RU2680801C2 - Compositions and methods of treating chronic inflammation and inflammatory diseases - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: group of inventions relates to the chemical and pharmaceutical industry and provides a pharmaceutical composition with anti-inflammatory activity, consisting of: one or more nonsteroidal anti-inflammatory drugs (NSAIDs) in an amount of 10 % to 30 % by weight based on the weight of the pharmaceutical composition; one or more solid fats in an amount of 20 % to 50 % by weight based on the weight of the pharmaceutical composition; partially hydrolysed glycerol lipid in an amount of 10 % to 30 % by weight of the pharmaceutical composition, where the partially hydrolysed glycerol lipid consists of a mixture of mono-, di- and triglycerides; polyethylene glycol (PEG) polymer in an amount of 5 % to 15 % by weight of the pharmaceutical composition; where the pharmaceutical composition does not contain an emulsifier. Pharmaceutical composition is prepared so that it is solid at a temperature of 15 °C or lower and has a melting point of 30 °C or higher. Invention also includes the use of this pharmaceutical composition in the manufacture of a medicinal agent for the treatment of chronic inflammation and a method of treating an individual suffering from chronic inflammation using the composition.EFFECT: group of inventions allows to obtain a new pharmaceutical composition in the form of a solid solution.46 cl, 4 dwg, 9 tbl, 12 ex

Description

This application, with partial continuation, claims priority in accordance with paragraph 120 of section 35 of the United States Code of US patent application 13/365824, filed February 3, 2012, application with partial continuation, which claims the priority of patent application PCT / GB2011 / 052115, filed October 31, 2011, an international patent application that claims the priority of GB 1018289.7, filed October 29, 2010, and claims the priority of the patent application US 13/365828, filed February 3, 2012, and claims the priority of GB 1113730.4, filed August 10, 2011, GB 1113729.6, filed 10 g August 2011, GB 1113728.8, filed on August 10, 2011 and GB 1101937.9, filed 4th February 2011, the entire contents of which are hereby incorporated by reference.

Inflammation involves activation of the immune system in response to harmful stimuli, such as, for example, a pathogen, infection, irritant, or cell damage. As a standard reaction, inflammation is a mechanism of innate immunity in contrast to acquired immunity, which is specific to each pathogen. Inflammation can be classified as acute or chronic. In general, acute inflammation is mediated by granulocytes, and chronic inflammation is mediated by mononuclear cells, such as monocytes and lymphocytes.

Acute inflammation is the body's initial defensive reaction to remove a damaging stimulus by maintaining tissue integrity and promoting tissue repair. It is part of the body’s natural defenses against injuries and diseases, and in the absence of acute inflammation, wounds and infections would never heal, and the increasing destruction of the tissue could jeopardize the survival of the body. The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells, mast cells, vascular endothelial cells and vascular smooth muscle cells. At the beginning of a harmful stimulus, these cells activate and release inflammatory mediating and sensitizing molecules, such as, for example, pro-inflammatory cytokines, pro-inflammatory prostaglandins, leukotrienes, histamine, serotonin, neutral proteases, bradykinin and nitric oxide. These inflammatory molecules modulate a complex series of biological events, including the cellular and extracellular components of the local vascular system, the immune system, and the damaged tissue site to enhance and form an inflammatory response. These events are responsible for the initiation of an acute inflammatory reaction, usually characterized by: 1) vasodilation, which increases blood flow into the tissue, which causes erythema (redness and fever), which can go beyond this area (exacerbation of the reaction); 2) the permeability of blood vessels, which increases the leakage of plasma into the tissue, thereby causing edema (edema); 3) a change in the excitability of some sensory neurons that cause increased sensitivity and pain; 4) stimulating the release of inflammation-inducing molecules, such as, for example, neuropeptides, such as substance P (SP) and the peptide associated with the calcitonin gene (CGRP), prostaglandins, and amino acids, such as glutamate, from peripheral nerve endings; and 5) increased migration of leukocytes, mainly granulocytes, from blood vessels to tissues. An acute inflammatory reaction requires constant stimulation to maintain and should be quickly stopped when the need disappears. Consequently, acute inflammation ceases after removal of the harmful stimulus.

However, strong or prolonged malicious stimulation results in a chronic inflammatory response that leads to an increasing shift in the type of cells present at the site of tissue damage. Chronic inflammation can be characterized as the simultaneous destruction and healing of tissue as a result of the inflammatory process, with the end result causing damage and not mediating healing. In fact, chronic inflammation is a disease. Since an inflammatory reaction can occur in any part of the body, chronic inflammation plays a role in the pathophysiology of a wide range of seemingly unrelated disorders that underlie a large and diverse group of human diseases. For example, chronic inflammation is associated with diseases as varied as cardiovascular diseases, cancers, allergies, obesity, diabetes, digestive diseases, degenerative diseases, autoimmune diseases, and Alzheimer's disease.

Attempts to treat chronic inflammation have limited success. This is due, in particular, to the fact that the etiology of chronic inflammation is a complex reaction based in part on various inflammation-inducing molecules and a variety of inflammation-mediating and sensitizing molecules, which apparently cause inflammation using duplicate mechanisms. In addition to blocking pro-inflammatory molecules, many anti-inflammatory drugs also inhibit regulatory cycles that release endogenous anti-inflammatory molecules. For example, 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. However, the NSAID not only prevents the synthesis of pro-inflammatory prostaglandins, these compounds also prevent the synthesis of anti-inflammatory prostaglandins. Therefore, NSAIDs have limited success because they block the endogenous anti-inflammatory response, which in some cases can prolong chronic inflammation. Thus, compounds, compositions, uses and methods predominantly inhibiting pro-inflammatory reactions would be highly desirable for the treatment of chronic inflammation.

Disclosed herein are pharmaceutical compositions and methods for treating an individual suffering from chronic inflammation. The pharmaceutical compositions disclosed herein are essentially a lipid delivery system that enables delivery of a therapeutic compound having an anti-inflammatory effect in a manner that more effectively inhibits a pro-inflammatory response. The end result is an improved treatment for chronic inflammation.

SUMMARY OF THE INVENTION

In aspects of the present disclosure, a pharmaceutical composition is disclosed comprising a therapeutic compound and a pharmaceutically acceptable adjuvant. A therapeutic compound may have an anti-inflammatory effect. In other aspects of the present disclosure, a pharmaceutical composition is disclosed comprising a therapeutic compound disclosed herein, a pharmaceutically acceptable solvent and a pharmaceutically acceptable adjuvant. In other aspects, the pharmaceutical compositions disclosed herein further comprise a pharmaceutically acceptable stabilizing agent.

In other aspects of the present disclosure, a method for preparing a pharmaceutical composition is disclosed, wherein the method comprises the step of contacting the therapeutic compound with a pharmaceutically acceptable adjuvant under conditions that allow the formation of the pharmaceutical composition. In other aspects of the present disclosure, a method for preparing a pharmaceutical composition is disclosed, wherein the method comprises the following steps: a) contacting a pharmaceutically acceptable solvent with a therapeutic compound under conditions that allow the therapeutic compound to dissolve in a pharmaceutically acceptable solvent, thereby forming a solution where the therapeutic compound has anti-inflammatory action and b) contacting the solution obtained in step (a) with a pharmaceutically acceptable adjuvant under conditions allowing the formation of a pharmaceutical composition. In other aspects, the preparation method disclosed herein further includes c) removing a pharmaceutically acceptable solvent from the pharmaceutical composition.

In other aspects of the present disclosure, a pharmaceutical composition is disclosed wherein the pharmaceutical composition is prepared in accordance with a method comprising the step of contacting a therapeutic compound with a pharmaceutically acceptable adjuvant under conditions that allow the formation of the pharmaceutical composition. In other aspects of the present disclosure, a pharmaceutical composition is disclosed wherein the pharmaceutical composition is prepared in accordance with a method comprising the steps of: a) contacting a pharmaceutically acceptable solvent with a therapeutic compound under conditions that allow the therapeutic compound to dissolve in a pharmaceutically acceptable solvent, thereby forming a solution where the therapeutic the compound has an anti-inflammatory effect, and b) contacting the solution obtained in stage (a) with armatsevticheski acceptable adjuvant under conditions allowing the formation of a pharmaceutical composition. In other aspects, a method of manufacturing a pharmaceutical composition disclosed herein further comprises c) removing a pharmaceutically acceptable solvent from the pharmaceutical composition.

In other aspects of the present disclosure, a method of treating an individual with chronic inflammation is disclosed, wherein the method comprises the step of administering to the individual in need of the pharmaceutical composition described herein, where administration reduces the symptom associated with chronic inflammation, thereby providing treatment for the individual.

In other aspects of the present disclosure, the use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment of chronic inflammation is disclosed.

In other aspects of the present disclosure, the use of the pharmaceutical composition described herein for the treatment of chronic inflammation is disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows the effects of the pharmaceutical composition disclosed herein on survival upon administration of a lethal dose of influenza virus A / PR / 8/34. Ibuprofen 335 μg = group A, oral administration = group B and ibuprofen 335 μg oil / ethanol orally (BC1054) = group C.

In FIG. 2 shows the effects of the pharmaceutical composition disclosed herein on in vivo levels of Th2 cytokines in the lungs of surviving mice. In FIG. 2A is a diagram of the effects of the pharmaceutical composition disclosed herein on in vivo levels of IL-10, while FIG. 2B shows a diagram of the effects of the pharmaceutical composition disclosed herein on in vivo levels of IL-4. BC1054 orally = group A, carrier orally = group B and BC1054 in the lipid composition orally = group C.

In FIG. Figure 3 shows the effects of the pharmaceutical composition disclosed herein on in vivo levels of Th2 cytokines in the lungs of surviving mice. In FIG. 3A shows a diagram of the effects of the pharmaceutical composition disclosed herein on in vivo levels of IL-10, FIG. 3B is a diagram of the effects of the pharmaceutical composition disclosed herein on in vivo levels of TNF-α; and in FIG. 3C shows a diagram of the effects of the pharmaceutical composition disclosed herein on in vivo levels of IFN-γ. BC1054 orally = group A, carrier orally = group B and BC1054 in the lipid composition orally = group C.

In FIG. 4 shows the effects of the pharmaceutical composition disclosed herein on arthritis using a mouse model of arthritis induced by anti-collagen antibodies (ACAIA). PBS = group A, Enbrel = group B, carrier methyl cellulose = group C, parent drug, 40 mg / kg = group D, carrier for BC1054 = group E; BC1054, 20 mg / kg = group F and BC1054, 30 mg / kg = group G.

DESCRIPTION

In aspects of the present description, in particular, a composition is disclosed. The composition disclosed herein is usually administered as a pharmaceutically acceptable composition. As used herein, the term “pharmaceutically acceptable” refers to any molecular unit or composition that does not produce an adverse, allergic, or other adverse or undesired reaction when introduced into the human body. As used herein, the term “pharmaceutically acceptable composition” is synonymous with “pharmaceutical composition” and means a therapeutically effective concentration of an active ingredient, such as, for example, any of the therapeutic compounds disclosed herein. The pharmaceutical composition disclosed herein is suitable for medical and veterinary use. The pharmaceutical composition may be administered to the individual alone or in combination with other additional active ingredients, agents, drugs or hormones.

The pharmaceutical composition disclosed herein may optionally include a pharmaceutically acceptable carrier that facilitates incorporation of the active ingredient into the pharmaceutically acceptable compositions. Used in this document, the term "pharmaceutically acceptable carrier" is synonymous with "pharmacological carrier" and means any carrier that essentially has no long-term or permanent harmful effects when taken and covers such terms as "pharmacologically acceptable carrier, stabilizer, diluent, additive, excipient or excipient. " Such a carrier is usually mixed with the active compound or allowed to dilute or enclose the active compound therein, and it may be a solid, semi-solid or liquid substance. It is understood that the active ingredients may be soluble or may be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharmaceutically acceptable carriers can be used, including, but not limited to, aqueous media such as, for example, water, saline, glycine, hyaluronic acid, and the like; solid carriers such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc .; solvents; dispersion media; coverings; antibacterial and antifungal agents; isotonic and delaying absorption agents; or any other inactive ingredient. The choice of a pharmaceutically acceptable carrier may depend on the route of administration. Unless any pharmacologically acceptable carrier is incompatible with the active ingredient, their use in pharmaceutically acceptable compositions is contemplated. Non-limiting examples of specific uses for 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. Hardman et al., Eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). These protocols are the usual procedures and any modifications are within the competence of a specialist in this field and come from the idea of this document.

The pharmaceutical composition disclosed herein may further include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity regulators, salts, antioxidants, osmotic pressure regulating agents, physiological substances, pharmacological substances, excipients, emulsifiers, wetting agents, sweeteners or flavoring agents, and the like. Various buffers and pH adjusting agents can be used to prepare the pharmaceutical composition disclosed herein, provided that the drug is pharmaceutically acceptable as a result. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline, and borate buffers. It is understood that acids or bases may be used to adjust the pH of the composition as necessary. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Suitable preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, phenylmercury nitrate, a stabilized chlorine dioxide composition, and chelating agents such as, for example, DTPA or DTPA bisamide, DTPA calcium and CaNaDTPA bisamide. The tonicity regulators used in the pharmaceutical composition include, without limitation, salts, such as, for example, sodium chloride, potassium chloride, mannitol or glycerin, and other pharmaceutically acceptable tonicity regulators. The pharmaceutical composition can be presented in the form of a salt, which can be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. Salts, as a rule, are better soluble in aqueous or other protic solvents than the corresponding free bases. It is understood that these and other substances known in the art of pharmacology can be included in the pharmaceutical composition.

In one embodiment, the pharmaceutical composition disclosed herein includes a therapeutic compound having an anti-inflammatory effect and a pharmaceutically acceptable adjuvant. In another embodiment, the pharmaceutical composition disclosed herein includes a therapeutic compound having an anti-inflammatory effect, a pharmaceutically acceptable solvent, and a pharmaceutically acceptable adjuvant. In aspects of this embodiment, the pharmaceutical composition disclosed herein may further comprise a pharmaceutically acceptable stabilizing agent. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may further comprise a pharmaceutically acceptable carrier, a pharmaceutically acceptable component, or both a pharmaceutically acceptable carrier and a pharmaceutically acceptable component.

In aspects of the present disclosure, in particular, a therapeutic compound is disclosed. A therapeutic compound is a compound that provides pharmacological activity or another direct effect in the diagnosis, treatment, mitigation, treatment or prevention of diseases, or affects the structure or any function of the human or animal body. The therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate or solvate salt, for example, hydrochloride. In addition, the therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers, including in the R or S enantiomer. Thus, the therapeutic compound disclosed herein may contain only the R-enantiomer, only the S-enantiomer, or a combination of both the R- and S-enantiomers of the therapeutic compound. The therapeutic compound disclosed herein may have an anti-inflammatory effect.

In an embodiment of the invention, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of an inflammation-inducing molecule. In an aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of substance P (SP), calcitonin gene peptide (CGRP), glutamate, or a combination thereof. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of SP, CGRP, glutamate, or a combination thereof, released from sensory neurons, for example, 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%, of at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering levels of SP, CGRP, glutamate, or a combination thereof, released from sensory neurons in the range of, for example, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 10% to about 90%, from about 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 10% to about 80%, from about 20% to about 80%, from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80%, or from about 60% to about 80%, from about 10% to about 70%, from about 20% to about 70%, from about 30% to about 70%, from about 40% to about 70%, or from about 50% to about 70%

Prostaglandins (PG) mediate the local inflammatory response and participate in all inflammatory functions by acting on prostaglandin receptors, as well as mediate inflammatory signals, including chemotaxis (in macrophages, neutrophils and eosinophils), vasodilation and algesia. However, the PG-mediated inflammatory response is self-extinguishing (self-resolving). The main factor in this downregulation is prostaglandin, called 15dPGJ2, which is an endogenous agonist of the gamma receptor signaling pathway activated by peroxisome proliferators (PPAR-γ). The PPARγ signaling pathway (1) induces apoptosis of M1 macrophage cells, thereby reducing the level of Th1 proinflammatory cytokines and (2) enhances the differentiation of monocytes into M2 macrophage cells. Macrophage M2 cells produce and release Th2 anti-inflammatory cytokines.

In an embodiment of the invention, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of inflammation-inducing prostaglandin. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of inflammation-inducing prostaglandin released from sensory neurons, for example, at least 10%, at least 15%, 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 at least 55%, at least 60%, at least 65%, at least m D 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of inflammation-inducing prostaglandin released from sensory neurons in the range of, for example, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 10% to pr about 90%, from about 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 10% to about 80%, from about 20% to about 80%, from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80% or from about 60% to about 80%, from about 10% to about 70%, from about 20% to about 70%, from about 30% to about 70%, from about 40% to about 70%, or from about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein has an anti-inflammatory effect substantially similar to that of 15dPGJ2. In aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect that is, for example, 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% from the action observed for 15dPGJ2. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect that ranges from, for example, from about 5% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 25% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 80% to about 90%, from about 25% to about 80%, from about 50% to about 80%, from about 60% to about 80%, from about 70% to about 80%, from about 25% to about 70%, from about 50% to about 70%, from about 25% to about 60%, from about 50% to about 60%, or from about 25% to about 50% of the action observed for 15dPGJ2.

Peroxisome Proliferator Activated Receptors (PPARs) are a group of nuclear receptors that function as transcription factors that regulate gene expression. It is known that all PPARs are heterodimerized with a retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes, called elements that respond to hormone proxisome proliferators (PPREs). PPARs play a significant role in the regulation of cell differentiation, development and metabolism (carbohydrates, lipids, proteins), as well as oncogenesis in higher organisms. The family includes three members, PPAR-α, PPAR-γ, and PPAR-δ (also known as PPAR-β). PPAR-α is expressed in the liver, kidneys, heart, muscles, adipose tissue, and other tissues. PPAR-δ is expressed in many tissues, but especially in the brain, adipose tissue and skin. PPAR-γ includes three alternatively spliced forms having different expression patterns. PPAR-γ1 is expressed in almost all tissues, including the heart, muscles, intestines, kidneys, pancreas, and spleen. PPAR-γ2 is expressed mainly in adipose tissue. PPAR-γ3 is expressed in macrophages, colon and white adipose tissue. Endogenous ligands for PPAR receptors include free fatty acids and eicosanoids. PPAR-γ is activated by PGJ2 (prostaglandins), while PPAR-α is activated by leukotriene B4.

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

In another embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of stimulating the PPAR-α signaling pathway. In aspects of this embodiment, the therapeutic compound disclosed herein stimulates the PPAR-α signaling pathway, for example by at least 5%, at least 15%, at least 25%, at least 50% at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of this embodiment, the therapeutic compound disclosed herein stimulates the PPAR-α signaling pathway in the range of, for example, from about 5% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 25% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 80% to about 90%, from about 25% to about 80%, from about 50% to about 80%, from about 60% to approx 80%, from about 70% to about 80%, from about 25% to about 70%, from about 50% to about 70%, from about 25% to about 60%, from about 50% to about 60%, or from about 25% to about 50%.

In another embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of stimulating the PPAR-δ signaling pathway. In aspects of this embodiment, the therapeutic compound disclosed herein stimulates the PPAR-δ signaling pathway, for example, at least 5%, at least 15%, at least 25%, at least 50% at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of this embodiment, the therapeutic compound disclosed herein stimulates a PPAR-δ signaling pathway in the range of, for example, from about 5% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 25% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 80% to about 90%, from about 25% to about 80%, from about 50% to about 80%, from about 60% to approx 80%, from about 70% to about 80%, from about 25% to about 70%, from about 50% to about 70%, from about 25% to about 60%, from about 50% to about 60%, or from about 25% to about 50%.

In another embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of stimulating the PPARγ signaling pathway. The therapeutic compound disclosed herein may be able to bind all PPAR-γ isoforms or may be able to selectively bind any of PPAR-γ1, PPAR-γ2 or PPAR-γ3, or any combination of two of them. In aspects of this embodiment, the therapeutic compound disclosed herein stimulates the PPARγ signaling pathway, for example by at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In other aspects of this embodiment, the therapeutic compound disclosed herein stimulates a PPARγ signaling pathway in the range of, for example, from about 5% to about 100%, from about 50% to about 100%, from about 60% to about 100% from about 70% to about 100%, from about 80% to about 100%, from about 25% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% up to about 90%, from about 80% to about 90%, from about 25% to about 80%, from about 50% to about 80%, from about 60% to approx 80%, from about 70% to about 80%, from about 25% to about 70%, from about 50% to about 70%, from about 25% to about 60%, from about 50% to about 60%, or from about 25% to about 50%.

Macrophages are activated and polarized into various phenotypes expressing unique molecules on the cell surface and secreting various sets of cytokines and chemokines. The classic M1 phenotype supports Th1 pro-inflammatory responses mediated by cytokines, such as, for example, interleukin-6 (IL-6), IL-12, and IL-23, while the alternative M2 phenotype generally supports anti-inflammatory processes controlled by IL-10. M2 cells can be further divided into subgroups, M2a, M2b and M2c, depending on the type of stimulation and subsequent expression of surface molecules and cytokines.

In yet another embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect, capable of enhancing the phenotypic transition from M1 to M2, which reduces the inflammatory response. In an aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of inducing apoptosis of M1 macrophage cells. In another aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of enhancing the differentiation of M2 macrophage cells. In yet another aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect that can induce apoptosis of M1 macrophage cells and enhance cell differentiation of M2 macrophages.

In a third embodiment of the invention, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of modulating Th1 and Th2 cytokines. In an aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering gamma interferon (IFNγ), tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), or a combination thereof released from Th1 cells. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of IFNγ, TNF-α, IL-12 or combinations thereof released from Th1 cells, for example, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at at least 90%. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of IFNγ, TNF-α, IL-12 or combinations thereof released from Th1 cells in the range of, for example, from about 5% to about 100%, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 10% about 90%, from about 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 10% to about 80%, from about 20% to about 80%, from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80% or from about 60% to about 80%, from about 10% to about 70%, from about 20% to about 70%, from about 30% to about 70%, from about 40% to about 70, or from about 50% to about 70%.

In another aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of increasing levels of IL-10 released from Th2 cells. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect that can increase the levels of IL-10 released from Th2 cells, for example, at least 10%, at least 15%, at least at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of increasing levels of IL-10 released from Th2 cells in the range of, for example, from about 5% to about 100%, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 10% to about 90%, from when Roughly 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 10% to about 80%, from about 20% to about 80%, from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80%, or from about 60% to about 80%, from about 10% to about 70%, from about 20% to about 70%, from about 30% to about 70%, from about 40% to about 70, or from about 50% to about 70% .

In another aspect of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of IFNγ, TNF-α, IL-12, or combinations thereof released from Th1 cells, and increasing the levels of IL-10 released from Th2 cells. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of IFNγ, TNF-α, IL-12 or combinations thereof released from Th1 cells, for example, by 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 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 Th2 cells, for example, at least at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has an anti-inflammatory effect capable of lowering the levels of IFNγ, TNF-α, IL-12 or combinations thereof released from Th1 cells in the range of, for example, from about 5% to about 100%, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 10% about 90%, from about 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 10% to about 80%, from about 20% to about 80%, from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80% or from about 60% to about 80%, from about 10% to about 70%, from about 20% to about 70%, from about 30% to about 70%, from about 40% to about 70%, or from about 50% to about 70%, and capable of increasing IL-10 levels, in released from Th2 cells, in the range of, for example, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50 % to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 10% to about 90%, from about 20% to about 90% from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 10% up to about 80%, from about 20% to about 80% from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80%, or from about 60% to about 80%, from about 10% to about 70%, from about 20% up to about 70%, from about 30% to about 70%, from about 40% to about 70%, or from about 50% to about 70%.

The therapeutic compound disclosed herein may have a logarithm of a partition coefficient (log P) indicating that the compound is soluble in an organic solvent. As used herein, the term “log P value” refers to the decimal logarithm of a distribution coefficient (P) for a compound and is a measure of lipophilicity. As a rule, P is defined as the ratio of the concentrations of the non-ionized compound in two phases of a mixture of two immiscible solvents at equilibrium. Thus, log P = Log10 (P), where P = [dissolved substance in immiscible solvent 1] / [dissolved substance in immiscible solvent 2]. As for the organic and aqueous phases, the log P value of the compound is constant for any pair of aqueous and organic solvents, and this value can be determined empirically by one of several phase separation methods known to one skilled in the art, including, for example, shake flask analysis, HPLC and interface analysis between two immiscible electrolyte solutions (ITIES).

In aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value indicating that the compound is substantially soluble in an organic solvent. In aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value indicating that the compound, for example, is 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. In aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value indicating that from about 50% to about 100% of the compound is soluble in an organic solvent, from about 60% to about 100% soluble in an organic solvent, from about 70% to about 100% soluble in an organic solvent, from about 80% to about 100% soluble in an organic solvent, or from about 90% to about 100% soluble in an organic solvent.

In aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value, for example, greater than 1.1, greater than 1.2, greater than 1.4, greater than 1.6, greater than 1.8, greater than 2, 0, above 2.2, above 2.4, above 2.6, above 2.8, above 3.0, above 3.2, above 3.4 or above 3.6. In other aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value in the range, for example, between 1.8 and 4.0, between 2.0 and 4.0, between 2.1 and 4.0 between 2.2 and 4.0 or between 2.3 and 4.0, between 2.4 and 4.0, between 2.5 and 4.0, between 2.6 and 4.0 or between 2.8 and 4.0. In other aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value in the range of, for example, 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. In further aspects of this embodiment, the therapeutic compound disclosed herein may have a log P value in the range, for example, 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.

The therapeutic compound disclosed herein may have a polar surface area that is hydrophobic. As used herein, the term “polar surface area” refers to the sum of the surfaces for all polar atoms in the structure of a compound and is a measure of hydrophobicity. Typically, these polar atoms include, for example, oxygen, nitrogen, and attached hydrogen atoms. In aspects of this embodiment, the therapeutic compound disclosed herein may have a polar surface area of, for example, 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 . In other aspects of this embodiment, the therapeutic compound disclosed herein may have a polar surface area in the range, for example, 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 nm ² , between 4.0 nm ² and 4.5 nm ^2, or between 4.5 nm ² and 5.5 nm ² . In further aspects of this embodiment, the therapeutic compound disclosed herein may have a polar surface area in the range, for example, 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 .

The therapeutic compound disclosed herein may be non-steroidal anti-inflammatory drugs (NSAIDs). NSAID is a large group of therapeutic compounds with analgesic, anti-inflammatory and antipyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenases. NSAID include, without limitation, Aceclofenac, acemetacin, Akhtar, alclofenac, alminoprofen, amfenac, Aloksipirin, aminophenazone, antrafenine, aspirin, azapropazone, Benorilat, benoxaprofen, Benzydamine, butibufen, celecoxib, Hlortenoksatsin, choline salicylate, Klometatsin, dexketoprofen, diclofenac, diflunisal , Emorphazone, Epirizole, Etodolac, Etoricoxib, Feklobuzon, Felbinak, Fenbufen, Glenfenin, Hydroxyethylsalicylate, Ibuprofen, Indomethacin, Indoprofen, Ketoprofen, Ketoroxene, Letrofenophen, Letrofox, Lethrofen Lethrofen, Ketorofen, Letrofen, Letrofen b, mefenamic acid, meloxicam, metamizole, methiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxamethacin, phenacetin, pipebuzon, pranoprofenoxinoflacofloxoflozencofone, salinofenoxalofazaloqualazone, proqualizofalacofalicoflozen Thiaramide, Tinoridine, Tolfenamic acid, Valdecoxib and Zomepirak.

NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylate derivatives NSAIDs, p-aminophenol derivatives NSAIDs, propionic acid derivatives NSAIDs, acetic acid derivatives NSAIDs, enolic acid derivatives NSAIDs, phenamic acid derivatives NSAIDs, non-selective inhibitors COX), selective cyclooxygenase 1 inhibitors (COX-1) and selective cyclooxygenase 2 inhibitors (COX-2). An NSAID may be a profen. Examples of suitable salicylate derived NSAIDs include, but are not limited to, acetylsalicylic acid (Aspirin), Diflunisal, and Salsalate. Examples of suitable p-aminophenol derivative NSAIDs include, but are not limited to, Paracetamol and Phenacetin. Examples of suitable propionic acid derivative NSAIDs include, but are not limited to, Alminoprofen, Benoxaprofen, Dexketoprofen, Phenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen and Suprofen. Examples of suitable acetic acid derivative NSAIDs include, but are not limited to, Aceclofenac, Acemetacin, Aktarit, Alcofenac, Amfenac, Clomethacin, Diclofenac, Etodolac, Felbinac, Fenclofenac, Indomethacin, Ketorolac, Metiazinofenacenocene, Napolecene, Napolecene, Napolecene, Napolecene, Napolecene, Napolecone, Napolecone, Metazinofenacamenocene, Napolecone, Napolecone, Naetophenol, and zomepirak. Examples of suitable NSAIDs derived from enolic acid (oxycams) include, without limitation, Droxicam, Isoxicam, Lornoxicam, Meloxicam, Pyroxicam and Tenoxicam. Examples of suitable phenamic acid derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of suitable COX-2 selective inhibitors include, but are not limited to, Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib.

The therapeutic compound disclosed herein may be a PPARγ agonist. Examples of suitable PPARγ agonists include, but are not limited to, Benzbromarone, cannabidiol, Cilostazol Curcumin, delta- (9) -tetrahydrocannabinol, glycyrrhetinic acid, Indomethacin, Irbesartan, Monastcin, mycophenolic acid, Resveratrol, 6-cholonazole, Telo-Shinolazide, Telo-Shinolazide, Telo-Shinolazide, Telo-Shinolazide, Telo-Shinolazide Pioglitazone and troglitazone, NSAID and fibrate. Other suitable PPARγ agonists are described in Masson and Caumont-Bertrand, PPAR Agonist Compounds, Preparation and Uses, US 2011/0195993, which is incorporated by reference in its entirety.

The therapeutic compound disclosed herein may be a nuclear receptor binding agent. Examples of suitable nuclear receptor binding agents include, but are not limited to, retinoic acid receptor binding agent (RAR), retinoid X receptor binding agent (RXR), hepatic X receptor binding agent (LXR), and binding agent vitamin D.

The therapeutic compound disclosed herein may be an anti-hyperlipidemic agent. There are several classes of anti-hyperlipidemic agents (also known as lipid-lowering agents). They can differ both in their effect on the cholesterol profile and in side effects. For example, some of them can lower the level of low density lipoproteins (LDL), while others can mainly increase the level of high density lipoproteins (HDL). In clinical use, the choice of agent will depend on the cholesterol profile, the risk of cardiovascular complications and / or the individual’s liver and kidney function. Examples of a suitable anti-hyperlipidemic agent include, but are not limited to, fibrate, statin, tocotrienol, niacin, bile acid sequestrants (resins), a cholesterol absorption inhibitor, pancreatic lipase inhibitor, and sympathomimetic amine.

The therapeutic compound disclosed herein may be fibrate. Fibrates are a class of amphipathic carboxylic acids capable of altering lipid levels. These therapeutic compounds are used in a number of metabolic disorders. One non-limiting use case is to use as an anti-hyperlipidemic agent, where it can lower levels of, for example, triglycerides and LDL, as well as increase HDL levels. Examples of suitable fibrates include, without limitation, bezafibrate, ciprofibrate, clofibrate, gemfibrozil and fenofibrate.

The therapeutic compound disclosed herein may be a statin. Statins (or HMG-CoA reductase inhibitors) are a class of therapeutic compounds used to lower LDL and / or cholesterol by inhibiting the HMG-CoA reductase enzyme, which plays a key role in liver cholesterol production. To compensate for the decrease in cholesterol availability, the synthesis of hepatic LDL receptors is increased, which leads to an increase in the clearance of LDL particles from the blood. Examples of suitable statins include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

The therapeutic compound disclosed herein may be tocotrienols. Tocotrienols are another class of HMG-CoA reductase inhibitors and can be used to lower blood LDL and / or cholesterol by increasing liver LDL receptors and / or lowering plasma LDL. Examples of suitable tocotrienols include, but are not limited to, γ-tocotrienol and δ-tocotrienol.

The therapeutic compound disclosed herein may be niacin. Niacins are a class of therapeutic compounds that can alter lipid levels. For example, niacin can lower LDL levels by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reduce triglyceride synthesis and VLDL secretion via the HM74 and HM74A or GPR109A receptor. These therapeutic compounds are used in a number of metabolic disorders. One non-limiting use case is the use as an anti-hyperlipidemic agent, where it can inhibit the breakdown of fats in adipose tissue. Since niacin blocks the breakdown of fats, this leads to a decrease in the content of free fatty acids in the blood and, as a result, reduces the secretion of very low density lipoproteins (VLDL) and liver cholesterol. By lowering VLDL levels, niacin can also increase HDL levels in the blood. Examples of suitable niacins include, but are not limited to, acipimox, niacin, nicotinamide, and vitamin B3.

The therapeutic compound disclosed herein may be a bile acid sequestrant. Bile acid sequestrants (also known as resins) are a class of therapeutic compounds used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestration and prevention of their reabsorption in the intestine. Bile acid sequestrants are particularly effective in lowering LDL and cholesterol by sequestering cholesterol-containing bile acids released into the intestines and preventing their reabsorption from the intestines. In addition, bile acid sequestrants can also increase HDL levels. Examples of suitable bile acid sequestrants include, but are not limited to, cholestyramine, Colesevelam, and Colestipol.

The therapeutic compound disclosed herein may be a cholesterol absorption inhibitor. Cholesterol absorption inhibitors are a class of therapeutic compounds that inhibit cholesterol absorption from the intestine. Decreased absorption of cholesterol leads to an increase in the number of LDL receptors on the cell surface and increased absorption of LDL cholesterol in these cells, which leads to a decrease in the level of LDL in blood plasma. Examples of suitable cholesterol absorption inhibitors include, but are not limited to, ezetimibe, phytosterol, sterol, and stanol.

The therapeutic compound disclosed herein may be a fat absorption inhibitor. Fat absorption inhibitors are a class of therapeutic compounds that inhibit the absorption of fats from the intestines. Reduced fat absorption reduces calorie intake. In one aspect, a fat absorption inhibitor inhibits pancreatic lipase, an enzyme that breaks down intestinal triglycerides. Examples of a suitable fat absorption inhibitor include, but are not limited to, Orlistat.

The 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 (norepinephrine) and / or dopamine. The sympathomimetic amine can act as an α-adrenergic agonist, β-adrenergic agonist, dopaminergic agonist, monoamine oxidase inhibitor (MAO), and COMT inhibitor. Such therapeutic compounds are, inter alia, used to treat cardiac arrest, low blood pressure, or even to delay premature labor. Examples of suitable sympathomimetic amines include, but are not limited to, Clenbuterol, Salbutamol, Ephedrine, Pseudoephedrine, Methamphetamine, Amphetamine, Phenylephrine, Isoproterenol, Dobutamine, Methylphenidate, Lisdexamphetamine, Catin, Cathinone, Methylphene Diphenylamine methylaminorex, pemoline, phenmetrazine and propylhexedrine.

