WO2014117999A1 - Compositions and methods for treating chronic inflammation and inflammatory diseases - Google Patents

Compositions and methods for treating chronic inflammation and inflammatory diseases Download PDF

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Publication number
WO2014117999A1
WO2014117999A1 PCT/EP2014/050627 EP2014050627W WO2014117999A1 WO 2014117999 A1 WO2014117999 A1 WO 2014117999A1 EP 2014050627 W EP2014050627 W EP 2014050627W WO 2014117999 A1 WO2014117999 A1 WO 2014117999A1
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pharmaceutically
oil
acceptable
pharmaceutical composition
peg
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PCT/EP2014/050627
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English (en)
French (fr)
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Robin Mark Bannister
John Brew
Wilson CAPARRÓS-WANDERLEY
Suzanne Jane Dilly
Olga Pleguezuelos Mateo
Gregory Alan Stoloff
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Biocopea Limited
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Priority to MX2015009058A priority Critical patent/MX366317B/es
Priority to KR1020157020598A priority patent/KR20150129664A/ko
Priority to EP14705479.5A priority patent/EP2950821A1/en
Priority to RU2015137659A priority patent/RU2680801C2/ru
Priority to SG11201505243PA priority patent/SG11201505243PA/en
Priority to CA2898017A priority patent/CA2898017A1/en
Priority to AU2014211715A priority patent/AU2014211715B2/en
Priority to BR112015015870-6A priority patent/BR112015015870B1/pt
Application filed by Biocopea Limited filed Critical Biocopea Limited
Priority to CN201480006334.8A priority patent/CN105120900A/zh
Priority to JP2015555630A priority patent/JP6474352B2/ja
Publication of WO2014117999A1 publication Critical patent/WO2014117999A1/en
Priority to ZA2015/05006A priority patent/ZA201505006B/en
Priority to IL239920A priority patent/IL239920A0/en
Priority to HK16106607.4A priority patent/HK1218621A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • Inflammation involves the activation of the immune system in response to harmful stimuli, such as, e.g. , a pathogen, infection, irritant, or damage to cells.
  • harmful stimuli such as, e.g. , a pathogen, infection, irritant, or damage to cells.
  • inflammation is a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen. Inflammation can be classified as either acute or chronic. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
  • Acute inflammation is an initial protective response of the body to remove an injurious stimulus by maintaining tissue integrity and contributing to tissue repair. It a part of the body's natural defense system against injury and disease, and in the absence of acute inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism.
  • the process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells, mastocytes, vascular endothelial cells, and vascular smooth muscle cells.
  • these cells undergo activation and release inflammatory mediating and sensitizing molecules, such as, e.g. , pro-inflammatory cytokines, proinflammatory prostaglandins, leukotrienes, histamine, serotonin, neutral proteases, bradykinin and nitric oxide.
  • inflammatory molecules modulate a complex series of biological events involving cellular and acellular components of the local vascular system, the immune system, and the injured tissue site to propagate and mature the inflammatory response. These events are responsible for eliciting an acute inflammatory response, typically characterized by 1 ) vasodilatation which increases blood flow into the tissue thereby causing erythema (redness and warmth), which may extend beyond this site (the flare response); 2) blood vessel permeability which increases plasma leakage into the tissue thereby causing edema (swelling); 3) alter the excitability of certain sensory neurons causing hypersensitivity and pain; 4) stimulate the release of inflammation inducing molecules such as, e.g.
  • neuropeptides like substance P (SP) and calcitonin gene-related peptide (CGRP), prostaglandins, and amino acids like glutamate, from the peripheral nerve endings; and 5) increase migration of leukocytes, mainly granulocytes, from the blood vessels into the tissue.
  • An acute inflammatory response requires constant stimulation to be sustained and must be actively terminated when no longer needed. Hence, acute inflammation ceases once the injurious stimulus has been removed.
  • severe or prolonged noxious stimulation results in a chronic inflammatory response that leads to a progressive shift in the type of cells present at the site of tissue injury.
  • Chronic inflammation may be characterized as the simultaneous destruction and healing of tissue from the inflammatory process, with the net result of provoking injury rather than mediating repair.
  • chronic inflammation is a disease.
  • chronic inflammation has been implicated in the pathophysiology of a wide range of seemingly unrelated disorders which underlay a large and varied group of human diseases.
  • chronic inflammation is involved in diseases as diverse as cardiovascular diseases, cancers, allergies, obesity, diabetes, digestive system diseases, degenerative diseases, auto-immune disorders, and Alzheimer's disease.
  • NSAIDs reduce inflammation by blocking the enzymatic activity of cyclooxygenase, a key enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and leukotrienes. Thus, NSAIDs reduce inflammation by preventing the synthesis of all prostaglandins.
  • NSAIDs not only prevents the synthesis of proinflammatory prostaglandins, these compounds also prevent the synthesis of anti-inflammatory prostaglandins. Hence, NSAIDs have limited success as they block endogenous anti-inflammatory response, which in some instances may prolong chronic inflammation. Therefore, compounds, compositions, uses, and methods preferentially inhibiting pro-inflammatory responses would be highly desirable for the treatment of chronic inflammation.
  • the present specification discloses pharmaceutical compositions and methods for treating an individual suffering from a chronic inflammation.
  • the pharmaceutical compositions disclosed herein are essentially a lipid delivery system that enables a therapeutic compound having anti-inflammatory activity to be delivered in a manner that more effectively inhibits a pro-inflammatory response. The end result is an improved treatment for chronic inflammation.
  • aspects of the present specification disclose a pharmaceutical composition comprising a therapeutic compound and a pharmaceutically-acceptable adjuvant.
  • a therapeutic compound may have an anti-inflammatory activity.
  • Other aspects of the present specification disclose a pharmaceutical composition comprising a therapeutic compound disclosed herein, a pharmaceutically-acceptable solvent, and a pharmaceutically-acceptable adjuvant.
  • the pharmaceutical compositions disclosed herein further comprise a pharmaceutically-acceptable stabilizing agent.
  • Other aspects of the present specification disclose a method of preparing a pharmaceutical composition, the method comprising the step of contacting a therapeutic compound with a pharmaceuticaily-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.
  • aspects of the present specification disclose a method of preparing a pharmaceutical composition, the method comprising the steps: a) contacting a pharmaceuticaily-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceuticaily-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the solution formed in step (a) with a pharmaceuticaily- acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.
  • the method of preparing disclosed herein further comprises c) removing the pharmaceuticaily-acceptable solvent from the pharmaceutical composition.
  • compositions the pharmaceutical composition made according to a method comprising the step of contacting a therapeutic compound with a pharmaceuticaily-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.
  • a pharmaceutical composition the pharmaceutical composition made according to a method comprising the steps: a) contacting a pharmaceuticaily-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceuticaily-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the solution formed in step (a) with a pharmaceuticaily-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.
  • the method of making a pharmaceutical composition disclosed herein further comprises c) removing the pharmaceuticaily-acceptable solvent from the pharmaceutical composition.
  • FIG. 1 shows the effects of a pharmaceutical composition disclosed herein on survival against Influenza A/PR/8/34 lethal challenge.
  • FIG. 2 shows the effects of a pharmaceutical composition disclosed herein on in vivo levels of Th2 cytokines in the lungs of surviving mice.
  • FIG. 2A shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of IL-10
  • FIG. 2B shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of IL-4.
  • FIG. 3 shows the effects of a pharmaceutical composition disclosed herein on in vivo levels of Th2 cytokines in the lungs of surviving mice.
  • Figure 3A shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of IL-10
  • Figure 3B shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of TNF-a
  • FIG. 3C shows a graph of the effects of a pharmaceutical composition disclosed herein on in vivo levels of IFN- ⁇ .
  • BC1054 ORAL Group A
  • Vehicle ORAL Group B
  • BC1054 Lipid ORAL Group C.
  • FIG. 4 shows the effects of a pharmaceutical composition disclosed herein on arthritis using an a- collagen antibody induced arthritis (ACAIA) murine model.
  • compositions disclosed herein are generally administered as a pharmaceutical acceptable composition.
  • pharmaceutical acceptable refers any molecular entity or composition that does not produce an adverse, allergic or other untoward or unwanted reaction when administered to an individual.
  • pharmaceutically acceptable composition is synonymous with “pharmaceutical composition” and means a therapeutically effective concentration of an active ingredient, such as, e.g., any of the therapeutic compounds disclosed herein.
  • a pharmaceutical composition disclosed herein is useful for medical and veterinary applications.
  • a pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active ingredients, agents, drugs or hormones.
  • a pharmaceutical composition disclosed herein may optionally include a pharmaceutically- acceptable carrier that facilitates processing of an active ingredient into pharmaceutically-acceptable compositions.
  • a pharmaceutically-acceptable carrier is synonymous with “pharmacological carrier” and means any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as "pharmacologically acceptable vehicle, stabilizer, diluent, additive, auxiliary or excipient.”
  • Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired carrier or diluent.
  • aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like
  • solid carriers such as, e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like
  • solvents dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.
  • Selection of a pharmacologically acceptable carrier can depend on the mode of administration.
  • any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated.
  • Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott 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 Therapeutics (Joel G.
  • a pharmaceutical composition disclosed herein can optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.
  • buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers.
  • antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.
  • Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, iactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition.
  • a pharmaceutical composition disclosed herein comprises a therapeutic compound having anti-inflammatory activity and a pharmaceutically-acceptable adjuvant.
  • a pharmaceutical composition disclosed herein comprises a therapeutic compound having anti-inflammatory activity, a pharmaceutically-acceptable solvent, and a pharmaceutically-acceptable adjuvant.
  • a pharmaceutical composition disclosed herein may further comprise a pharmaceutically-acceptable stabilizing agent.
  • a pharmaceutical composition disclosed herein may further comprise a pharmaceutically-acceptable carrier, a pharmaceutically-acceptable component, or both pharmaceutically-acceptable carrier and pharmaceutically-acceptable component.
  • a therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
  • a therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride. Additionally, therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers, including the R- or S-enantiomer.
  • the therapeutic compound disclosed herein may comprise a R- enantiomer only, a S-enantiomer only, or a combination of both a R-enantiomer and a S-enantiomer of a therapeutic compound.
  • a therapeutic compound disclosed herein may have anti-inflammatory activity.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of an inflammation inducing molecule.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of SP, CGRP, glutamate, or a combination thereof released from a sensory neuron by, e.g.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of SP, CGRP, glutamate, or a combination thereof released from a sensory neuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • Prostaglandins mediate a local inflammatory response and are involved in all inflammatory functions through action on prostaglandin receptors and mediate inflammatory signaling including chemotaxis (macrophages, neutrophils and eosinophils), vasodilation and algesia.
  • chemotaxis macrophages, neutrophils and eosinophils
  • vasodilation vasodilation
  • algesia the PG- mediated inflammatory response is self-limiting (resolving).
  • the principle resolution factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxisome proliferator-activator receptor gamma (PPAR- ⁇ ) signaling.
  • PPARy signaling pathway 1 induces apoptosis 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 and release Th2 anti-inflammatory cytokines.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of a inflammation inducing prostaglandin released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of a inflammation inducing prostaglandin released from a sensory neuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 00%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity substantially similar to 15dPGJ2.
  • a therapeutic compound disclosed herein an anti-inflammatory activity that is, e.g. , at least 5%, at least 15%, at least 25%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the activity observed for 15dPGJ2.
  • a therapeutic compound disclosed herein an anti-inflammatory activity that is in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%o to about 60%, about 50% to about 60%, or about 25% to about 50% of the activity observed for 15dPGJ2.
  • the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. All PPARs are known to heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes called peroxisome proliferator hormone response elements (PPREs). PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. The family comprises three members, PPAR-a, PPAR- ⁇ , and PPAR- ⁇ (also known as PPAR- ⁇ ).
  • PPAR-a is expressed in liver, kidney, heart, muscle, adipose tissue, as well as other tissues.
  • PPAR- ⁇ is expressed in many tissues but markedly in brain, adipose tissue, and skin.
  • PPAR- ⁇ comprises three alternatively-spliced forms, each with a different expression pattern.
  • PPAR- ⁇ is expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen.
  • PPAR-y2 is expressed mainly in adipose tissue.
  • PPAR-y3 is expressed in macrophages, large intestine, and white adipose tissue. Endogenous ligands for the PPARs include free fatty acids and eicosanoids.
  • PPAR- ⁇ is activated by PGJ2 (a prostaglandin), whereas PPAR-a is activated by leukotriene B4.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating all PPAR signaling pathways.
  • a therapeutic compound includes a PPAR pan-agonist.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating one or two of the PPAR signaling pathways.
  • Such a therapeutic compound includes a selective PPAR agonist.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating a PPAR-a signaling pathway.
  • a therapeutic compound disclosed herein stimulates a PPAR-a signaling pathway by, e.g., at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • a therapeutic compound disclosed herein stimulates a PPAR-a signaling pathway in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50%.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating a PPAR- ⁇ signaling pathway.
  • a therapeutic compound disclosed herein stimulates a PPAR- ⁇ signaling pathway by, e.g. , at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • a therapeutic compound disclosed herein stimulates a PPAR- ⁇ signaling pathway in a range from, e.g., about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50%.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of stimulating a PPARy signaling pathway.
  • a therapeutic compounds disclosed herein may be capable of binding to all isoforms of PPAR- ⁇ , or may be capable of selectively binding to either PPAR- ⁇ , PPAR-y2, PPAR-y3, or any combination of two thereof.
  • a therapeutic compound disclosed herein stimulates a PPARy signaling pathway by, e.g. , at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • a therapeutic compound disclosed herein stimulates a PPARy signaling pathway in a range from, e.g. , about 5% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 25% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 25% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 50% to about 70%, about 25% to about 60%, about 50% to about 60%, or about 25% to about 50%.
  • Macrophages are activated and polarized into distinct phenotypes expressing unique cell surface molecules and secreting discrete sets of cytokines and chemokines.
  • the classical M1 phenotype supports pro-inflammatory Th1 responses driven by cytokines such as, e.g., lnterleukin-6 (IL-6), IL-12 and IL-23, while the alternate M2 phenotype is generally supportive of anti-inflammatory processes driven by IL-10.
  • M2 cells can be further classified into subsets, M2a, M2b, and M2c, based on the type of stimulation and the subsequent expression of surface molecules and cytokines.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of promoting the resolving phenotypic change of M1 to M2.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of inducing apoptosis of Macrophage M1 cells.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of promoting differentiation of Macrophage M2 cells.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of inducing apoptosis of Macrophage M1 cells and promoting differentiation of Macrophage M2 cells.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of modulating Th1 and Th2 cytokines.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of Interferon- gamma (IFNy), Tumor necrosis factor-alpha (TNF-a), lnterleukin-12 (IL-12), or a combination thereof released from a Th1 cell.
  • IFNy Interferon-gamma
  • TNF-a Tumor necrosis factor-alpha
  • IL-12 lnterleukin-12
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of IFNy, TNF-a, IL-12, or a combination thereof released from a Th1 cell by, e.g.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of IFNy, TNF-a, IL-12, or a combination thereof released from a Th1 cell in a range from, e.g.
  • a therapeutic compound disclosed herein has an antiinflammatory activity capable of increasing the levels of IL-10 released from a Th2 cell.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of increasing the levels of IL-10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a therapeutic compound disclosed herein has an antiinflammatory activity capable of increasing the levels of IL-10 released from a Th2 cell in a range from, e.g. , about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • a therapeutic compound disclosed herein has an antiinflammatory activity capable of reducing the levels of IFNy, TNF-a, IL-12, or a combination thereof released from a Th1 cell and increasing the levels of IL-10 released from a Th2 cell.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of IFNy, TNF-a, IL-12, or a combination thereof released from a Th1 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%, and capable of increasing the levels of IL-10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a therapeutic compound disclosed herein has an anti-inflammatory activity capable of reducing the levels of IFNy, TNF-a, IL-12, or a combination thereof released from a Th1 cell in a range from, e.g.
  • a therapeutic compound disclosed herein may have a log P value indicating that the compound is soluble in an organic solvent.
  • log P value refers to the logarithm (base 10) of the partition coefficient (P) for a compound and is a measure of lipophilicity.
  • P is defined as the ratio of concentrations of a unionized compound in the two phases of a mixture of two immiscible solvents at equilibrium.
  • the log P value of a compound is constant for any given pair of aqueous and organic solvents, and its value can be determined empirically by one of several phase-partitioning methods known to one skilled in the art including, e.g. , a shake flask assay, a HPLC assay, and an interface between two immiscible electrolyte solutions (ITIES) assay.
  • a therapeutic compound disclosed herein may have a log P value indicating that the compound is substantially soluble in an organic solvent.
  • a therapeutic compound disclosed herein may have a log P value indicating that the compound 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.
  • a therapeutic compound disclosed herein may have a log P value indicating that the compound is between, e.g.
  • a therapeutic compound disclosed herein may have a log P value of, e.g. , more than 1.1 , more than 1.2, more than 1.4, more than 1.6, more than 1.8, more than 2.0, more than 2.2, more than 2.4, more than 2.6, more than 2.8, more than 3.0, more than 3.2, more than 3.4, or more than 3.6.
  • a therapeutic compound disclosed herein may have a log P value in the range of, e.g.
  • a therapeutic compound disclosed herein may have a log P value in the range of, e.g. , between 3.0 and 4.0, or between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 and 4.0, between 3.4 and 4.0, between 3.5 and 4.0, or between 3.6 and 4.0.
  • a therapeutic compound disclosed herein may have a log P value in the range of, e.g., between 2.0 and 2.5, between 2.0 and 2.7, between 2.0 and 3.0, or between 2.2 and 2.5.
  • a therapeutic compound disclosed herein may have a polar surface area that is hydrophobic.
  • the term "polar surface area” refers to the surface sum over all of the polar atoms in the structure of a compound and is a measure of hydrophobicity. Typically, these polar atoms include, e.g. , oxygen, nitrogen, and their attached hydrogens.
  • a therapeutic compound disclosed herein may have a polar surface area of, e.g. , less than 8.0 nm 2 , less than 7.0 nm 2 , less than 6.0 nm 2 , less than 5.0 nm 2 , less than 4.0 nm 2 , or less than 3.0 nm 2 .
  • a therapeutic compound disclosed herein may have a polar surface area in the range of, e.g. , between 3.0 nm 2 and 6.5 nm 2 , between 3.0 nm 2 and 6.0 nm 2 , between 3.0 nm 2 and 5.5 nm 2 , between 3.0 nm 2 and 5.0 nm 2 , between 3.0 nm 2 and 4.5 nm 2 , between 3.5 nm 2 and 6.5 nm 2 , between 3.5 nm 2 and 6.0 nm 2 , between 3.5 nm 2 and 5.5 nm 2 , between 3.5 nm 2 and 5.0 nm 2 , between 3.5 nm 2 and 4.5 nm 2 , between 4.0 nm 2 and 6.5 nm 2 , between 4.0 nm 2 and 6.0 nm 2 , between 4.0 nm 2 and 5.5 nm 2 , or between 4.0 nm 2 and 5.0 n
  • a therapeutic compound disclosed herein may have a polar surface area in the range of, e.g., between 2.0 nm 2 and 6.5 nm 2 , between 2.0 nm 2 and 6.0 nm 2 , between 2.0 nm 2 and 5.5 nm 2 , between 2.0 nm 2 and 5.0 nm 2 , between 2.0 nm 2 and 4.5 nm 2 , between 2.5 nm 2 and 6.5 nm 2 , between 2.5 nm 2 and 6.0 nm 2 , between 2.5 nm 2 and 5.5 nm 2 , between 2.5 nm 2 and 5.0 nm 2 , or between 2.5 nm 2 and 4.5 nm 2 .
  • 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, and anti-pyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase.
  • NSAIDs include, without limitation, Aceclofenac, Acemetacin, Actarit, Alcofenac, Alminoprofen, Amfenac, Aloxipirin, Aminophenazone, Antraphenine, Aspirin, Azapropazone, Benorilate, Benoxaprofen, Benzydamine, Butibufen, Celecoxib, Chlorthenoxacin, Choline Salicylate, Clometacin, Dexketoprofen, Diclofenac, Diflunisal, Emorfazone, Epirizole; Etodolac, Etoricoxib, Feclobuzone, Felbinac, Fenbufen, Fenclofenac, Flurbiprofen, Glafenine, Hydroxylethyl salicylate, Ibuprofen, Indometacin, Indoprofen, Ketoprofen, Ketorolac, Lactyl phenetidin, Loxoprofen, Lumirac
  • NSAIDs 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, 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, and a selective cyclooxygenase 2 (COX 2) inhibitor.
  • a NSAID may be a profen.
  • Examples of a suitable salicylate derivative NSAID include, without limitation, Acetylsalicylic acid (asprin), Diflunisal, and Salsalate.
  • Examples of a suitable p-amino phenol derivative NSAID include, without limitation, Paracetamol and Phenacetin.
  • Examples of a suitable propionic acid derivative NSAID include, without limitation, Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen, and Suprofen.
  • a suitable acetic acid derivative NSAID examples include, without limitation, Aceclofenac, Acemetacin, Actarit, Aicofenac, Amfenac, Clometacin, Diclofenac, Etodolac, Felbinac, Fenclofenac, Indometacin, Ketorolac, Metiazinic acid, Mofezolac, Nabumetone, Naproxen, Oxametacin, Sulindac, and Zomepirac.
  • a suitable enolic acid (Oxicam) derivative NSAID examples include, without limitation, Droxicam, Isoxicam, Lomoxicam, Meloxicam, Piroxicam, and Tenoxicam.
  • a suitable fenamic acid derivative NSAID examples include, without limitation, Flufenamic acid, Mefenamic acid, Meclofenamic acid, and Tolfenamic acid.
  • a suitable selective COX-2 inhibitors include, without limitation, Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib.
  • a therapeutic compound disclosed herein may be a PPARy agonist.
  • a suitable PPARy agonist include, without limitation, Benzbromarone, a cannabidiol, Cilostazol, Curcumin, Delta(9)- tetrahydrocannabinol, glycyrrhetinic acid, Indomethacin, Irbesartan, Monascin, mycophenolic acid, Resveratrol, 6-shogaol, Telmisartan, a thiazolidinedione like Rosiglitazone, Pioglitazone, and Troglitazone, a NSAID, and a fibrate.
