a VOD comprises an atherosclerosis. An atherosclerosis refersto a ion terized by a buildup of cholesterol and fatty deposits (called plaques) on the innerwalls of the arteries. These plaques can restrict blood flow to the heart muscle by physically clogging theartery or by causing abnormal artery tone and function. Rupture of atherosclerotic plaque is the mostcommon cause of an ia.

In an aspect of this embodiment, a VOD comprises a peripheral vascular disease (PVD).

Peripheral vascular disease (PVD), also known as peripheral arterial disease (PAD) or peripheral arteryocclusive disease (PAOD), refers to a condition characterized by an obstruction of large arteries notwithin the coronary, aortic arch ature, or brain. PVD can result from atherosclerosis, aninflammatory ses leading to stenosis, an sm, or thrombus formation. It causes either acuteor chronic ischemia. PVD also includes a subset of diseases classified as microvascular diseasesresulting from episodic narrowing of the arteries, such as, e.g., Raynaud's phenomenon, or widening ofthe arteries, such as, e.g., a vascular spasm. ms of PVD include, without limitation, pain,weakness, numbness, or cramping in muscles due to decreased blood flow, sores, wounds, or ulcers thatheal slowly or not at all, blueness or paleness in limb, coolness in limb, diminished hair and nail growth onaffected limb and digits. About 20% of patients with mild PAD may be asymptomatic.

In another embodiment, a vascular disease comprises a myopathy. Amyopathy refers to a condition characterized by the deterioration of myocardium function.

Symptoms and signs may mimic those of almost any form of heart disease and include chest pain andEKG alities. A mild cardiomyopathy is frequently asymptomatic. A more severe case isassociated with heart failure, arrhythmias, systemic zation and/or sudden cardiac death. Amyopathy may be classified functionally, as involving dilation, hypertrophy, or restriction.

A myopathy may also be fied as either extrinsic or intrinsic. An extrinsiccardiomyopathy refers to a cardiomyopathy where the primary pathology is outside the myocardium itself.

For example, an extrinsic cardiomyopathy may be caused by a metabolic/storage disorder, an endocrinedisorder, a neuromuscular disorder, a nutritional er, an inflammation, a toxicity (including drug andalcohol), an ischemia, and/or an ion (including Hepatitis C). miting examples of extrinsiccardiomyopathies include acromegaly, alcoholic myopathy, amyloidosis, Chagas disease,herapy, diabetic cardiomyopathy, hemochromatosis, hypertensive cardiomyopathy,hyperthyroidism, inflammatory cardiomyopathy, ic cardiomyopathy, muscular dystrophy, valvularcardiomyopathy, a cardiomyopathy secondary to a systemic metabolic disease, a cardiomyopathysecondary to a systemic nutritional disease, a ry artery disease, and a congenital heart disease.

An intrinsic myopathy refers to a cardiomyopathy where there is a weakness in the muscleof the heart that is not due to an identifiable external cause, i.e., of unknown . siccardiomyopathies comprise a variety of disease states due to its idiopathic nature and may be classifiedas genetic, mixed or acquired. Non-limiting examples of intrinsic cardiomyopathies include dilatedcardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM or HOCM), arrhythmogenic right ventricularcardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), paction cardiomyopathy, isolatedventricular non-compaction, mitochondrial myopathy, ubo cardiomyopathy, and Loefflerendocarditis.

In another embodiment, a cardiovascular disease comprises a vasculitis. itis is a variedgroup of disorders featuring inflammation of a vessel wall including lymphatic s and blood vesselslike veins (phlebitis), arteries (arteritis) and capillaries due to leukocyte migration and resultant damage.

The inflammation may affect any size blood vessel, anywhere in the body. It may affect either arteriesand/or veins. The inflammation may be focal, meaning that it affects a single location within a vessel; or itmay be widespread, with areas of inflammation scattered throughout a particular organ or tissue, or evenaffecting more than one organ system in the body. Vasculitis include, without limitation, Buerger'sdisease boangiitis obliterans), cerebral vasculitis (central nervous system vasculitis), Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell (temporal) arteritis,Golfer's vasculitis, Henoch-Schonlein purpura, hypersensitivity vasculitis gic vasculitis), Kawasakidisease, microscopic teritis/polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR),rheumatoid vasculitis, su arteritis, thrombophlebitis, Wegener‘s granulomatosis, and vasculitissecondary to connective tissue ers like systemic lupus erythematosus (SLE), rheumatoid arthritis(RA), relapsing polychondritis, Behcet's disease, or other connective tissue disorders, vasculitissecondary to viral infection.

In another embodiment, a vascular disease comprises an inflammatory heart disease. Aninflammatory heart disease refers to a condition terized by mation of the heart muscle and/orthe tissue surrounding it. Non-limiting examples of inflammatory heart disease include endocarditis,inflammatory cardiomegaly, and myocarditis.

In another embodiment, a cardiovascular disease comprises an ischemic heart disease.lschemic heart disease, or dial ischemia, refers to a condition characterized by reduced bloodsupply of the heart muscle, usually due to a ing or blockage of a coronary . Symptoms ofischemic heart disease include chest pain on exertion, in cold weather or emotional situations, acutechest pain, acute coronary syndrome, unstable angina, myocardial infarction, heart failure, ulty inbreathing or swelling of the extremities.

In another embodiment, a cardiovascular disease comprises a congestive heart failure. Acongestive heart failure, or congestive cardiac failure, refers to a condition characterized by a heartabnormality that cannot result from any structural or functional cardiac disorder that impairs the ability ofthe heart to fill with or pump a sufficient amount of blood throughout the body.

In another embodiment, a cardiovascular disease ses a hypertensive heart e. Ahypertensive heart disease refers to a condition characterized by high blood pressure, especiallylocalized high blood pressure. ions that can be caused by hypertensive heart e include,without limitation, left ventricular hypertrophy, coronary heart disease, congestive heart failure,hypertensive cardiomyopathy, and cardiac arrhythmias.

In another embodiment, a cardiovascular disease comprises a valvular heart disease. A valvularheart disease refers to a ion characterized by a malfunction of one or more valves of the heart.

Major heart valves which may be ed by ar heart disease, including, t limitation, tricuspidvalve, right aortic valve, mitral valve, and left aortic valve.

A composition or compound is administered to an individual. An individual is typically a humanbeing. Typically, any individual who is a candidate for a conventional cardiovascular disease treatment isa candidate for a cardiovascular disease treatment disclosed herein. Pre-operative evaluation llyincludes routine history and al examination in addition to thorough informed consent disclosing allrelevant risks and benefits of the procedure.

A pharmaceutical composition disclosed herein may comprise a eutic nd in atherapeutically effective amount. As used herein, the term “effective amount” is synonymous with“therapeutically ive ”, “effective dose”, or “therapeutically effective dose” and when used innce to treating a cardiovascular disease refers to the minimum dose of a therapeutic compounddisclosed herein necessary to achieve the desired therapeutic effect and includes a dose sufficient toreduce a symptom associated with a cardiovascular disease. The effectiveness of a euticcompound disclosed herein in treating a cardiovascular disease is determined by observing animprovement in an individual based upon one or more clinical symptoms, and/or physiological indicatorsassociated with the condition. An improvement in a cardiovascular e also can be indicated by areduced need for a concurrent therapy.

The appropriate effective amount of a therapeutic compound disclosed herein to be steredto an individual for a particular cardiovascular disease can be determined by a person of ordinary skill inthe art by taking into account factors, including, without limitation, the type of cardiovascular disease, thelocation of the cardiovascular disease, the cause of the cardiovascular disease, the severity of thecardiovascular disease, the degree of relief desired, the duration of relief d, the particulartherapeutic compound used, the rate of excretion of the therapeutic nd used, thepharmacodynamics of the therapeutic compound used, the nature of the other compounds to be includedin the composition, the particular route of administration, the particular characteristics, history and riskfactors of the patient, such as, e.g., age, weight, general health and the like, or any combination f.

Additionally, where repeated administration of a therapeutic compound is used, an effective amount of atherapeutic compound will further depend upon factors, including, without limitation, the frequency ofadministration, the half—life of the therapeutic compound, or any combination thereof. In is known by aperson of ordinary skill in the art that an effective amount of a therapeutic compound disclosed herein canbe extrapolated from in vitro assays and in vivo administration studies using animal models prior tostration to humans.

In aspects of this embodiment, a therapeutically effective amount of a therapeutic compoundsed herein reduces a symptom associated with a cardiovascular disease by, e.g., at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or at least 100%. In other aspects of this ment, a therapeutically effectiveamount of a therapeutic compound disclosed herein reduces a symptom associated with a cardiovasculardisease by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, atmost 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of thisembodiment, a therapeutically effective amount of a therapeutic compound disclosed herein reduces asymptom ated with a cardiovascular e by, e.g., about 10% to about 100%, about 10% toabout 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% toabout 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% toabout 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% toabout 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% toabout 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 therapeuticcompound disclosed 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 effective 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 day, at least 1.0 mg/kg/day, atleast 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 25day, at least 30 day, at least 35 mg/kg/day, at least 40 day, at least 45 mg/kg/day, orat least 50 mg/kg/day. In other aspects of this embodiment, an effective amount of a therapeuticcompound 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 mg/kg/day to about 15 mg/kg/day, about 0.001 day to about 20 mg/kg/day, about0.001 day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/dayWO 04654 to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 day, about 0.001 mg/kg/day to about75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic nd disclosed herein may be in the range of,9.9., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 day toabout 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100mg/kg/day. In still other aspects of this embodiment, an effective amount of a therapeutic compounddisclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1mg/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 toabout 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 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 0.1mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, an ive amount of a therapeutic compound disclosedherein may be in the range of, 6.9., about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day toabout 15 day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day to about 35 mg/kg/day, about 1mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45 day, about 1 day to about50 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 hereinmay be in the range of, 6.9., about 5 mg/kg/day to about 10 day, about 5 mg/kg/day to about 15mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 day to about 25 mg/kg/day, about 5mg/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 about40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/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 oneskilled in the art. For instance, treatment of a cardiovascular disease may se a one-timeadministration of an effective dose of a pharmaceutical composition disclosed herein. Alternatively,treatment of a cardiovascular disease may se multiple administrations of an ive dose of apharmaceutical composition carried out over a range of time periods, such as, 6.9., once daily, twicedaily, trice daily, once every few days, or once . The timing of administration can vary fromindividual to individual, depending upon such factors as the severity of an individual's symptoms. Fore, an effective dose of a pharmaceutical composition disclosed herein can be administered to anindividual once daily for an nite period of time, or until the individual no longer requires therapy. Aperson of ry skill in the art will recognize that the condition of the individual can be monitoredthroughout the course of treatment and that the effective amount of a pharmaceutical compositiondisclosed herein that is administered can be adjusted accordingly.