The 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 an ester modification. The ester group may be attached to the therapeutic compound, for example, through the carboxyl or hydroxyl functional groups present in the therapeutic compound. The ester of the therapeutic compound may have increased hydrophobicity, and thus may be dissolved in the smaller volume of the solvent disclosed herein. In some cases, the ester of the therapeutic compound can be combined directly with the adjuvant disclosed herein, thereby eliminating the need for a solvent. An ester of a therapeutic compound may allow the manufacture of the pharmaceutical composition disclosed herein in situations where the unesterified form of the same therapeutic compound is otherwise not miscible with the solvent disclosed herein. The ester of the therapeutic compound may also be delivered in a manner that more effectively inhibits the pro-inflammatory response, provided that the compound is combined with the adjuvant disclosed herein. In one embodiment of the invention, the therapeutic compound may react with an ethyl ester to form an ethyl ester of the therapeutic compound.

In another embodiment, the pharmaceutical composition disclosed herein does not contain the pharmaceutically acceptable solvent disclosed herein. In one aspect of this embodiment, the pharmaceutical composition comprises a therapeutic compound and a pharmaceutically acceptable adjuvant, but does not contain the pharmaceutically acceptable solvent disclosed herein.

The pharmaceutical composition disclosed herein may contain a therapeutic compound in an amount sufficient to provide a standard administration to an individual. In aspects of this embodiment, the pharmaceutical composition disclosed herein may include, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg t compounds therapeutically. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may include, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least th least 1400 mg or at least 1500 mg of the therapeutic compound. In further aspects of this embodiment, the pharmaceutical composition disclosed herein may range, for example, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 50 mg to about 150 mg, from about 100 mg to about 250 mg, from about 150 mg to about 350 mg, from about 250 mg to about 500 mg, from about 350 mg to about 600 mg, from about 500 mg to about 750 mg, from about 600 mg to about 900 mg, from about 750 mg to about 1000 mg, from about 850 mg to about 1200 mg, or from an example about 1000 mg to about 1500 mg. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may range, for example, from about 10 mg to about 250 mg, from about 10 mg to about 500 mg, from about 10 mg to about 750 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 1500 mg, from about 50 mg to about 250 mg, from about 50 mg to about 500 mg, from about 50 mg to about 750 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 250 mg, from about 100 mg to about Roughly 500 mg, from about 100 mg to about 750 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 1500 mg, from about 200 mg to about 500 mg, from about 200 mg to about 750 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 1500 mg, from about 5 mg to about 1500 mg, from about 5 mg to about 1000 mg, or from about 5 mg to about 250 mg.

In aspects of the present description, in particular, a pharmaceutically acceptable solvent is disclosed. A solvent is a liquid, solid, or gas in which another solid, liquid, or gaseous substance (solute) is dissolved, to give a solution. Solvents used in the pharmaceutical compositions disclosed herein include, but are not limited to, a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent, and a pharmaceutically acceptable non-polar solvent. Pharmaceutically acceptable polar aprotic solvents include, but are not limited to, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO). Pharmaceutically acceptable polar protic solvents include, but are not limited to, acetic acid, formic acid, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2- propanediol, methanol, glycerin and water. Pharmaceutically acceptable non-polar solvents include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, N-methyl-pyrrolidone (NMP), and diethyl ether.

The pharmaceutical composition disclosed herein may contain a solvent in an amount sufficient to dissolve the therapeutic compound disclosed herein. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain a solvent in an amount of, for example, 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) ./vol.), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v) vol.), less than about 25% (vol./vol.), less than about 20% (vol./vol.), less than about 15% (vol./vol.), less pr approximately 10% (vol. / vol.) of less than about 5% (vol. / vol.) or less than about 1% (vol. / vol.). In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain a solvent in an amount in the range of, for example, from about 1% (v / v) to 90% (v / v), from 1% (vol / vol) to 70% (vol / vol), from about 1% (vol / vol) to 60% (vol / vol), from about 1% (vol / vol) vol.) up to 50% (vol./vol.), from about 1% (vol./vol.) to 40% (vol./vol.), from about 1% (vol./vol.) to 30% (v / v), from about 1% (v / v) to 20% (v / v), from about 1% (v / v) to 10% (v / v) ), from about 2% (v / v) to 50% (v / v), from about 2% (v / v) to 40% (vol / v), from about 2% (about b./vol.) up to 30% (vol./vol.), from about 2% (vol./vol.) to 20% (vol./vol.), from about 2% (vol./vol.) up to 10% (v / v), from about 4% (v / v) to 50% (v / v), from about 4% (v / v) to 40% (vol. (v / v), from about 4% (v / v) to 30% (v / v), from about 4% (v / v) to 20% (v / v), about from 4% (v / v) to 10% (v / v), from about 6% (v / v) to 50% (vol / v), from about 6% (vol. v / v) up to 40% (v / v), from about 6% (v / v) to 30% (v / v), from about 6% (v / v) to 20 % (v / v), from about 6% (v / v) to 10% (v / v), from about 8% (v / v) to 50% (v / v) .), from about 8% (v / v) to 40% (v / v), from about 8% (v / v) to 30% (v / v), about 8% (v / v) to 20% (v / v), from about 8% (v / v) to 15% (v / v), or from about 8% (v / v) vol.) up to 12% (vol./vol.).

In one embodiment, the solvent may contain a pharmaceutically acceptable alcohol. As used herein, the term “alcohol” refers to an organic molecule containing a hydroxyl functional group (—OH) linked to a carbon atom, wherein the carbon atom is saturated. In aspects of this embodiment, the alcohol may be, for example, a C _2-4 alcohol, C _1-4 alcohol, C _1-5 alcohol, C _1-7 alcohol, C _1-10 alcohol, C _{1- 15} alcohol or C _1-20 alcohol. In other aspects of this embodiment, the alcohol may be, for example, primary alcohol, secondary alcohol, or tertiary alcohol. In other aspects of this embodiment, the alcohol may be, for example, an acyclic alcohol, a monohydroxy alcohol, a polyhydric alcohol (also known as a polyol or sugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof. Examples of the monohydric alcohol include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol, and 1-hexadecanol. Examples of the polyhydric alcohol include, but are not limited to, glycol, glycerin, erythritol, arabitol, xylitol, maltitol, sorbitol (glucite), mannitol, inositol, lactitol, galactitol (go) and isomalt. Examples of unsaturated aliphatic alcohols include, without limitation, prop-2-en-1-ol, 3,7-dimethylocta-2,6-dien-1-ol, and prop-2-in-1-ol. Examples of alicyclic alcohols include, without limitation, cyclohexan-1, 2,3,4,5,6-hexol and 2- (2-propyl) -5-methyl-cyclohexan-1-ol.

In another embodiment, the solvent may comprise an ester of a pharmaceutically acceptable alcohol and acid. Suitable pharmaceutically acceptable alcohols include those described herein. Suitable acids include, but are not limited to, acetic acid, butyric acid, and formic acid. Alcohol and acid esters include, but are not limited to, methyl acetate, methyl butyrate, methyl formate, ethyl acetate, ethyl butyrate, ethyl formate, propyl acetate, propyl butyrate, propyl formate, butyl acetate, butyl butyrate, butyl formate, isobutyl acetate, isobutyl butyl ethyl formate, butobenyl ethyl acetate, 1-hexadecyl butyrate and 1-hexadecyl formate.

In another embodiment, the solvent may include 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), monoisopropyl ether - (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 under the name TRANSCUTOL®.

In another embodiment, the solvent may include a pharmaceutically acceptable diol. A diol or dihydric alcohol is a chemical compound containing two hydroxyl groups (—OH groups).

In another embodiment, the solvent may include pharmaceutically acceptable propylene glycol. Propylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound of the formula C ₃ Η ₈ Ο ₂ or HO-CH ₂ -CHOH-CH ₃ .

In another embodiment, the solvent may include pharmaceutically acceptable dipropylene glycol. Dipropylene glycol is a mixture of three isomers of a chemical compound, 4-oxa-2,6-heptanediol, 2- (2-hydroxy-propoxy) propan-1-ol and 2- (2-hydroxy-1-methyl-ethoxy) propan-1 -ol.

In another embodiment, the solvent may include a pharmaceutically acceptable propylene glycol (PPG) polymer. PPG polymers, also known as polypropylene oxide (PPO) polymers or polyoxypropylene (POP) polymers, are prepared by polymerization of propylene oxide and are commercially available in a wide range of molar masses from 100 g / mol to 10,000,000 g / mol. Low molecular weight PPG polymers are liquids or fusible solids, while higher molecular weight PPG polymers are solids. PPG polymers 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 10000, PPG 11000, PPG 12000, PPG 13000, PPG 14000, PPG 15000, PPG 16000, PPG 17000, PPG 18000, PPG 19000 or PPG 20,000.

In another embodiment, the solvent may include a pharmaceutically acceptable polyethylene glycol (PEG) polymer. PEG polymers, also known as polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers, are prepared by ethylene oxide polymerization and are commercially available in a wide range of molar masses from 100 g / mol to 10,000,000 g / mol. Low molecular weight PEG polymers are liquids or fusible solids, while higher molecular weight PEG polymers are solids. PEG polymers include, without limitation, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250 , PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG 10000, PEG 11000, PEG 12000, PEG 13000, PEG 14000, PEG 15000, PEG 16000, PEG 17000, PEG 18000, PEG 19000 or PEG 20000.

In another embodiment, the solvent may comprise a pharmaceutically acceptable glyceride. Glycerides include substituted glycerin, where one, two or all three hydroxyl groups of glycerol are esterified with a fatty acid to form monoglycerides, diglycerides and triglycerides, respectively. In these compounds, each hydroxyl group of glycerol can be esterified with various fatty acids. In addition, glycerides can be acetylated to form acetylated monoglycerides, acetylated diglycerides and acetylated triglycerides.

In another embodiment, the solvent may comprise a pharmaceutically acceptable solid solvent. Solid solvents may be useful in the manufacture of the solid dosage form of the pharmaceutical composition disclosed herein. Typically, the solid solvent is melted to dissolve the therapeutic compound. Pharmaceutically acceptable solid solvents include, but are not limited to, menthol and PEG polymers with a molecular weight above about 20,000 g / mol.

In aspects of the present disclosure, in particular, a pharmaceutically acceptable adjuvant is disclosed. An adjuvant is a pharmacological agent that modifies the action of other agents, such as, for example, the therapeutic compound disclosed herein. In addition, the adjuvant disclosed herein can be used as a solvent that dissolves the therapeutic compound disclosed herein to form a solution in the adjuvant. The adjuvant disclosed herein facilitates the delivery of a therapeutic compound in such a way that it more effectively inhibits a pro-inflammatory response. In one embodiment, the adjuvant disclosed herein facilitates the delivery of a therapeutic compound disclosed herein to macrophages.

The pharmaceutical composition disclosed herein may contain a pharmaceutically acceptable adjuvant in an amount sufficient to be mixed with the solution disclosed herein or the emulsion disclosed herein. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain an adjuvant in an amount of, for example, at least 10% (v / v), at least 20% (v / v), at least 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) vol.), at least 90% (vol./ vol.), at least 95% (vol./about.) or at least 99% (vol./about.). In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain an adjuvant in an amount in the range of, for example, from about 30% (v / v) to about 99% (v / v), about 35% (v / v) to about 99% (v / v), from about 40% (v / v) to about 99% (v / v), from about 45% ( v / v) to about 99% (v / v), from about 50% (v / v) to about 99% (v / v), from about 30% (v / v) .) up to about 98% (v / v), from about 35% (v / v) to about 98% (v / v), from about 40% (vol / v) to about 98% (v / v), from example about 45% (v / v) to about 98% (v / v), from about 50% (v / v) to about 98% (v / v), from about 30% ( v / v) up to about 95% (v / v), from about 35% (v / v) to about 95% (v / v), from about 40% (v / v) .) to about 95% (v / v), from about 45% (v / v) to about 95% (v / v), or from about 50% (v / v) to about 95% (v / v). In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain an adjuvant in an amount in the range of, for example, from about 70% (v / v) to about 97% (v / v), about 75% (v / v) to about 97% (v / v), from about 80% (v / v) to about 97% (vol / v), from about 85% ( v / v) to about 97% (v / v), from about 88% (v / v) to about 97% (v / v), from about 89% (v / v) .) to about 97% (v / v), from about 90% (v / v) to about 97% (v / v), from about 75% (v / v) to about 96% (v / v), from an example about 80% (v / v) to about 96% (v / v), from about 85% (v / v) to about 96% (v / v), from about 88% ( v / v) to about 96% (v / v), from about 89% (v / v) to about 96% (v / v), from about 90% (v / v) .) up to about 96% (v / v), from about 75% (v / v) to about 93% (v / v), from about 80% (v / v) to about 93% (v / v), from about 85% (v / v) to about 93% (v / v), from about 88% (v / v) to about 93% (v / v) ./vol.), from about 89% (v / v) to about 93% (v / v) or from about 90% (v / v) to about 93% (v / v) )

In one embodiment, the adjuvant may be a pharmaceutically acceptable lipid. A lipid can generally be described as a hydrophobic or amphiphilic low molecular weight substance. The amphiphilic nature of certain lipids allows them to form structures such as vesicles, liposomes or membranes in an aqueous medium. Non-limiting examples of lipids include fatty acids, glycerolipids (e.g. monoglycerides, diglycerides and triglycerides), phospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids and polyketides. The pharmaceutical composition disclosed herein may contain a lipid, such as, for example, oil, oil-based liquid, fat, fatty acid, wax, fatty acid ester, salt of a fatty acid, fatty alcohol, glyceride (mono-, di- or triglyceride), partially hydrolyzed glycerolipid, phospholipids, glycol ether, sucrose ester, glycerol derivative, medium chain triglyceride, or a mixture thereof. Other examples of pharmaceutically acceptable lipids suitable as adjuvants are described, for example, in US 6923988, US 6451339, US 6383471, US 6294192 and US 6267985, the entire contents of which are incorporated herein by reference.

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable fatty acid. Fatty acid includes a long, unbranched hydrocarbon chain carboxylic acid, which may be either saturated or unsaturated. This structure provides the fatty acid with a polar, hydrophilic end and a non-polar hydrophobic end, which is insoluble in water. Most natural fatty acids have a hydrocarbon chain with an even number of carbon atoms, usually from 4 to 24 carbon atoms, and can be connected to functional groups containing oxygen, halogens, nitrogen and sulfur. Synthetic or unnatural fatty acids can have a hydrocarbon chain of any number of carbon atoms from 3 to 40. In the presence of a double bond, there is the possibility of cis or trans geometric isomerism, which significantly affects the configuration of the molecule. Cis double bonds cause bending of the fatty acid, an effect that is all the more pronounced the more double bonds are present in the chain. Most natural fatty acids have a cis configuration, although the trans form is present in some natural and partially hydrogenated fats and oils. Examples of fatty acids include, without limitation, caprylic acid (8: 0), pelargonic acid (9: 0), capric acid (10: 0), undecylic acid (11: 0), lauric acid (12: 0), tridecylic acid (13: 0), myristic acid (14: 0), myristoleic acid (14: 1), pentadecylic 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), lino enoic acid (18: 3), γ-linolenic acid (18: 3), stearidonic acid (18: 4), nonadecylic acid (19: 0), arachidonic acid (20: 0), eicosenoic acid (20: 1), dihomo-γ-linolenic acid (20: 3), minic acid (20: 3), arachidonic acid (20: 4), eicosapentaenoic acid (20: 5), genecosanoic acid (21: 0), behenic acid (22: 0) ), erucic acid (22: 1), docosahexaenoic acid (22: 6), tricosanoic acid (23: 0), lignoceric acid (24: 0), aceteroic acid (24: 1), pentacosanoic acid (25: 0), cerotinic acid (26: 0), heptacosanoic acid (27: 0), montanic acid slot (28: 0), nonacosanoic acid (29: 0), melissovy acid (30: 0), gentriacontanoic acid (31: 0), laceric acid (32: 0), psillastearic acid (33: 0), hedic acid ( 34: 0), ceroplastic acid (35: 0) and hexatriactyl acid (36: 0).

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable partially hydrogenated lipid. The hydrogenation process adds hydrogen atoms to the unsaturated lipid, eliminating double bonds and turning it into a partially or fully saturated lipid. Partial hydrogenation is a chemical rather than enzymatic process that converts some of the cis isomers into trans-unsaturated lipids instead of completely hydrogenating them. In the first reaction step, one hydrogen is added, with another coordinatively unsaturated carbon adhering to the catalyst. The second step is to add hydrogen to the remaining carbon atom, resulting in a saturated fatty acid. The first stage is reversible, so that hydrogen is re-adsorbed on the catalyst, and the double bond is formed again. The intermediate compound with only one added hydrogen atom does not contain a double bond and can rotate freely. Thus, the double bond can be re-formed either in the cis or trans form, of which the trans form is predominant regardless of the starting material.

In an embodiment of the invention, the adjuvant may be a pharmaceutically acceptable saturated or unsaturated fatty acid. In aspects of this embodiment, a saturated or unsaturated fatty acid contains, for example, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at at least 22, at least 24, at least 26, at least 28, or at least 30 carbon atoms. In other aspects of this embodiment, a saturated or unsaturated fatty acid contains, for example, from 4 to 24 carbon atoms, from 6 to 24 carbon atoms, from 8 to 24 carbon atoms, from 10 to 24 carbon atoms, from 12 to 24 carbon atoms, from 14 to 24 carbon atoms or from 16 to 24 carbon atoms, from 4 to 22 carbon atoms, from 6 to 22 carbon atoms, from 8 to 22 carbon atoms, from 10 to 22 carbon atoms, from 12 to 22 carbon atoms, from 14 to 22 carbon atoms or 16 to 22 carbon atoms, 4 to 20 carbon atoms, 6 to 20 carbon atoms, 8 to 20 carbon atoms and from 10 to 20 carbon atoms, from 12 to 20 carbon atoms, from 14 to 20 carbon atoms or from 16 to 20 carbon atoms. Being unsaturated, the fatty acid may have, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more or 6 or more double bonds.

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

In another embodiment, the adjuvant may contain one type of pharmaceutically acceptable fatty acid. In aspects of this embodiment, the adjuvant may contain only palmitic acid, only stearic acid, only oleic acid, only linoleic acid, or only linolenic acid.

In another embodiment, the adjuvant may contain many different pharmaceutically acceptable fatty acids. In aspects of this embodiment, the adjuvant may contain, for example, two or more different fatty acids, three or more different fatty acids, four or more different fatty acids, five or more different fatty acids, or six or more different fatty acids.

In other aspects of this embodiment, the 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. In other aspects of this embodiment, the adjuvant may comprise a ratio of (palmitic acid and / or stearic acid and / or oleic acid) :( linolenic acid and / or linoleic acid), for example at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1 at least 15: 1 or at least 20: 1. In other aspects of this embodiment, the adjuvant may comprise a ratio of (palmitic acid and / or stearic acid and / or oleic acid) :( linolenic acid and / or linoleic acid) in the range of, for example, from about 1: 1 to about 20: 1 from about 2: 1 to about 15: 1, from about 4: 1 to about 12: 1, or from about 6: 1 to about 10: 1.

In other aspects of this embodiment, the adjuvant may contain 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. In other aspects of this embodiment, the adjuvant may comprise a ratio of palmitic acid: stearic acid: linolenic acid: linoleic acid, for example 10: 10: 1: 1, 9: 9: 1: 1, 8: 8: 1: 1, 7 : 7: 1: 1, 6: 6: 1: 1, 5: 5: 1: 1, 4: 4: 1: 1, 3: 3: 1: 1, 2: 2: 1: 1 or 1: 1 : 1: 1. In other aspects of this embodiment, the adjuvant may comprise a palmitic acid: stearic acid: linolenic acid: linoleic acid ratio in the range of, for example, from about 10: 10: 1: 1 to about 6: 6: 1: 1, from about 8: 8: 1: 1 to about 4: 4: 1: 1 or from about 5: 5: 1: 1 to about 1: 1: 1: 1.

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable omega fatty acid. Non-limiting examples of omega fatty acids include omega-3, omega-6, omega-7, and omega-9. Omega-3 fatty acids (also known as n-3 fatty acids or ω-3 fatty acids) are a family of essential fatty unsaturated acids that have a common terminal carbon-carbon double bond in position n-3, i.e. a third bond, counting from the terminal methyl group of a fatty acid. Omega-3 fatty acids are “essential” fatty acids because they are vital for normal metabolism and cannot be synthesized in the human body. Omega-3 fatty acids include, but are not limited to, hexadecatrienoic acid (16: 3), linolenic acid (18: 3), stearidonic acid (18: 4), eicosatrienoic acid (20: 3), eicosatetraenoic acid (20: 4), eicosapentaenoic acid (20: 5), genecosapentaenoic acid (21: 5), docosapentaenoic acid (clupanodonic acid) (22: 5), docosahexaenoic acid (22: 6), tetracosapentaenoic acid (24: 5), tetracosehexaenoic acid (nisic acid) (24: 6).

Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids) are a family of unsaturated fatty acids that have a common terminal carbon-carbon double bond in position n-6, i.e. the sixth bond, counting from terminal methyl group of a fatty acid. Omega-6 fatty acids include, but are not limited to, linoleic acid (18: 2), γ-linolenic acid (18: 3), calendolic acid (18: 3), eicosadienoic acid (20: 2), dihomo-γ-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 (also known as n-7 fatty acids or ω-7 fatty acids) are a family of unsaturated fatty acids that have a common terminal carbon-carbon double bond at position n-7, i.e. a seventh bond, starting from terminal methyl group of a fatty acid. Omega-7 fatty acids include, but are not limited to, 5-dodecenoic acid (12: 1), 7-tetradecenoic acid (14: 1), 9-hexadecenoic acid (palmitoleic acid) (16: 1), 11-decenoic acid (vaccenic acid) (18: 1), 9Z, 11E-conjugated linoleic acid (rumenic acid) (18: 2), 13-eicosenoic acid (polynoic acid) (20: 1), 15-docosenoic acid (22: 1) and 17 -tetracosenoic acid (24: 1).

Omega-9 fatty acids (also known as n-9 fatty acids or ω-9 fatty acids) are a family of unsaturated fatty acids that have a common terminal carbon-carbon double bond at position n-9, i.e. the ninth bond, starting from terminal methyl group of a fatty acid. Omega-7 fatty acids include, but are not limited to, oleic acid (18: 1), elaidic acid (18: 1), eicosenoic acid (20: 1), midic acid (20: 3), erucic acid (22: 1), aceterucic acid (24: 1) and ricinoleic acid.

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable fat. Also known as high melting fat or solid fat, the fat includes any fatty acid that is solid at ordinary room temperature, such as, for example, about 20 ° C. Fats consist of a wide group of compounds that are usually soluble in organic solvents and usually insoluble in water. A fat suitable as a lipid suitable for the pharmaceutical compositions disclosed herein may be triglyceride, glycerol triester or any of several fatty acids.

A suitable lipid for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable oil. An oil, also known as liquid fat, includes any fatty acid that is a liquid at ordinary room temperature, such as, for example, about 20 ° C. An oil suitable as a lipid suitable for the pharmaceutical compositions disclosed herein may be a natural oil, a vegetable oil, or any substance that does not mix with water and gives a greasy feel. Examples of suitable natural oils include, but are not limited to, mineral oil, triacetin, ethyl oleate, hydrogenated natural oil, or mixtures thereof. Examples of suitable vegetable oils include, but are not limited to, almond oil, peanut oil, avocado oil, rapeseed oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hempseed oil, linseed oil (linseed oil seed), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soybean oil, sunflower oil, cocoa butter (cocoa butter), oil walnut, wheat germ oil or a mixture thereof. Each of these oils is commercially available from various sources well known to those skilled in the art.

Oil, as a rule, is a mixture of various fatty acids. For example, rapeseed oil obtained from Brassica napus seeds includes both omega-6 and omega-3 fatty acids in a ratio of about 2: 1. As another example, linseed oil obtained from Linum usitatissimum seeds includes about 7% palmitic acid, about 3.4-4.6% stearic acid, about 18.5-22.6% oleic acid, about 14, 2-17% linoleic acid and approximately 51.9-55.2% linolenic acid. As another example, cocoa butter derived from cocoa beans includes glycerides derived from palmitic acid, stearic acid, oleic acid, linoleic acid and arachinic acid, with a melting point of 34-38 ° C. In aspects of this embodiment, the pharmaceutical composition comprises an oil comprising 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 acids.

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable glycerolipid. Glycerolipids consist mainly of mono-, di- and tri-substituted glycerols. One group of glycerolipids is glycerides, where one, two, or all three hydroxyl groups of glycerol are esterified using the fatty acid disclosed herein to form monoglycerides, diglycerides, and triglycerides, respectively. In these compounds, each hydroxyl group of glycerol can be esterified using various fatty acids. In addition, glycerides can be acetylated to form acetylated monoglycerides, acetylated diglycerides and acetylated triglycerides. One group of glycerolipids is glycerides, where one, two or all three hydroxyl groups of glycerol have sugar residues attached via a glycosidic bond.

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable partially hydrolyzed glycerolipid. In an aspect of this embodiment, the pharmaceutically acceptable partially hydrolyzed glycerolipid is a triglyceride partially hydrolyzed into a mixture of mono-, di- and triglycerides.

A suitable lipid for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable fatty acid glycol ester. The pharmaceutically acceptable fatty acid glycol ester may be a glycol monoester, a glycol diester, or a glycol triester. Fatty acid glycol esters include, but are not limited to, ethylene glycol fatty acid ester, diethylene glycol fatty acid ester, propylene glycol fatty acid ester, dipropylene fatty acid ester. Non-limiting examples of glycol fatty acid esters include, for example, ethylene glycol caprylate, ethylene glycol pelargonate, ethylene glycol caprate, glycol undecylate, glycol laurate, ethylene glycol tridetsilat, ethylene glycol myristate, ethylene glycol miristolat, ethylene pentadetsiklat, ethylene glycol palmitate, ethylene glycol palmitoleat, ethylene sapienat, ethylene margarat, ethylene glycol stearate, ethylene glycol palmitostearate, ethylene glycol oleate, ethylene glycol elaidate, ethylene glycol vaccinate, ethylene glycol ikolya linoleate, ethylene linoelaidat, ethylene α-linolenate, ethylene glycol, γ-linolenate, ethylene stearidonat, ethylene kaprilokaprat, ethylene dikaprilokaprat, diethylene glycol caprylate, diethylene glycol pelargonate, diethylene glycol caprate, diethylene undecylate, diethylene glycol laurate, diethylene tridetsilat, diethylene glycol myristate, diethylene miristolat, diethylene pentadecyclate, diethylene glycol palmitate, diethylene glycol palmitoleate, diethylene glycol sapienate, diethylene glycol marga rat, diethylene glycol stearate, diethylene glycol palmitostearate, diethylene glycol oleate, diethylene elaidate, diethylene vaktsenat, diethylene glycol linoleate, diethylene linoelaidat, diethylene α-linolenate, diethylene γ-linolenate, diethylene stearidonat, diethylene kaprilokaprat, diethylene dikaprilokaprat, propylene glycol caprylate, propylene glycol pelargonate, propylene glycol caprate , propylene glycol undecylate, propylene glycol laurate, propylene glycol tridecylate, propylene glycol myristate, prop glycol miristolat, propylene pentadetsiklat, propylene glycol palmitate, propylene glycol palmitoleat, propylene sapienat, propylene margarat propylene stearate, propylene glycol palmitostearate, propylene glycol oleate, propylene glycol elaidate, propylene vaktsenat, propylene glycol linoleate, propylene glycol linoelaidat, propylene α-linolenate, propylene γ-linolenate, propylene stearidonate, propylene glycol caprylocaprate, propylene glycol dicaprilocaprate, dipropylene glycol caprylate, diprop ilenglikolya pelargonate, dipropylene glycol caprate, glycol undecylate, dipropylene glycol laurate, dipropylene tridetsilat, dipropylene glycol myristate, dipropylene miristolat, dipropylene pentadetsiklat, glycol palmitate, glycol palmitoleat, dipropylene sapienat, dipropylene margarat, glycol stearate, glycol palmitostearate, glycol oleate, glycol elaidate, dipropylene vaktsenat dipropylene glycol linoleate, dipropylene glycol The salt of linoelidate, dipropylene glycol α-linolenate, dipropylene glycol γ-linolenate, dipropylene glycol stearidonate, dipropylene glycol caprylocaprate, dipropylene glycol dicaprylocaprate, or any combination thereof.

A lipid suitable for the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable polyester fatty acid ester. The pharmaceutically acceptable ester of a polyester and a fatty acid may be a monoester of a fatty acid and a polyester, a diester of a fatty acid and a polyester, or a triester of a fatty acid and a polyester. The polyester and fatty acid ester includes, but is not limited to, PEG fatty acid ester, PEG fatty acid glyceryl glyceride, PEG fatty acid ester glyceride, PPG fatty acid ester, PPG fatty acid glyceryl, PPG ester glyceride and fatty acid. PEG or PPG may have a molecular weight of, for example, 5-20000 Da. Non-limiting examples of polyester and fatty acid esters include, for example, PEG caprylate, PEG pelargonate, PEG caprate, PEG undecylate, PEG laurate, PEG tridecylate, PEG myristate, PEG myristolate, PEG pentadecyclate, PEG palmitate, PEG palmitoleate, PEG sapiene margarate, PEG stearate, PEG palmitostearate, PEG oleate, PEG elaidate, PEG vaccinate, PEG linoleate, PEG linoelaidate, PEG α-linolenate, PEG γ-linolenate, PEG stearidonate, PEG caprylocapergate-pEG, PEG , PEG-glyceryl caprate, PEG-glyceryl undecylate, PEG-glyceryl laurate, PEG- lyceryl tridecylate, PEG-glyceryl myristate, PEG-glyceryl myristolate, PEG-glyceryl pentadecyclate, PEG-glyceryl palmitate, PEG-glyceryl palmitoleate, PEG-glyceryl sapienate, PEG-glyceryl margarate, PEG-glyceryl glyceryl, PEG-glyceryl glyceryl glyceryl oleate, PEG-glyceryl elaidate, PEG-glyceryl vaccinate, PEG-glyceryl linoleate, PEG-glyceryl linoelate, PEG-glyceryl-linolenate, PEG-glyceryl γ-linolenate, PEG-glyceryl stearidonate, PEG-glyceryl stearidonate, PEG-glyceryl stearidonate dicaprilocaprate, capryloyl-PEG glyceride, pelargonoyl-PEG glyceride, caproyl-PEG glyceride, undecyloyl-PEG glyceride, lauroyl-PEG glyceride, tridecyloyl-PEG glyceride, myristoyl-PEG glyceride, myristoloy-PEG glyceride, pentadecycloyl-PEG glyceride, palmitoyl-PEG glyceride, palmitoleoyl-PEG glyceride, sargyloide-PEG-glyceride-PEG glyceride, palmitostearoyl-PEG glyceride, oleoyl-PEG glyceride, elaidoyl-PEG glyceride, vaccenoyl-PEG glyceride, linoleoyl-PEG glyceride, linoelaidoyl-PEG glyceride, α-linolenoyl-PEG glyceride, γ-linolenoyl-PEG glyceride, γ-linolenoyl-PEG , caprylcaproyl-PEG glyceride, dicapril-caproyl-PEG glyceride, PPG caprylate, PPG pelargonate, PP G caprate, PPG undecylate, PPG laurate, PPG tridecylate, PPG myristate, PPG myristolate, PPG pentadecyclate, PPG palmitate, PPG palmitoleate, PPG sapienate, PPG margarate, PPG stearate, PPG palmitostearate, PPG oleate, PPG linateate, PPG lignate, PPG lignate, PPG lignate , PPG linoelaidate, PPG α-linolenate, PPG γ-linolenate, PPG stearidonate, caprilocaprate PPG, dicaprilocaprate PPG, PPG-glyceryl caprylate, PPG-glyceryl pelargonate, PPG-glyceryl caprate, PPG-glyceryl undecy glyceryl tridecylate, PPG-glyceryl myristate, PPG-glyceryl myristolate, PPG-glyceryl pentadecyclate, PPG-glyceryl palmitate, PPG-glycer sludge palmitoleate, PPG-glyceryl sapienate, PPG-glyceryl margarate, PPG-glyceryl stearate, PPG-glyceryl palmitostearate, PPG-glyceryl oleate, PPG-glyceryl elaidate, PPG-glyceryl vaccine, PPG-glyceryl, glyceryl glyceryl α-linolenate, PPG-glyceryl γ-linolenate, PPG-glyceryl stearidonate, PPG-glyceryl caprylocaprate, PPG-glyceryl dicaprilocaprate, capryloyl-PPG glyceride, pelargonoyl-PPG glyceride, caproyl PPG-glyceryl PPG glyceride glyceride, tridecyloyl-PPG glyceride, myristoyl-PPG glyceride, myristoloyl-PPG glyceride, pentadecycloyl-PPG gly ceride, palmitoyl-PPG glyceride, palmitoleoyl-PPG glyceride, sapienoyl-PPG glyceride, margaroyl-PPG glyceride, palmitostearoyl-PPG glyceride, palmitostearoyl-PPG glyceride, oleoyl-PPG glyceride, elaidoyl-glyceride glyceride, linoeloydoyl-PPG glyceride, α-linolenoyl-PPG glyceride, γ-linolenoyl-PPG glyceride, stearidonoyl-PPG glyceride, caprylcaproyl-PPG glyceride, dicaprylcaproyl-PPG glyceride, or any combination thereof.

Commercially available pharmaceutically acceptable esters of polyethers and fatty acids include, but are not limited to, caprylcaproyl-macrogol-8 glycerides (LABRASOL®), propylene glycol monopalmitostearate (MONOSTEOL®), glyceryl dibegenate (COMPRITOL® 888), glycerol behenate E (COM), glycerol behenate (COM) behenoyl-polyoxy-8 glycerides (COMPRITOL® HD5 ATO), triglycerine diisostearate (PLUROL® Diisostearique), PEG-8 beeswax (APIFIL®), lauroyl-macrogol-32 glycerides (GELUCIRE 44/14), stearoyl macrogol-32 GELUCIRE 50.13), propylene glycol dicaprilocaprate (LABRAFAC® PG), polyglycerol-3 dioleate (PLUROL® Oleique C C 497), propylene glycol monolaurate (type I), (LAUROGLYCOL® FCC), propylene glycol monolaurate (type II), (LAUROGLYCOL® 90), propylene glycol monocaprilate (type I) (CAPRYOL® PGMC), propylene glycol monocaprylate (type II) ® 90), linoleoyl-macrogol-6 glycerides (LABRAFIL® M2125CS), oleoyl-macrogol-6 glycerides (LABRAFIL® M1944CS), lauroyl-macrogol-6 glycerides (LABRAFIL® M2130CS), dipalmitosteeretaeroletaerogeorate (type I) (PRECIROL® ATO 5) and glycerol monolinoleate (MAISINE ™ 35-1).

