Intranasal Administration of Active Agents to the Central Nervous System

Abstract

Pharmaceutical compositions and methods for delivering a polypeptide to the central nervous system of a mammal via intranasal administration are provided. The polypeptide can be a catalytically active protein or an antibody, antibody fragment or antibody fragment fusion protein. The polypeptides are formulated with one or more specific agents.

1 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) a permeation enhancer in a concentration sufficient to enhance intranasal administration of the catalytically active peptide chain or the peptide chain comprising the antibody Fc or Fab fragment to the central nervous system of an animal.   
     
     
         2 . The pharmaceutical composition of  claim 1  wherein the catalytically active peptide chain is an enzyme. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the peptide chain comprising the antibody Fc or Fab fragment is a whole antibody. 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein the peptide chain comprising the antibody Fc or Fab fragment is a mimetibody. 
     
     
         5 . The pharmaceutical composition of  claim 1  in liquid form. 
     
     
         6 . The pharmaceutical composition of  claim 1  in powder or lyophilized form. 
     
     
         7 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) about 0.1 to about 1 g of chitosan glutamate or corresponding amounts of another chitosan salt per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state.   
     
     
         8 . The pharmaceutical composition of  claim 7  comprising about 0.5 g of chitosan glutamate per 100 ml of the pharmaceutical composition. 
     
     
         9 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) from about 0.125 g to about 1.0 g of a compound selected from the group consisting of 1-O-n-dodecyl-beta-D-maltopyranoside, 1-O-n-decyl-beta-D-maltopyranoside, 1-O-n-tetradecyl-beta-D-maltopyranoside, and beta-D-fructopyranosyl-alpha-glucopyranoside monododecanoate per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state.   
     
     
         10 . The pharmaceutical composition of  claim 9  comprising about 0.125 g to about 0.5 g of a compound selected from the group consisting of 1-O-n-dodecyl-beta-D-maltopyranoside, 1-O-n-decyl-beta-D-maltopyranoside, 1-O-n-tetradecyl-beta-D-maltopyranoside, and beta-D-fructopyranosyl-alpha-glucopyranoside monododecanoate per 100 ml of the pharmaceutical composition. 
     
     
         11 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) from about 5 ml to about 20 ml of propylene glycol per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state and the propylene glycol is at standard state.   
     
     
         12 . The pharmaceutical composition of  claim 11  comprising from about 10 ml to about 20 ml of propylene glycol per 100 ml of the pharmaceutical composition. 
     
     
         13 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) about 1 g to about 10 g of heptakis (2,6-di-O-methyl)-beta-cyclodextrin per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state.   
     
     
         14 . The pharmaceutical composition of  claim 13  comprising about 5 g of heptakis (2,6-di-O-methyl)-beta-cyclodextrin per 100 ml of the pharmaceutical composition. 
     
     
         15 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) about 1 g to about 5 g of 1,2-didecanoyl-sn-glycero-3-phosphocholine per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state and the 1,2-didecanoyl-sn-glycero-3-phosphocholine is emulsified in the aqueous buffer.   
     
     
         16 . The pharmaceutical composition of  claim 15  comprising about 2 g of 1,2-didecanoyl-sn-glycero-3-phosphocholine per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state and the 1,2-didecanoyl-sn-glycero-3-phosphocholine is emulsified in the aqueous buffer. 
     
     
         17 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) about 0.1 g to about 1 g of a compound selected from the group consisting of sodium glycocholate hydrate, taurocholic acid sodium salt hydrate, and sodium tauroursodeoxycholate per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state.   
     
     
         18 . The pharmaceutical composition of  claim 17  comprising about 1 g of a compound selected from the group consisting of sodium glycocholate hydrate, taurocholic acid sodium salt hydrate, and sodium tauroursodeoxycholate per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state. 
     
     
         19 . A pharmaceutical composition comprising:
 a) a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment; and   b) from about 1 ml to about 10 ml of tetrahydrofurfuryl-polyethyleneglycol per 100 ml of the pharmaceutical composition; wherein the diluent is an aqueous buffer at standard state and the tetrahydrofurfuryl-poyethylenglycol is at standard state.   
     
     
         20 . The pharmaceutical composition of  claim 1 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17  or  19  wherein the peptide chain comprising an antibody Fc fragment binds to a melanocortin 4 receptor comprising the amino acid sequence shown in SEQ ID NO: 2. 
     
     
         21 . The pharmaceutical composition of  claim 1 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17  or  19  wherein the peptide chain comprising an antibody Fc fragment comprises the amino acid sequence shown in SEQ ID NO: 3. 
     
     
         22 . A method of delivering a catalytically active peptide chain or a peptide chain comprising an antibody Fc or Fab fragment to the central nervous system of an animal comprising:
 a) providing the pharmaceutical composition of  claim 1 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17  or  19 ; and   b) administering the pharmaceutical composition to the nasal cavity of an animal; whereby the catalytically active peptide chain or the peptide chain comprising the antibody Fc or Fab fragment enters the central nervous system of the animal.   
     
     
         23 . A method of delivering a peptide chain comprising an antibody Fc fragment to the central nervous system of an animal comprising:
 a) providing the pharmaceutical composition of  claim 1 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17  or  19  wherein the peptide chain comprising the antibody Fc fragment binds to a melanocortin 4 receptor comprising the amino acid sequence shown in SEQ ID NO: 2; and   b) administering the pharmaceutical composition to the nasal cavity of an animal; whereby the peptide chain comprising the antibody Fc fragment enters the central nervous system of the animal.   
     
     
         24 . A method of delivering a peptide chain comprising an antibody Fc fragment to the central nervous system of an animal comprising:
 a) providing the pharmaceutical composition of  claim 1 ,  7 ,  9 ,  11 ,  13 ,  15 ,  17  or  19  wherein the peptide chain comprising the antibody Fc fragment comprises the amino acid sequence shown in SEQ ID NO: 3; and   b) administering the pharmaceutical composition to the nasal cavity of an animal; whereby the peptide chain comprising the antibody Fc fragment enters the central nervous system of the animal.