JP2013544802A - Inflammatory disease - Google Patents

Abstract

  The present invention relates to the treatment of inflammatory diseases, in particular Th-1 mediated inflammatory diseases. In particular, the present invention relates to the treatment of Th-1 mediated inflammatory diseases using a series of compositions and the use of these compositions in methods of treatment. The invention extends to adjuvants for use in the treatment of various medical conditions. The invention also provides pharmaceutical compositions and medicaments containing the adjuvant, and the use of the adjuvant in methods of treatment and for inducing an immune response.

Description

  The present invention relates to the treatment of inflammatory diseases, in particular Th-1 mediated inflammatory diseases. In particular, the present invention relates to the treatment of Th-1 mediated inflammatory diseases using a series of compositions and the use of these compositions in methods of treatment. The invention extends to adjuvants, particularly adjuvants for use in the treatment of various conditions. The invention also provides pharmaceutical compositions and medicaments containing the adjuvant, and the use of the adjuvant in methods of treatment and for inducing an immune response.

  Protection against disease is important for the survival of all animals, and the mechanism used for this purpose is the animal's immune system. The immune system is complex and includes two major parts: (i) innate immunity and (ii) adaptive immunity. The innate immune system includes cells and mechanisms that non-specifically protect the host from infection by invading microorganisms. Leukocytes involved in the innate immune system include phagocytic cells such as macrophages, neutrophils and dendritic cells, among others. The innate immune system can be fully functional before a pathogen enters the host.

  The adaptive immune system, on the other hand, is initiated only after the pathogen has entered the host, at which point it develops specific protection for that pathogen. The cells of the adaptive immune system are called lymphocytes, the two main types of which are B cells and T cells. B cells are involved in the production of neutralizing antibodies that circulate in plasma and lymph and form part of the humoral immune response. T cells function in both humoral immune responses and cellular immunity. There are several subsets of activated or effector T cells, which are the two main known as cytotoxic T cells (CD8 +) and type 1 helper T cells (Th1) and type 2 helper T cells (Th2) There are various types of “helper” T cells (CD4 +).

  Th1 cells promote a cellular adaptive immune response that involves activation of macrophages and in response to antigens promotes the release of various cytokines such as IFNγ, TNF-α and IL-12. These cytokines affect the function of other cells in adaptive and innate immune responses and cause microbial destruction. Usually, the Th1 response is more effective against intracellular pathogens such as viruses and bacteria that reside inside the host cell. However, the Th2 response is characterized by the release of IL-4, which causes B cell activation to produce neutralizing antibodies and induces humoral immunity. The Th2 response is more effective against extracellular pathogens such as parasites and toxins outside the host cell. Thus, humoral and cellular responses provide completely different mechanisms for invading pathogens.

  Interleukin-10 (IL-10), also known as human cytokine synthesis inhibitor (CSIF), is an anti-inflammatory cytokine. It is produced by lymphocytes to a lesser extent, mainly by monocytes, and has pleiotropic effects in immune regulation and inflammation. IL-10 down-regulates the expression of costimulatory molecules in Th1 cytokines (such as IFNγ, TNF-α and IL-12), MHC class II antigens, and macrophages. It also enhances B cell survival, proliferation, and antibody production. Furthermore, IL-10 can inhibit NF-κB activity and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggest the function of IL-10 as an essential immune regulator in the intestine, and Crohn's disease patients have shown promising responses to treatment with bacterially produced recombinant IL-10, This indicates the importance of this cytokine to attenuate excessive immunity in the human body.

  IL-10 is an effective target in inflammatory diseases and has been shown to be essential for immune tolerance and control of Th1 immunity (O'Garra et al., 2008, Immunol. Rev., 223: 114-31 ). Systemic administration of exogenous IL-10 in early clinical trials has shown some initial promise in the treatment of various diseases including rheumatoid arthritis, Crohn's disease, psoriasis and cystic fibrosis. However, problems associated with these early trials were probably administered systemically, either because the tissue levels of IL-10 were too low (IL-10 had a short half-life), or because IL-10 was not delivered properly. Exogenous IL-10 did not suppress excessive Th1 response, as expected. Therefore, the concentrations of IFNγ, TNF-α and IL-12 actually increased to harmful levels. It will be understood that these cytokines are pro-inflammatory.

  Furthermore, a serious side effect of excessive exogenous IL-10 administration is that it actually suppresses the immune system rather than modulating the immune system in a positive way, causing serious problems with immunity. It will be understood that IL-10, IL-4 and TGF-β are anti-inflammatory.

  Thus, in view of these issues, the art is clearly Th-1 mediated diseases, especially Th-1 mediated inflammatory diseases, that do not cause the immunity problems observed in previous IL-10 tests. There is a need for improved drugs for use in the treatment of. We studied the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in mice previously challenged with influenza virus using in vivo mouse tests. We prepared ibuprofen in combination with a highly lipophilic pharmaceutically acceptable vehicle, or adjuvant, which was then orally administered to challenge mice. We surprisingly found that ibuprofen administered orally in an oily formulation (i.e., adjuvant) was in percent survival compared to control mice that received oily vehicle alone or ibuprofen alone (not in oil). Observed to have a good effect. The inventors have also used in vivo assays to reveal that the concentration of IL-10 in the lungs of surviving animals is dramatically increased in mice administered the oily ibuprofen composition.

  Accordingly, in a first aspect, a therapeutically effective amount of a compound capable of increasing interleukin-10 (IL-10) production and lipids and alcohols for use in the treatment of Th-1 mediated diseases There is provided a pharmaceutical composition comprising a pharmaceutically acceptable vehicle containing wherein IL-10 is endogenously produced by Th2 cells, dendritic cells and / or macrophages.

  In a second aspect of the invention, a method is provided for preventing, treating and / or ameliorating a Th-1 mediated disease, wherein the method comprises interleukin-10 (IL) in a subject in need of such treatment. -10) administering a pharmaceutical composition comprising a therapeutically effective amount of a compound capable of increasing production and a pharmaceutically acceptable vehicle containing lipids and alcohols, wherein IL-10 is It is produced endogenously by Th2 cells, dendritic cells and / or macrophages.

  In a third aspect, there is provided the use of a pharmaceutical composition for treating a Th-1 mediated disease, wherein the composition is interleukin-10 (IL-10) by Th2 cells, dendritic cells and / or macrophages. A therapeutically effective amount of a compound capable of inducing endogenous production of), and a pharmaceutically acceptable vehicle containing lipids and alcohols.

FIG. 1 shows one embodiment of the composition of the first aspect (ie ibuprofen in lipids, herein represented as BC1054) for survival against lethal challenge with influenza A / PR / 8/34 ). 335 μg ibuprofen (BC1054 adjuvant oral) in lipid adjuvant was administered to challenged mice. Two controls were used: 335 μg ibuprofen in the absence of lipid adjuvant (BC1054 oral) and lipid adjuvant alone in the absence of ibuprofen (control oral). FIG. 2 shows the effect of a formulation containing 335 μg ibuprofen in lipid vehicle (BC1054 lipid oral) on IL-10 levels in the lungs of surviving mice in vivo. Two controls were used: 335 μg ibuprofen (BC1054 oral) and lipid vehicle alone (vehicle oral) in the absence of lipid adjuvant. FIG. 3 shows the effect of a formulation containing 335 μg ibuprofen in a lipid vehicle (BC1054 lipid oral) on IL-4 levels in the lungs of surviving mice in vivo. Two controls were used: 335 μg ibuprofen (BC1054 oral) and lipid vehicle alone (vehicle oral) in the absence of lipid adjuvant. FIG. 4 is a graph showing the effect of BC1054 formulation on IL-10 levels in the lungs of surviving mice. FIG. 5 is a graph showing the effect of BC1054 formulation on TNF-α levels in the lungs of surviving mice. FIG. 6 is a graph showing the effect of BC1054 formulation on IFN-γ levels in the lungs of surviving mice. FIG. 7 is a graph showing the effect of BC1054 formulation in a mouse model of anti-collagen antibody-induced arthritis (ACAIA).

  Surprisingly, as shown in FIG. 1, influenza induction in mice when ibuprofen is administered orally in a lipophilic formulation (eg, at least 30% w / w lipid) or in an adjuvant of the present invention. It is shown to be very effective in the treatment of respiratory collapse. Indeed, the application of a single dose of the pharmaceutical composition of the present invention transforms the 80% mortality model into an astonishing 80% survival outcome, which was totally unexpected. Although we do not wish to be bound by any theory, we believe that one explanation for this surprising observation is due to the lipophilicity of NSAIDs such as ibuprofen (ie log P 3.5). Possible, as a result of their rapid absorption into the systemic circulation through the lymphatic system when delivered in oily formulations with high lipid content (eg at least 30% (w / w) lipids) I think. When taking a drug / lipid formulation, the lipid is mixed with bile containing bile salts in the gastrointestinal tract and is a large lipoprotein particle consisting of triglycerides, phospholipids, cholesterol and proteins, and NSAIDs, micelles or chylomicrons To form a complex.

  The resulting oil / drug / bile salt complex (ie, micelles or chylomicrons) can then be absorbed into the intestinal lymphatic system by the nearby digestive tract. These micelles / chylomicrons containing compounds that promote IL-10 production are transported through the gastrointestinal lymphatic system to the central venous vasculature and then rapidly transported to the heart, where the venous blood rich in active compounds is produced by the heart. Thought to be sent to the lungs. As a result, the drug is delivered directly to the lung at a high concentration in oxygenated blood, increasing its bioavailability.

