Lipid and Nitrous Oxide Combination as Adjuvant for the Enhancement of the Efficacy of Vaccines

Abstract

The invention provides for a method of enhancing immunological responses to an antigen in a vaccine formulation, and for a vaccine formulation that provides for an enhanced immunological response to an antigen. In the method and formulation the antigen is administered with an adjuvant which adjuvant comprises a solution of nitrous oxide gas in a pharmaceutically acceptable carrier solvent for the gas and which adjuvant includes at least one fatty acid or ester or other suitable derivative thereof selected from the group consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid [C20: 5ω3], decosahexaenoic acid [C22: 6ω3], ricinoleic acid and derivatives thereof selected from the group consisting of the C1 to C6 alkyl esters thereof, the glycerol-polyethylene glycol esters thereof and the reaction product of hydrogenated natural oils composed largely of ricinoleic acid based oils, such as castor oil with ethylene oxide.

1 . A method of enhancing direct or subsequent immunological responses to an antigen in a vaccine formulation, comprising the step of administering a formulation of the antigen with an adjuvant which adjuvant comprises a solution of nitrous oxide gas in a pharmaceutically acceptable carrier solvent for the gas and which adjuvant includes at least one fatty acid or ester or other suitable derivative thereof selected from the group consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenicacid, arachidonic acid, eicosapentaenoic acid [C20: 5w3], decosahexaenoic acid [C22: 6w3], ricinoleic acid and derivatives thereof selected from the group consisting of the C1 to C6 alkylesters thereof, the glycerol-polyethylene glycol esters thereof and the reaction product of hydrogenated natural oils comprising ricinoleic acid based oils. 
   
   
       2 . A pharmaceutical preparation suitable for use as a vaccine comprising an antigen and an adjuvant which adjuvant comprises a solution of nitrous oxide in a pharmaceutically acceptable carrier solvent for the gas and which includes at least one fatty acid or ester or other suitable derivative thereof selected from the group consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid [C20: 5w3], decosahexaenoic acid [C22: 6w3], ricinoleic acid and the derivatives thereof selected from the group consisting of the C1 to C6 alkyl esters thereof, the glycerol-polyethylene glycol esters thereof and the reaction product of hydrogenated natural oils comprising ricinoleic acid based oils. 
   
   
       3 . The method of  claim 1  in which the antigen or antigens utilized in the method is or are selected from the group of antigens consisting of peptides, inactivated viruses, inactivated bacteria and virus-like particles (VLPs). 
   
   
       4 . The method of  claim 1  wherein the antigen is suitable to elicit an immunogenic response against the causative agent of an ailment, or infection by an agent, selected from the group consisting of: Bacillus Calmette-Gu6rin Cholera, Haemophilus Type B, Meningococcal, Pertussis, Pneumococcal, Tetanus, Typhoid, Diphtheria, Hepatitis A, Hepatitis B, Humanpapilloma virus, Influenza, Measles, Mumps, Poliomyelitis, Rabies, Rubella, Tick-borne Encephalitis, Varicella and Yellow Fever. 
   
   
       5 . The method of  claim 1  wherein the adjuvant includes eicosapentaenoic acid [C20: 5w3] and/or clecosahexaenoic acid [C22: 6w3] or modifications of these as additional long chain fatty acids to at least one of the other components of the carrier medium. 
   
   
       6 . The method of  claim 1  wherein the reaction product of hydrogenated natural oils composed largely of ricinoleic acid based oils with ethylene oxide is produced from castor oil of which the fatty acid content is known to be predominantly composed of ricinoleic acid. 
   
   
       7 . The method of  claim 1  wherein the carrier solvent for the nitrous oxide gas is selected from the group consisting of water and the pharmaceutically acceptable alcohols, ethers, oils or polymers including polyethylene glycol. 
   
   
       8 . The method or the preparation of  claim 22  wherein the oil is an organic oil selected from the group consisting of the essential oils based on long chain fatty acids having between 14 and 22 carbon atoms in the fatty acid including oils of natural or synthetic origin and including plant oils and animal oils. 
   
   
       9 . The method of  claim 1  wherein the solution is an aqueous solution saturated with nitrous oxide, the water being deionised and purified to be free of microbes andendotoxins. 
   
   
       10 . The method of  claim 1  wherein the formulation containing the antigen is in a liquid presentation for oral administration or in a nasal or bronchial or pulmonary spray formulation or in the form of an injectable formulation, and wherein the formulation incorporates, as part of the administration medium, water or acceptable other liquid into which the nitrous oxide is dissolved and a fatty acid and in which the fatty acid(s) or ester(s) thereof is either dissolved or suspended or emulsified along with the antigen by being formulated therewith. 
   
   
       11 . The method of  claim 1  wherein the formulation containing the antigen is formulated to be administered to the patient by being applied as a topical, buccal, nasal or vaginal cream, ointment, spray, lotion or as a suppository, and wherein the formulation used in making up such cream, ointment, spray, lotion or suppository incorporates, along with the antigen formulated therewith, a quantity of water or other liquid containing, and preferably saturated with, nitrous oxide, the long chain fatty acid(s) or ester(s) thereof and the antigen formulated therewith, and, additional optional excipients and carriers. 
   
   
       12 . A carrier solvent for the nitrous oxide gas for use as at least part of a vaccine formulation, comprising at least one fatty acid or ester thereof selected from the group consisting of oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid [C20: 5w3], decosahexaenoic acid [C22: 6w3], ricinoleic acid and derivatives thereof selected from the group consisting of the C1 to C6 alkylesters thereof, the glycerol-polyethylene glycol esters thereof and the reaction product of hydrogenated natural oils comprising ricinoleic acid based oils with ethylene oxide. 
   