A lipid suitable for the pharmaceutical compositions disclosed herein may be a mixture of pharmaceutically acceptable lipids. Examples of mixtures of pharmaceutically acceptable lipids include, but are not limited to, a mixture of one or more glycerolipids disclosed herein, a mixture of one or more glycol fatty acid esters disclosed herein, a mixture of several polyester and fatty acid esters disclosed herein, a mixture of several glycerides disclosed herein.

In aspects of this embodiment, the pharmaceutically acceptable lipid mixture comprises a mixture of mono-, di- and / or triglycerides having a melting point, for example, about 33 ° C, about 34 ° C, about 35 ° C, about 36 ° C, about 37 ° C, approximately 38 ° C, approximately 39 ° C, approximately 40 ° C, approximately 41 ° C, approximately 43 ° C, approximately 43 ° C, approximately 44 ° C, approximately 45 ° C, approximately 45 ° C, approximately 47 ° C, approximately 48 ° C, approximately 49 ° C, approximately 50 ° C. In aspects of this embodiment, the pharmaceutically acceptable lipid mixture comprises a mixture of mono-, di- and / or triglycerides having a melting point of, for example, from about 30 ° C to about 44 ° C, from about 30 ° C to about 45 ° C, from about 30 ° C to about 46 ° C, from about 30 ° C to about 47 ° C, from about 30 ° C to about 48 ° C, from about 30 ° C to about 49 ° C, from about 30 ° C to about 50 ° C, from about 32 ° C to about 44 ° C, from about 32 ° C to about 45 ° C, from about 32 ° C to about 46 ° C, from about 32 ° C to about 47 ° C, from approx. 32 ° C to about 48 ° C, from about 32 ° C to about 49 ° C, from about 32 ° C to about 50 ° C, from about 34 ° C to about 44 ° C, from about 34 ° C to about 45 ° C, from about 34 ° C to about 46 ° C, from about 34 ° C to about 47 ° C, from about 34 ° C to about 48 ° C, from about 34 ° C to about 49 ° C, from about 34 ° C to about 50 ° C, from about 36 ° C to about 44 ° C, from about 36 ° C to about 45 ° C, from about 36 ° C to about 46 ° C, from about 36 ° C to about 47 ° C, from about 36 ° C to about 48 ° C, from about 36 ° C to about 49 ° C, from about 36 ° C to about 50 ° C, from about 38 ° C to about 44 ° C, from at Roughly 38 ° C to about 45 ° C, from about 38 ° C to about 46 ° C, from about 38 ° C to about 47 ° C, from about 38 ° C to about 48 ° C, from about 38 ° C to about 49 ° C, from about 38 ° C to about 50 ° C, from about 40 ° C to about 44 ° C, from about 40 ° C to about 45 ° C, from about 40 ° C to about 46 ° C, from about 40 ° C to about 47 ° C, from about 40 ° C to about 48 ° C, from about 40 ° C to about 49 ° C, from about 40 ° C to about 50 ° C, from about 42 ° C to about 44 ° C, from about 42 ° C to about 45 ° C, from about 42 ° C to about 46 ° C, from about 42 ° C to about 47 ° C, from about 42 ° C to about 48 ° C, from about 42 ° C to about 49 ° C, or from about 42 ° C to about 50 ° C.

In other aspects of this embodiment, the pharmaceutically acceptable lipid mixture comprises a mixture of PEG esters and fatty acids having a melting point of, for example, 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 , approximately 48 ° C, approximately 49 ° C, approximately 50 ° C. In aspects of this embodiment, the pharmaceutically acceptable lipid mixture comprises a mixture of PEG esters and fatty acids having a melting point of, for example, from about 30 ° C to about 44 ° C, from about 30 ° C to about 45 ° C, from about 30 ° C to about 46 ° C, from about 30 ° C to about 47 ° C, from about 30 ° C to about 48 ° C, from about 30 ° C to about 49 ° C, from about 30 ° C to about 50 ° C, from about 32 ° C to about 44 ° C, from about 32 ° C to about 45 ° C, from about 32 ° C to about 46 ° C, from about 32 ° C to about 47 ° C, from about 32 ° C d about 48 ° C, from about 32 ° C to about 49 ° C, from about 32 ° C to about 50 ° C, from about 34 ° C to about 44 ° C, from about 34 ° C to about 45 ° C, from about 34 ° C to about 46 ° C, from about 34 ° C to about 47 ° C, from about 34 ° C to about 48 ° C, from about 34 ° C to about 49 ° C, from about 34 ° C to about 50 ° C, from about 36 ° C to about 44 ° C, from about 36 ° C to about 45 ° C, from about 36 ° C to about 46 ° C, from about 36 ° C to about 47 ° C, from about 36 ° C to about 48 ° C, from about 36 ° C to about 49 ° C, from about 36 ° C to about 50 ° C, from about 38 ° C to about 44 ° C, from about 38 ° C to about 45 ° C, from about 38 ° C to about 46 ° C, from about 38 ° C to about 47 ° C, from about 38 ° C to about 48 ° C, from about 38 ° C to about 49 ° C, from about 38 ° C to about 50 ° C, from about 40 ° C to about 44 ° C, from about 40 ° C to about 45 ° C, from about 40 ° C to about 46 ° C, from about 40 ° C to about 47 ° C, from about 40 ° C to about 48 ° C, from about 40 ° C to about 49 ° C, from about 40 ° C to about 50 ° C, from about 42 ° C to about 44 ° C, from about 42 ° C to about 45 ° C, from about 42 ° C to about 46 ° C, from about 42 ° C to about 47 ° C, from about 42 ° C to p imerno 48 ° C, from about 42 ° C to about 49 ° C or from about 42 ° C to about 50 ° C.

In other aspects of this embodiment, the pharmaceutically acceptable lipid mixture comprises a mixture of mono-, di- and / or triglycerides and PEG esters of fatty acids having a melting point of, for example, 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. In aspects of this embodiment, the pharmaceutically acceptable lipid mixture comprises a mixture of mono-, di- and / or triglycerides and PEG esters of fatty acids having a melting point of, for example, from about 30 ° C to about 44 ° C, from about 30 ° C to about 45 ° C, from about 30 ° C to about 46 ° C, from about 30 ° C to about 47 ° C, from about 30 ° C to about 48 ° C, from about 30 ° C to about 49 ° C from about 30 ° C to about 50 ° C, from about 32 ° C to about 44 ° C, from about 32 ° C to about 45 ° C, from about 32 ° C to about 46 ° C, from about 32 ° C d about 47 ° C, from about 32 ° C to about 48 ° C, from about 32 ° C to about 49 ° C, from about 32 ° C to about 50 ° C, from about 34 ° C to about 44 ° C, from about 34 ° C to about 45 ° C, from about 34 ° C to about 46 ° C, from about 34 ° C to about 47 ° C, from about 34 ° C to about 48 ° C, from about 34 ° C to about 49 ° C, from about 34 ° C to about 50 ° C, from about 36 ° C to about 44 ° C, from about 36 ° C to about 45 ° C, from about 36 ° C to about 46 ° C, from about 36 ° C to about 47 ° C, from about 36 ° C to about 48 ° C, from about 36 ° C to about 49 ° C, from about 36 ° C to about 50 ° C, from about 38 ° C to about 44 ° C, from about 38 ° C to about 45 ° C, from about 38 ° C to about 46 ° C, from about 38 ° C to about 47 ° C, from about 38 ° C to about 48 ° C, from about 38 ° C to about 49 ° C, from about 38 ° C to about 50 ° C, from about 40 ° C to about 44 ° C, from about 40 ° C to about 45 ° C, from about 40 ° C to about 46 ° C, from about 40 ° C to about 47 ° C, from about 40 ° C to about 48 ° C, from about 40 ° C to about 49 ° C, from about 40 ° C to about 50 ° C, from about 42 ° C to about 44 ° C, from about 42 ° C to about 45 ° C, from about 42 ° C to about 46 ° C, from about 42 ° C to p imerno 47 ° C, from about 42 ° C to about 48 ° C, from about 42 ° C to about 49 ° C or from about 42 ° C to about 50 ° C.

Commercially available mixtures of pharmaceutically acceptable lipids include, but are not limited to, mixtures of PEG-6 stearate and ethylene glycol palmitostearate and PEG-32 stearate (TEFOSE® 1500; TEFOSE® 63), mixtures of triceteareth-4 phosphate and ethylene glycol palmitostearate and diethylene glycol palmitosteose® 75 palmitostefa , mixtures of glycerol monostearate and PEG-75 stearate (GELOT®), mixtures of cetyl alcohol and ethoxylated fatty alcohols (setet-2, steareth-20) (EMULCIRE®), mixtures of saturated C ₁₀ -C ₁₈ triglycerides having a melting point of about 33 ° C (GELUCIRE® 33/01), a mixture of saturated triglycerides C ₁₀ -C ₁₈ having a melting point of about 39 ° C (GELUCIRE® 39/01), a mixture of saturated triglycerides C ₁₀ -C ₁₈ having a melting point of about 43 ° C (GELUCIRE® 43/01), a mixture of glycerol monostearate 40-55 ( type I) and diglycerides (GELEOL® Mono and Diglycerides), as well as a mixture of medium chain triglycerides (LABRAFAC® Lipophile WL 1349).

In aspects of the present disclosure, in particular, a pharmaceutically acceptable stabilizing agent is disclosed. The stabilizing agent reduces or eliminates the formation of esters of the therapeutic compound, which may result from undesired interaction with the particular solvent used. The stabilizing agent includes, without limitation, water, a tread acid containing a fatty acid component and acetic acid, ethyl acetate, sodium acetate / acetic acid (E262), monoglyceride, acetylated monoglyceride, diglyceride, acetylated monoglyceride, acetylated fatty acid and diglyceride.

In one embodiment, the pharmaceutically acceptable stabilizing agent may include a pharmaceutically acceptable emulsifier. An emulsifier (also known as an emulsifier) is a substance that stabilizes an emulsion containing a liquid dispersed phase and a liquid dispersed phase, increasing its kinetic stability. Thus, in a situation where the solvent and adjuvant used to create the pharmaceutical composition disclosed herein are usually not mixed, the emulsifier disclosed herein is used to create a uniform and stable emulsion. An emulsifier includes, without limitation, a surfactant, polysaccharide, lectin and phospholipid.

In one aspect of this embodiment, the emulsifier may include a surfactant. As used herein, the term “surfactant” refers to a natural or synthetic amphiphilic compound. The surfactant may be non-ionic, zwitterionic or ionic. Non-limiting examples of surfactants include polysorbates such as 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) such as Poloxamer 124 (PLURONIC® L44), Poloxamer 181 (PLURONIC® L61), Poloxamer 182 (PLURONIC® L62), Poloxamer 184 (PLURONIC® L64), Poloxamer 188 (PLURONIC® L64), Poloxamer 188 (PLURONIC® F68) Poloxamer 237 (PLURONIC® F87), Poloxamer 338 (PLURONIC® L108), Poloxamer 407 (PLURONIC® F127), polyoxyethylene glycol dodecyl esters such as BRIJ® 30 and BRIJ® 35; 2-dodecoxyethanol (LUBROL®-PX); polyoxyethylene octyl phenyl ether (TRITON® X-100); sodium dodecyl sulfate (SDS); 3 - [(3-cholamidopropyl) dimethylammonium] -1-propanesulfonate (CHAPS); 3 - [(3-cholamidopropyl) dimethylammonium] -2-hydroxy-1-propanesulfonate (CHAPSO); sucrose monolaurate; and sodium cholate. Other non-limiting examples of auxiliary surfactants can be found, for example, in Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, supra, (2001); and Rowe, supra, (2003), which are incorporated herein by reference in their entirety.

In an aspect of this embodiment, the emulsifier may include a polysaccharide. Non-limiting examples of polysaccharides include guar gum, agar, alginate, Calgene, dextran (e.g., dextran 1K, dextran 4K, dextran 40K, dextran 60K and dextran 70K), dextrin, glycogen, inulin, starch, a starch derivative (e.g., hydroxymethylated hydroxymethylated starch, hydroxymethylated starch, hydroxymethylated starch, hydroxymethylated starch, hydroxymethylated starch starch, hydroxypropylated starch, hydroxybutylated starch and hydroxypentylated starch), geta starch, cellulose, FICOLL, methyl cellulose (MC), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose sietilmetiltsellyulozu (HEMC), hydroxypropylmethylcellulose (HPMC); polyvinyl acetate (PVA); polyvinylpyrrolidones (PVP), also known as povidones, having a K value of less than or equal to 18, a K value of greater than 18 or less than or equal to 95, or a K value of greater than 95, like PVP 12 (KOLLIDON® 12), PVP 17 (KOLLIDON ® 17), PVP 25 (KOLLIDON® 25), PVP 30 (KOLLIDON® 30), PVP 90 (KOLLIDON® 90); and polyethyleneimines (PEI).

In an aspect of this embodiment, the emulsifier may include lectin. Lectins are sugar-binding proteins that are highly specific to their sugar molecules. Lectins can be classified by the sugar molecules with which they bind, and include, without limitation, mannose-binding lectins, galactose / N-acetylgalactosamine-binding lectins, N-acetylglucosamine-binding lectins, N-acetylneuramine-binding lectins, N-acetylneuctin-binding lectins and fucose binding lectins. Non-limiting examples of surfactants include concanavalin A, lentin lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, wheat vetch lectin, wheat germ agglutinin, elderberry lectin, Maackia agurentis leukoagglutinin, hematin agnutinis, hemataginutin from Ulex europaeus and lectin from Aleuria aurantia.

In an aspect of this embodiment, the emulsifier may include a phospholipid. The structure of the phospholipid usually contains a hydrophobic tail and a hydrophilic head and is amphipathic in nature. Most phospholipids contain diglyceride, a phosphate group and simple organic molecules such as choline; the only exception to this rule is sphingomyelin, which is a derivative of sphingosine instead of glycerol. Phospholipids include, without limitation, diacylglycerides and phosphosphingolipids. Non-limiting examples of diacylglycerides include phosphatidic acid (phosphatidate) (PA) phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin) (PC), and phosphatidylserine (PS), and phosphoinositides (phosphatidylinositol (PI), phosphatidylinositol, (PIT), bisphosphate (PIP2), and phosphatidylinositol triphosphate (PIP3). Non-limiting examples of phosphosphingolipids include ceramide phosphorylcholine (sphingomyelin) (SPH), ceramide phosphoryl ethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol.

In one embodiment, the pharmaceutically acceptable stabilizing agent does not contain a pharmaceutically acceptable emulsifier.

In another embodiment, the pharmaceutical composition does not contain a pharmaceutically acceptable emulsifier.

The pharmaceutical compositions disclosed herein act as a delivery system that enables more efficient delivery or targeted transfer of the therapeutic compound disclosed herein to a particular type of cell, tissue, organ or region of the body so as to more effectively inhibit pro-inflammatory reaction. This inhibition leads to an increase in the treatment of chronic inflammation. For example, the pharmaceutical composition disclosed herein can facilitate the delivery of a therapeutic compound disclosed herein to macrophages. One possible mechanism to achieve this selective biodistribution is to create the pharmaceutical compositions disclosed herein that take advantage of chylomicron functions. Chylomicrons are relatively large lipoprotein particles having a diameter of 75 nm to 1200 nm. Containing triglycerides (85-92%), phospholipids (6-12%), cholesterol (1-3%) and apolipoproteins (1-2%), chylomicrons transfer food lipids from the intestine to other places in the body. Chylomicrons are one of the five main groups of lipoproteins, others are VLDL, IDL, low density lipoproteins (LDL), high density lipoproteins (HDL), which allow fats and cholesterol to move in the bloodstream, which is an aqueous solution.

During digestion, fatty acids and cholesterol are processed in the gastrointestinal tract by the action of pancreatic juices, including lipases, and are emulsified by bile salts to form micelles. These micelles allow the absorption of lipids as free fatty acids by the absorbing cells of the small intestine, known as enterocytes. After entering the enterocytes, triglycerides and cholesterol are collected in immature chylomicrons. Immature chylomicrons mainly consists of triglycerides (85%) and contain some cholesterol and cholesterol esters. The main apolipoprotein component is apolipoprotein B-48 (APOB48). These immature chylomicrons are released from enterocytes by exocytosis into the mammary vessels, lymph vessels originating in the villi of the small intestine, and then are secreted into the bloodstream at the junction of the thoracic duct with the left subclavian vein.

During circulation in lymph and blood, chylomicrons exchange components with HDL. HDL gives apolipoprotein C-II (APOC2) and apolipoprotein E (APOE) to the immature chylomicron and thus turns it into a mature chylomicron (often referred to simply as “chylomicron”). APOC2 is a cofactor of lipoprotein lipase activity (LPL). After the triglycerides are distributed among storages, the chylomicron returns APOC2 to HDL (but retains APOE) and thus becomes the residual chylomicron, now measuring only 30-50 nm. APOB48 and APOE are important for identifying residual chylomicron in the liver for endocytosis and lipoprotein cleavage (VLDL, LDL and HDL). These lipoproteins are processed and stored in competent cells, including, for example, hepatocytes, adipocytes and macrophages. Thus, not limited to any particular theory, the authors suggest that when administered orally, the pharmaceutical composition disclosed herein can be processed into micelles while in the gastrointestinal tract, absorbed by enterocytes, and assemble into immature chylomicrons, remaining associated with residual chylomicrons absorbed by the liver and, finally, entering the macrophages that are present in inflamed tissues.

As another example, the pharmaceutical composition disclosed herein may facilitate the delivery of a therapeutic compound disclosed herein to dendritic cells. One possible mechanism to achieve this selective biodistribution is to create the pharmaceutical compositions disclosed herein that take advantage of the endocytosis / phagocytic activity of dendritic cells. Dendritic cells are immune cells that form part of the mammalian immune system. The main function of dendritic cells is to process antigenic 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 the innate and acquired immunity system. Dendritic cells are present in tissues in contact with the external environment, such as, for example, the skin (where there is a specialized type of dendritic cells called Langerhans cells) and the inner lining of the nose, lungs, stomach and intestines. These cells can also be found in an immature state in the blood. After activation, they migrate to the lymph nodes, where they interact with T and B cells to initiate and specialize an adaptive immune response. Dendritic cells are known to endocytize and phagocytize lipid particles as part of their environmental monitoring and antigen presentation processes. Not wanting to be limited to any particular theory, the authors suggest that, with topical or inhalation administration, the pharmaceutical composition disclosed herein can penetrate the skin or inner lining of the nose, lungs, stomach and intestines, endocytically / phagocytosed by dendritic cells, and ultimately get into T cells and / or B cells that are present in inflamed tissues.

In aspects of the present description, in particular, a method for producing the pharmaceutical composition disclosed herein is disclosed. The method disclosed herein includes the step of contacting a pharmaceutically acceptable adjuvant disclosed herein with a therapeutic compound disclosed herein under conditions allowing the therapeutic compound to dissolve in a pharmaceutically acceptable adjuvant, thereby forming a pharmaceutical composition disclosed in this document.

In aspects of the present description, in particular, a method for producing the pharmaceutical composition disclosed herein is disclosed. The method disclosed herein includes the steps of a) contacting a pharmaceutically acceptable solvent disclosed herein with a therapeutic compound disclosed herein under conditions allowing the therapeutic compound to dissolve in a pharmaceutically acceptable solvent, thereby forming a solution; and b) contacting the solution obtained in step (a) with a pharmaceutically acceptable adjuvant disclosed herein under conditions allowing the formation of a pharmaceutical composition. The production methods disclosed herein may further include step (c) of removing the pharmaceutically acceptable solvent from the pharmaceutical composition.

The amount of therapeutic compound that is contacted with a pharmaceutically acceptable solvent in step (a) of the method may be any desired amount. Factors used to determine the amount of therapeutic compound used include, but are not limited to, the final amount of the therapeutic compound desired in the pharmaceutical composition, the desired concentration of the therapeutic compound in solution, the hydrophobicity of the therapeutic compound, the lipophobicity of the therapeutic compound, the temperature at which the contacting step is carried out (a) , and the time during which the contacting stage is carried out (a).

The volume of the pharmaceutically acceptable solvent used in step (a) of the process may be any desired volume. Factors used to determine the amount of a pharmaceutically acceptable solvent used include, but are not limited to, the desired final amount of the pharmaceutical composition, the desired concentration of the therapeutic compound in solution, the hydrophobicity of the therapeutic compound, and the lipophobicity of the therapeutic compound.

In aspects of this embodiment, the amount of therapeutic compound that is contacted with the solvent in step (a) may be, for example, 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 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg or at least 1500 mg. In other aspects of this embodiment, the amount of therapeutic compound that is contacted with the solvent in step (a) may be in the range of, for example, from about 10 mg to about 100 mg, from about 50 mg to about 150 mg, from about 100 mg up to about 250 mg, from about 150 mg to about 350 mg, from about 250 mg to about 500 mg, from about 350 mg to about 600 mg, from about 500 mg to about 750 mg, from about 600 mg to about 900 mg, from about 750 mg to about 1000 mg, from about 850 mg to about 1200 mg or from pr approximately 1000 mg to about 1500 mg. In other aspects of this embodiment, the amount of therapeutic compound that dissolves in the solvent in step (a) may range from, for example, from about 10 mg to about 250 mg, from about 10 mg to about 500 mg, from about 10 mg up to about 750 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 1500 mg, from about 50 mg to about 250 mg, from about 50 mg to about 500 mg, from about 50 mg to about 750 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 1500 mg, from about 10 0 mg to about 250 mg, from about 100 mg to about 500 mg, from about 100 mg to about 750 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 1500 mg, from about 200 mg to about 500 mg, from about 200 mg to about 750 mg, from about 200 mg to about 1000 mg, or from about 200 mg to about 1500 mg.

Step (a) can be carried out at room temperature in order to allow the therapeutic compound to completely dissolve in a pharmaceutically acceptable solvent. However, in other embodiments of the method, step (a) can be performed at a temperature above room temperature. In aspects of this embodiment, step (a) can be performed at, for example, above 21 ° C, above 25 ° C, above 30 ° C, above 35 ° C or above 37 ° C, above 40 ° C, above 42 ° C, above 45 ° C, above 50 ° C, above 55 ° C or above 60 ° C. In aspects of this embodiment, step (a) can be carried out at a temperature of, for example, from about 20 ° C to about 30 ° C, from about 25 ° C to about 35 ° C, from about 30 ° C to about 40 ° C, from about 35 ° C to about 45 ° C, from about 40 ° C to about 50 ° C, from about 45 ° C to about 55 ° C, or from about 50 ° C to about 60 ° C. In some cases, step (a) can be performed at a temperature below room temperature in order to allow the therapeutic compound to completely dissolve in the solvent. However, in other embodiments of the method, step (a) can be performed at a temperature below room temperature, for example, below 10 ° C, above 5 ° C, above 0 ° C, above -10 ° C, or above -20 ° C. The contacting in step (a) may include mixing the therapeutic compound and a pharmaceutically acceptable solvent, for example, by stirring, inverting, voicing or shaking. Mixing can be carried out for, for example, 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 time until the therapeutic compound is completely dissolved in the solvent.

After contacting, the concentration of the therapeutic compound disclosed herein in the solution may be any desired concentration. In aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in a solution may be, for example, 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 1000 mg / ml, or at least 1200 mg / ml. In other aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in a solution may be, for example, at most 1000 mg / ml, at most 1100 mg / ml, at most 1200 mg / ml, at most 1300 mg / ml at most 1400 mg / ml, at most 1500 mg / ml, at most 2000 mg / ml, at most 2000 mg / ml or at most 3000 mg / ml. In other aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in a solution may range from, for example, from about 0.00001 mg / ml to about 3000 mg / ml, from about 0.0001 mg / ml to about 3000 mg / ml, from about 0.01 mg / ml to about 3000 mg / ml, from about 0.1 mg / ml to about 3000 mg / ml, from about 1 mg / ml to about 3000 mg / ml, from about 250 mg / ml to about 3000 mg / ml, from about 500 mg / ml to about 3000 mg / ml, from about 750 mg / ml to about 3000 mg / ml, from about 1000 mg / ml to about 30 00 mg / ml, from about 100 mg / ml to about 2000 mg / ml, from about 250 mg / ml to about 2000 mg / ml, from about 500 mg / ml to about 2000 mg / ml, from about 750 mg / ml up to about 2000 mg / ml, from about 1000 mg / ml to about 2000 mg / ml, from about 100 mg / ml to about 1500 mg / ml, from about 250 mg / ml to about 1500 mg / ml, from about 500 mg / ml to about 1500 mg / ml, from about 750 mg / ml to about 1500 mg / ml, from about 1000 mg / ml to about 1500 mg / ml, from about 100 mg / ml to about 1200 mg / ml, from about 250 mg / ml to about 1200 mg / ml, from about 500 mg / ml to about 1200 mg / ml, from about 750 mg / ml to about 1200 mg / ml, from about 1000 mg / ml to about 1200 mg / ml, from about 100 mg / ml to about 1000 mg / ml, from about 250 mg / ml to about 1000 mg / ml, from about 500 mg / ml to about 1000 mg / ml, from about 750 mg / ml to about 1000 mg / ml, from about 100 mg / ml to about 750 mg / ml, from about 250 mg / ml to about 750 mg / ml, from about 500 mg / ml to about 750 mg / ml, from about 100 mg / ml to about 500 mg / ml, from about 250 mg / ml to about 500 mg / ml, from about 0.00001 mg / ml to about 0.0001 mg / ml, from about 0.00001 mg / ml to about 0.001 mg / ml, from about 0.00001 mg / ml to approx Typically 0.01 mg / ml, from about 0.00001 mg / ml to about 0.1 mg / ml, from about 0.00001 mg / ml to about 1 mg / ml, from about 0.001 mg / ml to about 0, 01 mg / ml, from about 0.001 mg / ml to about 0.1 mg / ml, from about 0.001 mg / ml to about 1 mg / ml, from about 0.001 mg / ml to about 10 mg / ml, or from about 0.001 mg / ml to about 100 mg / ml.

The volume of the pharmaceutically acceptable adjuvant used in step (b) of the method may be any desired volume. Factors used to determine the volume of pharmaceutically acceptable adjuvant used include, but are not limited to, the desired final amount of the pharmaceutical composition, the desired concentration of therapeutic compound in the pharmaceutical composition, the solvent to adjuvant ratio used, and the miscibility of the solvent and adjuvant.

In aspects of this embodiment, the ratio of solvent to adjuvant may be, for example, 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 at least 1: 8, at least 1: 9, at least 1:10, at least 1:15, at least 1:20, or at least 1:25. In other aspects of this embodiment, the ratio of solvent to adjuvant may be in the range of, for example, from about 5: 1 to about 1:25, from about 4: 1 to about 1:25, from about 3: 1 to about 1:25 , from about 2: 1 to about 1:25, from about 0: 1 to about 1:25, from about 1: 1 to about 1:25, from about 1: 2 to about 1:25, from about 1: 3 to about 1:25, from about 1: 4 to about 1:25, from about 1: 5 to about 1:25, from about 5: 1 to about 1:20, from about 4: 1 to about 1:20, from about 3: 1 to about 1:20; from about 2: 1 to example about 1:20, from about 0: 1 to about 1:20, from about 1: 1 to about 1:20, from about 1: 2 to about 1:20, from about 1: 3 to about 1:20, from from about 1: 4 to about 1:20, from about 1: 5 to about 1:20, from about 5: 1 to about 1:15, from about 4: 1 to about 1:15, from about 3: 1 to about 1:15, from about 0: 1 to about 1:15, from about 2: 1 to about 1:15, from about 1: 1 to about 1:15, from about 1: 2 to about 1:15, from about 1: 3 to about 1:15, from about 1: 4 to about 1:15, from about 1: 5 to about 1:15, from about 5: 1 to about 1:12, from about 4: 1 to about 1 : 12, from example about 3: 1 to about 1:12, from about 2: 1 to about 1:12, from about 0: 1 to about 1:12, from about 1: 1 to about 1:12, from about 1: 2 to about 1:12, from about 1: 3 to about 1:12, from about 1: 4 to about 1:12, from about 1: 5 to about 1:12, from about 1: 6 to about 1:12, from about 1: 7 to about 1:12, from about 1: 8 to about 1:12, from about 5: 1 to about 1:10, from about 4: 1 to about 1:10, from about 3: 1 to about 1 : 10, from about 2: 1 to about 1:10, from about 0: 1 to about 1:10, from about 1: 1 to about 1:10, from about 1: 2 to about 1:10, from about 1 : 3 to approximate 1:10, from about 1: 4 to about 1:10, from about 1: 5 to about 1:10, from about 1: 6 to about 1:10, from about 1: 7 to about 1:10, or from about 1: 8 to about 1:10.

Stage (b) can be carried out at room temperature in order to allow the solution containing the therapeutic compound to form a pharmaceutical composition. However, in other embodiments of the method, step (b) can be carried out at a temperature above room temperature. In aspects of this embodiment, step (b) can be performed at, for example, above 21 ° C, above 25 ° C, above 30 ° C, above 35 ° C or above 37 ° C, above 40 ° C, above 42 ° C, above 45 ° C, above 50 ° C, above 55 ° C or above 60 ° C. In aspects of this embodiment, step (a) can be carried out at a temperature in the range of, for example, from about 20 ° C to about 30 ° C, from about 25 ° C to about 35 ° C, from about 30 ° C to about 40 ° C, from about 35 ° C to about 45 ° C, from about 40 ° C to about 50 ° C, from about 45 ° C to about 55 ° C, or from about 50 ° C to about 60 ° C. In some cases, step (b) can be performed at a temperature below room temperature in order to allow the therapeutic compound to completely dissolve in a pharmaceutically acceptable solvent. However, in other embodiments of the method, step (b) can be performed at a temperature below room temperature, for example, below 10 ° C, above 5 ° C, above 0 ° C, above -10 ° C, or above -20 ° C. The contacting in step (b) may include mixing the solution and a pharmaceutically acceptable adjuvant, for example, by stirring, inverting, voicing or shaking. Mixing can be carried out for, for example, 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 time until the formation of the pharmaceutical composition.

In some embodiments, a rapid cooling step may be used to lower the temperature of the pharmaceutical composition disclosed herein after it is formed. For example, the quick cooling step can be used in procedures where temperatures above room temperature are used to allow the therapeutic compound to completely dissolve in a pharmaceutically acceptable solvent and / or to allow the pharmaceutical composition to form from a solution containing the therapeutic compound. In aspects of this embodiment, the rapid cooling step results in a temperature drop of, for example, about 30 ° C in 20 minutes, about 25 ° C in 20 minutes, about 20 ° C in 20 minutes, about 15 ° C in 20 minutes, about 30 ° C in 15 minutes, about 25 ° C in 15 minutes, about 20 ° C in 15 minutes, about 15 ° C in 15 minutes, about 30 ° C in 10 minutes, about 25 ° C in 10 minutes, about 20 ° C in 10 minutes, about 15 ° C in 10 minutes, about 30 ° C in 5 minutes, about 25 ° C in 5 minutes, about 20 ° C in 5 minutes , at about 15 ° C in 5 minutes. In other aspects of this embodiment, the rapid cooling step reduces the temperature, for example, from about 20 ° C to about 30 ° C in 20 minutes, from about 20 ° C to about 30 ° C in 15 minutes, from about 20 ° C to about 30 ° C in 10 minutes, from about 20 ° C to about 30 ° C in 5 minutes, from about 15 ° C to about 25 ° C in 20 minutes, from about 15 ° C to about 25 ° C in 15 minutes from about 15 ° C to about 25 ° C in 10 minutes, from about 15 ° C to about 25 ° C in 5 minutes, from about 10 ° C to about 20 ° C in 20 minutes, from about 10 ° C to about 20 ° C in 15 minutes t about 10 ° C to about 20 ° C for 10 minutes, or from about 10 ° C to about 20 ° C for 5 minutes.

In other aspects of this embodiment, the rapid cooling step results in a temperature drop of, for example, about 2.0 ° C / minute, about 1.9 ° C / minute, about 1.3 ° C / minute, about 1.7 ° C / minute, approximately 1.6 ° C / minute, approximately 1.5 ° C / minute, approximately 1.4 ° C / minute, approximately 1.3 ° C / minute, approximately 1.2 ° C / minute, approximately 1.1 ° C / minute, approximately 1.0 ° C / minute, approximately 0.9 ° C / minute, approximately 0.8 ° C / minute, approximately 0.7 ° C / minute, approximately 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 imerno 0,1 ° C / minute. In other aspects of this embodiment, the rapid cooling step results in a temperature drop of, for example, from about 0.1 ° C to about 0.4 ° C / min, from about 0.2 ° C to about 0.6 ° C / minute, from about 0.4 ° C to about 0.8 ° C / minute, from about 0.6 ° C to about 1.0 ° C / minute, from about 0.8 ° C to about 1.2 ° C / minute, from about 1.0 ° C to about 1.4 ° C / minute, from about 1.2 ° C to about 1.6 ° C / minute, from about 1.4 ° C to about 1.8 ° C / minute, from about 1.6 ° C to about 2.0 ° C / minute, from about 0.1 ° C to about 0.5 ° C / minute, from at about 0.5 ° C to about 1.0 ° C / minute, from about 1.0 ° C to about 1.5 ° C / minute, from about 1.5 ° C to about 2.0 ° C / minute, from about 0.5 ° C to about 1.5 ° C / minute; or from about 1.0 ° C to about 2.0 ° C / minute.

In some embodiments, a temperature above room temperature may be used, applied either in step (a), or in step (b), or in both steps, to remove the solvent from the pharmaceutical composition. In another embodiment, removing the solvent from the pharmaceutical composition requires a separate step (c). In step (c), solvent removal from the pharmaceutical composition can be performed using one of a variety of procedures known in the art, including, but not limited to, evaporation, dialysis, evaporation, lyophilization, and filtration. These solvent removal procedures can be carried out at atmospheric pressure, under reduced pressure or in vacuum, and either at room temperature or at temperatures requiring heating.

In one embodiment, step (c) can completely remove the pharmaceutically acceptable solvent from the pharmaceutical composition disclosed herein. In aspects of this embodiment, step (c) may provide for removal of, for example, 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 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% of a pharmaceutically acceptable solvent from F the pharmaceutical composition disclosed herein.

Stage (C) is carried out at a temperature that allows the evaporation of the pharmaceutically acceptable solvent disclosed in this document, and thus, the temperature depends on the solvent. Factors that affect the evaporation temperature of the 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 used pressure, set time of complete evaporation. In general, the pharmaceutical composition will require heating if the evaporation step is carried out at atmospheric pressure, for example 1 atm. However, under high vacuum conditions, the evaporation stage can be carried out at a temperature below room temperature, for example, below 22 ° C.

