GB2487808A - Oral adjuvant or formulation comprising a lipid and an alcohol - Google Patents

Oral adjuvant or formulation comprising a lipid and an alcohol Download PDF

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Publication number
GB2487808A
GB2487808A GB1113728.8A GB201113728A GB2487808A GB 2487808 A GB2487808 A GB 2487808A GB 201113728 A GB201113728 A GB 201113728A GB 2487808 A GB2487808 A GB 2487808A
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GB
United Kingdom
Prior art keywords
oil
adjuvant
lipid
alcohol
composition according
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
GB1113728.8A
Other versions
GB201113728D0 (en
Inventor
Robin Mark Bannister
John Brew
Wilson Capaross-Wanderley
Olga Pleguezuelos
Gregory Alan Stoloff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biocopea Ltd
Original Assignee
Biocopea Ltd
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 Ltd filed Critical Biocopea Ltd
Publication of GB201113728D0 publication Critical patent/GB201113728D0/en
Priority to CA2816564A priority Critical patent/CA2816564A1/en
Priority to PCT/GB2011/052115 priority patent/WO2012056251A1/en
Priority to MX2013004817A priority patent/MX2013004817A/en
Priority to EP11784752.5A priority patent/EP2632431A1/en
Priority to CN2011800637601A priority patent/CN103282021A/en
Priority to BR112013010441A priority patent/BR112013010441A2/en
Priority to RU2013124514/15A priority patent/RU2013124514A/en
Priority to JP2013535515A priority patent/JP2013544802A/en
Priority to AU2011322255A priority patent/AU2011322255A1/en
Priority to SG2013033014A priority patent/SG189551A1/en
Priority to RU2013140776A priority patent/RU2635188C2/en
Priority to PCT/GB2012/050242 priority patent/WO2012104655A2/en
Priority to AU2012213218A priority patent/AU2012213218C1/en
Priority to BR112013019732-3A priority patent/BR112013019732B1/en
Priority to AU2012213217A priority patent/AU2012213217B2/en
Priority to NZ613812A priority patent/NZ613812B2/en
Priority to EP12704295.0A priority patent/EP2670389A1/en
Priority to US13/365,824 priority patent/US8895536B2/en
Priority to SG2013059357A priority patent/SG192620A1/en
Priority to RU2016138830A priority patent/RU2016138830A/en
Priority to NZ711187A priority patent/NZ711187B2/en
Priority to JP2013552271A priority patent/JP2014507429A/en
Priority to CA2826506A priority patent/CA2826506C/en
Priority to SG2013059365A priority patent/SG192621A1/en
Priority to MX2013008850A priority patent/MX364229B/en
Priority to CA2826452A priority patent/CA2826452C/en
Priority to JP2013552272A priority patent/JP2014504629A/en
Priority to PCT/GB2012/050241 priority patent/WO2012104654A1/en
Priority to CN201280007753.4A priority patent/CN103391767B/en
Priority to EP12704296.8A priority patent/EP2670390A2/en
Priority to NZ613805A priority patent/NZ613805B2/en
Priority to CN201280007770.8A priority patent/CN103391768B/en
Priority to US13/365,828 priority patent/US8895537B2/en
Priority to BR112013019734A priority patent/BR112013019734A2/en
Priority to EP18213159.9A priority patent/EP3494961B1/en
Priority to MX2013008851A priority patent/MX346224B/en
Priority to SG10201600854SA priority patent/SG10201600854SA/en
Priority to RU2013140775/15A priority patent/RU2013140775A/en
Publication of GB2487808A publication Critical patent/GB2487808A/en
Priority to ZA2013/05783A priority patent/ZA201305783B/en
Priority to ZA2013/05784A priority patent/ZA201305784B/en
Priority to US14/155,080 priority patent/US9265742B2/en
Priority to US14/155,147 priority patent/US10695431B2/en
Priority to US14/155,167 priority patent/US10695432B2/en
Priority to US14/155,108 priority patent/US9308213B2/en
Priority to US14/155,042 priority patent/US9271950B2/en
Priority to US14/520,141 priority patent/US9326958B2/en
Priority to US14/520,150 priority patent/US9381180B2/en
Priority to US14/520,159 priority patent/US9427422B2/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/en
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 US15/684,197 priority patent/US10363232B2/en
Priority to US15/684,214 priority patent/US10213381B2/en
Priority to US15/702,440 priority patent/US10231943B2/en
Priority to US15/794,178 priority patent/US10188619B2/en
Priority to US15/794,214 priority patent/US10143671B2/en
Priority to US15/794,197 priority patent/US10154975B2/en
Priority to US16/012,036 priority patent/US10426748B2/en
Priority to US16/166,272 priority patent/US10596132B2/en
Priority to US16/206,814 priority patent/US10588878B2/en
Priority to US16/206,789 priority patent/US10653778B2/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 US16/882,667 priority patent/US11224659B2/en
Priority to US16/882,666 priority patent/US11202831B2/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
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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Abstract

An oral adjuvant for pharmaceutical immunogen delivery, drug delivery devices comprising the adjuvant and methods of treatment using pharmaceutical formulations comprising the adjuvant (e.g. to treat Th1 cell mediated diseases) are disclosed wherein the adjuvant comprises a lipid and an alcohol arranged to stimulate uptake of the immunogen by dendritic cells and or macrophages. Preferably the adjuvant comprises at least 30% wax, lipid of oil and ethanol, preferably the lipid is linseed oil and preferably the adjuvant further comprises an NSAID such as ibuprofen or a PPAR-gamma agonist. The effects of ibuprofen formulated in 90% linseed oil, 10% ethanol on the survival of influenza challenged mice and a vaginal pessary comprising the ibuprofen formulation intended for administration to prevent premature labour are disclosed.

Description

t V.' INTELLECTUAL ..* PROPERTY OFFICE Application No. GB 1113728.8 RTMI Date:4 November 2011 The following terms are registered trademarks and should be read as such wherever they occur in this document: Enbrel Intellectual Properly Office is an operating name of the Patent Office www.ipo.gov.uk
INFLAMMATORY DISEASE
The present invention relates to the treatment of inflammatory diseases, and especially Th-1 mediated inflammatory diseases. In particular, the invention relates to the treatment of Th-l 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 a/ia phagocytic cells, such as macrophages, neutrophils and dendtitic cells. The innate system is fully functional before a pathogen enters the host.
In contrast, the adaptive system is only initiated after the pathogen has entered the host, at which point it develops a defence specific to that pathogen. The cells of the adaptive immune system are called lymphocytes, the two main categoties of which are B cells and T Cells. B cells are involved in the creation of neutrallsing 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.
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 Jhl) and Type 2 helper T cell (1h2).
Jo Thi cells promote a cell-mediated adaptive immune response, which involves the activation of macrophages and stimulates the release of vatious cytokines, such as IFNy, TNF-cx 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. Generally, Thi responses are more effective against intracellular pathogens, such as viruses and bacteria present inside host cells. A Th2 response, however, 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-iO (IL-b), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. It is produced primarily by monocytes and, to a lesser extent, by lymphocytes, and has pleiotropic effects in immunoregulation and inflammation. IL-i 0 down-regulates the expression of Thi cytokines (such as IFN7, TNF-o and IL-12), MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production.
Furthermore, IL-i 0 can block NF-xB 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 bactetia producing recombinant IL-i 0, showing the importance of this cytokine for counteracting excessive immunity in the human body.
IL-b is a validated target in inflammatory disease, and has been shown to be essential for immunotolerance and the control of Thi immunity (O'Garra et al., 2008, Immunol. Rev., 223:i i4-3i). Systemic administration of exogenous IL-iO in early clinical ttials showed 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 ttials were that systemically administered exogenous IL-10 did not dampen exaggerated Thi responses as predicted, possibly because tissue levels of IL-i 0 were too low (the half-life of IL-i 0 is short), or because IL-i 0 was not presented in the correct manner. Hence, concentrations of IFNy, TNF-a and IL-i2 actually increased to deletetious levels. It will be appreciated that these cytokines are pro-inflammatory.
Furthermore, a significant side effect of administering too much exogenous IL-lU 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-lU, IL-4 and TGF-f3 are anti-inflammatory.
