WO2012056251A1 - Maladie inflammatoire - Google Patents

Maladie inflammatoire Download PDF

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Publication number
WO2012056251A1
WO2012056251A1 PCT/GB2011/052115 GB2011052115W WO2012056251A1 WO 2012056251 A1 WO2012056251 A1 WO 2012056251A1 GB 2011052115 W GB2011052115 W GB 2011052115W WO 2012056251 A1 WO2012056251 A1 WO 2012056251A1
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WO
WIPO (PCT)
Prior art keywords
oil
lipid
adjuvant
alcohol
vehicle
Prior art date
Application number
PCT/GB2011/052115
Other languages
English (en)
Inventor
Robin Mark Bannister
John Brew
Gregory Alan Stoloff
Wilson Capaross-Wanderley
Olga Pleguezuelos Mateo
Original Assignee
Biocopea Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biocopea Limited filed Critical Biocopea Limited
Priority to CA2816564A priority Critical patent/CA2816564A1/fr
Priority to AU2011322255A priority patent/AU2011322255A1/en
Priority to MX2013004817A priority patent/MX2013004817A/es
Priority to CN2011800637601A priority patent/CN103282021A/zh
Priority to SG2013033014A priority patent/SG189551A1/en
Priority to RU2013124514/15A priority patent/RU2013124514A/ru
Priority to BR112013010441A priority patent/BR112013010441A2/pt
Priority to EP11784752.5A priority patent/EP2632431A1/fr
Priority to JP2013535515A priority patent/JP2013544802A/ja
Priority to EP18213159.9A priority patent/EP3494961B1/fr
Priority to EP12704296.8A priority patent/EP2670390A2/fr
Priority to CA2826452A priority patent/CA2826452C/fr
Priority to JP2013552271A priority patent/JP2014507429A/ja
Priority to RU2016138830A priority patent/RU2016138830A/ru
Priority to PCT/GB2012/050242 priority patent/WO2012104655A2/fr
Priority to BR112013019732-3A priority patent/BR112013019732B1/pt
Priority to MX2013008851A priority patent/MX346224B/es
Priority to SG10201600854SA priority patent/SG10201600854SA/en
Priority to NZ711187A priority patent/NZ711187B2/en
Priority to CA2826506A priority patent/CA2826506C/fr
Priority to RU2013140775/15A priority patent/RU2013140775A/ru
Priority to NZ613805A priority patent/NZ613805B2/en
Priority to PCT/GB2012/050241 priority patent/WO2012104654A1/fr
Priority to CN201280007770.8A priority patent/CN103391768B/zh
Priority to NZ613812A priority patent/NZ613812B2/en
Priority to US13/365,824 priority patent/US8895536B2/en
Priority to RU2013140776A priority patent/RU2635188C2/ru
Priority to JP2013552272A priority patent/JP2014504629A/ja
Priority to BR112013019734A priority patent/BR112013019734A2/pt
Priority to SG2013059357A priority patent/SG192620A1/en
Priority to AU2012213217A priority patent/AU2012213217B2/en
Priority to CN201280007753.4A priority patent/CN103391767B/zh
Priority to EP12704295.0A priority patent/EP2670389A1/fr
Priority to MX2013008850A priority patent/MX364229B/es
Priority to US13/365,828 priority patent/US8895537B2/en
Priority to AU2012213218A priority patent/AU2012213218C1/en
Priority to SG2013059365A priority patent/SG192621A1/en
Publication of WO2012056251A1 publication Critical patent/WO2012056251A1/fr
Priority to ZA2013/05783A priority patent/ZA201305783B/en
Priority to ZA2013/05784A priority patent/ZA201305784B/en
Priority to US14/155,108 priority patent/US9308213B2/en
Priority to US14/155,042 priority patent/US9271950B2/en
Priority to US14/155,080 priority patent/US9265742B2/en
Priority to US14/155,167 priority patent/US10695432B2/en
Priority to US14/155,147 priority patent/US10695431B2/en
Priority to US14/520,159 priority patent/US9427422B2/en
Priority to US14/520,141 priority patent/US9326958B2/en
Priority to US14/520,150 priority patent/US9381180B2/en
Priority to US14/821,687 priority patent/US9744132B2/en
Priority to US14/975,608 priority patent/US9737500B2/en
Priority to US14/975,599 priority patent/US9504664B2/en
Priority to JP2016015164A priority patent/JP6273304B2/ja
Priority to US15/043,327 priority patent/US9750810B2/en
Priority to US15/061,661 priority patent/US9775820B2/en
Priority to US15/169,619 priority patent/US10004704B2/en
Priority to US15/169,617 priority patent/US9693980B2/en
Priority to US15/195,623 priority patent/US9827215B2/en
Priority to US15/195,608 priority patent/US9820952B2/en
Priority to US15/219,245 priority patent/US9789075B2/en
Priority to US15/289,083 priority patent/US20170043016A1/en
Priority to US15/295,933 priority patent/US9795577B2/en
Priority to US15/614,592 priority patent/US10155042B2/en
Priority to US15/684,214 priority patent/US10213381B2/en
Priority to US15/684,197 priority patent/US10363232B2/en
Priority to US15/702,440 priority patent/US10231943B2/en
Priority to US15/794,197 priority patent/US10154975B2/en
Priority to US15/794,178 priority patent/US10188619B2/en
Priority to US15/794,214 priority patent/US10143671B2/en
Priority to US16/012,036 priority patent/US10426748B2/en
Priority to US16/166,272 priority patent/US10596132B2/en
Priority to US16/206,789 priority patent/US10653778B2/en
Priority to US16/206,814 priority patent/US10588878B2/en
Priority to US16/284,221 priority patent/US10835490B2/en
Priority to US16/525,520 priority patent/US10857114B2/en
Priority to US16/573,776 priority patent/US10849869B2/en
Priority to US16/729,363 priority patent/US20200129461A1/en
Priority to US16/818,668 priority patent/US11000493B2/en
Priority to US16/882,663 priority patent/US11154500B2/en
Priority to US16/882,666 priority patent/US11202831B2/en
Priority to US16/882,667 priority patent/US11224659B2/en
Priority to US17/107,724 priority patent/US11660276B2/en
Priority to US17/113,476 priority patent/US11730709B2/en
Priority to US17/146,950 priority patent/US11065218B2/en
Priority to US17/146,989 priority patent/US11103472B2/en
Priority to US17/230,855 priority patent/US11844773B2/en
Priority to US17/378,744 priority patent/US20210338617A1/en
Priority to US17/448,263 priority patent/US20220040102A1/en
Priority to US17/540,802 priority patent/US11826428B2/en
Priority to US17/646,241 priority patent/US11918654B2/en
Priority to US18/509,114 priority patent/US20240100002A1/en

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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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Definitions

  • the present invention relates to the treatment of inflammatory diseases, and especially Th-1 mediated inflammatory diseases.
  • the invention relates to the treatment of Th-1 mediated inflammatory diseases using a range of compositions, and to the use of these compositions in methods of treatment.
  • the invention extends to adjuvants, and in particular to adjuvants for use in treating a wide variety of medical conditions.
  • the invention also provides pharmaceutical compositions and medicaments comprising the adjuvant, and to uses of the adjuvant in methods of treatment and for eliciting an immune response.
  • the defence against disease is critical for the survival of all animals, and the mechanism employed for this purpose is the animal immune system.
  • the immune system is complex, and involves two main divisions, (i) innate immunity, and (ii) adaptive immunity.
  • the innate immune system includes the cells and mechanisms that defend the host from infection by invading organisms, in a non-specific manner.
  • Leukocytes which are involved with the innate system, include inter alia phagocytic cells, such as macrophages, neutrophils and dendritic cells.
  • the innate system is fully functional before a pathogen enters the host.
  • lymphocytes the two main categories of which are B cells and T Cells.
  • B cells are involved in the creation of neutralising antibodies that circulate in blood plasma and lymph and form part of the humoral immune response.