  • Other suitable PPARy agonists are described in Masson and Caumont-Bertrand, PPAR Agonist Compounds, Preparation and Uses, US 201 1/0195993, which is hereby incorporated by reference in its entirety.
  • a therapeutic compound disclosed herein may be a nuclear receptor binding agent.
  • suitable nuclear receptor binding agent include, without limitation, a Retinoic Acid Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor (LXR) binding agent and a Vitamin D binding agent.
  • RAR Retinoic Acid Receptor
  • RXR Retinoid X Receptor
  • LXR Liver X Receptor
  • a therapeutic compound disclosed herein may be an anti-hyperlipidemic agent.
  • anti-hyperlipidemic agents also known as hypolipidemic agents. They may differ in both their impact on the cholesterol profile and adverse effects. For example, some may lower low density lipoprotein (LDL), while others may preferentially increase high density lipoprotein (HDL).
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • a suitable anti- hyperlipidemic agent examples include, without limitation, a fibrate, a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, and a sympathomimetic amine.
  • a therapeutic compound disclosed herein may be a fibrate.
  • Fibrates are a class of amphipathic carboxylic acids with lipid level modifying properties. These therapeutic compounds are used for a range of metabolic disorders.
  • One non-limiting use is as an anti-hyperlipidemic agent where it may lower levels of, e.g., triglycerides and LDL as well as increase levels of HDL.
  • suitable fibrate include, without limitation, Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, and Fenofibrate.
  • a therapeutic compound disclosed herein may be a statin.
  • Statins or HMG-CoA reductase inhibitors
  • HMG-CoA reductase inhibitors are a class of therapeutic compounds used to lower LDL and/or cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver.
  • HMG-CoA reductase a class of therapeutic compounds used to lower LDL and/or cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver.
  • synthesis of hepatic LDL receptors is increased, resulting in an increased clearance of LDL particles from the blood.
  • suitable statin include, without limitation, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, and Simvastatin.
  • a therapeutic compound disclosed herein may be a tocotrienol.
  • Tocotrienols are anotehr class of HMG-CoA reductase inhibitors and may be used to lower LDL and/or cholesterol levels by inducing hepatic LDL receptor up-regulation and/or decreasing plasma LDL levels.
  • Examples of a suitable tocotrienol include, without limitation, a ⁇ -tocotrienol and a ⁇ - tocotrienol.
  • a therapeutic compound disclosed herein may be a niacin.
  • Niacins are a class of therapeutic compounds with lipid level modifying properties.
  • a niacin may lower LDL by selectively inhibiting hepatic diacyglycerol acyltransf erase 2, reduce triglyceride synthesis, and VLDL secretion through a receptor HM74 and HM74A or GPR109A.
  • These therapeutic compounds are used for a range of metabolic disorders.
  • One non-limiting use is as an anti-hyperlipidemic agent where it may inhibit the breakdown of fats in adipose tissue.
  • a niacin blocks the breakdown of fats, it causes a decrease in free fatty acids in the blood and, as a consequence, decreases the secretion of very-low-density lipoproteins (VLDL) and cholesterol by the liver. By lowering VLDL levels, a niacin may also increase the level of HDL in blood.
  • VLDL very-low-density lipoproteins
  • a niacin may also increase the level of HDL in blood.
  • 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
  • Bile acid sequestrants are a class of therapeutic compounds used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. Bile acid sequestrants are particularly effective for lowering LDL and cholesterol by sequestering the cholesterol-containing bile acids released into the intestine and preventing their reabsorption from the intestine.
  • a bile acid sequestrant may also raise HDL levels. Examples of a suitable bile acid sequestrant include, without limitation, Cholestyramine, Colesevelam, and Colestipol.
  • a therapeutic compound disclosed herein may be a cholesterol absorption inhibitor.
  • Cholesterol absorption inhibitors are a class of therapeutic compounds that inhibits the absorption of cholesterol from the intestine. Decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into these cells, thus decreasing levels of LDL in the blood plasma.
  • 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 absorption inhibitors are a class of therapeutic compounds that inhibits the absorption of fat from the intestine. Decreased fat absorption reduces caloric intake.
  • a fat absorption inhibitor inhibits pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Examples of a suitable fat absorption inhibitor include, without limitation, Orlistat.
  • a therapeutic compound disclosed herein may be a sympathomimetic amine.
  • Sympathomimetic amines are a class of therapeutic compounds that mimic the effects of transmitter substances of the sympathetic nervous system such as catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), and/or dopamine.
  • a sympathomimetic amine may act as an a-adrenergic agonist, a ⁇ - adrenergic agonist, a dopaminergic agonist, a monoamine oxidase (MAO) inhibitor, and a COMT inhibitor.
  • Such therapeutic compounds are used to treat cardiac arrest, low blood pressure, or even delay premature labor.
  • a suitable sympathomimetic amine examples include, without limitation, Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamfetamine, cathine, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4- methylaminorex, pemoline, phenmetrazine, and propylhexedrine.
  • a therapeutic compound disclosed herein may be an ester of a therapeutic compound.
  • An ester of a therapeutic compound increases the logP value relative to the same therapeutic compound, but without the ester modification.
  • An ester group may be attached to a therapeutic compound by, e.g. , a carboxylic acid or hydroxyl functional group present of the therapeutic compound.
  • An ester of a therapeutic compound may have an increased hydrophobicity, and as such, may be dissolved in a reduced volume of solvent disclosed herein.
  • an ester of a therapeutic compound may be combined directly with an adjuvant disclosed herein, thereby eliminating the need of a solvent.
  • An ester of a therapeutic compound may enable the making of a pharmaceutical composition disclosed herein, in situations where a non-esterified form of the same therapeutic compound is otherwise immiscible in a solvent disclosed herein.
  • An ester of a therapeutic compound may still be delivered in a manner that more effectively inhibits a pro-inflammatory response as long as the compound is combined with an adjuvant disclosed herein.
  • a therapeutic compound may be reacted with ethyl ester in order to form an ethyl ester of the therapeutic compound.
  • a pharmaceutical composition disclosed herein does not comprise a pharmaceutically-acceptable solvent disclosed herein.
  • a pharmaceutical composition comprises a therapeutic compound and a pharmaceutically-acceptable adjuvant, but does not comprise a pharmaceutically-acceptable solvent disclosed herein.
  • a pharmaceutical composition disclosed herein may comprise a therapeutic compound in an amount sufficient to allow customary administration to an individual.
  • a pharmaceutical composition disclosed herein may be, e.g.
  • a pharmaceutical composition disclosed herein may be, e.g.
  • a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg.
  • a pharmaceutical composition disclosed herein may be in the range of, e.g.
  • a solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous (the solute), resulting in a solution.
  • Solvents useful in the pharmaceutical compositions disclosed herein include, without limitation, a pharmaceutically-acceptable polar aprotic solvent, a pharmaceutically-acceptable polar protic solvent and a pharmaceutically-acceptable non-polar solvent.
  • a pharmaceutically-acceptable polar aprotic solvent includes, without limitation, dichloromethane (DC ), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO).
  • a pharmaceutically-acceptable polar protic solvent includes, without limitation, acetic acid, formic acid, ethanol, n-butanol, 1 -butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1 ,2 propan-diol, methanol, glycerol, and water.
  • a pharmaceutically-acceptable non-polar solvent includes, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1 ,4-Dioxane, chloroform, n-methyl-pyrrilidone (NMP), and diethyl ether.
  • a pharmaceutical composition disclosed herein may comprise a solvent in an amount sufficient to dissolve a therapeutic compound disclosed herein.
  • a pharmaceutical composition disclosed herein may comprise a solvent in an amount of, e.g., less than about 90% (v/v), less than about 80% (v/v), less than about 70% (v/v), less than about 65% (v/v), less than about 60% (v/v), less than about 55% (v/v), less than about 50% (v/v), less than about 45% (v/v), less than about 40% (v/v), less than about 35% (v/v), less than about 30% (v/v), less than about 25% (v/v), less than about 20% (v/v), less than about 15% (v/v), less than about 10% (v/v), less than about 5% (v/v), or less than about 1 % (v/v).
  • a pharmaceutical composition disclosed herein may comprise a solvent in an amount in a range of, e.g. , about 1 % (v/v) to 90% (v/v), about 1 % (v/v) to 70% (v/v), about 1 % (v/v) to 60% (v/v), about 1 % (v/v) to 50% (v/v), about 1 % (v/v) to 40% (v/v), about 1 % (v/v) to 30% (v/v), about 1 % (v/v) to 20% (v/v), about 1 % (v/v) to 10% (v/v), about 2% (v/v) to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v), about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v) to 50% (v/v), about 4% (v/v)
  • a solvent may comprise a pharmaceutically-acceptable alcohol.
  • the term "alcohol” refers to an organic molecule comprising a hydroxyl functional group (-OH) bond to a carbon atom, where the carbon atom is saturated.
  • the alcohol may be, e.g., a C 2 . 4 alcohol, a Ci_ 4 alcohol, a alcohol, a C-
  • an alcohol may be, e.g., a primary alcohol, a secondary alcohol, or a tertiary alcohol.
  • an alcohol may be, e.g., an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol (also known as a polyol or sugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.
  • a monohydric alcohol include, without limitation, methanol, ethanol, propanol, butanol, pentanol, and 1 -hexadecanol.
  • Examples of a polyhydric alcohol include, without limitation, glycol, glycerol, arabitol, erythritol, xylitol, maltitol, sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol), and isomalt.
  • Examples of an unsaturated aliphatic alcohol include, without limitation, prop-2-ene-1 -ol, 3,7-dimethylocta-2,6-dien-1 -ol, and prop-2-in-1 -ol.
  • Examples of an alicyclic alcohol include, without limitation, cyclohexane-1 ,2,3,4,5,6- hexol and 2 - (2-propyl)-5-methyl-cyclohexane-1-ol,
  • a solvent may comprise an ester of pharmaceutically-acceptable alcohol and an acid.
  • Suitable pharmaceutically-acceptable alcohols include the ones disclosed herein.
  • Suitable acids include, without limitation, acetic acid, butaric acid, and formic acid.
  • An ester of an alcohol and an acid include, without limitation, methyl acetate, methyl buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1-hexadecyl acetate, 1 -hexadecyl buterate, and -hexadecyl formate.
  • a solvent may comprise a pharmaceutically-acceptable glycol ether.
  • Glycol ethers are a group of solvents based on alkyl ethers of ethylene glycol.
  • Non-limiting examples include diethylene glycol monomethyl ether (2-(2-methoxyethoxy)ethanol), diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), diethylene glycol monopropyl ether (2-(2-propoxyethoxy)ethanol), diethylene glycol monoisopropyl ether (2-(2-isopropoxyethoxy)ethanol), and diethylene glycol mono-n- butyl ether (2-(2-butoxyethoxy)ethanol).
  • Diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol) is commercially available as TRANSCUTOL ® .
  • a solvent may comprise a pharmaceutically-acceptable diol.
  • a diol or double alcohol is a chemical compound containing two hydroxyl groups (-OH groups).
  • a solvent may comprise a pharmaceutically-acceptable propylene glycol.
  • Propylene glycol also called 1 ,2-propanediol or propane-1 ,2-diol, is an organic compound with formula C 3 H 8 0 2 or HO-CH2-CHOH-CH3.
  • a solvent may comprise a pharmaceutically-acceptable dipropylene glycol.
  • Dipropylene glycol is a mixture of three isomeric chemical compounds, 4-oxa-2,6-heptandiol, 2-(2- Hydroxy-propoxy)-propan-1 -ol, and 2-(2-Hydroxy-1-methyl-ethoxy)-propan-1 -ol.
  • a solvent may comprise a pharmaceutically-acceptable polypropylene glycol (PPG) polymer.
  • PPG polymers polymers also known as polypropylene oxide (PPO) polymers or polyoxypropylene (POP) polymers, are prepared by polymerization of propylene oxide and are commercially available over a wide range of molecular weights from 100 g/mol to 10,000,000 g/mol.
  • PPG polymers with a low molecular mass are liquids or low-melting solids, whereas PPG polymers of a higher molecular mass are solids.
  • a PPG polymer include, without limitation, PPG 100, PPG 200, PPG 300, PPG 400, PPG 500, PPG 600, PPG 700, PPG 800, PPG 900, PPG 1000, PPG 1100, PPG 1200, PPG 1300, PPG 1400, PPG 1500, PPG 1600, PPG 1700, PPG 1800, PPG 1900, PPG 2000, PPG 2100, PPG 2200, PPG 2300, PPG 2400, PPG 2500, PPG 2600, PPG 2700, PPG 2800, PPG 2900, PPG 3000, PPG 3250, PPG 3350, PPG 3500, PPG 3750, PPG 4000, PPG 4250, PPG 4500, PPG 4750, PPG 5000, PPG 5500, PPG 6000, PPG 6500, PPG 7000, PPG 7500, PPG 8000, PPG 8500, PPG 9000, PPG 9500, PPG 10,000, PPG 11 ,000, PPG 12,000, PPG
  • a solvent may comprise a pharmaceutically-acceptable polyethylene glycol (PEG) polymer.
  • PEG polymers also known as polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers, are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 100 g/mol to 10,000,000 g/mol. PEG polymers with a low molecular mass are liquids or low-melting solids, whereas PEG polymers of a higher molecular mass are solids.
  • a PEG polymer include, without limitation, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1 100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG 10,000, PEG 1 1 ,000, PEG 12,000, P
  • a solvent may comprise a pharmaceutically-acceptable glyceride.
  • Glycerides comprise a substituted glycerol, where one, two, or all three hydroxyl groups of the glycerol are each esterified using a fatty acid to produce monoglycerides, diglycerides, and triglycerides, respectively. In these compounds, each hydroxyl groups of glycerol may be esterified by different fatty acids. Additionally, glycerides may be acetylated to produce acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides.
  • a solvent may comprise a pharmaceutically-acceptable solid solvent.
  • Solid solvents may be useful in the manufacture of a solid dose formulation of a pharmaceutical composition disclosed herein. Typically, a solid solvent is melted in order to dissolve a therapeutic compound.
  • a pharmaceutically-acceptable solid solvent includes, without limitation, menthol and PEG polymers above about 20,000 g/mol.
  • An adjuvant is a pharmacological agent that modifies the effect of other agents, such as, e.g. , a therapeutic compound disclosed herein.
  • an adjuvant disclosed herein may be used as a solvent that dissolves a therapeutic compound disclosed herein, forming a adjuvant solution.
  • An adjuvant disclosed herein facilitates delivery of a therapeutic compound in a manner that more effectively inhibits a proinflammatory response.
  • an adjuvant disclosed herein facilitates the delivery of a therapeutic compound disclosed herein into macrophages.
  • a pharmaceutical composition disclosed herein may comprise a pharmaceutically-acceptable adjuvant in an amount sufficient to mix with a solution disclosed herein or an emulsion disclosed herein.
  • a pharmaceutical composition disclosed herein may comprise an adjuvant in an amount of, e.g., at least 10% (v/v), at least 20% (v/v), at least 30% (v/v), at least 35% (v/v), at least 40% (v/v), at least 45% (v/v), at least 50% (v/v), at least 55% (v/v), at least 60% (v/v), at least 65% (v/v), at least 70% (v/v), at least 75% (v/v), at least 80% (v/v), at least 85% (v/v), at least 90% (v/v), at least 95% (v/v), or at least 99% (v/v).
  • a pharmaceutical composition disclosed herein may comprise an adjuvant in an amount in a range of, e.g., about 30% (v/v) to about 99% (v/v), about 35% (v/v) to about 99% (v/v), about 40% (v/v) to about 99% (v/v), about 45% (v/v) to about 99% (v/v), about 50% (v/v) to about 99% (v/v), about 30% (v/v) to about 98% (v/v), about 35% (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% (
  • a pharmaceutical composition disclosed herein may comprise an adjuvant in an amount in a range of, e.g. , about 70% (v/v) to about 97% (v/v), about 75% (v/v) to about 97% (v/v), about 80% (v/v) to about 97% (v/v), about 85% (v/v) to about 97% (v/v), about 88% (v/v) to about 97% (v/v), about 89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97% (v/v), about 75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96% (v/v), about 85% (v/v) to about 96% (v/v), about 88% (v/v) to about 96% (v/v), about 89% (v/v) to about 96% (v/v), about 90% (v/v) to about 96% (v/v),
  • an adjuvant may be a pharmaceutically-acceptable lipid.
  • a lipid may be broadly defined as a hydrophobic or amphiphilic small molecule. The amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment.
  • Non-limiting examples, of lipids include fatty acids, glycerolipids (like monoglycerides, diglycerides, and triglycerides), phospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides.
  • a pharmaceutical composition disclosed herein may comprise a lipid such as, e.g.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable fatty acid.
  • a fatty acid comprises a carboxylic acid with a long unbranched hydrocarbon chain which may be either saturated or unsaturated. Thus arrangement confers a fatty acid with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water.
  • Most naturally occurring fatty acids have a hydrocarbon chain of an even number of carbon atoms, typically between 4 and 24 carbons, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur.
  • Synthetic or non-natural fatty acids may have a hydrocarbon chain of any number of carbon atoms from between 3 and 40 carbons.
  • fatty acids include, without limitation, Capryllic acid (8:0), pelargonic acid (9:0), Capric acid (10:0), Undecylic acid (1 1 :0), Erasmus acid (12:0), Tridecylic acid (13:0), Myristic acid (14:0), Myristoleic acid (14: 1 ), Pentadecyclic acid (15:0), Palmitic acid (16:0), Palmitoleic acid (16: 1 ), Sapienic acid (16: 1 ), Margaric acid (17:0), Stearic acid (18:0), Oleic acid (18: 1 ), Elaidic acid (18: 1 ), Vaccenic acid (18: 1 ), Linoleic acid (18:2), Linoelaidic acid (18:2), a-Linolenic acid (18:3), ⁇ -Linolenic acid (18:3), Stearidonic acid (18:4), Nonadecylic acid (19:0), Arachidic acid (20:0), Eicosenoic acid (20:1 ), Dihomo
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable partially hydrogenated lipid.
  • the process of hydrogenation adds hydrogen atoms to unsaturated lipid, eliminating double bonds and making them into partially or completely saturated lipid.
  • Partial hydrogenation is a chemical rather than enzymatic, that converts a part of cis-isomers into trans- unsaturated lipids instead of hydrogenating them completely.
  • one hydrogen is added, with the other, coordinatively unsaturated, carbon being attached to the catalyst.
  • the second step is the addition of hydrogen to the remaining carbon, producing a saturated fatty acid.
  • the first step is reversible, such that the hydrogen is readsorbed on the catalyst and the double bond is re-formed.
  • the intermediate with only one hydrogen added contains no double bond and can freely rotate. Thus, the double bond can re-form as either cis or trans, of which trans is favored, regardless the starting material.
  • an adjuvant may be a pharmaceutically-acceptable saturated or unsaturated fatty acid.
  • 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,
  • a saturated or unsaturated fatty acid comprises, e.g.
  • the fatty acid may have, e.g. , 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more double bonds.
  • a pharmaceutically-acceptable saturated or unsaturated fatty acid is liquid at room temperature.
  • the melting point of a fatty acid is largely determined by the degree of saturation/unsaturation of the hydrocarbon chain.
  • a saturated or unsaturated fatty acid has a melting point temperature of, e.g., 20°C or below, 15°C or below, 10°C or below, 5°C or below, 0°C or below, -5°C or below, -10°C or below, -15°C or below, or -20°C or below.
  • a saturated or unsaturated fatty acid has a melting point temperature in the range of, e.g.
  • an adjuvant may comprise one kind of pharmaceutically-acceptable fatty acid.
  • an adjuvant may comprise only palmitic acid, only stearic acid, only oleic acid, only linoleic acid, or only linolenic acid.
  • an adjuvant may comprise a plurality of different pharmaceutically- acceptable fatty acids.
  • an adjuvant may comprise, e.g., two or more different fatty acids, three or more different fatty acids, four or more different fatty acids, five or more different fatty acids, or six or more different fatty acids.
  • an adjuvant may comprise two or more different pharmaceutically-acceptable fatty acids including at least palmitic acid, stearic acid, oleic acid, linoleic acid and/or linolenic acid, and any combination thereof.
  • an adjuvant may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/or linoleic acid of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, or at least 20:1.
  • an adjuvant may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/or linoleic acid in a range of, e.g., about 1:1 to about 20:1, about 2:1 to about 15:1, about 4:1 to about 12:1, or about 6: 1 to about 10:1.
  • an adjuvant may comprise four or more different pharmaceutically-acceptable fatty acids including at least palmitic acid, stearic acid, oleic acid, linoleic acid and/or linolenic acid, and any combination thereof.
  • an adjuvant may comprise a ratio of palmitic acid;stearic acid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, 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.
  • 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.
  • an omega fatty acid include omega-3, omega-6, omega-7, and omega-9.
  • Omega-3 fatty acids also known as n-3 fatty acids or ⁇ -3 fatty acids
  • Omega-3 fatty acids are a family of essential unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-3 position, that is, the third bond, counting from the methyl end of the fatty acid.
  • the omega-3 fatty acids are "essential" fatty acids because they are vital for normal metabolism and cannot be synthesized by the human body.
  • An omega-3 fatty acid includes, without limitation, Hexadecatrienoic acid (16:3), a- Linolenic acid (18:3), Stearidonic acid (18:4), Eicosatrienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), Docosapentaenoic acid (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 ⁇ -6 fatty acids
  • Omega-6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-6 position, that is, the sixth bond, counting from the methyl end of the fatty acid.
  • An omega-6 fatty acid includes, without limitation, Linoleic acid (18:2), ⁇ -linolenic acid (18:3), Calendic acid (18:3), Eicosadienoic acid (20:2), Dihomo- ⁇ - linolenic acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22:2), Adrenic acid (22:4), Docosapentaenoic acid (22:5), Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid (24:5).
  • Omega-7 fatty acids are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-7 position, that is, the seventh bond, counting from the methyl end of the fatty acid.
  • An omega-7 fatty acid includes, without limitation, 5-Dodecenoic acid (12: 1 ), 7-Tetradecenoic acid (14: 1 ), 9-Hexadecenoic acid (Palmitoleic acid) (16:1 ), 1 1 -Decenoic acid (Vaccenic acid) (18: 1 ), 9Z.1 1 E conjugated Linoleic acid (Rumenic acid)(18:2), 13-Eicosenoic acid (Paullinic acid) (20: 1 ), 15-Docosenoic acid (22: 1 ), and 17-Tetracosenoic acid (24: 1 ).