  We believe that lymphatic absorption of the active compound (eg, ibuprofen) functions as a passive system that distributes the drug directly to the lungs, exposing the lungs to high concentrations of the compound. The present inventors have found that this delivery mechanism does not occur when using a general oral formulation that contains no lipids or only low levels of lipids, and instead is controlled by venous absorption controlled by the liver. It is absorbed through the vein and it is thought to release the drug into the systemic circulation relatively slowly. Thus, the inventors have found that high concentrations of lipids in the formulation vehicle used in the composition of the first aspect are in an influenza-induced respiratory collapse assay in mice, as described in the Examples. We believe that this may be the reason for the effectiveness of ibuprofen administered orally.

  As shown in FIG. 2, administration of the pharmaceutical composition of the present invention caused a dramatic increase in endogenous IL-10 production in the lungs of influenza challenged mice, which was totally unexpected. . Apparently, the active substance was administered in lipids when compared to the concentration of IL-10 produced in control mice (ie, animals that were administered oily vehicle alone or not ibuprofen alone). The IL-10 concentration produced in animals was much greater than the additive effect, suggesting that a synergistic effect is occurring.

  As described in Example 4 and shown in FIGS. 5-7, the inventors have shown that endogenous NSAIDs (such as ibuprofen) are endogenous from macrophages when prepared in oil and alcohol (eg, ethanol) adjuvants. It was demonstrated to activate IL-10 production. Accordingly, the compositions of the present invention are preferably adapted for use in promoting endogenous IL-10 production from dendritic cells and / or macrophages. One advantage of the composition of the present invention is that the composition of the present invention allows certain active compounds (ie drugs) to be formulated in lipids and taken orally so that the active compound (ie drug) is selective. To be introduced into macrophages and dendritic cells. Many disease symptoms are thought to be associated with low levels of IL-10 (ie, low IL-10 disorders) or in situations where the increase in IL-10 levels is too slow or insufficient, Any of these symptoms can be treated according to the present invention. Example 5 describes the effect of the composition of the present invention in a mouse model of anti-collagen antibody induced arthritis (ACAIA). Thus, a Th-1 mediated disease that can be treated can be a Th-1 mediated inflammatory disease, preferably a systemic inflammatory disease. The composition of the present invention may therefore be an anti-inflammatory pharmaceutical composition.

  Diseases to be treated include rheumatoid arthritis (RA); psoriatic arthritis; psoriasis; inflammatory bowel syndrome (IBD); Crohn's disease; ulcerative colitis; multiple sclerosis (MS); influenza including pandemic influenza Respiratory diseases such as those caused by viruses such as respiratory syncytial virus (RSV); cystic fibrosis (CF); herpes including genital herpes; asthma and allergies; sepsis and septic shock; bacterial pneumonia Bacterial meningitis; Dengue hemorrhagic fever; Diabetes type I; Endometriosis; Prostatitis; Uveitis; Uterine ripening; Alopecia areata; Ankylosing spondylitis; Celiac disease Dermatomyositis; Diabetes mellitus Type 1; Goodpasture syndrome; Graves' disease; Guillain-Barre syndrome; Juvenile idiopathic arthritis; Hashimoto's thyroiditis; Reduced purpura; lupus erythematosus; mixed connective tissue disease; myasthenia gravis; narcolepsy; osteoarthritis; pemphigus vulgaris; pernicious anemia; polymyositis; primary biliary cirrhosis; Sjogren's syndrome; temporal arteritis; vasculitis; Wegener's granulomatosis; and Th-1 mediated disease consisting of age-related macular degeneration.

  Th-1 mediated diseases can be virus-induced, bacterial-induced, or chemical-induced (eg, environment-induced). For example, viruses that cause Th-1 mediated diseases can cause chronic or acute infections, which can cause respiratory diseases. Suitably, the virus that causes a Th-1 mediated disease may be influenza.

  Preferably, the Th-1 mediated disease that can be treated is a systemic inflammatory disease such as inflammatory bowel syndrome (IBD), rheumatoid arthritis (RA) or cystic fibrosis (CF). The Th-1 mediated disease that can be treated is preferably IBD.

  The inventors are characterized in that IL-10 production exhibits a switch from a Th1 response to a Th2 response, and that such compounds can be used to treat Th-1 mediated diseases. As we realized, we studied a number of different compounds that could induce IL-10 production. The inventors have demonstrated that causing a switch from a Th1 response to a Th2 response by upregulating IL-10 production can be used to help treat Th-1 mediated hyperinflammation. In fact, FIG. 3 demonstrates not only that administration of the composition of the present invention increases IL-10 production, but it also causes an increase in IL-4 production, from a Th1 response to a Th2 response. Prove that the switch to was triggered. Advantageously, B cells are activated by inducing endogenous IL-10 release of Th2 cells, macrophages and / or dendritic cells by promoting Th2 responses, which activate neutralizing antibodies. Produce and induce humoral immunity. It will be appreciated that the Th2 response is much more effective than the Th1 response against extracellular pathogens such as parasites and toxins outside the host cell.

  By way of example, Th-1 mediated hyperinflammation occurs during a viral infection (eg, influenza as shown in the examples), so we have developed Th2 cells, macrophages upon administration of the composition to a subject. It is contemplated that endogenous IL-10 production by and / or dendritic cells can be used to treat respiratory collapse caused by viral infections. Some viruses, such as herpes simplex virus (HSV), are known to maintain their presence in the body by promoting Th1 immunity, thus causing a switch to Th2 immunity, It is known to aid in the treatment of herpes infections by allowing the body to attack the virus via natural killer cell immunity.

  IL-10 is a paracrine cytokine and therefore the compounds used in the first, second and third aspects of the invention are effective to increase endogenous IL-10 production paracrinely We believe that can be used. It will be appreciated that paracrine signaling may be a form of cell signaling in which the target cell is close to or local to the signal emitting cell. Thus, IL-10 can regulate the immune response at the site of inflammation in parallel with cell-cell interactions.

  Compounds that can increase endogenous IL-10 production can be recognized by Th2 cells, dendritic cells and / or macrophages. Preferably, however, compounds that can increase endogenous IL-10 production are recognized by dendritic cells and / or macrophages. Th2 cells, dendritic cells and / or macrophages can phagocytose compounds (such as lipid / drug chylomicrons) and react by pathways in each of these cell types, thereby producing IL-10 endogenously. Thus, preferably, IL-10 is produced by Th2 cells, dendritic cells and / or macrophages that are immunoresponsive. Advantageously, endogenous by immune responsive Th2 cells, dendritic cells and / or macrophages, unlike the production of IL-10 by non-immune cells causing an imbalance of the immune system that sometimes leads to infection and sometimes cancer The production of IL-10 ensures that the immune system remains balanced and thereby avoids infection.

  Thus, the immune system can naturally regulate itself, thereby reducing the risk of infection and cancer. As shown in FIGS. 4-6, the level of IL-10 generated by the regulatory process and the feedback loop can regulate (eg, reduce) the concentration of Th1 cytokines such as IFNγ, TNF-α and IL-12. Does not completely suppress their production. This can be important because these Th1 cytokines are necessary to protect the body from infection. Thus, by endogenously promoting IL-10 production, it is associated with immunity causing overproduction of IFNγ, TNF-α and IL-12 observed when cytokines are added exogenously Serious problems can be overcome.

  A compound that can induce the production of endogenous interleukin-10 (IL-10) by Th2 cells, dendritic cells and / or macrophages can be a non-steroidal anti-inflammatory drug (NSAID). The NSAID can be a propionic acid derivative, an acetic acid derivative, an enolic acid derivative, a fenamic acid derivative, or a selective or non-selective cyclooxygenase (COX) inhibitor. The NSAID can be profen.

  Examples of suitable propionic acid NSAID derivatives may include ibuprofen; naproxen; fenoprofen; ketoprofen; flurbiprofen; or oxaprozin. Examples of suitable acetic acid NSAID derivatives include aceclofenac; acemetacin; actarit; alclofenac; ampenac; clometacin; diclofenac; etodolac; felbinac; fenclofenac; indomethacin; sell. Examples of suitable enolic acid NSAID derivatives may include piroxicam; meloxicam; tenoxicam; droxicam; lornoxicam; or isoxicam. Examples of fenamic acid NSAID derivatives may include mefenamic acid; meclofenamic acid; flufenamic acid; or tolfenamic acid.

  In embodiments where the NSAID is a cyclooxygenase (COX) inhibitor, it can be either a cyclooxygenase 1 (COX 1) inhibitor or a cyclooxygenase 2 (COX 2) inhibitor. Examples of suitable COX inhibitors may include ibuprofen; celecoxib; etlicoxib; luminacoxib; meloxicam; rofecoxib; or valdecoxib.

  The NSAID can be selected from the group consisting of: That is, aluminoprofen; benoxaprofen; dexketoprofen; flurbiprofen; ibuprofen; indoprofen; ketoprofen; loxoprofen; pranoprofen; protidic acid; suprofen; Diclofenac; etodolac; felbinac; fenclofenac; indomethacin; ketorolac; methiazic acid; mofezolac; naproxen; oxametacin; sulindac; zomepirac; Azapropazone, benolylate, benzami Butybufen; chlortenoxazine; choline salicylate; diflunisal; emorfazone; epirisol; feclobzone; fenbufen; grafenine; hydroxyethyl salicylate; lactylphenetidine; mefenamic acid; Procazone; salicylamide; salsalate; thiaramide; tinolidine; and tolfenamic acid.

  Preferred NSAIDs may be aluminoprofen, benoxaprofen, dexketoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, pranoprofen, protidic acid, or suprofen. Preferably the NSAID is ibuprofen.

  NSAIDs can be used in the form of a pharmaceutically acceptable salt, solvate, or salt solvate, eg, a hydrochloride salt.

  The NSAIDs described herein can be provided as racemates or as individual enantiomers including R- or S-enantiomers. Thus, the NSAID can include R-ibuprofen or S-ibuprofen, or a combination thereof.