  • T cells play a role in both the humoral immune response and in cell-mediated immunity.
  • activator or effector T cells There are several subsets of activator or effector T cells, including cytotoxic T cells (CD8+) and "helper" T cells (CD4+), of which there are two main types known as Type 1 helper T cells (Thl) and Type 2 helper T cell (Th2).
  • Thl cells promote a cell-mediated adaptive immune response, which involves the activation of macrophages and stimulates the release of various cytokines, such as ⁇ , TNF- ⁇ and IL-12, in response to an antigen. These cytokines influence the function of other cells in the adaptive and innate immune responses, and result in the destruction of micro-organisms.
  • Thl responses are more effective against intracellular pathogens, such as viruses and bacteria present inside host cells.
  • a Th2 response is characterised by the release of IL-4, which results in the activation of B cells to make neutralising antibodies, which lead the humoral immunity.
  • Th2 responses are more effective against extracellular pathogens, such as parasites and toxins located outside host cells. Accordingly, the humoral and cell-mediated responses provide quite different mechanisms against an invading pathogen.
  • Interleukin-10 also known as human cytokine synthesis inhibitory factor (CSIF)
  • CCF human cytokine synthesis inhibitory factor
  • IL-10 down- regulates the expression of Thl cytokines (such as IFNy, TNF-a and IL-12), MHC class II antigens, and co- stimulatory molecules on Thl cytokines (such as IFNy, TNF-a and IL-12), MHC class II antigens, and co- stimulatory molecules on Thl cytokines (such as IFNy, TNF-a and IL-12), MHC class II antigens, and co- stimulatory molecules on Thl cytokines (such as IFNy, TNF-a and IL-12), MHC class II antigens, and co- stimulatory molecules on Thl cytokines (such as IFNy, TNF-a and IL-12), MHC class II antigens, and co- stimulatory molecules on Thl cytokines (such as IFNy, TNF-a and IL-12
  • IL-10 can block NF- ⁇ activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice have suggested the function of IL-10 as an essential immunoregulator in the intestinal tract, and patients with Crohn's disease react favorably towards treatment with bacteria producing recombinant IL-10, showing the importance of this cytokine for counteracting excessive immunity in the human body.
  • IL-10 is a validated target in inflammatory disease, and has been shown to be essential for immunotolerance and the control of Thl immunity (O'Garra et al., 2008, Immunol. Rev., 223:114-31).
  • Systemic administration of exogenous IL-10 in early clinical trials showed some initial promise in the treatment of various diseases, including rheumatoid arthritis, Crohn's disease, psoriasis and cystic fibrosis.
  • problems associated with these early trials were that systemically administered exogenous IL-10 did not dampen exaggerated Thl responses as predicted, possibly because tissue levels of IL-10 were too low (the half-life of IL-10 is short), or because IL-10 was not presented in the correct manner.
  • concentrations of IFNy, TNF-a and IL-12 actually increased to deleterious levels. It will be appreciated that these cytokines are pro-inflammatory. Furthermore, a significant side effect of administering too much exogenous IL-10 is that it actually suppresses the immune system, rather than positively modulating it, and so results in serious immune-related problems. It will be appreciated that IL-10, IL-4 and TGF- ⁇ are anti-inflammatory.
  • ibuprofen administered orally in an oily formulation i.e. the adjuvant
  • the inventors also determined with in vivo assays that the concentration of IL-10 in the lungs of the surviving animals dramatically increased in mice administered with the oily ibuprofen composition.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing interleukin-10 (IL-10) production, and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol, for use in treating a Thl -mediated disease, wherein the IL-10 is endogenously produced by Th2 cells, dendritic cells and/ or macrophages.
  • IL-10 interleukin-10
  • a method of preventing, treating and/or ameliorating a Thl -mediated disease comprising administering, to a subject in need of such treatment, a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing interleukin-10 (IL-10) production, and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol, wherein the IL-10 is endogenously produced by Th2 cells, dendritic cells and/ or macrophages.
  • IL-10 interleukin-10
  • a pharmaceutical composition for treating a Thl -mediated disease comprising a therapeutically effective amount of a compound which is capable of inducing endogenous production of interleukin-10 (IL-10) by Th2 cells, dendritic cells and/or macrophages and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol.
  • IL-10 interleukin-10
  • ibuprofen when administered orally in a lipophilic formulation (e.g. at least 30% w/w lipid), or the adjuvant of the invention, it is shown to be very effective in the treatment of influenza-induced respiratory collapse in mice. Indeed, application of a single dose of the pharmaceutical composition of the invention converted the 80% mortality model to an astonishing 80% survival outcome, and this was totally unexpected. Although the inventors do not wish to be bound by any theory, they believe that an explanation for this surprising observation may be due to the lipophilicity of NSAIDs, such as ibuprofen (i.e. log P 3.5), which, when delivered in an oily formulation having a high lipid content (e.g.
  • lipids are mixed with bile in the stomach, containing bile salts, and form complexes called micelles or chylomicrons, which are large lipoprotein particles that consist of triglycerides, phospholipids, cholesterol and proteins, and the NSAID.
  • the resultant oil/drug/bile salt complex i.e. micelles or chylomicron
  • the resultant oil/drug/bile salt complex may then be absorbed by the proximal gut into the enteric lymphatic system.
  • lymphatic absorption of the active compound e.g.
  • ibuprofen may be acting as a passive system of distribution of the drug directly to the lung, exposing the lung to high concentrations of the compound.
  • This delivery mechanism does not occur when using standard oral formulations, which contain no, or only low levels of lipid, which are instead absorbed via the hepatic portal vein, with liver-regulated venous absorption, which releases the drug into systemic circulation relatively slowly.
  • the high concentration of lipids in the pharmaceutical vehicle used in the composition of the first aspect may be the reason for the efficacy of the orally- administered ibuprofen in the influenza-induced respiratory collapse assay in mice, as described in the Examples.
  • NSAIDs such as ibuprofen
  • an oil and alcohol e.g. ethanol
  • compositions of the invention are adapted, in use, to stimulate endogenous production of IL-10 from dendritic cells and/or macrophages.
  • One advantage of the compositions of the invention is that they allow certain active compounds (i.e. drugs) to be formulated in lipid and taken orally such that they are preferentially loaded into macrophages and dendritic cells.
  • active compounds i.e. drugs
  • Numerous disease conditions are believed to be associated with low levels of IL-10 (i.e. hypo-IL- 10 disorders), or in situations where an increase in IL-10 concentration is either too slow or insufficient, and any of these conditions may be treated in accordance with the invention.
  • Example 5 describes the effects of the compositions of the invention in an anti-collagen antibody induced arthritis (ACAIA) murine model.
  • the Thl- mediated disease which may be treated, may be a Thl -mediated inflammatory disease, and preferably systemic inflammatory disease.
  • the composition of the invention therefore may be an anti-inflammatory pharmaceutical composition.
  • the disease to be treated may be selected from a group of Thl -mediated diseases consisting of rheumatoid arthritis (RA); psoriatic arthritis; psoriasis; inflammatory bowel syndrome (IBD); Crohn's disease; ulcerative colitis; multiple sclerosis (MS); flu, including pandemic flu; respiratory disorders, for example 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; coeliac disease;
  • RA rheumatoid arthritis
  • IBD inflammatory bowel syndrome
  • MS ulcerative colitis
  • flu including pandemic flu
  • idiopathic thrombocytopenic purpura idiopathic thrombocytopenic purpura
  • Lupus erythematosus mixed connective tissue disease
  • myasthenia gravis narcolepsy
  • osteoarthritis pemphigus vulgaris
  • pernicious anaemia polymyositis
  • primary biliary cirrhosis relapsing polychondritis
  • Sjogren's syndrome temporal arteritis
  • vasculitis Wegener's granulumatosis
  • age-related macular degeneration idiopathic thrombocytopenic purpura
  • Lupus erythematosus mixed connective tissue disease
  • myasthenia gravis narcolepsy
  • osteoarthritis pemphigus vulgaris
  • pernicious anaemia polymyositis
  • primary biliary cirrhosis relapsing polychondritis
  • Sjogren's syndrome temporal art
  • the Thl -mediated disease may be vitally, bactetially or chemically (e.g.
