Immunomodulatory compositions comprising a polymer matrix and an oil phase

Abstract

A pharmaceutical composition comprising a water-soluble polymer matrix in which are dispersed droplets of oil, the composition comprising at least one immunomodulator selected from an adjuvant, an antigen or a combination thereof. A method of manufacturing shaped compositions comprises mixing an aqueous solution of a water-soluble polymer with an oil-based liquid to form a water-in-oil emulsion, at least one of the aqueous solution and the oil-based liquid comprising an antigen or an adjuvant or a combination thereof, and then causing or allowing the resultant suspension to solidify into one or more beads or other shaped elements.

1 . A method of developing or inducing oral tolerance, the method comprising administering to a patient a pharmaceutical composition comprising a water-soluble polymer matrix in which an oil phase is dispersed, the composition comprising at least one immunomodulator selected from an adjuvant, an antigen or a combination thereof. 
     
     
         2 . The method of  claim 1 , wherein the development or induction of oral tolerance provides the treatment or prevention of a T-cell mediated autoimmune disorder. 
     
     
         3 . The method of  claim 2  wherein the T-cell mediated autoimmune disorder is selected from multiple sclerosis, rheumatoid arthritis, colitis, Crohn's disease, stroke, Alzheimer's disease, atherosclerosis or type 1 diabetes. 
     
     
         4 . The method of  claim 2  wherein the T-cell mediated autoimmune disorder is Th1-mediated colitis. 
     
     
         5 . The method of  claim 1 , wherein the development and/or induction of oral tolerance provides treatment or prevention of arthritis, autoimmune uveitis, autoimmune myasthenia gravis, insulin-dependent diabetes mellitus, transplantation rejection, thyroiditis or multiple sclerosis. 
     
     
         6 . The method of  claim 1 , wherein the development and/or induction of oral tolerance provides a treatment prevention of celiac disease, a food allergy or a general allergy. 
     
     
         7 . A method of preventing antibodies being raised against a biological pharmaceutical, the method comprising administering to an animal a pharmaceutical composition comprising a water-soluble polymer matrix in which an oil phase is dispersed, the composition comprising at least one immunomodulator selected from an adjuvant, an antigen or a combination thereof, wherein a tolerising amount of the composition is administered to the animal on one or more occasions before the biological pharmaceutical is administered to the animal. 
     
     
         8 . The composition of  claim 7 , wherein the animal is a human. 
     
     
         9 . The composition of  claim 7 , wherein the biological pharmaceutical is selected from a peptide, a protein or an antibody therapeutic. 
     
     
         10 . The method of  claim 1 , wherein the immunomodulator is selected from: type II collagen; S-antigens; Torpedo acetyl-choline receptor; allogenic cells; allopeptides; dietary specific peptides, proteins or antigens; thyroglobulin; tissue transglutaminase; gliadin; HLA-DQ218; copolymer I; or myelin antigens. 
     
     
         11 . The method of  claim 10 , wherein the antigen is selected from a modified-live or killed microorganism. 
     
     
         12 . The method of  claim 1 , wherein the immunomodulator comprises an antigen and an immunosuppressant. 
     
     
         13 . The method of  claim 12 , wherein the antigen is selected from a modified-live or killed microorganism. 
     
     
         14 . The method  claim 1 , wherein the immunosuppressant is selected from cyclosporin, tacrolimus, gancyclovir, etanercept, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, cortisol, aldosterone, dexamethasone, a cyclooxygenase inhibitor, a 5-lipoxygenase inhibitor, or leukotriene receptor antagonist. 
     
     
         15 . The method of  claim 12 , wherein the immunosuppressant is cyclosporin. 
     
     
         16 . The method of any  claim 12 , wherein the immunosuppressant is released in the intestine. 
     
     
         17 . The method of  claim 16 , wherein the immunosuppressant is also released at one or more other sites in the GI tract. 
     
     
         18 . The composition of  claim 1 , wherein the immunosuppressant is released in the colon. 
     
     
         19 . The method of  claim 18 , wherein the immunosuppressant is released at one or more other sites in the GI tract. 
     
