Nasal immunization
Compositions and methods for intranasal delivery of antigens for immunization of a mammal are disclosed. Antigens include peptides, proteins, peptidomimetics, DNA, RNA, carbohydrates and phospholipids. The compositions contain at least one antigen and a permeation enhancer. The permeation enhancer can be a macrocyclic permeation enhancer, such as a Hsieh enhancer.
1. A pharmaceutical composition for nasal immunization comprising:
a macrocyclic permeation enhancer, a liquid carrier, an emulsifying agent, and a therapeutically effective amount of an antigen; wherein said macrocyclic permeation enhancer is a Hsieh enhancer having the following structure:
wherein X is oxygen, sulfur or an imino group of the structure
wherein Y is oxygen, sulfur or an imino group of the structure
═N—R with the proviso that when Y is the imino group, X is an imino group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1 to R 6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11, wherein the antigen is selected from the group consisting of an Anthrax protective antigen, a carbohydrate, and DNA.
2. The composition of claim 1 , wherein said Hsieh enhancer is selected from the group consisting of 3-methylcyclopentadecanone, 9-cycloheptadecen-1-one, cyclohexadecanone, cyclopentadecanone, oxacyclohexadecan-2-one and mixtures thereof.
3. The composition of claim 1 , further comprising a crystallization inhibitor.
4. The composition of claim 1 , further comprising an enzyme inhibitor.
5. The composition of claim 4 , wherein said enzyme inhibitor is selected from the group consisting of leupeptin and aprotinin.
6. A method of immunizing a mammal comprising the steps of:
formulating a composition comprising: a macrocyclic permeation enhancer, a liquid carrier, an emulsifying agent, and a therapeutically effective amount of an antigen; wherein said macrocyclic permeation enhancer is a Hsieh enhancer having the following structure:
wherein X is oxygen, sulfur or an imino group of the structure
wherein Y is oxygen, sulfur or an imino group of the structure
═N—R with the proviso that when Y is the imino group, X is an imino group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1 to R 6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11, wherein the antigen is selected from the group consisting of an Anthrax protective antigen, a carbohydrate, and DNA; and,
administering the composition to the mammal by nasal administration.
7. The method of claim 6 , wherein said Hsieh enhancer is selected from the group consisting of 3-methylcyclopentadecanone, 9-cycloheptadecen-1-one, cyclohexadecanone, cyclopentadecanone, oxacyclohexadecan-2-one and mixtures thereof.
8. The method of claim 6 , further comprising a crystallization inhibitor.
9. The method of claim 6 , further comprising an enzyme inhibitor.
10. The method of claim 9 , wherein said enzyme inhibitor is selected from the group consisting of leupeptin and aprotinin.
11. A pharmaceutical composition for nasal immunization comprising: a macrocyclic permeation enhancer, a liquid carrier, an emulsifying agent, and a therapeutically effective amount of an antibody; wherein said macrocyclic permeation enhancer is a Hsieh enhancer.