  • a vims causing the Thl -mediated disease may cause a cht onic of acute infection, which may cause a t espitatoty disorder.
  • the virus causing the Thl -mediated disease may be Influenza.
  • the Thl -mediated disease which may be treated, is systemic inflammatory disease, for example inflammatory bowel syndrome (IBD), rheumatoid arthritis (RA) or cystic fibrosis (CF).
  • IBD inflammatory bowel syndrome
  • RA rheumatoid arthritis
  • CF cystic fibrosis
  • IL-10 production is a characteristic that indicates a switch from a Thl to a Th2 response, and that such compounds could be used to treat Thl -mediated diseases. They have demonstrated that inducing the switch from a Thl to a Th2 response by up-regula ing IL-10 production can be used to help treat Thl -mediated hyper-inflammation. Indeed, Figure 3 clearly shows that administration of the composition of the invention not only increases IL-10
  • Th2 production it also results in increased IL-4 production, proving that the switch from a Thl to a Th2 response has been induced.
  • B cells are activated, which produce neutralising antibodies, which lead the humoral immunity.
  • Th2 responses are much more effective against extracellular pathogens, such as parasites and toxins located outside host cells, than Thl responses.
  • Thl -mediated hyper-inflammation occurs during viral infections (e.g. influenza, as demonstrated in the Examples), and so the inventors believe that endogenously producing IL-10 by the Th2 cells, macrophages and/or dendritic cells upon administration of the composition to the subject could be used to treat a respiratory collapse caused by a viral infection.
  • viral infections e.g. influenza, as demonstrated in the Examples
  • HSV Herpes Simplex Virus
  • IL-10 is a paracrine cytokine, and that, therefore, the compound used in the first, second and third aspects of the invention can be effectively used to increase endogenous IL-10 production in a paracrine manner.
  • paracrine signalling can be a form of cell signalling in which the target cell is near or local to the signal-releasing cell.
  • IL-10 can control the immune response at sites of inflammation in tandem with cell-cell interactions.
  • the compound, which is capable of increasing endogenous IL-10 production may be recognised by Th2 cells, dendritic cells and/ or macrophages.
  • the compound, which is capable of increasing endogenous IL-10 production is recognised by dendritic cells and/ or macrophages.
  • Th2 cells, dendritic cells and/ or macrophages may phagocytise the compound (such as a lipid/ drug chylomicron), react with pathways in each of these cell types, and thereby endogenously produce IL-10.
  • the IL-10 is produced by Th2 cells, dendritic cells and/ or macrophages, which are immuno-competent.
  • IL-10 in contrast to producing IL-10 by nonimmune cells, which causes an imbalance in the immune system leading to infections and, in some cases cancer, endogenous production of IL-10 by immuno-competent Th2 cells, dendritic cells and/or macrophages, ensures that the immune system remains balanced, thereby avoiding infection.
  • the immune system is capable of regulating itself naturally, thereby reducing the risk of infections and cancer.
  • the levels of IL-10 generated due to the regulatory process and feedback loops may modulate (e.g. decrease) Thl cytokine concentration, such as IFNy, TNF-a and IL-12, but not suppress their production completely. This may be important because these Thl cytokines are needed to protect the body from infection.
  • Thl cytokine concentration such as IFNy, TNF-a and IL-12
  • the compound which is capable of inducing endogenous production of interleukin-10 (IL-10) by Th2 cells, dendritic cells and/or macrophages may be a non-steroidal antiinflammatory drug (NSAID).
  • the NSAID may be a propionic acid derivative, an acetic acid derivative, an enolic acid derivative, a fenamic acid derivative, or a selective- or non-selective cyclo-oxygenase (COX) inhibitor.
  • COX selective- or non-selective cyclo-oxygenase
  • the NSAID may be a profen.
  • Suitable propionic acid NSAID derivatives may include Ibuprofen;
  • acetic acid NSAID derivatives may include Aceclofenac; Acemetacin; Actarit;
  • suitable enolic acid NSAID derivatives may include Piroxicam; Meloxicam; Tenoxicam; Droxicam; Lornoxicam; or Isoxicam.
  • Fenamic acid NSAID derivatives may include Mefenamic acid; Meclofenamic acid; Flufenamic acid; or Tolfenamic acid.
  • the NSAID is a cyclooxygenase (COX) inhibitor
  • it may be either a cyclooxygenase 1 (COX 1) inhibitor or a cyclooxygenase 2 (COX 2) inhibitor.
  • COX inhibitors may include Ibuprofen; Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; or Valdecoxib.
  • the NSAID may be selected from a group consisting of: Alminoprofen; Benoxaprofen;
  • Pranoprofen Protizinic acid; Suprofen; Aceclofenac; Acemetacin; Actarit; Alcofenac;
  • Ketorolac Metiazinic acid; Mofezolac; Naproxen; Oxametacin; Sulindac; Zomepirac;
  • Celecoxib Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; Valdecoxib; Aloxipirin;
  • Aminophenazone Antraphenine; Aspirin; Azapropazone; Benorilate; Benzydamine;
  • Butibufen Chlorthenoxacin; Choline Salicylate; Diflunisal; Emorfazone; Epirizole;
  • Mefenamic acid Metamizole; Mofebutazone; Nabumetone; Nifenazone; Niflumic acid;
  • Phenacetin Pipebuzone; Propyphenazone; Proquazone; Salicylamide; Salsalate;
  • Tiaramide Tinoridine
  • Tolfenamic acid
  • a preferred NSAID may be Alminoprofen, Benoxaprofen, Dexketoprofen,
  • the NSAID is Ibuprofen.
  • the NSAID may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride.
  • NSAIDs described herein may be provided as racemates, or as individual enantiomers, including the R- or S-enantiomer.
  • the NSAID may comprise R-ibuprofen or S- ibuprofen, or a combination thereof.
  • S-ibuprofen may be used for the treatment of immune-mediated diseases which involve pain that is responsive to COX inhibitors, such as those described herein (e.g. Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; or Valdecoxib).
  • COX inhibitors such as those described herein (e.g. Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; or Valdecoxib).
  • COX inhibitors such as those described herein (e.g. Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; or Valdecoxib).
  • COX inhibitors such as those described herein (e.g. Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; or Valdecoxib).
  • diseases may include arthritis, rheumatoid arthritis, osteoarthritis,
  • R-ibuprofen may be used for the treatment of immune- mediated diseases which do not involve pain that is responsive to COX inhibitors.
  • immune- mediated diseases ma include psoriasis, inflammatory bowel disease, multiple sclerosis, pandemic flu, respiratory syncytial virus, cystic fibrosis, genital herpes, asthma, bacterial pneumonia, bacterial meningitis, dengue hemorrhagic fever, type I diabetes, prostatitis and pre-term labour.
  • the pharmaceutical vehicle may comprise 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) lipid.
  • the vehicle may comprise between about 35% and 99% (w/w) lipid, or between about 45% and 99% (w/w) lipid, or between about 50% and 99% (w/w) lipid, or between about 60% and 98% (w/w) lipid, or between about 70% and 97% (w/w) lipid, or between about 80% and 96% (w/w) lipid, or between about 85% and 95% (w/w) lipid, or between about 85% and 95% (w/w) lipid, or between about 88% and 94% (w/w) lipid, or between about 89% and 93% (w/w) lipid.
  • the pharmaceutical vehicle may comprise a lipid component selected from a group consisting of: an oil or oil-based liquid; a fat; a fatty acid (e.g. oleic acid, stearic acid or palmitic acid etc.), a fatty acid ester, a fatty alcohol, a glyceride (mono-, di- or triglyceride); a phospholipid; a glycol ester; a sucrose ester; a wax; a glycerol oleate derivative; a medium chain triglyceride; or a mixture thereof.