     
         20 . The method of  claim 1 , wherein the composition delivers the immunomodulator to the lower GI tract. 
     
     
         21 . The method of  claim 20 , wherein the composition delivers the immunomodulator to the colon or rectum. 
     
     
         22 . The method of  claim 1 , wherein the composition is for oral administration. 
     
     
         23 . The method of  claim 1 , wherein the composition comprises a coating to permit release of the immunomodulator in the intestine, colon and/or rectum. 
     
     
         24 . The method of  claim 23 , wherein the coating comprises a polymer. 
     
     
         25 . The method of  claim 24 , wherein the polymeric coating degrades in the presence of bacterial enzymes present in the colon. 
     
     
         26 . The method of  claim 25 , wherein the coating comprises a pore-former and a pH-independent polymer. 
     
     
         27 . The method of any  claim 1 , wherein the composition comprises one or more surfactants. 
     
     
         28 . The method of  claim 27 , wherein the one or more surfactants are selected from non-ionic surfactants. 
     
     
         29 . The method of  claim 27 , wherein at least a portion of the one or more surfactants. 
     
     
         30 . The method of  claim 29 , wherein the whole surfactant content of the composition is in the oil phase. 
     
     
         31 . The method of  claim 1 , wherein the composition comprises one or more agents to enhance adsorption of an antigen onto, and absorption by, mucosal surfaces and/or the underlying mucosal lymphoid tissue, M-cells, Peyer's patches or other immune relevant cells or cell systems. 
     
     
         32 . The method of  claim 1 , wherein the water-soluble polymer is selected from gelatin, agar, a polyethylene glycol, starch, casein, chitosan, soya bean protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phtalated gelatine, succinated gelatine, cellulosephtalate-acetate, oleoresin, polyvinylacetate, hydroxypropyl methyl cellulose, polymerisates of acrylic or methacrylic esters and polyvinylacetate-phthalate, or combinations thereof. 
     
     
         33 . The method of  claim 32 , wherein the water-soluble polymer is selected from gelatin, agar and carrageenan. 
     
     
         34 . The method of  claim 1 , which is in the form of a mini-bead. 
     
     
         35 . The method of  claim 34 , wherein the mini-bead has a diameter of from 0.5 mm to 5 mm. 
     
     
         36 . The method of  claim 34 , wherein the mini-bead has a diameter of from 0.5 mm to 2.5 mm. 
     
     
         37 . The method of  claim 1 , wherein the composition comprises a population of minibeads. 
     
     
         38 . The method of  claim 1 , wherein the composition comprises a first population of minibeads and a second population of minibeads, wherein the first and second populations of minibeads are different. 
     
     
         39 . The method of  claim 1 , wherein the composition is in the form of a product selected from a suppository, a pessary, a pill, a tablet, a paste and a fluid. 
     
     
         40 . The method of  claim 1 , wherein the oil phase comprises droplets of oil. 
     
     
         41 . The method of  claim 40 , wherein the oil consists of a single liquid oleo-phase. 
     
     
         42 . The method of  claim 41 , wherein the liquid oleo-phase contains suspended solids, or contains an additional internal water phase. 
     
     
         43 . The method of  claim 41 , wherein the oil comprises one or more oils selected from: fatty acids; fatty acid esters; esters of polyethylene glycols; hydrocarbon oils; and steroids. 
     
     
         44 . The method of  claim 43 , wherein the oil comprises macrogolglyceride and hydrocarbon oil together with one or more surfactants. 
     
     
         45 . The method of  claim 44 , wherein the oil comprises a combination of macrogolglyceride, and squalene together with one or more surfactants. 
     
     
         46 . The method of  claim 44 , wherein the surfactant comprises a non-ionic surfactant. 
     
     
         47 . The method according to  claim 1 , wherein the composition further comprises a pro-biotic. 
     
     
         48 . A method of developing or inducing oral tolerance, the method comprising administering to a patient a pharmaceutical composition comprising a water-soluble polymer matrix in which an oil phase is dispersed, the composition comprising one or more probiotics.