  In one embodiment, S-ibuprofen is a painful immune-mediated response to a COX inhibitor such as those described herein (eg, celecoxib; etoroxixib; luminacoxib; meloxicam; rofecoxib; or valdecoxib) Can be used for treatment of disease. Examples of such diseases can include arthritis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis and endometriosis.

  In another embodiment, R-ibuprofen may be used for the treatment of painless immune mediated diseases that respond to COX inhibitors. Examples of such diseases are psoriasis, inflammatory bowel disease, multiple sclerosis, pandemic influenza, respiratory syncytial virus, cystic fibrosis, genital herpes, asthma, bacterial pneumonia, bacterial meningitis , Dengue hemorrhagic fever, type I diabetes, prostatitis and preterm birth.

  The formulation vehicle is at least about 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% 95% or at least about 99% (w / w) lipids. The vehicle is about 35% to 99% (w / w) lipid, or about 45% to 99% (w / w) lipid, or about 50% to 99% (w / w) lipid, or about 60 % To 98% (w / w) lipid, or about 70% to 97% (w / w) lipid, or about 80% to 96% (w / w) lipid, or about 85% to 95% ( w / w) lipid, or about 85% to 95% (w / w) lipid, or about 88% to 94% (w / w) lipid, or about 89% to 93% (w / w) It may contain lipids.

  The formulation vehicle comprises the following group: oil or oily liquid; fat; fatty acid (eg oleic acid, stearic acid or palmitic acid), fatty acid ester, fatty alcohol, glyceride (mono-, di- or triglyceride); It may contain a lipid component selected from phospholipids; glycol esters; sucrose esters; waxes; glycerol oleate derivatives; medium chain fatty acid triglycerides; or mixtures thereof. Triglycerides are esters derived from glycerol and three fatty acids and are the main components of vegetable oils and animal fats.

  The term “oil” refers to an oil that is liquid at standard room temperature and can be used for any substance that does not mix with water and has a sticky feel. The term “fat” may refer to a fat that is solid at standard room temperature. The term “lipid” may thus refer to liquid or solid fats and other related substances.

  Suitable oils that can be used as the lipid component in the formulation vehicle can be natural or vegetable oils. Examples of suitable natural oils may be selected from the group consisting of linseed oil; soybean oil; palm fractionated oil; mineral oil; triacetin; ethyl oleate; hydrogenated natural oil; Examples of suitable vegetable oils are: rapeseed oil; olive oil; peanut oil; soybean oil; corn oil; safflower oil; arachis oil; sunflower oil; canola oil; walnut oil; almond oil; Coconut oil; cottonseed oil; rice bran oil; sesame oil; and refined palm oil; or a mixture thereof. Each of these oils is commercially available from a number of sources well known to those skilled in the art.

  The lipid component of the formulation vehicle may contain fatty acids containing 8 to 24 carbon atoms, 10 to 22 carbon atoms, 14 to 20 carbon atoms, or 16 to 20 carbon atoms. The lipid may be a saturated lipid or, for example, an unsaturated lipid having one, two, three or more double bonds. Lipids are myristic acid (C 14: 0); palmitic acid (C 16: 0); palmitoleic acid (C 16: 1); stearic acid (C 18: 0); oleic acid (C 18: 1); linoleic acid (C 18: 2); linolenic acid (C 18: 3) and arachidic acid (C 20: 0); or fatty acids selected from the group consisting of mixtures thereof. It will be appreciated that the first number shown in parentheses corresponds to the number of carbon atoms in the fatty acid and the second number corresponds to the number of double bonds (ie, the number of unsaturations).

The melting point of the oil is mainly determined by the saturation / unsaturation degree. Oleic acid _{(CH 3 (CH 2) 7} CH = CH (CH 2) 7 COOH), linoleic acid _{(CH 3 (CH 2) 4} (CH = CHCH 2) 2 (CH 2) 6 COOH), and linolenic acid ( The melting points of CH ₃ CH ₂ (CH═CHCH ₂ ) ₃ (CH ₂ ) ₆ COOH) are about 16 ° C., −5 ° C. and −11 ° C., respectively. Thus, the melting point of the lipid can be about -20 ° C to 20 ° C, or about -15 ° C to 16 ° C.

The lipid can include rapeseed oil. Rapeseed oil is obtained from Brassica napus and contains both omega-6 and omega-3 fatty acids in a ratio of about 2: 1. However, in the examples, linseed oil may be preferred because the inventors have discovered that linseed oil is particularly effective. Linseed oil, also known as flax seed oil, is a clear to yellowish oil obtained from the dry mature seeds of flax (Linum usitatissimum, Linaceae). The oil is obtained by cold pressing, sometimes followed by solvent extraction. Flaxseed oil is a mixture of various triglycerides with different fatty acid components. In linseed oil, the constituent fatty acids are of the following types: (i) saturated fatty acid palmitic acid (about 7%) and stearic acid (3.4-4.6%); (ii) monounsaturated oleic acid (18.5-22.6%) ); (Iii) diunsaturated linoleic acid (14.2-17%); and (iv) triunsaturated omega-3 fatty acid α-linolenic acid (51.9-55.2%). Linseed oil is also rich in omega-6 fatty acids. The structure of a typical triglyceride found in linseed oil can be represented by Formula I.

Thus, the lipid component of the formulation vehicle may contain omega 3 and / or omega 6 fatty acids. Omega-3 fatty acids are a group of unsaturated fatty acids that commonly have a final carbon-carbon double bond at the n-3 position, ie, the third bond from the methyl terminus of the fatty acid, and can be represented by Formula II.

On the other hand, omega-6 fatty acids are a group of unsaturated fatty acids having a final carbon-carbon double bond at the 6th bond, commonly counted from the n-6 position, that is, from the opposite end of the carboxyl group. It can be represented by III.

  Omega-3 and omega-6 fatty acids are derivatives of linolenic acid, the main difference being the number and exact position of double bonds. Thus, omega-3 and omega-6 will have substantially the same melting point as linolenic acid.

  Vehicles are approximately 90%, 80%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5 % Or less than about 1% (w / w) alcohol. Vehicle is about 1% -90% alcohol (w / w), or about 1% -70% (w / w) alcohol, or about 1% -60% (w / w) alcohol, or about 1 % To 50% (w / w) alcohol, or about 2% to 40% (w / w) alcohol, or about 4% to 30% (w / w) alcohol, or about 6% to 20% ( w / w) alcohol, or about 8-15% (w / w) alcohol. The alcohol can be an aliphatic alcohol.

The alcohol may be C _1-20 alcohol, C _1-15 alcohol, C _1-10 alcohol, C _1-5 alcohol, or C _2-4 alcohol. The alcohol can be menthol or a sugar alcohol such as glycerol, sorbitol, erythritol, xylitol, mannitol, isomalt, or maltitol.

  The alcohol can be ethanol, propanol, or butanol. In one preferred embodiment, the alcohol is ethanol.

  In one embodiment, the vehicle may contain about 60% to 95% (w / w) lipid and about 5% to 40% (w / w) alcohol. In another embodiment, the vehicle may contain about 80% to 95% (w / w) lipid and about 5% to 20% (w / w) alcohol.

  In one embodiment, the vehicle may contain about 60% to 95% (w / w) oil and about 5% to 40% (w / w) alcohol. In another embodiment, the vehicle may contain about 80% to 95% (w / w) lipid and about 5% to 20% (w / w) alcohol. For example, the vehicle may contain about 80% to 95% (w / w) olive oil, rapeseed oil or linseed oil, and about 5% to 20% (w / w) ethanol. In another embodiment, the vehicle may contain about 88% to 92% (w / w) lipid, and about 8% to 12% (w / w) alcohol. For example, the vehicle may contain about 88% to 92% (w / w) olive oil, rapeseed oil or linseed oil, and about 8% to 12% (w / w) ethanol. In another embodiment, the vehicle may contain about 90% (w / w) lipid and about 10% (w / w) alcohol. For example, the vehicle may contain about 90% (w / w) olive oil, rapeseed oil or linseed oil, and about 10% (w / w) ethanol, and optionally water.

  We believe that water has a tendency to increase the instability of NSAIDs. Thus, in a preferred embodiment, the vehicle is substantially anhydrous. Advantageously, the lack of water in the vehicle embodiment means that the stability of the NSAID in the composition is not compromised, resulting in product improvement.

  However, in some embodiments, the vehicle can optionally contain water. Vehicle is about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, less than 5%, or about 1 % (W / w) water may be included. Vehicle is about 1% to 70% (w / w) water, or about 1% to 60% (w / w) water, or about 1% to 50% (w / w) water, or about 2 % To 40% (w / w) water, or about 4% to 30% (w / w) water, or about 6% to 20% (w / w) water, or about 8% to 15% ( w / w) water.

  It will be appreciated that the composition can be used to treat Th1-mediated disease with monotherapy (ie, use of the composition alone). Alternatively, the composition can be used as an adjunct to or in combination with known treatments used to treat Th1-mediated diseases.

  The composition may have a number of different dosage forms, particularly depending on the method in which the composition is used. Thus, for example, the composition requires a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle solution, transdermal patch, liposome suspension dosage form, or treatment. It can be any other suitable dosage form that can be administered to humans or animals. It will be appreciated that the vehicle for the medicament of the present invention should be such that the subject being administered is well tolerated and preferably allows delivery of the medicament through the blood brain barrier or lungs. I will.

  Compositions containing the active compounds and lipids and alcohol vehicles (ie, adjuvants) can be used in a variety of ways. For example, oral administration may be required when the compound can be contained in a composition that can be taken orally, for example, in a tablet, capsule or liquid form. Alternatively, the composition can be administered into the bloodstream by injection. Injections can be intravenous (bolus or infusion) or subcutaneous (bolus or infusion). Alternatively, compositions containing the active compounds can be administered by inhalation (eg, intranasally or from the mouth).