  • a triglyceride is an ester derived from glycerol and three fatty acids, and is the main constituent of vegetable oil and animal fats.
  • oil can refer to a fat that is liquid at normal room temperature, and can be used for any substance that does not mix with water, and which has a greasy feel.
  • fat can refer to a fat that is solid at normal room temperature.
  • lipid can therefore refer to a liquid or solid fat, as well as to other related substances.
  • a suitable oil which may be used as the lipid component in the pharmaceutical vehicle, may be a natural oil or a vegetable oil.
  • suitable natural oils may be selected from a group consisting of linseed oil; soyabean oil; fractionated coconut oil; mineral oil; triacetin; ethyl oleate; a hydrogenated natural oil; or a mixture thereof.
  • suitable vegetable oils may be selected from a group consisting of 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; corn oil; cottonseed oil; rice bran oil; sesame oil; and refined palm oil; or a mixture thereof.
  • 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; corn oil; cottonseed oil; rice bran oil; sesame oil; and refined palm oil; or a mixture thereof.
  • the lipid component of the pharmaceutical vehicle may comprise a fatty acid comprising between 8 and 24 carbon atoms, between 10 and 22 carbon atoms, between 14 and 20 atoms, or between 16 and 20 atoms.
  • the lipid may be saturated or unsaturated, for example with one, two, three or more double bonds.
  • the lipid may comprise a fatty acid selected from a group consisting of 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 a mixture thereof.
  • the first number provided in the brackets corresponds to the number of carbon atoms in the fatty acid
  • the second number corresponds to the number of double bonds (i.e. unsaturation).
  • the melting point of the oil is largely determined by the degree of
  • the melting point of the lipid may be between about -20°C and 20°C, or between about -15°C and 16°C.
  • the lipid may comprise rapeseed oil.
  • Rapeseed oil is derived from Brassica napus, and contains both omega-6 and omega-3 fatty acids in a ratio of about 2:1. However, in the Examples, the inventors found that linseed oil was particularly effective, and so linseed oil may be preferred.
  • Linseed oil also known as flax seed oil, is a clear to yellowish oil obtained from the dried ripe seeds of the flax plant il ⁇ inum usitatissimum, Linaceae). The oil is obtained by cold pressing, sometimes followed by solvent extraction. Linseed oil is a mixture of various triglycerides that differ in terms of their fatty acid constituents.
  • the constituent fatty acids are of the following types: (i) the saturated acids palmitic acid (about 7%) and stearic acid (3.4-4.6%); (ii) the monounsaturated oleic acid (18.5-22.6%); (iii) the doubly unsaturated linoleic acid (14.2-17%); and (iii) the triply unsaturated omega-3 fatty acid oc-linolenic acid (51.9-55.2%). Linseed oil is also rich in omega-6 fatty acid.
  • the structure of a representative triglyceride found in linseed oil may be represented by formula I:
  • the lipid component of the pharmaceutical vehicle may comprise omega 3 and/ or omega 6 fatty acid.
  • Omega-3 fatty acids are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the «—3 position, i.e. the third bond from the methyl end of the fatty acid, and can be represented by formula II.
  • Omega-6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n ⁇ 6 position, i.e. the sixth bond, counting from the end opposite the carboxyl group, and can be represented by formula
  • Omega-3 and omega-6 fatty acids are derivatives of linolenic acid, the main difference being the number and exact position of the double bonds. Accordingly, omega-3 and omega-6 will have substantially the same melting points as linolenic acid.
  • the vehicle may comprise less than 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.
  • the vehicle may comprise between about 1% and 90% alcohol (w/w), or between about 1% and 70% (w/ w) alcohol, or between about 1 % and 60% (w/ w) alcohol, or between about 1 % and 50% (w/ w) alcohol, or between about 2% and 40% (w/ w) alcohol, or between about 4% and 30% (w/w) alcohol, or between about 6% and 20% (w/w) alcohol, or between about 8% and 15% (w/w) alcohol.
  • the alcohol may be an aliphatic alcohol.
  • the alcohol may be a O- 20 alcohol, a Ci-15 alcohol, a C1-10 alcohol, a C1-5 alcohol, or a C2 alcohol.
  • the alcohol may be menthol, or a sugar alcohol, such as glycerol, sorbitol, erythritol, xylitol, mannitol, isomalt or maltitol.
  • the alcohol may be ethanol, propanol or butanol. In one preferred embodiment, the alcohol is ethanol.
  • the vehicle may comprise between approximately 60% and 95% (w/ w) lipid and between about 5% and 40% (w/ w) alcohol. In another embodiment, the vehicle may comprise between approximately 80% and 95% (w/w) lipid and between about 5% and 20% (w/w) alcohol.
  • the vehicle may comprise between approximately 60% and 95% (w/ w) oil and between about 5% and 40% (w/ w) alcohol. In another embodiment, the vehicle may comprise between approximately 80% and 95% (w/w) lipid and between about 5% and 20% (w/ w) alcohol. For example, the vehicle may comprise between approximately 80% and 95% (w/w) olive oil, rapeseed oil or linseed oil, and between approximately 5% and 20% (w/ w) ethanol. In another embodiment, the vehicle may comprise between approximately 88% and 92% (w/w) lipid, and between
  • the vehicle may comprise between approximately 88% and 92% (w/w) olive oil, rapeseed oil or linseed oil, and between approximately 8% and 12% (w/w) ethanol.
  • the vehicle may comprise approximately 90% (w/ w) lipid, and approximately 10% (w/ w) alcohol.
  • the vehicle may comprise approximately 90% (w/w) olive oil, rapeseed oil or linseed oil, and approximately 10% (w/w) ethanol, and optionally water.
  • the vehicle is substantially anhydrous.
  • the absence of water in embodiments of the vehicle mean that the stability of the NSAID in the composition is not compromised, thereby providing an improved product.
  • the vehicle may optionally comprise water.
  • the vehicle may comprise less than about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less than about 1% (w/w) water.
  • the vehicle may comprise between about 1% and 70% (w/w) water, or between about 1% and 60% (w/ w) water, or between about 1 % and 50% (w/ w) water, or between about 2% and 40% (w/w) water, or between about 4% and 30% (w/w) water, or between about 6% and 20% (w/w) water, or between about 8% and 15% (w/w) water.
  • compositions may be used to treat a Thl -mediated disease in a monotherapy (i.e. use of the composition alone).
  • compositions may be used as an adjunct to, or in combination with, known therapies used in treating Thl -mediated diseases.
  • composition may have a number of different forms depending, in particular, on the manner in which the composition is to be used.
  • the manner in which the composition is to be used for example, the
  • composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment.
  • vehicle for medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given, and preferably enables delivery of the agents across the blood-brain barrier, or the lungs.
  • compositions comprising the active compound and the lipid and alcohol vehicle (i.e. the adjuvant) may be used in a number of ways.
  • oral administration may be required in which case the compound may be contained within a composition that may, for example be ingested orally in the form of a tablet, capsule or liquid.
  • compositions may be administered by injection into the blood stream. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion). Alternatively, the composition comprising the active compound may be administered by inhalation (e.g. intranasally, or by mouth). Compositions may also be formulated for topical use. For instance, ointments may be applied to the skin. Topical application to the skin is particularly useful for treating infections of the skin or as a means of transdermal delivery to other tissues.
  • the composition is orally administrable, i.e. for oral administration, as opposed to administration by injection or inhalation etc.
  • amount of the active compound that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physicochemical properties of the compound and whether the compound is being used as a monotherapy, or in a combined therapy.
  • the frequency of administration will also be influenced by the above-mentioned factors and particularly the half-life of the active compound within the subject being treated.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular active compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • a daily dose of between 0.00 ⁇ g/kg of body weight and 60mg/kg of body weight of the active compound may be used for treating Thl -mediated diseases depending upon which compound is used.