In one embodiment of the invention, the removal of the solvent from the pharmaceutical composition disclosed herein can be carried out at current atmospheric pressure and at a temperature above room temperature. In aspects of this embodiment, the removal of solvent from the pharmaceutical composition disclosed herein can be carried out at current atmospheric pressure and at a temperature, for example, above 25 ° C, above 30 ° C, above 35 ° C, above 40 ° C, above 45 ° C, above 50 ° C, above 55 ° C, above 60 ° C, above 65 ° C, above 70 ° C, above 80 ° C or above 25 ° C. In other aspects of this embodiment, the removal of solvent from the pharmaceutical composition disclosed herein can be carried out at current atmospheric pressure and at a temperature in the range of, for example, from about 25 ° C to about 100 ° C, from about 25 ° C to about 95 ° C, from about 25 ° C to about 90 ° C, from about 25 ° C to about 85 ° C, from about 25 ° C to about 80 ° C, from about 25 ° C to about 75 ° C, from about 25 ° C to about 70 ° C, from about 25 ° C to about 65 ° C, or from about 25 ° C to about 60 ° C.

In another embodiment, the removal of solvent from the pharmaceutical composition disclosed herein can be carried out under vacuum and at a temperature below room temperature. In aspects of this embodiment, the removal of solvent from the pharmaceutical composition disclosed herein can be carried out under vacuum and at, for example, below 20 ° C, below 18 ° C, below 16 ° C, below 14 ° C, below 12 ° C, below 10 ° C, below 8 ° C, below 6 ° C, below 4 ° C, below 2 ° C or below 0 ° C. In other aspects of this embodiment, the removal of solvent from the pharmaceutical composition disclosed herein can be carried out under vacuum and at a temperature in the range of, for example, from about -20 ° C to about 20 ° C, from about -20 ° C to about 18 ° C, from about -20 ° C to about 16 ° C, from about -20 ° C to about 14 ° C, from about -20 ° C to about 12 ° C, from about -20 ° C to about 10 ° C, from about -20 ° C to about 8 ° C, from about -20 ° C to about 6 ° C, from about -20 ° C to about 4 ° C, from about -20 ° C to about 2 ° C, from approximately -20 ° C to about 0 ° C, from about -15 ° C to about 20 ° C, from about -10 ° C to about 20 ° C, from about -5 ° C to about 20 ° C, from about 0 ° C to about 20 ° C, from about -10 ° C to about 20 ° C, from about -10 ° C to about 18 ° C, from about -10 ° C to about 16 ° C, from about -10 ° C to about 14 ° C from about -10 ° C to about 12 ° C, from about -10 ° C to about 10 ° C, from about -10 ° C to about 8 ° C, from about -10 ° C to about 6 ° C, from from about -10 ° C to about 4 ° C, from about -10 ° C to about 2 ° C, or from about -10 ° C to about 0 ° C.

The final concentration of the therapeutic compound disclosed herein in the pharmaceutical composition disclosed herein may be any desired concentration. In an aspect of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition may be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition may be, for example, 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 at least 100 mg / ml, at least 200 mg / ml, at least 500 mg / ml, at least 700 mg / ml, at least 1000 mg / ml, or at least 1200 mg / ml. In other aspects of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition may be, for example, at most 1000 mg / ml, at most 1100 mg / ml, at most 1200 mg / ml, at most 1300 mg / ml, at most 1400 mg / ml, at most 1500 mg / ml, at most 2000 mg / ml, at most 2000 mg / ml or at most 3000 mg / ml. In other aspects of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition may range from, for example, from about 0.00001 mg / ml to about 3000 mg / ml, from about 0.0001 mg / ml to about 3000 mg / ml, from about 0.01 mg / ml to about 3000 mg / ml, from about 0.1 mg / ml to about 3000 mg / ml, from about 1 mg / ml to about 3000 mg / ml, from about 250 mg / ml to about 3000 mg / ml, from about 500 mg / ml to about 3000 mg / ml, from about 750 mg / ml to about 3000 mg / ml, from about 1000 mg / ml to about 3000 mg / ml, from approx Roughly 100 mg / ml to about 2000 mg / ml, from about 250 mg / ml to about 2000 mg / ml, from about 500 mg / ml to about 2000 mg / ml, from about 750 mg / ml to about 2000 mg / ml from about 1000 mg / ml to about 2000 mg / ml, from about 100 mg / ml to about 1500 mg / ml, from about 250 mg / ml to about 1500 mg / ml, from about 500 mg / ml to about 1500 mg / ml, from about 750 mg / ml to about 1500 mg / ml, from about 1000 mg / ml to about 1500 mg / ml, from about 100 mg / ml to about 1200 mg / ml, from about 250 mg / ml to about 1200 mg / ml, from about 500 mg / ml to about 1200 mg / ml, from about 750 mg / ml to approx. Typically 1200 mg / ml, from about 1000 mg / ml to about 1200 mg / ml, from about 100 mg / ml to about 1000 mg / ml, from about 250 mg / ml to about 1000 mg / ml, from about 500 mg / ml to about 1000 mg / ml, from about 750 mg / ml to about 1000 mg / ml, from about 100 mg / ml to about 750 mg / ml, from about 250 mg / ml to about 750 mg / ml, from about 500 mg / ml to about 750 mg / ml, from about 100 mg / ml to about 500 mg / ml, from about 250 mg / ml to about 500 mg / ml, from about 0.00001 mg / ml to about 0.0001 mg / ml, from about 0.00001 mg / ml to about 0.001 mg / ml, from about 0.00001 mg / ml to about 0.01 mg / ml, about t about 0.00001 mg / ml to about 0.1 mg / ml, from about 0.00001 mg / ml to about 1 mg / ml, from about 0.001 mg / ml to about 0.01 mg / ml, from about 0.001 mg / ml to about 0.1 mg / ml, from about 0.001 mg / ml to about 1 mg / ml, from about 0.001 mg / ml to about 10 mg / ml, or from about 0.001 mg / ml to about 100 mg / ml .

A pharmaceutical composition prepared using the methods disclosed herein may be formulated for topical or systemic delivery using topical, enteral, or parenteral routes of administration. In addition, the therapeutic compound disclosed herein may be incorporated into a pharmaceutical composition individually, or may be incorporated into a single pharmaceutical composition together with one or more other therapeutic compounds disclosed herein.

A pharmaceutical composition obtained using the methods disclosed herein may be a liquid composition, a semi-solid composition, or a solid composition. The composition disclosed herein may be formulated so as to produce a single phase, such as, for example, an oil or a solid. Alternatively, the composition disclosed herein may be formulated so as to produce two phases, such as, for example, an emulsion. The pharmaceutical composition disclosed herein for such administration may be prepared in accordance with any method known in the art for the manufacture of pharmaceutical compositions. Semi-solid formulations suitable for topical administration include, but are not limited to, ointments, creams, balms, and gels.

The liquid composition can be obtained using various lipids, such as oils of other fatty acids, which remain liquid in a given temperature range. In an embodiment of the invention, the pharmaceutical composition disclosed herein is liquid at room temperature. In aspects of this embodiment, the pharmaceutical composition disclosed herein may be formulated to be a liquid at a temperature of, for example, about 25 ° C or higher, about 23 ° C or higher, about 2 ° C or higher, approximately 19 ° C or higher, approximately 17 ° C or higher, approximately 15 ° C or higher, approximately 12 ° C or higher, approximately 10 ° C or higher, approximately 8 ° C or higher, approximately 6 ° C or higher, approximately 4 ° C or higher or about 0 ° C or higher.

In liquid and semi-solid formulations, the concentration of the therapeutic compound disclosed herein can typically be from about 50 mg / ml to about 1000 mg / ml. In aspects of this embodiment, the therapeutically effective amount of a therapeutic compound disclosed herein may be, for example, from about 50 mg / ml to about 100 mg / ml, from about 50 mg / ml to about 200 mg / ml, from about 50 mg / ml to about 300 mg / ml, from about 50 mg / ml to about 400 mg / ml, from about 50 mg / ml to about 500 mg / ml, from about 50 mg / ml to about 600 mg / ml, from about 50 mg / ml to about 700 mg / ml, from about 50 mg / ml to about 800 mg / ml, from about 50 mg / ml to about 900 mg / ml, from about 50 mg / ml to about 1000 mg / ml, from about 100 mg / ml to about 200 mg / ml, from about 100 mg / ml to about 300 mg / ml, from about 100 mg / ml to about 400 mg / ml, from about 100 mg / ml to about 500 mg / ml, from about 100 mg / ml to about 600 mg / ml, from about 100 mg / ml to about 700 mg / ml, from about 100 mg / ml to about 800 mg / ml, from about 100 mg / ml to about 900 mg / ml, from about 100 mg / ml to about 1000 mg / ml, from about 200 mg / ml to about 300 mg / ml, from about 200 mg / ml to about 400 mg / ml, from about 200 mg / ml to about 500 mg / ml, from about 200 mg / ml to about 600 mg / ml, from an example about 200 mg / ml to about 700 mg / ml, from about 200 mg / ml to about 800 mg / ml, from about 200 mg / ml to about 900 mg / ml, from about 200 mg / ml to about 1000 mg / ml from about 300 mg / ml to about 400 mg / ml, from about 300 mg / ml to about 500 mg / ml, from about 300 mg / ml to about 600 mg / ml, from about 300 mg / ml to about 700 mg / ml, from about 300 mg / ml to about 800 mg / ml, from about 300 mg / ml to about 900 mg / ml, from about 300 mg / ml to about 1000 mg / ml, from about 400 mg / ml to about 500 mg / ml, from about 400 mg / ml to about 600 mg / ml, from about 400 mg / ml to about 700 mg / ml, from about 400 mg / ml to about 800 mg / ml, from about 400 mg / ml to about 900 mg / ml, from about 400 mg / ml to about 1000 mg / ml, from about 500 mg / ml to about 600 mg / ml, from about 500 mg / ml to about 700 mg / ml, from about 500 mg / ml to about 800 mg / ml, from about 500 mg / ml to about 900 mg / ml, from about 500 mg / ml about 1000 mg / ml, from about 600 mg / ml to about 700 mg / ml, from about 600 mg / ml to about 800 mg / ml, from about 600 mg / ml to about 900 mg / ml, or from about 600 mg / ml to about 1000 mg / ml.

In semi-solid and solid formulations, the amount of therapeutic compound disclosed herein can typically be from about 0.01% to about 45% by weight. In aspects of this embodiment, the amount of therapeutic compound disclosed herein may be, for example, from about 0.1% to about 45% by weight, from about 0.1% to about 40% by weight, from about 0.1% up to about 35% by weight, from about 0.1% to about 30% by weight, from about 0.1% to about 25% by weight, from about 0.1% to about 20% by weight, from about 0, 1% to about 15% by weight, from about 0.1% to about 10% by weight, from about 0.1% to about 5% by weight, from about 1% to about 45% by weight, from about 1% to approximate 40% by weight, from about 1% to about 35% by weight, from about 1% to about 30% by weight, from about 1% to about 25% by weight, from about 1% to about 20% by weight, from about 1% to about 15% by weight, from about 1% to about 10% by weight, from about 1% to about 5% by weight, from about 5% to about 45% by weight, from about 5% to about 40 % by weight, from about 5% to about 35% by weight, from about 5% to about 30% by weight, from about 5% to about 25% by weight, from about 5% to about 20% by weight, from about 5% to about 15% by weight, from about 5% about 10% by weight, from about 10% to about 45% by weight, from about 10% to about 40% by weight, from about 10% to about 35% by weight, from about 10% to about 30% by weight from about 10% to about 25% by weight, from about 10% to about 20% by weight, from about 10% to about 15% by weight, from about 15% to about 45% by weight, from about 15% to about 40% by weight, from about 15% to about 35% by weight, from about 15% to about 30% by weight, from about 15% to about 25% by weight, from about 15% to about 20% by weight, from about 20% to about 45% by ma ccc, from about 20% to about 40% by weight, from about 20% to about 35% by weight, from about 20% to about 30% by weight, from about 20% to about 25% by weight, from about 25% up to about 45% by weight, from about 25% to about 40% by weight, from about 25% to about 35% by weight, or from about 25% to about 30% by weight.

In one embodiment, the liquid composition comprises a therapeutic compound, glycol ether, partially hydrogenated fat, oil and alcohol. In an aspect of this embodiment, the liquid composition contains from about 15% to about 35% by weight of the therapeutic compound, from about 5% to about 25% by weight of glycol ether, from about 15% to about 40% by weight of partially hydrogenated fat, from about 15% to about 40% oil and from about 1% to about 15% alcohol. In another aspect of this embodiment, the liquid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 10% to about 20% by weight of glycol ether, from about 20% to about 35% by weight of partially hydrogenated fat, from from about 20% to about 35% oil; and from about 2% to about 10% alcohol. In yet another aspect of this embodiment, the liquid composition comprises from about 23% to about 27% by weight of the therapeutic compound, from about 13% to about 17% by weight of glycol ether, from about 25% to about 30% by weight of partially hydrogenated fat, from about 25% to about 30% oil; and from about 4% to about 8% alcohol. In a third aspect of this embodiment, the liquid composition comprises from about 24% to about 26% by weight of the therapeutic compound, from about 14% to about 16% by weight of glycol ether, from about 26% to about 28% by weight of partially hydrogenated fat, from from about 26% to about 28% oil; and from about 5% to about 7% alcohol. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

In another embodiment, the liquid composition comprises a therapeutic compound, glycol ether, glyceryl monolinoleate, oil and alcohol. In an aspect of this embodiment, the liquid composition contains from about 15% to about 35% by weight of the therapeutic compound, from about 5% to about 25% by weight of glycol ether, from about 15% to about 40% by weight of glyceryl monolinoleate, from about 15 % to about 40% oil and from about 1% to about 15% alcohol. In another aspect of this embodiment, the liquid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 10% to about 20% by weight of glycol ether, from about 20% to about 35% by weight of glyceryl monolinoleate, from about 20 % to about 35% oil and from about 2% to about 10% alcohol. In yet another aspect of this embodiment, the liquid composition comprises from about 23% to about 27% by weight of the therapeutic compound, from about 13% to about 17% by weight of glycol ether, from about 25% to about 30% by weight of glyceryl monolinoleate, from about 25% to about 30% oil and from about 4% to about 8% alcohol. In a third aspect of this embodiment, the liquid composition comprises from about 24% to about 26% by weight of the therapeutic compound, from about 14% to about 16% by weight of glycol ether, from about 26% to about 28% by weight of glyceryl monolinoleate, from about 26 % to about 28% oil and from about 5% to about 7% alcohol. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

In another embodiment, the liquid composition comprises ibuprofen, diethylene glycol monoethyl ether, glyceryl monolinoleate, oil and alcohol. In an aspect of this embodiment, the liquid composition contains from about 15% to about 35% by weight of ibuprofen, from about 5% to about 25% by weight of diethylene glycol monoethyl ether, from about 15% to about 40% by weight of glyceryl monolinoleate, from about 15 % to about 40% oil and from about 1% to about 15% alcohol. In another aspect of this embodiment, the liquid composition comprises from about 20% to about 30% by weight of ibuprofen, from about 10% to about 20% by weight of diethylene glycol monoethyl ether, from about 20% to about 35% by weight of glyceryl monolinoleate, from about 20 % to about 35% oil and from about 2% to about 10% alcohol. In yet another aspect of this embodiment, the liquid composition comprises from about 23% to about 27% by weight of ibuprofen, from about 13% to about 17% by weight of diethylene glycol monoethyl ether, from about 25% to about 30% by weight of glyceryl monolinoleate, from about 25% to about 30% oil and from about 4% to about 8% alcohol. In a third aspect of this embodiment, the liquid composition contains from about 24% to about 26% by weight of ibuprofen, from about 14% to about 16% by weight of diethylene glycol monoethyl ether, from about 26% to about 28% by weight of glyceryl monolinoleate, from about 26 % to about 28% oil and from about 5% to about 7% alcohol. In other aspects of this embodiment, ibuprofen may be a free acid or an ibuprofen salt. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

In one embodiment, the liquid composition comprises a therapeutic compound, an alcohol ester, and an oil. In an aspect of this embodiment, the liquid composition comprises from about 1% to about 10% by weight of a therapeutic compound, from about 1% to about 10% by weight of an alcohol ester, and from about 80% to about 98% of an oil. In another aspect of this embodiment, the liquid composition comprises from about 2% to about 8% by weight of a therapeutic compound, from about 1% to about 7% by weight of an alcohol ester, and from about 85% to about 97% of an oil. In yet another aspect of this embodiment, the liquid composition comprises from about 3% to about 7% by weight of a therapeutic compound, from about 2% to about 6% by weight of an alcohol ester, and from about 87% to about 95% of an oil. In a third aspect of this embodiment, the liquid composition comprises from about 4% to about 6% by weight of the therapeutic compound, from about 3% to about 5% by weight of an alcohol ester, and from about 90% to about 92% of an oil. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

In another embodiment, the liquid composition comprises a therapeutic compound, ethyl acetate and oil. In an aspect of this embodiment, the liquid composition comprises from about 1% to about 10% by weight of the therapeutic compound, from about 1% to about 10% by weight of ethyl acetate, and from about 80% to about 98% oil. In another aspect of this embodiment, the liquid composition comprises from about 2% to about 8% by weight of the therapeutic compound, from about 1% to about 7% by weight of ethyl acetate, and from about 85% to about 97% oil. In yet another aspect of this embodiment, the liquid composition comprises from about 3% to about 7% by weight of the therapeutic compound, from about 2% to about 6% by weight of ethyl acetate, and from about 87% to about 95% oil. In a third aspect of this embodiment, the liquid composition comprises from about 4% to about 6% by weight of the therapeutic compound, from about 3% to about 5% by weight of ethyl acetate, and from about 90% to about 92% oil. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

In another embodiment, the liquid composition comprises ibuprofen, ethyl acetate and oil. In an aspect of this embodiment, the liquid composition comprises from about 1% to about 10% by weight of ibuprofen, from about 1% to about 10% by weight of ethyl acetate, and from about 80% to about 98% oil. In another aspect of this embodiment, the liquid composition comprises from about 2% to about 8% by weight of ibuprofen, from about 1% to about 7% by weight of ethyl acetate, and from about 85% to about 97% oil. In yet another aspect of this embodiment, the liquid composition comprises from about 3% to about 7% by weight of ibuprofen, from about 2% to about 6% by weight of ethyl acetate, and from about 87% to about 95% oil. In a third aspect of this embodiment, the liquid composition comprises from about 4% to about 6% by weight of ibuprofen, from about 3% to about 5% by weight of ethyl acetate, and from about 90% to about 92% oil. In other aspects of this embodiment, ibuprofen may be a free acid or an ibuprofen salt. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

In one embodiment, the solid or semi-solid composition disclosed herein is formulated without a hydrophilic solvent such as water. Such formulations result in co-crystals of lipids and a therapeutic compound. In other words, such compositions do not form liposome emulsions and / or micellar particles that require a hydrophilic solvent.

In one embodiment, the solid composition comprises a therapeutic compound, solid fat, partially hydrogenated fat, and polyethylene glycol. In an aspect of this embodiment, the solid composition comprises from about 1% to about 30% by weight of the therapeutic compound, from about 8% to about 70% by weight of solid fat, from about 2% to about 65% by weight of partially hydrogenated fat, and from about 1% to about 15% polyethylene glycol. In another aspect of this embodiment, the solid composition comprises from about 10% to about 30% by weight of the therapeutic compound, from about 20% to about 50% by weight of solid fat, from about 10% to about 30% by weight of partially hydrogenated fat, and from about 5% to about 15% polyethylene glycol. In yet another aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 30% to about 50% by weight of solid fat, from about 10% to about 30% by weight of partially hydrogenated fat, and from about 7% to about 13% polyethylene glycol. In a third aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 35% to about 50% by weight of solid fat, from about 15% to about 25% by weight of partially hydrogenated fat, and about 7% to about 13% polyethylene glycol. In an additional aspect of this embodiment, the solid composition comprises from about 23% to about 27% by weight of the therapeutic compound, from about 41% to about 47% by weight of solid fat, from about 18% to about 22% by weight of partially hydrogenated fat, and from about 9% to about 11% polyethylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the solid composition comprises a therapeutic compound, a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, glyceryl monolinoleate and polyethylene glycol. In an aspect of this embodiment, the solid composition contains from about 1% to about 30% by weight of the therapeutic compound, from about 8% to about 70% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 2% to about 65% by weight of glyceryl monolinoleate and from about 1% to about 15% polyethylene glycol. In another aspect of this embodiment, the solid composition comprises from about 10% to about 30% by weight of the therapeutic compound, from about 20% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 10% to about 30% by weight of glyceryl monolinoleate and from about 5% to about 15% polyethylene glycol. In yet another aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 30% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from from about 10% to about 30% by weight of glyceryl monolinoleate and from about 7% to about 13% polyethylene glycol. In a third aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 35% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 5% to about 25% by weight of glyceryl monolinoleate and from about 7% to about 13% polyethylene glycol. In an additional aspect of this embodiment, the solid composition comprises from about 23% to about 27% by weight of the therapeutic compound, from about 41% to about 47% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 18% to about 22% by weight of glyceryl monolinoleate and from about 9% to about 11% polyethylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the solid composition comprises ibuprofen, a mixture of mono-, di- and triglycerides and esters of PEG and fatty acids, glyceryl monolinoleate and polyethylene glycol. In an aspect of this embodiment, the solid composition contains from about 1% to about 30% by weight of ibuprofen, from about 8% to about 70% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 2 % to about 65% by weight of glyceryl monolinoleate and from about 1% to about 15% polyethylene glycol. In another aspect of this embodiment, the solid composition comprises from about 10% to about 30% by weight of ibuprofen, from about 20% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 10 % to about 30% by weight of glyceryl monolinoleate and from about 5% to about 15% polyethylene glycol. In yet another aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of ibuprofen, from about 30% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 10% to about 30% by weight of glyceryl monolinoleate and from about 7% to about 13% polyethylene glycol. In a third aspect of this embodiment, the solid composition contains from about 20% to about 30% by weight of ibuprofen, from about 35% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 15 % to about 25% by weight of glyceryl monolinoleate and from about 7% to about 13% polyethylene glycol. In an additional aspect of this embodiment, the solid composition contains from about 23% to about 27% by weight of ibuprofen, from about 41% to about 47% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 18% to about 22% by weight of glyceryl monolinoleate and from about 9% to about 11% polyethylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the solid composition comprises a therapeutic compound, solid fat, partially hydrogenated fat, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the solid composition comprises from about 1% to about 30% by weight of the therapeutic compound, from about 8% to about 70% by weight of solid fat, from about 2% to about 65% by weight of partially hydrogenated fat, from from about 1% to about 15% polyethylene glycol; and from about 1% to about 15% propylene glycol. In another aspect of this embodiment, the solid composition comprises from about 10% to about 30% by weight of the therapeutic compound, from about 20% to about 50% by weight of solid fat, from about 10% to about 30% by weight of partially hydrogenated fat, from from about 5% to about 15% polyethylene glycol; and from about 5% to about 15% propylene glycol. In yet another aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 30% to about 50% by weight of solid fat, from about 10% to about 30% by weight of partially hydrogenated fat, from about 7% to about 13% polyethylene glycol; and from about 7% to about 13% propylene glycol. In a third aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 35% to about 50% by weight of solid fat, from about 15% to about 25% by weight of partially hydrogenated fat, from from about 7% to about 13% polyethylene glycol; and from about 7% to about 13% propylene glycol. In an additional aspect of this embodiment, the solid composition comprises from about 23% to about 27% by weight of the therapeutic compound, from about 41% to about 47% by weight of solid fat, from about 18% to about 22% by weight of partially hydrogenated fat, from about 9% to about 11% polyethylene glycol; and from about 9% to about 11% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the solid composition comprises a therapeutic compound, a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, glyceryl monolinoleate, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the solid composition contains from about 1% to about 30% by weight of the therapeutic compound, from about 8% to about 70% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 2% to about 65% by weight of glyceryl monolinoleate, from about 1% to about 15% polyethylene glycol and from about 1% to about 15% propylene glycol. In another aspect of this embodiment, the solid composition comprises from about 10% to about 30% by weight of the therapeutic compound, from about 20% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 10% to about 30% by weight of glyceryl monolinoleate, from about 5% to about 15% polyethylene glycol, and from about 5% to about 15% propylene glycol. In yet another aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 30% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from from about 10% to about 30% by weight of glyceryl monolinoleate, from about 7% to about 13% polyethylene glycol and from about 7% to about 13% propylene glycol. In a third aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of the therapeutic compound, from about 35% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 15% to about 25% by weight of glyceryl monolinoleate, from about 7% to about 13% polyethylene glycol and from about 7% to about 13% propylene glycol. In an additional aspect of this embodiment, the solid composition comprises from about 23% to about 27% by weight of the therapeutic compound, from about 41% to about 47% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 18% to about 22% by weight of glyceryl monolinoleate, from about 9% to about 11% polyethylene glycol and from about 9% to about 11% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the solid composition comprises ibuprofen, a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, glyceryl monolinoleate, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the solid composition contains from about 1% to about 30% by weight of ibuprofen, from about 8% to about 70% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 2 % to about 65% by weight of glyceryl monolinoleate, from about 1% to about 15% polyethylene glycol and from about 1% to about 15% propylene glycol. In another aspect of this embodiment, the solid composition comprises from about 10% to about 30% by weight of ibuprofen, from about 20% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 10 % to about 30% by weight of glyceryl monolinoleate, from about 5% to about 15% polyethylene glycol and from about 5% to about 15% propylene glycol. In yet another aspect of this embodiment, the solid composition comprises from about 20% to about 30% by weight of ibuprofen, from about 30% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 10% to about 30% by weight of glyceryl monolinoleate and from about 7% to about 13% polyethylene glycol and from about 7% to about 13% propylene glycol. In a third aspect of this embodiment, the solid composition contains from about 20% to about 30% by weight of ibuprofen, from about 35% to about 50% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 15 % to about 25% by weight of glyceryl monolinoleate, from about 7% to about 13% polyethylene glycol and from about 7% to about 13% propylene glycol. In an additional aspect of this embodiment, the solid composition contains from about 23% to about 27% by weight of ibuprofen, from about 41% to about 47% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 18% to about 22% by weight of glyceryl monolinoleate, from about 9% to about 11% polyethylene glycol and from about 9% to about 11% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the semi-solid composition comprises a therapeutic compound, solid fat, partially hydrogenated fat, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the semi-solid composition contains from about 15% to about 55% by weight of the therapeutic compound, from about 7% to about 20% by weight of solid fat, from about 20% to about 50% by weight of partially hydrogenated fat, from from about 7% to about 20% polyethylene glycol; and from about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 20% to about 50% by weight of the therapeutic compound, from about 8% to about 18% by weight of solid fat, from about 25% to about 45% by weight of partially hydrogenated fat, from about 8% to about 18% polyethylene glycol; and from about 2% to about 6% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 20% to about 50% by weight of the therapeutic compound, from about 10% to about 16% by weight of solid fat, from about 25% to about 45% by weight of partially hydrogenated fat, from from about 10% to about 16% polyethylene glycol; and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid composition comprises from about 20% to about 50% by weight of the therapeutic compound, from about 11% to about 15% by weight of solid fat, from about 30% to about 40% by weight of partially hydrogenated fat, from about 11% to about 15% polyethylene glycol; and from about 3% to about 5% propylene glycol. In a third aspect of this embodiment, the semi-solid composition contains from about 25% to about 44% by weight of the therapeutic compound, from about 12% to about 14% by weight of solid fat, from about 32% to about 39% by weight of partially hydrogenated fat, from from about 12% to about 14% polyethylene glycol; and from about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the semi-solid composition comprises a therapeutic compound, a mixture of mono-, di- and triglycerides and esters of PEG and fatty acids, glyceryl monolinoleate, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the semi-solid composition contains from about 15% to about 55% by weight of the therapeutic compound, from about 7% to about 20% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 20% to about 50% by weight of glyceryl monolinoleate, from about 7% to about 20% polyethylene glycol and from about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 20% to about 50% by weight of the therapeutic compound, from about 8% to about 18% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 25% to about 45% by weight of glyceryl monolinoleate, from about 8% to about 18% polyethylene glycol and from about 2% to about 6% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 20% to about 50% by weight of the therapeutic compound, from about 10% to about 16% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 25% to about 45% by weight of glyceryl monolinoleate, from about 10% to about 16% o polyethylene glycol and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid composition comprises from about 20% to about 50% by weight of the therapeutic compound, from about 11% to about 15% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 30% to about 40% by weight of glyceryl monolinoleate and from about 11% to about 15% polyethylene glycol and from about 3% to about 5% propylene glycol. In a third aspect of this embodiment, the semi-solid composition contains from about 25% to about 44% by weight of the therapeutic compound, from about 12% to about 14% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 32% to about 39% by weight of glyceryl monolinoleate, from about 12% to about 14% polyethylene glycol and from about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the semi-solid composition comprises ibuprofen, a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, glyceryl monolinoleate, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the semi-solid composition contains from about 15% to about 55% by weight of ibuprofen, from about 7% to about 20% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 20 % to about 50% by weight of glyceryl monolinoleate, from about 7% to about 20% polyethylene glycol and from about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 20% to about 50% by weight of ibuprofen, from about 8% to about 18% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 25 % to about 45% by weight of glyceryl monolinoleate, from about 8% to about 18% polyethylene glycol and from about 2% to about 6% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 20% to about 50% by weight of ibuprofen, from about 10% to about 16% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 25 % to about 45% by weight of glyceryl monolinoleate, from about 10% to about 16% polyethylene glycol and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid composition comprises from about 20% to about 50% by weight of ibuprofen, from about 11% to about 15% by weight of a mixture of mono-, di- and triglycerides and PEG esters and fatty acids, from about 30% to about 40% by weight of glyceryl monolinoleate and from about 1% to about 15% polyethylene glycol and from about 3% to about 5% propylene glycol. In a third aspect of this embodiment, the semi-solid composition contains from about 25% to about 44% by weight of ibuprofen, from about 12% to about 14% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 32 % to about 39% by weight of glyceryl monolinoleate, from about 12% to about 14% polyethylene glycol and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the semi-solid composition comprises a therapeutic compound, solid fat, partially hydrogenated fat, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the semi-solid composition contains from about 10% to about 35% by weight of the therapeutic compound as a free acid, from about 1% to about 30% by weight of the salt of the therapeutic compound, from about 7% to about 20% by weight solid fat, from about 20% to about 50% by weight of partially hydrogenated fat, from about 7% to about 20% polyethylene glycol and from about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 15% to about 30% by weight of the therapeutic compound as a free acid, from about 1% to about 25% by weight of the salt of the therapeutic compound, from about 10% to about 16% by weight solid fat, from about 25% to about 45% by weight of partially hydrogenated fat, from about 10% to about 16% polyethylene glycol and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid composition comprises from about 15% to about 30% by weight of the therapeutic compound as a free acid, from about 1% to about 25% by weight of the salt of the therapeutic compound, from about 11% to about 15% by weight solid fat mass, from about 30% to about 40% by weight of partially hydrogenated fat, from about 11% to about 15% polyethylene glycol, and from about 3% to about 5% propylene glycol. In a third aspect of this embodiment, the semi-solid composition comprises from about 20% to about 24% by weight of the therapeutic compound as a free acid, from about 5% to about 20% by weight of the salt of the therapeutic compound, from about 12% to about 14% by weight solid fat, from about 32% to about 39% by weight of partially hydrogenated fat, from about 12% to about 14% polyethylene glycol and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the semi-solid composition comprises a therapeutic compound, a mixture of mono-, di- and triglycerides and esters of PEG and fatty acids, glyceryl monolinoleate, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the semi-solid composition contains from about 10% to about 35% by weight of the therapeutic compound as a free acid, from about 1% to about 30% by weight of the salt of the therapeutic compound, from about 7% to about 20% by weight mixtures of mono-, di- and triglycerides and PEG esters of fatty acids, from about 20% to about 50% by weight of glyceryl monolinoleate, from about 7% to about 20% polyethylene glycol and from about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 15% to about 30% by weight of the therapeutic compound as a free acid, from about 1% to about 25% by weight of the salt of the therapeutic compound, from about 10% to about 16% by weight mixtures of mono-, di- and triglycerides and PEG esters of fatty acids, from about 25% to about 45% by weight of glyceryl monolinoleate, from about 10% to about 16% polyethylene glycol and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid composition comprises from about 15% to about 30% by weight of the therapeutic compound as a free acid, from about 1% to about 25% by weight of the salt of the therapeutic compound, from about 11% to about 15% by weight the weight of the mixture of mono-, di- and triglycerides and PEG esters of fatty acids, from about 30% to about 40% by weight of glyceryl monolinoleate and from about 11% to about 15% polyethylene glycol and from about 3% to about 5% propylene glycol. In a third aspect of this embodiment, the semi-solid composition comprises from about 20% to about 24% by weight of the therapeutic compound as a free acid, from about 5% to about 20% by weight of the salt of the therapeutic compound, from about 12% to about 14% by weight mixtures of mono-, di- and triglycerides and PEG esters of fatty acids, from about 32% to about 39% by weight of glyceryl monolinoleate, from about 12% to about 14% polyethylene glycol and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

In another embodiment, the semi-solid composition comprises ibuprofen, a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, glyceryl monolinoleate, polyethylene glycol and propylene glycol. In an aspect of this embodiment, the semi-solid composition contains from about 10% to about 35% by weight of ibuprofen as a free acid, from about 1% to about 30% by weight of ibuprofen salt, from about 7% to about 20% by weight of a mono mixture -, di- and triglycerides and esters of PEG and fatty acids, from about 20% to about 50% by weight of glyceryl monolinoleate, from about 7% to about 20% polyethylene glycol and from about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid composition contains from about 15% to about 30% by weight of ibuprofen as a free acid, from about 1% to about 25% by weight of ibuprofen salt, from about 10% to about 16% by weight of a mono mixture -, di- and triglycerides and esters of PEG and fatty acids, from about 25% to about 45% by weight of glyceryl monolinoleate, from about 10% to about 16% polyethylene glycol and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid composition comprises from about 15% to about 30% by weight of ibuprofen as a free acid, from about 1% to about 25% by weight of ibuprofen salt, from about 11% to about 15% by weight of the mixture mono-, di- and triglycerides and esters of PEG and fatty acids, from about 30% to about 40% by weight of glyceryl monolinoleate and from about 11% to about 15% polyethylene glycol and from about 3% to about 5% propylene glycol. In a third aspect of this embodiment, the semi-solid composition contains from about 20% to about 24% by weight of ibuprofen as a free acid, from about 5% to about 20% by weight of ibuprofen salt, from about 12% to about 14% by weight of a mono mixture -, di- and triglycerides and esters of PEG and fatty acids, from about 32% to about 39% by weight of glyceryl monolinoleate, from about 12% to about 14% polyethylene glycol and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, or PEG 700.