  The composition can also be prepared for topical use. For example, an ointment can be applied to the skin. Topical use on the skin is particularly useful for treating skin infections or as a means of transdermal delivery to other tissues.

  Preferably, the composition is orally administrable, i.e. for oral administration, rather than administration by injection or inhalation.

  The amount of active compound required is determined by its biological activity and bioavailability, which is likewise the method of administration, the physicochemical properties of the compound, and whether the compound is used as a monotherapy or in combination therapy It will be understood that it depends on whether it is used in The frequency of administration will also be influenced by the factors described above, and in particular the half-life of the active compound within the subject being treated.

  The optimal dosage to be administered can be determined by one skilled in the art and will depend on the particular active compound used, the strength of the preparation, the method of administration and the progression of the condition. Additional factors depending on the particular subject being treated will include the age, weight, sex, diet and timing of the subject, resulting in the need to adjust the dose.

  It will be appreciated that one skilled in the art can calculate the required dose and the optimal concentration of the active compound in the target tissue based on the pharmacokinetics of its activity. Known methods as commonly used in the pharmaceutical industry (eg, in vivo experiments, clinical trials, etc.) to establish specific formulations of active compounds and precise treatment regimes (such as daily dose and frequency of administration of compounds) Can be used.

  Usually, depending on which compound is used, a daily dose of 0.001 μg / kg body weight to 60 mg / kg body weight of active compound may be used for the treatment of Th1-mediated diseases. Suitably the daily dose is 0.01 μg / kg body weight to 40 mg / kg body weight, more suitably 0.01 μg / kg body weight to 30 mg / kg body weight, or 0.1 μg / kg body weight to 20 mg / kg body weight, most suitably Is about 0.1 μg / kg body weight to 15 mg / kg body weight.

  A daily dose of the active compound may be given as a single dose (eg, a once-daily oral dosage form). A suitable daily dose may be 0.07 μg to 3200 mg (ie assuming a body weight of 70 kg), or 0.70 μg to 1600 mg, or 10 mg to 800 mg.

  It is envisioned that the composition can be administered more than once to a subject in need of treatment. The composition may require more than one administration per day. By way of example, the composition may be administered twice daily (or more depending on the severity of the Th1-mediated disease being treated) from 0.07 μg to 3200 mg (assuming 70 kg body weight). Patients undergoing treatment may take the first dose upon waking up, followed by a second dose (if it is a two-dose regimen) at night, or every three or four hours thereafter. It is envisioned that the composition can be administered daily (two or more if necessary) after the trigger of the development of Th1-mediated inflammation.

  Alternatively, sustained release devices can be used to deliver optimal doses of the compounds of the invention to the patient without the need for repeated administration.

  The inventors also believe that the compositions of the invention may be immobilized on or within a support matrix or matrix to form a lipid rich formulation, which is a Th1-mediated disorder. Can be used as a delivery device to treat.

Therefore, in the fourth aspect of the present invention,
(I) a therapeutically effective amount of a compound capable of increasing endogenous interleukin-10 (IL-10) production by Th2 cells, dendritic cells and / or macrophages, and a pharmaceutical comprising a lipid and an alcohol A drug delivery device is provided that includes an acceptable vehicle; and (ii) a support matrix.

  The delivery device can be a pessary or vaginal ring that can be worn by a subject in need of treatment for a Th1-mediated condition. For example, the device can be used to treat any disease characterized by a decrease in IL-10 concentration. The concentration of IL-10 decreases in pregnant women as a result of feetus tolerance, which is known to initiate labor during labor. Thus, the delivery device can be used by pregnant women to prevent or delay preterm birth.

  The support matrix can be made from a suitable matrix material to support the composition therein or thereon. The composition can be immobilized on a matrix. In one embodiment, the matrix can include any substance that can melt at or near body temperature so that the matrix melts and releases the composition over time, which is absorbed by the subject.

  The support matrix can be a suitable gel or wax. Common for vaginal administration, such as glycerol, gelatin, glycogelatin, macrogol (polyethylene glycol), natural, synthetic or semi-synthetic hard fat, and fractionated palm kernel oil Can be used.

  The compositions described herein are used to increase endogenous IL-10 production levels by Th2 cells, dendritic cells and / or macrophages, thereby Th1 such as TNF-α and IL-12. Based on the inventors' discovery that cytokine levels can be reduced to cause a switch from Th1 to Th2, we have found that these effects of the compounds are useful in the production of clinically useful compositions. I think it can be utilized and used. As shown in FIGS. 4-6, we hypothesize that NSAIDs activate IL-10 production from macrophages when prepared in oil and alcohol.

  A “therapeutically effective amount” of an active compound causes an increase in the level of IL-10 and IFN-γ, and preferably a decrease in the concentration of TNF-α and IL-12, when administered to a subject, thereby Any amount that results in treatment of a Th1-mediated disease.

  For example, a therapeutically effective amount of the active compound used can be from about 0.07 μg to about 3200 mg, preferably from about 0.7 μg to about 1600 mg. The amount of active compound is about 7 μg to about 1200 mg, or about 7 μg to about 800 mg.

  A “subject” can be a vertebrate, mammal, or farm animal, preferably a human. Thus, the agents of the present invention may be used to treat any mammal, such as humans, livestock, pets, or may be used for other veterinary applications.

  As referred to herein, a “pharmaceutically acceptable vehicle” can be any combination of compounds known to those of skill in the art to be useful in the preparation of pharmaceutical compositions, but lipids (eg, at least 30% (w / w lipid)) and alcohol.

  In one embodiment, the pharmaceutically acceptable vehicle is a solid and the composition can be in powder or tablet form. In addition to lipid components and alcohol, solid pharmaceutically acceptable vehicles can also be used as flavoring agents, lubricants, solubilizers, suspending agents, dyes, fillers, glidants, compression aids, inert agents. It can contain one or more substances that can also function as binders, sweeteners, preservatives, dyes, coatings, or tablet disintegrants. The vehicle can also be an encapsulating material. In powders, the vehicle can be a finely divided solid which is a mixture with the finely divided active agent (ie, a compound which promotes endogenous IL-10 production). In tablets, the active substance can be mixed with a vehicle having the required compression properties in an appropriate ratio and compressed to the desired shape and size. Suitable solid vehicles can include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting point waxes and ion exchange resins.

  In yet another embodiment, the formulation vehicle may be a liquid and the pharmaceutical composition may be in the form of a solution. Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. The active compound can be dissolved or suspended in water, an organic solvent, a mixture of both or pharmaceutically acceptable liquid vehicles such as pharmaceutically acceptable oils or fats. In addition to lipid components, liquid vehicles can be solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure regulators. Other suitable pharmaceutical additives, such as agents, can be included. Suitable examples of liquid vehicles for oral administration include water (partially containing additives such as those described above, eg cellulose derivatives, preferably carboxymethylcellulose sodium solution), alcohols (monohydric and polyhydric alcohols, For example, glycols), and derivatives thereof, as well as oils (eg, fractionated palm oil and peanut oil). The vehicle can also be an oily ester such as ethyl oleate or isopropyl myristate.

  The composition preferably comprises other solutes or suspending agents (eg, enough salts or glucose to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 ( Orally administered in the form of a sterilized solution or suspension containing sorbitol copolymerized with ethylene oxide and its anhydride oleate).

  However, the composition may or may not contain a surfactant. Preferably the composition is not emulsified. Examples of surfactants that may or may not be included in the composition include phospholipids such as phosphatidylcholine (lecithin) and phosphatidylethanolamine; alkali metal salts of fatty acids, ammonium salts, and triethanolamine salts And (a) cationic surfactants (detergent) such as halogenated dimethyldialkylammonium halides and alkylpyridinium halides; (b) alkyl, aryl and olefin sulfonates; Anionic surfactants such as sulfates of alkyls, olefins, ethers and monoglycerides, and sulfosuccinates; (c) nonionics such as aliphatic amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers Surface activity Encompasses amphoteric surfactants such as imidazoline quaternary ammonium salts including (detergent), surfactant (detergent) - and (d) alkyl -b- aminopropionic acid esters, and 2-alkyl; (detergent). Other examples of detergents can include sodium dodecyl sulfate dimethyl sulfoxide. Preferably, the vehicle or adjuvant of the invention does not contain any of these surfactants.

  Many surfactants have some safety impact, ie many are not GRAS (not generally considered safe). Therefore, avoiding the use of surfactants avoids such safety concerns for the compositions of the present invention. In addition, without wishing to be bound by theory, we hypothesize that the elimination of surfactant results in improved active substance uptake and bioavailability in the subject being treated. .

  We believe that pharmaceutically acceptable vehicles may contain at least 30% (w / w) lipid, preferably in the absence of ethanol as much as possible.

  Accordingly, in a fifth aspect, a therapeutically effective amount of a compound capable of increasing interleukin-10 (IL-10) production for use in the treatment of Th-1 mediated diseases, and at least 30% There is provided a pharmaceutical composition comprising a pharmaceutically acceptable vehicle containing (w / w) lipids, wherein IL-10 is endogenously produced by Th2 cells, dendritic cells and / or macrophages.

In the sixth aspect,
(I) a therapeutically effective amount of a compound capable of increasing endogenous interleukin-10 (IL-10) production by Th2 cells, dendritic cells and / or macrophages, and at least 30% (w / w) There is provided a drug delivery device comprising a pharmaceutically acceptable vehicle containing a lipid of: and (ii) a support matrix.