  • the daily dose is between 0.00 ⁇ g/kg of body weight and 60mg/kg of body weight of the active compound.
  • the daily dose is between 0.00 ⁇ g/kg and 60mg/kg of body weight of the active compound.
  • daily doses of the active compound may be given as a single administration (e.g. a single daily oral dosage form).
  • a suitable daily dose may be between O.C ⁇ g and 3200mg (i.e. assuming a body weight of 70kg), or between 0.70 g and 1600mg, or between 1 Omg and 800mg.
  • the composition may be administered more than once to the subject in need of treatment.
  • the composition may require administration twice or more times during a day.
  • the composition may be administered as two (or more depending upon the severity of the Thl -mediated disease being treated) daily doses of between 0.07 g and 3200mg (i.e. assuming a body weight of 70kg).
  • a patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3- or 4- hourly intervals thereafter, and so on.
  • the composition may be administered every day (more than once if necessary) after the trigger for the Thl -mediated inflammation.
  • a slow release device may be used to provide optimal doses of
  • compositions of the invention may be immobilised on or in a support substrate or matrix forming a lipid-rich formulation, which may be used as a delivery device to treat Thl -mediated disorders.
  • a drug delivery device comprising: -
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing endogenous interleukin- 10 (TL-10) production by Th2 cells, dendritic cells and/or macrophages, and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol; and
  • the delivery device may be a pessary or a vaginal ring or the like, which may be worn by a subject requiring treatment of a Thl -mediated condition.
  • the device may be used to treat any disease characterised by a drop in IL-10 concentrations. It is known that the concentration of IL-10 decreases in pregnant women, as a result of foetus tolerance, and this initiates labour during child birth. Thus, the delivery device may be used by pregnant women to prevent or delay premature labour.
  • the support matrix may be made of a substrate material which is suitable for supporting the composition therein or thereon.
  • the composition may be immobilised on the matrix.
  • the matrix may comprise any material capable of melting at, or around, body temperature, such that, over time, the matrix dissolves thereby releasing the composition, which is absorbed by the subject.
  • the support matrix may a suitable gel or wax.
  • suitable gel or wax for example, conventional materials for vaginal administration may be used, such as glycerol, gelatin, glyco-gelatin, macrogols (polyethylene glycols), natural, synthetic or semi-synthetic hard fats, and fractionated palm kernel oil.
  • compositions described herein may be used to increase the levels of endogenous production of IL-10 by Th2 cells, dendritic cells and/or macrophages, and thereby reduce the levels of Thl cytokines, such as TNF-O and IL- 12, to trigger the Thl to Th2 switch, the inventors believe that these effects of the compounds may be harnessed and used in the manufacture of clinically useful compositions. As shown in Figures 4-6, the inventors hypothesise that NSAIDs, when formulated in oil and alcohol, activate IL-10 production from macrophages.
  • a “therapeutically effective amount” of the active compound is any amount which, when administered to a subject, results in increased levels of IL-10 and IFN- ⁇ , and preferably decreased concentrations of TNF-OC and IL-12, and thereby provides treatment of a Thl -mediated disease.
  • the therapeutically effective amount of the active compound used may be from about 0.07 g to about 3200 mg, and preferably from about 0.7 g to about 1600 mg.
  • the amount of the active compound is from about 7 g to about 1200mg, or from about 7 g to about 800 mg.
  • a “subject” may be a vertebrate, mammal, or domestic animal, and is preferably a human being.
  • medicaments according to the invention may be used to treat any mammal, for example human, livestock, pets, or may be used in other veterinary applications.
  • a "pharmaceutically acceptable vehicle” as referred to herein can be any combination of compounds known to those skilled in the art to be useful in formulating
  • compositions which comprises a lipid (e.g. at least 30% (w/w) lipid) and an alcohol.
  • a lipid e.g. at least 30% (w/w) lipid
  • the pharmaceutically acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet.
  • a solid pharmaceutically acceptable vehicle may comprise one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet-disintegrating agents.
  • the vehicle may also be an encapsulating material.
  • the vehicle may be a finely divided solid that is in admixture with the finely divided active agent (i.e. the compound which stimulates endogenous IL-10 production).
  • the active agent may be mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • Suitable solid vehicles may comprise, for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • the pharmaceutical 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 may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats.
  • the liquid vehicle may also comprise other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo- regulators.
  • liquid vehicles for oral administration may include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the vehicle can also be an oily ester, such as ethyl oleate or isopropyl myristate.
  • composition is preferably administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide), and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
  • bile salts for example, enough saline or glucose to make the solution isotonic
  • acacia gelatin
  • sorbitan monoleate sorbitan monoleate
  • polysorbate 80 oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
  • the composition may or may not comprise a surfactant.
  • the composition is not emulsified.
  • surfactants which may or not be included in the composition include a phospholipid, such as phosphatidylcholine (lecithin) and phosphatidyl ethanolamine; soaps and detergents, including fatty alkali metal, ammonium, and triethanolamine salts, and detergents, including (a) cationic detergents such as, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and
  • the vehicle or adjuvant of the invention does not comprise any of these surfactants.
  • Many surfactants have certain safety implications, i.e. many are not GRAS (generally regarded as safe).
  • the pharmaceutically acceptable vehicle may preferably comprise at least 30% (w/w) lipid, possibly in the absence of ethanol.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing interleukin-10 (IL-10) production, and a pharmaceutically acceptable vehicle comprising at least 30% (w/w) lipid, for use in treating a Thl -mediated disease, wherein the IL-10 is endogenously produced by Th2 cells, dendritic cells and/ or macrophages.
  • IL-10 interleukin-10
  • a drug delivery device comprising:-
  • composition comprising a therapeutically effective
  • a pharmaceutically acceptable vehicle comprising at least 30% (w/w) lipid
  • a method of preventing, treating and/ or ameliorating a Thl -mediated disease comprising administering, to a subject in need of such treatment, a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing interleukin-10 (IL-10) production, and a pharmaceutically acceptable vehicle comprising at least 30% (w/w) lipid, wherein the IL-10 is endogenously produced by Th2 cells, dendritic cells and/ or macrophages.
  • IL-10 interleukin-10
  • a pharmaceutical composition for treating a Thl -mediated disease comprising a therapeutically effective amount of a compound which is capable of inducing endogenous production of interleukin-10 (IL-10) by Th2 cells, dendritic cells and/or macrophages and a pharmaceutically acceptable vehicle comprising at least 30% (w/w) lipid.
  • IL-10 interleukin-10
  • an oral adjuvant for use in a pharmaceutical composition
  • a pharmaceutical composition comprising an immunogen, wherein the adjuvant comprises a lipid and an alcohol, and stimulates uptake of the immunogen by dendritic cells and/ or macrophages such that they modulate immunomodulatory cytokines, and wherein the immunomodulatory activity of the immunogen in the presence of the adjuvant is greater than its immunomodulatory activity in the absence of the adjuvant.
  • an adjuvant is a pharmacological or immunological agent, which modifies the effect of other active agents, such as a drug or a vaccine, while having few, if any, direct effects when administered by itself.
  • Adjuvants are frequently included in vaccines to enhance the recipient's immune response to an administered antigen or immunogen, while keeping the administered foreign material to a minimum.
  • immunological adjuvants have traditionally been viewed as substances that aid the immune response to an antigen or immunogen
  • adjuvants have also evolved as substances that can aid in stabilising formulations of antigens, especially vaccines administered for animal health.
  • the most commonly used adjuvants act by providing a long-lived cache of antigen or immunogen, which counteracts the typical characteristic of rapid clearance and degradation of free antigen. Consideration of which adjuvant to use must take into account the concomitant negative side-effects of adjuvants, such as undesirable inflammatory outcomes.
  • the adjuvant of the ninth aspect may be immunostimulatory and/ or immunoinhibiting.
