Compositions for the delivery of antigens

• US 5,958,457 A
• Filed: 05/10/1995
• Issued: 09/28/1999
• Est. Priority Date: 04/22/1993
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Santiago, Noemi B., Leone-Bay, Andrea, Haas, Susan
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/438,644
• Time in Patent Office: 1,602 Days
• Field of Search: 424/490, 424/489, 424/488, 424/455, 424/491
• US Class Current: 424/490
• CPC Class Codes: A61K 2039/5252 inactivated (killed)
• CPC Class Codes: A61K 2039/542 oral/gastrointestinal
• CPC Class Codes: A61K 2039/55544 Bacterial toxins
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/25 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 233/55 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/63 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/87 : of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/38 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/64 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/84 : with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/22 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 279/14 : being further substituted by carboxyl groups
• CPC Class Codes: C07K 1/1077 : by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
• CPC Class Codes: C07K 5/06043 : Leu-amino acid
• CPC Class Codes: C12N 2720/10034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Abstract

The present invention relates to compositions and methods for orally delivering antigens. The antigen and an adjuvant are combined with an acylated amino acid or polyamino acid and, a sulfonated amino acids or polyamino acid, or a salt of the foregoing.

Claims

1. A composition comprising:

(a) an antigen;

(b) an adjuvant;

(c) at least one carrier comprising a member selected from the groups consisting of;

(i) an acylated amino acid or a salt thereof;

(ii) a poly amino acid comprising at least one acylated amino acid or a salt thereof;

(iii) a sulfonated amino acid or a salt thereof;

(iv) a poly amino acid comprising at least one sulfonated amino acid or a salt thereof;

or

(v) any combination thereof;

wherein said adjuvant is selected from the group consisting of purified protein derivative (PPD), poly adenylic acid (poly A), polyuridylic acid (poly U), muramyl dipeptides, inulin, zymosan, levamisol, Corynebacterium parvum, polyphophazenes, bacterial toxins, bacterial toxin subunits, bacterial toxoids, or any combination thereof.

2. A composition as defined in claim 1, comprising a mixture.

3. A composition as defined in claim 1, comprising a microsphere.

4. A composition as defined in claim 1, wherein said antigen comprises a peptide.

5. A composition as defined in claim 1, wherein said adjuvant comprises a mucosal adjuvant.

6. A composition as defined in claim 1, wherein said carrier comprises an acylated amino acid or a salt thereof.

7. A composition as defined in claim 1, wherein said carrier comprises a poly amino acid comprising at least one acylated amino acid or a salt thereof.

8. A composition as defined in claim 1, wherein said carrier comprises a sulfonated amino acid or a salt thereof.

9. A composition as defined in claim 1, wherein said carrier comprises a poly amino acid comprising at least one sulfonated amino acid or a salt thereof.

10. A composition as defined in claim 1, wherein said carrier is selected from the group consisting of, N-cyclohexanoyl arginine;

a mixture of N-cyclohexanoyltyrosine and N-cyclohexanoylleucine;

a mixture of N-phenylsulfonylvaline, N-phenylsulfonylleucine, N-phenylsulfonylphenylalanine, N-phenylsulfonyllysine, and N-phenylsulfonylarginine; and

a mixture of N-benzoylvaline, N-benzoylleucine, N-benzoylphenylalanine, N-benzoyllysine, and N-benzoylarginine.

39. A composition as defined in claim 1, wherein said adjuvant is selected from the group consisting of E. coli heat labile enterotoxin (LT-OA), cholera toxin, diphtheria toxin, cholera toxin β

-subunits, E. coli heat labile enterotoxin subunits, or any combination thereof.

11. A composition comprising:

(a) ovalbumin;

(b) cholera toxin; and

(c) at least one carrier comprising a member selected from the groups consisting of;

(i) an acylated amino acid or a salt thereof;

(ii) a poly amino acid comprising at least one acylated amino acid or a salt thereof;

(iii) a sulfonated amino acid or a salt thereof;

(iv) a poly amino acid comprising at least one sulfonated amino acid or a salt thereof;

or

(v) any combination thereof.

12. A composition comprising:

(a) Infectious Bursal Disease Virus;

(b) cholera toxin;

(c) cholera toxin β

-subunit; and

(d) at least one carrier comprising a member selected from the groups consisting of;

(i) an acylated amino acid or a salt thereof;

(ii) a poly amino acid comprising at least one acylated amino acid or a salt thereof;

(iii) a sulfonated amino acid or a salt thereof;

(iv) a poly amino acid comprising at least one sulfonated amino acid or a salt thereof;

or

(v) any combination thereof.

13. A composition as defined in claim 12, comprising a microsphere.

14. A composition as defined in claim 12, wherein the carrier comprises a mixture of N-phenylsulfonylvaline, N-phenylsulfonylleucine, N-phenylsulfonylphenylalanine, N-phenylsulfonyllysine, and N-phenylsulfonylarginine;

and a stabilizer.

15. A composition as defined in claim 14, wherein said stabilizer comprises sodium 2-cyclohexylbutyrate.

16. A composition comprising:

(a) an antigen;

(b) an adjuvant;

(c) at least one carrier comprising at least one (i) amino acid or polyamino acid modified by reaction with an amino acid reactive modifying agent selected from the group consisting of benzene sulfonyl chloride, benzoyl chloride, hippuryl chloride and amino acid carbodiimide, or (ii) a salt of (i);

wherein said adjuvant is selected from the group consisting of polypeptide derivative (PPD), polyadenyic acid (poly A), polyuridylic acid (poly U), muramyl dipeptides, inulin, zymosan, levamisol, Corynebacterium parvum, polyphophazenes, bacterial toxins, bacterial toxin subunits, bacterial toxoids, or any combination thereof.