In one embodiment, upon administration to an individual, a pharmaceutical compositioncomprising a therapeutic compound disclosed herein results in a bio-distribution of the therapeuticnd different than a bio-distribution of the therapeutic compound included in the samepharmaceutical composition, except without an adjuvant disclosed herein.

In another embodiment, upon administration to an individual, a therapeutic compound of thepharmaceutical composition disclosed herein is delivered to a macrophage. Macrophages are one of thekey cell types ed to be involved in the control of the inflammation response. The resultant high levelof a eutic compound having an activity that normalizes lipid levels and/or anti-inflammatory activitypresent in the macrophages results in a clinically effective treatment of cardiovascular disease. In anaspect of this embodiment, upon administration to an dual, a therapeutically effective amount of aeutic compound of the pharmaceutical composition disclosed herein is preferentially delivered to amacrophage. In other aspect of this ment, upon stration to an individual, a therapeuticcompound of the pharmaceutical composition disclosed herein is substantially red to amacrophage. In yet other aspect of this embodiment, upon administration to an individual, the amount ofa therapeutic compound of the pharmaceutical composition disclosed herein delivered to a macrophageis, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of the total amount of thetherapeutic compound contained in the administered pharmaceutical composition. In still other aspects ofthis embodiment, upon stration to an individual, the amount of a therapeutic compound of thepharmaceutical 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% 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 contained in the stered ceuticalcomposition.

In another embodiment, upon administration to an individual, a pharmaceutical compositiondisclosed herein reduces c irritation. In an aspect of this embodiment, a pharmaceuticalcomposition disclosed herein substantially reduces gastric tion. In yet another embodiment, uponadministration to an dual, a pharmaceutical composition disclosed herein reduces gastric irritationwhen compared to the same pharmaceutical composition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In an aspect of this embodiment, a pharmaceutical compositiondisclosed herein substantially reduces gastric irritation when compared to the same pharmaceuticalcomposition disclosed herein, except t the pharmaceutically-acceptable nt. In other aspectsof this embodiment, a pharmaceutical composition disclosed herein reduces gastric tion by, e.g., atleast 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 least80%, 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% toabout 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%,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 about70%.

In another embodiment, upon administration to an individual, a pharmaceutical compositiondisclosed herein reduces intestinal irritation. In an aspect of this ment, a ceuticalcomposition disclosed herein substantially reduces intestinal tion. In yet another embodiment, uponadministration to an individual, a pharmaceutical ition disclosed herein reduces intestinal irritationwhen compared to the same pharmaceutical composition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In an aspect of this embodiment, a pharmaceutical compositiondisclosed herein substantially s intestinal irritation when compared to the same pharmaceuticalcomposition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In other aspectsof this embodiment, a pharmaceutical composition disclosed herein reduces inal irritation by, e.g., atleast 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 ed to the same pharmaceutical compositiondisclosed herein, except without the pharmaceutically—acceptable adjuvant. In yet other aspects of thisembodiment, a pharmaceutical 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 about100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% toabout 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% toabout 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% toabout 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%, about 10% toabout 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 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 pharmaceutical composition sed herein, except withoutthe pharmaceutically-acceptable adjuvant.

A pharmaceutical composition disclosed herein can also be administered to an dual incombination with other therapeutic compounds to increase the overall therapeutic effect of the ent.

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

Aspects of the t invention can also be described as follows:1. A pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeuticcompound has an ty that modulates the level of a lipid, a lipoprotein, or both; and b) apharmaceutical|y-acceptable adjuvant.

The pharmaceutical composition according to embodiment 1, wherein the composition furthercomprises a pharmaceutically—acceptable solvent.

A pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeuticcompound has an activity that modulates the level of a lipid, a lipoprotein, or both; b) apharmaceutical|y-acceptable solvent; and c) a pharmaceutically-acceptable adjuvant.

A ceutical ition comprising: a) a therapeutic compound, wherein the therapeuticcompound has an ty that modulates the level of a lipid, a otein, or both; b) aceutical|y-acceptable solvent; and c) a pharmaceutically-acceptable adjuvant, wherein theratio of the pharmaceutically-acceptable solvent to pharmaceutically—acceptable adjuvant is in a rangefrom about 0:1 to about 1:25.

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

The pharmaceutical composition ing to embodiments 1-5, n the activity that modulatesthe level of a lipid, a lipoprotein, or both has an anti-hyperlipidemia activity.

The pharmaceutical composition according to embodiment 6, wherein the anti—hyperlipidemia activityreduces the levels of VLDL, IDL, LDL, or a combination thereof by at least 10%.

The pharmaceutical composition according to embodiment 7, wherein the anti-hyperlipidemia tyincreases the level of HDL by, e.g., at least 2%The pharmaceutical composition according to embodiments 1-8, wherein the activity that modulatesthe level ofa lipid, a lipoprotein, or both reduces the level of an inflammation inducing prostaglandin.

. The ceutical composition according to embodiment 9, wherein the level of the inflammationinducing prostaglandin is reduced by at least 10%.11. The pharmaceutical composition according to embodiments 1-10, wherein the activity that modulatesthe level of a lipid, a otein, or both stimulates a PPAR signaling pathway.12. The pharmaceutical composition according to embodiment 11, wherein the PPAR signaling pathwayis stimulated by at least 10%.13. The pharmaceutical composition ing to embodiments 1-12, wherein the activity that modulatesthe level of a lipid, a lipoprotein, or both induces apoptosis of hage M1 cells, esdifferentiation of Macrophage M2 cells, or both.14. The pharmaceutical composition according to embodiments 1-13, wherein the activity that modulatesthe level of a lipid, a otein, or both reduces the levels of Interferon-gamma (lFNv), Tumornecrosis factor-alpha (TNF-d), Interleukin-12 (IL-12), or a combination thereof released from Th1cells, increases the levels of lL-1O released from a Th2 cell, or both.

. The pharmaceutical composition ing to embodiment 14, wherein the levels of lFNy, TNF-d, IL-12, or a combination thereof released from a Th1 cell are reduced by at least 10%.16. The pharmaceutical composition according to ment 14, wherein the levels of lL-10 releasedfrom a Th2 cell are increased by at least 10%.17. The pharmaceutical composition according to embodiments 1-16, n the activity that modulatesthe level ofa lipid, a lipoprotein, or both reduces the level of an inflammation inducing molecule.18. The pharmaceutical composition according to embodiment 17, wherein the inflammation inducingmolecule comprises substance P (SP), calcitonin elated e (CGRP), glutamate, or acombination thereof.19. The pharmaceutical composition ing to embodiments 1-18, n the therapeutic compoundhas a logP value indicating that the compound is soluble in an organic solvent.

. The pharmaceutical composition according to embodiments 1-19, wherein the therapeutic compoundhas a logP value of more than 1.0.21. The pharmaceutical composition according to embodiments 1-19, wherein the therapeutic compoundhas a IogP value of more than 2.0.22. The pharmaceutical composition according to embodiments 1-21, wherein the therapeutic compoundhas a polar surface area that is hydrophobic.23. The pharmaceutical composition according to embodiments 1-22, wherein the therapeutic compoundhas a polar surface area that is less than 8.0 nm2.24. The pharmaceutical composition according to ments 1-22, wherein the therapeutic compoundhas a polar surface area that is less than 6.0 an.

. The pharmaceutical composition according to embodiments 1-24, wherein the therapeutic compoundses a non-steroidal anti-inflammatory drug (NSAID).26. The pharmaceutical composition according to ment 25, wherein the NSAID comprises asalicylate 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 tive NSAID, anon-selective cyclo-oxygenase (COX) inhibitor, a ive cyclooxygenase 1 (COX 1) inhibitor, aselective cyclooxygenase 2 (COX 2) tor or a combination thereof.27. The pharmaceutical composition according to ments 1-26, wherein the therapeutic compoundcomprises a PPARV agonist.28. The ceutical ition according to embodiment 27, wherein the PPARV agonist comprisesMonascin, lrbesartan, Telmisartan, mycophenolic acid, Resveratrol, Delta(9)—tetrahydrocannabinol, acannabidiol, Curcumin, azol, Benzbromarone, 6—shogaol, glycyrrhetinic acid, athiazolidinedione, a NSAID, a fibrate, or a ation thereof.29. The pharmaceutical composition according to embodiments 1-28, wherein the therapeutic compoundcomprises a nuclear receptor binding agent.

. The pharmaceutical composition according to embodiment 29, wherein the nuclear receptor bindingagent comprises a Retinoic Acid Receptor (RAR) g agent, a Retinoid X Receptor (RXR) bindingagent, a Liver X Receptor (LXR) binding agent, a Vitamin D binding agent, or a combination thereof.31. The pharmaceutical composition according to embodiments 1-30, wherein the eutic compoundcomprises an anti-hyperlipidemic agent.