  • Omega-9 fatty acids are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-9 position, that is, the ninth bond, counting from the methyl end of the fatty acid.
  • An omega-9 fatty acid includes, without limitation, Oleic acid (18: 1 ), Elaidic acid (18: 1 ), Eicosenoic acid (20:1 ), Mead acid (20:3), Erucic acid (22: 1 ), Nervonic acid (24: 1 ), and Ricinoleic acid.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable fat.
  • a fat includes any fatty acid that is solid at normal room temperature, such as, e.g. about 20°C. Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water.
  • a fat suitable as a lipid useful in the pharmaceutical compositions disclosed herein may be a triglyceride, a triester of glycerol or any of several fatty acids.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable oil.
  • An oil also known as a liquid fat, includes any fatty acid that is liquid 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, a vegetable oil or any substance that does not mix with water and has a greasy feel. Examples of suitable natural oils include, without limitation, mineral oil, triacetin, ethyl oleate, a hydrogenated natural oil, or a mixture thereof.
  • suitable vegetable oils include, without limitation, almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seed oil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, theobroma oil (cocoa butter), walnut oil, wheat germ oil, or a mixture thereof.
  • avocado oil canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seed oil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, theobroma oil (cocoa butter), walnut oil, wheat germ oil, or a mixture thereof.
  • An oil is typically a mixture of various fatty acids.
  • Rapeseed oil obtained from the seeds of Brassica napus, includes both omega-6 and omega-3 fatty acids in a ratio of about 2:1.
  • linseed oil obtained from the seeds of Linum usitatissimum, includes abut 7% palmitic acid, about 3.4-4.6% stearic acid, about 18.5-22.6% oleic acid, about 14.2-17% linoleic acid, and about 51.9-55.2% ⁇ -linolenic acid.
  • theobroma oil obtained from the seeds of Theobroma cacao, includes glycerides derived from palmitic acid, stearic acid, oleic acid, linoleic acid, and arichidic acid, with melting point of 34-38°C.
  • a pharmaceutical composition comprises an oil including at least two different fatty acids, at least three different fatty acids, at least four different fatty acids, at least five different fatty acids, or at least six different fatty acids.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable 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 are each esterified using a fatty acid disclosed herein to produce monoglycerides, diglycerides, and triglycerides, respectively.
  • each hydroxyl groups of glycerol may be esterified by different fatty acids.
  • glycerides may be acetylated to produce acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides.
  • One group of glycerolipids is the glycerides, where one, two, or all three hydroxyl groups of glycerol have sugar residues attached via a glycosidic linkage.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable partially hydrolyzed glycerolipid.
  • a pharmaceutically- acceptable partially hydrolyzed glycerolipid is a triglyceride partially hydrolyzed into a mixture of mono-, di-, and triglycerides.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable glycol fatty acid ester.
  • a pharmaceutically-acceptable glycol fatty acid ester can be a monoester of a glycol, a diester of a glycol, or a triester of a glycol.
  • a glycol fatty acid ester include, without limitation, a ethylene glycol fatty acid ester, a diethylene glycol fatty acid ester, a propylene glycol fatty acid ester, and a dipropylene fatty acid ester.
  • Non-limiting examples of glycol fatty acid esters include, e.g.
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically- acceptable polyether fatty acid ester.
  • a pharmaceutically-acceptable polyether fatty acid ester can be a mono-fatty acid ester of a polyether, a di-fatty acid ester of a polyether, or a tri-fatty acid ester of a polyether.
  • a polyether fatty acid ester includes, without limitation, a PEG fatty acid ester, a PEG glyceryl fatty acid, a PEG fatty acid ester glyceride, a PPG fatty acid ester, a PPG glyceryl fatty acid, and a PPG fatty acid ester glyceride.
  • a PEG or PPG may be a molecular mass of, e.g. , 5-20,000.
  • Non-limiting examples of polyether fatty acid esters include, e.g. , a PEG caprylate, a PEG pelargonate, a PEG caprate, a PEG undecylate, a PEG laurate, a PEG tridecylate, a PEG myristate, a PEG myristolate, a PEG pentadecyclate, a PEG palmitate, a PEG palmitoleate, a PEG sapienate, a PEG margarate, a PEG stearate, a PEG palmitostearate, PEG oleate, PEG elaidate, PEG vaccinate, PEG linoleate, PEG linoelaidate, PEG a-linolenate, PEG ⁇ -linolenate, PEG stearidon
  • Comercially available pharmaceutically-acceptable polyether fatty acid esters include, without limitation, caprylocaproyl macrogol-8 glycerides (LABRASOL ® ), propylene glycol monopalmitostearate (MONOSTEOL ® ), glyceryl dibehenate (COMPRITOL ® 888), glycerol behenate (COMPRITOL ® E ATO), behenoyl pollyoxyl-8 glycerides (COMPRITOL ® HD5 ATO), triglycerol diisostearate (PLUROL ® Diisostearique), PEG-8 beeswax (APIFIL ® ), lauroyi macrogol-32 glycerides (GELUCIRE 44/14), stearoyl macrogol-32 glycerides (GELUCIRE 50.13), propylene glycol dicaprylocaprate (LABRAFAC ® PG), polyglycerol-3 dioleate (PLUROL ® Ol
  • a lipid useful in the pharmaceutical compositions disclosed herein may be a mixture of pharmaceutically-acceptable lipids.
  • mixtures of pharmaceutically-acceptable lipids include, without limitation, a mixture of one or more glycerolipids disclosed herein, a mixture of one or more glycol fatty acid esters disclosed herein, a mixture of more polyether fatty acid esters disclosed herein, a mixture of more glycerides disclosed herein.
  • a mixture of pharmaceutically-acceptable lipids includes a mixture of mono-, di- and/or triglycerides having a melting point of, e.g. , about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41 °C, about 43°C, about 43°C, about 44°C, about 45°C, about 45°C, about 47°C, about 48°C, about 49°C, about 50°C.
  • a mixture of pharmaceutically-acceptable lipids includes a mixture of mono-, di- and/or triglycerides having a melting point of, e.g. , about 30°C to about 44°C, about 30°C to about 45°C, about 30°C to about 46°C, about 30°C to about 47°C, about 30°C to about 48°C, about 30°C to about 49°C, about 30°C to about 50°C, about 32°C to about 44°C, about 32°C to about 45°C, about 32°C to about 46°C, about 32°C to about 47°C, about 32°C to about 48°C, about 32°C to about 49°C, about 32°C to about 50°C, about 34°C to about 44°C, about 34°C to about 45°C, about 34°C to about 46°C, about 34°C to about 47°C, about 34°C to about 48°C, about 34°C to about 49°C, about 34°C, about 34°C
  • a mixture of pharmaceutically-acceptable lipids includes a mixture PEG fatty acid esters having a melting point of, e.g., about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41 °C, about 43°C, about 43°C, about 44°C, about 45°C, about 45°C, about 47°C, about 48°C, about 49°C, about 50°C.
  • a mixture of pharmaceutically-acceptable lipids includes a mixture PEG fatty acid esters having a melting point of, e.g., about 30°C to about 44°C, about 30°C to about 45°C, about 30°C to about 46°C, about 30°C to about 47°C, about 30°C to about 48°C, about 30°C to about 49°C, about 30°C to about 50°C, about 32°C to about 44°C, about 32°C to about 45°C, about 32°C to about 46°C, about 32°C to about 47°C, about 32°C to about 48°C, about 32°C to about 49°C, about 32°C to about 50°C, about 34°C to about 44°C, about 34°C to about 45°C, about 34°C to about 46°C, about 34°C to about 47°C, about 34°C to about 48°C, about 34°C to about 49°C, about 34°C to about 50°C, about 36°C to about 44°
  • a mixture of pharmaceutically-acceptable lipids includes a mixture of mono-, di-, and/or triglycerides and PEG fatty acid esters having a melting point of, e.g. , about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41 °C, about 43°C, about 43°C, about 44°C, about 45°C, about 45°C, about 47°C, about 48°C, about 49°C, about 50°C.
  • a mixture of pharmaceutically-acceptable lipids includes a mixture of mono-, di-, and/or triglycerides and PEG fatty acid esters having a melting point of, e.g., about 30°C to about 44°C, about 30°C to about 45°C, about 30°C to about 46°C, about 30°C to about 47°C, about 30°C to about 48°C, about 30°C to about 49°C, about 30°C to about 50°C, about 32°C to about 44°C, about 32°C to about 45°C, about 32°C to about 46°C, about 32°C to about 47°C, about 32°C to about 48°C, about 32°C to about 49°C, about 32°C to about 50°C, about 34°C to about 44°C, about 34°C to about 45°C, about 34°C to about 46°C, about 34°C to about 47°C, about 34°C to about 48°C, about 34°C to about 34°C to about
  • Comercially available mixtures of pharmaceutically-acceptable lipids include, without limitation, mixtures of PEG-6 sterate and ethylene glycol palmitostearate and PEG-32 stearate (TEFOSE ® 1500; TEFOSE ® 63), mixtures of triceteareth-4 phosphate and ethylene glycol palmitostearate and diethylene glycol palmitostearate (SEDEFOS ® 75), mixtures of glycerol monostearate and PEG-75 stearate (GELOT ® ), mixtures of cetyl alcohol and ethoxylated fatty alcohols (seteth-2-, steareth-20) (EMULCIRE ® ), mixtures of saturated C 10 -C 8 triglycerides having a melting point around 33°C (GELUCIRE ® 33/01 ), mixtures of saturated C 0 -C 18 triglycerides having a melting point around 39°C (GELUCIRE ® 39/01 ), mixture
  • a stabilizing agent reduces or eliminates formation of esters of a therapeutic compound that may result as a unwanted reaction with the particular solvent used.
  • a stabilizing agent include, without limitation, water, a sacrificial acid comprising a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid (E262), a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated monoglyceride, an acetylated diglyceride, a fatty acid, and a fatty acid salt.
  • a pharmaceutically-acceptable stabilizing agent may comprise a pharmaceutically-acceptable emulsifying agent.
  • An emulsifying agent also known as an emulgent
  • An emulsifying agent is a substance that stabilizes an emulsion comprising a liquid dispersed phase and a liquid continuous phase by increasing its kinetic stability.
  • an emulsifying agent disclosed herein is used to create a homogenous and stable emulsion.
  • An emulsifying agent includes, without limitation, a surfactant, a polysaccharide, a lectin, and a phospholipid.
  • an emulsifying agent may comprise a surfactant.
  • surfactant refers to a natural or synthetic amphiphilic compound.
  • a surfactant can be non-ionic, zwitterionic, or ionic.
  • Non-limiting examples of surfactants include polysorbates like polysorbate 20 (TWEEN ® 20), polysorbate 40 (TWEEN ® 40), polysorbate 60 (TWEEN ® 60), polysorbate 61 (TWEEN ® 61 ), polysorbate 65 (TWEEN ® 65), polysorbate 80 (TWEEN ® 80), and polysorbate 81 (TWEEN ® 81 ); poloxamers (polyethylene-polypropylene copolymers), like Poloxamer 124 (PLURONIC ® L44), Poloxamer 181 (PLURONIC ® L61 ), Poloxamer 182 (PLURONIC ® L62), Poloxamer 184 (PLURONIC ® L64), Poloxamer 188 (PLURONIC ® F68), Poloxamer 237 (PLURONIC ® F87), Poloxamer 338 (PLURONIC ® L108), Poloxamer 407 (PLURONIC ® F127), poly
  • surfactant excipients 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.
  • an emulsifying agent may comprise a polysaccharide.
  • polysaccharides include guar gum, agar, alginate, calgene, a dextran (like dextran 1 K, dextran 4K, dextran 40K, dextran 60K, and dextran 70K), dextrin, glycogen, inulin, starch, a starch derivative (like hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxybutyl starch, and hydroxypentyl starch), hetastarch, cellulose, FICOLL, methyl cellulose (MC), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (HPMC); polyvinyl acetates (PVA); polyvinyl
  • an emulsifying agent may comprise a lectin.
  • Lectins are sugar- binding proteins that are highly specific for their sugar moieties. Lectins may be classified according to the sugar moiety that they bind to, and include, without limitation, mannose-binding lectins, galactose/N- acetylgalactosamine-binding lectins, N-acetylgluxosamine-binding lectins, N-acetylneuramine-binding lectins, N-acetylneuraminic acid-binding lectins, and fucose-binding lectins.
  • Non-limiting examples of surfactants include concanavain A, lentil lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairy vetch lectin, wheat germ agglutinin, elderberry lectin, Maackia anurensis leukoagglutinin, Maackia anurensis hemoagglutinin, Ulex europaeus agglutinin, and Aleuria aurantia lectin.
  • an emulsifying agent may comprise a phospholipid.
  • the structure of the phospholipid generally comprises a hydrophobic tail and a hydrophilic head and is amphipathic in nature.
  • Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from sphingosine instead of glycerol.
  • Phospholipids include, without limitation, diacylglycerides and phosphosphingolipids.
  • Non-limiting examples of diacylglycerides include a phosphatidic acid (phosphatidate) (PA), a phosphatidylethanolamine (cephalin) (PE), a phosphatidylcholine (lecithin) (PC), a phosphatidylserine (PS), and a phosphoinositide including phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol bisphosphate (PIP2), and phosphatidylinositol triphosphate (PIP3).
  • PA phosphatidic acid
  • PE phosphatidylethanolamine
  • PC phosphatidylcholine
  • PS a phosphatidylserine
  • PI phosphatidylinositol
  • PIP2 phosphatidylinositol bisphosphate
  • PIP3 phosphatidylinositol
  • Non-limiting examples of phosphosphingolipids include a ceramide phosphorylcholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol.
  • a pharmaceutically-acceptable stabilizing agent does not comprise a pharmaceutically-acceptable emulsifying agent.
  • a pharmaceutical composition does not comprise a pharmaceutically- acceptable emulsifying agent.
  • compositions disclosed herein act as a delivery system that enable a therapeutic compound disclosed herein to be more effectively delivered or targeted to a cell type, tissue, organ, or region of the body in a manner that more effectively inhibits a pro-inflammatory response. This inhibition results in an improved treatment of a chronic inflammation.
  • a pharmaceutical composition disclosed herein may facilitate the delivery of a therapeutic compound disclosed herein into macrophages.
  • the pharmaceutical compositions disclosed herein may be designed to take advantage of the activity of chylomicrons. Chylomicrons are relatively large lipoprotein particles having a diameter of 75 nm to 1 ,200 nm.
  • Chylomicrons transport dietary lipids from the intestines to other locations in the body. Chylomicrons are one of the five major groups of lipoproteins, the others being VLDL, IDL, low-density lipoproteins (LDL), high-density lipoproteins (HDL), that enable fats and cholesterol to move within the water-based solution of the bloodstream.
  • fatty acids and cholesterol undergo processing in the gastrointestinal tract by the action of pancreatic juices including lipases and emulsification with bile salts to generate micelles. These micelles allow the absorption of lipid as free fatty acids by the absorptive cells of the small intestine, known as enterocytes. Once in the enterocytes, triglycerides and cholesterol are assembled into nascent chylomicrons. Nascent chylomicrons are primarily composed of triglycerides (85%) and contain some cholesterol and cholesteryl esters. The main apolipoprotein component is apolipoprotein B- 48 (APOB48).
  • APOB48 apolipoprotein B- 48
  • nascent chylomicrons are released by exocytosis from enterocytes into lacteals, lymphatic vessels originating in the villi of the small intestine, and are then secreted into the bloodstream at the thoracic duct's connection with the left subclavian vein.
  • chylomicrons While circulating in lymph and blood, chylomicrons exchange components with HDL.
  • the HDL donates apolipoprotein C-ll (APOC2) and apolipoprotein E (APOE) to the nascent chylomicron and thus converts it to a mature chylomicron (often referred to simply as "chylomicron”).
  • APOC2 is the cofactor for lipoprotein lipase (LPL) activity.
  • LPL lipoprotein lipase
  • APOB48 and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdown into lipoproteins (VLDL, LDL and HDL). These lipoproteins are processed and stored by competent cells, including, e.g. , hepatocytes, adipocytes and macrophages.
  • a pharmaceutical composition disclosed herein can be processed into micelles while in the gastrointestinal tract, absorbed by enterocytes and assembled into nascent chylomicrons, remain associated with chylomicron remnants taken up by the liver, and ultimately loaded into macrophages which are present in inflamed tissues.
  • a pharmaceutical composition disclosed herein may facilitate the delivery of a therapeutic compound disclosed herein into dentritic cells.
  • One possible mechanism to achieve selective biodistribution of the pharmaceutical compositions disclosed herein may be to take advantage of the endocytotic/phagocytotic activity of dentritic cells.
  • Dendritic cells are immune cells forming part of the mammalian immune system. The main function of dendritic cells is to process antigen material and present it on the surface to other cells of the immune system. Thus, dendritic cells function as antigen- presenting cells that act as messengers between innate and adaptive immunity. Dendritic cells are present in tissues in contact with the external environment, such as, e.g.
  • Dendritic cells are known to endocytose and phagocytose lipid particles as part of their environmental monitoring and antigen presentation processes.
  • a pharmaceutical composition disclosed herein upon topical or inhalatory administration, can penetrate into the skin or inner lining of the nose, lungs, stomach and intestines, be endocytosed/phagocytosed by dentritic cells, and ultimately loaded into T cells and/or B cells which are present in inflamed tissues.
  • a method disclosed herein comprises the step of contacting a pharmaceutically-acceptable adjuvant disclosed herein with a therapeutic compound disclosed herein under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable adjuvant, thereby forming a pharmaceutical composition disclosed herein.
  • a method disclosed herein comprises the steps of a) contacting a pharmaceutically-acceptable solvent disclosed herein with a therapeutic compound disclosed herein under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution; and b) contacting the solution formed in step (a) with a pharmaceutically-acceptable adjuvant disclosed herein under conditions which allow the formation of a pharmaceutical composition.
  • the methods of preparing disclosed herein may further comprise a step (c) of removing the pharmaceutically-acceptable solvent from the pharmaceutical composition.
  • the amount of a therapeutic compound that is contacted with the pharmaceutically-acceptable solvent in step (a) of the method may be in any amount desired.
  • Factors used to determine the amount of a therapeutic compound used include, without limitation, the final amount the therapeutic compound desired in the pharmaceutical composition, the desired concentration of a therapeutic compound in the solution, the hydrophobicity of the therapeutic compound, the lipophobicity of the therapeutic compound, the temperature under which the contacting step (a) is performed, and the time under which the contacting step (a) is performed
  • the volume of a pharmaceutically-acceptable solvent used in step (a) of the method may be any volume desired.
  • Factors used to determine the volume of a pharmaceutically-acceptable solvent used include, without limitation, the final amount of a pharmaceutical composition desired, the desired concentration of a therapeutic compound in the solution, the hydrophobicity of the therapeutic compound, and the lipophobicity of the therapeutic compound.
  • the amount of a therapeutic compound that is contacted with the solvent in step (a) may be, e.g. , at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 , 100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg.
  • the amount of a therapeutic compound that is contacted with the solvent in step (a) may be in the range of, e.g. , about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg.
  • the amount of a therapeutic compound that is dissolved in the solvent in step (a) may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1 ,000 mg, about 10 mg to about 1 ,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1 ,000 mg, about 50 mg to about 1 ,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1 ,000 mg, about 100 mg to about 1 ,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1 ,000 mg, or about 200 mg to about 1 ,500 mg.
  • Step (a) may be carried out at room temperature, in order to allow a therapeutic compound to dissolve fully in the pharmaceutically-acceptable solvent.
  • Step (a) may be carried out at a temperature that is greater than room temperature.
  • Step (a) may be carried out at a temperature that is, e.g. , greater than 21 °C, greater than 25°C, greater than 30°C, greater than 35°C or greater than 37°C, greater than 40°C, greater than 42°C, greater than 45°C, greater than 50°C, greater than 55°C, or greater than 60°C.
  • Step (a) may be carried out at a temperature that is between, e.g.
  • Step (a) may be carried out at temperatures below room temperature, in order to allow a therapeutic compound to dissolve fully in solvent. However, in other embodiments of the method, step (a) may be carried out at a temperature that is less than room temperature, e.g. , less than 10°C, greater than 5°C, greater than 0°C, greater than -10°C or greater than -20°C.
  • the contacting in Step (a) may comprise mixing the therapeutic compound and the pharmaceutically-acceptable solvent, e.g. , by stirring, inversion, sonication, or vortexing.
  • the mixing may be carried out for, e.g. , at least 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds, or more, until the therapeutic compound is fully dissolved in the solvent.
  • the concentration of a therapeutic compound disclosed herein in the solution may be in any concentration desired.
  • the concentration of a therapeutic compound disclosed herein in the solution may be, e.g. , at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1 ,000 mg/mL, or at least 1 ,200 mg/mL.
  • the concentration of a therapeutic compound disclosed herein in the solution may be, e.g. , at most 1 ,000 mg/mL, at most 1 , 100 mg/mL, at most 1 ,200 mg/mL, at most 1 ,300 mg/mL, at most 1 ,400 mg/mL, at most 1 ,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL.
  • the concentration of a therapeutic compound disclosed herein in the solution may be in a range of, e.g.
  • the volume of a pharmaceutically-acceptable adjuvant used in Step (b) of the method may be any volume desired.
  • Factors used to determine the volume of a pharmaceutically-acceptable adjuvant used include, without limitation, the final amount of a pharmaceutical composition desired, the desired concentration of a therapeutic compound in the pharmaceutical composition, the ratio of solven adjuvant used , and the miscibility of solvent and adjuvant.
  • the ratio of solution:adjuvant may be, e.g., at least 5:1, at least 4:1, at least 3:1, at least 2:1, at least 0:1, at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, at least 1:20, or at least 1:25.