  • the adjuvant may be capable of enhancing the immunomodulatory activity of a subject administered with the adjuvant, resulting in the stimulation of the immune system, for treating hypo-immune conditions, such as cancer and immunosuppression, as well as inhibiting the immune system, for treating hyper-immune conditions.
  • Loading immunostimulating drugs (i.e. the immunogen) in macrophages and dendritic cells will promote their phenotype to enhance their capacity to clear cancer cells, bacteria and virus.
  • the oily adjuvant of the ninth aspect displays not only greater efficacy for promoting the immunological activity of an antigen or immunogen (e.g. ibuprofen), but also exhibits improved stability-conferring
  • oral adjuvant can mean that it is orally administrable, i.e. for oral administration, as opposed to administration by injection or inhalation etc.
  • a pharmaceutical composition comprising an immunogen and the adjuvant according to the ninth aspect.
  • a pharmaceutical composition according to the tenth aspect for use in therapy.
  • a pharmaceutical composition according to the tenth aspect for use in treating Thl -mediated disease, cancer, or a bacterial or viral infection.
  • a method of eliciting, in a subject, an effective immune response comprising administering, to a subject, an effective amount of the pharmaceutical composition of the tenth aspect.
  • the lipid and alcohol components of the adjuvant may be selected from any of the lipids (oil or fat) or alcohols described herein, in any of the described amounts.
  • the adjuvant may comprise 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) lipid.
  • the adjuvant may comprise between about 35% and 99% (w/w) lipid, or between about 45% and 99% (w/w) lipid, or between about 50% and 99% (w/w) lipid, or between about 60% and 98% (w/w) lipid, or between about 70% and 97% (w/w) lipid, or between about 80% and 96% (w/w) lipid, or between about 85% and 95% (w/w) lipid, or between about 85% and 95% (w/w) lipid, or between about 88% and 94% (w/w) lipid, or between about 89% and 93% (w/w) lipid.
  • a suitable oil which may be used as the lipid component in the adjuvant, may be a natural oil or a vegetable oil.
  • suitable natural oils may be selected from a group consisting of linseed oil; soyabean oil; fractionated coconut oil; mineral oil;
  • suitable vegetable oils may be selected from a group consisting of rapeseed oil; olive oil; peanut oil; soybean oil; corn oil; safflower oil; arachis oil; sunflower oil; canola oil;
  • the lipid may comprise linseed oil.
  • the adjuvant may comprise less than about 90%, 80%, 70%, 65%, 60%, 55%, 50%,
  • the adjuvant may comprise between about 1% and 90% alcohol (w/w), or between about 1 % and 70% (w/ w) alcohol, or between about 1 % and 60% (w/ w) alcohol, or between about 1% and 50% (w/w) alcohol, or between about 2% and 40% (w/w) alcohol, or between about 4% and 30% (w/w) alcohol, or between about 6% and 20% (w/w) alcohol, or between about 8% and 15% (w/w) alcohol.
  • the alcohol may be an aliphatic alcohol.
  • the alcohol may be a O- 20 alcohol, a Ci-15 alcohol, a C1-10 alcohol, a C1-5 alcohol, or a C2-4 alcohol.
  • the alcohol may be menthol, or a sugar alcohol, such as glycerol, sorbitol, erythritol, xylitol, mannitol, isomalt or maltitol.
  • the alcohol may be ethanol, propanol or butanol. In one preferred embodiment, the alcohol is ethanol.
  • the adjuvant may or may not comprise water.
  • the adjuvant is anhydrous.
  • the adjuvant does not comprise a hydrophilic surfactant, or any of the surfactants described herein.
  • the adjuvant is capable, in use, of stimulating or inducing the dendritic cells and/ or macrophages in a subject treated with the pharmaceutical composition, to take up the immunogen, such that the concentration of immunomodulatory cytokines is modulated.
  • the immunomodulatory cytokine which is modulated may be selected from a group of cytokines including IL-10; IL4; TNF-a; and IFN- ⁇ .
  • the adjuvant may stimulate the dendritic cells and/or macrophages in the subject to produce or increase production of an immunomodulatory cytokine.
  • the cytokine which is produced or increased may be IL-10 and/ or TNF- a and/ or IL-4.
  • the adjuvant may stimulate the dendritic cells and/or macrophages in the subject to stop or decrease production of an immunomodulatory cytokine.
  • the cytokine for which production is decreased or prevented may be IFN- ⁇ .
  • the immunogen present in the composition may be a pharmaceutically active agent having a log P value of greater than 2.0 and/ or a polar surface area of between about 25 A 2 and 70 A 2 .
  • the immunogen may preferably be a small molecule having a molecular weight of less than 1000 Da.
  • log P value will be known to the skilled person, and can refer to the ratio of concentrations of a compound (i.e. the immunogen) in the two phases of a mixture of two immiscible solvents at equilibrium.
  • the immunogen may have a log P value which is greater than 3.0, 4.0, 5.0 or 6.0.
  • the immunogen may have a log P value which is less than 7.0, 6.0, 5.0, 4.0 or 3.0.
  • the immunogen may have a log P value of between 2.0 and 7.0, or between 3.0 and 6.0, or between 3.0 and 5.0.
  • the immunogen may have a log P value of between 2.0 and 4.0, or between 2.1 and 4.0, or between 2.2 and 4.0, or between 2.3 and 4.0.
  • the immunogen may have a log P value of between 2.5 and 4.0, or between 3.0 and 4.0, or between 3.1 and 4.0. In another embodiment, the immunogen may have a log P value of between 3.3 and 4.0, or between 3.5 and 4.0. In yet another embodiment, the immunogen may have a log P value of between 2.0 and 3.0, or between 2.0 and 2.7, or between 2.0 and 2.5. In a further embodiment, the immunogen may have a log P value of between 2.2 and 2.5.
  • the immunogen may have a polar surface area of between 35 A 2 and 65 A 2 , or between 40 A 2 and 60 A 2 , or between 45 A 2 and 55 A 2 . In another embodiment, the immunogen may have a polar surface area of between 30 A 2 and 50 A 2 , or between 35 A 2 and 45 A 2 , or between 40 A 2 and 60 A 2 .
  • the immunogen may comprise a peroxidase proliferator- activator receptor gamma (PPAR- ⁇ ) agonist.
  • PPAR- ⁇ agonist can mean any molecule that is capable of binding to, and triggering a response from, the peroxidase proliferator- activator receptor gamma (PPAR- ⁇ ).
  • This receptor is also known as the glitazone receptor, or nuclear receptor subfamily 1, group C, member 3 (NR1C3).
  • PPAR- ⁇ is a type II nuclear receptor that, in humans, is encoded by the PPAR- ⁇ gene. Two isoforms of PPAR- ⁇ are detected in humans, i.e.
  • PPAR- ⁇ which is found in nearly all tissues except in muscle, and PPAR- ⁇ 2, which is mostly found in adipose tissue and the intestine.
  • the PPAR- ⁇ agonist present in the composition may be capable of binding to either PPAR- ⁇ or PPAR-y2.
  • the table below provides a list of preferred PPAR- ⁇ agonists, which may be used in the compositions of the invention.
  • the PPAR- ⁇ agonist may be a compound selected from the table.
  • the PPAR- ⁇ agonist may be a fibrate.
  • the fibrate may be selected from the group of fibrates consisting of bezafibrate; ciprofibrate; clofibrate; gemfibrozil; and fenofibrate.
  • the PPAR- ⁇ agonist may be selected from the group of agonists including Monascin; Irbesartan; Telmisartan; Mycophenolic acid; Resveratrol; Delta(9)-tetrahydrocannabinol; Cannabidiol; Curcumin; Cilostazol; Benzbromarone; 6- shogaol; and Glycyrrhetinic acid.
  • the immunogen may be a non-steroidal anti-inflammatory drug (NSAID).
  • NSAID non-steroidal anti-inflammatory drug
  • the immunogen may be any of the NSAIDs described herein, for example ibuprofen.
