Claims for Patent: 5,589,463

Summary for Patent: 5,589,463

Title:	Oral delivery of biologically active substances bound to vitamin B12
Abstract:	Complex of a drug, hormone, bio-active peptide, or immunogen with the carrier molecule vitamin B12 and a method for delivering the complex to the intestine of a host vertebrate in order to deliver the complex to the circulation of the host and thereby elicit a pharmacological response to the drug, hormone, bio-active molecule or to elicit a systemic immune response to the immunogen. The invention also provides a method for the production of the complex. Further, the invention provides medicaments containing the complex.
Inventor(s):	Russell-Jones; Gregory J. (Willoughby, AU), Howe; Peter (West Pennant Hills, AU), de Aizpurua; Henry J. (Bexley, AU), Burge; Geoffery L. (Thornleigh, AU)
Assignee:	Biotechnology Autralia Pty., Ltd. (Roseville, AU)
Application Number:	08/479,635
Patent Claims:	1. An orally administrable complex comprising an antigen or hapten that is covalently linked via a cross-linking agent to a vitamin B12 carrier molecule, wherein (A) said carrier molecule is capable of binding in vivo to intrinsic factor, thereby enabling uptake and transport of the complex from the intestinal lumen of a vertebrate host via intrinsic factor to the systemic circulation of said host, and (B) said cross-linking agent links said antigen or hapten to a carboxyl group of an acid-hydrolyzed propionamide side chain adjacent to ring A, ring B or ring C of said carrier molecule, and said antigen or hapten is an allergen, protein, polysaccharide or secretory product selected from the group consisting of polysaccharides, grass pollen, weed pollen, tree pollen, plant pollen, cat hair, dog hair, pig hair, other epithelia, house dust mite, wheat chaff, kapok, a protein from or immunogens against influenza, measles, Rubella, smallpox, yellow fever, diphtheria, tetanus, cholera, plague, typhus, BCG, tuberculosis causing agents, Haemophilus influenzae, Neisseria catarrhalis, Klebsiella pneumoniae, pneumococci, streptococci, a malarial parasite or the causative agent of coccidiosis in chickens, a secretory product from diphtheria, tetanus, cholera, plague, typhus, tuberculosis causing agents, Haemophilus influenzae, Neisseria catarrhalis, Klebsiella pneumoniae, pneumococci, streptococci, and Streptococcus mutans. 2. A complex according to claim 1, wherein said vitamin B12 carrier molecule is selected from the group consisting of cyanocobalamin, aquocobalamin, adenosylcobalamin, methylcobalamin, hydroxycobalamin, cyanocobalamin carbanilide, 5-0-methylbenzylcobalamin, desdimethyl, monoethylamide and methylamide analogues of cyanocobalamin, aquocobalamin, adenosylcobalamin, methylcobalamin, hydroxycobalamin, cyanocobalamin carbanilide and 5-0-methylbenzylcobalamin, coenzyme B12, 5'-deoxyadenosyl-cobalamin, chlorocobalamin, sulphitocobalamin, nitrocobalamin, thiocyanatocobalamin, adenosylcyanocobalamin, cobalamin lactone, cobalamin lactam, vitamin B12 anilide, vitamin B12 propionamide, and a vitamin B12 molecule in which one or two corrin ring side chains are free carboxylic acids. 3. A complex according to claim 1, wherein said vitamin B12 carrier molecule includes a central metal atom selected from the group consisting of Ni and Zn. 4. A complex according to claim 1, wherein said cross-linking agent is selected from the group consisting of N-(4-azidophenylthio)phthalimide, 4,4'-dithiobis-phenylazide, dithiobis(succinimidylpropionate), dimethyl-3,3'-dithiobispropionimidate.2HCl, 3,3'-dithiobis(sulphosuccinimidyl-propionate), ethyl-4-azidophenyl-1,4-dithiobutyrimidate.HCl, N-succinimidyl-(4-azidophenyl)-1,3'-dithiopropionate, sulphosuccinimidyl-2-(m-azido-o-nitrobenzamido)-ethyl-1,3'-dithiopropionat e, sulphosuccinimidyl-2-(p-azidosalicylamido)-ethyl-1,3'-dithiopropionate, N-succinimidyl-3-(2-pyridyldithio)propionate, sulphosuccinimidyl-(4-azidophenyldithio)-propionate and 2-iminothiolane. 5. A complex according to claim 1, wherein said cross-linking agent is bis(2-(succinimidyloxycarbonyloxy)ethyl)sulphone. 6. A formulation comprising (i) a complex according to claim 1 and (ii) an orally and pharmaceutically acceptable carrier or diluent. 7. A formulation according to claim 6, wherein said formulation is in an oral delivery form selected from the group consisting of a capsule, a tablet, an emulsion, a viscous colloidal dispersion, an elixir, a gel and a paste. 8. A method of treating a patient with an antigen or hapten, comprising the steps of (1) providing an orally administrable complex comprising said antigen or hapten covalently linked via a cross-linking agent to a vitamin B12 carrier molecule, wherein (A) said carrier molecule is capable of binding in vivo to intrinsic factor, thereby enabling uptake and transport of the complex from the intestinal lumen of said patient via intrinsic factor to the systemic circulation of said patient, and (B) said cross-linking agent links said antigen or hapten to a carboxyl group of an acid-hydrolyzed propionamide side chain adjacent to ring A, ring B or ring C of said carrier molecule; and (2) orally administering said complex to said patient so as to elicit a physiological effect associated with the presence of said antigen or hapten in the systemic circulation of said patient. 9. A complex according to claim 1, wherein said vitamin B12 carrier molecule is a cyanocobalamin methylamide or a cobalamin ethylamide. 10. A complex according to claim 1, wherein said vitamin B12 carrier molecule is selected from the group consisting of 5,6-dichlorobenzimidazolecobalamin, 5-hydroxybenzimidazole-cobalamin, and trimethylbenzimidazolecobalamin.

Details for Patent 5,589,463

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Allermed Laboratories, Inc.	N/A	animal allergens, standardized cat hair	Injection	103473	03/12/1974		2013-12-31