Soluble needle arrays for delivery of influenza vaccines

Abstract

Influenza vaccines are administered using solid biodegradable microneedles. The microneedles are lubricated from the influenza vaccine in combination with solid excipient(s) and, after penetrating the skin, they dissolve in situ and release the vaccine to the immune system. The influenza vaccine is (i) a purified influenza virus surface antigen vaccine, rather than a live vaccine or a whole-virus or split inactivated vaccine (ii) an influenza vaccine prepared from viruses grown in cell culture, not eggs, (iii) a monovalent influenza vaccine e.g. for immunising against a pandemic strain, (iv) a bivalent vaccine, (v) a tetravalent or >4 -valent vaccine, (vi) mercury-free vaccine, or (vii) a gelatin-free vaccine.

1 . A skin patch comprising a plurality of solid biodegradable microneedles, wherein the microneedles comprise a mixture of (i) a biosoluble and biodegradable matrix material and (ii) influenza vaccine selected from the group consisting of a purified influenza virus surface antigen vaccine, art influenza vaccine prepared from viruses grown in cell culture, a monovalent influenza vaccine, a bivalent vaccine, a tetravalent or >4-valent vaccine, a mercury-free vaccine, and a gelatin-free vaccine. 
     
     
         2 . A process for preparing a skin patch comprising a plurality of solid biodegradable microneedles, comprising steps of: (i) mixing a biosoluble and biodegradable matrix material with an influenza vaccine selected from the group consisting of a purified influenza virus surface antigen vaccine, art influenza vaccine prepared from viruses grown in cell culture, a monovalent influenza vaccine, a bivalent vaccine, a tetravalent or >-4-valent vaccine, a mercury-free vaccine, and a gelatin-free vaccine; and (ii) adding the mixture from step (i) to a mold containing cavities for forming microneedles. 
     
     
         3 . An aqueous liquid or solid material comprising (i) a biosoluble and biodegradable matrix material and (ii) an influenza vaccine selected from the group consisting of a purified influenza. virus surface antigen vaccine, an influenza vaccine prepared from viruses grown in cell culture, a monovalent influenza vaccine, a bivalent vaccine, a tetravalent or >4-valent vaccine, a mercury-free vaccine, and a gelatin-free vaccine. 
     
     
         4 . The patch, process or material of any one of  claims 1 - 3 , wherein the influenza vaccine is a purified influenza virus surface antigen vaccine. 
     
     
         5 . A skin patch comprising a plurality of solid biodegradable microneedles, wherein the microneedles comprise a mixture of (i) a biosoluble and biodegradable matrix material and (ii) an influenza virus hemagglutinin, wherein the amount of influenza virus hemagglutinin per patch is ≤16 μg per strain. 
     
     
         6 . The patch of  claim 5 , wherein the patch comprises a whole virus inactivated influenza vaccine, a split virus influenza vaccine, or a purified influenza virus surface antigen vaccine. 
     
     
         7 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is an influenza vaccine prepared from viruses grown in cell culture. 
     
     
         8 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is a monovalent influenza vaccine. 
     
     
         9 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is a bivalent influenza vaccine. 
     
     
         10 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is a tetravalent influenza vaccine. 
     
     
         11 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is a >4-valent influenza vaccine. 
     
     
         12 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is a mercury-free influenza vaccine. 
     
     
         13 . The patch, process or material of any one of  claims 1 - 6 , wherein the influenza vaccine is a gelatin-free influenza vaccine. 
     
     
         14 . The patch, process or material of any preceding claim, wherein the matrix material comprises one or more carbohydrates. 
     
     
         15 . The patch, process or material of  claim 14 , wherein the matrix material comprises a cellulose and/or a dextrin and/or a disaccharide. 
     
     
         16 . The patch or process of any preceding claim, wherein the microneedles are 100-2500 μm long and are tapered with a skin-facing point. 
     
     
         17 . The patch or process of any preceding claim, wherein a single patch has >20 microneedles. 
     
     
         18 . The patch or process of any preceding claim, wherein the patch has an area of ≤2 cm 2 . 
     
     
         19 . The patch or process of any preceding claim, wherein a skin-facing area of the patch includes an adhesive to facilitate adherence to a subject's skin. 
     
     
         20 . The patch, process or material of any preceding claim, comprising between 0.5-50 μg or detergent per μg of hemagglutinin. 
     
     
         21 . The patch, process or material of any preceding claim, containing 1-15 μg, of hemagglutinin per influenza virus strain. 
     
     
         22 . A method of raising an immune response in a subject, comprising the step of applying a patch of any preceding claim to the subject's skin, such that the patch's microneedles penetrate the skin's dermis. 
     
     
         23 . A process for determining the amount of influenza hemagglutinin in a skin patch, wherein (a) the patch comprises a biosoluble & biodegradable matrix material and an influenza vaccine, and (b) the process comprises steps of (i) dissolving the patch in a solvent to provide a dissolved patch solution; and (ii) assaying hemagglutinin in the dissolved patch solution by enzyme-linked immunosorbent assay (ELISA). 
     
     
         24 . The process of  claim 23 , wherein the ELISA is a capture ELISA using immobilised anti-hemagglutinin antibodies. 
     
     
         25 . The process of  claim 23  or  claim 24 , wherein the influenza vaccine is a multivalent influenza vaccine, and wherein the ELISA separately uses strain-specific anti-hernagglutinin antibody for each strain.