  • the ratio of solution:adjuvant may be in a range of, e.g., about 5:1 to about 1:25, about 4:1 to about 1:25, about 3:1 to about 1:25, about 2:1 to about 1:25, about 0:1 to about 1:25, about 1:1 to about 1:25, about 1:2 to about 1:25, about 1:3 to about 1:25, about 1:4 to about 1:25, about 1:5 to about 1:25, about 5:1 to about 1:20, about 4:1 to about 1:20, about 3:1 to about 1:20, about 2:1 to about 1:20, about 0:1 to about 1:20, about 1:1 to about 1:20, about 1:2 to about 1:20, about 1:3 to about 1:20, about 1:4 to about 1:20, about 1:5 to about 1:20, about 5:1 to about 1:15, about 4:1 to about 1:15, about 3:1 to about 1:15, about 0:1 to about 1:15, about 2:1 to about 1:15, about 1:1 to about 1:15, about 1:2 to about 1:15, about 1:3 to about 1:15, about 1:4 to about 1:15,
  • Step (b) may be carried out at room temperature, in order to allow the solution comprising the therapeutic compound to form the pharmaceutical composition. However, in other embodiments of the method, Step (b) may be carried out at a temperature that is greater than room temperature. In aspects of this embodiment, Step (b) may be carried out at a temperature that is, e.g., greater than 21°C, greater than 25°C, greater than 30°C, greater than 35°C or greater than 37°C, greater than 40°C, greater than 42°C, greater than 45°C, greater than 50°C, greater than 55°C, or greater than 60°C.
  • Step (a) may be carried out at a temperature that is between, e.g., about 20°C to about 30 °C, about 25°C to about 35 °C, about 30°C to about 40 °C, about 35°C to about 45 °C, about 40°C to about 50 °C, about 45°C to about 55 °C, or about 50°C to about 60 °C.
  • Step (b) may be carried out at temperatures below room temperature, in order to allow a therapeutic compound to dissolve fully in a pharmaceutically-acceptable solvent.
  • step (b) may be carried out at a temperature that is less than room temperature, e.g., less than 10°C, greater than 5°C, greater than 0°C, greater than -10°C or greater than -20°C.
  • the contacting in Step (b) may comprise mixing the solution and the pharmaceutically-acceptable adjuvant, e.g., by stirring, inversion, sonication, or vortexing.
  • the mixing may be carried out for, e.g., at least 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds, or more, until the pharmaceutical composition is formed,
  • a rapid cooling step may be used to reduce the temperature of a pharmaceutical composition disclosed herein after its formation.
  • a rapid cooling step may be used in procedures were temperatures greater than room temperature are used to allow a therapeutic compound to dissolve fully in the pharmaceutically-acceptable solvent and/or to allow the solution comprising the therapeutic compound to form the pharmaceutical composition.
  • a rapid cooling step results in a temperature decrease of, e.g.
  • a rapid cooling step results in a temperature decrease of, e.g.
  • a rapid cooling step results in a temperature decrease of, e.g., about 2.0°C/minute, about 1.9°C/minute, about 1.8°C/minute, about 1.7°C/minute, about 1.6°C/minute, about 1.5°C/minute, about 1.4°C/minute, about 1.3°C/minute, about 1.2°C/minute, about 1 .1 °C/minute, about 1.0°C/minute, about 0.9°C/minute, about 0.8°C/minute, about 0.7°C/minute, about 0.6°C/minute, about 0.5°C/minute, about 0.4°C/minute, about 0.3°C/minute, about 0.2°C/minute, or about 0.1 °C/minute.
  • a rapid cooling step results in a temperature decrease of, e.g., about 0.1 °C to about 0.4°C/minute, about 0.2°C to about 0.6°C/minute, about 0.4°C to about 0.8°C/minute, about 0.6°C to about 1.0°C/minute, about 0.8°C to about 1.2°C/minute, about 1.0°C to about 1.4°C/minute, about 1.2°C to about 1.6°C/minute, about 1.4°C to about 1.8°C/rminute, about 1.6°C to about 2.0°C/minute, about 0.1 °C to about 0.5°C/minute, about 0.5°C to about 1.0°C/minute, about 1.0°C to about 1.5°C/minute, about 1.5°C to about 2.0°C/minute, about 0.5°C to about 1.5°C/minute, or about 1.0°C to about 2.0°C/minute.
  • Step (c) temperatures greater than room temperature employed in either Step (a) or Step (b) or both may be used to remove the solvent from a pharmaceutical composition.
  • removal of solvent from a pharmaceutical composition requires a separate Step (c).
  • Step (c) the solvent removal from a pharmaceutical composition may be accomplished using one of a variety of procedures known in the art, including, without limitation, evaporation, dialyzation, distillation, lypholization, and filtration. These removal procedures may be done under conditions of ambient atmosphere, under low pressure, or under a vacuum and either at ambient temperature or at temperatures requiring heating.
  • Step (c) may result in the complete removal of a pharmaceutically- acceptable solvent from the pharmaceutical composition disclosed herein.
  • Step (c) may result in, e.g. , at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, or at least 99% removal of a pharmaceutically-acceptable solvent from the pharmaceutical composition disclosed herein.
  • Step (c) 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 solvent disclosed herein include, without limitation, the particular solvent used, the amount of solvent present, the particular therapeutic compound present, the particular adjuvant present, the stability of the therapeutic compound present, the reactivity of the therapeutic compound present, the particular atmospheric pressure used, the time desired for complete evaporation.
  • a pharmaceutical composition will require heating if the evaporation step is conducted at ambient pressure, e.g., 1 atm. However, under high vacuum conditions, the evaporation step may be conducted at temperatures below ambient temperature, e.g., less than 22 °C.
  • removal of solvent from the pharmaceutical composition disclosed herein may be carried out at ambient atmospheric pressure and at a temperature above ambient temperature.
  • removal of solvent from the pharmaceutical composition disclosed herein may be carried out at ambient atmospheric pressure and at a temperature of, e.g. , more than 25°C, more than 30°C, more than 35°C, more than 40°C, more than 45°C, more than 50°C, more than 55°C, more than 60°C, more than 65°C, more than 70°C, more than 80°C, or more than 25°C.
  • removal of solvent from the pharmaceutical composition disclosed herein may be carried out at ambient atmospheric pressure and at a temperature in a range of, e.g.
  • removal of solvent from the pharmaceutical composition disclosed herein may be carried out under vacuum and at a temperature below ambient temperature.
  • removal of solvent from the pharmaceutical composition disclosed herein may be carried out under vacuum and at a temperature of, e.g., less than 20°C, less than 18°C, less than 16°C, less than 14°C, less than 12°C, less than 10°C, less than 8°C, less than 6°C, less than 4°C, less than 2°C, or less than 0°C.
  • removal of solvent from the pharmaceutical composition disclosed herein may be carried out under vacuum and at a temperature in a range of, e.g., about -20°C to about 20°C, about -20°C to about 18°C, about -20°C to about 16°C, about -20°C to about 14°C, about - 20°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 20°C, about -10°C to about 20°C, about -5°C to about 20°C, about 0°C to about 20°C, about -10°C to about 20°C, about -10°C to about 18°C, about -10°C to about 16°C, about -10°C to about 14°C, about - 10
  • the final concentration of a therapeutic compound disclosed herein in a pharmaceutical composition disclosed herein may be of any concentration desired.
  • the final concentration of a therapeutic compound in a pharmaceutical composition may be a therapeutically effective amount.
  • the final concentration of a therapeutic compound in a pharmaceutical composition may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1 ,000 mg/mL, or at least 1 ,200 mg/mL.
  • the concentration of a therapeutic compound disclosed herein in the solution may be, e.g. , at most 1 ,000 mg/mL, at most 1 ,100 mg/mL, at most 1 ,200 mg/mL, at most 1 ,300 mg/mL, at most 1 ,400 mg/mL, at most 1 ,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL.
  • the final concentration of a therapeutic compound in a pharmaceutical composition may be in a range of, e.g.
  • a pharmaceutical composition produced using the methods disclosed herein may be formulated for either local or systemic delivery using topical, enteral or parenteral routes of administration. Additionally, a therapeutic compound disclosed herein may be formulated by itself in a pharmaceutical composition, or may be formulated together with one or more other therapeutic compounds disclosed herein in a single pharmaceutical composition.
  • a pharmaceutical composition produced using the methods disclosed herein may be a liquid formulation, semi-solid formulation, or a solid formulation.
  • a formulation disclosed herein can be produced in a manner to form one phase, such as, e.g. , an oil or a solid. Alternatively, a formulation disclosed herein can be produced in a manner to form two phase, such as, e.g. , an emulsion.
  • a pharmaceutical composition disclosed herein intended for such administration may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Semisolid formulations suitable for topical administration include, without limitation, ointments, creams, salves, and gels.
  • a liquid formulation may be formed by using various lipids like oils of other fatty acids that remain as liquids in the temperature range desired.
  • a pharmaceutical composition disclosed herein is liquid at room temperature.
  • a pharmaceutical composition disclosed herein may be formulated to be a liquid at a temperature of, e.g. , about 25°C or higher, about 23°C or higher, about 21 °C or higher, about 19°C or higher, about 17°C or higher, about 15°C or higher, about 12°C or higher, about 10°C or higher, about 8°C or higher, about 6°C or higher, about 4°C or higher, or about 0°C or higher.
  • a concentration of a therapeutic compound disclosed herein typically may be between about 50 mg/mL to about 1 ,000 mg/mL.
  • a therapeutically effective amount of a therapeutic compound disclosed herein may be from, e.g., about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to about 200 mg/mL, about 50 mg/mL to about 300 mg/mL, about 50 mg/mL to about 400 mg/mL, about 50 mg/mL to about 500 mg/mL, about 50 mg/mL to about 600 mg/mL, about 50 mg/mL to about 700 mg/mL, about 50 mg/mL to about 800 mg/mL, about 50 mg/mL to about 900 mg/mL, about 50 mg/mL to about 1 ,000 mg/mL, about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 300 mg/mL, about 100 mg/mL to about
  • an amount of a therapeutic compound disclosed herein typically may be between about 0. 01 % to about 45% by weight.
  • an amount of a therapeutic compound disclosed herein may be from, e.g., about 0.1 % to about 45% by weight, about 0.1 % to about 40% by weight, about 0.1 % to about 35% by weight, about 0.1 % to about 30% by weight, about 0.1 % to about 25% by weight, about 0.1 % to about 20% by weight, about 0.1 % to about 15% by weight, about 0.1 % to about 10% by weight, about 0.1 % to about 5% by weight, about 1 % to about 45% by weight, about 1 % to about 40% by weight, about 1 % to about 35% by weight, about 1 % to about 30% by weight, about 1 % to about 25% by weight, about 1 % to about 20% by weight, about 1 % to about 15% by weight, about 1 % to about 10% by weight, about % to about 45% by weight, about 1 % to about 40% by weight, about 1
  • a liquid formulation comprises a therapeutic compound, a glycol ether, a partially-hydrogenated fat, an oil, and an alcohol.
  • a liquid formulation comprises about 15% to about 35% by weight of therapeutic compound, about 5% to about 25% by weight of glycol ether, about 15% to about 40% by weight of partially-hydrogenated fat, about 15% to about 40% of an oil, and about 1 % to about 15% of an alcohol.
  • a liquid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 10% to about 20% by weight of glycol ether, about 20% to about 35% by weight of partially-hydrogenated fat, about 20% to about 35% of an oil, and about 2% to about 10% of an alcohol.
  • a liquid formulation comprises about 23% to about 27% by weight of therapeutic compound, about 13% to about 17% by weight of glycol ether, about 25% to about 30% by weight of partially- hydrogenated fat, about 25% to about 30% of an oil, and about 4% to about 8% of an alcohol.
  • a liquid formulation comprises about 24% to about 26% by weight of therapeutic compound, about 14% to about 16% by weight of glycol ether, about 26% to about 28% by weight of partially-hydrogenated fat, about 26% to about 28% of an oil, and about 5% to about 7% of an alcohol.
  • an oil is rapeseed oil or theobroma oil.
  • a liquid formulation comprises a therapeutic compound, a glycol ether, a glyceryl monoiinoleate, an oil, and an alcohol.
  • a liquid formulation comprises about 15% to about 35% by weight of therapeutic compound, about 5% to about 25% by weight of glycol ether, about 15% to about 40% by weight of glyceryl monoiinoleate, about 15% to about formulation comprises about 20% to about 30% by weight of therapeutic compound, about 10% to about 20% by weight of glycol ether, about 20% to about 35% by weight of glyceryl monolinoleate, about 20% to about 35% of an oil, and about 2% to about 10% of an alcohol.
  • a liquid formulation comprises about 23% to about 27% by weight of therapeutic compound, about 13% to about 17% by weight of glycol ether, about 25% to about 30% by weight of glyceryl monolinoleate, about 25% to about 30% of an oil, and about 4% to about 8% of an alcohol.
  • a liquid formulation comprises about 24% to about 26% by weight of therapeutic compound, about 14% to about 16% by weight of glycol ether, about 26% to about 28% by weight of glyceryl monolinoleate, about 26% to about about 28% of an oil, and about 5% to about 7% of an alcohol.
  • an oil is rapeseed oil or theobroma oil.
  • a liquid formulation comprises an ibuprofen, a diethylene glycol monoethyl ether, a glyceryl monolinoleate, an oil, and an alcohol.
  • a liquid formulation comprises about 15% to about 35% by weight of an ibuprofen, about 5% to about 25% by weight of diethylene glycol monoethyl ether, about 15% to about 40% by weight of glyceryl monolinoleate, about 15%> to about 40%> of an oil, and about 1 % to about 15% of an alcohol.
  • a liquid formulation comprises about 20% to about 30%> by weight of an ibuprofen, about 10% to about 20% by weight of diethylene glycol monoethyl ether, about 20% to about 35% by weight of glyceryl monolinoleate, about 20% to about 35% of an oil, and about 2% to about 10% of an alcohol.
  • a liquid formulation comprises about 23% to about 27% by weight of an ibuprofen, about 13% to about 17% by weight of diethylene glycol monoethyl ether, about 25% to about 30%> by weight of glyceryl monolinoleate, about 25% to about 30% of an oil, and about 4% to about 8% of an alcohol.
  • a liquid formulation comprises about 24% to about 26% by weight of an ibuprofen, about 14% to about 16% by weight of diethylene glycol monoethyl ether, about 26% to about 28% by weight of glyceryl monolinoleate, about 26% to about 28% of an oil, and about 5% to about 7% of an alcohol.
  • an ibuprofen may be a free acid of a salt of ibuprofen.
  • an oil is rapeseed oil or theobroma oil.
  • a liquid formulation comprises a therapeutic compound, an ester of an alcohol, and an oil.
  • a liquid formulation comprises about 1 % to about 10% by weight of therapeutic compound, about 1 % to about 10% by weight of an ester of an alcohol, and about 80% to about 98% of an oil.
  • a liquid formulation comprises about 2% to about 8% by weight of therapeutic compound, about 1 % to about 7% by weight of an ester of an alcohol, and about 85% to about 97% of an oil.
  • a liquid formulation comprises about 3% to about 7% by weight of therapeutic compound, about 2% to about 6% by weight of an ester of an alcohol, and about 87% to about 95% of an oil.
  • a liquid formulation comprises about 4% to about 6% by weight of therapeutic compound, about 3% to about 5% by weight of an ester of an alcohol, and about 90% to about 92% of an oil.
  • an oil is rapeseed oil or theobroma oil.
  • a liquid formulation comprises a therapeutic compound, an ethyl acetate, and an oil.
  • a liquid formulation comprises about 1 % to about 10% by weight of therapeutic compound, about 1 % to about 10% by weight of an ethyl acetate, and about 80% to about 98% of an oil. In another aspect of this embodiment, a liquid formulation comprises about 2% to about 8% by weight of therapeutic compound, about 1 % to about 7% by weight of an ethyl acetate, and about 85% to about 97% of an oil. In yet another aspect of this embodiment, a liquid formulation comprises about 3% to about 7% by weight of therapeutic compound, about 2% to about 6% by weight of an ethyl acetate, and about 87% to about 95% of an oil.
  • a liquid formulation comprises about 4% to about 6% by weight of therapeutic compound, about 3% to about 5% by weight of an ethyl acetate, and about 90% to about 92% of an oil.
  • an oil is rapeseed oil or theobroma oil.
  • a liquid formulation comprises an ibuprofen, an ethyl acetate, and an oil.
  • a liquid formulation comprises about 1 % to about 10% by weight of an ibuprofen, about 1 % to about 10% by weight of an ethyl acetate, and about 80% to about 98% of an oil.
  • a liquid formulation comprises about 2% to about 8% by weight of an ibuprofen, about 1 % to about 7% by weight of an ethyl acetate, and about 85% to about 97% of an oil.
  • a liquid formulation comprises about 3% to about 7% by weight of an ibuprofen, about 2% to about 6% by weight of an ethyl acetate, and about 87% to about 95% of an oil.
  • a liquid formulation comprises about 4% to about 6% by weight of an ibuprofen, about 3% to about 5% by weight of an ethyl acetate, and about 90% to about 92% of an oil.
  • an ibuprofen may be a free acid of a salt of ibuprofen.
  • an oil is rapeseed oil or theobroma oil.
  • a solid or semi-solid formulation disclosed herein is formulated without a hydrophilic solvent like water. Such formulations result in the formation of co-crystals of the lipids and therapeutic compound. Stated another way, such formulations do not form liposomal emulsions and/or micellular particles, which require hydrophilic solvent.
  • a solid formulation comprises a therapeutic compound, a hard fat, a partiaily- hydrogenated fat, and a polyethylene glycol.
  • a solid formulation comprises about 1 % to about 30% by weight of therapeutic compound, about 8% to about 70% by weight of hard fat, about 2% to about 65% by weight of partiaily-hydrogenated fat, and about 1 % to about 15% of polyethylene glycol.
  • a solid formulation comprises about 10% to about 30% by weight of therapeutic compound, about 20% to about 50% by weight of hard fat, about 10% to about 30% by weight of partiaily-hydrogenated fat, and about 5% to about 15% of polyethylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 30% to about 50% by weight of hard fat, about 10% to about 30% by weight of partiaily-hydrogenated fat, and about 7% to about 13% of polyethylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 35% to about 50% by weight of hard fat, about 15% to about 25% by weight of partially-hydrogenated fat, and about 7% to about 13% of polyethylene glycol.
  • a solid formulation comprises about 23% to about 27% by weight of therapeutic compound, about 41 % to about 47% by weight of hard fat, about 18% to about 22% by weight of partially- hydrogenated fat, and about 9% to about 1 1 % of polyethylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a solid formulation comprises a therapeutic compound, a mixture of mono-, di- and triglycerides and PEG fatty acid esters, a glyceryl monoiinoleate, and a polyethylene glycol.
  • a solid formulation comprises about 1 % to about 30% by weight of therapeutic compound, about 8% to about 70% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 2% to about 65% by weight of a glyceryl monoiinoleate, and about 1 % to about 15% of polyethylene glycol.
  • a solid formulation comprises about 10% to about 30% by weight of therapeutic compound, about 20% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monoiinoleate, and about 5% to about 15% of polyethylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 30% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monoiinoleate, and about 7% to about 13% of polyethylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 35% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 15% to about 25% by weight of a glyceryl monoiinoleate, and about 7% to about 13% of polyethylene glycol.
  • a solid formulation comprises about 23% to about 27% by weight of therapeutic compound, about 41 % to about 47% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 18% to about 22% by weight of a glyceryl monoiinoleate, and about 9% to about 1 1 % of polyethylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a solid formulation comprises an ibuprofen, a mixture of mono- di-, and triglycerides and PEG fatty acid esters, a glyceryl monoiinoleate, and a polyethylene glycol.
  • a solid formulation comprises about 1 % to about 30% by weight of an ibuprofen, about 8% to about 70% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 2% to about 65% by weight of a glyceryl monoiinoleate, and about 1 % to about 15% of polyethylene glycol.
  • a solid formulation comprises about 10% to about 30% by weight of an ibuprofen, about 20% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monoiinoleate, and about 5% to about 5% of polyethylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of an ibuprofen, about 30% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monolinoleate, and about 7% to about 13% of polyethylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of an ibuprofen, about 35% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 15% to about 25% by weight of a glyceryl monolinoleate, and about 7% to about 13% of polyethylene glycol.
  • a solid formulation comprises about 23% to about 27% by weight of an ibuprofen, about 41 % to about 47% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 18% to about 22% by weight of a glyceryl monolinoleate, and about 9% to about 1 1 % of polyethylene glycol.
  • a polyethylene glycol is, e.g. , a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a solid formulation comprises a therapeutic compound, a hard fat, a partially-hydrogenated fat, a polyethylene glycol, and a propylene glycol.
  • a solid formulation comprises about 1 % to about 30% by weight of therapeutic compound, about 8% to about 70% by weight of hard fat, about 2% to about 65% by weight of partially-hydrogenated fat, about 1 % to about 15% of polyethylene glycol, and about 1 % to about 15% of propylene glycol.
  • a solid formulation comprises about 10% to about 30% by weight of therapeutic compound, about 20% to about 50% by weight of hard fat, about 10% to about 30% by weight of partially-hydrogenated fat, about 5% to about 15% of polyethylene glycol, and about 5% to about 15% of propylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 30% to about 50% by weight of hard fat, about 10% to about 30% by weight of partially-hydrogenated fat, about 7% to about 13% of polyethylene glycol, and about 7% to about 13% of propylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 35% to about 50% by weight of hard fat, about 15% to about 25% by weight of partially-hydrogenated fat, about 7% to about 13% of polyethylene glycol, and about 7% to about 13% of propylene glycol.
  • a solid formulation comprises about 23% to about 27% by weight of therapeutic compound, about 41 % to about 47% by weight of hard fat, about 18% to about 22% by weight of partially- hydrogenated fat, about 9% to about 1 1 % of polyethylene glycol, and about 9% to about 1 1 % of propylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a solid formulation comprises a therapeutic compound, a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, a glyceryl monolinoleate, a polyethylene glycol, and a propylene glycol.
  • a solid formulation comprises about 1 % to about 30% by weight of therapeutic compound, about 8% to about 70% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 2% to about 65% by weight of a glyceryl monolinoleate, about 1 % to about 15% of polyethylene glycol, and about 1 % to about 15% of propylene glycol.
  • a solid formulation comprises about 10% to about 30% by weight of therapeutic compound, about 20% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monolinoleate, about 5% to about 15% of polyethylene glycol, and about 5% to about 15%o of propylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 30% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monolinoleate, and about 7% to about 13% of polyethylene glycol, and about 7% to about 13% of propylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of therapeutic compound, about 35% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 15% to about 25% by weight of a glyceryl monolinoleate, about 7% to about 13% of polyethylene glycol, and about 7% to about 13% of propylene glycol.
  • a solid formulation comprises about 23% to about 27%) by weight of therapeutic compound, about 41 % to about 47% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 18% to about 22% by weight of a glyceryl monolinoleate, about 9% to about 11 % of polyethylene glycol, and about 9% to about 1 1 % of propylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a solid formulation comprises an ibuprofen, a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, a glyceryl monolinoleate, a polyethylene glycol, and a propylene glycol.