WO 04654 32. The pharmaceutical composition ing to embodiment 31, wherein the anti-hyperlipidemic agentcomprises a fibrate, a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterolabsorption inhibitor, a pancreatic lipase inhibitor, a sympathomimetic amine, or a combination thereof.33. The pharmaceutical composition according to embodiment 31, wherein the fibrate comprisesBezafibrate, ibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a ation thereof.34. The pharmaceutical composition according to embodiment 31, wherein the statin comprisesAtorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or acombination thereof.

. The pharmaceutical composition according to embodiment 31, wherein the niacin comprisesacipimox, niacin, namide, vitamin B3, or a combination f.36. The pharmaceutical composition according to embodiment 31, wherein the bile acid sequestrantcomprises Cholestyramine, Colesevelam, Colestipol, or a combination thereof.37. The pharmaceutical composition according to embodiment 31, wherein the cholesterol absorptioninhibitor comprises Ezetimibe, a phytosterol, a sterol, a stanol, or a ation thereof.38. The ceutical composition according to embodiment 31, n the fat absorption inhibitorcomprises Orlistat39. The ceutical composition according to embodiment 31, wherein the sympathomimetic aminecomprises Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine,phenylephrine, terenol, dobutamine, methylphenidate, lisdexamfetamine, cathine, cathinone,methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4-methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof.40. The pharmaceutical composition ing to embodiments 1-39, wherein the therapeutic compoundcomprises an ester of a therapeutic compound.41. The ceutical ition according to embodiments 1-40, wherein the therapeutic compoundcomprises an ester of a therapeutic compound according to ments 25-39.42. The pharmaceutical composition according to embodiments 1-41, wherein the pharmaceuticallyacceptablesolvent is less than about 20% (v/v).43. The pharmaceutical composition according to embodiments 1-42, wherein the pharmaceutically-able solvent comprises a pharmaceuticaIIy-acceptable polar aprotic solvent, apharmaceutically-acceptable polar protic t, a pharmaceutically-acceptable non-polar solvent, ora ation thereof.44. The pharmaceutical composition according to embodiments 1-43, wherein the pharmaceutically-acceptable solvent ses a pharmaceutically-acceptable alcohol.45. The pharmaceutical composition according to embodiment 44, wherein the pharmaceutically-acceptable alcohol comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, anunsaturated tic alcohol, an alicyclic alcohol, or a combination thereof.46. The pharmaceutical composition according to embodiment 44, wherein the ceutically-acceptable alcohol comprises a C1_20 alcohol.47. The pharmaceutical composition according to ment 44, wherein the pharmaceutically-acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or acombination thereof.48. The pharmaceutical composition according to ments 1-47, wherein the pharmaceutically-acceptable solvent comprises a ceutically-acceptable ester of pharmaceutically-acceptablealcohol and an acid.49. The pharmaceutical composition according to embodiment 48, wherein the pharmaceutically-acceptable ester comprises methyl acetate, methyl buterate, methyl formate, ethyl e, ethylbuterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate,butyl formate, yl e, isobutyl buterate, yl formate, pentyl acetate, pentyl buterate,pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate, and 1-hexadecyl formate, or acombination thereof.50. The pharmaceutical composition ing to embodiments 1-49, wherein the pharmaceutically-acceptable solvent comprises a pharmaceutically-acceptable polyethylene glycol (PEG) polymer.51. The pharmaceutical composition according to embodiment 50, wherein the pharmaceutically-acceptable polyethylene glycol (PEG) polymer is less than about 2,000 g/mol.52. The pharmaceutical composition according to embodiment 50, wherein the pharmaceutically-acceptable polyethylene glycol (PEG) polymer is more than about 2,000 g/mol.53. The pharmaceutical composition according to embodiments 1-52, wherein the ceutically-acceptable solvent comprises a pharmaceutically-acceptable glyceride.