  • Figure 1 shows the effect of one embodiment of the composition of the first aspect (i.e. ibuprofen in lipid, which is denoted herein as BC1054), on survival against Influenza A/PR/8/34 lethal challenge.
  • BC1054 adjuvant oral 335 g of ibuprofen in a lipid adjuvant (BC1054 adjuvant oral) was administered to the challenged mice.
  • Two controls were used, i.e. 335 g of ibuprofen in the absence of the lipid adjuvant (BC1054 oral) and lipid adjuvant only in the absence of ibuprofen (control oral);
  • Figure 2 shows the effect of the formulation comprising 335 g ibuprofen in lipid vehicle (BC1054 lipid oral) in vivo on the IL-10 levels in the lungs of surviving mice.
  • Two controls were used, i.e. 335 g of ibuprofen in the absence of the lipid adjuvant (BC1054 oral) and lipid vehicle only (vehicle oral);
  • Figure 3 shows the effect of the formulation comprising 335 ⁇ g ibuprofen in lipid vehicle (BC1054 lipid oral) in vivo on the IL-4 levels in the lungs of surviving mice.
  • Two controls were used, i.e. 335 g of ibuprofen in the absence of the lipid adjuvant
  • Figure 4 is a graph showing the effect of the BC1054 formulation on IL-10 levels in the lungs of surviving mice;
  • Figure 5 is a graph showing the effect of the BC1054 formulation on TNF-alpha levels in the lungs of surviving mice;
  • Figure 6 is a graph showing the effect of the BC1054 formulation on IFN-gamma levels in the lungs of surviving mice.
  • Figure 7 is a graph showing the effects of the BC1054 formulation in an anti-collagen antibody induced arthritis (ACAIA) murine model.
  • the inventors carried out a range of in vivo mouse experiments in order to determine the effects of ibuprofen on influenza-challenged mice.
  • the inventors have
  • ibuprofen when administered orally in an oil-based formulation (90% linseed oil; 10% ethanol), results in a surprising increase in the concentration of endogenous IL-10 and IL-4. They observed a concomitant reduction in the viral symptoms (i.e. increase in survival rate), and believe that this is because of the elevated IL-10 concentration.
  • Group A received an oral gavage of ibuprofen at a dose of 335 ⁇ g/animal (equivalent to 20mg/kg/day ; i.e. 1200 mg per person day as maximum standard dose) dissolved in ⁇ of 10% Ethanol, and 90% linseed oil; • Group B was the first control in which mice received vehicle only (gavage of 10% Ethanol and 90% linseed oil); and
  • Group C was the second control in which mice were orally administered with a dose of 335.6 g/ animal in ⁇ DMSO (no lipid).
  • Figure 1 represents the average animal survival, and plotted in Figure 1.
  • Figure 1 clearly shows that the first control (i.e. oral administration of the lipid vehicle only) had an 80% mortality rate, and that the second control (i.e. oral administration of ibuprofen only) exhibited a mortality rate of 60%.
  • the inventors were surprised to observe that a single dose of BC1054 (i.e. ibuprofen in oil) converted the 80% mortality rate of the first negative control to an 80% survival rate, and this was totally unexpected.
  • Lungs collected at the end of the in vivo phase of the experiment described in Example 1 were homogenized at 4°C, and the supernatant was collected and stored at -70°C. 60 ⁇ ⁇ of capture antibody diluted in coating buffer was added per well. The plate was sealed and incubated overnight at 4°C. Wells were then aspirated and washed with 300 ⁇ / of well wash buffer. After the last wash, the plates were inverted and blotted on absorbent paper to remove any residual buffer. Plates were washed with
  • the two controls i.e. oral administration of ibuprofen only, and oral administration of the lipid vehicle only
  • the test compound, BC1054 resulted in an IL-10 concentration of 6000pg/mg.
  • this value of IL-10 is much higher than would have been expected if the activity of the lipid vehicle and ibuprofen was merely additive (the value would have been only
  • IL-4 is a Th2 cytokine
  • mice administered with BC1054 had much higher concentrations of IL-4 than either of the two control groups. Accordingly, the inventors have demonstrated that the switch from a Thl to a Th2 response has been induced. Inducing the switch from a Thl to a Th2 response by up-regulating IL-10 production (and IL-4) can be used to help treat Thl -mediated hyper-inflammation.
  • the inventors have prepared a delivery device made of a support matrix onto which the lipid-rich BC1054 composition is immobilised, and which can be easily used for treating any Thl -mediated disorder.
  • the delivery device is formed in the shape of a pessary, with a waxy support matrix.
  • Conventional materials for vaginal administration include glycerol/gelatin, glyco-gelatin, macrogols (polyethylene glycols), natural, synthetic or semi-synthetic hard fats, and fractionated palm kernel oil, each having BC1054 immobilised thereon.
  • the support matrix melts at body temperature, so that, over time, the composition is released and absorbed by the subject.
  • the inventors are aware that premature labour can be caused in pregnant mothers due to a drop in IL-10 concentrations. Therefore, the pessary can be worn by a pregnant woman, such that the BC1054 formulation is released, resulting in an increase in endogenous IL-10 production, thereby preventing premature labour.
  • Example 4 - IL10. TNF-alpha and IFN-gamma
  • the inventors carried out further experiments to show which cytokines are stimulated upon administration of the BC1054 formulation.
  • Lungs were taken from fatally HlNl infected mice, and IL-10, TNFa and IFNy levels of mice subsequently treated with BC1054 (formulation of the invention) and ibuprofen (not in oil/ ethanol vehicle) were measured.
  • the data are shown in Figures 4- 6.
  • the levels are related to the effect of each treatment on lethality (i.e. a surrogate for the anti-inflammatory activity of IL-10).
  • Example 5 An i-collagen antibody induced arthritis (ACAIA) murine model
  • the inventors investigated the effects of the BC1054 formulation in an ACAIA mouse model, a model showing similarities with system inflammation.
  • mice on day 0, were intravenously injected with a single inoculation with anti- collagen II monoclonal antibody (2 mg in 200 ⁇ ), followed by an intraperitoneal injection of lipopolysaccaride (LPS, 50 g in 200 ⁇ ) at day 3. From day 3 and daily until day 8 and then on days 10 and 12, paw volumes (plethysmography) and arthritis scores were taken. The same animals were also treated daily from days 0 to day 11 , with either oral gavage of vehicle (1% methylcellulose or BC1054 vehicle), 10 mg/kg of positive control, Enbrel (intraperitoneal), 40 mg/kg ibuprofen (oral), 20 mg/kg BC1054 or 30 mg/kg BC1054.
  • vehicle 1% methylcellulose or BC1054 vehicle
  • Enbrel intraperitoneal
  • 40 mg/kg ibuprofen oral
  • mice infected with a H1N1 virus can be effectively treated by administration of a single oral dose of ibuprofen present in an oily formulation.
  • any compound which is capable of increasing IL-10 production when formulated in a carrier having a high concentration of lipid, and orally administered will result in a much higher bioavailability in the lung.
  • Achieving a high concentration of an NSAID for example, such as ibuprofen, in the lung will be advantageous, when treating Thl - mediated disorders, for example a respiratory disorder caused by viral infections.

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Abstract

L'invention porte sur le traitement de maladies inflammatoires et, en particulier, de maladies inflammatoires médiées par Th-1. En particulier, l'invention porte sur le traitement de maladies inflammatoires médiées par Th-1 à l'aide d'une gamme de compositions, et sur l'utilisation de ces compositions dans des procédés de traitement. L'invention s'étend à des adjuvants destinés à être utilisés dans le traitement d'une grande diversité d'états médicaux. L'invention porte également sur des compositions pharmaceutiques et des médicaments comprenant l'adjuvant, et sur des utilisations de l'adjuvant dans des procédés de traitement et pour déclencher une réponse immunitaire.
