Active agent transport systems

• US 6,221,367 B1
• Filed: 09/29/1997
• Issued: 04/24/2001
• Est. Priority Date: 06/15/1992
• Status: Expired due to Fees

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Leone-Bay, Andrea, Sarubbi, Donald J., Milstein, Sam J., Leipold, Harry
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Channavajjala, Lakshmi
• Application Number:
  US08/939,939
• Time in Patent Office: 1,303 Days
• Field of Search: 424/489, 424/490, 424/421, 424/400, 514/573
• US Class Current: 424/400
• 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 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• 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 47/183 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• 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 9/0019 : Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 : Nose
• CPC Class Codes: A61K 9/0056 : Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• 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: A61K 9/4858 : Organic compounds
• 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 233/47 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/48 : having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 233/51 : having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/52 : with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
• 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 233/83 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/84 : of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 233/87 : of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/34 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• 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 235/52 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/60 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• 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 235/82 : with the carbon 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 235/84 : 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 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• 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: E04F 2011/1048 : with lighting means

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. A method for preparing a subcutaneously deliverable biologically active agent, said method comprising:

(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 said native state and is conformationally between said native and denatured states; and

(b) exposing said biologically active agent to a complexing perturbant to reversibility transform said biologically active agent to said intermediate state and to form a subcutaneously deliverable supramolecular complex,

said perturbant having a molecular weight ranging from about 150 to about 600 daltons, and having at least one hydrophilic moiety and at least one hydrophobic moiety,

said supramolecular complex comprising said perturbant non-covalently complexed with said biologically active agent;

said biologically active agent not forming a microsphere with said perturbant; and

said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

2. A method as defined in claim 1, wherein said intermediate state has Δ

G ranging from about −

20 kcal/mole to about 20 kcal/moles relative to said native state.

3. A method as defined in 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.

4. A method as defined in claim 3, 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.

13. A subcutaneous delivery composition comprising a mimetic of the subcutaneous delivery composition prepared by the method of claim 1.

5. A subcutaneous 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;

wherein said intermediate state is reversible to said native state and is conformationally between a native conformational and a denatured conformational state of said biologically active agent, said composition is not a microsphere, said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent, and said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, (4-methylphenyl)cyclohexane acetic acid, and salts thereof.

6. A composition as defined in claim 5, 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.

7. A composition as defined in claim 6, 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.

8. A dosage unit form comprising:

(A) a composition as defined in claim 5; 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.

9. A method for preparing an agent which is capable of being deliverable by the subcutaneous route to a subject in need of said agent, said method comprising:

(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 said native state and is conformationally between said native and denatured states;

(b) exposing said biologically active agent to a complexing perturbant to reversibly transform said biologically active agent to said intermediate state and to form a subcutaneously deliverable supramolecular complex,

said perturbant having a molecular weight between about 150 and about 600 daltons, and having at least one hydrophilic moiety and one hydrophilic moiety,

said supramolecular complex comprising said perturbant non-covalently complexed with said biologically active agent,

said biologically active agent not forming a microsphere with aid perturbant, and

said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent; and

(c) preparing a mimetic of said supramolecular complex,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

10. A method as defined in claim 9, wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.

11. A method for preparing an agent which is capable of being delivered by the subcutaneous route to a subject in need of said agent, said method comprising:

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

(b) exposing said biologically active agent to a perturbant to reversibly transform said biologically active agent to said intermediate state, wherein said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent; and

(c) preparing a mimetic of said intermediate state,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

12. A method as defined in claim 11, wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.

14. A method for preparing a sublingually deliverable biologically active agent, said method comprising:

(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 said native state and is conformationally between said native and denatured states; and

(b) exposing said biologically active agent to a complexing perturbant to reversibility transform said biologically active agent to said intermediate state and to form a subcutaneously deliverable supramolecular complex,

said perturbant having a molecular weight ranging from about 150 to about 600 daltons, and having at least one hydrophilic moiety and at least one hydrophobic moiety,

said supramolecular complex comprising said perturbant non-covalently complexed with said biologically active agent;

said biologically active agent not forming a microsphere with said perturbant; and

said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

15. A method as defined in claim 14, wherein said intermediate state has Δ

G ranging from about −

20 kcal/mole to about 20 kcal/moles relative to said native state.

16. A method as defined in claim 14, 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.

17. A method as defined in claim 16, 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.

26. An oral delivery composition comprising a mimetic of the oral delivery composition prepared by the method of claim 14.