WO 04654 54. The pharmaceutical composition according to embodiment 53, wherein the pharmaceutically-acceptable glyceride comprises a monoglyceride, a diglyceride, a triglyceride, an acetylatedmonoglyceride, an acetylated eride, an ated triglyceride, or a combination thereof.55. The pharmaceutical composition according to embodiments 1-54, wherein the pharmaceutically-acceptable solvent is a liquid at 20°C.56. The pharmaceutical composition according to embodiments 1-54, wherein the pharmaceuticallyacceptablesolvent is a solid at 20°C.57. The pharmaceutical composition according to embodiment 56, wherein the pharmaceutically-acceptable solid solvent comprises menthol.58. The pharmaceutical composition ing to embodiments 1-57, wherein the adjuvant is at least80% (v/v).59. The pharmaceutical composition according to embodiments 1-58, wherein the pharmaceutically-acceptable adjuvant is a liquid at 20°C.60. The pharmaceutical ition according to embodiments 1-58, wherein the pharmaceutically-acceptable adjuvant is a solid at 20°C.61. The pharmaceutical composition according to embodiments 1-60, wherein the pharmaceutically-acceptable adjuvant comprises a pharmaceutically-acceptable lipid.62. The pharmaceutical composition according to ment 61, wherein the pharmaceutically-acceptable lipid comprises a saturated fatty acid, an unsaturated fatty acid, or a combination thereof.63. The pharmaceutical ition according to embodiment 61 or 62, wherein the pharmaceutically-acceptable lipid comprises two or more saturated or unsaturated fatty acids.64. The pharmaceutical composition ing to embodiment 63, wherein the two or more saturated orunsaturated fatty acids includes ic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or acombination thereof.65. The pharmaceutical composition according to embodiments 62-64, wherein the rated fatty acidhas a melting point temperature of 20°C or below.66. The pharmaceutical composition according to embodiments 62-64, n the unsaturated fatty acidis a solid at 20°C. 2012/05024167. The pharmaceutical composition according to embodiments 62-64, wherein the unsaturated fatty acidcomprises an omega fatty acid.68. The pharmaceutical composition according to embodiment 61, wherein the pharmaceutically-acceptable lipid comprises a pharmaceutically-acceptable oil.69. The ceutical composition according to embodiment 68, wherein the pharmaceutically-acceptable oil comprises almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, cornoil, 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.70. The pharmaceutical composition according to embodiments 1-69, wherein the pharmaceuticalcomposition further comprises a pharmaceutically-acceptable stabilizing agent.71. The pharmaceutical composition according to embodiment 70, wherein the pharmaceutically-acceptable izing agent comprises water, a cial acid comprising a fatty acid ent andacetic acid, ethyl acetate, a sodium acetate/acetic acid, a monoglyceride, an acetylatedmonoglyceride, a diglyceride, an acetylated diglyceride, a fatty acid, a fatty acid salt, or a combinationthereof.72. The pharmaceutical composition according to embodiment 70, wherein the pharmaceutically-acceptable stabilizing agent comprises a pharmaceutically-acceptable emulsifying agent.73. The pharmaceutical composition according to embodiment 72, wherein the pharmaceutically-acceptable emulsifying agent comprises a surfactant, a ccharide, a lectin, a phospholipid, or acombination f.74. The ceutical composition according to embodiments 1-71, wherein the pharmaceuticalcomposition does not comprise a pharmaceuticalIy-acceptable emulsifying agent.75. A method of preparing a pharmaceutical composition, the method sing the step of contacting atherapeutic compound with a pharmaceutically-acceptable adjuvant under conditions which allow theformation of the pharmaceutical composition.76. A method of preparing a pharmaceutical composition, the method sing the steps: a) contactinga ceutically—acceptable solvent with a eutic compound under conditions which allow thetherapeutic compound to dissolve in the pharmaceutically-acceptable t, thereby forming asolution, wherein the therapeutic compound has nflammatory activity, and b) contacting thesolution formed in step (a) with a pharmaceutically—acceptable adjuvant under conditions which allowthe formation of the pharmaceutical composition.77. A method of preparing a pharmaceutical composition, the method comprising the steps: a) contactinga pharmaceutically—acceptable solvent with a therapeutic compound under conditions which allow thetherapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming asolution, n the therapeutic compound has anti-inflammatory activity, and b) contacting thesolution formed in step (a) with a pharmaceutically—acceptable adjuvant under conditions which allowthe formation of the pharmaceutical ition, wherein the ratio of the pharmaceutically-acceptablet to pharmaceuticaIly-acceptable nt is in a range from about 0:1 to about 1:25.78. The method according to embodiments 75-77, wherein the therapeutic compound has a logP valueindicating that the compound is soluble in an organic solvent.79. The method according to embodiment 75-78, wherein the therapeutic nd has a logP value ofmore than 1.0.80. The method according to embodiment 75-78, wherein the eutic compound has a logP value ofmore than 2.0.81. The method according to embodiments 75-80, wherein the therapeutic compound has a polar surfacearea that is hydrophobic.82. The method according to embodiments 75-81, wherein the therapeutic compound has a polar surfacearea that is less than 8.0 nmz.83. The method according to ments 75-81, wherein the therapeutic compound has a polar surfacearea that is less than 6.0 nmz.84. The method according to embodiments 75-83, wherein the therapeutic compound comprises a non-steroidal anti-inflammatory drug (NSAID).85. The method ing to embodiment 84, wherein the NSAID comprises a salicylate derivativeNSAID, a p—amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acidderivative NSAID, an enolic acid derivative NSAID, a c acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selectivecyclooxygenase 2 (COX 2) inhibitor, or a combination thereof.86. The method according to embodiments 75-85, n the therapeutic compound comprises aPPARV agonist.87. The method according to embodiment 86, wherein the PPARy t comprises Monascin,lrbesartan, Telmisartan, mycophenolic acid, Resveratrol, Delta(9)—tetrahydrocannabinol, aidiol, in, Cilostazol, Benzbromarone, aol, glycyrrhetinic acid, athiazolidinedione, a NSAID, a e, or a combination thereof.88. The method according to embodiments 75-87, wherein the therapeutic compound comprises anuclear receptor binding agent.89. The method according to embodiment 88, wherein the nuclear receptor binding agent comprises aRetinoic Acid or (RAR) binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver XReceptor (LXR) binding agent, a Vitamin D binding agent, or a combination f.90. The method according to embodiments 75-89, wherein the therapeutic compound comprises an anti-ipidemic agent.91. The method according to embodiment 90, wherein the anti-hyperlipidemic agent comprises a fibrate,a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, apancreatic lipase inhibitor, a sympathomimetic amine, or a combination thereof.92. The method according to embodiment 91, wherein the fibrate comprises Bezafibrate, ibrate,Clofibrate, rozil, Fenofibrate, or a combination thereof.93. The method according to embodiment 91, wherein the statin comprises Atorvastatin, Fluvastatin,atin, statin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof.94. The method according to embodiment 91, wherein the niacin comprises acipimox, niacin,nicotinamide, n B3, or a ation thereof.95. The method according to embodiment 91, wherein the bile acid sequestrant comprisesCholestyramine, Colesevelam, Colestipol, or a combination thereof.96. The method according to embodiment 91, wherein the cholesterol absorption inhibitor comprisesEzetimibe, a phytosterol, a sterol, a stanol, or a combination thereof.97. The method ing to embodiment 91, wherein the fat absorption inhibitor comprises Orlistat98. The method according to embodiment 91, wherein the sympathomimetic amine comprisesClenbuterol, amol, ephedrine, pseudoephedrine, methamphetamine, amphetamine,phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamfetamine, cathine, cathinone,methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4-aminorex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof. 2012/05024199. The method according to embodiments 75-98, n the therapeutic compound comprises an esterof a therapeutic compound.100. The method according to embodiments 75-99, wherein the therapeutic compound comprises anester of a therapeutic compound according to embodiments 78-99.101. The method according to embodiments 76-100, wherein the pharmaceutically-acceptable solvent isless than about 20% (WV).102. The method according to embodiments 76-101, wherein the pharmaceutically—acceptable solventcomprises a pharmaceutically-acceptable polar aprotic solvent, a pharmaceutically—acceptable polarprotic solvent, a ceutically-acceptable non-polar solvent, or a combination thereof.103. The method according to embodiments 76-102, wherein the pharmaceutically—acceptable solventcomprises a pharmaceutically-acceptable alcohol.104. The method ing to embodiment 103, wherein the pharmaceutically-acceptable alcoholcomprises an c alcohol, a monohydric alcohol, a dric alcohol, an unsaturated aliphaticl, an alicyclic alcohol, or a combination thereof.105. The method according to ment 103, wherein the pharmaceutically-acceptable alcoholcomprises a C120 alcohol.106. The method according to embodiment 103, wherein the pharmaceutically-acceptable alcoholcomprises methanol, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a combination thereof.107. The method according to embodiment 103, wherein the pharmaceutically—acceptable solventcomprises a pharmaceutically-acceptable ester of pharmaceutically—acceptable alcohol and an acid.108. The method according to ment 107, wherein the pharmaceutically-acceptable esterses methyl acetate, methyl buterate, methyl formate, ethyl acetate, ethyl te, ethylformate, 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, or a combination f.109. The method according to ments 76-108, wherein the pharmaceutically-acceptable solvent isa pharmaceutically—acceptable polyethylene glycol (PEG) r.110. The method according to embodiment 109, wherein the pharmaceutically—acceptable polyethyleneglycol (PEG) polymer is less than about 2,000 g/mol.111. The method according to embodiment 109, wherein the pharmaceutically—acceptable polyethyleneglycol (PEG) polymer is more than about 2,000 g/mol.112. The method according to embodiments 76-111, wherein the pharmaceutically—acceptable solventcomprises a pharmaceutical|y-acceptable glyceride.113. The method according to embodiments 112, wherein the ceutically-acceptable glyceride is amonoglyceride, a diglyceride, a triglyceride, an acetylated monoglyceride, an acetylated diglyceride,an acetylated triglyceride, or a combination thereof.114. The method according to embodiments 76-113, wherein the ceutically-acceptable solvent isa liquid at 20°C.115. The method according to ments 76-113, wherein the pharmaceutically-acceptable solvent isa solid at 20°C.116. The method according to embodiment 113, wherein the pharmaceutical|y-acceptable solid solvent is117. The method according to ments 75-116, wherein the pharmaceutically—acceptable adjuvantis at least 80% (WV).118. The method according to embodiments 75-117, wherein the pharmaceutically—acceptable adjuvantis a liquid at 20°C.119. The method according to embodiments 75-117, wherein the pharmaceutically—acceptable adjuvantis a solid at 20°C.120. The method according to ments 75-119, wherein the pharmaceutically—acceptable adjuvantcomprises a ceutical|y-acceptable lipid.121. The method ing to ment 120, wherein the pharmaceutically—acceptable lipid sesa pharmaceutically-acceptable saturated fatty acid, an unsaturated fatty acid, or a combinationthereof.122. The method according to embodiment 120 or 121, wherein the pharmaceutically-acceptable lipidcomprises two or more pharmaceutically—acceptable saturated or unsaturated fatty acids.123. The method according to embodiments 122, wherein the two or more pharmaceutically-acceptablesaturated or unsaturated fatty acids include palmitic acid, stearic acid, oleic acid, linoleic acid,linolenic acid, or a combination thereof.124. The method ing to embodiments 121-123, n the pharmaceuticaIIy-acceptableunsaturated fatty acid has a melting point temperature of 20°C or below.125. The method according to embodiments 121-123, wherein the pharmaceuticaIIy-acceptableunsaturated fatty acid is a solid at 20°C.126. The method according to embodiments 121-125, wherein the pharmaceutically-acceptableunsaturated fatty acid comprises an omega fatty acid.127. The method according to embodiments 120-126, n the pharmaceutically-acceptable lipidcomprises a ceuticaIIy-acceptable oil.128. The method according to embodiment 127, wherein the pharmaceutically-acceptable oil comprisesalmond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, peanut oil, ed oil, rice bran oil,safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or acombination thereof.129. The method according to ments 76 or 78-128, wherein in step(b) the ratio of thepharmaceutically-acceptable solvent to pharmaceutically-acceptable adjuvant is in a range fromabout 0:1 to about 1:25.130. The method according to embodiments 75-129, wherein the step (a) further comprising contacting apharmaceuticaIIy-acceptable stabilizing agent with the pharmaceuticaIIy-acceptable t and thetherapeutic compound.131.The method according to embodiment 130, wherein the pharmaceuticaIIy-acceptable stabilizingagent comprises water, a sacrificial acid sing a fatty acid component and acetic acid, ethylacetate, 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.132. The method according to embodiment 130 or 131, wherein the ceuticaIIy-acceptablestabilizing agent comprises a ceutically-acceptable emulsifying agent.133. The method according to embodiment 132, wherein the pharmaceutically-acceptable emulsifyingagent comprises a surfactant, a polysaccharide, a lectin, a phospholipid, or a combination thereof.134. The method according to embodiments 75-131, wherein the pharmaceutical composition does notcomprise a pharmaceuticaIIy-acceptable emulsifying agent.135. The method according to embodiments , wherein the method further comprises removing thepharmaceutically-acceptable solvent from the pharmaceutical composition.136. The method according to embodiment 135, wherein at least 5% the pharmaceutically-acceptablesolvent is removed from the pharmaceutical composition.137. The method according to embodiment 135 or 136, wherein at, removal of solvent from thepharmaceutical composition disclosed herein is carried out at a ature of less than 20°C.138. The method according to embodiments 75-137, n the pharmaceutical composition made isaccording to embodiments 1-74.139 A method of treating an individual with a cardiovascular disease, the method comprising the step of:administering to the individual in need thereof a pharmaceutical ition according toembodiments 1-74, n administration results in a reduction in a symptom associated with thecardiovascular e, thereby treating the individual.140. Use of a pharmaceutical composition according to embodiments 1-74 in the cture of amedicament for the treatment of a cardiovascular disease.141. Use of a pharmaceutical composition according to embodiments 1-74 for the ent of acardiovascular disease.142. The method according to embodiment 139 or the use ing to embodiment 140 or 141, whereinthe cardiovascular disease is associated with a hyperlipidemia, a coronary heart disease, anatherosclerosis, a peripheral vascular disease, a cardiomyopathy, a vasculitis, an inflammatoryheart disease, an ischemic heart disease, a congestive heart failure, a hypertensive heart disease, avalvular heart disease, a hypertension, myocardial infarction, a diabetic c conditions, ananeurysm; an embolism, a dissection, a pseudoaneurysm, a vascular malformation, a vascularnevus, a thrombosis, a varicose vein, or a stroke.143. The method or use according to embodiment 142, wherein the hyperlipidemia is idemia,hypercholesterolemia, hyperglyceridemia, hypertriglyceridemia, hyperlipoproteinemia, orhyperchylomicronemia, and ed ipidemia.144. The method or use according to embodiment 143, wherein the hyperlipoproteinemia ishyperlipoproteinemia type la, ipoproteinemia type lb, hyperlipoproteinemia type lc,hyperlipoproteinemia type Ila, hyperlipoproteinemia type llb, hyperlipoproteinemia type III,hyperlipoproteinemia type IV, or hyperlipoproteinemia type V.145. The method or use according to embodiment 142, wherein the vascular occlusive disease (VOD) isan atherosclerosis, a peripheral vascular disease, or a stenosis.146. The method or use according to embodiment 142, n the cardiomyopathy is an extrinsicmyopathy or an intrinsic myopathy.147. The method or use according to embodiment 146, wherein the extrinsic myopathy isacromegaly, alcoholic myopathy, amyloidosis, Chagas disease, chemotherapy, diabeticcardiomyopathy, hemochromatosis, hypertensive cardiomyopathy, hyperthyroidism, inflammatorycardiomyopathy, ischemic cardiomyopathy, muscular dystrophy, valvular myopathy, acardiomyopathy secondary to a systemic metabolic disease, a cardiomyopathy secondary to asystemic nutritional disease, a coronary artery disease, or a congenital heart disease.148. The method or use according to embodiment 146, wherein the intrinsic cardiomyopathy is dilatedmyopathy (DCM), hypertrophic cardiomyopathy (HCM or HOCM), arrhythmogenic rightventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), noncompactioncardiomyopathy, isolated ventricular non-compaction, mitochondrial myopathy, Takotsubocardiomyopathy, or Loeffler endocarditis.149. The method or use according to embodiment 142, wherein the vasculitis is a r's disease, anarteritis, a cerebral vasculitis, a Churg-Strauss arteritis, a obulinemia, an essentialobulinemic vasculitis, a giant cell tis, a Golfer's vasculitis, a Henoch-Schonlein purpura, ahypersensitivity vasculitis, a Kawasaki e, a tis, a microscopic polyarteritis/polyangiitis, apolyarteritis nodosa, a algia rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis,a thrombophlebitis, a Wegener's granulomatosis, or a vasculitis secondary to connective tissuedisorder, or vasculitis secondary to viral infection.150. The method or use according to embodiment 149, wherein the vasculitis secondary to connectivetissue disorder is systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), relapsingpolychondritis, Behcet's disease.151. The method or use according to embodiment 142, n the inflammatory heart disease is anendocarditis, an inflammatory cardiomegaly, or a myocarditis.152. The method according to embodiments 139 or 142-151 or the use according to embodiments 140-151, wherein upon administration to an individual, the pharmaceutical ition comprising thetherapeutic nd according to ments 1-74 results in a bio-distribution of the therapeuticcompound different than a bio-distribution of the therapeutic compound included in the samepharmaceutical composition, except without the pharmaceuticaIIy-acceptable adjuvant.153. The method according to embodiments 139 or 142-152 or the use according to embodiments 140-152, wherein upon administration to an individual, the amount of the therapeutic compound of thepharmaceutical composition according to embodiments 1-74 delivered to a macrophage is at least% of the total amount of the therapeutic compound contained in the administered pharmaceuticalition.154. The method according to embodiments 139 or 142-153 or the use according to embodiments 140-153, wherein upon administration to an individual, the pharmaceutical ition ing toembodiments 1—74 reduces intestinal irritation by at least 5% when compared to the pharmaceuticalcomposition according to embodiments 1-74, except without the pharmaceutically-acceptableadjuvant.155. The method according to embodiments 139 or 142-154 or the use according to embodiments 140-154, wherein upon stration to an individual, the pharmaceutical composition according toembodiments 1-74 reduces c irritation by at least 5% when ed to the pharmaceuticalcomposition according to embodiments 1-74, except without the pharmaceutically-acceptableadjuvant.