The solid or semi-solid composition disclosed herein takes advantage of the different melting points of various adjuvants, such as fatty acids. The formation of a solid or semi-solid dosage form can be accomplished by varying the appropriate concentrations of fatty acids containing the pharmaceutical composition disclosed herein. For example, linolenic acid has a melting point (T _m ) of about −11 ° 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 and stearic acid has a T _{m of} about 67-72 ° C. An increase in the proportion (s) of palmitic, stearic or oleic acids increases the overall melting temperature of the composition, while, conversely, an increase in the proportion (s) of linoleic and linolenic acids would lower the melting temperature of the composition. Thus, by controlling the types and amounts of adjuvant components added, the composition disclosed herein can be made to be substantially solid or semi-solid at room temperature, but melted when ingested and reaches body temperature. The resulting molten composition readily forms micelles, which are absorbed by the intestines, assemble into chylomicrons, and are ultimately absorbed by macrophages. The solid dosage form may be a powder, granule, tablet, capsule or suppository.

In an embodiment of the invention, the pharmaceutical composition disclosed herein is solid at room temperature. In aspects of this embodiment, the pharmaceutical composition disclosed herein may be formulated to be solid at, for example, about 35 ° C or lower, about 33 ° C or lower, about 31 ° C or lower, about 29 ° C or lower, approximately 27 ° C or lower, approximately 25 ° C or lower, approximately 23 ° C or lower, approximately 21 ° C or lower, approximately 19 ° C or lower, approximately 17 ° C or lower, approximately 15 ° C or lower, approximately 12 ° C or lower, approximately 10 ° C or lower, approximately 8 ° C or lower, approximately 6 ° C or lower, approximately 4 ° C or lower sludge and about 0 ° C or lower.

In other aspects of this embodiment, the disclosed pharmaceutical composition has a melting point of, for example, 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. In other aspects of this embodiment, the disclosed pharmaceutical composition has a melting point in the range of, for example, from about 5 ° C to about 24 ° C, from about 10 ° C to about 24 ° C, from about 22 ° C to about 24 ° C, from about 23 ° C to about 25 ° C, from about 24 ° C to about 26 ° C, from about 25 ° C to about 27 ° C, from about 26 ° C to about 28 ° C, from about 27 ° C to about 29 ° C, from about 28 ° C to about 30 ° C, from about 29 ° C to about 31 ° C, from about 30 ° C to about 32 ° C, from about 31 ° C to about 33 ° C, from about 32 ° C to about 34 ° C or from about 33 ° C to about 35 ° C. In other aspects of this embodiment, the disclosed pharmaceutical composition has a melting point in the range of, for example, from about 22 ° C to about 26 ° C, from about 24 ° C to about 28 ° C, from about 26 ° C to about 30 ° C, from about 28 ° C to about 32 ° C; or from about 30 ° C to about 34 ° C.

In aspects of the present description, in particular, a method of treating an individual with chronic inflammation is disclosed. In one embodiment of the invention, the method includes the step of administering to the individual in need thereof the pharmaceutical composition disclosed herein, wherein administration reduces the symptom associated with chronic inflammation, thereby providing treatment for the individual.

In aspects of the present description, in particular, the treatment of an individual suffering from chronic inflammation is disclosed. As used herein, the term “treatment” refers to a reduction or elimination in a subject of a clinical symptom of chronic inflammation; or delaying or preventing the individual from developing a clinical symptom of chronic inflammation. For example, the term "treatment" can mean a decrease in the symptom of a condition characterized by chronic inflammation, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75 %, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. The actual symptoms associated with chronic inflammation are well known and can be determined by one of ordinary skill in the art, taking into account factors including, but not limited to, the location of chronic inflammation, the cause of chronic inflammation, the severity of chronic inflammation, and / or the tissue or organ affected by chronic inflammation . Those of skill in the art will know the appropriate symptoms or signs associated with a particular type of chronic inflammation, and will know how to determine if a person is a candidate for the treatment disclosed herein.

Symptoms of chronic inflammation include, without limitation, edema, hyperemia, erythema, bruising, soreness, stiffness, swelling, fever, chills, nasal congestion, a feeling of heaviness in the head, breathing problems, fluid retention, blood clots, loss of appetite, palpitations, granuloma formation, fibrinous phenomena, pus, inviscid serous fluid or ulcers and pain. The actual symptoms associated with chronic inflammation are well known and can be determined by one of ordinary skill in the art, taking into account factors including, but not limited to, the location of the inflammation, the cause of the inflammation, the severity of the inflammation, the affected tissue or organ, and the associated disease.

Specific models of chronic inflammation are observed during certain situations that occur in the body, for example, when inflammation occurs on the surface of the epithelium or with the participation of purulent bacteria. For example, granulomatous inflammation is inflammation resulting from the formation of granulomas that appear with a limited but diverse set of diseases, including, without limitation, tuberculosis, leprosy, sarcoidosis, and syphilis. Purulent inflammation is inflammation resulting from the formation of a large amount of pus, which consists of neutrophils, dead cells and fluid. Infection with purulent bacteria, such as staphylococci, is characteristic of this kind of inflammation. Serous inflammation is inflammation resulting from an abundant effusion of an inviscid serous fluid, which is usually produced by the mesothelial cells of the serous membranes, but can also accumulate from blood plasma. Blisters are an example of this model of inflammation. Ulcerative inflammation is inflammation resulting from necrotic tissue loss on the surface of the epithelium, exposing the lower layers and forming an ulcer.

A symptom of chronic inflammation can be associated with a large group of unrelated disorders that underlie various diseases and disorders. The immune system is often associated with chronic inflammatory diseases, as demonstrated by allergic reactions and some myopathies, where many disorders of the immune system lead to abnormal inflammation. Non-immune diseases with an etiological origin from chronic inflammatory processes include cancer, atherosclerosis, and coronary heart disease. Non-limiting examples of diseases having chronic inflammation as a symptom include, but are not limited to, acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis of the liver, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, colds, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetes mellitus, neuropathy, diabetes, neuropathy, diabetes diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondelitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, g ngivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, purulent hydradenitis, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, cystitis, interstitial inflammation, insulinitis ischemia, coronary heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, diffuse sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis media, pancreatitis, pericarditis, tuberculosis, tuberculosis, tuberculosis , peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoid sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, complication after surgery, synovitis, tendonitis, teninosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, head injury, transplant rejection, trigonitis, tuberculosis, tumor, urethritis, urine , uveitis, vaginitis, vasculitis and vulvitis. See also Eric R. First, Application of Botulinum Toxin to the Management of Neurogenic Inflammatory Disorders, US Pat. No. 6,063,768, the entire contents of which are incorporated herein by reference.

In one embodiment, the chronic inflammation is inflammation of the tissues. Tissue inflammation is a chronic inflammation that is limited to a specific tissue or organ. In an aspect of this embodiment, tissue inflammation includes, for example, skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreas inflammation, kidney inflammation, bladder inflammation, inflammation of the stomach, inflammation of the intestines, inflammation of neurons and inflammation of the brain.

In another embodiment, the chronic inflammation is systemic inflammation. Although the processes associated with it are identical to those in tissue inflammation, systemic inflammation is not limited to a specific tissue, but actually spreads to the entire body, including the endothelium and other organ systems. If this is the result of an infection, the term sepsis is used, where the term bacterial sepsis is used for bacteremia, and the term viral sepsis is used for virimia. Vasodilation and organ dysfunction are serious problems associated with a widespread infection that can lead to septic shock and death.

In another embodiment, chronic inflammation includes arthritis. Arthritis includes a group of pathological conditions associated with damage to the joints of the body due to inflammation of the synovial membrane, including, without limitation, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies such as ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis inflammatory bowel disease enteropathic arthritis, Whipple's disease and Behcet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline s synovitis, metabolic arthritis), pseudogout (disease that occurs due to deposits of calcium pyrophosphate crystals) and Still's disease. Arthritis can affect one joint (monoarthritis), from two to four joints (oligoarthritis), or five or more joints (polyarthritis), and can either be an autoimmune disease or not an autoimmune disease.

In another embodiment, chronic inflammation includes an autoimmune disease. Autoimmune diseases can be generally divided into systemic and organ-specific autoimmune diseases, depending on the main clinical and pathological signs of each disease. Systemic autoimmune diseases include, but are not limited to, systemic lupus erythematosus (SLE), Sjogren's syndrome, scleroderma, rheumatoid arthritis, and polymyositis. Local autoimmune diseases can be endocrinological (type I diabetes, Hashimoto’s thyroiditis, Addison’s disease, etc.), dermatological (pemphigus vulgaris), hematologic (autoimmune hemolytic anemia), nerve (multiple sclerosis), or may include almost any limited tissue body mass . Types of autoimmune diseases include, without limitation, acute disseminated encephalomyelitis (ADEM), Addison's disease, allergies or hypersensitivity, amyotrophic lateral sclerosis, antiphospholipid antibody syndrome (APS), arthritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmune hepatitis, autoimmunity bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease (COPD), type I diabetes mellitus (IDDM), endometriosis, fibromyalgia, Goodpasture syndrome, Graves disease a, Guillain-Barré syndrome (GBS), Hashimoto's thyroiditis, purulent hydradenitis, idiopathic thrombocytopenic purpura, inflammatory bowel disease, interstitial cystitis, lupus (including discoid lupus erythematosus, medical lupus erythematosus, lupus erythematosus, and lupus erythematosus lupus erythematosus), morpheus, multiple sclerosis (MS), myasthenia gravis, myopathy, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, recurrence conductive disseminated encephalomyelitis (multiphase disseminated encephalomyelitis), rheumatic disease, schizophrenia, scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis and vitiligo. See Pamela D. Van Schaack & Kenneth L. Tong, Treatment of Autoimmune Disorder with a Neurotoxin, US Patent Publication 2006/138059, the entire contents of which are hereby incorporated by reference.

In another embodiment, chronic inflammation includes myopathy. Myopathies occur when the immune system erroneously attacks muscle components, leading to inflammation in the muscles. Myopathy includes inflammatory myopathy and autoimmune myopathy. Myopathies include, without limitation, dermatomyositis, myositis with inclusion bodies, and polymyositis.

In another embodiment, the chronic inflammation is vasculitis. Vasculitis is a diverse group of diseases characterized by inflammation of the vascular wall, including lymphatic vessels and blood vessels such as veins (phlebitis), arteries (arteritis), and capillaries resulting from leukocyte migration associated with damage. Inflammation can affect a blood vessel of any size in any part of the body. It can affect arteries and / or veins. Inflammation can be focal, which means that it affects one place in the vessel, or it can be widespread, with areas of inflammation scattered over a specific organ or tissue, or even can affect more than one organ system in the body. Vasculitis includes, without limitation, Buerger’s disease (thromboangiitis obliterans), cerebral vasculitis (central nervous system vasculitis), Charge-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell (temporary) arteritis, golfer's vasculitis, purple purpura Genoa Schoen hypersensitivity (allergic vasculitis), Kawasaki disease, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, polymyalgia rheumatism (PMR), rheumatoid vasculitis, Takayasu arteritis, gra ulematoz Wegener and vasculitis secondary with connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), relapsing polychondritis, Behcet's disease or other connective tissue diseases, vasculitis, secondary to viral infection.

In another embodiment, the chronic inflammation is a skin disease. Skin diseases include, but are not limited to, acne, including acne vulgaris, bullous pemphigoid, dermatitis, including atopic dermatitis and chronic actinic dermatitis, eczema such as atopic eczema, contact eczema, xerotic eczema, seborrheic dermatitis, dyshidrosis, discoid eczema, venous herpetiform dermatitis, neurodermatitis and autoecematization, and stasis dermatitis, purulent hydradenitis, lichen planus, psoriasis, including plaque psoriasis, nail psoriasis, drop-shaped psoriasis, psoriasis of the scalp and scalp, reverse psoriasis, pustular psoriasis, erythrodermic psoriasis and psoriatic arthritis, rosacea and scleroderma, including morphea.

In another embodiment, chronic inflammation is a gastrointestinal upset. Gastrointestinal disorders include, but are not limited to, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease, and ulcerative colitis, such as ulcerative proctitis, left-sided colitis, pancolitis, and fulminant colitis.

In another embodiment, the chronic inflammation is a cardiovascular disease. When LDL cholesterol is embedded in the walls of arteries, it can trigger an immune response. Chronic inflammation can eventually damage the arteries, which can lead to cracking. Cardiovascular disease is any of a number of specific diseases that affect the heart itself and / or the blood vessel system, especially the veins and arteries leading to and from the heart. There are over 60 types of cardiovascular diseases, including, but not limited to, hypertension, endocarditis, myocarditis, heart valve dysfunction, congestive heart failure, myocardial infarction, diabetes-related cardiovascular diseases, blood vessel inflammation such as arteritis, phlebitis, vasculitis arterial occlusion disease, such as atherosclerosis and stenosis, inflammatory cardiomegaly, peripheral artery disease, aneurysm, embolism, stratification of blood vessels, pseudo-aneurysm, vascular malformac july, vascular nevus, thrombosis, thrombophlebitis, varicose veins, stroke. Symptoms of a cardiovascular disease affecting the heart include, without limitation, chest pain or chest discomfort (angina pectoris), pain in one or both arms, left shoulder, neck, jaw or back, shortness of breath, dizziness, palpitations, nausea abnormal heartbeat, feeling tired. Symptoms of a cardiovascular disease affecting the brain include, without limitation, sudden numbness or weakness of the face, arm, or legs, especially on one side of the body, sudden confusion or problems with speech or speech understanding, sudden vision problems in one or both eyes, sudden dizziness, difficulty walking or loss of balance or coordination, sudden severe headache with an unknown cause. Symptoms of a cardiovascular disease affecting the legs, pelvis, and / or arms include, but are not limited to, lameness resulting from muscle pain or cramps, and a cold or numbness in the legs or toes, especially at night.

In another embodiment, the chronic inflammation is cancer. Inflammation controls the microenvironment around the tumor, promoting its proliferation, survival, and migration. For example, fibrinous inflammation is the result of a significant increase in vascular permeability, which allows fibrin to pass through the blood vessels. If there is an appropriate procoagulant stimulus, for example, cancer cells, then fibrinous exudate precipitates. This is often observed in serous cavities, where the transformation of fibrinous exudate into a scar can occur between the serous membranes, limiting their functions. In another example, the cancer is an inflammatory cancer, such as an NF-κB mediated inflammatory cancer.

In another embodiment, chronic inflammation includes pharmacologically induced inflammation. Some drugs or exogenous chemicals are known to affect inflammation. For example, vitamin A deficiency causes an increase in the inflammatory response. Some types of illicit effects of some illegal drugs, such as cocaine and ecstasy, may result from their activation of transcription factors that are closely associated with inflammation (e.g., NF-κB).

In another embodiment, chronic inflammation includes an infection. An infectious organism can go beyond the immediate tissue through the circulatory system or the lymphatic system, through which it can spread to other parts of the body. If the body is not restrained by acute inflammation, it can gain access to the lymphatic system through nearby lymphatic vessels. An infection of the lymphatic vessels is known as lymphangitis, and an infection of the lymph nodes is called lymphadenitis. The pathogen can access the bloodstream through lymphatic drainage in the circulatory system. Infections include, but are not limited to, bacterial cystitis, bacterial encephalitis, pandemic influenza, viral encephalitis, and viral hepatitis (A, B, and C).

In another embodiment, the chronic inflammation is an injury to a tissue or organ. Injuries to a tissue or organ include, but are not limited to, a burn, a cut wound, a wound, a puncture wound, or injury.

In another embodiment, the chronic inflammation is transplant rejection. Graft rejection occurs when a transplanted organ or tissue is not accepted by the recipient’s body because the recipient’s immune system attacks the transplanted organ or tissue. The adaptive immune response and transplant rejection are mediated by both T-cell and humoral immune (via antibodies) mechanisms. Graft rejection can be classified as super acute rejection, acute rejection, or chronic rejection. Chronic rejection of a transplanted organ or tissue is a rejection that occurs as a result of a poorly understood chronic inflammatory and immune response against transplanted tissue. Also included in the term “transplant rejection” is transplant versus host syndrome (GVDH). GVDH is a common complication of allogeneic bone marrow transplantation, in which the functional immune cells in the transplanted brain recognize the recipient as foreign and organize an immunological attack. It can also occur with a blood transfusion under certain circumstances. GVDH is divided into acute and chronic forms. The acute and chronic forms of GVDH appear to include different subtypes of immune cells, different sets of cytokines, slightly different targets, and a different response to treatment.

In another embodiment, the chronic inflammation is a Th1-mediated inflammatory disease. In a well-functioning immune system, the immune response should include a well-balanced pro-inflammatory Th1 response and anti-inflammatory Th2 response, which can cope with the immunological stimulus. In general, after the initiation of a pro-inflammatory Th1 response, the body relies on the anti-inflammatory response elicited by the Th2 response to counteract this Th1 response. This counteracting response includes the release of Th2-type cytokines, such as, for example, IL-4, IL-5 and IL-13, which are associated with increased IgE and eosinophilic responses in atopy, as well as IL-10, which has an anti-inflammatory effect. Th1-mediated inflammatory disease includes the excess pro-inflammatory response provided by Th1 cells, which leads to chronic inflammation. Th1-mediated disease can be induced by viruses, bacteria, or chemicals (e.g., environmental factors). For example, a virus that causes Th1-mediated disease can cause a chronic or acute infection that can cause respiratory distress or flu.

In another embodiment, the chronic inflammation is a chronic neurogenic inflammation. Chronic neurogenic inflammation refers to an inflammatory response initiated and / or supported by the release of inflammatory molecules, like SP or CGRP, that are released from peripheral sensory nerve endings (i.e., efferent function as opposed to the normal afferent signaling pathway to the spinal cord in these nerves). Chronic neurogenic inflammation includes both primary and secondary neurogenic inflammation. As used herein, the term “primary” neurogenic inflammation refers to tissue inflammation (inflammatory symptoms) that is triggered or resulting from the release of substances from the primary sensory nerve endings (eg, C and A-delta fibers). As used herein, the term “secondary” neurogenic inflammation refers to tissue inflammation initiated by non-neuronal sources (eg, seeping from the vascular bed or obtained from interstitial tissue, for example, from mast cells or immune cells) of inflammatory mediators, such as peptides or cytokines stimulating sensory nerve endings and causing the release of inflammatory mediators from nerves. The final effect of both forms (primary and secondary) of chronic neurogenic inflammation is the presence of an inflammatory condition that is supported by sensitization of peripheral sensory nerve fibers. The physiological consequences of chronic neurogenic inflammation depend on the affected tissue, including, for example, skin pain (allodynia, hyperalgesia), joint pain and / or arthritis, visceral pain and dysfunction, pulmonary dysfunction (asthma, COPD) and bladder dysfunction (pain, hyperactive bladder).

The composition or compound is administered to an individual. An individual is usually a person. Typically, any individual who is a candidate for the conventional treatment of chronic inflammation is a candidate for the treatment of chronic inflammation disclosed herein. A preoperative examination usually includes a routine medical history and physical examination in addition to a detailed informed consent, revealing all the significant risks and benefits of the procedure.

The pharmaceutical composition disclosed herein may contain a therapeutic compound in a therapeutically effective amount. As used herein, the term “effective amount” is synonymous with “therapeutically effective amount”, “effective dose” or “therapeutically effective dose”, and when used in the treatment of chronic inflammation, refers to the minimum dose of the therapeutic compound disclosed herein required achieve the desired therapeutic effect, and includes a dose sufficient to reduce the symptoms associated with chronic inflammation. The effectiveness of a therapeutic compound disclosed herein in the treatment of chronic inflammation can be determined by observing an improvement in an individual's condition based on one or more clinical symptoms and / or physiological parameters associated with the condition. An improvement in severe pain can also be indicated by a decrease in the need for concomitant therapy.

A suitable effective amount of a therapeutic compound disclosed herein for administration to an individual in a particular chronic inflammation can be determined by one of ordinary skill in the art, taking into account factors including, without limitation, the type of chronic inflammation, location of chronic inflammation, cause of chronic inflammation, severity of chronic inflammation , desired degree of relief of chronic inflammation, desired duration of relief of chronic inflammation, specific use the therapeutic compound to be used, the excretion rate 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 specific composition, the specific route of administration, specific characteristics, medical history and patient risk factors, such as, for example, age, weight, general health, etc., or any combination of the above. In addition, when re-administering the therapeutic compound is used, the effective amount of the therapeutic compound will also depend on factors including, without limitation, frequency of administration, half-life of the therapeutic compound, or any combination thereof. One of ordinary skill in the art knows that 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.

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

In other aspects of this embodiment, the therapeutically effective amount of a therapeutic compound disclosed herein is typically in the range of from about 0.001 mg / kg / day to about 100 mg / kg / day. In aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be, for example, 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 by at least 50 mg / kg / day. In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may range from, for example, from about 0.001 mg / kg / day to about 10 mg / kg / day, from about 0.001 mg / kg / day to about 15 mg / kg / day, from about 0.001 mg / kg / day to about 20 mg / kg / day, from about 0.001 mg / kg / day to about 25 mg / kg / day, from about 0.001 mg / kg / day up to about 30 mg / kg / day, from about 0.001 mg / kg / day to about 35 mg / kg / day, from about 0.001 mg / kg / day to about 40 mg / kg / day, from about 0.001 mg / kg / day to about 45 mg / kg / day, from about 0.001 mg / kg / day to about 50 mg / kg / day, from about 0.001 mg / kg / day to about 75 mg / kg / day, or from about 0.001 mg / kg / day to about 100 mg / kg / day. In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may range from, for example, from about 0.01 mg / kg / day to about 10 mg / kg / day, from about 0.01 mg / kg / day to about 15 mg / kg / day, from about 0.01 mg / kg / day to about 20 mg / kg / day, from about 0.01 mg / kg / day to about 25 mg / kg / day, from about 0.01 mg / kg / day to about 30 mg / kg / day, from about 0.01 mg / kg / day to about 35 mg / kg / day, from about 0.01 mg / kg / day to about 40 mg / kg / day, from about 0 01 mg / kg / day to about 45 mg / kg / day, from about 0.01 mg / kg / day to about 50 mg / kg / day, from about 0.01 mg / kg / day to about 75 mg / kg / day or from about 0.01 mg / kg / day to about 100 mg / kg / day. In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may range from, for example, from about 0.1 mg / kg / day to about 10 mg / kg / day, from about 0.1 mg / kg / day to about 15 mg / kg / day, from about 0.1 mg / kg / day to about 20 mg / kg / day, from about 0.1 mg / kg / day to about 25 mg / kg / day, from about 0.1 mg / kg / day to about 30 mg / kg / day, from about 0.1 mg / kg / day to about 35 mg / kg / day, from about 0.1 mg / kg / day to about 40 mg / kg / day, from about 0.1 mg / kg / day to about 45 mg / kg / day, from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.1 mg / kg / day to about 75 mg / kg / day or from about 0.1 mg / kg / day to about 100 mg / kg / day.

In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may range from, for example, from about 1 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 15 mg / kg / day, from about 1 mg / kg / day to about 20 mg / kg / day, from about 1 mg / kg / day to about 25 mg / kg / day, from about 1 mg / kg / day up to about 30 mg / kg / day, from about 1 mg / kg / day to about 35 mg / kg / day, from about 1 mg / kg / day to about 40 mg / kg / day, from about 1 mg / kg / day about 45 mg / kg / day, from about 1 mg / kg / day to about 50 mg / kg / day, from about 1 mg / kg / day to about 75 mg / kg / day, or from about 1 mg / kg / day to about 100 mg / kg / day. In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may range from, for example, from about 5 mg / kg / day to about 10 mg / kg / day, from about 5 mg / kg / day to about 15 mg / kg / day, from about 5 mg / kg / day to about 20 mg / kg / day, from about 5 mg / kg / day to about 25 mg / kg / day, from about 5 mg / kg / day up to about 30 mg / kg / day, from about 5 mg / kg / day to about 35 mg / kg / day, from about 5 mg / kg / day to about 40 mg / kg / day, from about 5 mg / kg / day about 45 mg / kg / day, from about 5 mg / kg / day to about 50 mg / kg / day, from about 5 mg / kg / day to about 75 mg / kg / day, or from about 5 mg / kg / day to about 100 mg / kg / day.

The dosage may be a single dose or a cumulative dose (with repeated administration) and can be easily determined by a person skilled in the art. For example, treatment of chronic inflammation may include a single administration of an effective dose of the pharmaceutical composition disclosed herein. Alternatively, the treatment of chronic inflammation may include repeated administration of an effective dose of the pharmaceutical composition in a range of time intervals, such as, for example, once a day, twice a day, three times a day, once every few days or once a week . The time of administration may vary for each individual individual, depending on factors such as the severity of symptoms in the individual. For example, an effective dose of the pharmaceutical composition disclosed herein may be administered to an individual once a day for an indefinite period of time, or until he no longer needs treatment. A person skilled in the art will understand that the condition of the individual can be monitored throughout the course of treatment, and the effective amount of the administered pharmaceutical composition, which is disclosed herein, can be adjusted accordingly.

Various routes of administration may be suitable for administering a therapeutic compound disclosed herein in accordance with the method for treating chronic inflammation disclosed herein. The pharmaceutical composition may be administered to an individual by any of a variety of means, depending, for example, on the type of chronic inflammation to be treated, the location of the chronic inflammation to be treated, the particular therapeutic compound or composition used, or another compound to be included in the composition, and medical history, risk factors, and individual symptoms. Essentially, topical, enteral, or parenteral routes of administration may be suitable for the treatment of chronic inflammation disclosed herein, and such routes include both topical and systemic delivery of the therapeutic compound or composition disclosed herein. Compositions containing either one therapeutic compound disclosed herein, or two or more therapeutic compounds disclosed herein are intended for inhalation, local, intranasal, sublingual, injectable, infusion, instillation, rectal and / or vaginal use and may be obtained in accordance with any method known in the art for the manufacture of pharmaceutical compositions.

In one embodiment, when administered to an individual, a pharmaceutical composition comprising a therapeutic compound disclosed herein results in a biodistribution of a therapeutic compound different from that of a therapeutic compound included in the same pharmaceutical composition with the exception of the adjuvant disclosed herein.

In another embodiment, when administered to an individual, the therapeutic compound in the pharmaceutical composition disclosed herein is delivered to macrophages. Macrophages are one of the key cell types that are thought to be involved in controlling the inflammation response. The resulting high level of therapeutic compound having an anti-inflammatory effect present in macrophages results in a clinically effective treatment of chronic inflammation. In an aspect of this embodiment, when administered to an individual, a therapeutically effective amount of a therapeutic compound in the pharmaceutical composition disclosed herein is preferably delivered to macrophages. In another aspect of this embodiment, when administered to an individual, the therapeutic compound in the pharmaceutical composition disclosed herein is substantially delivered to macrophages. In another aspect of this embodiment, when administered to an individual, the amount of therapeutic compound in the pharmaceutical composition disclosed herein that is delivered to macrophages is, for example, 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 at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, m at least 85%, at least 90%, at least 95%, or at least 100% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition. In further aspects of this embodiment, when administered to an individual, the amount of therapeutic compound in the pharmaceutical composition disclosed herein that is delivered to macrophages is in the range of, for example, from about 5% to about 100%, from about 10% to about 100 %, from about 15% to about 100%, from about 20% to about 100%, from about 25% to about 100%, from about 30% to about 100%, from about 35% to about 100%, from about 40 % to about 100%, from about 45% to about 100%, from about 50% to about 100%, from about 5% to about 90%, from about 10% to about 90%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 45% to about 90%, from about 50% to about 90%, from about 5% to about 80%, from about 10% to about 80%, from about 15% to about 80%, from about 20% to about 80%, from about 25% to about 80%, from about 30% to about 80%, from about 35% to about 80%, from about 40% to about 80%, from about 45% up to about 80%, from about 50% to about 80%, from about 5% to about 70%, from about 10% to about 70%, from about 15% to about 70%, from about 20% to about 70%, from about 25% to about 70%, from about 30% to about 70%, from about 35% to about 70%, from about 40% to about 70%, from about 45% to about 70%, or from about 50% to approximately 70% of the total therapeutic compound contained in the administered pharmaceutical composition.

In another embodiment, when administered to an individual, a therapeutic compound in the pharmaceutical composition disclosed herein is delivered to dendritic cells. Dendritic cells are one of the key cell types that are believed to coordinate the interaction between innate and acquired immunity. The resulting high level of a therapeutic compound having an analgesic effect present in dendritic cells results in a clinically effective treatment of chronic inflammation. In an aspect of this embodiment, when administered to an individual, a therapeutically effective amount of a therapeutic compound in the pharmaceutical composition disclosed herein is preferably delivered to dendritic cells. In another aspect of this embodiment, when administered to an individual, the therapeutic compound in the pharmaceutical composition disclosed herein is substantially delivered to dendritic cells. In yet another aspect of this embodiment, when administered to an individual, the amount of therapeutic compound in the pharmaceutical composition disclosed herein that is delivered to dendritic cells is, for example, 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 at least 60%, at least 65%, at least 70%, at least 75%, at least e 80%, at least 85%, at least 90%, at least 95%, or at least 100% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition. In further aspects of this embodiment, when administered to an individual, the amount of therapeutic compound in the pharmaceutical composition disclosed herein that is delivered to dendritic cells is in the range of, for example, from about 5% to about 100%, from about 10% to about 100%, from about 15% to about 100%, from about 20% to about 100%, from about 25% to about 100%, from about 30% to about 100%, from about 35% to about 100%, from about 40% to about 100%, from about 45% to about 100%, from but 50% to about 100%, from about 5% to about 90%, from about 10% to about 90%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 45% to about 90%, from about 50% to about 90%, from about 5% to about 80%, from about 10% to about 80%, from about 15% to about 80%, from about 20% to about 80%, from about 25% to about 80%, from about 30% to about 80 %, from about 35% to about 80%, from about 40% to about 80%, from ol about 45% to about 80%, from about 50% to about 80%, from about 5% to about 70%, from about 10% to about 70%, from about 15% to about 70%, from about 20% to about 70%, from about 25% to about 70%, from about 30% to about 70%, from about 35% to about 70%, from about 40% to about 70%, from about 45% to about 70%, or from about 50% to about 70% of the total therapeutic compound contained in the administered pharmaceutical composition.

In another embodiment, when administered to an individual, the pharmaceutical composition disclosed herein reduces gastric irritation. In an aspect of this embodiment, the pharmaceutical composition disclosed herein substantially reduces gastric irritation. In yet another embodiment, when administered to an individual, the pharmaceutical composition disclosed herein reduces stomach irritation when compared with the same pharmaceutical composition as disclosed herein, except for the absence of a pharmaceutically acceptable adjuvant. In an aspect of this embodiment, the pharmaceutical composition disclosed herein substantially reduces gastric irritation when compared with the same pharmaceutical composition as disclosed herein, except for the absence of a pharmaceutically acceptable adjuvant. In other aspects of this embodiment, the pharmaceutical composition disclosed herein reduces stomach irritation, for example by at least 5%, at least 10%, at least 15%, at least 20%, by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, the pharmaceutical composition disclosed herein reduces stomach irritation in the range of, for example, from about 5% to about 100%, from about 10% to about 100%, from about 15% to about 100%, from about 20% to about 100%, from about 25% to about 100%, from about 30% to about 100%, from about 35% to about 100%, from about 40% to about 100%, from about 45% to about 100%, from about 50% to about 100%, from about 5% to about 90%, from about 10% to about 90%, from about 15% to 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 45% to about 90%, from about 50% to about 90%, from about 5% to about 80%, from about 10% to about 80%, from about 15% to about 80%, from about 20% to about 80%, from about 25% to about 80%, from about 30% to about 80%, from about 35% to about 80%, from about 40% to about 80%, from about 45% to about 80%, from about 50% to about 80%, from about 5% to about 70%, from about 10% to pr about 70%, from about 15% to about 70%, from about 20% to about 70%, from about 25% to about 70%, from about 30% to about 70%, from about 35% to about 70%, from about 40% to about 70%, from about 45% to about 70%, or from about 50% to about 70%.

In another embodiment, when administered to an individual, the pharmaceutical composition disclosed herein reduces intestinal irritation. In an aspect of this embodiment, the pharmaceutical composition disclosed herein substantially reduces intestinal irritation. In yet another embodiment, when administered to an individual, the pharmaceutical composition disclosed herein reduces intestinal irritation when compared with the same pharmaceutical composition as disclosed herein, except for the absence of a pharmaceutically acceptable adjuvant. In an aspect of this embodiment, the pharmaceutical composition disclosed herein substantially reduces intestinal irritation when compared with the same pharmaceutical composition as disclosed herein, except for the absence of a pharmaceutically acceptable adjuvant. In other aspects of this embodiment, the pharmaceutical composition disclosed herein reduces intestinal irritation, for example by at least 5%, at least 10%, at least 20%, at least 30%, by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% when compared with the same pharmaceutical composition as disclosed herein, except for the absence of a pharmaceutically acceptable adjuvant. In other aspects of this embodiment, the pharmaceutical composition disclosed herein reduces intestinal irritation in the range of, for example, from about 5% to about 100%, from about 10% to about 100%, from about 15% to about 100%, from about 20% to about 100%, from about 25% to about 100%, from about 30% to about 100%, from about 35% to about 100%, from about 40% to about 100%, from about 45% to about 100%, from about 50% to about 100%, from about 5% to about 90%, from about 10% to about 90%, from about 15% to at 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 45% to about 90%, from about 50% to about 90%, from about 5% to about 80%, from about 10% to about 80%, from about 15% to about 80%, from about 20% to about 80%, from about 25% to about 80%, from about 30% to about 80%, from about 35% to about 80%, from about 40% to about 80%, from about 45% to about 80%, from about 50% to about 80%, from about 5% to about 70%, from about 10% to about 70%, from about 15% to about 70%, from about 20% to about 70%, from about 25% to about 70%, from about 30% to about 70%, from about 35% to about 70%, from from about 40% to about 70%, from about 45% to about 70%, or from about 50% to about 70% when compared with the same pharmaceutical composition as disclosed herein, except for the absence of a pharmaceutically acceptable adjuvant.

The 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. Using multiple compounds to treat a disease can increase beneficial effects while reducing side effects.

Aspects of the present invention may also be described as follows:

1. A pharmaceutical composition comprising: a) a therapeutic compound, wherein the therapeutic compound has an anti-inflammatory effect; and b) a pharmaceutically acceptable adjuvant.

2. The pharmaceutical composition of embodiment 1, wherein the composition further comprises a pharmaceutically acceptable solvent.

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

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

5. The pharmaceutical composition according to option 2 or 3, in which the ratio of pharmaceutically acceptable solvent and pharmaceutically acceptable adjuvant is in the range from about 0: 1 to about 1:25.

6. The pharmaceutical composition according to options 1-5, in which the anti-inflammatory effect reduces the level of the molecule causing inflammation.