  In a seventh aspect, there is provided a method for preventing, treating and / or ameliorating a Th-1 mediated disease, the method comprising interleukin-10 (IL-10) in a subject in need of such treatment. Administering a pharmaceutical composition comprising a therapeutically effective amount of a compound capable of increasing production, and a pharmaceutically acceptable vehicle containing at least 30% (w / w) lipid, wherein IL -10 is produced endogenously by Th2 cells, dendritic cells and / or macrophages.

  In an eighth aspect, there is provided the use of a pharmaceutical composition for treating a Th-1-mediated disease, wherein the composition comprises endogenous interleukin-10 (by Th2 cells, dendritic cells and / or macrophages). A therapeutically effective amount of a compound capable of inducing the production of IL-10), as well as a pharmaceutically acceptable vehicle containing at least 30% (w / w) lipid.

  Based on the results demonstrating the surprising immunomodulatory effects of lipid / alcohol vehicles described herein (see FIGS. 2-6), we have effectively demonstrated the immunomodulatory activity of a wide range of immunogenic compounds. Consider developing a new adjuvant that can be used to enhance.

  Thus, according to a ninth aspect of the present invention there is provided an oral adjuvant for use in a pharmaceutical composition containing an immunogen, wherein the adjuvant comprises lipids and alcohols, dendritic cells and / or Promotes uptake of immunogens by macrophages, allowing them to modulate immunoregulatory cytokines, and the immunomodulatory activity of the immunogen in the presence of adjuvant is greater than its immunomodulatory activity in the absence of adjuvant.

  Adjuvants are pharmacological or immunological substances that alter the effect of other active substances such as drugs or vaccines, but have little, if any, direct effect when administered alone. It will be understood. Adjuvants are often included in vaccines to enhance the recipient's immune response to the administered antigen or immunogen while minimizing the administered foreign material. Although such immunological adjuvants are traditionally thought of as substances that assist the immune response to antigens or immunogens, adjuvants are also used to stabilize antigen formulations, particularly vaccines administered for animal health. It has also been developed as a material that can be useful for crystallization.

  The most commonly used adjuvants act by providing a long-term cache of antigen or immunogen, countering the typical property of rapid clearance and degradation of free antigen. The consideration of which adjuvant to use must take into account the negative side effects of concurrent adjuvants, such as undesirable inflammatory outcomes. For example, many patients suffer from “flu-like” symptoms that occur after vaccination or swelling and tenderness at the injection site. It is particularly important to reduce such systemic and local undesirable side effects while still providing the maximal enhancement of the immune response, and much research and development of new and improved adjuvants. Continue to promote.

  The adjuvant of the ninth aspect can be immunostimulatory and / or immunosuppressive. Advantageously, the adjuvant can improve the immunomodulatory activity of the subject administered the adjuvant, causing stimulation of the immune system to treat immunocompromised conditions such as cancer and immunosuppression, and likewise In order to treat hyperimmune conditions, the immune system can be suppressed. Giving immunopotentiators (ie immunogens) to macrophages and dendritic cells promotes their phenotype to enhance their ability to remove cancer cells, bacteria and viruses.

  Advantageously, as shown in the figure, the oily adjuvant of the ninth aspect not only exhibits greater efficacy to enhance the immunological activity of the antigen or immunogen (eg ibuprofen), but also the antigen or It shows improved stability-imparting properties against the immunogen and does not cause negative side effects in subjects receiving adjuvants.

  The term “oral adjuvant” may mean that it can be administered orally, ie for oral administration, rather than by injection or inhalation.

  In a tenth aspect of the present invention, there is provided a pharmaceutical composition comprising an immunogen and the adjuvant of the ninth aspect.

  In an eleventh aspect, a pharmaceutical composition of the tenth aspect for use in therapy is provided.

  In a twelfth aspect, there is provided the pharmaceutical composition of the tenth aspect for use in the treatment of a Th1-mediated disease, cancer, or bacterial or viral infection.

  In a thirteenth aspect, a method for inducing an effective immune response in a subject is provided, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the tenth aspect.

  The lipid and alcohol components of the adjuvant can be selected from any lipid (oil or fat) or alcohol described herein in any amount described. For example, the adjuvant is at least about 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 95% or at least about 99% (w / w) lipids. The adjuvant is about 35% to 99% (w / w) lipid, or about 45% to 99% (w / w) lipid, or about 50% to 99% (w / w) lipid, or about 60 % To 98% (w / w) lipid, or about 70% to 97% (w / w) lipid, or about 80% to 96% (w / w) lipid, or about 85% to 95% ( w / w) lipid, or about 85% to 95% (w / w) lipid, or about 88% to 94% (w / w) lipid, or about 89% to 93% (w / w) It may contain lipids.

  Suitable oils that can be used as the lipid component in the adjuvant can be natural or vegetable oils. Examples of suitable natural oils may be selected from the group consisting of linseed oil; soybean oil; palm fractionated oil; mineral oil; triacetin; ethyl oleate; hydrogenated natural oil; Examples of suitable vegetable oils are: rapeseed oil; olive oil; peanut oil; soybean oil; corn oil; safflower oil; arachis oil; sunflower oil; canola oil; walnut oil; Coconut oil; cottonseed oil; rice bran oil; sesame oil; and refined palm oil; or a mixture thereof. In one preferred embodiment, the lipid may comprise linseed oil.

  Adjuvants are about 90%, 80%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5 % Or less than about 1% (w / w) alcohol. Adjuvant is about 1% -90% alcohol (w / w), or about 1% -70% (w / w) alcohol, or about 1% -60% (w / w) alcohol, or about 1 % To 50% (w / w) alcohol, or about 2% to 40% (w / w) alcohol, or about 4% to 30% (w / w) alcohol, or about 6% to 20% ( w / w) alcohol, or about 8-15% (w / w) alcohol.

The alcohol can be an aliphatic alcohol. The alcohol may be C _1-20 alcohol, C _1-15 alcohol, C _1-10 alcohol, C _1-5 alcohol, or C _2-4 alcohol. The alcohol can be menthol or a sugar alcohol such as glycerol, sorbitol, erythritol, xylitol, mannitol, isomalt or maltitol. The alcohol can be ethanol, propanol, or butanol. In one preferred embodiment, the alcohol is ethanol.

  The adjuvant may or may not contain water. Preferably, the adjuvant is anhydrous. Preferably, the adjuvant does not contain a hydrophilic surfactant or any of the surfactants described herein.

  Adjuvants, when used, can stimulate or induce dendritic cells and / or macrophages to take up the immunogen and regulate the concentration of immunoregulatory cytokines in subjects treated with the pharmaceutical composition. . The immunoregulatory cytokine to be modulated can be selected from the group of cytokines including IL-10; IL4; TNF-α; and IFN-γ.

  As illustrated in FIGS. 2, 3, 4 and 5, in one embodiment, the adjuvant stimulates the subject's dendritic cells and / or macrophages to produce or produce immunoregulatory cytokines. Can be increased. For example, the cytokine produced or increased can be IL-10 and / or TNF-α and / or IL-4.

  As illustrated in FIG. 6, in another embodiment, an adjuvant may stimulate the subject's dendritic cells and / or macrophages to stop or reduce the production of immunoregulatory cytokines. For example, the cytokine whose production is reduced or prevented can be IFN-γ.

The immunogen present in the composition can be a pharmaceutically active agent having a log P value greater than 2.0 and / or a polar surface area of about 25 ^{2 to} 70 ² . The immunogen may preferably be a small molecule having a molecular weight of less than 1000 Da.

  The term “log P value” is known to those skilled in the art and may refer to the concentration ratio of a compound (ie, immunogen) in the two phases of a mixture of two immiscible solvents at equilibrium. The immunogen may have a log P value greater than 3.0, 4.0, 5.0 or 6.0. The immunogen may have a log P value of less than 7.0, 6.0, 5.0, 4.0 or 3.0. In one embodiment, the immunogen may have a log P value of 2.0 to 7.0, or 3.0 to 6.0, or 3.0 to 5.0. The immunogen may have a log P value of 2.0-4.0, or 2.1-4.0, or 2.2-4.0, or 2.3-4.0. In another embodiment, the immunogen may have a log P value of 2.5-4.0, or 3.0-4.0, or 3.1-4.0. In another embodiment, the immunogen can have a log P value of 3.3-4.0, or 3.5-4.0. In yet another embodiment, the immunogen may have a log P value of 2.0-3.0, or 2.0-2.7, or 2.0-2.5. In a further embodiment, the immunogen may have a log P value between 2.2 and 2.5.

The term “polar surface area” is also known to those skilled in the art and may refer to the sum of the surfaces of all polar atoms (usually oxygen and nitrogen) in the structure, including bonded hydrogen. In one embodiment, the immunogen may have a polar surface area of 35 ^{2 to} 65 ² , or 40 ^{2 to} 60 ² , or 45 ^{2 to} 55 ² . In another embodiment, the immunogen may have a polar surface area of 30 ^{2 to} 50 ² , or 35 ^{2 to} 45 ² , or 40 ^{2 to} 60 ² .

  In one embodiment, the immunogen may comprise a peroxisome proliferator activated receptor gamma (PPAR-γ) agonist.

  The term “PPAR-γ agonist” can mean any molecule that can bind to and elicit a response from the peroxisome proliferator-activated receptor gamma (PPAR-γ). This receptor is also known as the glitazone receptor, or nuclear receptor subfamily 1 group C member 3 (NR1C3). PPAR-γ is a type II nuclear receptor encoded by the PPAR-γ gene in humans. In humans, two isoforms of PPAR-γ are detected, namely PPAR-γ1 found in almost all tissues except muscle, and PPAR-γ2 found mainly in adipose tissue and intestine. The PPAR-γ agonist present in the composition can bind to either PPAR-γ1 or PPAR-γ2.