EXAMPLES The following non-limiting examples are ed for illustrative purposes only in order to facilitatea more complete tanding of representative ments now contemplated. These examplesshould not be construed to limit any of the embodiments described in the present specification, includingthose pertaining to the compounds, alcohols, lipids, pharmaceutical compositions, methods of preparingpharmaceutical compositions, or methods or uses of treating a chronic inflammation or diseaseassociated with chronic inflammation.

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

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

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

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

As a first step, experiments were conducted to the miscibility of a solvent in an adjuvant like oil in theabsence of a therapeutic compound. In these experiments 0.5 mL l was ted with tendifferent volumes of rapeseed oil (Table 1). Each mixture was tested at 22°C and at 37°C in which theethanol and oil were initially heated in a water bath before being mixed together. Mixing was attempted byvortex mixing for 20 seconds, and the containers were allowed to settle before visual assessment, eitherimmediately, or after 24 hours. Each mixture was evaluated to determine whether or not the ethanol andrapeseed oil form immiscible layers, or a homogeneous mixture. The results 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 ible layers ateither 22°C or at 37°C, either immediately or after 24 hours of incubation, indicating that the ethanol andoil did not mix well at these ratios. However, in solvent:adjuvant ratios above 1:7 a homogeneous mixturewas formed under all conditions tested.

Table 1. Liquid Formulations without Therapeutic compoundComponents TemperatureSolvent nt 22°C 37°CRatio(mL) (mL) Immediate 24 hours Immediate 24 hours0.5 0.5 1:1 |L |L |L |L0.5 1.0 1:2 |L |L |L |L0.5 1.5 IL IL IL0.5 2.0 1:4 |L |L |L |L0.5 2.5 IL IL IL0.5 3.0 1:6 |L |L |L |L0.5 3.5 1:7 HM HM HM HM0.5 4.0 1:8 HM HM HM HM0.5 4.5 HM HM HM0.5 5.0 HM HM HMlL, Immiscible layers.

HM, neous mixture.

Once the appropriate ratios of alcohol and lipid necessary to form a homogenous mixture weredetermined, it was next ined whether contacting a therapeutic compound first in a t beforecontacting with an adjuvant would result in the compound dissolving in the ts. To conduct thesements, either 1,000 mg or 1,200 mg of ibuprofen was dissolved into 0.5 mL of ethanol. Theresulting alcohol solution was then contacted with rapeseed oil at two different solvent:adjuvant ratios (1 :2and 1:9). Each mixture was tested at 20°C and at 37°C in which the ethanol solution and oil were initiallyheated in a water bath before being mixed together. Mixing was attempted by vortex mixing for 20seconds, and the containers were allowed to settle before visual assessment, either immediately, or after24 hours. Each mixture was evaluated to determine whether or not the ethanol on and ed oilform immiscible layers, or a homogeneous mixture. The results are summarized in Table 2. In stto the ion in the absence of a therapeutic compound, when ibuprofen is present in the ethanol, itcaused the ethanol and oil to form a homogeneous mixture under all conditions tested in solvent:adjuvantratios above 1:2. This observation was very surprising because, although not wish to be bound by anyWO 04654 theory, it appears that a eutic compound may be having some effect on the manner in which anadjuvant and solvent interact with each other, such that a neous mixture is formed in a way thatdoes not occur when the therapeutic compound is absent. In addition, the results indicate that atherapeutic compound can be formulated at clinically useful concentrations.

Table 2. Liquid Formulations with Therapeutic CompoundComponentscompound Solvent Adiuvant(mg) (mt) (mm "amlL, lmmiscible layers.

HM, neous mixture.

Example 2Liquid Formulations of ceutical Composition This example illustrates how to make a pharmaceutical ition as sed herein as aliquid formulation.

To prepare a ceutical composition disclosed herein using gemfibrozil, the ingformulations were examined. In these experiments, 600 mg gemfibrozil was contacted with entvolumes of ethanol, as the solvent, warmed to 37°C, and the resulting solution was then contacted withdifferent volumes of linseed oil, as the adjuvant, warmed to 37°C (Table 3). Each formulation wasevaluated to determine whether or not the ethanol and linseed oil form immiscible layers, a clearhomogeneous mixture, as well as whether or not the gemfibrozil crystallized out of solution. The resultsare summarized in Table 3.

Like fen in Example 1 above, gemfibrozil remained insoluble in the oil alone and did notdissolve to substantially measureable degree. The formulation comprising 0.2 mL ethanol was unable tocompletely dissolve gemfibrozil. In addition, although the formulation comprising 0.3 mL ethanol wascapable of dissolving gemfibrozil, the therapeutic compound began to crystallizing out of solution within 3hours and complete crystallization occurred within 48 hours. All other formulations tested were eof dissolving gemfibrozil and forming a pharmaceutical composition disclosed herein. However, only theformulation comprising 0.5 mL l appeared to for a stable pharmaceutical composition in thatgemfibrozil remained completely dissolved after three weeks.

Table 3. Liquid Formulatlons WIth Therapeutlc CompoundCompound Solvent Adjuvant 22°C("‘91) ("‘L) <le —mHM, Clear homogeneous e.

CR, Crystallization.

IM, Immiscible.

Example 3Liquid Formulations of Pharmaceutical Composition This e illustrates how to make a pharmaceutical composition as sed herein as aliquid formulation.

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

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

Since certain fatty acids are liquid at room temperature, while others are solid, an ation ofthe different fatty acids was undertaken in an effort to evaluate the ial of each fatty acid in themanufacture of a solid formulation. This understanding would enable the development of a wide array ofsolid 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 possible to prepare apharmaceutical composition disclosed herein that could be formulated using only one of these fatty acidsto be a solid or semi-solid at 22°C (simulating room temperature conditions), but melt into a liquid at 37°C(simulating internal body temperature conditions after ion).

Four different test formulations were prepared and evaluated on their ability to form a solid doseformulation at 22°C and melt into a homogeneous on at 37°C without forming a suspension (Table4). ation 1 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, and theresulting solution was then mixed with 200 mg of stearic acid (Tm of about 67-72°C) and heated at 60°Cfor 30 minutes to form a homogeneous solution. ation 1 solidified immediately upon g to22°C. Formulation 1 remained a solid even after incubating at 37°C overnight. Formulation 2 wasprepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, and the resulting solution was thenmixed with 200 mg of palmitic acid (Tm of about 61-62°C) and heated at 60°C for 30 minutes to form ahomogeneous on. Formulation 2 solidified about 1 hour after cooling to 22°C. Incubating at 37°Covernight cause Formulation 2 to completely melt into a clear homogenous liquid. However, Formulation2 once again solidified about 1 hour after cooling to 22°C. Formulation 3 was prepared by dissolving 200mg of Ibuprofen into 400 mg of menthol, and the resulting on was then mixed with 200 mg of linoleicacid (Tm of about -5°C) and heated at 37°C for 2 hours to form a homogeneous solution. Formulation 3remained a , even after cooling to 22°C for 72 hours. Formulation 4 was prepared by dissolving 200mg of Ibuprofen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg ofnic acid (Tm of about -11°C) and heated at 37°C for 2 hours to form a neous solution.