In view of these problems, there is, therefore, clearly a need in the art for improved medicaments for use in the treatment of Thi -mediated diseases, and especially Thi-mediated inflammatory disorders, which do not suffer the immune-related problems observed in previous IL-lU trials. The inventors investigated, using in vivo mouse studies, the effects of non-steroidal anti-inflammatory drugs (NSAID), such as ibuprofen, on mice that had been previously challenged with influenza virus. The inventors formulated ibuprofen in combination with a highly llpophillc pharmaceutically acceptable vehicle, or adjuvant, which was then orally administered to challenged test mice. They observed that ibuprofen administered orally in an oily formulation (i.e. the adjuvant) resuhed in surprisingly positive effects on the percentage survival rate compared to the control mice which had been administered with just the oily vehicle or just ibuprofen (not in oil). The inventors also determined with in vivo assays that the concentration of IL-lU in the lungs of the surviving animals dramatically increased in mice administered with the oily ibuprofen composition.
Hence, in a first aspect, there is provided a pharmaceutical composition comptising a therapeutically effective amount of a compound which is capable of increasing interleukin-1U (IL-lU) production, and a pharmaceutically acceptable vehicle comptising a lipid and an alcohol, for use in treating a Thi -mediated disease, wherein the IL-lU is endogenously produced by Th2 cells, dendtitic cells and/or macrophages.
In a second aspect of the invention, there is provided a method of preventing, treating and/or ameliorating a Thi-mediated disease, the method comptising administeting, to a subject in need of such treatment, a pharmaceutical composition comptising a Jo therapeutically effective amount of a compound which is capable of increasing interleukin-1U (IL-lU) production, and a pharmaceutically acceptable vehicle comptising a lipid and an alcohol, wherein the IL-b is endogenously produced by Th2 cells, dendritic cells and/or macrophages.
In a third aspect, there is provided use of a pharmaceutical composition for treating a Thi-mediated disease, the composition comprising a therapeutically effective amount of a compound which is capable of inducing endogenous production of interleukin-lO (IL-b) by Th2 cells, dendritic cells and/or macrophages and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol.
Surprisingly, as shown in Figure 1, when ibuprofen is administered orally in a lipophilic formulation (e.g. at least 3O% 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 astounding 8O% 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 surptising 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. at least 30% (w/w) lipid), results in them being rapidly absorbed into the systemic circulation via the lymphatic system.
When a drug/lipid formulation is swallowed, the 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 ttiglycerides, phospholipids, cholesterol and proteins, and the NSAID.
The resultant oil/drug/bile salt complex (i.e. micelles or chylomicron) may then be absorbed by the proximal gut into the entetic lymphatic system. These micelles/chylomicrons, carrying the compound which stimulates IL-lO production, are believed to be transported via the gut lymphatic system to the central venous vasculature, and then rapidly to the heart, which pumps the active compound-tich venous blood to the lung. As a result, the drug is delivered in high concentrations in oxygenated blood directly to the lung increasing its bioavailability.
The inventors believe that 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. The inventors believe that 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. Accordingly, the inventors believe that 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 desctibed in the Examples.
As shown in Figure 2, administration of the pharmaceutical composition of the invention results in a dramatic increase in the production of endogenous IL-lU in the lungs of influenza-challenged mice, and this was totally unexpected. Clearly, when compared to the concentrations of IL-I 0 that were produced in the control mice (i.e. animals that had been administered with just the oily vehicle or just ibuprofen and no oil), the IL-b concentrations produced in animals administered with the active agent in lipid were much more than additive, suggesting that a synergistic effect has occurred.
As desctibed in Example 4, and as shown in Figures 5-7, the inventors have demonstrated that NSAIDs (such as ibuprofen), when they are formulated in an oil and alcohol (e.g. ethanol) adjuvant, activate endogenous IL-b 0 production from macrophages. Thus, it is preferred that the compositions of the invention are adapted, in use, to stimulate endogenous production of IL-b 0 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 dendtitic cells. Numerous disease conditions are believed to be associated with low levels of IL-lU (i.e. hypo-IL-disorders), or in situations where an increase in IL-b concentration is either too Jo slow or insufficient, and any of these conditions may be treated in accordance with the invention. Example 5 desctibes the effects of the compositions of the invention in an anti-collagen antibody induced arthtitis (ACAIA) murine model. Thus, the Thi-mediated disease, which may be treated, may be a Thi -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 Thi -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; dermatomyositis; diabetes mellitus Type i; Goodpasture's syndrome; Graves' disease; Guillain-Barré syndrome; juvenile idiopathic arthritis; Hashimoto's thyroiditis; idiopathic thrombocytopenic purpura; Lupus erythematosus; mixed connective tissue disease; myasthenia gravis; narcolepsy; osteoarthritis; pemphigus vulgaris; pernicious anaemia; polymyositis; primary biliary cirrhosis; relapsing polychondritis; Sjögren's syndrome; temporal artetitis; vasculitis; Wegener's granulumatosis; and age-related macular degeneration.
The Thi -mediated disease may be virally, bacterially or chemically (e.g. environmentally) induced. For example, a virus causing the Thi -mediated disease may cause a chronic or acute infection, which may cause a respiratory disorder. Suitably, the virus causing the Thi -mediated disease may be Influenza.
Preferably, the Thi-mediated disease, which may be treated, is systemic inflammatory disease, for example inflammatory bowel syndrome (IBD), rheumatoid arthtitis (IRA) or cystic fibrosis (CE). The Thi-mediated disease, which may be treated, is preferably IBD.
The inventors cartied out investigations on a number of different compounds that can induce IL-lU production, as they were aware that IL-lU production is a charactetistic that indicates a switch from a ThI to a Th2 response, and that such compounds could be used to treat Thi-mediated diseases. They have demonstrated that inducing the switch from a ThI to a Th2 response by up-regulating IL-b production can be used to help treat ThI -mediated hyper-inflammation. Indeed, Figure 3 clearly shows that administration of the composition of the invention not only increases IL-I 0 production, it also results in increased IL-4 production, proving that the switch from a Thi to a Th2 response has been induced, Advantageously, by stimulating a Th2 response, by inducing the endogenous release of IL-I 0 of Th2 cells, macrophages and/or dendritic cells, B cells are activated, which produce neutrallsing antibodies, which lead the humoral immunity. It will be appreciated that Th2 responses are much more effective against extracellular pathogens, such as parasites and toxins located outside host cells, than Thl responses.
By way of example, ThI -mediated hyper-inflammation occurs duting viral infections (e.g. influenza, as demonstrated in the Examples), and so the inventors believe that endogenously producing IL-I 0 by the Th2 cells, macrophages and/or dendtitic cells upon administration of the composition to the subject could be used to treat a respiratory collapse caused by a viral infection. It is known that some viruses, such as Herpes Simplex Virus (HSV), maintain their presence in the body by stimulating Thi immunity, and that therefore, ttiggeting a switch to Th2 immunity would help treat herpes infections by allowing the body to attack the virus through natural killer cell immunity.
The inventors are of the view that IL-lO is a paractine 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-lU production in a paractine manner. It will be appreciated that paractine signalling can be a form of cell signaffing in which the target cell is near or local to the signal-releasing cell. Thus, IL-i 0 can control the immune response at sites of inflammation in tandem with cell-cell interactions.
The compound, which is capable of increasing endogenous IL-lU production, may be recognised by Th2 cells, dendritic cells and/or macrophages. Preferably, however, the compound, which is capable of increasing endogenous IL-i 0 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-b. Preferably, therefore, the IL-b is produced by Th2 cells, dendritic cells and/or macrophages, which are immuno-competent. Advantageously, in contrast to producing IL-lO by non-immune cells, which causes an imbalance in the immune system leading to infections and, in some cases cancer, endogenous production of IL-b by immuno-competent Th2 cells, dendritic cells and/or macrophages, ensures that the immune system remains balanced, thereby avoiding infection.
Hence, the immune system is capable of regulating itself naturally, thereby reducing the risk of infections and cancer. As shown in Figures 4-6, the levels of IL-I 0 generated due to the regulatory process and feedback loops may modulate (e.g. decrease) Thi cytokine concentration, such as IFNy, TNF-cx and IL-12, but not suppress their production completely. This may be important because these Thi cytokines are needed to protect the body from infection. Thus, by stimulating production of IL-lO endogenously, it is possible to overcome the significant immune-related problems that are observed when the cytokine is added exogenously, resulting in over-production of IEN7, TNF-ct and IL-l2.