   
       13 . The preparation of  claim 2  wherein the formulation is made up to be suited to transdermal application as an injectable, ointment, cream or lotion or is in the form of a skin patch providing a reservoir for the formulation. 
   
   
       14 . The method of  claim 1  wherein the fatty acid component of the composition is constituted by the complex known as Vitamin F Ethyl Ester. 
   
   
       15 . The method of  claim 1  wherein the formulation is prepared to be adapted for mucosal administration and in particular nasal administration. 
   
   
       16 . A vaccine comprising a preparation as claimed in  claim 2  wherein the preparation includes one or more antigens that renders it suitable for use as a vaccine selected from the group consisting of: Bacillus Calmette-Gu6rin Vaccine, Cholera Vaccine, Haemophilus Type B Conjugate Vaccine, Meningococcal Polysaccharide Vaccine, Pertussis Vaccine, Pneumococcal Polysaccharide Vaccine, Tetanus Vaccine, Typhoid Vaccine, Diphtheria Vaccine Tetanus VaccineInactivated Hepatitis A VaccineHepatitis B Vaccine (peptide) Inactivated Influenza Vaccine (Whole Virion) Inactivated Influenza Vaccine (Split Virion) Inactivated Influenza Vaccine (Surface Antigen) Measles Vaccine, LiveMumps Vaccine, LiveInactivated Poliomyelitis VaccinePoliomyelitis Vaccine, Live (Oral) Rabies VaccineRubella Vaccine, LiveTick-borne Encephalitis Vaccine, InactivatedVaricella Vaccine LiveYellow Fever VaccineDiphtheria and Tetanus VaccineDiphtheria, Tetanus and Pertussis VaccineDiphtheria, Tetanus and Pertussis (Acellular Component) VaccineDiphtheria, Tetanus and Pertussis (Acellular Component) and Haemophilus Type B Conjugate VaccineDiphtheria, Tetanus and Pertussis (Acellular Component) and Hepatitis B (peptide) VaccineDiphtheria, Tetanus and Pertussis (Acellular Component) and Inactivated Poliomyelitis VaccineHepatitis A (Inactivated) and Hepatitis B (rDNA) VaccineMeasles, Mumps and Rubella Vaccine, Live. 
   
   
       17 . (canceled) 
   
   
       18 . (canceled) 
   
   
       19 . (canceled) 
   
   
       20 . The preparation of  claim 2  in which the antigen or antigens utilized in the formulation is or are selected from the group of antigens consisting of peptides, inactivated viruses, inactivated bacteria and virus-like particles (VLPs). 
   
   
       21 . The preparation of  claim 2  wherein the antigen is suitable to elicit an immunogenic response against the causative agent of an ailment, or infection by an agent, selected from the group consisting of: Bacillus Calmette-Gu6rin Cholera, Haemophilus Type B, Meningococcal, Pertussis, Pneumococcal, Tetanus, Typhoid, Diphtheria, Hepatitis A, Hepatitis B, Humanpapilloma virus, Influenza, Measles, Mumps, Poliomyelitis, Rabies, Rubella, Tick-borne Encephalitis, Varicella and Yellow Fever. 
   
   
       22 . The preparation of  claim 2  wherein the adjuvant includes eicosapentaenoic acid [C20: 5w3] and/or clecosahexaenoic acid [C22: 6w3] or modifications of these as additional long chain fatty acids to at least one of the other components of the carrier medium. 
   
   
       23 . The preparation of  claim 2  wherein the reaction product of hydrogenated natural oils comprising ricinoleic acid based oils with ethylene oxide is produced from castor oil of which the fatty acid content is predominantly composed of ricinoleic acid. 
   
   
       24 . The preparation of  claim 2  wherein the carrier solvent for the nitrous oxide gas is selected from the group consisting of water and the pharmaceutically acceptable alcohols, ethers, oils or polymers including polyethylene glycol. 
   
   
       25 . The preparation of  claim 2  wherein the solution is an aqueous solution saturated with nitrous oxide, the water being deionized and purified to be free of microbes and endotoxins. 
   
   
       26 . The preparation of  claim 2  wherein the formulation containing the antigen is in a liquid presentation for oral administration or in a nasal or bronchial or pulmonary spray formulation or in the form of an injectable formulation, and wherein the formulation—incorporates, as part of the administration medium, water or acceptable other liquid into which the nitrous oxide is dissolved and a fatty acid and in which the fatty acid(s) or ester(s) thereof is either dissolved or suspended or emulsified along with the antigen by being formulated therewith. 
   
   
       27 . The preparation of  claim 2  wherein the formulation containing the antigen is formulated to be administered to the patient by being applied as a topical, buccal, nasal or vaginal cream, ointment, spray, lotion or as a suppository, and wherein the formulation used in making up such cream, ointment, spray, lotion or suppository incorporates, along with the antigen formulated therewith, a quantity of water or other liquid containing, and preferably saturated with, nitrous oxide, the long chain fatty acid(s) or ester(s) thereof and the antigen formulated therewith, and additional optional excipients and carriers. 
   
   
       28 . The preparation of  claim 2  wherein the reaction product is castor oil with ethylene oxide. 
   
   
       29 . The method of  claim 1  wherein the reaction product is castor oil with ethylene oxide. 
   
   
       30 . The preparation of  claim 2  wherein the fatty acid component of the composition is constituted by the complex known as Vitamin F Ethyl Ester. 
   
   
       31 . The preparation of  claim 2  wherein the formulation is prepared to be adapted for mucosal administration and in particular nasal administration.