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

Table 4. Solid Formulations with Therapeutic CompoundCompound Solvent Adjuvant 22°C 37°C(mg) (mg) (mg) Upon Cooling 24 hours 72 hours400 200 (stearic acid) 2:1 Solid Solid400 200 (palmitic acid) 2:1 Solid Liquid: Liquid400 200 (linolenic acid) 2:1 Liquid Based on these data, a solid dosage form of a pharmaceutical composition disclosed herein canbe made. For example, a pharmaceutical composition will be formulated to be solid or semi-solid at22°C, but melt into a proper clear solution (and not a suspension) at 37°C (Table 5).

Table 5. Solid Formulations of Pharmaceutical itionsCompound 600 mg IbuprofenSolvent 500mg MethanolAdjuvant 000mg Palmitic acid000mg Stearic acid50mg Linolenic acid250mg Linoleic acidRatioVolumeConcentration 120 mg/mLExample 5Animal Model for Intestinal Erosion To assess whether a ceutical 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 animals were challenged with one with one of seven ent ents.

Group A was a control in which each mouse was orally administered 1% methylcellulose/O.5%polysorbate 80 vehicle only. Group B was a control in which each mouse was orally administeredt/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil). Group C was a control inwhich each mouse was orally administered 150 mg/kg aspirin. Group D was a control in which eachmouse was orally administered 100 mg/kg ibuprofen suspended in 1% cellulose/O.5% polysorbate80. Group E was the mental group in which each mouse was administered a pharmaceuticalition disclosed herein (BC1054-100) comprising 100 mg/kg of ibuprofen, 10% ethanol, and 90%d oil. Group F was a control in which each mouse was orally administered 100 mg/kg ibuprofensuspended in 1% methylcellulose/0.5% rbate 80. Group G was the experimental group in whicheach mouse was administered a pharmaceutical composition disclosed herein (BC1054-200) comprising200 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Animals were sacrificed 4 hours aftertreatment and the stomachs were examined for degree of hemorrhage and severity of mucosal erosivelesions. 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 morerelative to Group C (aspirin-treated l group), which was set to 100%, was considered a positivescore for gastric irritation.

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

Table 6. Results from Intestinal ErOSIon AssayMeanGroup % Aspirin ErosionUlceration Score1 Positivescore for gastric erosion.

Example 6Animal Model for a Respiratory Inflammation To assess the effectiveness of a ceutical composition disclosed herein in treating arespiratory inflammation, ments were conducted using a viral-induce influenza murine model.

C57BLK/6 female mice (6-7 weeks old) were divided into three experimental groups containingten animals each. On day 1, animals received an intranasal lethal dose (50 pL total, 25 tril) ofInfluenza A/PR/8/34 under halothane-induced anaesthesia. On day 3, post-challenge with the virus, thes ed one of three treatments. Group A was a control in which each mouse was orallyadministered 335.6 pg of ibuprofen dissolved in 10 pL DMSO (no adjuvant). Group B was a control inwhich each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and90% linseed oil). Group C was the experimental group in which each mouse was administered apharmaceutical composition disclosed herein (BC1054) comprising 335.6 pg of ibuprofen, 10% ethanol,and 90% linseed oil. A dose of 335.6 pg of ibuprofen in the mouse is equivalent to 20mg/kg/day, or 1200mg/day for a human (the maximum standard dose for ibuprofen). Animals were weighed, and monitoredfor signs of infection daily for up to day 6 when all animals were . Figure 1 y shows that oraladministration of the solvent/adjuvant vehicle only (Group B) had an 80% mortality rate and that oraladministration of ibuprofen only (Group A) exhibited a mortality rate of 60%. However, a single oraladministration of 801054 reduced the mortality rate to only 20%.

To determination of levels of IL-1O and IL-4, an ELISA was performed using a 96-well platecoated with a capture antibody for |L-1O or |L-4. Lungs collected from the culled mice were homogenizedat 4°C, and the supernatant collected and stored at -70°C until needed. Thawed s were vortexedfor 30 seconds immediately before adding to the ELISA plate. Serial dilutions were performed within theplate with both the sample and the standards by pipetting 60 pL of assay diluent into each well. The platewas sealed and incubated for 2 hours at room temperature. For |L-4, 60 pL of working or wasadded (Detection Antibody + SAv—HRP reagent) to each well. The plate was sealed and incubated for 1hour at room temperature. For |L-10, 60 pL of detection antibody was diluted in assay diluent to eachwell. Plates were washed and 60pL of SAv-HRP enzyme was diluted in assay diluent and added to theplate. The plate was sealed and ted for 20 minutes at room temperature. Plates were then washedten times. 60 pL of ate solution were added to each well and the plate was incubated for 30 minutesat room temperature in the dark. 60 pL of stop solution was added to each well and absorbance was readat 450 nm. |L-10 and IL-4 concentrations were expressed as pg/mg of lung . These results indicatethat a pharmaceutical composition disclosed herein was effective in ng a respiratory inflammation.

Results show that animals from the Group A (ibuprofen-treated control group) and Group B(solvent/adjuvant vehicle-treated l group) controls exhibited 2600 pg/mg and 2000 pg/mg of IL-10,respectively (). However, Group C (BC1054-treated experimental group) revealed an |L-1O 2012/050241concentration of 6000 pg/mg, 3-fold higher than that seen in the control animals. These result also showsthat s from the Group A (ibuprofen-treated control group) and Group B (solvent/adjuvant vehicle-treated control group) controls exhibited 6900 pg/mg and 5400 pg/mg of |L-4, respectively, while Group C(BCIO54—treated experimental group) exhibited an |L-4 concentration of 8300 pg/mg (). Takentogether, synergistic increase in |L-10 levels and/or the increase in lL-4 levels suggest that at least part ofthe efficacy ed for 801054 was by ng a switch from a Th1 to a Th2 response.

Further experiments were done to further determine which cell types were stimulated to releasecytokines upon administration of a BC1054. C57BLK/6 female mice (6-7 weeks old) were divided intothree experimental groups containing ten animals each. On day 1, animals received an intranasal lethaldose (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 whicheach mouse was orally administered 335.6 ug of ibuprofen dissolved 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 inwhich each mouse was administered a pharmaceutical composition disclosed herein (BC1054)comprising 335.6 pg of ibuprofen, 10% l, and 90% linseed oil. Lungs collected from y-ed mice were homogenized at 4°C, and the supernatant collected, stored, and |L-10, TNFd andIFNv levels measured using an ELISA.

The results show that Group A ofen-treated l group) and Group C (BC1054-treatedexperimental group) animals exhibited an increased |L-10 levels (). However, these |L-1Oincreases were associated with very different pharmacodynamic s, and the pattern of pro-inflammatory cytokine reduction ghts the source of the |L-10 and its relevance to the effect onsurvival. For example, TNFor (which is macrophage-related cytokine) was not as markedly inhibited (FIGBB) in Group A (ibuprofen-treated control group) animals, s the levels of lFNy (which is alymphocyte-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 pooroutcome. However, in Group C (BC1054-treated experimental group) animals, TNFd levels weremarkedly lowered (FIG 38), while lFNy levels were largely unaffected (FIG 3C). This trates that apharmaceutical composition disclosed herein shows a protective effect on the H1N1-induced lethalitythrough, in part, a macrophage—derived |L—10 levels rather than lymphocyte-derived |L10.

Example 7Case Studies for the Treatment of a Cardiovascular Disease A 49 year old male diagnosed with hypercholesterolemia (LDL of 4.35 ) was placed on apharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% l,and 90% linseed oil (600 mg bid) for 7 days. After 5 days of treatment the patient’s LDL levels hadnormalized to 3.89 mmol/L. The normalization of LDL level persisted for 2 months after cessation ofB01054 dosing, as determined at the last examination.

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

Example 8Treatment of Cardiovascular Disease A 62 year old female is diagnosed with elevated cholesterol levels. A physician determines thatthe elevated cholesterol level is due to a hypercholesterolemia. The woman is treated by oralstration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.

Alternatively, the woman is treated by oral administration a pharmaceutical composition comprising aPPAR-v t as disclosed herein taken thrice daily. atively, the woman is treated by oraladministration a pharmaceutical composition sing Gemfibrozil as disclosed herein taken twicedaily. The woman’s condition is monitored and after about 1 week of treatment tests tes there isreduced level of cholesterol in her blood. At one and three month check-ups, the woman continues tohave blood cholesterol levels in a normal range. This reduction in a hypercholesterolemia symptomindicates successful treatment with the pharmaceutical composition disclosed . A similar type oforal administration of a pharmaceutical composition disclosed herein will be used to treat a patientsuffering from other forms of, such as, 9.9., dyslipidemia, hypercholesterolemia, hyperglyceridemia,hypertriglyceridemia, hyperchylomicronemia, combined hyperlipidemia, or hyperlipoproteinemia includinghyperlipoproteinemia is hyperlipoproteinemia type la, hyperlipoproteinemia type lb, hyperlipoproteinemiatype lc, hyperlipoproteinemia type Ila, hyperlipoproteinemia type llb, hyperlipoproteinemia type III,hyperlipoproteinemia type IV, and ipoproteinemia type V,. In a similar manner, any of thetherapeutic compounds such as, 6.9., a NSAID like a salicylate derivative NSAID, a p-amino phenolderivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, aselective xygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2) tor; a PPARVagonist; a nuclear receptor binding agent; or an anti-hyperlipidemic agent like a e, a statin, atocotrienol, a niacin, a bile acid sequestrants, a cholesterol absorption inhibitor, a atic lipaseinhibitor, or a sympathomimetic amine, will be formulated into a pharmaceutical composition andadministered to the patient as described above.