7. The pharmaceutical composition according to option 6, in which the inflammation causing molecule includes a substance P (SP), a peptide associated with the calcitonin gene (CGRP), glutamate, or a combination thereof.

8. The pharmaceutical composition according to option 7, in which the anti-inflammatory effect reduces the level of SP, CGRP, glutamate, or a combination thereof, by at least 10%.

9. The pharmaceutical composition according to options 1-8, in which the anti-inflammatory effect reduces the level of inflammation-causing prostaglandin.

10. The pharmaceutical composition according to option 9, in which the level causing inflammation of the prostaglandin is reduced by at least 10%.

11. The pharmaceutical composition according to options 1-10, in which the anti-inflammatory effect stimulates the PPAR signaling pathway.

12. The pharmaceutical composition according to option 1, in which the PPAR signaling pathway is stimulated by at least 10%.

13. The pharmaceutical composition according to options 1-12, in which the anti-inflammatory effect causes apoptosis of M1 macrophage cells, promotes the differentiation of M2 macrophage cells, or performs both actions.

14. The pharmaceutical composition according to options 1-13, in which anti-inflammatory effect, reducing levels of gamma interferon (IFNγ), tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), or a combination thereof, released from Th1- cell, increases the level of IL-10 released from Th2 cells, or or performs both actions.

15. The pharmaceutical composition of embodiment 14, wherein the levels of IFNγ, TNF-α, IL-12, or combinations thereof released from Th1 cells, are reduced by at least 10%.

16. The pharmaceutical composition of embodiment 14, wherein the level of IL-10 released from Th2 cells is increased by at least 10%.

17. The pharmaceutical composition of embodiments 1-16, wherein the therapeutic compound has a logP value indicating that the compound is soluble in an organic solvent.

18. The pharmaceutical composition of embodiments 1-17, wherein the therapeutic compound has a logP value of greater than 1.0.

19. The pharmaceutical composition of embodiments 1-17, wherein the therapeutic compound has a logP value of greater than 2.0.

20. The pharmaceutical composition according to options 1-19, in which the therapeutic compound has a polar surface area that is hydrophobic.

21. The pharmaceutical composition of embodiments 1-20, wherein the therapeutic compound has a polar surface area that is less than 8.0 nm ² .

22. The pharmaceutical composition according to options 1-20, in which the therapeutic compound has a polar surface area that is less than 6.0 nm ² .

23. The pharmaceutical composition of embodiments 1-22, wherein the therapeutic compound comprises a non-steroidal pain medication (NSAID).

24. The pharmaceutical composition of embodiment 23, wherein the NSAID comprises a salicylate derivative, an NSAID-p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, non-selective inhibitor cyclooxygenase (COX), a selective inhibitor of cyclooxygenase 1 (COX 1), a selective inhibitor of cyclooxygenase 2 (COX 2), or a combination thereof.

25. The pharmaceutical composition of embodiments 1-24, wherein the therapeutic compound comprises a PPARγ agonist.

26. The pharmaceutical composition according to option 25, in which the PPARγ agonist includes Monascin, Irbesartan, Telmisartan, mycophenolic acid, Resveratrol, delta (9) -tetrahydrocannabinol, cannabidiol, Curcumin, Cilostazol, Benzbromarone, 6-shogaolazohydric acid, glycidia fibrate or a combination thereof.

27. The pharmaceutical composition of embodiments 1-26, wherein the therapeutic compound comprises a nuclear receptor binding agent.

28. The pharmaceutical composition of embodiment 27, wherein the nuclear receptor binding agent comprises a retinoic acid receptor binding agent (RAR), a retinoid X receptor binding agent (RXR), a liver X receptor binding agent (LXR), an agent binding vitamin D and their combination.

29. The pharmaceutical composition according to options 1-28, in which the therapeutic compound contains an anti-hyperlipidemic agent.

30. The pharmaceutical composition of embodiment 29, wherein the anti-hyperlipidemic agent includes fibrate, statin, tocotrienol, niacin, bile acid sequestrants (resins), a cholesterol absorption inhibitor, pancreatic lipase inhibitor, sympathomimetic amine, or a combination thereof.

31. The pharmaceutical composition of embodiment 29, wherein the fibrate comprises bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, or a combination thereof.

32. The pharmaceutical composition of embodiment 29, wherein the statin comprises Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof.

33. The pharmaceutical composition of embodiment 29, wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof.

34. The pharmaceutical composition according to option 29, in which the sequestrant of bile acids includes cholestyramine, colestipol, wheelset, or a combination thereof.

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

36. The pharmaceutical composition of embodiment 29, wherein the fat absorption inhibitor comprises Orlistat.

37. The pharmaceutical composition according to option 29, in which the sympathomimetic amine includes Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamphetamine, cathine, cathinone, methacinone benzene, cocaine, cokezene, cokezene, cokezene, cocaine, MDPV), 4-methylaminorex, pemoline, phenmethrazine, propylhexedrine, or a combination thereof.

38. The pharmaceutical composition of embodiments 1-37, wherein the therapeutic compound comprises an ester of the therapeutic compound.

39. The pharmaceutical composition according to options 1-38, in which the therapeutic compound contains an ester of the therapeutic compound according to options 23-37.

40. The pharmaceutical composition of embodiments 1-39, wherein the pharmaceutically acceptable solvent is less than about 20% (v / v).

41. The pharmaceutical composition of embodiments 1-40, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent, a pharmaceutically acceptable non-polar solvent, or a combination thereof.

42. The pharmaceutical composition of embodiments 1-41, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable alcohol.

43. The pharmaceutical composition of embodiment 42, wherein the pharmaceutically acceptable alcohol comprises an acyclic alcohol, a monohydroxy alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.

44. The pharmaceutical composition of embodiment 42, wherein the pharmaceutically acceptable alcohol comprises a C _1-20 alcohol.

45. The pharmaceutical composition of embodiment 42, wherein the pharmaceutically acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a combination thereof.

46. The pharmaceutical composition of embodiments 1-45, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable ester of a pharmaceutically acceptable alcohol and acid.

47. The pharmaceutical composition of Embodiment 46 wherein the pharmaceutically acceptable ester comprises methyl acetate, methyl butyrate, methyl formate, ethyl acetate, ethyl butyrate, ethyl formate, propyl acetate, propyl butyrate, propyl formate, butyl acetate, butyl butyrate, butyl formate, isobutyl butyl butyl butyl butyl butyl butyl buty butyl butyl butyl formate, and 1-hexadecyl acetate, 1-hexadecyl butyrate and 1-hexadecyl formate, or a combination thereof.

48. The pharmaceutical composition of embodiments 1-47, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable glycol ether, a pharmaceutically acceptable dihydric alcohol, 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 of them.

49. The pharmaceutical composition of 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) and diethylene glycol mono-n-butyl ether (2- (2-butoxyethoxy) ethanol), or any combination thereof.

50. The pharmaceutical composition of embodiment 48, wherein the molar mass of the pharmaceutically acceptable polypropylene glycol (PPG) polymer or the pharmaceutically acceptable polyethylene glycol (PEG) polymer is less than about 2000 g / mol.

51. The pharmaceutical composition of embodiment 48, wherein the molar mass of the pharmaceutically acceptable polypropylene glycol (PPG) polymer or the pharmaceutically acceptable polyethylene glycol (PEG) polymer is greater than about 2000 g / mol.

52. The pharmaceutical composition of embodiments 1-51, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable glyceride.

53. The pharmaceutical composition of embodiment 52, wherein the pharmaceutically acceptable glyceride comprises a monoglyceride, diglyceride, triglyceride, acetylated monoglyceride, acetylated diglyceride, acetylated triglyceride, or a combination thereof.

54. The pharmaceutical composition of embodiments 1-53, wherein the pharmaceutically acceptable solvent is a liquid at 20 ° C, or in which the pharmaceutically acceptable solvent is a solid at 20 ° C.

55. The pharmaceutical composition of embodiment 54, wherein the pharmaceutically acceptable solid solvent comprises menthol.

56. The pharmaceutical composition of embodiments 1-55, wherein the adjuvant is at least 80% (v / v).

57. The pharmaceutical composition according to options 1-56, in which the pharmaceutically acceptable adjuvant is a liquid at 20 ° C.

58. The pharmaceutical composition of embodiments 1-56, wherein the pharmaceutically acceptable adjuvant is a solid at 20 ° C.

59. The pharmaceutical composition of embodiments 1-58, wherein the pharmaceutically acceptable adjuvant contains a pharmaceutically acceptable lipid.

60. The pharmaceutical composition of embodiment 59, wherein the pharmaceutically acceptable lipid comprises a saturated fatty acid, an unsaturated fatty acid, or a combination thereof.

61. The pharmaceutical composition of embodiment 59 or 60, wherein the pharmaceutically acceptable lipid comprises two or more saturated or unsaturated fatty acids.

62. The pharmaceutical composition of embodiment 61, wherein the two or more saturated or unsaturated fatty acids include palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof.

63. The pharmaceutical composition according to options 60-62, in which the unsaturated fatty acid has a melting point of 20 ° C or lower, or the unsaturated fatty acid is solid at 20 ° C.

64. The pharmaceutical composition according to options 60-62, in which the unsaturated fatty acid contains omega fatty acid.

65. The pharmaceutical composition of embodiment 59, wherein the pharmaceutically acceptable lipid comprises a pharmaceutically acceptable oil.

66. The pharmaceutical composition of embodiment 65 wherein the pharmaceutically acceptable oil comprises almond oil, peanut oil, avocado oil, rapeseed 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, soya bean oil, soybean oil, sunflower oil, cocoa bean oil, oil from walnut, wheat germ oil, or a combination thereof.

67. The pharmaceutical composition of embodiment 59, wherein the pharmaceutically acceptable lipid comprises a pharmaceutically acceptable glycerolipid, a pharmaceutically acceptable glycol fatty acid ester, a pharmaceutically acceptable polyester and fatty acid ester, a mixture of pharmaceutically acceptable lipids, or any combination thereof.

68. The pharmaceutical composition of embodiments 1-67, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable stabilizing agent.

69. The pharmaceutical composition of embodiment 68, wherein the pharmaceutically acceptable stabilizing agent comprises water, a tread acid containing a fatty acid component and acetic acid, ethyl acetate, sodium acetate / acetic acid, monoglyceride, acetylated monoglyceride, diglyceride, acetylated monoglyceride acid, acetylated fatty acid, acetylated monoglyceride, acetylated fatty acid salt or a combination thereof.

70. The pharmaceutical composition of embodiment 68, wherein the pharmaceutically acceptable stabilizing agent comprises a pharmaceutically acceptable emulsifier.

71. The pharmaceutical composition of embodiment 70, wherein the pharmaceutically acceptable emulsifier comprises a surfactant, polysaccharide, lectin, phospholipid, or a combination thereof.

72. The pharmaceutical composition according to options 1-69, in which the pharmaceutical composition does not contain a pharmaceutically acceptable emulsifier.

73. A method of obtaining a pharmaceutical composition, comprising the step of contacting the therapeutic compound with a pharmaceutically acceptable adjuvant under conditions allowing the formation of the pharmaceutical composition.

74. A method of preparing a pharmaceutical composition comprising the following steps: a) contacting a pharmaceutically acceptable solvent with a therapeutic compound under conditions that allow the therapeutic compound to dissolve in a pharmaceutically acceptable solvent, thereby forming a solution wherein the therapeutic compound has an anti-inflammatory effect, and b) contacting the solution, obtained in stage (a) with a pharmaceutically acceptable adjuvant under conditions allowing the formation of a pharmaceutical composition ii.

75. A method of obtaining a pharmaceutical composition comprising the following steps: a) contacting a pharmaceutically acceptable solvent with a therapeutic compound under conditions allowing the therapeutic compound to dissolve in a pharmaceutically acceptable solvent, thereby forming a solution wherein the therapeutic compound has an anti-inflammatory effect, and b) contacting the solution, obtained in stage (a) with a pharmaceutically acceptable adjuvant under conditions allowing the formation of a pharmaceutical composition uu, wherein the ratio of pharmaceutically acceptable solvent and a pharmaceutically acceptable adjuvant is in the range from about 0: 1 to about 1:25.

76. The method of embodiments 73-75, wherein the therapeutic compound has a logP value indicating that the compound is soluble in an organic solvent.

77. The method according to options 73-76, in which the therapeutic compound has a logP value above 1.0.

78. The method of embodiments 73-76, wherein the therapeutic compound has a logP value of greater than 2.0.

79. The method according to options 73-78, in which the therapeutic compound has a polar surface area that is hydrophobic.

80. The method according to options 73-79, in which the therapeutic compound has a polar surface area that is less than 8.0 nm ² .

81. The method according to options 73-79, in which the therapeutic compound has a polar surface area that is less than 6.0 nm ² .

82. The method of embodiments 73-81, wherein the therapeutic compound comprises a non-steroidal anti-inflammatory agent (NSAID).

83. The method of embodiment 82 wherein the NSAID comprises an NSAID salicylate derivative, an NSAID p-aminophenol derivative, an NSAID propionic acid derivative, an NSAID acetic acid derivative, an NSAID enol acid derivative, an NSAID phenamic acid derivative, and a non-selective cyclooxygenase inhibitor. (COX), a selective cyclooxygenase 1 inhibitor (COX 1), a selective cyclooxygenase 2 inhibitor (COX 2), or a combination thereof.

84. The method of embodiments 73-83, wherein the therapeutic compound comprises a PPARγ agonist.

85. The method of embodiment 84, wherein the PPARγ agonist comprises Monascin, Irbesartan, Telmisartan, mycophenolic acid, Resveratrol, delta (9) -tetrahydrocannabinol, cannabidiol, Curcumin, Cilostazole, Benzbromarone, 6-Shogaol, glycyridiratin azide, tyrindiratinid, NS or a combination thereof.

86. The method of embodiments 73-85, wherein the therapeutic compound comprises a nuclear receptor binding agent.

87. The method of embodiment 86, wherein the nuclear receptor binding agent comprises a retinoic acid receptor binding agent (RAR), a retinoid X receptor binding agent (RXR), a liver X receptor binding agent (LXR), an agent, Vitamin D binding and combination thereof.

88. The method of embodiments 73-87, wherein the therapeutic compound comprises an anti-hyperlipidemic agent.

89. The method of embodiment 88, wherein the anti-hyperlipidemic agent comprises fibrate, statin, tocotrienol, niacin, bile acid sequestrants (resins), a cholesterol absorption inhibitor, pancreatic lipase inhibitor, sympathomimetic amine, or a combination thereof.

90. The method of embodiment 89, wherein the fibrate comprises Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a combination thereof.

91. The method of embodiment 89, wherein the statin comprises Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof.

92. The method of embodiment 89, wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof.

93. The method of embodiment 89, wherein the bile acid sequestrant comprises cholestyramine, colestipol, kolesevel, or a combination thereof.

94. The method of embodiment 89, wherein the cholesterol absorption inhibitor comprises Ezetimibe, phytosterol, sterol, stanol, or a combination thereof.

95. The method of embodiment 89, wherein the fat absorption inhibitor comprises Orlistat.

96. The method of embodiment 89, wherein the sympathomimetic amine comprises Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, lisdexamphetamine, cathine, cathinone, benzene, benzene, benzene, benzene, benzene, benzene ), 4-methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof.

97. The method of embodiments 73-96, wherein the therapeutic compound comprises an ester of the therapeutic compound.

98. The method of embodiments 73-97, wherein the therapeutic compound comprises an ester of the therapeutic compound of embodiments 111-126.

99. The method of embodiments 74-98, wherein the pharmaceutically acceptable solvent is less than about 20% (v / v).

100. The method of embodiments 74-99, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent, a pharmaceutically acceptable non-polar solvent, or a combination thereof.

101. The method of embodiments 74-100, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable alcohol.

102. The method of embodiment 101, wherein the pharmaceutically acceptable alcohol comprises an acyclic alcohol, a monohydroxy alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.

103. The method of embodiment 101, wherein the pharmaceutically acceptable alcohol comprises a C _1-20 alcohol.

104. The method of embodiment 101, wherein the pharmaceutically acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a combination thereof.

105. The method of embodiment 101, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable ester of a pharmaceutically acceptable alcohol and acid.

106. The method of embodiment 105, wherein the pharmaceutically acceptable ester comprises methyl acetate, methyl butyrate, methyl formate, ethyl acetate, ethyl butyrate, ethyl formate, propyl acetate, propyl butyrate, propyl formate, butyl acetate, butyl butyrate, butyl formate, isobutyl acetate, isobutyl butyl butyrate, pentobutyl butyrate, pentobutyl butyrate, pentobutyl butyrate, isobutyl butyl butyrate 1-hexadecyl acetate, 1-hexadecyl butyrate and 1-hexadecyl formate or a combination thereof.

107. The method of embodiments 74-106, wherein the pharmaceutically acceptable solvent is a pharmaceutically acceptable polyethylene glycol (PEG) polymer.

108. The method of embodiment 107, wherein the molar mass of the pharmaceutically acceptable polyethylene glycol (PEG) polymer is less than about 2000 g / mol.

109. The method of embodiment 107, wherein the molar mass of the pharmaceutically acceptable polyethylene glycol (PEG) polymer is greater than about 2000 g / mol.

110. The method of embodiments 74-109, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable glyceride.

111. The method of embodiment 110, wherein the pharmaceutically acceptable glyceride comprises monoglyceride, diglyceride, triglyceride, acetylated monoglyceride, acetylated diglyceride, acetylated triglyceride, or a combination thereof.

112. The method of embodiments 74-111, wherein the pharmaceutically acceptable solvent is a liquid at 20 ° C.

113. The method of embodiments 74-111, wherein the pharmaceutically acceptable solvent is a solid at 20 ° C.

114. The method of embodiment 113, wherein the pharmaceutically acceptable solid solvent comprises menthol.

115. The method according to options 73-114, in which the adjuvant is at least 80% (vol./vol.).

116. The method according to options 73-115, in which the pharmaceutically acceptable adjuvant is a liquid at 20 ° C.

117. The method according to embodiments 73-115, wherein the pharmaceutically acceptable adjuvant is a solid at 20 ° C.

118. The method of embodiments 73-117, wherein the pharmaceutically acceptable adjuvant comprises a pharmaceutically acceptable lipid.

119. The method of embodiment 118, wherein the pharmaceutically acceptable lipid comprises saturated fatty acid, unsaturated fatty acid, or a combination thereof.

120. The method of embodiment 118 or 119, wherein the pharmaceutically acceptable lipid comprises two or more saturated or unsaturated fatty acids.

121. The method of embodiment 120, wherein the two or more saturated or unsaturated fatty acids include palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof.

122. The method of embodiments 119-121, wherein the pharmaceutically acceptable unsaturated fatty acid has a melting point of 20 ° C. or lower.

123. The method of embodiments 119-121, wherein the pharmaceutically acceptable unsaturated fatty acid is a solid at 20 ° C.

124. The method of embodiments 119-123, wherein the pharmaceutically acceptable unsaturated fatty acid comprises omega fatty acid.

125. The method of embodiments 118-124, wherein the pharmaceutically acceptable lipid comprises a pharmaceutically acceptable oil.

126. The method of embodiment 125, wherein the pharmaceutically acceptable oil comprises almond oil, peanut oil, avocado oil, rapeseed oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soybean oil, sunflower oil, walnut oil, wheat germ oil or their mbinatsiyu.

127. The method of embodiments 74 or 76-126, wherein in step (b), the ratio of the pharmaceutically acceptable solvent to the pharmaceutically acceptable adjuvant is in the range of from about 0: 1 to about 1:25.

128. The method of embodiments 73-127, wherein step (a) further comprises contacting the pharmaceutically acceptable stabilizing agent with a pharmaceutically acceptable solvent and therapeutic compound.

129. The method of embodiment 128, wherein the pharmaceutically acceptable stabilizing agent comprises water, a tread acid containing a fatty acid component and acetic acid, ethyl acetate, sodium acetate / acetic acid, monoglyceride, acetylated monoglyceride, acetylated monoglyceride, diglyceride, acetylated fattyl diglyceride fatty acid salt or a combination thereof.

130. The method of embodiment 128 or 129, wherein the pharmaceutically acceptable stabilizing agent comprises a pharmaceutically acceptable emulsifier.

131. The method of embodiment 130, wherein the pharmaceutically acceptable emulsifier comprises a surfactant, polysaccharide, lectin, phospholipid, or a combination thereof.

132. The method according to options 73-129, in which the pharmaceutical composition does not contain a pharmaceutically acceptable emulsifier.

133. The method of embodiments 74-132, wherein the method further comprises removing a pharmaceutically acceptable solvent from the pharmaceutical composition.

134. The method of embodiment 133, wherein at least 5% of the pharmaceutically acceptable solvent is removed from the pharmaceutical composition.

135. The method according to option 133 or 134, in which the removal of solvent from the pharmaceutical composition disclosed herein is carried out at a temperature below 20 ° C.

136. The method according to options 73-135, in which the pharmaceutical composition is made according to options 1-72.

137. A method of treating an individual with chronic inflammation, where the method includes the step of administering to the individual in need of the pharmaceutical composition of embodiments 1-72, wherein administration reduces the symptom associated with chronic inflammation, thereby providing treatment for the individual.

138. The use of the pharmaceutical composition according to options 1-72 in the manufacture of a medicinal product for the treatment of chronic inflammation.

139. The use of the pharmaceutical composition according to options 1-72 for the treatment of chronic inflammation.

140. The method of embodiment 137 or the use of embodiment 138 or 139, in which chronic inflammation is associated with acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, ho angitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, colds, dacryadenitis, diabetic dermatitis, diabetic dermatitis, dermatitis, diabetes retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, ep condelitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, purulent hydradenitis, Huntington’s disease, hyperlipidemic pancreatitis, infection, hyperlipidemia, pancreatitis, disease, inflammatory cardiomegaly, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, coronary heart disease, rattin, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (X syndrome), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, osteomephoritis, osteoarthritis, omeneopenia, ohomitomei, omitenomei, omitenomei, omitenomei, omitenomei, omitenomeitis, osteomyelitis, osteoporosis, osteitis, otitis media, pancreatitis, Parkinson's disease, mumps, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, stump monia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, stenomyelitis, colitis, stomatitis, sinusitis, surgery, synovitis, tendonitis, tenninosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, Pujol, urethritis, ursitom, uveitis, vaginitis, vulvitis, or vasculitis.

141. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is inflammation of the tissue.

142. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is systemic inflammation.

143. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is arthritis.

144. The method or application of embodiment 140 or 143, wherein the arthritis is monoarthritis, oligoarthritis or polyarthritis.

145. The method or application of embodiment 140 or 143, wherein the arthritis may be an autoimmune disease or a non-autoimmune disease.

146. The method or application of embodiment 140 or 143, wherein the arthritis is osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, septic arthritis, spondyloarthropathy, gout, pseudogout or Still's disease.

147. The method or application of embodiment 146, wherein the spondyloarthropathy is ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis associated with inflammatory bowel disease, enteropathic arthritis, Whipple's disease and Behcet's disease.

148. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is an autoimmune disease.

149. The method or application of embodiment 140 or 148, wherein the autoimmune disease is a systemic autoimmune disease or an organ-specific autoimmune disease.

150. The method or application of embodiment 140 or 148, wherein the autoimmune disease is acute disseminated encephalomyelitis (ADEM), Addison’s disease, allergy or hypersensitivity, amyotrophic lateral sclerosis, antiphospholipid antibody syndrome (APS), arthritis, autoimmune hemolytic anemia, , autoimmune disease of the inner ear, autoimmune pancreatitis, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease (COPD), type I diabetes mellitus (IDDM), endometriosis, syndrome Goodpasture rum, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto thyroiditis, purulent hydradenitis, idiopathic thrombocytopenic purpura, inflammatory bowel disease, interstitial cystitis, lupus erythematosus, lupus erythematosus, nonmedus erythematosus, non-median erythematosus lupus erythematosus and systemic lupus erythematosus), morpheus, multiple sclerosis (MS), myasthenia gravis, myopathy, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary ny cirrhosis, recurrent disseminated encephalomyelitis, rheumatism, schizophrenia, scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis and vitiligo.

151. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is myopathy.

152. The method or application of embodiment 137 or 148, wherein the myopathy is dermatomyositis, inclusion body myositis, or polymyositis.

153. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is vasculitis.

154. The method or application of embodiment 140 or 153, wherein the vasculitis is Buerger’s disease, arteritis, cerebral vasculitis, Charge-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell arteritis, golfer's vasculitis, Genocha-Shenlein purple, vasculitis hyper , Kawasaki disease, phlebitis, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, rheumatic polymyalgia (PMR), rheumatoid vasculitis, Takayasu arteritis, thrombophlebitis, Wegener granulomatosis or VA sculitis secondary to connective tissue diseases, or vasculitis secondary to viral infection.

155. The method of embodiment 137 or the use of embodiment 138 or 139, wherein chronic inflammation is associated with a skin disease.

156. The method or application of embodiment 140 or 155, wherein the skin disease is dermatitis, eczema, stasis dermatitis, purulent hydradenitis, psoriasis, acne or scleroderma.

157. The method or application of embodiment 156, wherein the eczema is atopic eczema, contact eczema, xerotic eczema, seborrheic dermatitis, dyshidrosis, discoid eczema, venous eczema, herpetiform dermatitis, neurodermatitis, or auto-eczematization.

158. The method or application of embodiment 156, wherein the psoriasis is plaque psoriasis, nail psoriasis, teardrop psoriasis, scalp psoriasis, reverse psoriasis, pustular psoriasis, or erythrodermic psoriasis.

159. The method of embodiment 137 or the use of embodiment 138 or 139, wherein chronic inflammation is associated with a gastrointestinal upset.

160. The method or application of embodiment 140 or 159, wherein the gastrointestinal upset is an irritable bowel syndrome or inflammatory bowel disease.

161. The method or application of embodiment 160, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

162. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is associated with a cardiovascular disease.

163. The method or application of embodiment 140 or 162, wherein the cardiovascular disease is hypertension, heart valve dysfunction, congestive heart failure, myocardial infarction, diabetic heart disease, blood vessel inflammation, arterial occlusion disease, peripheral artery disease, aneurysm, embolism, stratification of blood vessels, pseudo-aneurysm, vascular malformation, vascular nevus, thrombosis, thrombophlebitis, varicose veins or stroke.

164. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is associated with cancer.

165. The method of embodiment 137 or the use of embodiment 138 or 139, wherein chronic inflammation is associated with pharmacologically induced inflammation.

166. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is associated with an infection.

167. The method or application of embodiment 140 or 166, wherein the infection is bacterial cystitis, bacterial encephalitis, pandemic influenza, viral encephalitis, viral hepatitis A, viral hepatitis B or viral hepatitis C.

168. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is associated with a tissue or organ injury.

169. The method of embodiment 137 or the use of embodiment 138 or 139, wherein chronic inflammation is associated with transplant rejection or graft-versus-host syndrome.

170. The method of embodiment 137 or the use of embodiment 138 or 139, wherein chronic inflammation is associated with a Th1-mediated inflammatory disease.

171. The method of embodiment 137 or the use of embodiment 138 or 139, wherein the chronic inflammation is associated with chronic neurogenic inflammation.

172. The method of embodiments 137 or 140-171, or the use of embodiments 138-171, wherein when administered to an individual, a pharmaceutical composition comprising a therapeutic compound of embodiments 1-72 results in a biodistribution of the therapeutic compound different from the biodistribution of the therapeutic compound included in the same pharmaceutical composition with the exception of the adjuvant disclosed herein.

173. The method according to options 137 or 140-172 or the use according to options 138-172, wherein when administered to an individual, the amount of the therapeutic compound in the pharmaceutical composition according to embodiments 1-72 delivered to macrophages is at least 5% of the total amount of the therapeutic compound contained in the administered pharmaceutical composition.

174. The method according to options 137 or 140-173 or the application according to options 138-173, wherein when administered to an individual, the pharmaceutical composition according to options 1-72 reduces intestinal irritation by at least 5% compared with the pharmaceutical composition according to options 1-72 except for the absence of a pharmaceutically acceptable adjuvant.

175. The method according to options 137 or 140-171 or the use according to options 138-174, wherein when administered to an individual, the pharmaceutical composition according to options 1-72 reduces gastric irritation by at least 5% compared with the pharmaceutical composition according to options 1-72 except for the absence of a pharmaceutically acceptable adjuvant.

176. A solid pharmaceutical composition comprising: a) about 10% -30% by weight of a non-steroidal anti-inflammatory drug (NSAID), where the NSAID has an anti-inflammatory effect, b) from about 20% to about 50% by weight of a mixture of mono-, di- and triglycerides and esters of PEG and fatty acids, c) from about 10% to about 30% by weight of glyceryl monolinoleate, and d) from about 5% to about 15% PEG.

177. The solid pharmaceutical composition of embodiment 176, wherein the NSAID is from about 20% to about 30% by weight of the pharmaceutical composition.

178. The solid pharmaceutical composition of Embodiment 176 or 177, wherein the mixture of mono-, di- and triglycerides and PEG esters and fatty acids is from about 35% to about 45% by weight of the pharmaceutical composition.

179. The solid pharmaceutical composition of any one of embodiments 176-178, wherein the glyceryl monolinoleate is from about 15% to about 25% by weight of the pharmaceutical composition.

180. The solid pharmaceutical composition of any one of embodiments 176-179, wherein the PEG is from about 7% to about 13% by weight of the pharmaceutical composition.

181. The solid pharmaceutical composition of any one of embodiments 176-180, wherein the NSAID is from about 23% to about 27% by weight of the pharmaceutical composition, the mixture of mono-, di- and triglycerides and PEG esters and fatty acids is from about 41 % to about 47% by weight of the pharmaceutical composition, glyceryl monolinoleate is from about 18% to about 22% by weight of the pharmaceutical composition, and PEG is from about 9% to about 11% by weight of the pharmaceutical composition.

182. The solid pharmaceutical composition of any one of embodiments 176-181, wherein the solid pharmaceutical composition further comprises from about 5% to about 15% propylene glycol.

183. The solid pharmaceutical composition of any one of embodiments 176-182, wherein the NSAID is from about 23% to about 27% by weight of the pharmaceutical composition, the mixture of mono-, di- and triglycerides and PEG esters and fatty acids is from about 41 % to about 47% by weight of the pharmaceutical composition, glyceryl monolinoleate is from about 18% to about 22% by weight of the pharmaceutical composition, PEG is from about 9% to about 11% by weight of the pharmaceutical composition, and propylene glycol is from about 9% to but 11% by weight of the pharmaceutical composition.

184. A liquid pharmaceutical composition comprising: a) from about 15% to about 35% by weight of a non-steroidal anti-inflammatory drug (NSAID), wherein the NSAID has an anti-inflammatory effect; b) from about 5% to about 25% by weight of diethylene glycol monoethyl ether; c) from about 15% to about 40% by weight of glyceryl monolinoleate; and d) from about 15% to about 40% oil.

185. The liquid pharmaceutical composition of embodiment 184, wherein the NSAID is from about 20% to about 30% by weight of the pharmaceutical composition.

186. A liquid pharmaceutical composition according to embodiment 184 or 185, wherein the diethylene glycol monoethyl ether comprises from about 10% to about 20% by weight of the pharmaceutical composition.

187. The liquid pharmaceutical composition according to any one of embodiments 184-186, wherein the glyceryl monolinoleate comprises from about 20% to about 35% by weight of the pharmaceutical composition.

188. The liquid pharmaceutical composition of any one of embodiments 184-187, wherein the oil comprises from about 20% to about 35% by weight of the pharmaceutical composition.

189. The liquid pharmaceutical composition according to any one of embodiments 184-188, wherein the NSAID is from about 23% to about 27% by weight of the pharmaceutical composition, diethylene glycol monoethyl ether is from about 13% to about 17% by weight of the pharmaceutical composition, glyceryl monolinoleate is from about 25% to about 30% by weight of the pharmaceutical composition, and the oil is from about 25% to about 30% by weight of the pharmaceutical composition.

190. The liquid pharmaceutical composition of any one of embodiments 184-189, wherein the liquid pharmaceutical composition further comprises about 2% to about 10% alcohol.

191. The liquid pharmaceutical composition of embodiment 190, wherein the alcohol is ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2-propanediol or methanol.

192. The liquid pharmaceutical composition according to any one of embodiments 184-191, wherein the NSAID is from about 23% to about 27% by weight of the pharmaceutical composition, diethylene glycol monoethyl ether is from about 13% to about 17% by weight of the pharmaceutical composition, glyceryl monolinoleate is from about 25% to about 30% by weight of the pharmaceutical composition, oil is from about 25% to about 30% by weight of the pharmaceutical composition, and alcohol is from about 4% to about 8% by weight of the pharmaceutical composition tion.

193. A semi-solid pharmaceutical composition comprising: a) from about 20% to about 50% by weight of a non-steroidal anti-inflammatory drug (NSAID), where the NSAID has an anti-inflammatory effect, b) from about 8% to about 18% by weight of a mono-, di- and triglycerides and complex PEG and fatty acid esters, c) from about 25% to about 45% by weight of glyceryl monolinoleate, d) from about 8% to about 18% PEG; and e) from about 2% to about 6% propylene glycol.

194. The semi-solid pharmaceutical composition of embodiment 193, wherein the mixture of mono-, di- and triglycerides and PEG esters and fatty acids is from about 10% to about 16% by weight of the pharmaceutical composition.

195. The semi-solid pharmaceutical composition of Embodiment 193 or 194, wherein the PEG is from about 10% to about 16% by weight of the pharmaceutical composition.

196. The semi-solid pharmaceutical composition of any one of embodiments 193-195, wherein the NSAID is from about 25% to about 44% by weight of the pharmaceutical composition, a mixture of mono-, di- and triglycerides and PEG esters and fatty acids is from about 12 % to about 14% by weight of the pharmaceutical composition, glyceryl monolinoleate is from about 32% to about 39% by weight of the pharmaceutical composition, PEG is from about 12% to about 14% by weight of the pharmaceutical composition, and propylene glycol is from about 3% to about 5% by weight of the pharmaceutical composition.

197. A semi-solid pharmaceutical composition comprising: a) from about 15% to about 30% by weight of the free acid of a non-steroidal anti-inflammatory drug (NSAID), where the NSAID has an anti-inflammatory effect, b) from about 1% to about 25% by weight of the NSAID salt where the NSAID has an anti-inflammatory effect, c) from about 8% to about 18% by weight of a mixture of mono-, di- and triglycerides and PEG esters of fatty acids, d) from about 25% to about 45% by weight of glyceryl monolinoleate, e ) from about 8% to about 18% PEG; and f) from about 2% to about 6% propylene glycol.

EXAMPLES

The following non-limiting examples are provided for illustrative purposes, only to facilitate a more complete understanding of the provided typical embodiments of the invention. These examples should not be construed as limiting any of the embodiments disclosed herein, including those related to compounds, alcohols, lipids, pharmaceutical compositions, methods for producing pharmaceutical compositions, or methods or uses for treating chronic inflammation or a disease associated with chronic inflammation.

