Active agent transport systems

• US 6,245,359 B1
• Filed: 09/30/1997
• Issued: 06/12/2001
• Est. Priority Date: 06/15/1992
• Status: Expired due to Fees

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Leone-Bay, Andrea, Wang, Nai Fang, Sarubbi, Donald J., Milstein, Sam J., Barantsevitch, Evgueni, Santiago, Noemi B
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/941,616
• Time in Patent Office: 1,351 Days
• Field of Search: 424/490, 424/489, 424/491, 424/450, 424/488, 424/451
• US Class Current: 424/490
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• 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 38/28 Insulins
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• 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: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61Q 13/00 Formulations or additives for perfume preparations essential oils or perfumes per se C11B9/00
• 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 235/54 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than 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

Abstract

Methods for transporting a biologically active agent across a cellular membrane or a lipid bilayer. A first method includes the steps of:

(a) providing a biologically active agent which can exist in a native conformational state, a denatured conformational state, and an intermediate conformational state which is reversible to the native state and which is conformationally between the native and denatured states;

(b) exposing the biologically active agent to a complexing perturbant to reversibly transform the biologically active agent to the intermediate state and to form a transportable supramolecular complex; and

(c) exposing the membrane or bilayer to the supramolecular complex, to transport the biologically active agent across the membrane or bilayer. The perturbant has a molecular weight between about 150 and about 600 daltons, and contains at least one hydrophilic moiety and at least one hydrophobic moiety. The supramolecular complex comprises the perturbant non-covalently bound or complexed with the biologically active agent. In the present invention, the biologically active agent does not form a microsphere after interacting with the perturbant. A method for preparing an orally administrable biologically active agent comprising steps (a) and (b) above is also provided as are oral delivery compositions.

Additionally, mimetics and methods for preparing mimetics are contemplated.

Claims

1. An oral delivery composition comprising a supramolecular complex comprising:

(a) a biologically active agent in an intermediate conformational state non-covalently complexed with

(b) a complexing perturbant having a molecular weight ranging from about 150 to about 600 and having at least one hydrophilic moiety and at least one hydrophobic moiety;

said intermediate conformational state being reversible to a native state, said intermediate conformational state being between said native conformational state and a denatured conformational state of said biologically active agent, and said composition not being a microsphere.

2. The composition of claim 1, wherein said biologically active agent is selected from the group consisting of a peptide, a micropolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination of the foregoing.

3. The composition of claim 2 wherein said biologically-active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or any combination of any of the foregoing.

4. The composition of claim 1, wherein said perturbant is selected from the group consisting of

(a) a proteinoid;

(b) an acylated amino acid;

(c) an acylated poly amino acid;

(d) a sulfonated amino acid;

(e) a sulfonated poly amino acid;

(f) an acylated aldehyde of an amino acid;

(g) an acylated ketone of an amino acid;

(h) an acylated aldehyde of a poly amino acid;

(i) an acylated ketone of a poly amino acid; and

(j) a carboxylic acid having the formula

5. A dosage unit form comprising

(A) a composition as defined in claim 1;

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.

6. An oral delivery composition comprising a peptide mimetic of a peptidic biologically active agent having a native state, a denatured state, and an intermediate state conformationally between said native and denatured states, wherein said intermediate state is reversible to said native state.