PCT/GB2011/052115 2010-10-29 2011-10-31 Maladie inflammatoire WO2012056251A1 (fr)

Priority Applications (89)

Application Number Priority Date Filing Date Title
CA2816564A CA2816564A1 (fr) 2010-10-29 2011-10-31 Maladie inflammatoire
AU2011322255A AU2011322255A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
MX2013004817A MX2013004817A (es) 2010-10-29 2011-10-31 Enfermedad inflamatoria.
CN2011800637601A CN103282021A (zh) 2010-10-29 2011-10-31 炎症性疾病
SG2013033014A SG189551A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
RU2013124514/15A RU2013124514A (ru) 2010-10-29 2011-10-31 Воспалительное заболевание
BR112013010441A BR112013010441A2 (pt) 2010-10-29 2011-10-31 doença inflamatória
EP11784752.5A EP2632431A1 (fr) 2010-10-29 2011-10-31 Maladie inflammatoire
JP2013535515A JP2013544802A (ja) 2010-10-29 2011-10-31 炎症性疾患
EP18213159.9A EP3494961B1 (fr) 2011-02-04 2012-02-03 Compositions et procédés pour le traitement de l'inflammation chronique et de maladies inflammatoires
EP12704296.8A EP2670390A2 (fr) 2011-02-04 2012-02-03 Compositions et méthodes pour traiter l'inflammation chronique et les maladies inflammatoires
CA2826452A CA2826452C (fr) 2011-02-04 2012-02-03 Compositions et methodes de traitement de maladies cardiovasculaires
JP2013552271A JP2014507429A (ja) 2011-02-04 2012-02-03 心血管疾患の治療のための組成物および方法
RU2016138830A RU2016138830A (ru) 2011-02-04 2012-02-03 Составы и способы для лечения сердечно-сосудистых заболеваний
PCT/GB2012/050242 WO2012104655A2 (fr) 2011-02-04 2012-02-03 Compositions et méthodes pour traiter l'inflammation chronique et les maladies inflammatoires
BR112013019732-3A BR112013019732B1 (pt) 2011-02-04 2012-02-03 Composição farmacêutica e seu uso no tratamento de doenças cardiovasculares
MX2013008851A MX346224B (es) 2011-02-04 2012-02-03 Composiciones y metodos para el tratamiento de inflamacion cronica y enfermedades inflamatorias.
SG10201600854SA SG10201600854SA (en) 2011-02-04 2012-02-03 Compostions And Methods For Treating Chronic Inflammation And Inflammatory Diseases
NZ711187A NZ711187B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular disease
CA2826506A CA2826506C (fr) 2011-02-04 2012-02-03 Compositions et methodes pour traiter l'inflammation chronique et les maladies inflammatoires
RU2013140775/15A RU2013140775A (ru) 2011-02-04 2012-02-03 Составы и способы для лечения сердечно-сосудистых заболеваний
NZ613805A NZ613805B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
PCT/GB2012/050241 WO2012104654A1 (fr) 2011-02-04 2012-02-03 Compositions et méthodes de traitement de maladies cardiovasculaires
CN201280007770.8A CN103391768B (zh) 2011-02-04 2012-02-03 治疗慢性炎症和炎性疾病的组合物和方法
NZ613812A NZ613812B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating chronic inflammation and inflammatory diseases
US13/365,824 US8895536B2 (en) 2010-10-29 2012-02-03 Compositions and methods for treating chronic inflammation and inflammatory diseases
RU2013140776A RU2635188C2 (ru) 2011-02-04 2012-02-03 Композиции и способы для лечения хронического воспаления и воспалительных заболеваний
JP2013552272A JP2014504629A (ja) 2011-02-04 2012-02-03 慢性炎症および炎症性疾患を治療するための組成物および方法
BR112013019734A BR112013019734A2 (pt) 2011-02-04 2012-02-03 composições e métodos para tratar inflamação crônica e doenças inflamatórias
SG2013059357A SG192620A1 (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases
AU2012213217A AU2012213217B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
CN201280007753.4A CN103391767B (zh) 2011-02-04 2012-02-03 治疗心血管疾病的组合物和方法
EP12704295.0A EP2670389A1 (fr) 2011-02-04 2012-02-03 Compositions et méthodes de traitement de maladies cardiovasculaires
MX2013008850A MX364229B (es) 2011-02-04 2012-02-03 Composiciones y metodos para tratar enfermedades cardiovasculares.
US13/365,828 US8895537B2 (en) 2010-10-29 2012-02-03 Compositions and methods for treating cardiovascular diseases
AU2012213218A AU2012213218C1 (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases
SG2013059365A SG192621A1 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
ZA2013/05783A ZA201305783B (en) 2011-02-04 2013-07-31 Composition and methods for treating cardiovascular diseases
ZA2013/05784A ZA201305784B (en) 2011-02-04 2013-07-31 Compositions and methods for treating chronic inflammation and inflammatory diseases
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US14/155,080 US9265742B2 (en) 2010-10-29 2014-01-14 Compositions and methods for treating inflammatory pain
US14/155,167 US10695432B2 (en) 2010-10-29 2014-01-14 Solid solution compositions and use in severe pain
US14/155,147 US10695431B2 (en) 2010-10-29 2014-01-14 Solid solution compositions and use in cardiovascular disease
US14/520,159 US9427422B2 (en) 2010-10-29 2014-10-21 Compositions for treating cardiovascular diseases
US14/520,141 US9326958B2 (en) 2010-10-29 2014-10-21 Compositions for treating chronic inflammation and inflammatory diseases
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US14/821,687 US9744132B2 (en) 2010-10-29 2015-08-07 Solid solution compositions and use in chronic inflammation
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JP2016015164A JP6273304B2 (ja) 2011-02-04 2016-01-29 慢性炎症および炎症性疾患を治療するための組成物および方法
US15/043,327 US9750810B2 (en) 2010-10-29 2016-02-12 Compositions and methods for treating chronic inflammation and inflammatory diseases
US15/061,661 US9775820B2 (en) 2010-10-29 2016-03-04 Solid solution compositions and use in chronic inflammation
US15/169,619 US10004704B2 (en) 2010-10-29 2016-05-31 Compositions and methods for treating chronic inflammation and inflammatory diseases
US15/169,617 US9693980B2 (en) 2010-10-29 2016-05-31 Compositions and methods for treating chronic inflammation and inflammatory diseases
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US15/289,083 US20170043016A1 (en) 2010-10-29 2016-10-07 Solid Solution Compositions and Use in Severe Pain
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US17/107,724 US11660276B2 (en) 2010-10-29 2020-11-30 Compositions and methods for treating chronic inflammation and inflammatory diseases
US17/113,476 US11730709B2 (en) 2010-10-29 2020-12-07 Compositions and methods for treating severe pain
US17/146,950 US11065218B2 (en) 2010-10-29 2021-01-12 Compositions and methods for treating chronic inflammation and inflammatory diseases
US17/146,989 US11103472B2 (en) 2010-10-29 2021-01-12 Oral suspensions comprising a non-steroidal anti-inflammatory drug (NSAID)
US17/230,855 US11844773B2 (en) 2010-10-29 2021-04-14 Solid solution compositions and use in chronic inflammation
US17/378,744 US20210338617A1 (en) 2010-10-29 2021-07-18 Compositions and Methods for Treating Chronic Inflammation and Inflammatory Diseases
US17/448,263 US20220040102A1 (en) 2010-10-29 2021-09-21 Solid Solution Compositions and Use in Chronic Inflammation
US17/540,802 US11826428B2 (en) 2010-10-29 2021-12-02 Solid solution compositions comprising cannabidiols
US17/646,241 US11918654B2 (en) 2010-10-29 2021-12-28 Solid solution compositions and use in severe pain
US18/509,114 US20240100002A1 (en) 2010-10-29 2023-11-14 Compositions and Methods for Treating Chronic Inflammation and Inflammatory Diseases

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GB201018289D0 (en) 2010-12-15
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