  • a solid formulation comprises about 1 % to about 30% by weight of an ibuprofen, about 8% to about 70% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 2% to about 65% by weight of a glyceryl monolinoleate, about 1 % to about 15% of polyethylene glycol, and about 1 % to about 15%) of propylene glycol.
  • a solid formulation comprises about 10% to about 30% by weight of an ibuprofen, about 20% to about 50%) by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10%) to about 30%) by weight of a glyceryl monolinoleate, about 5% to about 15% of polyethylene glycol, and about 5% to about 15%) of propylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of an ibuprofen, about 30% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of a glyceryl monolinoleate, and about 7% to about 13% of polyethylene glycol, and about 7% to about 13% of propylene glycol.
  • a solid formulation comprises about 20% to about 30% by weight of an ibuprofen, about 35% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 15% to about 25% by weight of a glyceryl monolinoleate, about 7% to about 13% of polyethylene glycol, and about 7% to about 13% of propylene glycol.
  • a solid formulation comprises about 23% to about 27% by weight of an ibuprofen, about 41 % to about 47% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 18% to about 22% by weight of a glyceryl monolinoleate, about 9% to about 1 1 % of polyethylene glycol, and about 9% to about 1 1 % of propylene glycol.
  • a polyethylene glycol is, e.g. , a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a semi-solid formulation comprises a therapeutic compound, a hard fat, a partially-hydrogenated fat, a polyethylene glycol, and a propylene glycol.
  • a semi-solid formulation comprises about 15% to about 55% by weight of therapeutic compound, about 7% to about 20% by weight of hard fat, about 20% to about 50% by weight of partially- hydrogenated fat, about 7% to about 20% of polyethylene glycol, and about 1 % to about 8% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of therapeutic compound, about 8% to about 18% by weight of hard fat, about 25% to about 45% by weight of partially-hydrogenated fat, about 8% to about 18% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of therapeutic compound, about 10% to about 16% by weight of hard fat, about 25% to about 45% by weight of partially-hydrogenated fat, about 10% to about 16% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of therapeutic compound, about 1 1 % to about 15% by weight of hard fat, about 30% to about 40% by weight of partially- hydrogenated fat, about 1 1 % to about 15% of polyethylene glycol, and about 3% to about 5% of propylene glycol.
  • a semi-solid formulation comprises about 25% to about 44% by weight of therapeutic compound, about 12% to about 14% by weight of hard fat, about 32% to about 39% by weight of partially-hydrogenated fat, about 12% to about 14% of polyethylene glycol, and about 4% of propylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a semi-solid formulation comprises a therapeutic compound, a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, a glyceryl monolinoleate, a polyethylene glycol, and a propylene glycol.
  • a semi-solid formulation comprises about 15% to about 55% by weight of therapeutic compound, about 7% to about 20% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 20% to about 50% by weight of a glyceryl monolinoleate, about 7% to about 20% of polyethylene glycol, and about 1 % to about 8% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of therapeutic compound, about 8% to about 18% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 25% to about 45% by weight of a glyceryl monolinoleate, about 8% to about 18% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of therapeutic compound, about 10% to about 16% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 25% to about 45% by weight of a glyceryl monolinoleate, about 10% to about 16% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of therapeutic compound, about 1 1 % to about 15% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 30% to about 40% by weight of a glyceryl monolinoleate, and about 1 1 % to about 15% of polyethylene glycol, and about 3% to about 5% of propylene glycol.
  • a semi-solid formulation comprises about 25% to about 44% by weight of therapeutic compound, about 12% to about 14% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 32% to about 39% by weight of a glyceryl monolinoleate, about 12% to about 14% of polyethylene glycol, and about 4% of propylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a semi-solid formulation comprises an ibuprofen, a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, a glyceryl monolinoleate, a polyethylene glycol, and a propylene glycol.
  • a semi-solid formulation comprises about 15% to about 55% by weight of an ibuprofen, about 7% to about 20% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 20% to about 50% by weight of a glyceryl monolinoleate, about 7% to about 20% of polyethylene glycol, and about 1 % to about 8% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of an ibuprofen, about 8% to about 18% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 25% to about 45% by weight of a glyceryl monolinoleate, about 8% to about 18% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 50% by weight of an ibuprofen, about 10% to about 16% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 25% to about 45% by weight of a glyceryl monolinoleate, about 10% to about 16% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semisolid formulation comprises about 20% to about 50% by weight of an ibuprofen, about 1 1 % to about 15% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 30% to about 40% by weight of a glyceryl monolinoleate, and about 1 1 % to about 15% of polyethylene glycol, and about 3% to about 5% of propylene glycol.
  • a semi-solid formulation comprises about 25% to about 44% by weight of an ibuprofen, about 12% to about 14% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 32% to about 39% by weight of a glyceryl monolinoleate, about 12% to about 14% of polyethylene glycol, and about 4% of propylene glycol.
  • a polyethylene glycol is, e.g. , a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a semi-solid formulation comprises a therapeutic compound, a hard fat, a partially-hydrogenated fat, a polyethylene glycol, and a propylene glycol.
  • a semi-solid formulation comprises about 10% to about 35% by weight of a free acid of a therapeutic compound, about 1 % to about 30% by weight of a salt of a therapeutic compound, about 7% to about 20% by weight of hard fat, about 20% to about 50% by weight of partially-hydrogenated fat, about 7% to about 20% of polyethylene glycol, and about 1 % to about 8% of propylene glycol.
  • a semi-solid formulation comprises about 15% to about 30% by weight of a free acid of a therapeutic compound, about 1 % to about 25% by weight of a salt of a therapeutic compound, about 10% to about 16% by weight of hard fat, about 25% to about 45% by weight of partially- hydrogenated fat, about 10% to about 16% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 15% to about 30% by weight of a free acid of a therapeutic compound, about 1 % to about 25% by weight of a salt of a therapeutic compound, about 1 1 % to about 15% by weight of hard fat, about 30% to about 40% by weight of partially-hydrogenated fat, about 11 % to about 15% of polyethylene glycol, and about 3% to about 5% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 24% by weight of a free acid of a therapeutic compound, about 5% to about 20% by weight of a salt of a therapeutic compound, about 12% to about 1 % by weight of hard fat, about 32% to about 39% by weight of partially-hydrogenated fat, about 12% to about 14% of polyethylene glycol, and about 4% of propylene glycol.
  • a polyethylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a semi-solid formulation comprises a therapeutic compound, a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, a glyceryl monolinoleate, a polyethylene glycol, and a propylene glycol.
  • a semi-solid formulation comprises about 10% to about 35% by weight of a free acid of a therapeutic compound, about 1 % to about 30% by weight of a salt of a therapeutic compound, about 7% to about 20% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 20% to about 50% by weight of a glyceryl monolinoleate, about 7% to about 20% of polyethylene glycol, and about 1 % to about 8% of propylene glycol.
  • a semi-solid formulation comprises about 15% to about 30% by weight of a free acid of a therapeutic compound, about 1 % to about 25% by weight of a salt of a therapeutic compound, about 10% to about 16% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 25% to about 45% by weight of a glyceryl monolinoleate, about 10% to about 16% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 15% to about 30% by weight of a free acid of a therapeutic compound, about 1 % to about 25% by weight of a salt of a therapeutic compound, about 11 % to about 15% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 30% to about 40% by weight of a glyceryl monolinoleate, and about 1 1 % to about 15% of polyethylene glycol, and about 3% to about 5% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 24% by weight of a free acid of a therapeutic compound, about 5% to about 20% by weight of a salt of a therapeutic compound, about 12% to about 14% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 32% to about 39% by weight of a glyceryl monolinoleate, about 12% to about 14% of polyethylene glycol, and about 4% of propylene glycol.
  • a polyethylene glycol is, e.g. , a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a semi-solid formulation comprises an ibuprofen, a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, a glyceryl monolinoleate, a polyethylene glycol, and a propylene glycol.
  • a semi-solid formulation comprises about 10% to about 35% by weight of a free acid of an ibuprofen, about 1 % to about 30% by weight of a salt of an ibuprofen, about 7% to about 20% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 20% to about 50% by weight of a glyceryl monolinoleate, about 7% to about 20% of polyethylene glycol, and about 1 % to about 8% of propylene glycol.
  • a semi-solid formulation comprises about 15% to about 30% by weight of a free acid of an ibuprofen, about 1 % to about 25% by weight of a salt of an ibuprofen, about 10% to about 16% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 25% to about 45% by weight of a glyceryl monolinoleate, about 10% to about 16% of polyethylene glycol, and about 2% to about 6% of propylene glycol.
  • a semi-solid formulation comprises about 15% to about 30% by weight of a free acid of an ibuprofen, about 1 % to about 25% by weight of a salt of an ibuprofen, about 1 1 % to about 15% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 30% to about 40% by weight of a glyceryl monolinoleate, and about 1 1 % to about 15% of polyethylene glycol, and about 3% to about 5% of propylene glycol.
  • a semi-solid formulation comprises about 20% to about 24% by weight of a free acid of an ibuprofen, about 5% to about 20% by weight of a salt of an ibuprofen, about 12% to about 14% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters, about 32% to about 39% by weight of a glyceryl monolinoleate, about 12% to about 14% of polyethylene glycol, and about 4% of propylene glycol.
  • a polyethylene glycol is, e.g. , a PEG 100, a PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG 700.
  • a solid or semi-solid formulation disclosed herein takes advantage of the different melting point temperatures of the various adjuvants like fatty acids. Formation of a solid or semi-solid dosage form can be by modifying the respective concentrations of the fatty acids comprising a pharmaceutical composition disclosed herein.
  • linolenic acid has a melting point temperature (T m ) of about -1 1 °C
  • linoleic acid has a T m of about -5°C
  • oleic acid has a T m of about 16°C
  • palmitic acid has a T m of about 61-62°C
  • Stearic acid has a T m of about 67-72°C.
  • a pharmaceutical composition disclosed herein can be made that is substantially solid or semi-solid at room temperature, but melts when it is ingested, and reaches body temperature.
  • the resulting melted composition readily forms micelles which are absorbed by the intestine, assembled into chylomicrons, and ultimately absorbed by macrophages.
  • the solid dosage form may be a powder, granule, tablet, capsule or suppository.
  • a pharmaceutical composition disclosed herein is solid at room temperature.
  • a pharmaceutical composition disclosed herein may be formulated to be a solid at a temperature of, e.g. , about 35°C or lower, about 33°C or lower, about 31 °C or lower, about 29°C or lower, about 27°C or lower, about 25°C or lower, about 23°C or lower, about 21 °C or lower, about 19°C or lower, about 17°C or lower, about 15°C or lower, about 12°C or lower, about 10°C or lower, about 8°C or lower, about 6°C or lower, about 4°C or lower, or about 0°C or lower.
  • a pharmaceutical composition disclosed has a melting point temperature of, e.g. , 5 °C or higher, 10 °C or higher, 15 °C or higher, 22°C or higher, 23°C or higher, 24°C or 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.
  • a pharmaceutical 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.
  • 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 to about 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 a chronic inflammation.
  • the method comprises the step of administering to an individual in need thereof a pharmaceutical composition disclosed herein, wherein administration reduces a symptom associated with the chronic inflammation, thereby treating the individual.
  • aspects of the present specification disclose, in part, treating an individual suffering from a chronic inflammation.
  • the term “treating,” refers to reducing or eliminating in an individual a clinical symptom of a chronic inflammation; or delaying or preventing in an individual the onset of a clinical symptom of a chronic inflammation.
  • the term “treating” can mean reducing a symptom of a condition characterized by a chronic inflammation by, e.g.
  • the actual symptoms associated with chronic inflammation are well known and can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the location of the chronic inflammation, the cause of the chronic inflammation, the severity of the chronic inflammation, and/or the tissue or organ affected by the chronic inflammation. Those of skill in the art will know the appropriate symptoms or indicators associated with a specific type of chronic inflammation and will know how to determine if an individual is a candidate for treatment as disclosed herein.
  • Chronic inflammation symptoms include, without limitation, edema, hyperemia, erythema, bruising, tenderness, stiffness, swollenness, fever, chills, stuffy nose, stuffy head, breathing problems, fluid retention, blood clots, loss of appetite, increased heart rate, formation of granulomas, fibrinous, pus, non-viscous serous fluid, or ulcer and pain.
  • the actual symptoms associated with a chronic inflammation are well known and can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the location of the inflammation, the cause of the inflammation, the severity of the inflammation, the tissue or organ affected, and the associated disorder.
  • granulomatous inflammation is an inflammation resulting from the formation of granulomas arising from a limited but diverse number of diseases, include, without limitation, tuberculosis, leprosy, sarcoidosis, and syphilis.
  • Purulent inflammation is an inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation.
  • Serous inflammation is an inflammation resulting from copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma. Skin blisters exemplify this pattern of inflammation. Ulcerative inflammation is an inflammation resulting from the necrotic loss of tissue from the epithelial surface, exposing lower layers and forming an ulcer.
  • a chronic inflammation symptom can be associated with a large, unrelated group of disorders which underlay a variety of diseases and disorders.
  • the immune system is often involved with chronic inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation.
  • Non-immune diseases with etiological origins in chronic inflammatory processes include cancer, atherosclerosis, and ischaemic heart disease.
  • Non-limiting examples of disorders exhibiting chronic inflammation as a symptom include, without limitation, acne, acid reflux/heartburn, age related macular degeneration (AMD), allergy, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis
  • a chronic inflammation comprises a tissue inflammation.
  • Tissue inflammation is a chronic inflammation that is confined to a particular tissue or organ.
  • a tissue inflammation comprises, e.g., a skin inflammation, a muscle inflammation, a tendon inflammation, a ligament inflammation, a bone inflammation, a cartilage inflammation, a lung inflammation, a heart inflammation, a liver inflammation, a pancreatic inflammation, a kidney inflammation, a bladder inflammation, a stomach inflammation, an intestinal inflammation, a neuron inflammation, and a brain inflammation.
  • a chronic inflammation comprises a systemic inflammation.
  • systemic inflammation is not confined to a particular tissue but in fact overwhelms the body, involving the endothelium and other organ systems.
  • sepsis is applied, with the terms bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis.
  • Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
  • a chronic inflammation comprises an arthritis.
  • Arthritis includes a group of conditions involving damage to the joints of the body due to the inflammation of the synovium including, without limitation osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies like ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple disease and Behcet disease, septic arthritis, gout (also known as gouty arthritis, crystal synovitis, metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease. Arthritis can affect a single joint (monoarthritis), two to four joints (oligoarthritis) or five or more joints (polyarthritis) and can be either an auto-immune disease or a non- autoimmune disease.
  • a chronic inflammation comprises an autoimmune disorder.
  • Autoimmune diseases can be broadly divided into systemic and organ-specific autoimmune disorders, depending on the principal clinico-pathologic features of each disease.
  • Systemic autoimmune diseases include, without limitation, systemic lupus erythematosus (SLE), Sjogren's syndrome, Scleroderma, rheumatoid arthritis and polymyositis.
  • Local autoimmune diseases may be endocrinologic (Diabetes Mellitus Type 1 , Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus vulgaris), hematologic (autoimmune haemolytic anemia), neural (multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.
  • endocrinologic Diabetes Mellitus Type 1 , Hashimoto's thyroiditis, Addison's disease etc.
  • dermatologic pemphigus vulgaris
  • hematologic autoimmune haemolytic anemia
  • neural multiple sclerosis
  • Types of autoimmune disorders include, without limitation, acute disseminated encephalomyelitis (ADEM), Addison's disease, an allergy or sensitivity, amyotrophic lateral sclerosis, anti-phospholipid antibody syndrome (APS), arthritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune pancreatitis, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's thyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, inflammatory bowel disease, interstitial cystitis, lupus (including discoid lupus erythematosus, drug- induced l
  • a chronic inflammation comprises a myopathy.
  • Myopathies are caused when the immune system inappropriately attacks components of the muscle, leading to inflammation in the muscle.
  • a myopathy includes an inflammatory myopathy and an auto-immune myopathy.
  • Myopathies include, without limitation, dermatomyositis, inclusion body myositis, and polymyositis.
  • a chronic inflammation comprises a vasculitis.
  • Vasculitis is a varied group of disorders featuring inflammation of a vessel wall including lymphatic vessels and blood vessels like 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 arteries and/or veins.
  • the inflammation may be focal, meaning that it affects a single location within a vessel; or it may be widespread, with areas of inflammation scattered throughout a particular organ or tissue, or even affecting more than one organ system in the body.
  • Vasculitis include, without limitation, Buerger's disease (thromboangiitis 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 (allergic vasculitis), Kawasaki disease, microscopic polyarteritis/polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu arteritis, Wegener's granulomatosis, and vasculitis secondary to connective tissue disorders like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), relapsing polychondritis, Behcet
  • a chronic inflammation comprises a skin disorder.
  • Skin disorders include, without limitation, an acne, including acne vulgaris, a bullous phemigoid, a dermatitis, including atopic dermatitis and chronic actinic dermatitis, an eczema like atopic eczema, contact eczema, xerotic eczema, seborrhoeic dermatitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis, neurodermatitis, and autoeczematization, and statis dermatitis, hidradenitis suppurativa, lichen planus, psoriasis including plaqure psoriasis, nail psoriasis, guttate psoriasis, scalp psoriasis, inverse psoriasis, pustular
  • a chronic inflammation comprises a gastrointestinal disorder.
  • a gastrointestinal disorder includes, without limitation, irritable bowel disease, an inflammatory bowel disease including Crohn's disease and an ulcerative colitis like ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis.
  • a chronic inflammation comprises a cardiovascular disease. When LDL cholesterol becomes embedded in arterial walls, it can invoke an immune response. Chronic inflammation eventually can damage the arteries, which can cause them to burst. Cardiovascular disease is any of a number of specific diseases that affect the heart itself and/or the blood vessel system, especially the veins and arteries leading to and from the heart.
  • cardiovascular disorders including, without limitation, a hypertension, endocarditis, myocarditis, heart valve dysfunction, congestive heart failure, myocardial infarction, a diabetic cardiac conditions, blood vessel inflammation like arteritis, phlebitis, vasculitis; arterial occlusive disease like arteriosclerosis and stenosis, inflammatory cardiomegaly, a peripheral arterial disease; an aneurysm; an embolism; a dissection; a pseudoaneurysm; a vascular malformation; a vascular nevus; a thrombosis; a thrombphlebitis; a varicose veins; a stroke.
  • a hypertension endocarditis, myocarditis, heart valve dysfunction, congestive heart failure, myocardial infarction, a diabetic cardiac conditions, blood vessel inflammation like arteritis, phlebitis, vasculitis; arterial occlusive disease like arteriosclerosis and steno
  • Symptoms of a cardiovascular disorder affecting the heart include, without limitation, chest pain or chest discomfort (angina), pain in one or both arms, the left shoulder, neck, jaw, or back, shortness of breath, dizziness, faster heartbeats, nausea, abnormal heartbeats, feeling fatigued.
  • Symptoms of a cardiovascular disorder affecting the brain include, without limitation, sudden numbness or weakness of the face, arm, or leg, especially on one side of the body, sudden confusion or trouble speaking or understanding speech, sudden trouble seeing in one or both eyes, sudden dizziness, difficulty walking, or loss of balance or coordination, sudden severe headache with no known cause.
  • Symptoms of a cardiovascular disorder affecting the legs, pelvis and/or arm include, without limitation, claudication, which is a pain, ache, or cramp in the muscles, and cold or numb feeling in the feet or toes, especially at night.
  • a chronic inflammation comprises a cancer.
  • Inflammation orchestrates the microenvironment around tumors, contributing to proliferation, survival and migration.
  • fibrinous inflammation results from a large increase in vascular permeability which allows fibrin to pass through the blood vessels.
  • an appropriate procoagulative stimulus such as cancer cells, a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.
  • a cancer is an inflammatory cancer like a NF-KB-driven inflammatory cancer.
  • a chronic inflammation comprises a pharmacologically-induced inflammation.
  • Certain drugs or exogenic chemical compounds are known to affect inflammation.
  • Vitamin A deficiency causes an increase in an inflammatory response.
  • Certain illicit drugs such as cocaine and ecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. NF-KB).
  • a chronic inflammation comprises an infection.
  • An infectious organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels.
  • An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis.
  • lymphadenitis An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis.
  • a pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system. Infections include, without limitation, bacterial cystitis, bacterial encephalitis, pandemic influenza, viral encephalitis, and viral hepatitis (A, B and C).
  • a chronic inflammation comprises a tissue or organ injury.
  • Tissue or organ injuries include, without limitation, a burn, a laceration, a wound, a puncture, or a trauma.
  • a chronic inflammation comprises a transplant rejection.
  • Transplant rejection occurs when a transplanted organ or tissue is not accepted by the body of the transplant recipient because the immune system of the recipient attacks the transplanted organ or tissue.
  • An adaptive immune response, transplant rejection is mediated through both T cell mediated and humoral immune (antibodies) mechanisms.
  • a transplant rejection can be classified as a hyperacute rejection, an acute rejection, or a chronic rejection.
  • Chronic rejection of a transplanted organ or tissue is where the rejection is due to a poorly understood chronic inflammatory and immune response against the transplanted tissue.
  • GVHD graft-versus-host disease
  • GVHD is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack. It can also take place in a blood transfusion under certain circumstances. GVHD is divided into acute and chronic forms. Acute and chronic GVHD appear to involve different immune cell subsets, different cytokine profiles, somewhat different host targets, and respond differently to treatment.
  • a chronic inflammation comprises a Th1 -mediated inflammatory disease.
  • an immune response should result in a well balanced proinflammatory Th1 response and anti-inflammatory Th2 response that is suited to address the immune challenge.
  • Th2 type cytokines such as, e.g. , IL-4, IL-5, and IL-13 which are associated with the promotion of IgE and eosinophilic responses in atopy, and also IL-10, which has an anti-inflammatory response.
  • Th1 -mediated inflammatory disease involves an excessive pro-inflammatory response produced by Th1 cells that leads to chronic inflammation.
  • the Th1 -mediated disease may be virally, bacterially or chemically (e.g. environmentally) induced.
  • a virus causing the Th1-mediated disease may cause a chronic or acute infection, which may cause a respiratory disorder or influenza.
  • a chronic inflammation comprises a chronic neurogenic inflammation.