The table below provides a list of preferred PPAR-γ agonists that can be used in the compositions of the present invention. Thus, the PPAR-γ agonist can be a compound selected from the table.

  In one preferred embodiment, the PPAR-γ agonist can be a fibrate. Ogata et al., 2009, Atherosclerosis 205 (2): 413-419 describes the PPAR-γ agonist properties of genfibrozil and bezafibrate, fibrates. The fibrate can be selected from the group of fibrates consisting of bezafibrate; ciprofibrate; clofibrate; genfibrozil; and fenofibrate.

  In yet another embodiment, the PPAR-γ agonist is monasin; irbesartan; telmisartan; mycophenolic acid; resveratrol; delta (9) -tetrahydrocannabinol; cannabidiol; curcumin; cilostazol; benzbromarone; All; and a group of agonists including glycyrrhetinic acid.

  In another embodiment, the immunogen can be a non-steroidal anti-inflammatory drug (NSAID). The immunogen can be any NSAID described herein, eg, ibuprofen.

  All features described in this specification (including any of the appended claims, abstracts and drawings) and / or every step of any method or process disclosed are at least such features. And / or may be combined with any of the above aspects in any combination other than combinations in which some of the steps are mutually exclusive.

  Embodiments of the invention are further described, by way of example only, by the following examples and the accompanying drawings.

  We conducted various in vivo mouse experiments to investigate the effect of ibuprofen on influenza challenge mice. In the results described below, the inventors have shown that when ibuprofen is administered orally in an oily formulation (90% linseed oil; 10% ethanol), the concentration of endogenous IL-10 and IL-4 Convincingly demonstrated that it caused a surprising increase. We simultaneously observe a decrease in viral symptoms (ie, increased survival), which is believed to be due to an increase in IL-10 concentration.

Example 1-In vivo mouse survival test Procedure:
Five groups (n = 10) of female C57BLK / 6 mice (6-7 weeks old) were divided into 5 experimental groups, each containing 10 animals. On day 1, animals were inoculated with a lethal dose (50 μl total, 25 μl nostril) of influenza A / PR / 8/34 intranasally under halothane-induced anesthesia.

On day 3 after virus challenge, animals received the following treatments: That is,
Group A is ibuprofen at a dose of 335.6 μg / animal dissolved in 100 μl of 10% ethanol and 90% linseed oil (20 mg / kg / day; ie equivalent to 1200 mg per person per day as the maximum standard dose) Of oral gavage.

Group B was the first control in which mice received vehicle only (gavage with 10% ethanol and 90% linseed oil).

Group C was a second control in which mice were orally administered a dose of 335.6 μg / animal in 10 μl DMSO (without lipid).

  All animals were weighed and observed for signs of infection daily until day 6 of sacrifice. FIG. 1 shows the average animal survival rate and is displayed in FIG.

  FIG. 1 shows that the first control (ie, oral administration of lipid vehicle alone) had 80% mortality and the second control (ie, oral administration of ibuprofen only) showed 60% mortality. Make it explicit. However, the inventors were surprised to observe that a single dose of BC1054 (ie ibuprofen in oil) changed 80% mortality of the first negative control to 80% survival. This was totally unexpected.

Example 2 Measurement of IL-10 and IL-4 Concentrations Lungs collected at the end of the in vivo stage of the experiment described in Example 1 were homogenized at 4 ° C. and supernatants were collected at −70 ° C. Saved with. 60 μl per well of capture antibody diluted in coating buffer was added. The plate was sealed and incubated overnight at 4 ° C. The wells were then aspirated and washed with 300 μL / well wash buffer. After the last wash, the plate was placed on absorbent paper to absorb moisture and remove the remaining buffer. Plates were washed with 180 μL / well assay diluent and incubated for 1 hour at room temperature. The sample was vortexed for 30 seconds just before being added to the plate. Serial dilutions with both samples and standards were performed in the plates by dispensing 60 μL of assay diluent into each well. The plate was sealed and incubated for 2 hours at room temperature. Subsequently, IL-4 and IL-10 assays were performed. For IL-4, 60 μL of working detector (detection antibody + SAv-HRP reagent) was added to each well. The plate was sealed and incubated for 1 hour at room temperature. For IL-10, 60 μL of detection antibody was diluted in each well with assay diluent.

  The plate was washed and 60 μL of SAv-HRP enzyme was diluted with assay diluent and added to the plate. The plate was sealed and incubated for 20 minutes at room temperature. The plate was then washed 10 times. 60 μl of substrate solution was added to each well and the plate was incubated for 30 minutes in the dark at room temperature. 60 μl of stop solution was added to each well and the absorbance at 450 nm was measured. IL-10 and IL-4 concentrations were expressed as pg / mg lung tissue and then displayed in FIGS.

  As seen in FIG. 2, the two controls (ie, oral administration of ibuprofen only and oral administration of lipid vehicle only) resulted in only 2600 pg / mg and 2000 pg / mg IL-10, respectively. However, the inventors were surprised to see that the test compound, BC1054, resulted in an IL-10 concentration of 6000 pg / mg. Clearly, this IL-10 value is much higher than would be expected if the lipid vehicle and ibuprofen activities were merely additive (the value would have been only 4600 pg / mg). The fact that the IL-10 concentration in animals receiving BC1054 was 6000 pg / mg suggests that the effect is synergistic (ie, 24% higher than expected). We assume that this increase in endogenous IL-10 production contributed at least to a significant increase in survival as shown in FIG.

  FIG. 3 shows the concentration of each IL-4 in the animals that survived the assay of FIG. It can be seen that IL-4 is a Th2 cytokine and that mice administered BC1054 have much higher concentrations of IL-4 than either of the two control groups. Thus, the inventors have demonstrated that switching from a Th1 response to a Th2 response was caused. Induction of switching from a Th1 response to a Th2 response by up-regulating IL-10 production (and IL-4) can be used to help treat Th1-mediated hyperinflammation.

Example 3- Pessary We have made a delivery device that is made of a lipid-rich BC1054 composition with an immobilized support matrix that can be easily used to treat any Th1-mediated disorder. The delivery device is formed in the form of a pessary by a waxy support matrix. Commonly used materials for intravaginal administration include glycerol / gelatin, glycogelatin, macrogol (polyethylene glycol), natural, synthetic or semi-synthetic hard fat, and palm kernel fractionation oil, on each of which It has BC1054 immobilized. The support matrix melts at body temperature, thereby releasing the composition over time and being absorbed by the subject.

  The inventors recognize that preterm birth can be caused by a sudden drop in IL-10 concentration in a pregnant mother. Thus, the pessary can be worn on a pregnant woman so that the BC1054 formulation is released, causing an increase in endogenous IL-10 production, thereby preventing preterm birth.

Example 4 IL10, TNF-α and IFN-γ
We conducted further experiments to show which cytokines are stimulated upon administration of the BC1054 formulation.

  Lungs are removed from mice with lethal H1N1 infection and subsequently measured for IL-10, TNFα and IFNγ levels in mice treated with BC1054 (formulation of the invention) and ibuprofen (not in oil / ethanol vehicle) did. The data is shown in FIGS. That level is associated with the effect of each treatment on mortality (ie, an alternative to the anti-inflammatory activity of IL-10).

  As shown in FIG. 4, administration of ibuprofen alone or BC1054 formulation to mice caused an increase in IL-10 levels. However, we have observed that these increases in IL-10 are associated with very different pharmacodynamic effects. The pattern of inflammatory cytokine reduction highlights its association with the source of IL-10 and its effect on the virus survival model. Importantly, as shown in FIG. 6, the level of IFNγ (which is a lymphocyte-derived cytokine) was significantly lower in ibuprofen-treated mice compared to BC1054-treated mice, which was associated with poor outcome. .

  Furthermore, as shown in FIG. 5, TNFα (which is a macrophage-related cytokine) was not significantly suppressed. However, in BC1054-treated mice, TNFα levels were significantly reduced, but IFNγ levels were hardly affected. This indicates that BC1054 has its protective effect against lethality of H1N1 through IL-10 levels derived from macrophages rather than lymphocyte-derived IL10 ("Immunobiology, 5th edition-The Immune System in Health and Disease ", Charles A Janeway (Jr), Paul Travers, Mark Walport and Mark J Shlomchik. New York: Garland Science; 2001).

Example 5 Anti-Collagen Antibody-Induced Arthritis (ACAIA) Mouse Model We examined the effect of the BC1054 formulation in the ACAIA mouse model, which is a model showing similarity to systemic inflammation.

Materials and methods
On day 0, BALB / c mice were given a single inoculation with a single inoculation of anti-collagen II monoclonal antibody (2 mg in 200 μl) followed by ip injection of lipopolysaccharide (LPS, 50 μg in 200 μl) on day 3. An injection was made. Limb volume (plethysmography) and arthritis scores were recorded daily from day 3 to day 8, then on days 10 and 12. The same animals were administered daily from day 0 to day 11 by gavage of vehicle (1% methylcellulose or BC1054 vehicle), 10 mg / kg positive control embrel (intraperitoneal), 40 mg / kg ibuprofen (oral). ), Treated with either 20 mg / kg BC1054 or 30 mg / kg BC1054. Throughout the entire experiment (12 days), animals were examined daily for clinical signs (overall findings of animal health) and body weight. The total arthritis score is as follows: 0 = no signs of arthritis, 1 = mild but clear ankle / wrist redness and swelling, or the number of affected fingers Obvious redness or swelling limited to 2; moderate to severe ankle / wrist redness and swelling, 3 = redness and swelling of the entire limb, including fingers, 4 = maximally inflamed multiple The limbs containing the joints of the individual limbs are used to sum the arthritic scores of the individual limbs.