18. A sublingual 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;

wherein said intermediate state is reversible to said native state and is conformationally between a native conformational and a denatured conformational state of said biologically active agent, said composition is not a microsphere, said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent, and said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, (4-methylphenyl)cyclohexane acetic acid, and salts thereof.

19. A composition as defined in claim 18, 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.

20. A composition as defined in claim 19, 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.

21. A dosage unit form comprising:

(A) a composition as defined in claim 18, 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.

22. A method for preparing an agent which is capable of being administered by the sublingual route to a subject in need of said agent, said method comprising:

(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 said native state and is conformationally between said native and denatured states;

(b) exposing said biologically active agent to a complexing perturbant to reversibility transform said biologically active agent to said intermediate state and to form a subcutaneously deliverable supramolecular complex,

said perturbant having a molecular weight ranging from about 150 to about 600 daltons, and having at least one hydrophilic moiety and one hydrophobic moiety,

said supramolecular complex comprising said perturbant non-covalently complexed with said biologically active agent, and

said biologically active agent not forming a microsphere with said perturbant;

wherein said perturbant is in an amount effective for sublingual delivery of said biologically active agent; and

(c) preparing a mimetic of said supramolecular complex,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

23. A method as defined in claim 22, wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.

24. A method for preparing an agent which is capable of being administered by the sublingual route to a subject in need of said agent, said method comprising:

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

(b) exposing said biologically active agent to a perturbant to reversibly transform said biologically active agent to said intermediate state, wherein said perturbant is in an amount effective for sublingual delivery of said biologically active agent; and

(c) preparing a mimetic of said intermediate state,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

25. A method as defined in claim 24, wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.

27. A method for preparing an intranasally deliverable biologically active agent, said method comprising:

(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 said native state and is conformationally between said native and denatured states; and

(b) exposing said biologically active agent to a complexing perturbant to reversibility transform said biologically active agent to said intermediate state and to form an intranasally deliverable supramolecular complex,

said perturbant having a molecular weight ranging from about 150 to about 600 daltons, and having at least one hydrophilic moiety and at least one hydrophobic moiety,

said supramolecular complex comprising said perturbant non-covalently complexed with said biologically active agent; and

said biologically active agent not forming a microsphere with said perturbant;

said perturbant being present in an amount effective for intranasal delivery of said biologically active agent,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

28. A method as defined in claim 27, wherein said intermediate state has Δ

G ranging from about −

20 kcal/mole to about 20 kcal/moles relative to said native state.

29. A method as defined in claim 27, 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.

30. A method as defined in claim 29, 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.

39. An oral delivery composition comprising a mimetic of the oral delivery composition prepared by the method of claim 27.

31. An intranasal 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;

wherein said intermediate state is reversible to said native state and is conformationally between a native conformational and a denatured conformational state of said biologically active agent, said composition is not a microsphere, said perturbant being present in an amount effective for intranasal delivery of said biologically active agent, and said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, (4-methylphenyl)cyclohexane acetic acid, and salts thereof.

32. A composition as defined in claim 31, 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.

33. A composition as defined in claim 32, 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.

34. A dosage unit form comprising:

(A) a composition as defined in claim 31, 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.

35. A method for preparing an agent which is capable of being administered by the intranasal route to a subject in need of said agent, said method comprising:

(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 said native state and is conformationally between said native and denatured states; and

(b) exposing said biologically active agent to a complexing perturbant to reversibility transform said biologically active agent to said intermediate state and to form an intranasally administrable supramolecular complex,

said perturbant having a molecular weight ranging from about 150 and about 600 daltons, and having at least one hydrophilic moiety and at least one hydrophobic moiety,

said supramolecular complex comprising said perturbant non-covalently complexed with said biologically active agent, and

said biologically active agent not forming a microsphere with said perturbant;

wherein said perturbant is in an amount effective for intranasal delivery of said biologically active agent; and

(c) preparing a mimetic of said supramolecular complex,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

36. A method as defined in claim 35, wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.

37. A method for preparing an agent which is capable of being administered by the intranasal route to a subject in need of said agent, said method comprising:

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

(b) exposing said biologically active agent to a complexing perturbant to reversibly transform said biologically active agent to said intermediate state, wherein said perturbant is in an amount effective for intranasal delivery of said biologically active agent; and

(c) preparing a mimetic of said intermediate state,

wherein said perturbant is selected from the group consisting of cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, cyclohexane acetic acid, and salts thereof.

38. A method as defined in claim 37, wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.