  • Chronic neurogenic Inflammation refers to an inflammatory response initiated and/or maintained through the release of inflammatory molecules like SP or CGRP which released from peripheral sensory nerve terminals (; ' .e., an efferent function, in contrast to the normal afferent signaling to the spinal cord in these nerves).
  • Chronic neurogenic inflammation includes both primary inflammation and secondary neurogenic inflammation.
  • primary neurogenic inflammation refers to tissue inflammation (inflammatory symptoms) that is initiated by, or results from, the release of substances from primary sensory nerve terminals (such as C and A-delta fibers).
  • secondary neurogenic inflammation refers to tissue inflammation initiated by non-neuronal sources (e.g. , extravasation from vascular bed or tissue interstitium-derived, such as from mast cells or immune cells) of inflammatory mediators, such as peptides or cytokines, stimulating sensory nerve terminals and causing a release of inflammatory mediators from the nerves.
  • inflammatory mediators such as peptides or cytokines
  • the net effect of both forms (primary and secondary) of chronic neurogenic inflammation is to have an inflammatory state that is maintained by the sensitization of the peripheral sensory nerve fibers.
  • the physiological consequence of the resulting chronic neurogenic inflammation depends on the tissue in question, producing, such as, e.g. , cutaneous pain (allodynia, hyperalgesia), joint pain and/or arthritis, visceral pain and dysfunction, pulmonary dysfunction (asthma, COPD), and bladder dysfunction (pain, overactive bladder).
  • a composition or compound is administered to an individual.
  • An individual is typically a human being.
  • any individual who is a candidate for a conventional chronic inflammation treatment is a candidate for a chronic inflammation treatment disclosed herein.
  • Pre-operative evaluation typically includes routine history and physical examination in addition to thorough informed consent disclosing all relevant risks and benefits of the procedure.
  • a pharmaceutical composition disclosed herein may comprise a therapeutic compound in a therapeutically effective amount.
  • the term "effective amount” is synonymous with “therapeutically effective amount", “effective dose”, or “therapeutically effective dose” and when used in reference to treating a chronic inflammation refers to the minimum dose of a therapeutic compound disclosed herein necessary to achieve the desired therapeutic effect and includes a dose sufficient to reduce a symptom associated with a chronic inflammation.
  • the effectiveness of a therapeutic compound disclosed herein in treating a chronic inflammation can be determined by observing an improvement in an individual based upon one or more clinical symptoms, and/or physiological indicators associated with the condition. An improvement in a chronic inflammation also can be indicated by a reduced need for a concurrent therapy.
  • the appropriate effective amount of a therapeutic compound disclosed herein to be administered to an individual for a particular chronic inflammation can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, the type of chronic inflammation, the location of the chronic inflammation, the cause of the chronic inflammation, the severity of the chronic inflammation, the degree of relief desired, the duration of relief desired, the particular therapeutic compound used, the rate of excretion of the therapeutic compound used, the pharmacodynamics of the therapeutic compound used, the nature of the other compounds to be included in the composition, the particular formulation, the particular route of administration, the particular characteristics, history and risk factors of the patient, such as, e.g. , age, weight, general health and the like, or any combination thereof.
  • an effective amount of a therapeutic compound will further depend upon factors, including, without limitation, the frequency of administration, the half-life of the therapeutic compound, or any combination thereof.
  • an effective amount of a therapeutic compound disclosed herein can be extrapolated from in vitro assays and in vivo administration studies using animal models prior to administration to humans.
  • a therapeutically effective amount of a therapeutic compound disclosed herein reduces a symptom associated with a chronic inflammation by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%.
  • a therapeutically effective amount of a therapeutic compound disclosed herein reduces a symptom associated with a chronic inflammation by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%.
  • a therapeutically effective amount of a therapeutic compound disclosed herein reduces a symptom associated with a chronic inflammation by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.
  • a therapeutically effective amount of a therapeutic compound disclosed herein generally is in the range of about 0. 001 mg/kg/day to about 100 mg/kg/day.
  • 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 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day.
  • an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25 mg/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 1 mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 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 one skilled in the art.
  • treatment of a chronic inflammation may comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein.
  • treatment of a chronic inflammation may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g. , once daily, twice daily, trice daily, once every few days, or once weekly.
  • the timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms.
  • an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.
  • a person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.
  • Various routes of administration can be useful for administering a therapeutic compound disclosed herein, according to a method of treating a chronic inflammation disclosed herein.
  • a pharmaceutical composition may be administered to an individual by any of a variety of means depending, e.g., on the type of the chronic inflammation to be treated, the location of the chronic inflammation to be treated, the specific therapeutic compound or composition used, or other compound to be included in the composition, and the history, risk factors and symptoms of the individual.
  • topical, enteral or parenteral routes of administration may be suitable for of treating a chronic inflammation disclosed herein and such routes include both local and systemic delivery of a therapeutic compound or composition disclosed herein.
  • compositions comprising either a single therapeutic compound disclosed herein, or two or more therapeutic compounds disclosed herein are intended for inhaled, topical, intranasal, sublingual, injection, infusion, instillation, rectal and/or vaginal use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • a pharmaceutical composition comprising a therapeutic compound disclosed herein results in a bio-distribution of the therapeutic compound different than a bio-distribution of the therapeutic compound included in the same pharmaceutical composition, except without an adjuvant disclosed herein.
  • a therapeutic compound of the pharmaceutical composition disclosed herein upon administration to an individual, is delivered to a macrophage.
  • Macrophages are one of the key cell types believed to be involved in the control of the inflammation response.
  • the resultant high level of a therapeutic compound having anti-inflammatory activity present in the macrophages results in a clinically effective treatment of chronic inflammation.
  • a therapeutically effective amount of a therapeutic compound of the pharmaceutical composition disclosed herein upon administration to an individual, is preferentially delivered to a macrophage.
  • a therapeutic compound of the pharmaceutical composition disclosed herein upon administration to an individual, is substantially delivered to a macrophage.
  • the amount of a therapeutic compound of the pharmaceutical composition disclosed herein delivered to a macrophage is, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition.
  • the amount of a therapeutic compound of the pharmaceutical composition disclosed herein delivered to a macrophage is in a range of, e.g., about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%, about
  • a therapeutic compound of the pharmaceutical composition disclosed herein upon administration to an individual, is delivered to a dentritic cell.
  • Dendritic cells are one of the key cell types believed to coordinate the interplay between innate and adaptive immunity.
  • the resultant high level of a therapeutic compound having anti-pain activity present in the dentritic cells results in a clinically effective treatment of chronic inflammation.
  • a therapeutically effective amount of a therapeutic compound of the pharmaceutical composition disclosed herein upon administration to an individual, is preferentially delivered to a dentritic cell.
  • a therapeutic compound of the pharmaceutical composition disclosed herein upon administration to an individual, is substantially delivered to a dentritic cell.
  • the amount of a therapeutic compound of the pharmaceutical composition disclosed herein delivered to a dentritic cell is, e.g. , at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition.
  • the amount of a therapeutic compound of the pharmaceutical composition disclosed herein delivered to a dentritic cell is in a range of, e.g. , about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%
  • a pharmaceutical composition disclosed herein upon administration to an individual, reduces gastric irritation. In an aspect of this embodiment, a pharmaceutical composition disclosed herein substantially reduces gastric irritation. In yet another embodiment, upon administration to an individual, a pharmaceutical composition disclosed herein reduces gastric irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In an aspect of this embodiment, a pharmaceutical composition disclosed herein substantially reduces gastric irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces gastric irritation by, e.g.
  • At least 5% at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
  • a pharmaceutical composition disclosed herein reduces gastric irritation in a range of, e.g., about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70% 70%, about 30% to about
  • a pharmaceutical composition disclosed herein upon administration to an individual, reduces intestinal irritation. In an aspect of this embodiment, a pharmaceutical composition disclosed herein substantially reduces intestinal irritation. In yet another embodiment, upon administration to an individual, a pharmaceutical composition disclosed herein reduces intestinal irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In an aspect of this embodiment, a pharmaceutical composition disclosed herein substantially reduces intestinal irritation when compared to the same pharmaceutical composition disclosed herein, except without the pharmaceutically-acceptable adjuvant. In other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces intestinal irritation by, e.g.
  • a pharmaceutical composition disclosed herein reduces intestinal irritation by, e.g.
  • a pharmaceutical composition disclosed herein can also be administered to an individual in combination with other therapeutic compounds to increase the overall therapeutic effect of the treatment.
  • the use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
  • a pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeutic compound has an anti-inflammatory activity; and b) a pharmaceutically-acceptable adjuvant.
  • the pharmaceutical composition according to embodiment 1 wherein the composition further comprises a pharmaceutically-acceptable solvent.
  • a pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeutic compound has an anti-inflammatory activity; b) a pharmaceutically-acceptable solvent; and c) a pharmaceutically-acceptable adjuvant.
  • a pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeutic compound has an anti-inflammatory activity; b) a pharmaceutically-acceptable solvent; and c) a pharmaceutically-acceptable adjuvant, wherein the ratio of the pharmaceutically-acceptable solvent to pharmaceutically-acceptable adjuvant is in a range from about 0:1 to about 1 :25.
  • the pharmaceutical composition according to embodiments 1 -5, wherein the anti-inflammatory activity reduces the level of an inflammation inducing molecule.
  • the pharmaceutical composition according to embodiment 6, wherein the inflammation inducing molecule comprises substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof.
  • the pharmaceutical composition according to embodiment 7, wherein the anti-inflammatory activity reduces the level of SP, CGRP, glutamate, or a combination thereof by at least 10%.
  • the pharmaceutical composition according to embodiments 1 -8, wherein the anti-inflammatory activity reduces the level of an inflammation inducing prostaglandin.
  • the pharmaceutical composition according to embodiments 1 -10, wherein the anti-inflammatory activity stimulates a PPAR signaling pathway.
  • the pharmaceutical composition according to embodiment 1 1 wherein the PPAR signaling pathway is stimulated by at least 10%.
  • the pharmaceutical composition according to embodiments 1-12, wherein the anti-inflammatory activity induces apoptosis of Macrophage M1 cells, promotes differentiation of Macrophage M2 cells, or both.
  • IFNy Interferon-gamma
  • TNF-a Tumor necrosis factor-alpha
  • IL-12 lnterleukin-12
  • NSAID non-steroidal anti-inflammatory drug
  • 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 thereof.
  • COX non-selective cyclo-oxygenase
  • COX 1 selective cyclooxygenase 1
  • COX 2 selective cyclooxygenase 2
  • RAR Retinoic Acid Receptor
  • RXR Retinoid X Receptor
  • LXR Liver X Receptor
  • Vitamin D binding agent or a combination thereof.
  • the anti-hyperlipidemic agent comprises a fibrate, a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, a sympathomimetic amine, or a combination thereof.
  • the fibrate comprises Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a combination thereof.
  • statin comprises Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof.
  • niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof.
  • bile acid sequestrant comprises Cholestyramine, Colesevelam, Colestipol, or a combination thereof.
  • cholesterol absorption inhibitor comprises Ezetimibe, a phytosterol, a sterol, a stanol, or a combination thereof.
  • the fat absorption inhibitor comprises Orlistat
  • the sympathomimetic amine comprises Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamfetamine, cathine, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4- methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof.
  • the pharmaceutical composition according to embodiment 42 wherein the pharmaceutically- acceptable alcohol comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.
  • the pharmaceutical composition according to embodiment 42, wherein the pharmaceutically- acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1 -hexadecanol, or a combination thereof.
  • composition according to embodiment 46 wherein the pharmaceutically- acceptable ester comprises methyl acetate, methyl buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1 -hexadecyl acetate, 1 -hexadecyl buterate, and 1 -hexadecyl formate, or a combination thereof.
  • compositions 1 -47 wherein the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable glycol ether, a pharmaceutically- acceptable diol, a pharmaceutically-acceptable propylene glycol, a pharmaceutically-acceptable dipropylene glycol, a pharmaceutically-acceptable polypropylene glycol (PPG) polymer, a pharmaceutically-acceptable polyethylene glycol (PEG) polymer, or any combination thereof.
  • the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable glycol ether, a pharmaceutically- acceptable diol, a pharmaceutically-acceptable propylene glycol, a pharmaceutically-acceptable dipropylene glycol, a pharmaceutically-acceptable polypropylene glycol (PPG) polymer, a pharmaceutically-acceptable polyethylene glycol (PEG) polymer, or any combination thereof.
  • PPG polypropylene glycol
  • PEG polyethylene glycol
  • composition according to embodiment 48 wherein the pharmaceutically- acceptable glycol ether comprises diethylene glycol monomethyl ether (2-(2-methoxyethoxy)ethanol), diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), diethylene glycol monopropyl ether (2- (2-propoxyethoxy)ethanol), diethylene glycol monoisopropyl ether (2-(2-isopropoxyethoxy)ethanol), diethylene glycol mono-n-butyl ether (2-(2-butoxyethoxy)ethanol), or any combination thereof.
  • the pharmaceutically- acceptable glycol ether comprises diethylene glycol monomethyl ether (2-(2-methoxyethoxy)ethanol), diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), diethylene glycol monopropyl ether (2- (2-propoxyethoxy)ethanol), diethylene glycol monoisopropyl ether (2-(2-isopropoxyethoxy)ethanol), diethylene glycol mono-n-but
  • the pharmaceutical composition according to embodiment 48 wherein the pharmaceutically- acceptable polypropylene glycol (PPG) polymer or the pharmaceutically-acceptable polyethylene glycol (PEG) polymer is less than about 2,000 g/mol.
  • the pharmaceutical composition according to embodiments 1 -51 wherein the pharmaceutically- acceptable solvent comprises a pharmaceutically-acceptable glyceride.
  • the pharmaceutical composition according to embodiment 52 wherein the pharmaceutically- acceptable glyceride comprises a monoglyceride, a diglyceride, a triglyceride, an acetylated monoglyceride, an acetylated diglyceride, an acetylated triglyceride, or a combination thereof.
  • the pharmaceutical composition according to embodiments 1 -53 wherein the pharmaceutically- acceptable solvent is a liquid at 20°C or wherein the pharmaceutically-acceptable solvent is a solid at 20°C.
  • the pharmaceutical composition according to embodiment 61 wherein the two or more saturated or unsaturated fatty acids includes palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof.
  • the pharmaceutical composition according to embodiments 60-62 wherein the unsaturated fatty acid has a melting point temperature of 20°C or below or wherein the unsaturated fatty acid is a solid at 20°C.
  • the pharmaceutical composition according to embodiments 60-62, wherein the unsaturated fatty acid comprises an omega fatty acid.
  • composition according to embodiment 65 wherein the pharmaceutically- acceptable oil comprises almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, theobroma oil, walnut oil, wheat germ oil, or a combination thereof.
  • the pharmaceutically- acceptable oil comprises almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, theobroma oil, walnut oil, wheat germ oil, or a combination thereof.
  • composition according to embodiment 59 wherein the pharmaceutically- acceptable lipid comprises a pharmaceutically-acceptable glycerolipid, a pharmaceutically-acceptable glycol fatty acid ester, a pharmaceutically-acceptable polyether fatty acid ester, a mixture of pharmaceutically-acceptable lipids, or any combination thereof.
  • composition according to embodiments 1 -67, wherein the pharmaceutical composition further comprises a pharmaceutically-acceptable stabilizing agent.
  • composition according to embodiment 68 wherein the pharmaceutically- acceptable stabilizing agent comprises water, a sacrificial acid comprising a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid, a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated diglyceride, a fatty acid, a fatty acid salt, or a combination thereof.
  • a sacrificial acid comprising a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid, a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated diglyceride, a fatty acid, a fatty acid salt, or a combination thereof.
  • composition according to embodiment 68 wherein the pharmaceutically- acceptable stabilizing agent comprises a pharmaceutically-acceptable emulsifying agent.
  • composition according to embodiment 70 wherein the pharmaceutically- acceptable emulsifying agent comprises a surfactant, a polysaccharide, a lectin, a phospholipid, or a combination thereof.
  • a method of preparing a pharmaceutical composition comprising the step of contacting a therapeutic compound with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.
  • a method of preparing a pharmaceutical composition comprising the steps: a) contacting a pharmaceutically-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the solution formed in step (a) with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition.
  • a method of preparing a pharmaceutical composition comprising the steps: a) contacting a pharmaceutically-acceptable solvent with a therapeutic compound under conditions which allow the therapeutic compound to dissolve in the pharmaceutically-acceptable solvent, thereby forming a solution, wherein the therapeutic compound has anti-inflammatory activity, and b) contacting the solution formed in step (a) with a pharmaceutically-acceptable adjuvant under conditions which allow the formation of the pharmaceutical composition, wherein the ratio of the pharmaceutically-acceptable solvent to pharmaceutically-acceptable adjuvant is in a range from about 0: 1 to about 1 :25.
  • the therapeutic compound has a logP value indicating that the compound is soluble in an organic solvent.
  • NSAID nonsteroidal anti-inflammatory drug
  • 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 thereof.
  • COX non-selective cyclo-oxygenase
  • the PPARy agonist comprises Monascin, Irbesartan, Telmisartan, mycophenolic acid, Resveratrol, Delta(9)-tetrahydrocannabinol, a cannabidiol, Curcumin, Cilostazol, Benzbromarone, 6-shogaol, glycyrrhetinic acid, a thiazolidinedione, a NSAID, a fibrate, or a combination thereof.
  • the nuclear receptor binding agent comprises a Retinoic Acid Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor (LXR) binding agent, a Vitamin D binding agent, or a combination thereof.
  • RAR Retinoic Acid Receptor
  • RXR Retinoid X Receptor
  • LXR Liver X Receptor
  • Vitamin D binding agent or a combination thereof.
  • the anti-hyperlipidemic agent comprises a fibrate, a statin, a tocotrienol, a niacin, a bile acid sequestrants (resin), a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, a sympathomimetic amine, or a combination thereof.
  • the fibrate comprises Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a combination thereof.
  • statin comprises Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof.
  • niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof.
  • bile acid sequestrant comprises Cholestyramine, Colesevelam, Colestipol, or a combination thereof.
  • the cholesterol absorption inhibitor comprises Ezetimibe, a phytosterol, a sterol, a stanol, or a combination thereof.
  • the sympathomimetic amine comprises Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamfetamine, cathine, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV), 4- methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof.
  • the pharmaceutically-acceptable solvent comprises a pharmaceutically-acceptable polar aprotic solvent, a pharmaceutically-acceptable polar protic solvent, a pharmaceutically-acceptable non-polar solvent, or a combination thereof.
  • the pharmaceutically-acceptable alcohol comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.
  • the pharmaceutically-acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1 -hexadecanol, or a combination thereof.
  • the pharmaceutically-acceptable solvent comprises a pharmaceutically-acceptable ester of pharmaceutically-acceptable alcohol and an acid.
  • the pharmaceutically-acceptable ester comprises methyl acetate, methyl buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1 -hexadecyl acetate, 1 -hexadecyl buterate, and 1-hexadecyl formate, or a combination thereof.
  • the method according to embodiments 73-117, wherein the pharmaceutically-acceptable adjuvant comprises a pharmaceutically-acceptable lipid.
  • the pharmaceutically-acceptable lipid comprises a pharmaceutically-acceptable saturated fatty acid, an unsaturated fatty acid, or a combination thereof.
  • the pharmaceutically-acceptable lipid comprises two or more pharmaceutically-acceptable saturated or unsaturated fatty acids.
  • the two or more pharmaceutically-acceptable saturated or unsaturated fatty acids include palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof.
  • the method according to embodiments 1 19-121 wherein the pharmaceutically-acceptable unsaturated fatty acid has a melting point temperature of 20°C or below.
  • the method according to embodiments 119-121 wherein the pharmaceutically-acceptable unsaturated fatty acid is a solid at 20°C.
  • the pharmaceutically-acceptable oil comprises almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or a combination thereof.
  • step(b) The method according to embodiments 74 or 76-126, wherein in step(b) the ratio of the pharmaceutically-acceptable solvent to pharmaceutically-acceptable adjuvant is in a range from about 0: 1 to about 1 :25.
  • step (a) further comprising contacting a pharmaceutically-acceptable stabilizing agent with the pharmaceutically-acceptable solvent and the therapeutic compound.
  • the pharmaceutically-acceptable stabilizing agent comprises water, a sacrificial acid comprising a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid, a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated diglyceride, a fatty acid, a fatty acid salt, or a combination thereof.
  • the pharmaceutically-acceptable emulsifying agent comprises a surfactant, a polysaccharide, a lectin, a phospholipid, or a combination thereof.
  • a method of treating an individual with a chronic inflammation comprising the step of: administering to the individual in need thereof a pharmaceutical composition according to embodiments 1 -72, wherein administration results in a reduction in a symptom associated with the chronic inflammation, thereby treating the individual.
  • arthritis is an osteoarthritis, a rheumatoid arthritis, a juvenile idiopathic arthritis, a septic arthritis, a spondyloarthropathy, a gout, a pseudogout, or Still's disease.
  • spondyloarthropathy is an ankylosing spondylitis, a reactive arthritis (Reiter's syndrome), a psoriatic arthritis, an enteropathic arthritis associated with inflammatory bowel disease, a Whipple disease or a Behcet disease.
  • autoimmune disorder is a systemic autoimmune disorder or an organ-specific autoimmune disorder.
  • the autoimmune disorder is an acute disseminated encephalomyelitis (ADEM), an Addison's disease, an allergy, an anti- phospholipid antibody syndrome (APS), an autoimmune hemolytic anemia, an autoimmune hepatitis, an autoimmune inner ear disease, a bullous pemphigoid, a celiac disease, a Chagas disease, a chronic obstructive pulmonary disease (COPD), a diabetes mellitus type 1 (IDDM), an endometriosis, a Goodpasture's syndrome, a Graves' disease, a Guillain-Barre syndrome (GBS), a Hashimoto's thyroiditis, a hidradenitis suppurativa, an idiopathic thrombocytopenic purpura, an inflammatory bowel disease, an interstitial cystitis, a lupus (including a discoid lupus ery
  • ADAM acute disseminated encephalomy
  • myopathy is a dermatomyositis, an inclusion body myositis, or a polymyositis.
  • vasculitis is a Buerger's disease, an arteritis, a cerebral 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, a Kawasaki disease, a phlebitis, a microscopic polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, a thrombophlebitis, a Wegener's granulomatosis, or a vasculitis secondary to connective
  • the skin disorder is a dermatitis, an eczema, a statis dermatitis, a hidradenitis suppurativa, a psoriasis, a rosacea or a scleroderma.