The compound which is capable of inducing endogenous production of interleukin-lO (IL-i 0) by Th2 cells, dendtitic cells and/or macrophages may be a non-steroidal anti-inflammatory drug (NSAID). The NSAID may be a propionic acid detivative, an acetic acid detivative, an enolic acid derivative, a fenamic acid derivative, or a selective-or non-selective cyclo-oxygenase (COX) inhibitor. The NSAID may be a profen.
Examples of suitable propionic acid NSAID detivatives may include Ibuprofen; Naproxen; Fenoprofen; Ketoprofen; Flurbiprofen; or Oxaprozin. Examples of suitable acetic acid NSAID detivatives may include Aceclofenac; Acemetacin; Actatit; Alcofenac; Amfenac; Clometacin; Diclofenac; Etodolac; Felbinac; Fenclofenac; Indometacin; Ketorolac; Metiazinic acid; Mofezolac; Naproxen; Oxametacin; Sullndac; or Zomepirac. 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; Elufenamic acid; or Tolfenamic acid.
In embodiments where the NSAID is a cyclooxygenase (COX) inhibitor, it may be either a cyclooxygenase 1 (COX 1) inhibitor or a cyclooxygenase 2 (COX 2) inhibitor.
Examples of suitable COX inhibitors may include Ibuprofen; Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; or Valdecoxib.
The NSAID may be selected from a group consisting of: Alminoprofen; Benoxaprofen; Dexketoprofen; Flurbiprofen; Ibuprofen; Indoprofen; Ketoprofen; Loxoprofen; Pranoprofen; Protizinic acid; Suprofen; Aceclofenac; Acemetacin; Actarit; Alcofenac; Amfenac; Clometacin; Diclofenac; Etodolac; Felbinac; Fenclofenac; Indometacin; Ketorolac; Metiazinic acid; Mofe2olac; Naproxen; Oxametacin; Sulindac; Zomepirac; Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; Valdecoxib; Aloxipirin; Aminophenazone; Antraphenine; Aspirin; Azapropazone; Benorilate; Benzydamine; Butibufen; Chlorthenoxacin; Choline Salicylate; Difiunisal; Emorfazone; Epirizole; Feclobuzone; Fenbufen; Glafenine; Hydroxylethyl salicylate; Lactyl phenetidin; Mefenamic acid; Metamizole; Mofebutazone; Nabumetone; Nifenazone; Niflumic acid; Phenacetin; Pipebuzone; Propyphenazone; Proquazone; Salicylamide; Salsalate; Tiaramide; Tinoridine; and Tolfenamic acid.
A preferred NSAID may be Alminoprofen, Benoxaprofen, Dexketoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Pranoprofen protizininic acid, or Suprofen. Preferably, 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.
-10 -NSAIDs described herein may be provided as racemates, or as individual enantiomers, including the R-or S-enantiomer. Thus, the NSAID may comprise R-ibuprofen or S-ibuprofen, or a combination thereof.
In one embodiment, 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). Examples of such diseases may include arthritis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis and endometriosis.
In another embodiment, R-ibuprofen may be used for the treatment of immune-mediated diseases which do not involve pain that is responsive to COX inhibitors.
Examples of such 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%, 2O%, 3QO,/, 3 5%, 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 glycetide (mono-, di-or tti-so glycetide); a phospholipid; a glycol ester; a sucrose ester; a wax; a glycerol oleate detivative; a medium chain triglyceride; or a mixture thereof. A ttiglycetide is an ester -11 -derived from glycerol and three fatty acids, and is the main constituent of vegetable oil and animal fats.
The term "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. The term "fat" can refer to a fat that is solid at normal room temperature. The term "lipid" can therefore refer to a liquid or solid fat, as weli 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. Examples of suitable natural oils may be selected from a group consisting of linseed oil; soyabean oil; fractionated coconut oil; mineral oil; ttiacetin; ethyl oleate; a hydrogenated natural oil; or a mixture thereof. Examples of 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. Each of these oils is commercially available from a number of sources well recognized by those skilled in the art.
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. It will be appreciated that the first number provided in the brackets corresponds to the number of carbon atoms in the fatty acid, and that 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 saturation/unsaturation. The melting points of oleic acid -12 - (CH3(CH2)7CHCH(CH2)7COOH), linoleic acid (CH3(CH2)4(CHCHCH2)2(CH46COOH), and of linolenic acid (CH3CH2(CHCHCH43(CH2)6COOH), are about 16°C, -5°C and -11°C, respectively.
Thus, 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 (Linum 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.
For linseed oil, 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%); (Ei) the doubly unsaturated linoleic acid (14.2-17%); and (iii) the ttiply unsaturated omega-3 fatty acid a-linolenic acid (51.9-55.2%). Linseed oil is also tich in omega-6 fatty acid. The structure of a representative triglyceride found in linseed oil may be represented by formula I: // Thus, 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 n-3 position, i.e. the third bond from the methyl end of the fatty acid, and can be represented by formula II.
-13 -HO4\V\YN/N/N,'N/'FN/ II Omega-6 fatty acids, on the other hand, 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 iii 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%, 7Q%, 65%, 60Vo, 55%, 5Qo/t 45%, 43%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less than about 1% (w/w) alcohol. The vehicle may comprise between about l% and 9O% alcohol (w/w), or between about l% and 70% (w/w) alcohol, or between about 1% and 6O% (w/w) alcohol, or between about I % and SO% (w/w) alcohol, or between about 2% and 40% (w/w) alcohol, or between about 4% and 3O% (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 allphatic alcohol.
The alcohol may be a C120 alcohol, a C115 alcohol, a C110 alcohol, a C15 alcohol, or a 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. -14-
In one embodiment, 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.
In one embodiment, the vehicle may comprise between approximately 60% and 95% (w/w) oil and between about S% and 40% (w/w) alcohol. In another embodiment, the vehicle may comprise between approximately 8O% and 95% (w/w) lipid and between about S% and 2O% (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 approximately 8% and 12% (w/w) alcohol. For example, 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. In another embodiment, the vehicle may comprise approximately 90% (w/w) lipid, and approximately 10% (w/w) alcohol. For example, the vehicle may comprise approximately 9O% (w/w) olive oil, rape seed oil or linseed oil, and approximately 10% (w/w) ethanol, and optionally water.
The inventors believe that water has a tendency to increase the instability of NSAIDs.
Thus, in a preferred embodiment, the vehicle is substantially anhydrous.
Advantageously, 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.
However, in some embodiments, 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.
-15 -It wifi be appreciated that the composition may be used to treat a Thi-mediated disease in a monotherapy (i.e. use of the composition alone). Alternatively, the compositions may be used as an adjunct to, or in combination with, known therapies used in treating Thi-mediated diseases.
The composition may have a number of different forms depending, in particular, on the manner in which the composition is to be used. Thus, 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. It will be appreciated that the 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 bartier, or the lungs.
Compositions comptising the active compound and the lipid and alcohol vehicle (i.e. the adjuvant) may be used in a number of ways. For instance, 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.
Alternatively, the composition may be administered by injection into the blood stream.
Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion).
Alternatively, the composition comptising 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.
Preferably, the composition is orally administrable, i.e. for oral administration, as Jo opposed to administration by injection or inhalation etc. -16 -It will be appreciated that the amount of the active compound that is required is determined by its biological activity and bioavailabillty, 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.
It will be appreciated that a skilled person will be able to calculate required doses, and optimal concentrations of the active compound at a target tissue, based upon the pharmacokinetics of the active. Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo expetimentation, clinical trials, etc.), may be used to establish specific formulations of the active compound and precise therapeutic regimes (such as daily doses of the compounds and the frequency of administration).
Generally, a daily dose of between 0.001g/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. Suitably, the daily dose is between 0.01 pg/kg of body weight and 40mg/kg of body weight, more suitably between 0.01 pg/kg of body weight and 30mg/kg of body weight or between 0.1 Lg/kg and 20 mg/kg body weight, and most suitably between approximately 0.1kg/kg and 15 mg/kg body weight.
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 0.07kg and -17 - 3200mg (i.e. assuming a body weight of 70kg), or between O.7Otg and 1600mg, or between 10mg and 800mg.