17. A composition as defined in claim 16, comprising a mixture.

18. A composition as defined in claim 16, comprising a microsphere.

19. A composition as defined in claim 16, wherein said antigen comprises a peptide.

20. A composition as defined in claim 16, wherein said adjuvant comprises a mucosal adjuvant.

21. A composition as defined in claim 16, wherein said carrier comprises an acylated amino acid or a salt thereof.

22. A composition as defined in claim 16, wherein said carrier comprises a poly amino acid comprising at least one acylated amino acid or a salt thereof.

23. A composition as defined in claim 16, wherein said carrier comprises a sulfonated amino acid or a salt thereof.

24. A composition as defined in claim 16, wherein said carrier comprises a poly amino acid comprising at least one sulfonated amino acid or a salt thereof.

25. A composition as defined in claim 16, wherein said carrier is selected from the group consisting of, N-cyclohexanoyl arginine;

a mixture of N-cyclo-hexanoyltyrosine and N-cyclohexanoylleucine;

a mixture of N-phenylsulfonylvaline, N-phenylsulfonylleucine, N-phenylsulfonylphenylalanine, N-phenylsulfonyllysine, and N-phenylsulfonylarginine; and

a mixture of N-benzoylvaline, N-benzoylleucine, N-benzoyl-phenylalanine, N-benzoyllysine, and N-benzoylarginine.

30. A dosage unit form comprising

(A) a composition according to claim 16;

and

(B) (a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

31. A dosage unit form according to claim 30 comprising a tablet, a capsule, or a liquid.

32. A method for administering an antigen to an animal, said method comprising orally administering a composition as defined in claim 16.

34. A method for preparing a composition as defined in claim 16, said method comprising mixing an antigen, an adjuvant, and a carrier comprising at least one carrier comprising at least one

(i) amino acid or polyamino acid modified by reaction with an amino acid reactive modifying agent selected from the group consisting of benzene sulfonyl chloride, benzoyl chloride, hippuryl chloride and amino acid carbodiimide, or

(ii) a salt of (i);

wherein said adjuvant is selected from the group consisting of purified protein derivative(PPD), polyadenylic acid (poly A), polyuridylic acid (poly U), muramyl dipeptides, inulin, zymosan, levamisol, Corynebacterium parvum, polyphophazenes, bacterial toxins, bacterial toxin subunits, bacterial toxoids, or any combination thereof.

40. A composition as defined in claim 16, wherein said adjuvant is selected from the group consisting of E. coli heat labile enterotoxin (LT-OA), cholera toxin, diphtheria toxin, cholera toxin β

-subunits, E. coli heat labile enterotoxin subunits, or any combination thereof.

41. A method as defined in claim 34, wherein said adjuvant is selected from the group consisting of E. coli heat labile enterotoxin (LT-OA), cholera toxin, diphtheria toxin, cholera toxin β

-subunits, E. coli heat labile enterotoxin subunits, or any combination thereof.

26. A composition comprising:

(a) ovalbumin;

(b) cholera toxin; and

(c) at least one carrier comprising at least one (i) amino acid or polyamino acid modified by reaction with an amino acid reactive modifying agent selected from the group consisting of benzene sulfonyl chloride, benzoyl chloride, hippuryl chloride and amino acid carbodiimide, or (ii) a salt of (i).

27. A composition comprising:

(a) Infectious Bursal Disease Virus;

(b) cholera toxin;

(c) cholera toxin β

-subunit; and

(d) at least one carrier comprising at least one (i) amino acid or polyamino acid modified by reaction with an amino acid reactive modifying agent selected from the group consisting of benzene sulfonyl chloride, benzoyl chloride, hippuryl chloride and amino acid carbodiimide, or (ii) a salt of (i).

28. A composition as defined in claim 27, comprising a microsphere.

29. A composition as defined in claim 28, wherein said carrier is selected from the group consisting of a benzene amide of an amino acid and a benzene sulfonamide of an amino acid.

33. A method for immunizing chickens, said method comprising orally administering a composition as defined in claim 27.

37. A composition as defined in claim 27, wherein the carrier comprises a mixture of N-phenylsulfonylvaline, N-phenylsulfonylleucine, N-phenylsulfonylphenylalanine, N-phenylsulfonyllysine, and N-phenylsulfonylarginine;

and a stabilizer.

38. A composition as defined in claim 37, wherein said stabilizer comprises sodium 2-cyclohexylbutyrate.

35. A method for preparing microspheres, said method comprising:

(A) solubilizing, in a solvent, at least one carrier to provide a carrier solution; and

(B) contacting said carrier solution with an antigen, an adjuvant, and a precipitator solution in which said carrier is insoluble;

wherein said carrier comprises at least one carrier comprising at least one

(i) amino acid or polyamino acid modified by reaction with an amino acid reactive modifying agent selected from the group consisting of benzene sulfonyl chloride, benzoyl chloride, hippuryl chloride and amino acid carbodiimide, or

(ii) a salt of (I);

wherein said adjuvant is selected from the group consisting of purified protien derivative (PPD), polyadenylic acid (poly A), polyuridylic acid (poly U), muramyl dipeptides, inulin, zymosan, levamisol, Corynebacterium parvum, polyphophazenes, bacterial toxins, bacterial toxin subunits, bacterial toxoids, or any combination thereof.

36. A method as defined in claim 35, wherein said carrier solution has a pH within a first range and said precipitator solution has a pH within a second range, said first range being different than said second range.

42. A method as defined in claim 35, herein said adjuvant is selected from the group consisting of E. coli heat labile enterotoxin (LT-OA), cholera toxin, diphtheria toxin, cholera toxin β

-subunits, E. coli heat labile enterotoxin subunits, or any combination thereof.