  • eczema is an atopic eczema, a contact eczema, a xerotic eczema, a seborrhoeic dermatitis, a dyshidrosis, a discoid eczema, a venous eczema, a dermatitis herpetiformis, a neurodermatitis, or an autoeczematization.
  • psoriasis is a plaqure psoriasis, a nail psoriasis, a guttate psoriasis, a scalp psoriasis, an inverse psoriasis, a pustular psoriasis, or an erythrodermis psoriasis.
  • the cardiovascular disease is a hypertension, heart valve dysfunction, congestive heart failure, myocardial infarction, a diabetic cardiac conditions, a blood vessel inflammation, arterial occlusive disease, a peripheral arterial disease, an aneurysm, an embolism, a dissection, a pseudoaneurysm, a vascular malformation, a vascular nevus, a thrombosis, a thrombphlebitis, a varicose veins, or a stroke.
  • the cardiovascular disease is a hypertension, heart valve dysfunction, congestive heart failure, myocardial infarction, a diabetic cardiac conditions, a blood vessel inflammation, arterial occlusive disease, a peripheral arterial disease, an aneurysm, an embolism, a dissection, a pseudoaneurysm, a vascular malformation, a vascular nevus, a thrombosis, a thrombphlebitis, a varicose veins, or
  • the infection is a bacterial cystitis, a bacterial encephalitis, a pandemic influenza, a viral encephalitis, a viral hepatitis A, a viral hepatitis B, or a viral hepatitis C.
  • the amount of the therapeutic compound of the pharmaceutical composition according to embodiments 1-72 delivered to a macrophage is at least 5% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition.
  • the pharmaceutical composition according to embodiments 1 -72 reduces intestinal irritation by at least 5% when compared to the pharmaceutical composition according to embodiments 1-72, except without the pharmaceutically-acceptable adjuvant.
  • the pharmaceutical composition according to embodiments 1 -72 reduces gastric irritation by at least 5% when compared to the pharmaceutical composition according to embodiments 1 -72, except without the pharmaceutically-acceptable adjuvant.
  • a solid pharmaceutical composition comprising: a) about 10% to 30% by weight of a non-steroidal anti-inflammatory drug (NSAID), wherein the NSAID has an anti-inflammatory activity; b) about 20% to about 50% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters; c) about 10% to about 30% by weight of a glyceryl monolinoleate, and d) about 5% to about 15% of a PEG.
  • NSAID non-steroidal anti-inflammatory drug
  • solid pharmaceutical composition according to any one of embodiments 176-181 , wherein the solid pharmaceutical composition further comprises about 5% to about 15% propylene glycol.
  • a liquid pharmaceutical composition comprising: a) about 15% to about 35% by weight of nonsteroidal anti-inflammatory drug (NSAID), wherein the NSAID has an anti-inflammatory activity; b) about 5% to about 25% by weight of diethylene glycol monoethyl ether; c) about 15% to about 40% by weight of a glyceryl monolinoleate; and d) about 15% to about 40% of an oil.
  • NSAID nonsteroidal anti-inflammatory drug
  • liquid pharmaceutical composition according to any one of embodiments 184-186, wherein the glyceryl monolinoleate is about 20% to about 35% by weight of the pharmaceutical composition.
  • liquid pharmaceutical composition according to any one of embodiments 184-187, wherein the oil is about 20% to about 35% by weight of the pharmaceutical composition.
  • liquid pharmaceutical composition according to any one of embodiments 184-188, wherein the NSAID is about 23% to about 27% by weight of the pharmaceutical composition, the diethylene glycol monoethyl ether is about 13% to about 17% by weight of the pharmaceutical composition, the glyceryl monolinoleate is about 25% to about 30% by weight of the pharmaceutical composition, and the oil is about 25% to about 30% by weight of the pharmaceutical composition.
  • the liquid pharmaceutical composition according to any one of embodiments 184-189, wherein the liquid pharmaceutical composition further comprises about 2% to about 10% of an alcohol.
  • liquid pharmaceutical composition according to embodiment 190, wherein the alcohol is ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1 ,2 propan-diol, or methanol.
  • liquid pharmaceutical composition according to any one of embodiments 184-191 , wherein the NSAID is about 23% to about 27% by weight of the pharmaceutical composition, the diethylene glycol monoethyl ether is about 13% to about 17% by weight of the pharmaceutical composition, the glyceryl monolinoleate is about 25% to about 30% by weight of the pharmaceutical composition, the oil is about 25% to about 30% by weight of the pharmaceutical composition, and the alcohol is about 4% to about 8% by weight of the pharmaceutical composition.
  • the NSAID is about 23% to about 27% by weight of the pharmaceutical composition
  • the diethylene glycol monoethyl ether is about 13% to about 17% by weight of the pharmaceutical composition
  • the glyceryl monolinoleate is about 25% to about 30% by weight of the pharmaceutical composition
  • the oil is about 25% to about 30% by weight of the pharmaceutical composition
  • the alcohol is about 4% to about 8% by weight of the pharmaceutical composition.
  • a semi-solid pharmaceutical composition comprising: a) about 20% to about 50% by weight of nonsteroidal anti-inflammatory drug (NSAID), wherein the NSAID has an anti-inflammatory activity; b) about 8% to about 18% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters; c) about 25% to about 45% by weight of a glyceryl monolinoleate; d) about 8% to about 18% of a PEG; and e) about 2% to about 6% of a propylene glycol.
  • NSAID nonsteroidal anti-inflammatory drug
  • the semi-solid pharmaceutical composition according to any one of emmbodiments 193-195, wherein the NSAID is about 25% to about 44% by weight of the pharmaceutical composition, the mixture of mono-, di-, and triglycerides and PEG fatty acid esters is about 12% to about 14% by weight of the pharmaceutical composition, the glyceryl monolinoleate is about 32% to about 39% by weight of the pharmaceutical composition, the PEG is about 12% to about 14% by weight of the pharmaceutical composition, and the propylene glycol is about 3% to about 5% by weight of the pharmaceutical composition.
  • the NSAID is about 25% to about 44% by weight of the pharmaceutical composition
  • the mixture of mono-, di-, and triglycerides and PEG fatty acid esters is about 12% to about 14% by weight of the pharmaceutical composition
  • the glyceryl monolinoleate is about 32% to about 39% by weight of the pharmaceutical composition
  • the PEG is about 12% to about 14% by weight of the pharmaceutical composition
  • a semi-solid pharmaceutical composition comprising: a) about 15% to about 30% by weight of a free acid of a non-steroidal anti-inflammatory drug (NSAID), wherein the NSAID has an anti-inflammatory activity; b) about 1 % to about 25% by weight of a salt of a NSAID, wherein the NSAID has an antiinflammatory activity; c) about 8% to about 18% by weight of a mixture of mono-, di-, and triglycerides and PEG fatty acid esters; d) about 25% to about 45% by weight of a glyceryl monolinoleate; e) about 8% to about 18% of a PEG; and f) about 2% to about 6% of a propylene glycol.
  • NSAID non-steroidal anti-inflammatory drug
  • This example illustrates how to make a pharmaceutical composition as disclosed herein as a liquid formulation.
  • ibuprofen remained insoluble in the oil and did not dissolve to substantially measureable degree. Ibuprofen remained insolubility even if the mixture was mixed by vortexing for 20 seconds, the contacting was done at 20°C or 37°C, and/or the mixture was allowed to incubate for 24 hours at 20°C or 37°C.
  • ibuprofen has a logP value of 3.6; such a high logP value is indicative of a compound that would readily soluble in an adjuvant like oil.
  • a therapeutic compound may be having some effect on the manner in which an adjuvant and solvent interact with each other, such that a homogeneous mixture is formed in a way that does not occur when the therapeutic compound is absent.
  • the results indicate that a therapeutic compound can be formulated at clinically useful concentrations.
  • This example illustrates how to make a pharmaceutical composition as disclosed herein as a liquid formulation.
  • a liquid pharmaceutical composition disclosed herein using ibuprofen was prepared. About 4 g ibuprofen was contacted with 3.6 mL of ethyl acetate, as the solvent, and the resulting solution was then contacted with 76.4 mL of rapeseed oil, as the adjuvant. The resulting pharmaceutical composition had a solven adjuvant ratio of about 1 :21. This pharmaceutical composition was then placed in a round bottom flask and subjected to low pressure on a rotary evaporator. The temperature was kept low and evaporation continued to constant weight. The total volume lost was 3.65% of the total weight. The resulting liquid no longer retained the characteristic ethyl acetate odor/taste, indicating that there was a substantial removal of ethyl acetate form the pharmaceutical composition.
  • This example illustrates how to make a pharmaceutical composition as disclosed herein as a solid formulation.
  • Formulation 2 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg of palmitic acid (T m of about 61 -62°C) and heated at 60°C for 30 minutes to form a homogeneous solution.
  • T m palmitic acid
  • Formulation 2 solidified about 1 hour after cooling to 22°C. Incubating at 37°C overnight cause Formulation 2 to completely melt into a clear homogenous liquid. However, Formulation 2 once again solidified about 1 hour after cooling to 22°C.
  • Formulation 3 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg of linoleic acid (T m of about -5°C) and heated at 37°C for 2 hours to form a homogeneous solution. Formulation 3 remained a liquid, even after cooling to 22°C for 72 hours.
  • Formulation 4 was prepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, and the resulting solution was then mixed with 200 mg of linolenic acid (T m of about -1 TC) and heated at 37°C for 2 hours to form a homogeneous solution. Formulation 4 remained a liquid, even after cooling to 22°C for 72 hours.
  • a solid dosage form of a pharmaceutical composition disclosed herein can be made.
  • a pharmaceutical composition will be formulated to be solid or semi-solid at 22°C, but melt into a proper clear solution (and not a suspension) at 37°C (Table 5).
  • ibuprofen To prepare a solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. About 15 g ibuprofen was contacted with about 9.0 mL of diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), as the solvent, about 33 g GELUCIRE ® 39/01 (Gattefosse), a waxy solid having a melting point of between 37°C to 41 °C and comprising a mixture of saturated C 0 - Ci8 triglycerides, as the adjuvant, and about 3.6 mL isopropanol.
  • diethylene glycol monoethyl ether 2-(2-ethoxyethoxy)ethanol
  • GELUCIRE ® 39/01 Gattefosse
  • a waxy solid having a melting point of between 37°C to 41 °C and comprising a mixture of saturated C 0 - Ci8 triglycerides, as the adjuvant, and about 3.6
  • the mixture was added to a vessel heated to about 40°C to about 50°C and stirred until all components of the mixture dissolved, cooled to about 30°C, and then aliquoted by poring into molds and cooled to room temperature.
  • the resulting pharmaceutical composition had a solventadjuvant ratio of about 1 :3.67.
  • This pharmaceutical composition produced 75 solid tablets each containing about 200 mg ibuprofen. [0206] To prepare a solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed.
  • ibuprofen was contacted with about 12.0 mL of diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), as the solvent, about 16 g GELUCIRE ® 43/01 (Gattefosse), a waxy solid having a melting point of between 41 °C to 45°C and comprising a mixture of saturated C 10 - Ci8 triglycerides, and about 16 g AISINE ® 35-1 (Gattefosse), a glyceryl monolinoleate, as the adjuvant, and about 3.6 mL isopropanol.
  • diethylene glycol monoethyl ether 2-(2-ethoxyethoxy)ethanol
  • the mixture was added to a vessel heated to about 40°C to about 50°C and stirred until all components of the mixture dissolved, cooled to about 30°C, and then aliquoted by poring into molds and cooled to room temperature.
  • the resulting pharmaceutical composition had a solventadjuvant ratio of about 1 :2.67.
  • This pharmaceutical composition produced 100 solid tablets each containing about 200 mg ibuprofen.
  • a solid pharmaceutical composition disclosed herein using ibuprofen the following method was performed. About 80 g ibuprofen, about 152 g GELUCIRE ® 43/01 (Gattefosse), a waxy solid having a melting point of between 41 °C to 45°C and comprising a mixture of saturated C 10 -C 18 triglycerides, and about 72 mL MAISINE ® 35-1 (Gattefosse), a glyceryl monolinoleate, and about 32 mL PEG 400 were added to a vessel heated to about 50°C to about 60°C and stirred until all components of the mixture dissolved. The heated mixture is cooled to about 40°C, and then aliquoted by poring into molds and cooled to room temperature. This pharmaceutical composition produced 400 solid tablets each containing about 200 mg ibuprofen.
  • a solid pharmaceutical composition disclosed herein using ibuprofen the following method was performed. About 1.1 g ibuprofen sodium salt, about 1.9 g GELUCIRE ® 43/01 (Gattefosse), a waxy solid having a melting point of between 41 °C to 45°C and comprising a mixture of saturated Ci 0 - Ci8 triglycerides, and about 0.9 mL MAISINE ® 35-1 (Gattefosse), a glyceryl monolinoleate, about 0.4 mL PEG 400, and about 0.3 mL propylene glycol were added to a vessel heated to about 50°C to about 60°C and stirred until all components of the mixture dissolved. The heated mixture is cooled to about 40°C, and then aliquoted by poring into molds and cooled to room temperature. This pharmaceutical composition produced 5 solid tablets each containing about 200 mg ibuprofen.
  • a solid pharmaceutical composition disclosed herein using ibuprofen the following method was performed. About 5 g ibuprofen free acid, about 5 g ibuprofen sodium salt, about 3 g GELUCIRE ® 43/01 (Gattefosse), a waxy solid having a melting point of between 41 °C to 45°C and comprising a mixture of saturated C 10 -C 18 triglycerides, and about 8 mL MAISINE ® 35-1 (Gattefosse), a glyceryl monolinoleate, about 3 mL PEG 400, and about 1 mL propylene glycol were added to a vessel heated to about 50°C to about 60°C and stirred until all components of the mixture dissolved. The heated mixture is cooled to about 40°C, and then aliquoted by poring into molds and cooled to room temperature.
  • This pharmaceutical composition produced 50 solid tablets each containing about 200 mg ibuprofen.
  • a semi-solid pharmaceutical composition disclosed herein using ibuprofen the following method was performed. About 1 g ibuprofen free acid, about 0.2 g ibuprofen sodium salt, about 0.6 g GELUCIRE ® 43/01 (Gattefosse), a waxy solid having a melting point of between 41 °C to 45°C and comprising a mixture of saturated C 10 -Ci 8 triglycerides, and about 1.6 mL MAISINE ® 35-1 (Gattefosse), a glyceryl monolinoleate, about 0.6 mL PEG 400, and about 0.15 mL propylene glycol were added to a vessel heated to about 50°C to about 60°C and stirred until all components of the mixture dissolved. The heated mixture is cooled to room temperature and aliquoited into an appropriate container.
  • This pharmaceutical composition produced a semisolid ointment having a concentration of ibuprofen that is about 400 mg/mL
  • a semi-solid pharmaceutical composition disclosed herein using ibuprofen the following method was performed. About 5 g ibuprofen free acid, about 5 g ibuprofen sodium salt, about 3 g GELUCIRE ® 43/01 (Gattefosse), a waxy solid having a melting point of between 41 °C to 45°C and comprising a mixture of saturated C 0 -C 18 triglycerides, and about 8 mL MAISINE ® 35-1 (Gattefosse), a glyceryl monolinoleate, about 3 mL PEG 400, and about 1 mL propylene glycol were added to a vessel heated to about 50°C to about 60°C and stirred until all components of the mixture dissolved. The heated mixture is cooled to room temperature and aliquoited into an appropriate container.
  • This pharmaceutical composition produced a semisolid ointment having a concentration of ibuprofen that is about 650 mg/mL.
  • 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 different treatments.
  • Group A was a control in which each mouse was orally administered 1 % methylcellulose/0.5% polysorbate 80 vehicle only.
  • Group B was a control in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil).
  • Group C was a control in which each mouse was orally administered 150 mg/kg aspirin.
  • Group D was a control in which each mouse was orally administered 100 mg/kg ibuprofen suspended in 1 % methylcellulose/0.5% polysorbate 80.
  • Group E was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054-100) comprising 100 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil.
  • Group F was a control in which each mouse was orally administered 100 mg/kg ibuprofen suspended in 1 % methylcellulose/0.5% polysorbate 80.
  • Group G was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054-200) comprising 200 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Animals were sacrificed 4 hours after treatment and the stomachs were examined for degree of hemorrhage and severity of mucosal erosive lesions.
  • Gastric irritation was scored as follows: 0, no lesions; 1 , hyperemia; 2, one or two slight lesions; 3, more than two slight lesions or severe lesions; and 4, very severe lesions. A score of 50% or more relative to Group C (aspirin-treated control group), which was set to 100%, was considered a positive score for gastric irritation.
  • Results are shown in Table 6.
  • Group D 100 mg/kg of ibuprofen-treated control group
  • Group F 200 mg/kg of ibuprofen-treated control group
  • Group E BC1054-100-treated experimental group
  • Group G BC1054-200-treated experimental group
  • results demonstrate that that a pharmaceutical composition disclosed herein reduced the extent to which a therapeutic compound may cause mucosal lesions and cause gastric irritation.
  • mice C57BLK 6 female mice (6-7 weeks old) were divided into three experimental groups containing ten animals each.
  • animals received an intranasal lethal dose (50 pL total, 25 pL/nostril) of Influenza A/PR/8/34 under halothane-induced anaesthesia.
  • Group A was a control in which each mouse was orally administered 335.6 pg of ibuprofen dissolved in 10 pL DMSO (no adjuvant).
  • Group B was a control in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil).
  • Group C was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054) 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 1200 mg/day for a human (the maximum standard dose for ibuprofen).
  • Animals were weighed, and monitored for signs cf infection daily for up to day 6 when all animals were culled.
  • Figure 1 clearly shows that oral administration of the solvent/adjuvant vehicle only (Group B) had an 80% mortality rate and that oral administration of ibuprofen only (Group A) exhibited a mortality rate of 60%.
  • a single oral administration of BC1054 reduced the mortality rate to only 20%.
  • IL-10 60 pL of detection antibody was diluted in assay diluent to each well. Plates were washed and 60pL of SAv-HRP enzyme was diluted in assay diluent and added to the plate. The plate was sealed and incubated for 20 minutes at room temperature. Plates were then washed ten times. 60 pL of substrate solution were added to each well and the plate was incubated for 30 minutes at room temperature in the dark. 60 pL of stop solution was added to each well and absorbance was read at 450 nm. IL-10 and IL-4 concentrations were expressed as pg/mg of lung tissue. These results indicate that a pharmaceutical composition disclosed herein was effective in treating a respiratory inflammation.
  • Results show that animals from the Group A (ibuprofen-treated control group) and Group B (solvent/adjuvant vehicle-treated control group) controls exhibited 2600 pg/mg and 2000 pg/mg of IL-10, respectively (FIG. 2A). However, Group C (BC1054-treated experimental group) revealed an IL-10 concentration of 6000 pg/mg, 3-fold higher than that seen in the control animals.
  • Group B was a control in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil) (no ibuprofen).
  • Group C was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054) comprising 335.6 pg of ibuprofen, 10% ethanol, and 90% linseed oil. Lungs collected from fatally- infected mice were homogenized at 4°C, and the supernatant collected, stored, and IL-10, TNFct and IFNy levels measured using an ELISA.
  • TNFa which is macrophage-related cytokine
  • IFNy which is a lymphocyte-derived cytokine
  • FIG. 3C This cytokine release pattern was associated with a poor outcome.
  • TNFa levels were markedly lowered (FIG 3B), while IFNy levels were largely unaffected (FIG 3C).
  • mice C57BI/6 male mice (6-7 weeks old) were divided into seven experimental groups containing at least ten animals each.
  • colitis was induced in mice from Groups B-G by intrarectal administration of 100 pL of TNBS (4 mg) in 50% ethanol under isoflurane anesthesia. Animals were dosed either once or three times a day from day -1 to day 5 with one of seven different treatments.
  • Group A was a control in which each mouse was orally administered ethanol vehicle only.
  • Group B was a control in which each mouse was orally administered 1 % methylcellulose vehicle only.
  • Group C was a control in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil).
  • Group D was a control in which each mouse was orally administered 3 mg/kg of Prednisolone.
  • Group E was a control in which each mouse was orally administered 20 mg/kg of ibuprofen suspended in 1 % methylcellulose (1 mL/kg) (no adjuvant).
  • Group F was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054- 20) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil.
  • Group G was the experimental group in which each mouse was administered a pharmaceutical composition disclosed herein (BC1054- 30) comprising 30 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil.
  • Results from these experiments are shown in Table 7.
  • Group B TNBS-treated control group
  • Group A untreated ethanol control group
  • All other group comparisons showed no difference in mean weight change.
  • Group B TNBS-treated control group
  • Group D Prednisolone-treated control group
  • Group F Group F
  • Group G Group G (BC1054-30-treated experimental group) all showed a statistically significant increase in mean colon length when compared to Group B (TNBS-treated control group).
  • Group B TNBS-treated control group
  • Group A untreated ethanol control group
  • All other group comparisons showed no difference in mean colon weight.
  • Group D Prednisolone-treated control group
  • Group G Group G
  • both Group F BC1054-20-treated experimental group
  • Group G BC1054-30-treated experimental group
  • a pharmaceutical composition disclosed herein was effective in treating an inflammatory bowel disease.
  • mice Male BALB/c mice were divided into eight groups, each containing 10 animals. To induce arthritic symptoms, mice from all eight groups were intravenously injected with 200 pL of an antibody solution comprising a 2 mg cocktail of four a-collagen II monoclonal antibodies (ARTHRITOMABTM, MD Biosciences) on study day 0 (study commencement), followed by a 200 pL intraperitoneal injection of a solution comrpsing 50 pg of lipopolysaccaride (LPS) at day 3. From day 3 and daily until day 8 and then on days 10 and 12, paw thickness (plethysmography) and arthritis scores were taken.
  • an antibody solution comprising a 2 mg cocktail of four a-collagen II monoclonal antibodies (ARTHRITOMABTM, MD Biosciences) on study day 0 (study commencement)
  • LPS lipopolysaccaride
  • Group A was a control in which each mouse was orally administered phosphor-buffered saline (PBS) vehicle only.
  • Group B was a control in which each mouse was intraperitoneally administered 10 mg/kg of etanercept (ENBREL ® , Wyeth) in PBS.