Example 1

Liquid Formulations of Pharmaceutical Composition

This example illustrates how to make the pharmaceutical composition disclosed herein in the form of a liquid composition.

First, 2,400 mg of ibuprofen was directly added to 2.0 ml of rapeseed oil in an attempt to dissolve the therapeutic compound directly in the adjuvant to a concentration of 1,200 mg / ml. However, ibuprofen remained insoluble in oil and essentially did not noticeably dissolve. Ibuprofen remained insoluble even if the mixture was vortexed for 20 seconds, contacted at 20 ° C or 37 ° C, and / or the mixture was incubated for 24 hours at 20 ° C or 37 ° C. The insolubility of ibuprofen in rapeseed oil was unexpected, given that ibuprofen has a logP value of 3.6; such a high logP indicates that the compound will readily dissolve in an adjuvant such as oil.

Since it was not possible to dissolve ibuprofen directly in oil, despite the high logP value, the next time they tried to dissolve the therapeutic agent in a solvent in order to first obtain a solution containing the compound. As a first step, experiments were conducted on the miscibility of a solvent and an adjuvant, such as oil, in the absence of a therapeutic compound. In these experiments, 0.5 ml of ethanol was mixed with ten different volumes of rapeseed oil (table 1). Each mixture was tested at 22 ° C and at 37 ° C, when ethanol and oil were initially heated in a water bath, and then mixed together. Mixing was carried out on a vortex for 20 seconds, and the contents in the containers were allowed to settle before visual assessment, either immediately or after 24 hours. Each mixture was evaluated to determine whether or not ethanol and rapeseed oil form immiscible layers or a homogeneous mixture. The results are summarized in table 1. Mixtures containing solvent: adjuvant in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5 and 1: 6 formed immiscible layers at 22 ° C or at 37 ° C, immediately or after 24 hours of incubation, indicating that ethanol and oil do not mix well in these ratios. However, with solvent: adjuvant ratios greater than 1: 7, a homogeneous mixture is formed under all conditions tested.

Table 1
Liquid formulations without therapeutic compound Components Temperature Solvent (ml) Adjuvant (ml) Ratio 22 ° C 37 ° C Immediately After 24 hours Immediately After 24 hours 0.5 0.5 1: 1 NA NA NA NA 0.5 1,0 1: 2 NA NA NA NA 0.5 1,5 1: 3 NA NA NA NA

0.5 2.0 1: 4 NA NA NA NA 0.5 2,5 1: 5 NA NA NA NA 0.5 3.0 1: 6 NA NA NA NA 0.5 3,5 1: 7 GM GM GM GM 0.5 4.0 1: 8 GM GM GM GM 0.5 4,5 1: 9 GM GM GM GM 0.5 5,0 1:10 GM GM GM GM NS, immiscible layers
GM, homogeneous mixture

After the appropriate alcohol-lipid ratios necessary for the formation of a homogeneous mixture were determined, it was further determined whether contacting the therapeutic compound with a solvent before contacting with an adjuvant would lead to the dissolution of the compound in solvents. To conduct these experiments, either 1000 mg or 1200 mg of ibuprofen was dissolved in 0.5 ml of ethanol. The resulting alcoholic solution was then mixed with rapeseed oil in two different solvent: adjuvant ratios (1: 2 and 1: 9). Each mixture was tested at 20 ° C and at 37 ° C when the ethanol and oil solution was initially heated in a water bath and then mixed together. Mixing was carried out on a vortex for 20 seconds, and the contents in the containers were allowed to settle before visual assessment, either immediately or after 24 hours. Each mixture was evaluated to determine whether or not ethanol solution and rapeseed oil form immiscible layers or a homogeneous mixture. The results are summarized in table 2. In contrast to the situation in the absence of a therapeutic compound, if ibuprofen is present in ethanol, this results in a homogeneous mixture of ethanol and oil under any conditions tested with solvent: adjuvant ratios greater than 1: 2. This observation was very unexpected, therefore, although not wanting to be bound by any theory, the inventors suggest that the therapeutic compound may have a definite effect on how the adjuvant and the solvent interact with each other to form a homogeneous mixture that does not occurs in the absence of a therapeutic compound. In addition, the results indicate that the therapeutic compound may be formulated in clinically suitable concentrations.

table 2
Therapeutic compounds Components Temperature Compound (mg) Solvent (ml) Adjuvant (ml) Ratio 22 ° C 37 ° C Immediately After 24 hours Immediately After 24 hours 500 0.5 1,0 1: 2 GM GM GM GM 600 0.5 1,0 1: 2 GM GM GM GM 500 0.5 4,5 1: 9 GM GM GM GM 600 0.5 4,5 1: 9 GM GM GM GM NS, immiscible layers
GM, homogeneous mixture

Example 2

Liquid Formulations of Pharmaceutical Composition

This example illustrates how to make the pharmaceutical composition disclosed herein in the form of a liquid composition.

To obtain the pharmaceutical composition disclosed herein using gemfibrozil, the following formulations were tested. In these experiments, 600 mg of gemfibrozil was mixed with various volumes of ethanol as a solvent heated to 37 ° C, and the resulting solution was then mixed with various volumes of linseed oil as an adjuvant heated to 37 ° C (table 3). Each formulation was evaluated to determine whether ethanol and linseed oil would form immiscible layers or a clear, uniform mixture, and whether gemfibrozil would crystallize from solution. The results are summarized in table 3.

Like ibuprofen in Example 1, gemfibrozil alone remained insoluble in oil and did not substantially dissolve. A composition containing 0.2 ml of ethanol could not completely dissolve gemfibrozil. In addition, although a composition containing 0.3 ml of ethanol was able to dissolve gemfibrozil, the therapeutic compound began to crystallize from the solution after 3 hours, and complete crystallization occurred in 48 hours. All other formulations tested were able to dissolve gemfibrozil and form the pharmaceutical composition disclosed herein. However, only a composition containing 0.5 ml of ethanol was apparently necessary for a stable pharmaceutical composition in which gemfibrozil remained completely dissolved after three weeks.

Table 3
Therapeutic compounds Components Temperature Compound (mg) Solvent (ml) Adjuvant (ml) Ratio 22 ° C Immediately 3 weeks 600 0 1,0 - NA There is no data 600 0.2 - - NA There is no data 600 0.3 0.6 1: 2 KR KR 600 0.4 0.4 1: 1 GM KR 600 0.4 0.8 1: 2 GM KR 600 0.5 1,0 1: 2 GM GM GM, transparent homogeneous mixture
Raman crystallization
NS, immiscible layers

Example 3

Liquid formulations of pharmaceutical compositions

This example illustrates how to make the pharmaceutical composition disclosed herein in the form of a liquid composition.

To obtain the liquid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. About 4 g of ibuprofen was mixed with 3.6 ml of ethyl acetate as a solvent, and the resulting solution was then mixed with 76.4 ml of rapeseed oil as an adjuvant. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1:21. This pharmaceutical composition was then placed in a round bottom flask and left at low pressure on a rotary evaporator. The temperature was kept low, and evaporation was continued until a constant weight was achieved. Lost total volume was 3.65% of the total mass. The resulting liquid no longer retained the characteristic smell / taste of ethyl acetate, which indicated the practical removal of ethyl acetate from the pharmaceutical composition.

The following method was performed using ibuprofen to prepare the liquid pharmaceutical composition disclosed herein. About 2 g of ibuprofen was mixed with 1.2 ml of diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol) as solvent, 2.2 ml of MAISINE® 35-1 (glyceryl monolinoleate, Gattefosse) and 2.2 ml of rapeseed oil as adjuvant, and the resulting mixture was then mixed with 0.46 ml of isopropanol. The mixture was added to the vessel, heated from about 40 ° C to about 50 ° C and stirred until all components of the mixture were completely dissolved, and then cooled to a temperature of about 30 ° C. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1: 3.67. This pharmaceutical composition was then aliquoted to obtain 10 liquid capsules, each of which contained approximately 200 mg of ibuprofen.

Example 4

The solid composition of the pharmaceutical composition

This example illustrates how to make the pharmaceutical composition disclosed herein as a solid composition.

Since some fatty acids are liquid at room temperature, while others are solid, various fatty acids have been studied in an attempt to evaluate the feasibility of using each fatty acid to formulate a solid composition. These data will contribute to the development of a wide range of solid formulations by controlling the relative content of each fatty acid. As a first experiment, linolenic acid, linoleic acid, palmitic acid, and stearic acid were evaluated to determine whether it is possible to obtain the pharmaceutical composition disclosed herein that could be formulated using only one of these fatty acids to be solid or semi-solid at 22 ° C (temperature simulating room temperature conditions), but melting into a liquid at 37 ° C (temperature simulating internal body temperature conditions after administration).

Four different test formulations were prepared and evaluated for their ability to form a solid drug formulation at 22 ° C and melt to a homogeneous solution at 37 ° C without the formation of a suspension (Table 4). Composition 1 was prepared by dissolving 200 mg of ibuprofen in 400 mg of menthol, and the resulting solution was mixed with 200 mg of stearic acid (T _m approximately 67-72 ° C) and heated at 60 ° C for 30 minutes until a homogeneous solution was formed. Composition 1 hardened immediately after cooling to 22 ° C. Composition 1 remained solid even after incubation at 37 ° C. overnight. Composition 2 was prepared by dissolving 200 mg of ibuprofen in 400 mg of menthol, and the resulting solution was mixed with 200 mg of palmitic acid (T _m approximately 61-62 ° C) and heated at 60 ° C for 30 minutes until a homogeneous solution was formed. Composition 2 solidified within about 1 hour after cooling to 22 ° C. Incubation at 37 ° C overnight caused the composition 2 to completely melt to a clear, homogeneous liquid. However, the composition 2 hardened again within about 1 hour after cooling to 22 ° C. Composition 3 was prepared by dissolving 200 mg of ibuprofen in 400 mg of menthol, and the resulting solution was mixed with 200 mg of linoleic acid (T _m about -5 ° C) and heated at 37 ° C for 2 hours to form a homogeneous solution. Composition 3 remained liquid even after cooling to 22 ° C for 72 hours. Composition 4 was prepared by dissolving 200 mg of ibuprofen in 400 mg of menthol, and the resulting solution was mixed with 200 mg of linolenic acid (T _m about -11 ° C) and heated at 37 ° C for 2 hours to form a homogeneous solution. Composition 4 remained liquid even after cooling to 22 ° C for 72 hours.

Table 4
Solid Compounds with Therapeutic Compound Components Temperature Compound (mg) Solvent (ml) Adjuvant (ml) Ratio 22 ° C 37 ° C After cooling 24 hours 72 hours 200 400 200 (stearic acid) 2: 1 Solid Solid - 200 400 200 (palmitic acid) 2: 1 Solid Liquid - 200 400 200 (linoleic acid) 2: 1 Liquid Liquid Liquid 200 400 200 (linolenic acid) 2: 1 Liquid Liquid Liquid

Based on these data, a solid dosage form of the pharmaceutical composition disclosed herein can be made. For example, the pharmaceutical composition will be formulated to be solid or semi-solid at 22 ° C, but melted into the correct clear solution (rather than suspension) at 37 ° C (table 5).

Table 5
Solid Formulations of Pharmaceutical Compositions Compound 600 mg ibuprofen Solvent 500 mg methanol 2000 mg palmitic acid 2000 mg stearic acid 250 mg linolenic acid 250 mg linoleic acid Ratio 1: 9 Volume 5 ml Concentration 120 mg / ml

To obtain the solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. About 15 g of ibuprofen was mixed with about 9.0 ml of diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol) as a solvent, about 33 g of GELUCIRE® 39/01 (Gattefosse), a waxy solid having a melting point of 37 ° C to 41 ° C and containing a mixture of saturated C ₁₀ -C ₁₈ triglycerides as adjuvant and 3.6 ml of isopropanol. The mixture was added to the vessel, heated from about 40 ° C to about 50 ° C and stirred until all components of the mixture were dissolved, cooled to about 30 ° C, and then aliquoted, poured into molds, and cooled to room temperature. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1: 3.67. This pharmaceutical composition gave 75 hard tablets, each containing 200 mg of ibuprofen.

To obtain the solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. About 20 g of ibuprofen was mixed with about 12.0 ml of diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol) as a solvent, about 16 g of GELUCIRE® 43/01 (Gattefosse), a waxy solid having a melting point of 41 ° C to 45 ° C and containing a mixture of saturated C ₁₀ -C ₁₈ triglycerides, and about 16 g of MAISINE® 35-1 (glyceryl monolinoleate, Gattefosse) as an adjuvant and about 3.6 ml of isopropanol. The mixture was added to the vessel, heated from about 40 ° C to about 50 ° C and stirred until all components of the mixture were dissolved, cooled to about 30 ° C, and then aliquoted, poured into molds, and cooled to room temperature. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1: 2.67. This pharmaceutical composition gave 100 hard tablets, each containing 200 mg of ibuprofen.

To obtain the solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. Approximately 80 g of ibuprofen, approximately 152 g of GELUCIRE® 43/01 (Gattefosse), a waxy solid having a melting point of 41 ° C to 45 ° C and containing a mixture of saturated C ₁₀ -C ₁₈ triglycerides, approximately 72 ml of MAISINE® 35- 1 (glyceryl monolinoleate, Gattefosse) and about 32 ml of PEG400 were added to the vessel, heated from about 50 ° C to about 60 ° C and stirred until all components of the mixture were dissolved. The hot mixture was cooled to about 40 ° C, and then aliquoted, poured into molds, and cooled to room temperature. This pharmaceutical composition gave 400 hard tablets, each containing 200 mg of ibuprofen.

To obtain the solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. Approximately 1.1 g of ibuprofen sodium salt, approximately 1.9 g of GELUCIRE® 43/01 (Gattefosse), a waxy solid having a melting point of 41 ° C to 45 ° C and containing a mixture of saturated C ₁₀ -C ₁₈ triglycerides, approximately 0.9 ml MAISINE® 35-1 (glyceryl monolinoleate, Gattefosse), about 0.4 ml PEG 400 and about 0.3 ml propylene glycol were added to the vessel, heated from about 50 ° C to about 60 ° C and stirred until all components were dissolved mixtures. The hot mixture was cooled to about 40 ° C, and then aliquoted, poured into molds, and cooled to room temperature. This pharmaceutical composition gave 5 hard tablets, each containing 200 mg of ibuprofen.

To obtain the solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. About 5 g of ibuprofen in free acid form, about 5 g of ibuprofen sodium, about 3 g of GELUCIRE® 43/01 (Gattefosse), a waxy solid with a melting point of 41 ° C to 45 ° C and containing a mixture of saturated C ₁₀ - C ₁₈ triglycerides, about 8 ml of MAISINE® 35-1 (glyceryl monolinoleate, Gattefosse), about 3 ml of PEG 400 and about 1 ml of propylene glycol were added to the vessel, heated from about 50 ° C to about 60 ° C and stirred until all components of the mixture were dissolved . The hot mixture was cooled to about 40 ° C, and then aliquoted, poured into molds, and cooled to room temperature. This pharmaceutical composition gave 50 hard tablets, each containing 200 mg of ibuprofen.

Example 5

Semi-solid pharmaceutical composition

This example illustrates how to make the pharmaceutical composition disclosed herein in the form of a semi-solid composition suitable for topical administration.

To obtain the semi-solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. About 1 g of ibuprofen in the free acid form, about 0.2 g of ibuprofen sodium, about 0.6 g of GELUCIRE® 43/01 (Gattefosse), a waxy solid having a melting point of 41 ° C to 45 ° C and containing a mixture saturated C ₁₀ -C ₁₈ triglycerides, about 1.6 ml MAISINE® 35-1 (glyceryl monolinoleate, Gattefosse), about 0.6 ml PEG 400 and about 0.15 ml propylene glycol were added to the vessel, heated from about 50 ° C to about 60 ° C and stirred until all components of the mixture are dissolved. The hot mixture was cooled to room temperature and aliquoted in appropriate containers. This pharmaceutical composition gave a semi-solid ointment having an ibuprofen concentration of about 400 mg / ml.

To obtain the semi-solid pharmaceutical composition disclosed herein, the following method was carried out using ibuprofen. About 5 g of ibuprofen in free acid form, about 5 g of ibuprofen sodium, about 3 g of GELUCIRE® 43/01 (Gattefosse), a waxy solid with a melting point of 41 ° C to 45 ° C and containing a mixture of saturated C ₁₀ - C ₁₈ triglycerides, about 8 ml of MAISINE® 35-1 (glyceryl monolinoleate, Gattefosse), about 3 ml of PEG 400 and about 1 ml of propylene glycol were added to the vessel, heated from about 50 ° C to about 60 ° C and stirred until all components of the mixture were dissolved . The hot mixture was cooled to room temperature and aliquoted in appropriate containers. This pharmaceutical composition gave a semi-solid ointment having an ibuprofen concentration of about 650 mg / ml.

Example 6

Animal model of intestinal erosion

To evaluate whether gastric irritation reduces the pharmaceutical composition disclosed herein, experiments were performed using a mouse model of intestinal erosion.

Sprague-Dawley rats were divided into seven experimental groups containing five animals each. After fasting overnight, the animals received one of seven different effects. Group A was a control in which each vehicle was orally administered only with vehicle (1% methyl cellulose / 0.5% polysorbate 80). Group B was a control, in which each solvent was orally administered only with a solvent / adjuvant (through a gastric tube, 10% ethanol and 90% linseed oil). Group C was a control in which 150 mg / kg of aspirin was orally administered to each mouse. Group D was a control in which each mouse was orally administered with 100 mg / kg ibuprofen resuspended in 1% methyl cellulose / 0.5% polysorbate 80. Group E was an experimental group in which each mouse was administered the pharmaceutical composition disclosed in this document (BC1054-100) containing 100 mg / kg ibuprofen, 10% ethanol and 90% linseed oil. Group F was a control in which each mouse was orally administered with 100 mg / kg ibuprofen resuspended in 1% methyl cellulose / 0.5% polysorbate 80. Group G was an experimental group in which each mouse was administered the pharmaceutical composition disclosed in this document (BC1054-200) containing 200 mg / kg ibuprofen, 10% ethanol and 90% linseed oil. Animals were sacrificed 4 hours after administration of the compounds, and stomachs were examined to determine the degree of hemorrhage and the severity of erosive damage to the mucosa. Gastric irritation was evaluated as follows: 0, no damage; 1, hyperemia; 2, one or two small damage; 3, more than two minor damage or severe damage; and 4, very severe damage. A score of 50% or more relative to group C (control group with aspirin administration), which was taken as 100%, was considered a positive assessment of gastric irritation.

The results are shown in table 6. In group D (the control group receiving 100 mg / kg ibuprofen) and group F (the control group receiving 200 mg / kg ibuprofen), gastric injuries were observed, which were 75% and 95%, respectively, in severity regarding damage induced in group C (control group receiving aspirin). However, in group E (experimental group receiving BC1054-100) and group G (experimental group receiving BC1054-200), gastric injuries were observed, which were 20% and 40%, respectively, in severity relative to the lesions observed in group C (control the group receiving aspirin). These results indicate that the pharmaceutical composition disclosed herein reduces the extent to which the therapeutic compound can cause mucosal damage and gastric irritation.

Table 6
Intestinal erosion analysis results Group The average score for ulcerative lesions % of erosion caused by aspirin A 0 0 B 0 0 C four (one hundred) D 3 75 ¹ E 0.8 twenty F 3.8 95 ¹ G 1,6 40 ¹ Positive assessment for the presence of erosion of the stomach

Example 7

Animal model of respiratory inflammation

In order to evaluate the effectiveness of the pharmaceutical composition disclosed herein, experiments were performed using a mouse model of viral flu in the treatment of respiratory inflammation.

6-7 week old female C57BLK mice were divided into three experimental groups containing 10 animals each. On the 1st day, the animals received an intranasal lethal dose (25 μl / nasal opening, only 50 μl) of the influenza strain A / PR / 8/34 under halotan anesthesia. On the 3rd day, after infection with the virus, the animals received one of three treatment options. Group A was a control in which 335.6 μg of ibuprofen dissolved in 10 μl of DMSO (without adjuvant) was orally administered to each mouse. Group B was a control, in which each solvent was orally administered only with a solvent / adjuvant (10% ethanol and 90% linseed oil were passed through a probe). Group C was an experimental group in which each mouse was administered the pharmaceutical composition disclosed herein (BC1054) containing 335.6 μg ibuprofen, 10% ethanol and 90% linseed oil. A dosage of 335.6 mcg in a mouse is equivalent to 20 mg / kg / day or 1200 mg / day in humans (maximum standard dose for ibuprofen). Animals were weighed daily and signs of infection were observed until day 6 when the animals were sacrificed. Figure 1 clearly shows that the oral administration of only the solvent / adjuvant (group B) gave a mortality rate of 80%, and the oral administration of only ibuprofen (group A) gave a mortality rate of 60%. However, a single oral administration of BC1054 reduced mortality to just 20%.

To determine the levels of IL-10 and IL-4, an enzyme-linked immunosorbent assay (ELISA) was performed using a 96-well plate coated with an exciting antibody to IL-10 or IL-4. Slaughtered mice collected lungs and homogenized at 4 ° C, collected the supernatant and stored at -70 ° C until analysis. Thawed samples were shaken on a vortex for 30 sec. immediately before adding to the ELISA plate. Serial dilutions were performed in each plate, both for the sample and for the standards, by pipetting 60 μl of assay buffer for dilution into each well. The tablet was sealed and incubated for 2 hours at room temperature. For IL-4, 60 μl of the working detection mixture (detection antibody + SAv-HRP reagent) was added to each well. The tablet was sealed and incubated for 1 hour at room temperature. For IL-10, 60 μl of detection antibody diluted in assay dilution buffer was added to each well. The plates were washed and 60 μl Sav-HRP enzyme diluted in assay dilution buffer was added. The tablet was sealed and incubated for 20 minutes. at room temperature. The tablets were then washed 10 times. 60 μl of substrate solution was added to each well, and the plate was incubated for 30 minutes. at room temperature in the dark. 60 μl stop solution was added to each well and absorbance was measured at 450 nm. Concentrations of IL-10 and IL-4 were expressed in pg / mg lung tissue. These results indicate that the pharmaceutical composition disclosed herein has been effective in the treatment of respiratory inflammation.

The results show that animals from group A (receiving the ibuprofen control group) and group B (receiving the solvent / adjuvant of the control group) had an IL-10 content of 2600 g / mg and 2000 pg / ml, respectively (Fig. 2A). However, in group C (the experimental group receiving BC1054), an IL-10 concentration of 6000 pg / ml was detected, three times higher than that observed in control animals. These results also showed that animals from group A (receiving the ibuprofen control group) and group B (receiving the solvent / adjuvant of the control group) had 6900 pg / mg and 5400 pg / ml IL-4, respectively, whereas in group C (treated BC1054 experimental group), the concentration of IL-4 was 8300 pg / mg (Fig. 2B). Together, a synergistic increase in the levels of IL-10 and / or IL-4 suggests that at least part of the action observed for BC1054 is caused by a switch of the response from Th1 to Th2.

Additional experiments were conducted to determine which cell types were stimulated to release cytokines with BC1054. 6-7 week old female C57BLK mice were divided into three experimental groups containing 10 animals each. On the 1st day, the animals received an intranasal lethal dose (25 μl / nasal opening, only 50 μl) of the H1 / N1 influenza strain under halotan anesthesia. On the 3rd day after infection with the virus, the animals received one of three treatment options. Group A was a control in which 335.6 μg of ibuprofen dissolved in 10 μl of DMSO (without adjuvant) was orally administered to each mouse. Group B was a control, in which each solvent was orally administered only with a solvent / adjuvant (10% ethanol and 90% linseed oil were passed through a probe). Group C was an experimental group in which each mouse was administered the pharmaceutical composition disclosed herein (BC1054) containing 335.6 μg ibuprofen, 10% ethanol and 90% linseed oil. Lungs collected from deadly infected mice were homogenized at 4 ° C, supernanate was collected, stored, and IL-10, TNF-α, and IFNγ levels were measured using an ELISA method.

The results show that animals from group A (receiving the ibuprofen control group) and group C (receiving the experimental group BC1054) had an increased level of IL-10 (Fig. 3A). However, this increase in IL-10 has been associated with very different pharmacodynamic effects, and the pattern of decreased pro-inflammatory cytokines underlines the source of IL-10 and its relationship to survival. For example, TNF-α (which is a macrophage-bound cytokine) was not significantly inhibited (Fig. 3B) in animals from group A (treated with ibuprofen control group), while levels of IFNγ (which is a lymphocytic cytokine) were markedly reduced in this group by compared with animals from group C (receiving experimental group BC1054) (Fig. 3C). This cytokine release model is associated with poor prognosis. However, in animals from group C (treated with BC1054 experimental group), the levels of TNF-α were significantly reduced (Fig. 3B), while the levels of IFNγ remained practically unchanged (Fig. 3C). This experiment demonstrates that the pharmaceutical composition disclosed herein provides a protective effect against H1N1-induced mortality by, inter alia, increasing levels of macrophage IL-10 rather than lymphocyte IL-10.

Example 8

Animal model of inflammatory bowel disease

To evaluate the effectiveness of the pharmaceutical composition disclosed herein in the treatment of inflammatory bowel disease, experiments were performed using a mouse model of colitis induced by TBS.

6-7 week old male C57Bl / 6 mice were divided into seven experimental groups containing at least ten animals each. On day 0, colitis was induced in mice from B-G groups by intrectal injection of 100 μl TNBS (4 mg) in 50% ethanol under isofuran anesthesia. From day -1 to the 5th day, animals received one or three times a day one of seven different effects. Group A was a control group in which only ethanol vehicle was orally administered to each mouse. Group B was a control group in which each mouse was orally administered with vehicle 1% methylcellulose. Group C was a control group in which each mouse was administered only a solvent / adjuvant (through a probe of 10% ethanol and 90% linseed oil). Group D was a control group in which 3 mg / kg of prednisolone was orally administered to each mouse. Group E was a control group in which each mouse was orally administered with 20 mg / kg of ibuprofen resuspended in 1% methylcellulose (1 mg / kg) (without adjuvant). Group F was an experimental group in which each mouse was administered the pharmaceutical composition disclosed herein (BC1054-20) containing 20 mg / kg ibuprofen, 10% ethanol and 90% linseed oil. Group G was an experimental group in which each mouse was administered the pharmaceutical composition disclosed herein (BC1054-20) containing 30 mg / kg ibuprofen, 10% ethanol and 90% linseed oil. All animals were weighed daily and visually evaluated for diarrhea and / or bloody stools. On the 3rd and 5th day, the severity of colitis was assessed in all animals using video endoscopy, with which images were obtained, and the severity of colitis was visually evaluated by the observer “blindly” on a scale from 0 to 4 as follows: 0, normal ; 1, loss of vascularization; 2, loss of vascularization and friability; 3, friability and erosion; and 4, ulceration and bleeding. After endoscopy on the 5th day, the animals were sacrificed, the colon was removed and its length and weight were measured. Serum samples were taken and the colon was fixed in 10% formalin. An additional piece of colon tissue was collected, weighed, and frozen in liquid nitrogen.

The results of these experiments are presented in Table 7. Group B (control group receiving TNBS) showed a statistically significant difference in average weight change compared to group A (control group receiving ethanol), all other comparison groups showed no difference in average weight change. Group B (the control group treated with TNBS) showed a statistically significant decrease in the average length of the colon compared to group A (the control group received ethanol). In addition, group D (receiving prednisone control group), group F (receiving BC1054-20 experimental group) and group G (receiving BC1054-30 experimental group) all showed a statistically significant increase in the average length of the colon compared to group B (receiving TNBS control group). Although Group B (the TNBS-treated control group) showed a statistically significant increase in the average colon weight compared to Group A (the ethanol-treated control group), all other comparison groups showed no difference in the average colon weight. Regarding the endoscopic assessment of colitis, group D (the prednisolone-treated control group) showed a statistically significant decrease in the average colitis score on both day 3 and day 5 compared with group B (the control group received TNBS). Similarly, both group F (receiving the BC1054-20 experimental group) and group G (receiving the BC1054-30 experimental group) showed a statistically significant decrease in mean colitis score on day 5 compared with group B (receiving the TNBS control group ) These results indicate that the pharmaceutical composition disclosed herein is effective in treating inflammatory bowel disease.

Table 7
Results for inflammatory bowel disease Group Average animal weight The average length of the colon The average weight of the colon Endoscopic assessment of the severity of colitis 3rd day 5th day A 215 mg 0.2 0 B 21.98 g ¹ 7.3 cm ² 295 mg ⁶ 3,1 2.7 C 239 mg 2.9 2,4 D 8.4 cm ³ 267 mg 2,3 ⁷ 1.8 ⁸ E 267 mg 2.7 2.2 F 8.4 cm ⁴ 258 mg 2.6 1.9 ⁹ G 7.9 cm ⁵ 284 mg 2,4 1.4 ¹⁰

¹ Statistically significant difference compared with group A (p = 0.029).
² Statistically significant difference compared with group A (p = 0.001).
³ Statistically significant difference compared with group B (p = 0.001).
⁴ Statistically significant difference compared with group B (p = 0.001).
⁵ Statistically significant difference compared with group B (p = 0.034).
⁶ Statistically significant difference compared with group A (p = 0.009)
⁷ Statistically significant difference compared with group B (p = 0.005)
⁸ Statistically significant difference compared with group B (p = 0.002)
⁹ Statistically significant difference compared with group B (p = 0.045)
¹⁰ Statistically significant difference compared with group B (p = 0.002)

Example 9

Animal model of systemic arthritis

To evaluate the effectiveness of the pharmaceutical composition disclosed herein, in the treatment of arthritis, experiments were performed using the mouse model of arthritis induced by antibodies to collagen (ACAIA), which mimics systemic arthritis, such as rheumatoid arthritis.

Male BALB / c mice were divided into eight groups, each of which included 10 animals. To induce arthritis symptoms, mice from all eight groups were injected intravenously with 200 μl of a solution containing 2 mg of a cocktail of four monoclonal antibodies to collagen II (ARTHRITOMAB ™, MD Biosciences) on the 0-day of the study (start of the study), followed by administration of using an intraperitoneal injection of 200 μl of a solution containing 50 μg of lipopolysaccharide (LPS) on day 3. Starting from the 3rd day and daily until the 8th day, and then on days 10 and 12, the thickness of the paws was recorded (using plethysmography) and assessment of arthritis on a scale. The same animals also received treatment daily from the 0th to the 11th day, where the animals received one of six treatment options (effects). Group A was a control in which each vehicle was orally administered only with vehicle, phosphoric buffered saline (PBS). Group B was a control in which each mouse was injected intraperitoneally with 10 mg / kg etanercept (ENBREL®, Wyeth) in PBS. Group C was a control in which only 1% methylcellulose was orally administered to each mouse. Group D was a control in which each mouse was orally administered with 40 mg / kg of ibuprofen resuspended in 1% methylcellulose (1 ml / kg) (without adjuvant). Group E was a control, in which each solvent was orally administered only with a solvent / adjuvant (via a gastric tube, 10% ethanol and 90% linseed oil). Group F was an experimental group in which each mouse was orally administered with the pharmaceutical composition disclosed herein (BC1054-20) containing 20 mg / kg ibuprofen, 10% ethanol and 90% flaxseed oil. Group G was an experimental group in which each mouse was orally administered with the pharmaceutical composition disclosed herein (BC1054-30) containing 30 mg / kg ibuprofen, 10% ethanol and 90% flaxseed oil. Throughout the experiment (12 days), the animals were monitored daily for clinical signs (general observation of the animal’s health) and body weight. The overall arthritis score is determined by summing the arthritis score for individual paws using the following scale: 0 = no signs of arthritis, 1 = slight but definite redness and swelling of the ankles / wrists or visible redness or swelling limited to individual fingers, regardless of the number of fingers affected, 2 = moderate to severe redness and swelling of the ankle / wrist, 3 = redness and swelling of the entire paw, including fingers, 4 = most inflamed limb involving several joints.

The results of this experiment are shown in FIG. 4. As expected, animals from group B (receiving the etanercept of the control group) showed the best results, with the lowest paw thickness of about 1.6 mm on day 12. For the two pharmaceutical compositions, animals from group F (receiving BC1054-20 experimental group) and group G (receiving BC1054-30 experimental group) showed almost similar results, where the mice from group G had a paw thickness of only 1.7 mm, and the mice from groups F had a paw thickness of about 1.73 mm. Animals from the negative control group (receiving the PBS carrier of the control group), group C (receiving the cellulose carrier of the control group) and group E (receiving the solvent / adjuvant of the control group), as well as from group D (receiving the ibuprofen control group) had significantly worse indicators with a paw thickness of 1.9 mm or more compared with animals from groups F and G. These results show that the pharmaceutical composition disclosed herein is effective for the treatment of arthritis.

Example 10

Animal model of systemic arthritis

To evaluate the effectiveness of the pharmaceutical composition disclosed herein, in the treatment of arthritis, experiments were performed using the mouse model of arthritis induced by antibodies to collagen (ACAIA), which mimics systemic arthritis, such as rheumatoid arthritis.

Male BALB / c mice were divided into eight groups, each of which contained 10 animals. To induce arthritis symptoms, mice from all eight groups were injected intravenously with 200 μl of a solution containing 2 mg of a cocktail of four monoclonal antibodies to collagen II (ARTHRITOMAB ™, MD Biosciences) on the 0-day of the study (start of the study), followed by administration of using an intraperitoneal injection of 200 μl of a solution containing 50 μg of lipopolysaccharide (LPS) on day 3. Each group received a control or test treatment (effect) daily, carried out on days 0-11, as follows: mice from group 1 (1M) three times a the day was administered orally repair of a carrier containing 1% methylcellulose; group 2 (2M) mice were injected intraperitoneally with a positive control preparation containing 10 mg / kg etanercept (ENBREL®, Wyeth); group 3 (3M) mice were dosed once daily with 20 mg / kg of a test liquid formulation containing ibuprofen and rapeseed oil (BC1054 LF-RO); mice from group 4 (4M) were injected orally three times a day with 20 mg / kg of a test liquid formulation containing ibuprofen and rapeseed oil (BC1054 LF-RO); group 5 (5M) mice were orally administered 20 mg / kg of a test liquid composition containing ibuprofen and glyceryl monolinoleate (MAISINE® 35-1, Gattefosse) (BC1054 LF-MA) three times a day; group 6 (6M) mice were orally administered 20 mg / kg of a test liquid formulation containing ibuprofen and cocoa butter (BC1054 LF-TO); mice from group 7 (7M) three times a day were orally administered control drug 1 containing 20 mg / kg ibuprofen; and mice from group 8 (8M) were orally administered 20 mg / kg three times a day with a test solid containing ibuprofen and a waxy solid having a melting point in the range of 37 ° C to 41 ° C and containing a mixture of saturated C ₁₀ -C ₁₈ triglycerides (GELUCIRE® 39/01, Gattefosse) (BC1054 LF-GE) (table 8). The administered dose was calculated on the assumption that each animal weighs an average of 20 g. Each mouse was injected with a fixed volume of 100 μl, with the exception of animals receiving a positive control (2M), which were injected with 200 μl.