A 58 year old male is complains of chest pains, shortness of breath and dizziness. A physicianines that the breathing difficulty is due to an atherosclerosis. The man is treated by oralstration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.

Alternatively, the man is treated by oral administration a pharmaceutical composition comprising a PPAR-y t as disclosed herein taken thrice daily. Alternatively, the man is treated by oral administration apharmaceutical composition sing Gemfibrozil as disclosed herein taken twice daily. The man’s 2012/050241condition is monitored and after about 3 weeks of treatment the man indicates there is improvement in hisability to breath and he is not experiencing as much dizziness. At two and three month check-ups, theman indicates that he continues to have improved breathing, no dizziness and no recent chest pains.

This ion in a sclerosis symptoms indicate successful treatment with the pharmaceuticalcomposition disclosed herein. A similar type of oral administration of a pharmaceutical compositiondisclosed herein will be used to treat a patient suffering from another form of vascular occlusive diseasesuch as, e.g., a eral ar disease or a stenosis. In a similar manner, any of the therapeuticcompounds such as, e.g., a NSAID like a salicylate derivative NSAID, a o phenol tiveNSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivativeNSAID, a fenamic acid derivative NSAID, a lective cyclo—oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, a ive cyclooxygenase 2 (COX 2) inhibitor; a PPARy agonist; anuclear or binding agent; or an anti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol, aniacin, a bile acid sequestrants, a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, or asympathomimetic amine, will be formulated into a pharmaceutical composition and administered to thepatient as described above.

A 67 year old male suffering from alcoholism complains of pressure on his chest and numbnessin his left shoulder. A physician determines that the re and ss are due to an alcoholiccardiomyopathy. The man is treated by oral administration a pharmaceutical ition comprisingfen as disclosed herein taken twice daily. Alternatively, the man is treated by oral administration apharmaceutical composition comprising a PPAR-v agonist as disclosed herein taken thrice daily.

Alternatively, the man is treated by oral administration a pharmaceutical composition singGemfibrozil as disclosed herein taken twice daily. The man’s condition is monitored and after about 3weeks of treatment the man indicates there is reduced numbness. At two and three month check-ups,the man indicates that he continues to have improved sensation in his shoulder and has not had a recentepisode of chest pressure. This reduction in alcoholic cardiomyopathy symptoms indicates successfultreatment with the pharmaceutical composition disclosed herein. A similar type of oral administration of apharmaceutical composition disclosed herein will be used to treat a patient suffering from acardiomyopathy, such as, e.g., an extrinsic cardiomyopathy like acromegaly, amyloidosis, Chagasdisease, chemotherapy, diabetic cardiomyopathy, hemochromatosis, hypertensive cardiomyopathy,hyperthyroidism, inflammatory myopathy, ischemic cardiomyopathy, muscular dystrophy, valvularcardiomyopathy, a cardiomyopathy secondary to a ic metabolic disease, a cardiomyopathysecondary to a systemic nutritional disease, a coronary artery disease, or a congenital heart disease; oran intrinsic cardiomyopathy like dilated cardiomyopathy (DCM), hypertrophic myopathy (HCM orHOCM), arrhythmogenic right ventricular myopathy (ARVC), restrictive cardiomyopathy (RCM),noncompaction cardiomyopathy, isolated ventricular non-compaction, mitochondrial myopathy, Takotsubocardiomyopathy, or Loeffler endocarditis. In a similar manner, any of the therapeutic compounds such as,e.g., a NSAID like a late derivative NSAID, a p-amino phenol derivative NSAID, a nic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acidderivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX1) tor, a selective cyclooxygenase 2 (COX 2) inhibitor; a PPARv agonist; a nuclear receptor bindingWO 04654 agent; or an anti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol, a niacin, a bile acidsequestrants, a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, or a sympathomimeticamine, will be formulated into a ceutical composition and administered to the t as describedabove.

A 73 year old female complains of muscle cramping and cold sensation down her right leg. Aphysician determines that the ms are due to arteritis of the femoral artery. The woman is treatedby oral administration a pharmaceutical composition comprising fen as disclosed herein taken twicedaily. Alternatively, the woman is treated by oral administration a pharmaceutical composition comprisinga PPAR-y t as disclosed herein taken thrice daily. Alternatively, the woman is treated by oraladministration a pharmaceutical composition comprising Gemfibrozil as disclosed herein taken twicedaily. The woman’s condition is monitored and after about 3 weeks of treatment the woman indicates thatshe has reduced muscle cramping and no cold sensations on her leg. At two and three month check-ups,the woman indicates that she still does not have muscle cramping or cold ions. This reduction inarteritis symptoms 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 treata patient ing from another type of vasculitis, such as, e.g., a Buerger's disease, an arteritis, acerebral vasculitis, a Churg-Strauss arteritis, a cryoglobulinemia, an essential cryoglobulinemic vasculitis,a giant cell arteritis, a Golfer's vasculitis, a Henoch-Schonlein purpura, a hypersensitivity vasculitis, aki disease, a phlebitis, a microscopic polyarteritis/polyangiitis, a polyarteritis nodosa, apolymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, a thrombophlebitis, aWegener's omatosis, a vasculitis secondary to viral infection, or a vasculitis secondary toconnective tissue disorder ing systemic lupus erythematosus (SLE), rheumatoid arthritis (RA),relapsing polychondritis, or Behcet's disease. In a similar , any of the therapeutic compoundssuch as, e.g., a NSAID like a salicylate derivative NSAID, a o phenol derivative NSAID, a propionicacid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acidderivative NSAID, a non-selective oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor; a PPARV agonist; a nuclear or bindingagent; or an anti-hyperlipidemic agent like a fibrate, a , a tocotrienol, a niacin, a bile acidsequestrants, a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, or a sympathomimeticamine, will be formulated into a pharmaceutical composition and administered to the patient as describedabove.

A 37 year old male complains of chest pains. A physician determines that the pain is due to anendocarditis. The man is treated by oral administration a pharmaceutical composition singibuprofen as disclosed herein taken twice daily. Alternatively, the man is treated by oral administration apharmaceutical composition comprising a PPAR-y agonist as disclosed herein taken thrice daily.

Alternatively, the man is treated by oral administration a pharmaceutical composition comprisingGemfibrozil as sed herein taken twice daily. The man‘s condition is monitored and after about 1week of treatment the man indicates there is d chest pain. At one and three month check-ups, theman indicates that he ues to have no chest pain. This reduction in a endocarditis symptomindicates successful treatment with the pharmaceutical composition disclosed herein. A similar type oforal administration of a pharmaceutical composition sed herein will be used to treat a patientsuffering from another type of inflammatory heart disease, such as, e.g., an inflammatory cardiomegaly ora myocarditis. In a similar manner, any of the eutic compounds such as, e.g., a NSAID like asalicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, anacetic 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 selectivecyclooxygenase 2 (COX 2) inhibitor; a PPARy agonist; a nuclear receptor binding agent; or an anti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol, a , a bile acid sequestrants, a cholesterolabsorption tor, a pancreatic lipase inhibitor, or a homimetic amine, will be formulated into aceutical ition and administered to the patient as described above.

A 59 year old female complains about having a shortness of breath and is diagnosed with highblood pressure. A physician ines that the joint stiffness and swelling is due to a hypertensivedisease. The woman is treated by oral administration a pharmaceutical composition comprising ibuprofenas disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration aceutical composition comprising a PPAR-y agonist as disclosed herein taken thrice daily.

Alternatively, the woman is treated by oral administration a pharmaceutical composition comprisingrozil as disclosed herein taken twice daily. The woman’s condition is monitored and after about 3weeks of treatment the woman indicates that her breathing is improving and her blood pressure is withinthe normal range. At two and three month check-ups, the woman indicates that she continues to breathely and her blood pressure is within the normal range. This reduction in a ensive symptomindicates sful treatment with the pharmaceutical composition disclosed herein. A similar type oforal administration of a pharmaceutical ition disclosed herein will be used to treat a patientsuffering from a cardiovascular disease, such as, e.g., a coronary heart disease, an ischemic heartdisease, a congestive heart failure, a hypertensive heart disease, a valvular heart disease, ahypertension, myocardial infarction, a diabetic cardiac conditions, an aneurysm; an embolism, adissection, a pseudoaneurysm, a vascular malformation, a vascular nevus, a thrombosis, a varicose vein,or a stroke. In a similar manner, any of the therapeutic compounds such as, e.g., a NSAID like alate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, anacetic acid tive 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 selectivecyclooxygenase 2 (COX 2) inhibitor; a PPARy agonist; a nuclear receptor binding agent; or an anti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol, a , a bile acid sequestrants, a cholesterolabsorption inhibitor, a pancreatic lipase inhibitor, or a sympathomimetic amine, will be formulated into apharmaceutical composition and administered to the patient as described above.

In closing, it is to be understood that although aspects of the present specification are ghtedby ing to specific embodiments, one skilled in the art will readily appreciate that these sedembodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, itshould 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 oralternative configurations of the disclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the t specification. Lastly, the terminology used herein isfor the purpose of describing particular embodiments only, and is not intended to limit the scope of thepresent ion, which is d solely by the claims. Accordingly, the present invention is not limited tothat precisely as shown and described.

Certain embodiments of the present invention are described herein, including the best modeknown to the inventors for carrying out the invention. Of course, variations on these describedembodiments will become apparent to those of ry skill in the art upon reading the ingption. The inventor expects d artisans to employ such variations as riate, and theinventors intend for the present invention to be practiced otherwise than specifically described .

Accordingly, this invention includes all modifications and equivalents of the subject matter d in theclaims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unlessise indicated herein or othenNise clearly contradicted by context.