It is envisaged that 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. As an example, the composition may be administered as two (or more depending upon the severity of the Thi-mediated disease being treated) daily doses of between 0.07.ig 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. It is envisaged that the composition may be administered every day (more than once if necessary) after the trigger for the Thl -mediated inflammation.
Alternatively, a slow release device may be used to provide optimal doses of compounds according to the invention to a patient without the need to administer repeated doses.
The inventors also believe that compositions of the invention may be immobilised on or in a support substrate or mattix forming a lipid-tich formulation, which may be used as a delivery device to treat Thi -mediated disorders.
Hence, in a fourth aspect of the invention, there is provided a drug delivery device comprising:- (i) a pharmaceutical composition comptising a therapeutically effective amount of a compound which is capable of increasing endogenous interleukin- (IL-b) production by Th2 cells, dendtitic cells and/or macrophages, and a pharmaceutically acceptable vehicle comptising a lipid and an alcohol; and (ii) a support mattix.
The delivery device may be a pessary or a vaginal ting or the like, which may be worn by a subject requiting treatment of a Thi-mediated condition. For example the device -18 -may be used to treat any disease characterised by a drop in IL-b concentrations. It is known that the concentration of IL-I 0 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. In one embodiment, 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. 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.
Based on their findings that the compositions desctibed herein may be used to increase the levels of endogenous production of IL-I 0 by Th2 cells, dendtitic cells and/or macrophages, and thereby reduce the levels of ThI cytokines, such as TNF-a and IL- 12, to trigger the ThI 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-b 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-b 0 and IFN-y, and preferably decreased concentrations of TNF-cz and IL-12, and thereby provides treatment of a Thi-mediated disease.
For example, the therapeutically effective amount of the active compound used may be from about 0.07 Lg to about 3200 mg, and preferably from about 0.7 pg to about 1600 -19 -mg. The amount of the active compound is from about 7 jig to about 1200mg, or from about 7 jig to about 800 mg.
A "subject" may be a vertebrate, mammal, or domestic animal, and is preferably a human being. Hence, 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 pharmaceutical compositions, but which comptises a lipid (e.g. at least 3O% (w/w) lipid) and an alcohol.
In one embodiment, the pharmaceuticaliy acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet. In addition to the lipid component and alcohol, a solid pharmaceutically acceptable vehicle may comprise one or more substances which may also act as flavouting agents, lubticants, 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 matetial. In powders, the vehicle may be a finely divided solid that is in admixture with the finely divided active agent @.e. the compound which stimulates endogenous IL-b production). In tablets, 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, dexttin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
In yet another embodiment, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition may be in the form of a solution. Liquid vehicles are used in prepating solutions, suspensions, emulsions, syrups, elixirs and pressutized compositions. The active compound may be dissolved or suspended in a -20 -pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. In addition to the lipid component, 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. Suitable examples of 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 polyhydtic 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 mytistate.
The 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 anhydtides copolymerized with ethylene oxide), and the like.
However, the composition may or may not comprise a surfactant. Preferably, the composition is not emulsified. Examples of 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 pytidinium halides; (b) anionic detergents such as alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; (c) non-ionic detergents such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and (d) amphoteric detergents such as alkyl-b-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts. Another example of a detergent may include so sodium dodecyl sulphate dimethyl sulphoxide. Preferably, the vehicle or adjuvant of the invention does not comptise any of these surfactants.
-21 -Many surfactants have certain safety implications, i.e. many are not GRAS (generally regarded as safe). Therefore, avoiding the use of a surfactant circumvents such safety concerns for the compositions of the invention. In addition, although not wishing to be bound by theory, the inventors hypothesise that exclusion of a surfactant results in improved uptake and bioavailability of the active agent in the subject being treated.
The inventors believe that the pharmaceutically acceptable vehicle may preferably comprise at least 30% (w/w) lipid, possibly in the absence of ethanol.
Thus, in a fifth aspect, there is provided a pharmaceutical composition comptising a therapeutically effective amount of a compound which is capable of increasing interleukin-lO (IL-b) production, and a pharmaceutically acceptable vehicle comptising at least 30% (w/w) lipid, for use in treating a Thi-mediated disease, wherein the IL-b is endogenously produced by Th2 cells, dendritic cells and/or macrophages.
In a sixth aspect, there is provided a drug delivery device comptising:- (i) a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing endogenous interleukin-lO (IL-b) production by Th2 cells, dendtitic cells and/or macrophages, and a pharmaceutically acceptable vehicle comptising at least 30% (w/w) lipid; and (ii) a support mattix.
In a seventh aspect, there is provided a method of preventing, treating and/or ameliorating a Thi -mediated disease, the method comprising administeting, to a subject in need of such treatment, a pharmaceutical composition comptising a therapeutically effective amount of a compound which is capable of increasing interleukin-b 0 (IL-10) production, and a pharmaceutically acceptable vehicle comptising at least 3O% (w/w) lipid, wherein the IL-b is endogenously produced by Th2 cells, dendtitic cells and/or so macrophages.
-22 -In eighth aspect, there is provided use of a pharmaceutical composition for treating a Thi-mediated disease, the composition comprising a therapeutically effective amount of a compound which is capable of inducing endogenous production of interleukin-1 0 (IL-b) by Th2 cells, dendritic cells and/or macrophages and a pharmaceutically acceptable vehicle comprising at least 30?/o (w/w) lipid.
Based on the results demonstrating the surprising immunomodulatory effects of the lipid/alcohol vehicle described herein (see Figures 2-6), the inventors believe that they have effectively developed a novel adjuvant, which can be used to enhance the immunomodulatory activity of a wide range of immunogenic compounds.
Thus, according to a ninth aspect of the invention, there is provided an oral adjuvant, for use in a pharmaceutical composition comptising an immunogen, wherein the adjuvant comptises 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.
It will be appreciated that 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 matetial to a minimum.
Although such 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.
Jo The most commonly used adjuvants act by providing a long-lived cache of antigen or immunogen, which counteracts the typical charactetistic of rapid clearance and degradation of free antigen. Consideration of which adjuvant to use must take into -23 -account the concomitant negative side-effects of adjuvants, such as undesirable inflammatory outcomes. For example, many patients suffer "flu-like" symptoms or swe1]ing and tenderness at an injection site occurring after a vaccination. Reducing such systemic and local unwanted side-effects, while still providing maximal enhancement of an immune response, is especially important and continues to drive much of the research and development of new, improved adjuvants.
The adjuvant of the ninth aspect may be immunostimulatory and/or immunoinhibiting.
Advantageously, 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 immuno-suppression, 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, bactetia and virus.
Advantageously, as shown in the Figures, 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 charactetistics on the antigen or immunogen, and does not induce negative side-effects in subjects administered with the adjuvant.
The term "oral adjuvant" can mean that it is orally administrable, i.e. for oral administration, as opposed to administration by injection or inhalation etc. According to a tenth aspect of the invention, there is provided a pharmaceutical composition comptising an immunogen and the adjuvant according to the ninth aspect.
According to an eleventh aspect, there is provided a pharmaceutical composition Jo according to the tenth aspect, for use in therapy. -24-
According to a twelfth aspect, there is provided a pharmaceutical composition according to the tenth aspect, for use in treating ThI -mediated disease, cancer, or a bacterial or viral infection.
According to a thirteenth aspect, there is provided a method of eliciting, in a subject, an effective immune response, the method 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. For example, the adjuvant may comprise at least about I O%, 20%, 30%, 35%, 40%, 4S%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 9ftVo, 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°/b 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. Examples of 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. Examples of suitable vegetable oils may be selected from a group consisting of rape seed 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; tice bran oil; sesame oil; and refined palm oil; or a mixture thereof. In one preferred embodiment, the lipid may comprise linseed oil.
The adjuvant may comptise less than about 90%, 80%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less than about 1°/b (w/w) alcohol.
The adjuvant may comprise between about 1% and 90% alcohol (w/w), or between -25 -about I % 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 3Q% (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 C12o alcohol, a alcohol, a C110 alcohol, a C15 alcohol, or a C24 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. Preferably, the adjuvant is anhydrous.
Preferably, the adjuvant does not comprise a hydrophillc 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-lO; 1L4; TNF-a; and IFN-y.
As illustrated in Figures 2, 3, 4 and 5, in one embodiment, the adjuvant may stimulate the dendritic cells and/or macrophages in the subject to produce or increase production of an immunomodulatory cytokine. For example, the cytokine which is produced or increased may be IL-lU and/or TNF- and/or IL-4.