  The results of this experiment are shown in FIG. As can be seen, as expected, the positive control embrel showed the best results, with the smallest limb thickness of about 1.6 mm on day 12. The two test formulations (ie 20 mg / kg BC1054 or 30 mg / kg BC1054) showed the next best results, 30 mg / kg BC1054 yielding a limb thickness of only 1.7 mm, 20 mg / kg BC1054 produced a limb thickness of approximately 1.73 mm. Negative controls (ie PBS, 40 mg / kg ibuprofen only, vehicle only, vehicle methoxycellulose were significantly worse than BC1054 and had a limb thickness greater than 1.9 mm. Demonstrates that can be used to treat systemic inflammation, such as arthritis.

Summary In summary, we found that ibuprofen significantly increased endogenous IL-10 production when administered orally in a lipophilic vehicle (ie, flaxseed oil), and thus survival in influenza challenged mice. I was surprised to see that the rate improved dramatically. The promising results of in vivo mouse experiments clearly demonstrate that mice infected with H1N1 virus can be effectively treated by a single oral administration of ibuprofen present in oily formulations. Thus, any compound capable of increasing IL-10 production will provide much higher bioavailability in the lung when prepared in a carrier with high concentrations of lipid and administered orally. For example, the realization of high concentrations in the lung of NSAIDs such as ibuprofen would be advantageous in treating respiratory diseases caused by Th1-mediated disorders such as viral infections.

  However, in animals treated with BC1054 only, IL-10 signal is associated with improved survival. In the same lung, mice treated with ibuprofen have a more pronounced down-regulation of IFN-γ (ie, a T cell-derived cytokine), and IL-10 in ibuprofen mice may be derived from T cells It is shown that. However, mice treated with BC1054 have a more pronounced downregulation of pulmonary TNF-α (ie, macrophage-derived cytokines), and IL-10 in mice treated with BC1054 may be derived from macrophages Is high, indicating that this leads to the strong anti-inflammatory effect observed.

  Thus, in summary, this is the basis for ibuprofen present in the oral lipid adjuvant of the present invention being preferentially taken up by macrophages, resulting in new surprising anti-inflammatory pharmacological effects as shown by the IBD and RA model data It is.

As described in Example 4 and shown in FIG. 4 , the inventors have shown that when NSAIDs (such as ibuprofen) are prepared in oil and alcohol (eg ethanol) adjuvant, endogenous IL- from macrophages. 10 demonstrated to activate production. Accordingly, the compositions of the present invention are preferably adapted for use in promoting endogenous IL-10 production from dendritic cells and / or macrophages. One advantage of the composition of the present invention is that the composition of the present invention allows certain active compounds (ie drugs) to be formulated in lipids and taken orally so that the active compound (ie drug) is selective. To be introduced into macrophages and dendritic cells. Many disease symptoms are thought to be associated with low levels of IL-10 (ie, low IL-10 disorders) or in situations where the increase in IL-10 levels is too slow or insufficient, Any of these symptoms can be treated according to the present invention. Example 5 describes the effect of the composition of the present invention in a mouse model of anti-collagen antibody induced arthritis (ACAIA). Thus, a Th-1 mediated disease that can be treated can be a Th-1 mediated inflammatory disease, preferably a systemic inflammatory disease. The composition of the present invention may therefore be an anti-inflammatory pharmaceutical composition.

The formulation vehicle is at least about 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% 95% or at least about 99% (w / w) lipids. The vehicle is about 35% to 99% (w / w) lipid, or about 45% to 99% (w / w) lipid, or about 50% to 99% (w / w) lipid, or about 60 % To 98% (w / w) lipid, or about 70% to 97% (w / w) lipid, or about 80% to 96% (w / w) lipid, or about 85% to 95% ( lipid w / w), or it may contain a lipid of the lipid of from about 88% ~94% (w / w ) or about 89% ~93%, (w / w).

Suitable oils that can be used as the lipid component in the formulation vehicle can be natural or vegetable oils. Examples of suitable natural oils may be selected from the group consisting of linseed oil; soybean oil; palm fractionated oil; mineral oil; triacetin; ethyl oleate; hydrogenated natural oil; Examples of suitable vegetable oils are: rapeseed oil; olive oil; peanut oil; soybean oil; corn oil; safflower oil; arachis oil; sunflower oil; canola oil; walnut oil; oil; coconut oil; cottonseed oil; rice bran oil; can be selected from the group consisting of or mixtures thereof; sesame oil; and refined palm oil. Each of these oils is commercially available from a number of sources well known to those skilled in the art.

In one embodiment, the pharmaceutically acceptable vehicle is a solid and the composition can be in powder or tablet form. In addition to the lipid component and alcohol, the solid pharmaceutically acceptable vehicle, the 矯 taste agents, lubricants, solubilizers, suspending agents, dyes, fillers, glidants, compression aids, inert binding agents, sweeteners, preservatives, may also function as the Kutsugaezai or tablet disintegrating agents, may comprise one or more substances. The vehicle can also be an encapsulating material. In powders, the vehicle can be a finely divided solid which is a mixture with the finely divided active agent (ie, a compound which promotes endogenous IL-10 production). In tablets, the active substance can be mixed with a vehicle having the required compression properties in an appropriate ratio and compressed to the desired shape and size. Suitable solid vehicles can include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting point waxes and ion exchange resins.

The lipid and alcohol components of the adjuvant can be selected from any lipid (oil or fat) or alcohol described herein in any amount described. For example, the adjuvant is at least about 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %, 95% or at least about 99% (w / w) lipids. The adjuvant is about 35% to 99% (w / w) lipid, or about 45% to 99% (w / w) lipid, or about 50% to 99% (w / w) lipid, or about 60 % To 98% (w / w) lipid, or about 70% to 97% (w / w) lipid, or about 80% to 96% (w / w) lipid, or about 85% to 95% ( lipid w / w), or it may contain a lipid of the lipid of from about 88% ~94% (w / w ) or about 89% ~93%, (w / w).

Suitable oils that can be used as the lipid component in the adjuvant can be natural or vegetable oils. Examples of suitable natural oils may be selected from the group consisting of linseed oil; soybean oil; palm fractionated oil; mineral oil; triacetin; ethyl oleate; hydrogenated natural oil; Examples of suitable vegetable oils are: rapeseed oil; olive oil; peanut oil; soybean oil; corn oil; safflower oil; arachis oil; sunflower oil; canola oil; walnut oil; oil; coconut oil; cottonseed oil; rice bran oil; can be selected from the group consisting of or mixtures thereof; sesame oil; and refined palm oil. In one preferred embodiment, the lipid may comprise linseed oil.

The results of this experiment are shown in FIG. As can be seen, as expected, the positive control embrel showed the best results, with the smallest limb thickness of about 1.6 mm on day 12. The two test formulations (ie 20 mg / kg BC1054 or 30 mg / kg BC1054) showed the next best results, 30 mg / kg BC1054 yielding a limb thickness of only 1.7 mm, 20 mg / kg BC1054 produced a limb thickness of approximately 1.73 mm. Negative control (i.e., PBS, 40 mg / kg ibuprofen alone, vehicle alone, vehicle methyl cellulose scan is significantly worse than BC1054, had a thickness of more limbs 1.9 mm. Thus, these data, the formulation of the present invention Clearly demonstrate that it can be used to treat systemic inflammation such as arthritis.

Claims (60)