Groupings of alternative embodiments, elements, or steps of the present invention are not to beconstrued as tions. Each group member may be referred to and claimed individually or in anycombination with other group members disclosed herein. It is anticipated that one or more members of agroup may be included in, or deleted from, a group for s of convenience and/or ability.

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

Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter,property, term, and so forth used in the present ication and claims are to be tood as beingmodified in all instances by the term “about." As used herein, the term “about” means that thecharacteristic, item, quantity, parameter, property, or term so ied encompasses a range of plus orminus 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 thespecification and attached claims are approximations that may vary. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to the scope of the claims, each calindication should at least be construed in light of the number of reported significant digits and by applyingordinary rounding techniques. Notwithstanding that the cal ranges and values setting forth thebroad scope of the invention are approximations, the numerical ranges and values set forth in the specificexamples are reported as precisely as possible. Any numerical range or value, however, inherentlycontains certain errors necessarily resulting from the standard deviation found in their respective testingmeasurements. Recitation of numerical ranges of values herein is merely intended to serve as aand method of referring individually to each separate numerical value falling within the range.

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

The terms “a," “an,” “the” and similar referents used in the context of describing the tinvention (especially in the context of the following claims) are to be construed to cover both the singularand the plural, unless otherwise indicated herein or clearly contradicted by context. All methodsdescribed herein can be performed in any suitable order unless othenNise ted herein or othen/viseclearly dicted by context. The use of any and all examples, or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the present invention and does not pose alimitation on the scope of the invention othenNise claimed. No language in the present specificationshould be construed as indicating any non-claimed element essential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in the claims using consisting of orconsisting essentially of language. When used in the claims, whether as filed or added per ent,the tion term “consisting of” excludes any element, step, or ient not specified in the claims.

The transition term “consisting essentially of” limits the scope of a claim to the specified materials or stepsand those that do not materially affect the basic and novel teristic(s). Embodiments of the presentinvention so claimed are inherently or expressly bed and enabled herein.

All patents, patent publications, and other publications referenced and fied in the presentspecification are individually and expressly orated herein by reference in their entirety for thepurpose of describing and disclosing, for example, the compositions and ologies described insuch publications that might be used in connection with the present invention. These publications areprovided solely for their disclosure prior to the filing date of the present application. Nothing in this regardshould be construed as an admission that the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as to the date or representation as to thecontents of these documents is based on the ation ble to the applicants and does notconstitute any admission as to the correctness of the dates or contents of these documents.

Claims (26)

1. A pharmaceutical composition sing: a) a therapeutic compound having a log P value of greater than 2.0, wherein the therapeutic compound comprises a non-steroidal anti-inflammatory drug (NSAID), a PPARɣ agonist, and/or an ester thereof; with the proviso that the PPARɣ agonist is not a fibrate; b) about 1% to about 20% (v/v) of a pharmaceutically-acceptable solvent, wherein the solvent comprises a pharmaceutically-acceptable liquid polyethylene glycol polymer; and c) at least 50% by weight of the total pharmaceutical composition of a pharmaceutically-acceptable lipid-adjuvant, the pharmaceuticallyacceptable lipid-adjuvant including at least 25% by weight of the total pharmaceutical composition a first pharmaceutically-acceptable lipidadjuvant that is solid at a temperature of about 20°C and at least 20% by weight of the total pharmaceutical composition a second pharmaceuticallyacceptable lipid-adjuvant that is liquid at a ature of about 20°C; wherein the first pharmaceutically-acceptable lipid-adjuvant is a fatty acid having at least 12 carbons, a glycerolipid, a sphingolipid, a sterol lipid, a prenol lipid, a saccharolipid, or a tide; wherein the pharmaceutical composition is formulated to be solid at a temperature of about 15ºC or lower and have a g point temperature of about 25°C or .

2. A pharmaceutical composition sing: a) a therapeutic compound having a log P value of greater than 2.0, wherein the therapeutic compound ses a non-steroidal anti-inflammatory drug (NSAID), a PPARɣ agonist, and/or an ester thereof; with the proviso that the PPARɣ agonist is not a fibrate; and b) at least 50% by weight of the total pharmaceutical composition of a pharmaceutically-acceptable lipid-adjuvant, the pharmaceuticallyacceptable lipid-adjuvant including at least 25% by weight of the total pharmaceutical composition a first ceutically-acceptable lipidadjuvant that is solid at about a ature of about 20°C and at least 20% by weight of the total pharmaceutical composition a second pharmaceutically-acceptable lipid-adjuvant that is liquid at about a temperature of about 20°C; wherein the first pharmaceutically-acceptable lipid-adjuvant is a fatty acid having at least 12 carbons, a glycerolipid, a sphingolipid, a sterol lipid, a prenol lipid, a saccharolipid, or a polyketide; wherein the pharmaceutical ition is formulated to be solid at a temperature of about 15°C or lower and have a melting point temperature of about 25°C or higher.

3. The ceutical composition according to Claim 1 or Claim 2, 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) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor or a combination f.

4. The pharmaceutical composition ing to Claim 3, wherein the late tive NSAID is Acetylsalicylic acid, Diflunisal or Salsalate.

5. The pharmaceutical composition according to Claim 3, wherein the p-amino phenol derivative NSAID is Paracetamol or Phenacetin.

6. The pharmaceutical composition ing to Claim 3, wherein the propionic acid derivative NSAID is Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen or Suprofen.

7. The pharmaceutical composition according to Claim 3, wherein the acetic acid derivative NSAID is Aceclofenac, Acemetacin, Actarit, Alcofenac, Amfenac, Clometacin, Diclofenac, Etodolac, ac, Fenclofenac, Indometacin, Ketorolac, inic acid, Mofezolac, tone, Naproxen, Oxametacin, Sulindac or Zomepirac.

8. The pharmaceutical composition according to Claim 3, wherein the enolic acid derivative NSAID is Droxicam, Isoxicam, Lornoxicam, cam, Piroxicam or Tenoxicam.

9. The pharmaceutical composition according to Claim 3, wherein the fenamic acid derivative NSAID is Flufenamic acid, Mefenamic acid, Meclofenamic acid or Tolfenamic acid.

10. The pharmaceutical composition ing to Claim 3, wherein the ive COX-2 inhibitors is Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, Meloxicam, Parecoxib, Rofecoxib or Valdecoxib.

11. The pharmaceutical composition according to Claim 1 or Claim 2, wherein the PPARγ agonist comprises Monascin, Irbesartan, Telmisartan, mycophenolic acid, Resveratrol, 9)-tetrahydrocannabinol, a cannabidiol, Curcumin, Cilostazol, Benzbromarone, 6-shogaol, glycyrrhetinic acid, a thiazolidinedione, or a combination thereof.

12. The pharmaceutical composition ing to any one of Claims 1 or 3-11, wherein the pharmaceutically-acceptable solvent is less than about 15% (v/v).

13. The ceutical composition according to Claim 12, wherein the pharmaceutically-acceptable solvent is from about 8% (v/v) to about 15% (v/v).

14. The pharmaceutical composition according to Claim 13, wherein the pharmaceutically-acceptable solvent is from about 8% (v/v) to about 12% (v/v).

15. The pharmaceutical composition according to any one of Claims 1 or 3-14, wherein the pharmaceutically-acceptable polyethylene 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 f.

16. The pharmaceutical composition according to any one of Claims 1-15, wherein the pharmaceutically-acceptable lipid-adjuvant is in an amount of at least 60% by weight of the total pharmaceutical composition.

17. The pharmaceutical composition according to any one of Claims 1-16, wherein the first pharmaceutically-acceptable lipid-adjuvant es a first glycerolipid consisting of a triglyceride or an acetylated triglyceride and of the second pharmaceutically-acceptable lipid-adjuvant e a second glycerolipid consisting of a monoglyceride or an acetylated monoglyceride.

18. The pharmaceutical composition according to Claim 17, wherein the first olipid comprises a pharmaceutically-acceptable ceride and of the second glycerolipid comprises a pharmaceutically-acceptable monoglyceride.

19. A method of preparing a pharmaceutical composition as defined in any one of claims 1 or 3-18, the method sing the steps: a) contacting the ceutically-acceptable solvent with the therapeutic compound 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 the pharmaceuticallyacceptable adjuvant under ions which allow the formation of the pharmaceutical composition.

20. The method according to Claim 19, wherein step (a) further comprises contacting a pharmaceutically-acceptable stabilizing agent with the pharmaceutically- acceptable solvent and the eutic compound, wherein the pharmaceutically-acceptable stabilizing agent is not an emulsifying agent.

21. Use of a pharmaceutical composition as defined in any one of Claims 1-18 in the manufacture of a ment for the treatment of a cardiovascular disease.

22. A pharmaceutical composition as defined in any one of Claims 1-18 for use in the treatment of a cardiovascular disease.

23. The use according to Claim 21 or the pharmaceutical composition of Claim 22, wherein the cardiovascular disease is associated with a hyperlipidemia, a ry heart disease, an atherosclerosis, a eral vascular disease, a cardiomyopathy, a vasculitis, an inflammatory heart disease, an ischemic heart disease, a congestive heart failure, a hypertensive heart disease, a valvular heart disease, a hypertension, dial infarction, a diabetic cardiac ions, an aneurysm; an embolism, a dissection, a pseudoaneurysm, a vascular malformation, a vascular nevus, a thrombosis, a varicose vein, or a stroke.

24. The pharmaceutical composition according to any one of Claims 1-18 or 22, substantially as hereinbefore described with reference to the examples and accompanying figures.

25. The method ing to Claim 19 or Claim 20, substantially as hereinbefore described with reference to the examples and accompanying figures.

26. The use according to Claim 21 or Claim 23, substantially as hereinbefore described with reference to the examples and accompanying figures.