As illustrated in Figure 6, in another embodiment, the adjuvant may stimulate the dendritic cells and/or macrophages in the subject to stop or decrease production of an immunomodulatory cytokine. For example, the cytokine for which production is Jo decreased or prevented may be IFN-y.
-26 -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 A2 70 A2. The immunogen may preferably be a small molecule having a molecular weight of less than 1000 Da.
The term "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. In one embodiment, 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. In another embodiment, 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 term "polar surface area" will also be known to the skilled person, and can refer to the surface sum over all of the polar atoms in its structure (usually oxygen and nitrogen), also including attached hydrogens. In one embodiment, the immunogen may have a polar surface area of between 35 A2 and 65 A2, or between 40 A2 and 60 A2, or between 45 A2 and 55 A2. In another embodiment, the immunogen may have a polar surface area of between 30 A2 and 50 A2, or between 35 A2 and 45 A2, or between 40 A2 and 60A2.
In one embodiment, the immunogen may comprise a peroxidase proliferator-activator so receptor gamma (PPAR-y) agonist.
-27 -The term "PPAR-y agonist" can mean any molecule that is capable of binding to, and triggering a response from, the peroxidase proliferator-activator receptor gamma (PPAR-y). This receptor is also known as the gllta2one receptor, or nuclear receptor subfamily 1, group C, member 3 (NR1 C3). PPAR-y is a type II nuclear receptor that, in humans, is encoded by the PPAR-y gene. Two isoforms of PPAR-y are detected in humans, i.e. PPAR-yl, which is found in nearly all tissues except in muscle, and PPAR-y2, which is mostly found in adipose tissue and the intestine. The PPAR-y agonist present in the composition may be capable of binding to either PPAR-yl or PPAR-y2.
The table below provides a list of preferred PPAR-y agonists, which may be used in the compositions of the invention. Thus, the PPAR-y agonist may be a compound selected
from the table.
Table 1 -PPAR-y agonists Drug C Log P Gemfibrozil 3.8 Bezafibrate 3.8 Ciprofibrate 3.4 Clofibrate 3.3 Fenofibrate 5.2 Ibuprofen 3.5 Diclofenac 4.4 Indomethacin 4.3 Monascin 3.2 Irbesartan 4.1 Telmisartan 6.9 Mycophenolic acid 3.2 Resveratrol 3.1 Delta(9)-7.0 tetrahydrocannabinol _________________ Cannabidiol 6.5 Curcumin 3.2 Cilostazol 3.1 Benzbromarone 5.7 6-shogaol 3.7 Glycyrrhetinic acid 6.4 In one preferred embodiment, the PPAR-y agonist may be a fibrate. Ogata et al., 2009, Atherosclerosis 205(2): 41 3-41 9, describes the PPAR-y agonist properties of the -28 -fibrates, gemfibrozil and bezafibrate. The fibrate may be selected from the group of fibrates consisting of bezafibrate; ciprofibrate; clofibrate; gemfibrozil; and fenofibrate.
In yet another embodiment, the PPAR-y 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.
In another embodiment, the immunogen may be a non-steroidal anti-inflammatory drug (NSAID). The immunogen may be any of the NSAIDs described herein, for
example ibuprofen.
All of the features described herein (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.
Embodiments of the invention will now be further described, by way of example only, with reference to the following Examples, and to the accompanying diagrammatic drawings, in which:-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 BC1 054), on survival against Influenza A/PR/8/34 lethal challenge. 335pg of ibuprofen in a lipid adjuvant (BCI 054 adjuvant oral) was administered to the challenged mice. Two controls were used, i.e. 335 pg of ibuprofen in the absence of the lipid adjuvant (BCI 054 oral) and lipid adjuvant only in the absence of ibuprofen (control oral); Figure 2 shows the effect of the formulation comptising 335pg ibuprofen in lipid vehicle (BC1 054 lipid oral) in vivo on the IL-i 0 levels in the lungs of surviving mice.
Two controls were used, i.e. 33Sig of ibuprofen in the absence of the lipid adjuvant Jo (BC1 054 oral) and lipid vehicle only (vehicle oral); Figure 3 shows the effect of the formulation comptising 33Sg ibuprofen in lipid vehicle (BCI 054 lipid oral) in vivo on the IL-4 levels in the lungs of surviving mice. Two -29 -controls were used, i.e. 335ig of ibuprofen in the absence of the lipid adjuvant (BC1 054 oral) and lipid vehicle only (vehicle oral); Figure 4 is a graph showing the effect of the BC1 054 formulation on IL-i 0 levels in the lungs of surviving mice; Figure 5 is a graph showing the effect of the BC1 054 formulation on TNF-alpha levels in the lungs of surviving mice; Figure 6 is a graph showing the effect of the BC1 054 formulation on IFN-gamma levels in the lungs of surviving mice; and Figure 7 is a graph showing the effects of the BC1OS4 formulation in an anti-collagen antibody induced arthritis (ACAIA) murine model.
Examples
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 convincingly demonstrated in the results described below that ibuprofen, when administered orally in an oil-based formulation (9O% linseed oil; iO% ethanol), results in a surptising increase in the concentration of endogenous IL-b 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-i 0 concentration.
Example I -In vivo mouse survival studies Protocol: Five groups (nlO) of C57BLK/6 female mice (6-7 weeks old), were divided into five expetimental groups containing ten animals each. On day I, animals received an intranasal lethal dose (50 il total, 25 pl nostril) of Influenza A/PR/8/34 under halothane-induced anaesthesia.
On day 3, post-challenge with the virus, the animals received the following treatments: * Group A received an oral gavage of ibuprofen at a dose of 335.6kg/animal (equivalent to 20mg/kg/day; i.e. 1200 mg per person day as maximum standard dose) dissolved in lOOpi of 10% Ethanol, and 90% linseed oil; -30 - * 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 contro' in which mice were orally administered with a dose of 335.6 pg/animal in lOpi DM50 (no lipid).
The animals were weighed, and monitored for signs of infection daily up to day 6 when all animals were culled. Figure 1 represents the average animal survival, and plotted in Figure 1.
Figure 1 dearly shows that the first control (i.e. oral administration of the lipid vehicle only) had an 80% mortality rate, and that the second control @.e. oral administration of ibuprofen only) exhibited a mortality rate of 60%. However the inventors were surprised to observe that a single dose of BC1054 @.e. ibuprofen in oil) converted the 8O% mortality rate of the first negative control to an 80% survival rate, and this was totally unexpected.
Example 2 -Determination of IE-lO and IE-4 concentrations Eungs coliected at the end of the in vivo phase of the experiment desctibed in Example I were homogenized at 4°C, and the supernatant was collected and stored at -70°C. 60 vL 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 300vE/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 I 80pE/well of assay diluents and incubated at room temperature for 1 hour. Samples were vortexed for 30secs immediately before adding to the plate. Setial dilutions were performed within the plate with both the sample and the standards by pipetting 601iE of assay diluent into each well. The plate was sealed and incubated for 2 hours at room temperature. IL-4 and TE-lO assays were then carried out. For IE-4, 60pE of working detector was added (Detection Antibody + SAv-HRP reagent) to each well. The plate was sealed and incubated for 1 hour at room temperature. For JE-lO, 60pL of detection antibody was diluted in assay diluent to each well.
-31 -Plates were washed and 60pL of SAv-HRP enzyme was diluted in assay diluent and added to the plate. The plate was sealed and incubated for 20 minutes at room temperature. Plates were then washed ten times. 60v1 of substrate solution were added to each well and the plate was incubated for 30minutes at room temperature in the dark. 6O1fl of stop solution was added to each well and absorbance was read at 450nm.
IL-i 0 and IL-4 concentrations were expressed as pg/mg of lung tissue, and then plotted in Figures 2 and 3.
As can be seen in Figure 2, the two controls (i.e. oral administration of ibuprofen only, and oral administration of the lipid vehicle only) resulted in only 2600pg/mg and 2000pg/mg IL-lO, respectively. However, the inventors were astounded to see that the test compound, BC1 054, resulted in an IL-i 0 concentration of 6000pg/mg. Clearly, this value of IL-lO 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 4600pg/mg). The fact that the IL-b concentration in BCiO54-administered animals was 6000pg/mg suggests that the effects are synergistic (i.e. 24% higher than expected).