Table 8
Description of test groups and dosage levels Group The size Impact Dosage Volume Way Scheme 1M 10 Carrier no 5 ml / kg BY Thrice a day 2M 10 Etanercept 10 mg / kg 10 ml / kg WB Once a day 3M 10 BC1054 LF-RO 20 mg / kg 5 ml / kg BY Once a day 4M 10 BC1054 LF-RO 20 mg / kg 5 ml / kg BY Thrice a day 5M 10 BC1054 LF-MA 20 mg / kg 5 ml / kg BY Thrice a day

6M 10 BC1054 LF-TO 20 mg / kg 5 ml / kg BY Thrice a day 7M 10 Ibuprofen 20 mg / kg 5 ml / kg BY Thrice a day 8M 10 BC1054 SF-GE 20 mg / kg 5 ml / kg BY Thrice a day WB = intraperitoneally
PO = oral

Arthritis development monitoring and clinical examinations were performed in all mice on the 0th day of the study, shortly before the induction of arthritis and then on study days 3-7, 9, 10 and 12 (completion of the study). To assess the development of arthritis, both the assessment of arthritis on a scale and the measurement of the thickness of the paws (plethysmography) were performed. The assessment of arthritis was based on a visual determination of the signs of arthritis using a scale of 0-4 in ascending order of severity with a rating of 0 indicating the absence of arthritic symptoms a rating of 1 indicating a slight but definite redness and swelling of the ankle / wrist or visible redness or swelling limited to individual fingers, regardless of the number of fingers affected; a rating of 2 indicating moderate to severe redness and swelling of the ankle / wrist; a rating of 3, indicating redness and swelling of the entire paw, including fingers; and a score of 4, indicating the most inflamed limb involving multiple joints. The thickness of the paws was measured for both hind legs directly above the paw pad and below the calcaneus using a digital caliper (Kroeplin, Munich, Germany). The mean values of the thickness measurements of the paws were determined, and, if necessary, data analysis using ANOVA with Tukey retrospective analysis was used to determine the significance of treatment effects.

A clinical examination included an assessment of changes in body weight, skin, fur, eyes, mucous membranes, the appearance of secretions and waste products (e.g. diarrhea), and autonomic activity (e.g., lacrimation, salivation, piloerection, pupil size, unusual breathing). Changes in gait, posture and response to manipulation, as well as the presence of strange behavior, tremors, convulsions, coma and sleep, were also noted. Serum was collected at termination of the study.

The incidence of arthritis increased in all groups starting on day 3. In group 1M, the incidence of animals peaked on day 7, when 9 out of 10 animals showed signs of arthritis, which remained relatively constant until the end of the study. In mice from the 2M group receiving etanercept, the peak incidence occurred on the 6th day, when 9 out of 10 animals showed signs of the disease, but decreased to 1 out of 10 animals on the 12th day. The peak incidence of arthritis in animals from groups 3M and 4M treated with BC1054 LS-RO once or three times a day fell on the 7th day (9/10 and 7/10 animals, respectively), and this frequency decreased to 4 / 10 mice in both groups on day 12. The incidence of arthritis reached a maximum on day 6 in animals from the 5M group treated with BC1054 LS-MA when 8/10 animals became ill, and the incidence ranged from 6 to 8 animals (out of 10) until the end of the study. On the 6th day, 9 out of 10 animals showed arthritis in the 6M group treated with BC1054 SF-TO, but this ratio also changed and came to 7/10 on the 12th day. In the 7M group receiving ibuprofen, the peak incidence of arthritis was recorded on the 6th day with 8 patients out of 10 animals, and this ratio remained relatively constant until the end of the study. In 8M mice treated with BC1054 LS-GE, the peak incidence occurred on day 6 with 9 out of 10 animals showing signs of arthritis, but this ratio decreased to 4/10 on day 12.

Clinical signs associated with LPS administration appeared in all groups after LPS administration on day 3. They disappeared in all groups on the 12th day. In the course of this study, animal mortality was not recorded or significant differences in body weight were not observed between the group receiving the carrier and the groups receiving the test products.

The results for the average thickness of the paws are shown in table 9. The average thickness of the hind legs in animals from group 1M (receiving the carrier) was 1.72 ± 0.01 per day 0. The thickness increased and reached a maximum of 2.33 ± 0.15 by 9- day and amounted to 2.17 ± 0.11 on the 12th day. In mice from the 2M group receiving Etanercept, the average thickness of the hind legs was 1.70 ± 0.02 per day 0. It increased, reaching a peak of 1.96 ± 0.05 on day 6, before decreasing back to 1.77 ± 0.02 on the 12th day. Treatment with etanercept resulted in a significant decrease in paw volume compared with mice from the positive control group on days 9, 10 and 12. In the 3M group, which received BC1054 LS-RO once a day, the hind paw thickness was 1.71 ± 0.02 on day 0. On the 7th day, edema in this group reached a peak of 1.96 ± 0.05, and after that it remained relatively constant. A significant decrease in the mean paw edema was observed on days 6 and 9 after administration of BC1054 LS-RO. The average thickness of the hind legs in the 4M group, which received BC1054 LS-RO three times a day, increased to 1.97 ± 0.08 on the 10th day (from 1.70 ± 0.03 on day 0), from the 10th paw volume remained relatively constant until the end of the study. The administration of BC1054 LS-RO three times a day resulted in a significant decrease in the average thickness of the paws compared to mice treated with vehicle (group 1M) on days 6, 7 and 9. Mice from group 5M treated with BC1054 LS-MA had peak paw volume per 7th day (1.97 ± 0.05 versus 1.69 ± 0.02 per day 0), in this group there was a significant decrease in this indicator on the 6th and 9th day, compared with animals from the group 1M receiving vehicle. In animals of group 6M treated with BC1054 LS-TO, the average thickness of the hind legs was 1.74 ± 0.01 per day 0. It increased to a peak value of 2.05 ± 0.10 on the 7th day before the reverse decrease to 1 , 94 ± 0.06 on the 12th day. No significant differences were observed between animals treated with BC1054 LS-TO (group 6M) and animals treated with vehicle (group 1M). In the group that received ibuprofen (group 7M), the thickness of the hind legs was 1.71 ± 0.02 per day 0. On the 7th day, the tumor in this group reached its peak at 2.15 ± 0.10 before decreasing up to 2.02 ± 0.08 on the 12th day. No significant differences were observed when comparing this group with the control group 1M. Animals from group 8M, which were injected BC1054 LS-GE, showed a slight increase in the thickness of the hind legs from 1.72 ± 0.02 per day 0 to 1.85 ± 0.06 on the 7th day, which remained relatively constant, amounting to 1 , 77 ± 0.03 on the 12th day. The introduction of BC1054 LS-GE led to a significant reduction in edema of the paws in animals (group 8M) compared with the control group, which was introduced the carrier (group 1M) on days 6, 7, 9, 10 and 12.

Table 9
The average thickness of the hind legs Group Number Impact The average thickness of the hind legs (mm) 0 3 four 5 6 7 9 10 12 1M 10 Carrier 1.72 ± 0.01 1.72 ± 0.02 1.63 ± 0.02 1.69 ± 0.02 2.03 ± 0.09 2.26 ± 0.13 2.33 ± 0.15 2.32 ± 0.15 2.17 ± 0.11 2M 10 Etaner 1.70 ± 0.02 1.73 ± 0.03 1.64 ± 0.02 1.63 ± 0.02 1.96 ± 0.05 1.95 ± 0.04 1.88 ± 0.03 * 1.80 ± 0.04 * 1.77 ± 0.02 * 3M 10 BC1054 LF-RO 1.71 ± 0.02 1.75 ± 0.02 1.68 ± 0.02 1.71 ± 0.03 1.78 ± 0.03 * 1.96 ± 0.05 1.91 ± 0.08 * 1.94 ± 0.10 1.90 ± 0.08 4M 10 BC1054 LF-RO 1.70 ± 0.03 1.70 ± 0.01 1.61 ± 0.02 1.65 ± 0.03 1.75 ± 0.03 * 1.89 ± 0.07 * 1.91 ± 0.09 * 1.97 ± 0.08 1.93 ± 0.07 5M 10 BC1054 LF-MA 1.69 ± 0.02 1.73 ± 0.02 1.66 ± 0.02 1.67 ± 0.02 1.79 ± 0.04 * 1.97 ± 0.05 1.92 ± 0.06 * 1.96 ± 0.07 1.91 ± 0.06 6M 10 BC1054 LF-TO 1.74 ± 0.01 1.72 ± 0.03 1.64 ± 0.01 1.70 ± 0.03 1.91 ± 0.06 2.05 ± 0.10 1.96 ± 0.09 1.99 ± 0.07 1.94 ± 0.06 7M 10 Ibupro-hair dryer 1.71 ± 0.02 1.72 ± 0.01 1.64 ± 0.02 1.71 ± 0.02 1.90 ± 0.05 2.15 ± 0.10 2.08 ± 0.11 2.07 ± 0.11 2.0 ± 0.08 8M 10 BC1054 SF-GE 1.72 ± 0.02 1.71 ± 0.02 1.63 ± 0.01 1.67 ± 0.03 1.78 ± 0.03 * 1.85 ± 0.06 * 1.73 ± 0.04 * 1.83 ± 0.03 * 1.77 ± 0.03 *

Considering the above data, a significant anti-arthritic effect was observed in the group of animals 3M treated once a day with BC1054 LS-RO, the group of animals 4M treated three times a day with BC1054 LS-RO, the group of animals 5M treated with three times a day BC1054 LS-MA, and a group of animals 8M, received three times a day BC1054SF-GE.

Example 11

Examples of treatments for chronic inflammation

A 47-year-old woman who was diagnosed with reactive arthritis in one knee was treated with the pharmaceutical composition disclosed herein (BC1054) containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil (1200 mg, once every day), over a 3-day period, and it was found that the swelling and pain began to disappear after 1 day and completely disappeared after 3 days. Ineffective standard ibuprofen treatment was subsequently discontinued. For 3 months of observation, no signs of reactive arthritis were observed.

A 50-year-old man was diagnosed with a meson ankle fracture. The patient took 30 mg of codeine with 500 mg of paracetamol twice a day, along with 10 mg of diclofenac three times a day for 8 months to control severe pain. The patient underwent a 5-day course of the pharmaceutical composition disclosed in the present description (BC1054), containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil (600 mg twice a day), after 2 days reported a significant reduction in his pain. and then after 3 days he reported that the pain was completely under control. Subsequently, he stopped taking codeine, paracetamol and diclofenac, and after 2 months of observation, the patient still did not experience pain.

A 33-year-old woman diagnosed with stress-related eczema exacerbated eczema on her arms and chest. The pharmaceutical composition disclosed herein (BC1054) containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil (1200 mg, once daily) was administered for 7 days. After a couple of hours, the itching in the affected area stopped, after 1 day a noticeable decrease in edema at the site of the lesion was reported. After 2-3 days, erythema disappeared in eczema-affected areas, and after 7 days, the lesions completely disappeared. In the past, the patient used emollient creams and hydrocortisone-containing creams that worsened the skin condition and often led to a course of antibiotics. The patient noted that her response to BC1054 treatment was quick and complete, and there was a noticeable improvement in relation to previously used pharmacological treatments.

A 85-year-old man was diagnosed with reactive osteoarthritis with severe swelling and severe pain in both knees. Within 1 year, the patient was prescribed prednisone and an NSAID to control arthritis, which had no effect. In addition, the patient took glucosamine daily. Despite significant pharmacological intervention, relapses were regularly observed in the patient, resulting in a significant limitation in mobility. The patient underwent a 10-day course of treatment with the pharmaceutical composition disclosed in this document (BC1054) containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil (400 mg, three times a day), and experienced a marked improvement in the 3rd day and complete improvement after completion of the course. The patient reported that his mobility returned to normal, and he remained in remission when examined after 1 month.

38-year-old man with reactive osteoarthritis in 1 knee for 6 months (pain and swelling). During this period, the patient tried a wide range of pharmacological treatments: prednisone, Humira and sulfasalazine, along with an NSAID for pain control. Only sulfasalazine had a noticeable effect, but the patient did not like the side effects, so he asked to cancel sulfasalazine. 2 weeks after discontinuation of sulfasalazine, the patient had a relapse of reactive arthritis and he began a 4-day course of the pharmaceutical composition disclosed in this document (BC1054) containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil (600 mg twice per day), after which there was a complete remission of arthritis. 2 weeks after discontinuation of treatment, a relapse of arthritis occurred and the patient underwent another 4-day course of treatment with BC1054, again achieving complete remission. This time, arthritis recurred after 1 week. With this in mind, the patient received the final 10-day course of BC1054. Subsequently, arthritis remained in remission for 11 months (at the time of the last examination).

A 49-year-old man diagnosed with hypercholesterolemia (LDL 4.35 mmol / L) received a course of the pharmaceutical composition disclosed herein (BC1054) containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil, (600 mg twice a day) for 7 days. After 5 days of treatment, the patient's LDL levels returned to 3.89 mmol / L. Normalization of LDL levels continued for 2 months after cessation of BC1054 administration, as was established at the last examination.

A 60-year-old man with newly diagnosed hypercholesterolemia (LDL 4.31 mmol / L) received a course of the pharmaceutical composition disclosed herein (BC1054) containing 20 mg / kg ibuprofen, 10% ethanol and 90% rapeseed oil (1200 mg once per day) to lower LDL to the normal range. After 5 days of treatment, the patient's LDL levels decreased to 3.36 mmol / L. The patient was monitored for 1 month, and his LDL level remained within the normal range, despite the absence of additional BC1054 administration.

Example 12

Chronic inflammation treatment

A 62-year-old woman complains of poor mobility and swelling in the joints and is diagnosed with rheumatoid arthritis. The doctor determines that poor mobility and swelling of the joints are the result of chronic inflammation. A woman receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the woman is monitored, and after about 3 days of treatment, the woman indicates that the mobility of the joints increases and the edema decreases. At follow-up appointments after one and three months, the woman indicates that she still has increased joint mobility and reduced swelling in the treatment area. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any monoarthritis, oligoarthritis or polyarthritis, such as, for example, osteoarthritis, juvenile idiopathic arthritis, septic arthritis, spondyloarthropathy (including ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, pain zn Whipple disease or Behcet), synovitis, gout, pseudogout, or Still's disease, as well as bursitis, rheumatism and tenosynovitis. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 58-year-old man complains of shortness of breath and is diagnosed with chronic obstructive pulmonary disease (COPD). The doctor determines that difficulty breathing is the result of chronic inflammation. A man receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, a man is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the male is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the man is monitored, and after about 3 days of treatment, the man indicates that there is an improvement in his ability to breathe. At follow-up appointments after one and three months, the man indicates that he still has improved breathing. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat patients suffering from chronic inflammation associated with asthma, bronchiolitis, bronchitis, emphysema, laryngitis, pharyngitis, pleurisy, pneumonia, rhinitis, sinusitis, or any other type of chronic respiratory diseases. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 67-year-old man complains of muscle pain and is diagnosed with dermatomyositis. The doctor determines that the pain is the result of chronic inflammation. A man receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, a man is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the male is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the man is monitored, and after about 3 days of treatment, the man indicates that the pain has decreased. In control receptions after one and three months, the man indicates that he continues to increase muscle mobility and decrease pain. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat patients suffering from chronic inflammation associated with inclusion myositis, myasthenia gravis, polymyositis, or any other type of inflammatory myopathy, as well as fasciitis, fibrosis, myositis, neuromyotonia, tendinosis or tendonitis. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 73-year-old woman complains of wheezing while breathing and is diagnosed with Charg-Strauss arteritis. The doctor determines that wheezing is the result of chronic inflammation. A woman receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the woman is monitored, and after about 3 days of treatment, the woman indicates that the wheezing has disappeared. At follow-up appointments after one and three months, the woman indicates that she does not have wheezing when breathing. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any vasculitis, such as, for example, Burger disease, cerebral vasculitis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell arteritis, player vasculitis golf, Genoch-Shenlein purpura, hypersensitivity vasculitis, Kawasaki disease, phlebitis, microscopic polyarteritis / polyangiitis, polyarter nodosa rheumatoid polymyalgia (PMR), rheumatoid vasculitis, Takayasu arteritis or Wegener's granulomatosis, as well as arteritis, carditis, endocarditis, heart disease, high blood pressure, inflammatory cardiomegaly, coronary heart disease, myocarditis, pericarditis, phlebitis, pylephlebitis or thrombosis. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

The 37-year-old man complains of redness and a diagnosis of rosacea. The doctor determines that redness is the result of chronic inflammation. A man receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, a man is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the male is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the man is monitored, and after about 3 days of treatment, the man indicates that the redness has decreased. At follow-up appointments after one and three months, the man indicates that he continues to have improved skin color and reduced redness. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat patients suffering from chronic inflammation associated with acne, cervicitis, dermatitis, eczema (including atopic dermatitis, contact eczema, xerotic eczema, seborrheic dermatitis, dyshidrosis, discoid eczema , venous eczema, herpetiform dermatitis, neurodermatitis or auto-ekzematization), endometritis, gingivitis, glossitis, purulent hydradenitis, keratitis, keratoconjunctivitis, mastitis , Psoriasis (including plaque psoriasis, nail psoriasis, guttate psoriasis, scalp psoriasis, inverse psoriasis, pustular psoriasis or erythrodermic psoriasis), scleroderma, stasis dermatitis, stomatitis, tonsillitis, vaginitis, vulvitis or vitiligo. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 33-year-old woman complains of abdominal pain and diarrhea and is diagnosed with Crohn's disease. The doctor determines that abdominal pain and diarrhea are the result of chronic inflammation. A woman receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the woman is monitored, and after about 3 days of treatment, the woman indicates that the abdominal pain is reduced and the diarrhea has disappeared. At follow-up appointments after one and three months, the woman indicates that she still has less pain and diarrhea. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat a patient suffering from neurogenic inflammation associated with any inflammatory bowel disease, such as, for example, ulcerative colitis (including ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis) any irritable bowel syndrome, as well as colitis, enteritis, enterocolitis, gastritis, gastroenteritis, metabolic syndrome (Syndrome X), spastic colon Coy or any other gastrointestinal disease. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 46-year-old man complains of fever, joint pain and fatigue, and is diagnosed with systemic lupus erythematosus. The doctor determines that these symptoms are caused by chronic inflammation. A man receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, a man is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the male is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the man is monitored, and after about 3 days of treatment, the man indicates that his health has improved, the fever has gone, the pain in the joints has decreased, and he is not tired. At follow-up appointments, after one and three months, the man indicates that he still has less pain in the joints and does not suffer from fever or fatigue. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat patients suffering from chronic inflammation associated with any other systemic autoimmune disease, including, without limitation, antiphospholipid antibody syndrome (APS), bullous pemphigoid, Chagas disease, discoid lupus erythematosus, drug systemic lupus erythematosus, Goodpasture syndrome, Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, lupus new ozhdennyh, pernicious anemia, polymyalgia rheumatica, rheumatoid arthritis, scleroderma, Sjogren's syndrome, subacute cutaneous lupus erythematosus, or Wegener's granulomatosis. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 58-year-old man complains of depression, sensitivity to cold, weight gain, forgetfulness, constipation, and he has been diagnosed with Hashimoto's thyroiditis. The doctor determines that these symptoms are caused by chronic inflammation. A man receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, a man is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the male is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the man is monitored, and after about 3 days of treatment, the man indicates that he has reduced all the symptoms that he complained about. At the control receptions after one and three months, the man indicates that he does not experience depression, sensitivity to cold, weight gain, forgetfulness and constipation. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat patients suffering from chronic inflammation associated with any other local autoimmune disease, including, without limitation, acute disseminated encephalomyelitis (ADEM), Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis (including primary biliary cirrhosis), autoimmune disease of the inner ear, celiac disease, Crohn's disease, type I diabetes mellitus, endometriosis, gigantocl accurate arteritis, Graves' disease, interstitial cystitis, lupus nephritis, multiple sclerosis, morphine, pemphigus vulgaris, recurrent disseminated encephalomyelitis, sclerosing cholangitis, ulcerative colitis, or vitiligo. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

A 59-year-old woman complains of poor mobility and swelling in the joints and is diagnosed with reactive arthritis. The doctor determines that poor joint mobility and edema are the result of chronic inflammation. A woman receives treatment by oral administration of a pharmaceutical composition containing ibuprofen disclosed herein taken twice daily. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing aspirin disclosed herein taken three times a day. Alternatively, the woman is treated by oral administration of the pharmaceutical composition containing naproxen disclosed herein taken twice daily. The condition of the woman is monitored, and after about 3 days of treatment, the woman indicates that the mobility of the joints has increased and the edema has decreased. At follow-up appointments after one and three months, the woman indicates that she still has increased joint mobility and reduced swelling in the affected area. This reduction in the symptom of chronic inflammation indicates successful treatment using the pharmaceutical composition disclosed herein. A similar type of oral administration of the pharmaceutical composition disclosed herein will be used to treat a patient suffering from chronic inflammation associated with any monoarthritis, oligoarthritis or polyarthritis, such as, for example, osteoarthritis, juvenile idiopathic arthritis, septic arthritis, spondyloarthropathy (including ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, pain zn Whipple disease or Behcet), synovitis, gout, pseudogout, or Still's disease, as well as bursitis, rheumatism and tenosynovitis. Similarly, any of the therapeutic compounds, such as, for example, an NSAID is a salicylate derivative, an NSAID is a p-aminophenol derivative, an NSAID is a propionic acid derivative, an NSAID is an acetic acid derivative, an NSAID is an enolic acid derivative, an NSAID is a phenamic acid derivative, is non-selective cyclooxygenase inhibitor (COX), selective cyclooxygenase 1 inhibitor (COX 1), selective cyclooxygenase 2 inhibitor (COX 2) or fibrate will be incorporated into the pharmaceutical composition and administered to a patient as described above.

In conclusion, it should be understood that although aspects of the present description are illuminated by reference to specific embodiments, one skilled in the art will readily understand that these disclosed embodiments are merely illustrative of the principles of the subject disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, protocol and / or reagent, etc. described in this document. As such, various modifications or changes or alternative configurations of the disclosed subject matter may be made in accordance with the teachings of this description without departing from the gist of the present description. Finally, the terminology used herein is intended to describe specific embodiments and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that which exactly corresponds to what is shown and described.

Some embodiments of the present invention are described herein, including the best method known to the inventors for carrying out the invention. Of course, variations of these described options will be apparent to those skilled in the art after reading the above description. The inventor expects those skilled in the art to use such options when necessary, and the inventors assume that the present invention will be practiced differently than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter set forth in the appended claims in accordance with applicable law. Moreover, any combination of the above embodiments in all possible embodiments is encompassed by the invention, unless otherwise indicated herein or clearly contrary to the context.

The division into groups of alternative options, elements or steps of the present invention should not be construed as limiting. Each member of the group may be indicated and claimed individually or in any combination with other members of the group disclosed herein. It is contemplated that one or more members of the group may be included in or removed from the group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, it is believed that the description contains a group modified in such a way that a written description of all Markush groups used in the appended claims is respected.

Unless otherwise indicated, all numbers expressing a characteristic, subject, quantity, parameter, property, term, etc. used in the present description and claims are to be understood as modified in all cases by the term “about”. As used herein, the term “about” means that a characteristic, item, quantity, parameter, property or term thus described encompasses a range of plus or minus ten percent above and below the value indicated by the characteristic, item, quantity, parameter, property or term. Accordingly, unless otherwise indicated, the numerical parameters set forth in the description and the attached claims are approximate values that are subject to change. At least not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indicator should be understood in light of the number of indicated significant digits and using conventional rounding methods. Although the numerical ranges and values defining the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are indicated as accurately as possible. Any numerical range or value, however, by its nature, contains some errors that inevitably arise from the standard deviation found in their respective test measurements. The enumeration of numerical ranges of values in this document serves only as a brief way of individually referencing each individual numerical value within the range. Unless otherwise indicated, each individual value of a numerical range is included in the present description, as if it were individually indicated in this document.

Singular forms and similar indications used in the context of the description of the present invention (especially in the context of the following claims) should be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contrary to the context. All methods described herein may be performed in any suitable order, unless otherwise indicated or clearly contrary to the context. The use of any and all examples or generic terminology (for example, “such as”) in this document is intended only to better illuminate the present invention and does not impose restrictions on the scope of the invention claimed otherwise. No terminology in the present description should not be construed as an indication of any undeclared element necessary for the practical implementation of the invention.

The specific embodiments disclosed herein may be further limited in the claims using the phrase “consisting of” or “consisting essentially of”. When used in the filed claims or as amended, the transferable term “consisting of” excludes any element, step or ingredient not specified in the claims. The transferable term “consisting essentially of” limits the scope of the invention to the materials or steps indicated and those that do not significantly affect the basic and new features. Embodiments of the present invention claimed in this manner are, by nature or directly described and available herein.

All patents, patent publications, and other publications referenced and defined herein are individually and expressly fully incorporated herein by reference for the purpose of describing and disclosing, for example, the compositions and methods described in such publications that may be used in the present invention. . These publications are for disclosure only prior to the filing date of this application. Nothing in this regard should be construed as an assumption that the inventors are not entitled to retroactively disclose such disclosure based on a previous invention or for any other reason. All statements to date or representation regarding the content of these documents are based on information available to applicants and do not imply any assumption regarding the correct dates or contents of these documents.

Claims (52)

1. A pharmaceutical composition for treating chronic inflammation, comprising: a) from 10% to 30% non-steroidal anti-inflammatory drugs (NSAIDs) by weight of the pharmaceutical composition; b) from 20% to 50% solid fat by weight of the pharmaceutical composition; c) from 10% to 30% of a partially hydrolyzed glycerolipid by weight of the pharmaceutical composition, wherein the partially hydrolyzed glycerolipid consists of a mixture of mono-, di- and triglycerides; and d) from 5% to 15% polyethylene glycol (PEG) polymer by weight of the pharmaceutical composition, where the pharmaceutical composition does not contain an emulsifier, and where the pharmaceutical composition is solid at a temperature of 15 ° C or lower and has a melting point of 30 ° C or higher. 2. The pharmaceutical composition according to claim 1, in which the NSAID is from 20% to 30% by weight of the pharmaceutical composition. 3. The pharmaceutical composition according to claim 2, in which the NSAID is present in an amount of from 25% to 30% by weight of the pharmaceutical composition. 4. The pharmaceutical composition according to claim 1, wherein the NSAID is a non-selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX1) inhibitor, a selective cyclooxygenase 2 inhibitor (COX2), or a combination thereof. 5. The pharmaceutical composition according to claim 4, in which the NSAID includes a salicylate derivative, an NSAID p-aminophenol derivative, an NSAID propionic acid derivative, an NSAID acetic acid derivative, an NSAID enolic acid derivative, an NSAID derivative of phenamic acid or a derivative thereof a combination. 6. The pharmaceutical composition of claim 5, wherein the NSAID derivative of propionic acid includes Alminoprofen, Benoxaprofen, Dexketoprofen, Phenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen or Suprofen. 7. The pharmaceutical composition according to claim 6, in which the NSAID derivative of propionic acid is a pharmaceutically acceptable form of Ibuprofen. 8. The pharmaceutical composition according to claim 1, in which solid fat is present in an amount of from 30% to 50% by weight of the pharmaceutical composition. 9. The pharmaceutical composition of claim 8, in which the solid fat is present in an amount of from 35% to 45% by weight of the pharmaceutical composition. 10. The pharmaceutical composition of claim 8, in which the solid fat has a melting point from 40 ° C to 46 ° C. 11. The pharmaceutical composition of claim 8, in which the solid fat contains triglyceride or glycerol triester. 12. The pharmaceutical composition according to claim 11, in which the triglyceride contains a mixture of saturated C ₁₀ -C ₁₈ triglycerides having a melting point between 41 ° C and 45 ° C. 13. The pharmaceutical composition according to item 12, in which the triglyceride contains a mixture of saturated C ₁₀ -C ₁₈ triglycerides having a melting point of 43 ° C. 14. The pharmaceutical composition according to claim 1, in which the partially hydrolyzed glycerolipid is present in an amount of from 15% to 30% by weight of the pharmaceutical composition. 15. The pharmaceutical composition according to 14, where the partially hydrolyzed glycerolipid is present in an amount of from 15% to 25% by weight of the pharmaceutical composition. 16. The pharmaceutical composition of claim 15, wherein the partially hydrolyzed glycerolipid comprises glyceryl monolinoleate. 17. The pharmaceutical composition according to claim 1, in which the PEG polymer is present in an amount of from 8% to 15% by weight of the pharmaceutical composition. 18. The pharmaceutical composition according to 17, in which the PEG polymer is present in an amount of from 7% to 13% by weight of the pharmaceutical composition. 19. The pharmaceutical composition of claim 18, wherein the pharmaceutically acceptable PEG polymer is present in an amount of from 8% to 12% by weight of the pharmaceutical composition. 20. The pharmaceutical composition according to claim 19, in which the PEG polymer is present in an amount of from 9% to 11% by weight of the pharmaceutical composition. 21. The pharmaceutical composition according to claim 1, in which the PEG polymer is a liquid PEG polymer. 22. The pharmaceutical composition according to item 21, in which the molar mass of the pharmaceutically acceptable PEG polymer is less than 2000 g / mol. 23. The pharmaceutical composition according to claim 22, wherein the liquid PEG polymer is PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, or a combination thereof. 24. The pharmaceutical composition according to claim 1 or 2, additionally containing from 5% to 15% propylene glycol (PPG) polymer by weight of the pharmaceutical composition. 25. The pharmaceutical composition according to paragraph 24, in which the PPG polymer is present in an amount of from 8% to 15% by weight of the pharmaceutical composition. 26. The pharmaceutical composition according A.25, in which the PPG polymer is present in an amount of from 7% to 13% by weight of the pharmaceutical composition. 27. The pharmaceutical composition according p, in which the pharmaceutically acceptable PPG polymer is present in an amount of from 8% to 12% by weight of the pharmaceutical composition. 28. The pharmaceutical composition according to item 27, in which the PPG polymer is present in an amount of from 9% to 11% by weight of the pharmaceutical composition. 29. The pharmaceutical composition according to paragraph 24, in which the PPG polymer is a liquid PPG polymer. 30. The pharmaceutical composition according to clause 29, in which the molar mass of the pharmaceutically acceptable PPG polymer is less than 2000 g / mol. 31. The pharmaceutical composition of claim 30, wherein the liquid PPG polymer is PPG 100, PPG 200, PPG 300, PPG 400, PPG 500, PPG 600, PPG 700, PPG 800, PPG 900, PPG 1000, or a combination thereof. 32. The use of the pharmaceutical composition according to any one of claims 1 to 31 in the manufacture of a medicament for the treatment of chronic inflammation. 33. The application of claim 32, wherein the chronic inflammation is associated with acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, bronchitis, 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, colds, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic diabetes diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondelitis, epididymitis, fasciitis, f bromialgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, purulent hydradenitis, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, inflammatory disease, inflammatory disease, cariitis, inflammatory insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, coronary heart disease, keratitis, keratoconjunctivitis, laryngitis volume lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (Syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteomeopeni osteitis, otitis media, pancreatitis, Parkinson's disease, mumps, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis volume, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, complications, stomatosis, stomatitis, stomatitis, stomatitis, stomatitis tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, ginitom, vasculitis or vulvitis. 34. The use of claim 32, wherein the chronic inflammation is tissue inflammation or systemic inflammation. 35. The application of claim 32, wherein the chronic inflammation is an autoimmune disease or non-autoimmune disease. 36. The application of claim 32, wherein the chronic inflammation is associated with arthritis, myopathy, vasculitis, skin disease, gastrointestinal disease, cardiovascular disease, cancer, drug inflammation, infection, tissue or organ damage, transplant rejection, syndrome graft versus host, Th1-mediated inflammatory disease, chronic neurogenic inflammation. 37. The use of the pharmaceutical composition according to any one of claims 1 to 31 for the treatment of chronic inflammation. 38. The use of claim 37, wherein the chronic inflammation is associated with acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, bronchitis, 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, colds, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic diabetes diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondelitis, epididymitis, fasciitis, f bromialgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, purulent hydradenitis, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, inflammatory disease, inflammatory disease, cariitis, inflammatory insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, coronary heart disease, keratitis, keratoconjunctivitis, laryngitis volume lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (Syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteomeopeni osteitis, otitis media, pancreatitis, Parkinson's disease, mumps, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis volume, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, complications, stomatosis, stomatitis, stomatitis, stomatitis, stomatitis tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, ginitom, vasculitis or vulvitis. 39. The application of clause 37, in which the chronic inflammation is an inflammation of the tissue or systemic inflammation. 40. The use of claim 37, wherein the chronic inflammation is an autoimmune disease or non-autoimmune disease. 41. The application of clause 37, in which chronic inflammation is associated with arthritis, myopathy, vasculitis, skin disease, gastrointestinal disease, cardiovascular disease, cancer, drug inflammation, infection, tissue or organ damage, transplant rejection, syndrome graft versus host, Th1-mediated inflammatory disease, chronic neurogenic inflammation. 42. A method of treating an individual with chronic inflammation, wherein the method includes the step of administering to the individual in need of the pharmaceutical composition according to any one of claims 1-31. 43. The method according to § 42, in which chronic inflammation is associated with acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, colds, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic neuropathy, and diabetic neuropathy ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondelitis, epididymitis, fasciitis, fibro ialgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, purulent hydradenitis, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, inflammatory carcinoma, inflammatory disease, inflammatory insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, coronary heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (Syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, oste osteopenitis, osteo-oopheomeritis, oste osteopenitis, osteo-oopheomeritis, osteo-oopheomeritis, osteo-oopheomeritis, osteo-oopheomeritis, osteo-oopheomeritis, osteo-oopheomeritis, osteo-osteopenitis, otitis media, pancreatitis, Parkinson's disease, mumps, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stomatitis, stomatitis, insomnia, stomatitis, stomatitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vagina that vasculitis or vulvitis. 44. The method of claim 42, wherein the chronic inflammation is tissue inflammation or systemic inflammation. 45. The method of claim 42, wherein the chronic inflammation is an autoimmune disease or non-autoimmune disease. 46. The method according to § 42, in which chronic inflammation is associated with arthritis, myopathy, vasculitis, skin disease, gastrointestinal disease, cardiovascular disease, cancer, drug inflammation, infection, tissue or organ damage, transplant rejection, syndrome graft versus host, Th1-mediated inflammatory disease, chronic neurogenic inflammation.

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