  An oral adjuvant for use in a pharmaceutical composition containing an immunogen, wherein the adjuvant contains lipids and alcohol and promotes uptake of the immunogen by dendritic cells and / or macrophages, which are immunomodulating An oral adjuvant characterized in that it regulates sex cytokines and the immunomodulatory activity of the immunogen in the presence of adjuvant is greater than its immunomodulatory activity in the absence of adjuvant.   The adjuvant is at least about 10%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% The adjuvant of claim 1, comprising 95%, or at least about 99% (w / w) lipid.   About 35% to 99% (w / w) lipid, or about 45% to 99% (w / w) lipid, or about 50% to 99% (w / w) lipid, or about 60% to 98% (w / w) lipid, or about 70% to 97% (w / w) lipid, or about 80% to 96% (w / w) lipid, or about 85% to 95% (W / w) lipid, or about 85% to 95% (w / w) lipid, or about 88% to 94% (w / w) lipid, or about 89% to 93% (w / w) The adjuvant of any one of Claim 1 or 2 containing the lipid of these.   The adjuvant according to any one of claims 1 to 3, wherein the adjuvant contains natural oil or vegetable oil.   The natural oil is selected from the group consisting of linseed oil; soybean oil; palm fractionation oil; mineral oil; triacetin; ethyl oleate; hydrogenated natural oil; or a mixture thereof, and examples of suitable vegetable oils are rapeseed oil; olive oil; Peanut oil; soybean oil; corn oil; safflower oil; arachis oil; sunflower oil; canola oil; walnut oil; almond oil; avocado oil; castor oil; coconut oil; The adjuvant of claim 4, which can be selected from the group consisting of: oil; sesame oil; and refined palm oil; or mixtures thereof.   The adjuvant according to any one of claims 1 to 5, wherein the lipid contains linseed oil.   The adjuvant is about 90%, 80%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, The adjuvant according to any one of claims 1 to 6, comprising less than 5% or less than about 1% (w / w) alcohol.   About 1% to 90% alcohol (w / w), or about 1% to 70% (w / w) alcohol, or about 1% to 60% (w / w) alcohol, or about 1% to 50% (w / w) alcohol, or about 2% to 40% (w / w) alcohol, or about 4% to 30% (w / w) alcohol, or about 6% to 20% 8. Adjuvant according to any one of the preceding claims, containing (w / w) alcohol, or about 8% to 15% (w / w) alcohol. Wherein the alcohol is an aliphatic alcohol, for example, a C _1-20 alcohol, C _1-15 alcohols, C _1-10 alcohols, C _1-5 alcohols or C _2-4 alcohol, any of the preceding claims The adjuvant according to claim 1.   Adjuvant according to any one of claims 1 to 9, wherein the alcohol is ethanol, propanol or butanol, preferably ethanol.   The adjuvant according to any one of claims 1 to 9, wherein the alcohol is menthol or a sugar alcohol such as glycerol, sorbitol, erythritol, xylitol, mannitol, isomalt, or maltitol.   The adjuvant according to any one of claims 1 to 11, wherein the adjuvant is anhydrous.   The adjuvant according to any one of claims 1 to 12, wherein the adjuvant does not contain a hydrophilic surfactant.   14. Adjuvant according to any one of claims 1 to 13, wherein the immunomodulatory cytokine to be modulated is selected from the group of cytokines comprising IL-10; IL4; TNF-α; and IFN-γ.   The adjuvant stimulates dendritic cells and / or macrophages of the subject to produce or increase production of immunological cytokines such as IL-10 and / or TNF-α and / or IL-4 The adjuvant according to any one of claims 1 to 14, wherein the adjuvant is used.   16. The adjuvant of any one of the preceding claims, wherein the adjuvant stimulates dendritic cells and / or macrophages in the subject to stop or reduce the production of immunological cytokines such as IFN-γ. The adjuvant according to 1. The adjuvant according to any one of the preceding claims, wherein the immunogen present in the composition is a pharmaceutically active substance having a log P value greater than 2.0 and / or a polar surface area of about 25 ^{2 to} 70 ^2. .   The adjuvant according to any one of claims 1 to 17, wherein the immunogen is a small molecule having a molecular weight of less than 1000 Da.   The adjuvant according to any one of claims 1 to 18, wherein the immunogen has a log P value greater than 3.0, 4.0, 5.0 or 6.0. The immunogen, 35Å ² ~65Å ² or 40Å having ^{2 ~60Å 2} or polar surface area of 45Å ² ~55Å ^2,, adjuvant according to any one of claims 1 to 19,.   21. The adjuvant of any one of claims 1 to 20, wherein the immunogen comprises a peroxisome proliferator activated receptor gamma (PPAR-γ) agonist.   The adjuvant according to claim 21, wherein the PPAR-γ agonist is a compound selected from Table 1.   The adjuvant according to claim 21 or 22, wherein the PPAR-γ agonist is a fibrate selected from the group of fibrates consisting of bezafibrate; ciprofibrate; clofibrate; genfibrozil; and fenofibrate.   The PPAR-γ agonist comprises monasin; irbesartan; telmisartan; mycophenolic acid; resveratrol; delta (9) -tetrahydrocannabinol; cannabidiol; curcumin; cilostazol; benzbromarone; 23. Adjuvant according to claim 21 or 22, selected from the group of agonists comprising.   The adjuvant according to any one of claims 1 to 22, wherein the immunogen is a non-steroidal anti-inflammatory drug (NSAID), for example ibuprofen.   26. A pharmaceutical composition comprising an immunogen and an adjuvant according to any one of claims 1-25.   27. A pharmaceutical composition according to claim 26 for use in therapy.   27. A pharmaceutical composition according to claim 26 for use in the treatment of Th1-mediated disease, cancer, or bacterial or viral infection.   27. A method of inducing an effective immune response in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 26.   A pharmaceutically acceptable agent containing a therapeutically effective amount of a compound capable of increasing interleukin-10 (IL-10) production and lipids and alcohols for use in the treatment of Th-1 mediated diseases A pharmaceutical composition comprising a vehicle, wherein IL-10 is endogenously produced by Th2 cells, dendritic cells and / or macrophages.   32. The composition of claim 30, wherein the compound capable of increasing endogenous IL-10 production is recognized by dendritic cells and / or macrophages.   32. The composition according to claim 30 or 31, wherein the Th-1 mediated disease is a Th-1 mediated inflammatory disease, preferably a systemic inflammatory disease.   Rheumatoid arthritis (RA); psoriatic arthritis; psoriasis; inflammatory bowel syndrome (IBD); Crohn's disease; ulcerative colitis; multiple sclerosis (MS); Diseases such as those caused by viruses such as respiratory syncytial virus (RSV); cystic fibrosis (CF); herpes including genital herpes; asthma and allergy; sepsis and septic shock; bacterial pneumonia; Selected from the group of Th-1 mediated diseases consisting of meningitis; dengue hemorrhagic fever; type I diabetes; endometriosis; prostatitis; uveitis; uterine ripening; 33. The composition according to any one of claims 30 to 32.   34. A composition according to any one of claims 30 to 33, wherein the Th-1 mediated disease is virus-induced, bacterial-induced, or chemical-induced (eg environment-induced).   35. The Th1-mediated disease is a systemic inflammatory disease, such as inflammatory bowel syndrome (IBD), rheumatoid arthritis (RA) or cystic fibrosis (CF). A composition according to 1.   36. The composition of any one of claims 30 to 35, wherein the compound is used to increase paracrine endogenous IL-10 production.   37. The composition of any one of claims 30 to 36, wherein the compound modulates Th1 cytokine concentrations such as IFNγ, TNF-α and IL-12.   The compound capable of inducing endogenous production of interleukin-10 (IL-10) by Th2 cells, dendritic cells and / or macrophages is a non-steroidal anti-inflammatory drug (NSAID). 38. The composition according to any one of 37.   39. The composition of claim 38, wherein the NSAID is a propionic acid derivative, an acetic acid derivative, an enolic acid derivative, a fenamic acid derivative, or a selective or non-selective cyclooxygenase (COX) inhibitor.   The compound is aluminoprofen; benoxaprofen; dexketoprofen; flurbiprofen; ibuprofen; indoprofen; ketoprofen; loxoprofen; pranoprofen; protisic acid; suprofen; aceclofenac; Crometacin; diclofenac; etodolac; felbinac; fenclofenac; indomethacin; ketorolac; methaziazine acid; mofezolac; naproxen; oxametacin; Aspirin; azapropazone; benolylate; benzi Methyl; Butibufen; Chlortenoxazine; Choline salicylate; Diflunisal; Emorphazone; Epirisol; Feclobzone; Fenbufen; Grafenine; Hydroxyethyl salicylate; Lactylphenetidine; Mefenamic acid; 40. The composition of any one of claims 30-39, selected from the group consisting of: procazone; salicylamide; salsalate; thiaramide; tinolidine; and tolfenamic acid.   41. Any of claims 30-40, wherein the compound is aluminoprofen, benoxaprofen, dexketoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, pranoprofen, protisic acid, or suprofen. The composition according to claim 1.   42. The composition according to any one of claims 30 to 41, wherein the compound is ibuprofen.   43. A composition according to any one of claims 38 to 42, wherein the composition comprises the R- or S-enantiomer of NSAID.   44. The composition of claim 43, wherein the composition comprises R-ibuprofen.   44. The composition of claim 43, wherein the composition comprises S-ibuprofen.   46. A composition according to any one of claims 30 to 45, wherein the lipid component of the vehicle is as defined in any one of claims 2-6.   47. The lipid component of the formulation vehicle contains a fatty acid comprising 8-24 carbon atoms, 10-22 carbon atoms, 14-20 carbon atoms, or 16-20 carbon atoms. Composition.   The lipid is myristic acid (C 14: 0); palmitic acid (C 16: 0); palmitoleic acid (C 16: 1); stearic acid (C 18: 0); oleic acid (C 18: 1); 48. Any of claims 30-47, comprising a fatty acid selected from the group consisting of acids (C 18: 2); linolenic acid (C 18: 3) and arachidic acid (C 20: 0); or mixtures thereof. 2. The composition according to item 1.   49. A composition according to any one of claims 30 to 48, wherein the alcohol component of the vehicle is as defined in any one of claims 7-11.   50. Any of claims 30-49, wherein the vehicle comprises about 80% to 95% (w / w) linseed oil, and about 5% to 20% (w / w) ethanol, and optionally water. The composition according to claim 1.   51. The composition of any one of claims 26-28 and 30-50, wherein the composition is orally administrable.   52. A composition according to any one of claims 26 to 28 and 30 to 51, wherein the vehicle does not contain a hydrophilic surfactant. (I) a therapeutically effective amount of a compound capable of increasing endogenous interleukin-10 (IL-10) production by Th2 cells, dendritic cells and / or macrophages, and a pharmaceutical comprising a lipid and an alcohol An acceptable vehicle; and (ii) a drug delivery device comprising a support matrix.   54. A drug delivery device according to claim 53, wherein the device comprises a pharmaceutical composition according to any one of claims 30-52.   55. A drug delivery device according to claim 53 or 54, wherein the device is a pessary, a vaginal ring or the like.   56. The drug delivery device according to any one of claims 53 to 55, wherein the device is worn by a subject in need of treatment for a Th1-mediated condition.   57. The drug delivery device according to any one of claims 53 to 56, wherein the delivery device is used by a pregnant woman to prevent or delay preterm birth.   58. Any of claims 53-57, wherein the support matrix contains a substance that can be melted at or near body temperature so that the matrix dissolves over time to release the composition, which is absorbed by the subject. 2. A drug delivery device according to item 1.   59. The support matrix of claims 54 to 58, wherein the support matrix is a gel or wax, such as glycerol / gelatin, glycogelatin, macrogol (eg, polyethylene glycol), natural, synthetic or semi-synthetic hard fat, or palm kernel fractionation oil The drug delivery device according to any one of claims.   A method for preventing, treating and / or ameliorating a Th-1-mediated disease, wherein said method increases interleukin-10 (IL-10) production in a subject in need of such treatment Administering a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable vehicle containing lipids and alcohol, wherein IL-10 is expressed by Th2 cells, dendritic cells and / or macrophages A method characterized by being produced endogenously.

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