The inventors postulate that this increase in endogenous IL-lU production has at least contributed to the significant increase in survival shown in Figure 1.
Referring to Figure 3, there is shown the respective concentrations of IL-4 in the surviving animals from the assay of Figure i. IL-4 is a Th2 cytokine, and it can be seen that mice administered with BC1 054 had much higher concentrations of IL-4 than either of the two control groups. Accordingly, the inventors have demonstrated that the switch from a Thi to a Th2 response has been induced. Inducing the switch from a Thi to a Th2 response by up-regulating IL-i 0 production (and IL-4) can be used to help treat Thi -mediated hyper-infiammation.
Example 3 -Pessarv
The inventors have prepared a delivery device made of a support mattix onto which the lipid-tich BCiO54 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 mattix. Conventional matetials for vaginal administration that have -32 -been used 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-b concentrations. Therefore, the pessary can be worn by a pregnant woman, such that the BC1 054 formulation is released, resulting in an increase in endogenous IL-lU production, thereby preventing premature labour.
Example 4-ILl 0, TNF-alpha and IFN-gamma The inventors carried out further experiments to show which cytokines are stimulated upon administration of the BCl054 formulation.
Lungs were taken from fatally H1N1 infected mice, and IL-lU, TNFoc and IFNy levels of mice subsequently treated with BC1 054 (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-b).
As shown in Figure 4, administration to the mice of either ibuprofen on its own, or the BC1OS4 formulation, resulted in increased IL-b levels. However, the inventors observed that these increases in IL-b were associated with very different pharmacodynamic effects. The pattern of pro-inflammatory cytokine reduction highlights the source of the IL-lU and its relevance to the effect on the viral survival model. Importantly, as shown in Figure 6, the levels of IFNy (which is a lymphocyte-detived cytokine) were markedly lowered in the ibuprofen-treated mice compared to BC1OS4-treated mice, which was associated with a poor outcome.
so Moreover, as shown in Figure 5, TNFa (which is macrophage-related cytokine) was not as markedly inhibited. However, in BC1 054-treated mice, TNFoc levels were markedly lowered in the BCl054-treated mice whilst IFNy levels were largely unaffected. This -33 -demonstrates that the BC1054 is having its protective effect on the lethality of HIN1 through macrophage-derived IL-lO levels rather than lymphocyte-derived 1L10 ("Immunobiology, 5th edition -The Immune System in Health and Disease", Charles Ajaneway Qr), Paul Travers, Mark Walport and Markj Shlomchik. New York: Garland Science; 2001).
Example 5 -Anti-collagen antibody induced arthritis (ACAIA) murine model The inventors investigated the effects of the BC1 054 formulation in an ACAIA mouse model, a model showing similarities with system inflammation.
Materials and Methods BALB/c mice, on day 0, were intravenously injected with a single inoculation with anti-collagen II monoclonal antibody (2 mg in 200 v1) followed by an intraperitoneal injection of lipopolysaccaride (LPS, 50 g in 200 il) at day 3. From day 3 and daily until day 8 and then on days 10 and 12, paw volumes (plethysmography) and arthtitis 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 BCI 054 vehicle), 10 mg/kg of positive control, Enbrel (intrapetitoneal), 40 mg/kg ibuprofen (oral), 20 mg/kg BCI 054 or 30 mg/kg BC1 054. Through the entire expetiment (12 days), animals were checked daily for clinical signs (general observations of the health of the animal) and body weights.
Total arthtitis scores are determined by summing the arthtitis scores of individual paws using the following grades: 0 no signs of arthritis, 1 mild but definite redness and swelling of the ankle/wtist or apparent redness or swelling limited to individual digits, regardless of the number of affected digits, 2 moderate to severe redness and swelling of the ankle/wtist, 3 redness and swelling of the entire paw including digits, 4 maximally inflamed limb with involvement of multiple joints.
The results of this expetiment are shown in Figure 7. As can be seen, as expected, the io positive control, Enbrel, showed the best results, with the lowest paw thicknesses at about 1.6mm on day 12. The two test formulations (i.e. 20 mg/kg BC1054 or 30 mg/kg BC1OS4) displayed the next best results, with 30 mg/kg BCIOS4 producing a paw -34-thickness of only 1.7mm, and)0 mg/kg BCI 054 producing a paw thickness of about 1.73mm. The negative controls (i.e. PBS, 40mg/kg ibuprofen alone, vehicle alone, and vehicle methoxycellulose) performed significantly worse than BC1 054 with paw thicknesses of 1.9mm and over. Therefore, these data clearly demonstrate that the formulation of the invention can be used to treat systemic inflammation, such as arthritis.
Summary
In summary, the inventors were surprised to observe that ibuprofen, when administered orally in a lipophilic excipient (i.e. linseed oil), significantly increased endogenous IL-b production, and thus surprisingly improved survival in influenza-challenged mice. The encouraging results of the in vivo mouse studies clearly demonstrate that mice infected with a H1N1 virus can be effectively treated by administration of a single oral dose of ibuprofen present in an oily formulation. Hence, any compound which is capable of increasing IL-I 0 production, when formulated in a cartier 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.
However, only in the BC1054-treated animals, is the IL-b signal accompanied by an improvement in survival. In the same lungs, there is a more pronounced down-regulation of IFN-gamma @.e. a T-cell-detived cytokine) for ibuprofen-treated mice, demonstrating that IL-b 0 in the ibuprofen mice is likely to come from T-cells. However, in BC1 054-treated mice, there is a more pronounced down-regulation of pulmonary TNF-alpha (i.e. a macrophage-derived cytokine), demonstrating that IL-in BC1054-treated mice is more likely to come from macrophages, which results in the profound anti-inflammatory effects that were observed.
so In summary, therefore, this is evidence that ibuprofen present in the oral lipid adjuvant of the invention is more preferentially taken up by macrophages, resulting in the new -35 -and surpñsing anti-inflammatory pharmacology as demonstrated by TBD and BA model data.

Claims (30)

  1. -36 -CLAIMS1. An oral adjuvant, for use in a pharmaceutica' composition comprising an immunogen, wherein the adju\Tant comprises a lipid and an alcohol, and stimulates uptake of the immunogen by dendritic cells and/or macrophages such that they modulate immunomodubtory 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.
  2. 2. An adjuvant according to claim 1, wherein the adjuvant comprises at least about 10%, 20%, 30%, 35%, 40%, 45%, 5Q%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least about 99% w/w) lipid.
  3. 3. An adjuvant according to either claim I or 2, wherein the adjuvant comprises 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.
  4. 4. An adjuvant according to any: preceding claim, wherein the adjuvant comprises a natural oil or a vegetahlc oiL
  5. 5. An adjuvant according to claim 4, wherein the natural oil is 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 Examples of suitable vegetable oils may he selected from a group consisting of rapes eed 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 io bran oil; sesame oil; and refined palm oil; or a mixture thereof
  6. 6. An adjuvant according to any preceding claim, wherein the lipid comprises linseed oil
  7. 7. An adjuvant according toy preceding dnini, wherein the adjuvant comprises less than about 90%, 80%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, lO%, 5%, or less than about 1% (w/w) alcohoL
  8. 8. An adjuvant according to any preceding daim, wherein the adjuv-ant comprises 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
  9. 9. An adjuvant according to any preceding dthm, wherein the alcohol is an aliphatic alcohol, for example a Ci..2a alcohol, a (:1-15 alcohol, a Ci..io alcohol, a Ci-s alcohol, or a (:2-4 alcohoL
  10. 10. An adjuvant according to any preceding daim, wherein the alcohol is ethanol, propanol or butanol, preferably ethanoL
  11. 11. An adjuvant according to any one of claims 1-9, wherein the alcohol is menthol, or a sugar alcohol, such as glycerol, sorbitol, erythritol, xylitol, niannitol, isomalt or maltitoL
  12. 12. An adjuvant according to any preceding claim, wherein the adjuvant is anhydrous.
  13. 13. An adjuvant according to any preceding claim, wherein the adjuv-ant does not comprise a hydrophilic surfactant.-38 -
  14. 14. An adjuvant according to any preceding claim, wherein the immunomodulatory cytokine which is modulated is selected from a group of cytokines including IL-ID; 1L4; TNF-oq and IFN-y.