  • Group C was a control in which each mouse was orally administered 1 % methylcellulose vehicle only.
  • Group D was a control in which each mouse was orally administered 40 mg/kg of ibuprofen suspended in 1 % methylcellulose (1 mL/kg) (no adjuvant).
  • Group E was a control in which each mouse was orally administered solvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseed oil).
  • Group F was the experimental group in which each mouse was orally administered a pharmaceutical composition disclosed herein (BC1054-20) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil.
  • Group G was the experimental group in which each mouse was orally administered a pharmaceutical composition disclosed herein (BC1054-30) comprising 30 mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil.
  • the negative control Group A PBS vehicle-treated control group
  • Group C methoxycellulose vehicle-treated control group
  • Group E solvent/adjuvant vehicle-treated control group
  • Group D ibuprofen-treated control group
  • mice Male BALB/c mice were divided into eight groups, each containing 10 animals. To induce arthritic symptoms, mice from all eight groups were intravenously injected with 200 ⁇ _ of an antibody solution comprising a 2 mg cocktail of four a-collagen II monoclonal antibodies (ARTHRITOMABTM, MD Biosciences) on study day 0 (study commencement), followed by a 200 pL intraperitoneal injection of a solution containing 100 pg lipopolysaccharide (LPS) on study day 3.
  • ARTHRITOMABTM a-collagen II monoclonal antibodies
  • mice were treated orally with a vehicle preparation containing 1 % methyl cellulose administered thrice daily;
  • Group 2 mice (2M) were treated intraperitoneally with a positive control preparation containing 10mg/kg etanercept (ENBREL ® , Wyeth) administered once daily;
  • Group 3 mice were treated orally with a 20mg/kg test liquid formulation comprising ibuprofen and rapeseed oil (BC1054 LF-RO) administered once daily;
  • mice (4M) were treated orally with a 20mg/kg test liquid formulation comprising ibuprofen and rapeseed oil (BC1054 LF-RO) administered thrice daily;
  • Group 5 mice were treated orally with a 20mg/kg test liquid formulation comprising ibuprofen and a glyceryl monolinoleate (MAISINE ® 35-1 , Gattef
  • the arthritis score was based on visual assessment of arthritis reactions using a 0-4 scale in ascending order of severity with Grade 0 indicating no arthritis reaction; Grade 1 indicating mild, but definite redness and swelling of the ankle/wrist or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; Grade 2 indicating moderate to severe redness and swelling of the ankle/wrist; Grade 3 indicating redness and swelling of the entire paw including digits; and Grade 4 indicating maximally inflamed limb with involvement of multiple joints.
  • Paw thickness was measured for both hind paws just above the foot pad and below the calcaneum using a dial caliper (Kroeplin, Kunststoff, Germany). Mean values for paw thickness measurements were determined, and where appropriate, analysis of the data by ANOVA with Tukey post hoc analysis was applied to determine significance of treatment effects.
  • Clinical examinations included changes in body weight, condition of skin, fur, eyes, mucous membranes, occurrence of secretions and excretions (e.g. diarrhea), and autonomic activity (e.g. lacrimation, salivation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling, as well as the presence of unusual behavior, tremors, convulsions, sleep and coma were also noted. Serum was collected at study termination.
  • mice treated with BC1054 LS-MA had peak paw volume at day 7 (1.97 ⁇ 0.05 from 1.69 ⁇ 0.02 on day 0), this group had significantly reduced measurements on day 6 and day 9 when compared to the vehicle treated Group 1 M animals.
  • mean rear paw thickness began at 1.74 ⁇ 0.01 on day 0. This increased to a peak of 2.05 ⁇ 0.10 on day 7 before decreasing back to 1.94 ⁇ 0.06 on day 12.
  • No significant differences were recorded between BC1054 LS-TO-treated animals (Group 6M) and those treated with vehicle control (Group 1 M).
  • rear paw thickness was 1.71 ⁇ 0.02 on day 0.
  • a 47 year old female was diagnosed with reactive arthritis in one knee was treated with a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (1200 mg uid) over a 3 day period and found that the swelling and pain started to go away after 1 day and was completely better after 3 days. Ineffective standard ibuprofen treatment was subsequently ceased. At a 3 month follow up, no signs of the reactive arthritis have been observed.
  • BC1054 a pharmaceutical composition disclosed herein
  • a 50 year old male was diagnosed with a chronically inflamed ankle after a Hyundai neuve fracture in the ankle.
  • the patient was taking 30 mg codeine with 500 mg paracetamol bid, along with 10 mg diclofenac tid for 8 months to control pain.
  • He took a 5 day course of a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid) and after 2 days reported a significant improvement in his pain, and then after 3 days he reported that the pain was completely controlled. He has subsequently ceased the codeine, paracetamol and diclofenac, and after a 2 month follow the patient is still pain free.
  • a 33 year old female diagnosed with stress related eczema had an acute flare of moderate eczema on arms and chest.
  • a pharmaceutical composition disclosed herein comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (1200 mg uid) was administered for 7 days. After a couple of hours the lesion ceased itching, after 1 day a noticeable improvement in lesion swelling was reported. 2-3 days later the eczema lesions erythema had resolved and after 7 days the lesions had completely disappeared. In the past the patient had used emollients and hydrocortisone creams, which made the lesions worse and would often lead to a course of antibiotics. The patient commented that her response to the BC1054 treatment was quick and complete, and was a marked improvement on previously pharmacological therapies.
  • the patient experienced a flare of the reactive arthritis and commenced a 4 day course of a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid), experiencing complete remission of the arthritis.
  • BC1054 a pharmaceutical composition disclosed herein
  • the arthritis began to flare again and the patient was put on another 4 day treatment of BC1054, again experiencing complete remission. This time the arthritis flared again 1 week later. To account for this, the patient was given a final 10 day course of BC1054. Subsequently, the arthritis remained in remission for 11 months, as per the last examination.
  • a 49 year old male diagnosed with hypercholesterolemia (LDL of 4.35 mmol/L) was placed on a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid) for 7 days. After 5 days of treatment the patient's LDL levels had normalized to 3.89 mmol/L. The normalization of LDL level persisted for 2 months after cessation of BC1054 dosing, as determined at the last examination.
  • a 60 year old male newly diagnosed with hypercholesterolemia (LDL of 4.31 mmol/L) was given a course of a pharmaceutical composition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (1200 mg uid) to lower LDL levels to within the normal range.
  • BC1054 a pharmaceutical composition disclosed herein
  • the patients LDL levels were lowered to 3.36 mmol/L.
  • a 62 year old female complains of joint stiffness and swelling and is diagnosed with rheumatoid arthritis.
  • a physician determines that the joint stiffness and swelling is due to chronic inflammation.
  • the woman is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the woman's condition is monitored and after about 3 days of treatment the woman indicates there is reduced joint stiffness and swelling. At one and three month check-ups, the woman indicates that she continues to have reduced joint stiffness and swelling in the area treated.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any monoarthritis, oligoarthritis, or polyarthritis, such as, e.g.
  • osteoarthritis juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy (including ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple disease or Behcet disease), a synovitis, gout, pseudogout, or Still's disease, as well as, a bursitis, a rheumatic fever, or a tenosynovitis.
  • spondyloarthropathy including ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple disease or Behcet disease
  • a synovitis gout, pseudogout, or Still's disease, as well as, a bursitis, a rheumatic fever, or a tenosynovitis.
  • any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo- oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID e.g., 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
  • a 58 year old male complains of breathing difficulty and is diagnosed with chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a physician determines that the breathing difficulty is due to chronic inflammation.
  • the man is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the man's condition is monitored and after about 3 days of treatment the man indicates there is improvement in his ability to breath. At one and three month check-ups, the man indicates that he continues to have improved breathing.
  • This reduction in a chronic inflammation symptom indicates successful treatment with the pharmaceutical composition disclosed herein.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with an asthma, a bronchiolitis, a bronchitis, an emphysema, a laryngitis, a pharyngitis, a pleuritis, a pneumonitis, a rhinitis, a sinusitis, or any other type of chronic respiratory disorder.
  • any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a nonselective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID e.g., 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 nonselective cycl
  • a 67 year old male complains of muscle soreness and is diagnosed with dermatomyositis.
  • a physician determines that the soreness is due to chronic inflammation.
  • the man is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the man's condition is monitored and after about 3 days of treatment the man indicates there is reduced soreness.
  • a chronic inflammation symptom indicates successful treatment with the pharmaceutical composition disclosed herein.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with an inclusion body myositis, a myasthenia gravis, a polymyositis or any other type of inflammatory myopathy, as well as, a fasciitis, a fibrositis, a myositis, a neuromyotonia, a tendinosis, or a tendonitis.
  • any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID e.g., 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
  • a 73 year old female complains of wheezing when she breathes and is diagnosed with Churg- Strauss arteritis. A physician determines that the wheezing is due to chronic inflammation.
  • the woman is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the woman's condition is monitored and after about 3 days of treatment the woman indicates that she no longer is wheezing. At one and three month check-ups, the woman indicates that she still does not wheeze when she breathes.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any vasculitis, such as, e.g., a Buerger's disease, a cerebral vasculitis, a cryoglobulinemia, an essential cryoglobulinemic vasculitis, a giant cell arteritis, a Golfer's vasculitis, a Henoch-Schonlein purpura, a hypersensitivity vasculitis, a Kawasaki disease, a microscopic polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, or a Wegener's granulomatosis, as well as, an arteritis, a cardit
  • vasculitis such as, e.g., a Buer
  • any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID e.g., 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
  • a 37 year old male complains of skin redness and is diagnosed with rosacea.
  • a physician determines that the redness is due to chronic inflammation.
  • the man is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the man's condition is monitored and after about 3 days of treatment the man indicates there is reduced skin redness. At one and three month check-ups, the man indicates that he continues to have improved skin tone and reduced redness This reduction in a chronic inflammation symptom indicates successful treatment with the pharmaceutical composition disclosed herein.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with an acne, a cervicitis, a dermatitis, an eczema (including an atopic eczema, a contact eczema, a xerotic eczema, a seborrhoeic dermatitis, a dyshidrosis, a discoid eczema, a venous eczema, a dermatitis herpetiformis, a neurodermatitis, or an autoeczematization), an endometritis, a gingivitis, a glossitis, a hidradenitis suppurativa, a keratitis, a keratoconjunctivitis, a mastitis, a psoriasis (including a plaqure psoriasis, a nail
  • any of the therapeutic compounds such as, e.g. , a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID such as, e.g. , a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fena
  • a 33 year old female complains of abdominal pain and diarrhea and is diagnosed with Crohn's disease. A physician determines that the abdominal pain and diarrhea is due to chronic inflammation.
  • the woman is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the woman's condition is monitored and after about 3 days of treatment the woman indicates that there is a reduction in abdominal pain and she no longer has diarrhea. At one and three month check-ups, the woman indicates that she continues to have reduced abdominal pain and diarrhea.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from neurogenic inflammation associated with any inflammatory bowel disease, such as, e.g. , an ulcerative colitis (including ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis), any irritable bowel disease, as well as, a colitis, an enteritis, an enterocolitis, a gastritis, a gastroenteritis, a metabolic syndrome (syndrome X), a spastic colon, or any other gastrointestinal disorder.
  • any of the therapeutic compounds such as, e.g.
  • a salicylate derivative NSAID a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • COX non-selective cyclo-oxygenase
  • a 46 year old male complains of fever, joint pains, and fatigue and is diagnosed with systemic lupus erythematosus. A physician determines that these symptoms are due to chronic inflammation.
  • the man is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the man's condition is monitored and after about 3 days of treatment the man indicates there is improvement in his health, his fever is gone, the pain in his joints is reduced and his is not as tired.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any other systemic autoimmune disorder, including, without limitation, an anti-phospholipid antibody syndrome (APS), a bullous pemphigoid, a Chagas disease, a discoid lupus erythematosus, a drug-induced lupus erythematosus, a Goodpasture's syndrome, a Guillain-Barre syndrome, an idiopathic thrombocytopenic purpura, a myasthenia gravis, a neonatal lupus, a pernicious anemia, a polymyalgia rheumatica, a rheumatoid arthritis, a scleroderma,
  • APS anti-phospholipid antibody syndrome
  • APS anti-phospholipid antibody syndrome
  • Chagas disease a discoid lupus erythematosus
  • any of the therapeutic compounds such as, e.g., a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID e.g., 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
  • a 58 year old male complains of depression, sensitivity to cold, weight gain, forgetfulness, and constipation and is diagnosed with Hashimoto's thyroiditis. A physician determines that these symptoms are due to chronic inflammation.
  • the man is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the man is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the man's condition is monitored and after about 3 days of treatment the man indicates there is reduction in all the symptoms complained of.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any other local autoimmune disorder, including, without limitation, an acute disseminated encephalomyelitis (ADEM), an Addison's disease, an autoimmune hemolytic anemia, an autoimmune hepatitis (including primary biliary cirrhosis), an autoimmune inner ear disease, a celiac disease, a Crohn's disease, a diabetes mellitus type 1 , an endometriosis, a giant cell arteritis, a Graves' disease, an interstitial cystitis, a lupus nephritis, a multiple sclerosis, a morphea, a pemphigu
  • any of the therapeutic compounds such as, e.g. , a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID such as, e.g. , a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fena
  • a 59 year old female complains of joint stiffness and swelling and is diagnosed with reactive arthritis. A physician determines that the joint stiffness and swelling is due to chronic inflammation.
  • the woman is treated by oral administration a pharmaceutical composition comprising ibuprofen as disclosed herein taken twice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising aspirin as disclosed herein taken thrice daily.
  • the woman is treated by oral administration a pharmaceutical composition comprising naproxen as disclosed herein taken twice daily.
  • the woman's condition is monitored and after about 3 days of treatment the woman indicates there is reduced joint stiffness and swelling. At one and three month check-ups, the woman indicates that she continues to have reduced joint stiffness and swelling in the area treated.
  • a similar type of oral administration of a pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any monoarthritis, oligoarthritis, or polyarthritis, such as, e.g., osteoarthritis, juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy (including ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple disease or Behcet disease), a synovitis, gout, pseudogout, or Still's disease, as well as, a bursitis, a rheumatic fever, or a tenosynovitis.
  • any monoarthritis such as, e.g., osteoarthritis, juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy (including ankylosing spondylitis, reactive arthritis (Reiter's syndrome
  • any of the therapeutic compounds such as, e.g. , a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulated into a pharmaceutical composition and administered to the patient as described above.
  • a salicylate derivative NSAID such as, e.g. , a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017004142A1 (en) 2015-06-29 2017-01-05 Children's Medical Center Corporation Treatment for myopathy
US10004704B2 (en) 2010-10-29 2018-06-26 Infirst Healthcare Limited Compositions and methods for treating chronic inflammation and inflammatory diseases
US10143671B2 (en) 2010-10-29 2018-12-04 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US10155042B2 (en) 2010-10-29 2018-12-18 Infirst Healthcare Limited Compositions and methods for treating chronic inflammation and inflammatory diseases
US10213381B2 (en) 2010-10-29 2019-02-26 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US10363232B2 (en) 2010-10-29 2019-07-30 Infirst Healthcare Limited Compositions and methods for treating severe pain
US10695431B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US10695432B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in severe pain
WO2020247385A1 (en) * 2019-06-03 2020-12-10 Immunolux International Corp. Smallpox vaccine and stem cells for treatment of disease
RU2752764C1 (ru) * 2020-12-14 2021-08-03 Общество с ограниченной ответственностью "Тривиум-ХХI" (ООО "Тривиум-ХХI") Фармацевтическая композиция, обладающая противовоспалительным действием
RU2760220C1 (ru) * 2021-06-02 2021-11-22 Федеральное государственное бюджетное научное учреждение «Научно-исследовательский институт ревматологии имени В.А. Насоновой» (ФГБНУ НИИР им. В.А. Насоновой) Способ определения клинически значимой усталости у больного ревматоидным артритом на фоне 5-летней терапии базисными противовоспалительными препаратами или базисными противовоспалительными препаратами в комплексе с генно-инженерными биологическими препаратами и/или психофармакотерапией и сопутствующего расстройства тревожно-депрессивного спектра
US11202831B2 (en) 2010-10-29 2021-12-21 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US11224659B2 (en) 2010-10-29 2022-01-18 Infirst Healthcare Limited Solid solution compositions and use in severe pain
US11730709B2 (en) 2010-10-29 2023-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain
RU2814076C1 (ru) * 2023-05-03 2024-02-21 Григорий Константинович Сергеев Способ комплексной оценки результатов лечения остеомиелита бедренной кости у лабораторных крыс

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108283637A (zh) * 2018-04-04 2018-07-17 无锡市儿童医院 辛伐他汀的应用
WO2019195943A1 (en) * 2018-04-13 2019-10-17 Urban Juve Provisions Inc. Cannabis root extract, method of manufacture, method of use
EP4054549A4 (en) 2019-11-06 2023-12-06 Smartech Topical, Inc. TOPICAL FORMULATIONS OF CYCLO-OXYGENASE INHIBITORS AND THEIR USE
RU2749857C1 (ru) * 2019-12-23 2021-06-17 Псарева Нелли Александровна Способ борьбы со средним и наружным отитом

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2331458A (en) * 1997-11-21 1999-05-26 Gursharan Singh Moonga Solvent compositions for gelatin capsules
US6063768A (en) 1997-09-04 2000-05-16 First; Eric R. Application of botulinum toxin to the management of neurogenic inflammatory disorders
WO2000076478A1 (en) * 1999-06-14 2000-12-21 Cosmo S.P.A. Controlled release and taste masking oral pharmaceutical compositions
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
US6923988B2 (en) 1999-11-23 2005-08-02 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20060138059A1 (en) 2004-12-28 2006-06-29 Vair Larry L Jr Corona-treated polypropylene liquid filtration media
US20100099767A1 (en) * 2007-03-13 2010-04-22 Adrian Francis Davis Topical Pharmaceutical Formulation
US20110195993A1 (en) 2008-05-26 2011-08-11 Christophe Masson Ppar agonist compounds, preparation and uses
WO2012104655A2 (en) * 2011-02-04 2012-08-09 Biocopea Limited Compostions and methods for treating chronic inflammation and inflammatory diseases

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143934A (en) * 1990-11-21 1992-09-01 A/S Dumex (Dumex Ltd.) Method and composition for controlled delivery of biologically active agents
GB9613858D0 (en) * 1996-07-02 1996-09-04 Cortecs Ltd Hydrophobic preparations
BR9811058A (pt) * 1997-07-29 2000-09-05 Upjohn Co Formulação auto-emulsificante para compostos lipofìlicos
US8663692B1 (en) * 1999-05-07 2014-03-04 Pharmasol Gmbh Lipid particles on the basis of mixtures of liquid and solid lipids and method for producing same
AU4917900A (en) * 1999-05-07 2000-11-21 Pharmasol Gmbh Lipid particles on the basis of mixtures of liquid and solid lipids and method for producing same
US6455067B1 (en) * 2000-05-24 2002-09-24 Sang-A Pharmaceutical Co., Ltd. Transdermal patch for nonsteroidal antiinflammatory drug(s)
US20030105141A1 (en) * 2001-04-17 2003-06-05 Ping Gao Finely self-emulsifiable pharmaceutical composition
EP1651210A1 (en) * 2003-07-31 2006-05-03 Pharmacia & Upjohn Company LLC Dispersible formulation of an anti-inflammatory agent
BRPI0518484A2 (pt) * 2004-11-24 2008-11-18 Merck & Co Inc composiÇço, cÁpsula, e, processo para preparar a mesma
US20090041829A1 (en) * 2005-04-28 2009-02-12 Galenica Technology Ab Pharmaceutical dosage forms comprising a lipid phase
US20070249725A1 (en) * 2006-02-17 2007-10-25 Hubbard David R Pharmaceutical formulations of sympathetic antagonist for the treatment of chronic muscle pain

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6063768A (en) 1997-09-04 2000-05-16 First; Eric R. Application of botulinum toxin to the management of neurogenic inflammatory disorders
GB2331458A (en) * 1997-11-21 1999-05-26 Gursharan Singh Moonga Solvent compositions for gelatin capsules
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6451339B2 (en) 1999-02-26 2002-09-17 Lipocine, Inc. Compositions and methods for improved delivery of hydrophobic agents
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
WO2000076478A1 (en) * 1999-06-14 2000-12-21 Cosmo S.P.A. Controlled release and taste masking oral pharmaceutical compositions
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6923988B2 (en) 1999-11-23 2005-08-02 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20060138059A1 (en) 2004-12-28 2006-06-29 Vair Larry L Jr Corona-treated polypropylene liquid filtration media
US20100099767A1 (en) * 2007-03-13 2010-04-22 Adrian Francis Davis Topical Pharmaceutical Formulation
US20110195993A1 (en) 2008-05-26 2011-08-11 Christophe Masson Ppar agonist compounds, preparation and uses
WO2012104655A2 (en) * 2011-02-04 2012-08-09 Biocopea Limited Compostions and methods for treating chronic inflammation and inflammatory diseases

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALFONSO R. GENNARO: "REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 20th ed.", 2000, LIPPINCOTT, WILLIAMS & WILKINS
CSIZMAZIA E ET AL: "Penetration enhancer effect of sucrose laurate and Transcutol on ibuprofen", JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, ED. DE SANTÉ, FR, vol. 21, no. 5, September 2011 (2011-09-01), pages 411 - 415, XP009168551, ISSN: 1773-2247 *
HOWARD C. ANSEL ET AL.,: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
JOEL G. HARDMAN ET AL.,: "Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed.", 2001, MCGRAW-HILL PROFESSIONAL
RAYMOND C. ROWE ET AL.: "Handbook of Pharmaceutical Excipients 4th edition", 2003, APHA PUBLICATIONS

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US10973912B2 (en) 2015-06-29 2021-04-13 President And Fellows Of Harvard College Treatment for myopathy
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RU2760220C1 (ru) * 2021-06-02 2021-11-22 Федеральное государственное бюджетное научное учреждение «Научно-исследовательский институт ревматологии имени В.А. Насоновой» (ФГБНУ НИИР им. В.А. Насоновой) Способ определения клинически значимой усталости у больного ревматоидным артритом на фоне 5-летней терапии базисными противовоспалительными препаратами или базисными противовоспалительными препаратами в комплексе с генно-инженерными биологическими препаратами и/или психофармакотерапией и сопутствующего расстройства тревожно-депрессивного спектра
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