  15. 15. An adjuvant according to any preceding claim, wherein the adjuvant stimulates the dendritic cells and/or macrophages in the subject to produce or increase production of an immunological cytokine, for example IL-i 0 and/or TNE-oc and/or IL-4.
  16. 16. An adjuvant according to any preceding claim, wherein the adjuvant stimulates the dendritic cells and/or macrophages in the subject to stop or decrease production of an immunological cytokine, for example IFN-y.
  17. 17. An adjuvant according to any preceding claim, wherein the immunogen present in the composition is a pharmaceutically active agent having a log P value of greater than 2.0 and/or a polar surface area of between about 25 A2 and 70 A2.
  18. 18. An adjuvant according to any preceding claim, wherein the immunogen is a small molecule having a molecular weight of less than 1000 Da.
  19. 19. An adjuvant according to any preceding claim, wherein the immunogen has a log P value which is greater than 3.0, 4.0, 5.0 or 6.0.
  20. 20. An adjuvant according to any preceding claim, wherein the immunogen has a polar surface area of between 35 A2 and 65 A2, or between 40 A2 and 60 A2, or between A2and 55 A2.
  21. 21. An adjuvant according to any preceding claim, wherein the immunogen comptises a peroxidase proliferator-activator receptor gamma PPAR-y) agonist.
  22. 22. An adjuvant according to claim 2i, wherein the PPAR-y agonist is a compound selected from Table 1.-39 -
  23. 23. An adjuvant according to either claim 21 or 22, wherein the PPAR-y agonist is a fibrate, which is selected from the group of uIbrates consisting of bezafibrate; ciprofibrate; clofibrate; gemfibrozil; and fenofibrate.
  24. 24. An adjuvant according to either claim 21 or 22, wherein the PPAR-y agonist is selected from the group of agonists including Monascin; Irbesartan; Telmisartan; Mycophenolic acid; Resveratrol; Delta(9)-tetrahydrocannahinol; Cannabidiol; Curcumin; Cilostazol; Benzhromarone; 6-shogaol; and Glycyrrhetinic acid.
  25. 25. An adjuvant according to any one of claims 1-22, wherein the immunogen is a non-steroidal anti-inflammatory drug (NSAID), for example ibuprofen.
  26. 26. A pharmaceutical composition comprising an immunogen and the adjuvant according to any preceding claim.
  27. 27. A pharmaceutical composition according to claim 26, for use in therapy.
  28. 28. A pharmaceutical composition according to claim 26, for use in treating Thi-mediated disease, cancer, or a bacterial or viral infection.
  29. 29. A method of eliciting, in a subject, an effective immune response, the method comprising administering, to a subject, an effective amount of the pharmaceutical composition of claim 26.
  30. 30. A pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing interleukin-i0 (IL-10) production, and a pharmaceutically acceptable vehicle comptising a lipid and an alcohol, for use in treating a Thi -mediated disease, wherein the IL-10 is endogenously produced by Th2 io cells, dendritic cells and/or macrophages. -40 -31. A composition according to claim 30, wherein the compound, which is capable of increasing endogenous IL-lO production, is recognised by dendritic cells and/or macrophages.32. A composition according to either claim 30 or 31, wherein the Thi -mediated disease is a Thl-mediated inflammatory disease, preferably systemic inflammatory disease.33. A composition according to any one of claims 3 0-32, wherein the disease is selected from a group of Thl -mediated diseases consisting of rheumatoid arthritis (RA; psoriatic arthritis; psoriasis; inflammatory bowel syndrome qBD); Crohn's disease; ulcerative colitis; multiple sclerosis (IN/IS); flu, including pandemic flu; respiratory disorders, for example those caused by viruses, such as respiratory syncytial virus (RSV); cystic fibrosis (CE); herpes, including genital herpes; asthma and allergies; sepsis and septic shock; bacterial pneumonia; bacterial meningitis; dengue hemorrhagic fever; diabetes Type II; endomettiosis; prostatitis; uveitis; utetine tipening; and age-related macular degeneration.34. A composition according to any one of claims 3 0-33, wherein the Thi -mediated disease is virally, bacterially or chemically (e.g. environmentally) induced.35. A composition according to any one of claims 30-34, wherein the Thi -mediated disease is systemic inflammatory disease, for example inflammatory bowel syndrome (IBD), rheumatoid arthritis (IRA) or cystic fibrosis (CE).36. A composition according to any one of claims 30-35, wherein the compound is used to increase endogenous IL-lO production in a paracrine manner.37. A composition according to any one of claims 30-36, wherein the compound io modulates Thi cytokine concentration, such as IENy, TNF-a and IL-12. -41 -38. A composition according to any one of claims 30-37, wherein the compound, winch is capable of inducing endogenous production of interleukin-1 0 (IL-i 0) by Th2 cells, dendritic cells and/or macrophages, is a non-steroidal anti-inflammatory drug (NSAID).39. A composition according to claim 38, wherein the NSAI[D is 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.40. A composition according to any one of claims 3 0-39, wherein the compound is selected from a group consisting of: Alminoprofen; Benoxaprofen; Dexketoprofen; Flurbiprofen; Ibuprofen; Indoprofen; Ketoprofen; Loxoprofen; Pranoprofen; Protizinic acid; Suprofen; Aceclofenac; Acemetacin; Actarit; Aicofenac; Amfenac; Clometacin; Diclofenac; Ltodolac; Felbinac; Fenclofenac; Indometacin; Ketorolac; Metiazinic acid; Mofezolac; Naproxen; Oxametacin; Sulindac; Zomepirac; Celecoxib; Etoricoxib; Lumiracoxib; Meloxicam; Rofecoxib; Valdecoxib; Aloxipirin; Aminophenazone; Antraphenine; Aspitin; Azapropazone; Benotilate; Benzydamine; Butibufen; Chiorthenoxacin; Choline Salicylate; Diflunisal; Emorfazone; Epirizole; Feclobuzone; Fenbufen; Glafenine; Hydroxylethyl salicylate; Lactyl phenetidin; Mefenamic acid; Metamizole; Mofehutazone; Nabumetone; Nifenazone; Niflumic acid; Phenacetin; Pipebuzone; Propvphenazone; Proquazone; Salicylamide; Salsalate; Tiaramide; Tinoridine; and Tolfenamic acid.41. A composition according to any one of claims 3 0-40, wherein the compound is Alminoprofen, Benoxaprofen, Dexketoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Pranoprofen protizininic acid, or Suprofen.42. A composition according to any one of claims 30-41, wherein the compound is Ihuprofen.43. A composition according to any one of claims 38 to 42, wherein the composition comprises the R-or S-enantiomer of the N SAID.44. A composition according to ditn 43, wherein the composition comprises R-ibuprofen.45. A composition according to dnim 43, wherein the composition comprises S-ibuprofen.46. A composition according to any one of claims 30-45, wherein the lipid component of the vehicle is as defined in anyone of daims 2-6.47. A composition according to any one of claims 30-46, wherein the lipid component of the pharmaceutical vehicle comprises a fatty add comprising between 8 and 24 carbon atoms, between 10 and 22 carbon atoms, between 14 and 20 atoms, or between 16 and 20 atoms.48. A composition according to any one of dninis 30-47, wherein the lipid comprises a fatty add selected from a group consisting of myristic acid (C 14:0); palmitic acid (C 16:0); palmitoleic add (C 16:1); stearic add (C 18:0); oleic add (C 18:1); linoleic add (C 18:2); linolenic add (C 18:3) and arachidic add (C 20:0); or a mixture thereof.49. A composition according to any one of claims 30-48, wherein the alcohol component of the vehicle is as defined in any one of claims 7-11.50. A composition according to any one of dnims 30-49, wherein the vehicle comprises between approximately 80% and 95% (w/w) linseed oil, and between approximately 5% and 20% (w/w) ethanol, and optionally water.51. A composition according to any preceding claim, wherein the composition is orally administrable. -43 -52. A composition according to any preceding claim, wherein the vehicle does not comprise a hydrophilic surfactant.53. A drug delivery device comprising:- (i) a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capable of increasing endogenous interleukin-lO (IL-lU) production by Th2 cells, dendritic cells and/or macrophages, and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol; and @i) a support matrix.54. A drug delivery device according to claim 53, wherein the device comprises the pharmaceutical composition defined in any one of claims 30 to 52.55. A drug delivery device according to either claim 53 or claim 54, wherein the device is a pessary, a vaginal ting, or the like.56. A drug delivery device according to any one of claims 53 to 55, wherein the device is worn by a subject requiting treatment of a Th 1-mediated condition.57. A drug delivery device according to any one of claims 53 to 56, wherein the delivery device is used by pregnant women to prevent or delay premature labour.58. A drug delivery device according to any one of claims 53 to 57, wherein the support mattix comprises a matetial 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.59. A drug delivery device according to any one of claims 54 to 58, wherein the Jo support matrix is a gel or wax, for example glycerol/gelatin, glyco-gelatin, macrogol (e.g. polyethylene glycol), natural, synthetic or semi-synthetic hard fat, or fractionated palm kernel oil.60. A method of preventing, treating and/or ameliorating a Thi -mediated disease, the method comprising administering, to a subject in need of such treatment, a pharmaceutical composition comprising a therapeutically effective amount of a compound which is capahie of increasing interleukin-1 0 (IL-i 0) production, and a pharmaceutically acceptable vehicle comprising a lipid and an alcohol, wherein the IL-is endogenously produced by Th2 cells, dendritic cells and/or macrophages.
GB1113728.8A 2010-10-29 2011-08-10 Oral adjuvant or formulation comprising a lipid and an alcohol Withdrawn GB2487808A (en)

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CA2816564A CA2816564A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
PCT/GB2011/052115 WO2012056251A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
MX2013004817A MX2013004817A (en) 2010-10-29 2011-10-31 Inflammatory disease.
EP11784752.5A EP2632431A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
CN2011800637601A CN103282021A (en) 2010-10-29 2011-10-31 Inflammatory disease
BR112013010441A BR112013010441A2 (en) 2010-10-29 2011-10-31 inflammatory disease
RU2013124514/15A RU2013124514A (en) 2010-10-29 2011-10-31 INFLAMMATORY DISEASE
JP2013535515A JP2013544802A (en) 2010-10-29 2011-10-31 Inflammatory disease
AU2011322255A AU2011322255A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
SG2013033014A SG189551A1 (en) 2010-10-29 2011-10-31 Inflammatory disease
RU2013140776A RU2635188C2 (en) 2011-02-04 2012-02-03 Compositions and methods for treatment of chronic inflammation and inflammatory diseases
PCT/GB2012/050242 WO2012104655A2 (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases
AU2012213218A AU2012213218C1 (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases
BR112013019732-3A BR112013019732B1 (en) 2011-02-04 2012-02-03 PHARMACEUTICAL COMPOSITION AND ITS USE IN THE TREATMENT OF CARDIOVASCULAR DISEASES
AU2012213217A AU2012213217B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
NZ613812A NZ613812B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating chronic inflammation and inflammatory diseases
EP12704295.0A EP2670389A1 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
US13/365,824 US8895536B2 (en) 2010-10-29 2012-02-03 Compositions and methods for treating chronic inflammation and inflammatory diseases
SG2013059357A SG192620A1 (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases
RU2016138830A RU2016138830A (en) 2011-02-04 2012-02-03 COMPOSITIONS AND METHODS FOR TREATMENT OF CARDIOVASCULAR DISEASES
NZ711187A NZ711187B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular disease
JP2013552271A JP2014507429A (en) 2011-02-04 2012-02-03 Compositions and methods for the treatment of cardiovascular disease
CA2826506A CA2826506C (en) 2011-02-04 2012-02-03 Compositions 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
MX2013008850A MX364229B (en) 2011-02-04 2012-02-03 COMPOSITIONS and METHODS FOR TREATING CARDIOVASCULAR DISEASES.
CA2826452A CA2826452C (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
JP2013552272A JP2014504629A (en) 2011-02-04 2012-02-03 Compositions and methods for treating chronic inflammation and inflammatory diseases
PCT/GB2012/050241 WO2012104654A1 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
CN201280007753.4A CN103391767B (en) 2011-02-04 2012-02-03 The compositions for the treatment of cardiovascular disease and method
EP12704296.8A EP2670390A2 (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases
NZ613805A NZ613805B2 (en) 2011-02-04 2012-02-03 Compositions and methods for treating cardiovascular diseases
CN201280007770.8A CN103391768B (en) 2011-02-04 2012-02-03 Treat chronic inflammatory disease and the compositions of inflammatory diseases and method
US13/365,828 US8895537B2 (en) 2010-10-29 2012-02-03 Compositions and methods for treating cardiovascular diseases
BR112013019734A BR112013019734A2 (en) 2011-02-04 2012-02-03 compositions and methods for treating chronic inflammation and inflammatory diseases
EP18213159.9A EP3494961B1 (en) 2011-02-04 2012-02-03 Compositions and methods for treating chronic inflammation and inflammatory diseases
MX2013008851A MX346224B (en) 2011-02-04 2012-02-03 Compostions and methods for treating chronic inflammation and inflammatory diseases.
SG10201600854SA SG10201600854SA (en) 2011-02-04 2012-02-03 Compostions And Methods For Treating Chronic Inflammation And Inflammatory Diseases
RU2013140775/15A RU2013140775A (en) 2011-02-04 2012-02-03 COMPOSITIONS AND METHODS FOR TREATMENT OF 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
US14/155,080 US9265742B2 (en) 2010-10-29 2014-01-14 Compositions and methods for treating inflammatory pain
US14/155,147 US10695431B2 (en) 2010-10-29 2014-01-14 Solid solution compositions and use in cardiovascular disease
US14/155,167 US10695432B2 (en) 2010-10-29 2014-01-14 Solid solution compositions and use in severe pain
US14/155,108 US9308213B2 (en) 2010-10-29 2014-01-14 Solid solution compositions and use in chronic inflammation
US14/155,042 US9271950B2 (en) 2010-10-29 2014-01-14 Compositions for treating chronic inflammation and inflammatory diseases
US14/520,141 US9326958B2 (en) 2010-10-29 2014-10-21 Compositions for treating chronic inflammation and inflammatory diseases
US14/520,150 US9381180B2 (en) 2010-10-29 2014-10-21 Compositions and methods for treating chronic inflammation and inflammatory diseases
US14/520,159 US9427422B2 (en) 2010-10-29 2014-10-21 Compositions for treating cardiovascular diseases
US14/821,687 US9744132B2 (en) 2010-10-29 2015-08-07 Solid solution compositions and use in chronic inflammation
US14/975,608 US9737500B2 (en) 2010-10-29 2015-12-18 Compositions and methods for treating severe pain
US14/975,599 US9504664B2 (en) 2010-10-29 2015-12-18 Compositions and methods for treating severe pain
JP2016015164A JP6273304B2 (en) 2011-02-04 2016-01-29 Compositions and methods for treating chronic inflammation and inflammatory diseases
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
US15/195,623 US9827215B2 (en) 2010-10-29 2016-06-28 Solid solution compositions and use in chronic inflammation
US15/195,608 US9820952B2 (en) 2010-10-29 2016-06-28 Solid solution compositions and use in chronic inflammation
US15/219,245 US9789075B2 (en) 2010-10-29 2016-07-25 Compositions and methods for treating cardiovascular diseases
US15/289,083 US20170043016A1 (en) 2010-10-29 2016-10-07 Solid Solution Compositions and Use in Severe Pain
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US15/684,214 US10213381B2 (en) 2010-10-29 2017-08-23 Solid solution compositions and use in chronic inflammation
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US15/794,178 US10188619B2 (en) 2010-10-29 2017-10-26 Solid solution compositions and use in chronic inflammation
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US15/794,197 US10154975B2 (en) 2010-10-29 2017-10-26 Solid solution compositions and use in chronic inflammation
US16/012,036 US10426748B2 (en) 2010-10-29 2018-06-19 Compositions and methods for treating chronic inflammation and inflammatory diseases
US16/166,272 US10596132B2 (en) 2010-10-29 2018-10-22 Solid solution compositions and use in chronic inflammation
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US16/206,789 US10653778B2 (en) 2010-10-29 2018-11-30 Compositions and methods for treating chronic inflammation and inflammatory diseases
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US16/882,667 US11224659B2 (en) 2010-10-29 2020-05-25 Solid solution compositions and use in severe pain
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US17/113,476 US11730709B2 (en) 2010-10-29 2020-12-07 Compositions and methods for treating severe pain
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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
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