Active agent transport systems

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.

In the claims:  
     
         1 . A method for delivering, by the subcutaneous route, a biologically active agent to a subject in need of said 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;    (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 between 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; and  
   (c) subcutaneously administering said supramolecular complex to said subject.    
     
     
         2 . A method as defined in    claim 1   , further comprising 
 (d) after said administering step, removing said perturbant from said supramolecular complex to transform said biologically active agent to said native state.    
     
     
         3 . A method as defined in    claim 2   , wherein step (d) comprises diluting said supramolecular complex.  
     
     
         4 . A method as defined in    claim 1   , wherein said intermediate state has a ΔG ranging from about −20 kcal/mole to about 20 kcal/moles relative to said native state.  
     
     
         5 . A method as defined in    claim 1   , wherein said biologically active agent is selected from the group consisting of a peptide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination of the foregoing.  
     
     
         6 . A method as defined in    claim 5   , 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.  
     
     
         7 . A method as defined in    claim 1   , wherein said perturbant comprises a proteinoid.  
     
     
         8 . A method as defined in    claim 1   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         9 . A method as defined in    claim 1   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         10 . A method as defined in    claim 1   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         11 . A method as defined in    claim 1   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         12 . A method as defined in    claim 1   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2 to C 10  alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         13 . 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.  
   
     
     
         14 . A method as defined in    claim 13   , wherein said intermediate state has ΔG ranging from about −20 kcal/mole to about 20 kcal/moles relative to said native state.  
     
     
         15 . A method as defined in    claim 13   , 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.  
     
     
         16 . A method as defined in    claim 15   , 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.  
     
     
         17 . A method as defined in    claim 13   , wherein said perturbant comprises a proteinoid.  
     
     
         18 . A method as defined in    claim 13   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         19 . A method as defined in    claim 13   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         20 . A method as defined in    claim 13   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         21 . A method as defined in    claim 13   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         22 . A method as defined in    claim 13   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2 to C 10  alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         23 . 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 and said composition is not a microsphere; and said perturbant being present in an amount effective for subcutaneous delivery of said biologically active agent.    
     
     
         24 . A composition as defined in    claim 23   , 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.  
     
     
         25 . A composition as defined in    claim 24   , 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 . A composition as defined in    claim 23   , wherein said perturbant comprises a proteinoid.  
     
     
         27 . A composition as defined in    claim 23   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         28 . A composition as defined in    claim 46   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         29 . A composition as defined in    claim 23   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         30 . A composition as defined in    claim 23   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         31 . A composition as defined in    claim 23   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2  to C 10  alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         32 . A dosage unit form comprising: 
 (A) a composition as defined in    claim 23   ; 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.  
   
     
     
         33 . 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 said 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.    
     
     
         34 . A method as defined in    claim 33   , wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.  
     
     
         35 . 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.    
     
     
         36 . A method as defined in    claim 35   , wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.  
     
     
         37 . A subcutaneous delivery composition comprising a mimetic of the subcutaneous delivery composition prepared by the method of    claim 13   .  
     
     
         38 . A method for delivering, by the sublingual route, a biologically active agent to a subject in need of said 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;    (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 between 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 sublingual delivery of said biologically active agent; and  
   (c) sublingually administering said supramolecular complex to said subject.    
     
     
         39 . A method as defined in    claim 38   , further comprising 
 (d) after said administering step, removing said perturbant from said supramolecular complex to transform said biologically active agent to said native state.    
     
     
         40 . A method as defined in    claim 39   , wherein step (d) comprises diluting said supramolecular complex.  
     
     
         41 . A method as defined in    claim 38   , wherein said intermediate state has a ΔG ranging from about −20 kcal/mole to about 20 kcal/moles relative to said native state.  
     
     
         42 . A method as defined in    claim 38   , wherein said biologically active agent is selected from the group consisting of a peptide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination of the foregoing.  
     
     
         43 . A method as defined in    claim 42   , 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.  
     
     
         44 . A method as defined in    claim 38   , wherein said perturbant comprises a proteinoid.  
     
     
         45 . A method as defined in    claim 38   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         46 . A method as defined in    claim 38   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         47 . A method as defined in    claim 38   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         48 . A method as defined in    claim 38   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         49 . A method as defined in    claim 38   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2  to C 10 alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         50 . 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 sublingually 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 sublingual delivery of said biologically active agent.  
   
     
     
         51 . A method as defined in    claim 50   , wherein said intermediate state has ΔG ranging from about −20 kcal/mole to about 20 kcal/moles relative to said native state.  
     
     
         52 . A method as defined in    claim 50   , 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.  
     
     
         53 . A method as defined in    claim 52   , 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.  
     
     
         54 . A method as defined in    claim 50   , wherein said perturbant comprises a proteinoid.  
     
     
         55 . A method as defined in    claim 50   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         56 . A method as defined in    claim 50   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         57 . A method as defined in    claim 50   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         58 . A method as defined in    claim 50   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         59 . A method as defined in    claim 50   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2  to C 10 alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         60 . 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 and said composition is not a microsphere; and said perturbant being present in an amount effective for sublingual delivery of said biologically active agent.  
   
     
     
         61 . A composition as defined in    claim 60   , 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.  
     
     
         62 . A composition as defined in    claim 61   , 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.  
     
     
         63 . A composition as defined in    claim 60   , wherein said perturbant comprises a proteinoid.  
     
     
         64 . A composition as defined in    claim 60   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         65 . A composition as defined in    claim 60   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         66 . A composition as defined in    claim 60   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         67 . A composition as defined in    claim 60   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         68 . A composition as defined in    claim 60   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2  to C 10  alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         69 . A dosage unit form comprising: 
 (A) a composition as defined in    claim 60   ; 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.  
   
     
     
         70 . 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 reversibly transform said biologically active agent to said intermediate state and to form a sublingually administrable 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 said perturbant; and  
 said perturbant being present in an amount effective for sublingual delivery of said biologically active agent; and  
   (c) preparing a mimetic of said supramolecular complex.    
     
     
         71 . A method as defined in    claim 70   , wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.  
     
     
         72 . 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.    
     
     
         73 . A method as defined in    claim 72   , wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.  
     
     
         74 . An oral delivery composition comprising a mimetic of the oral delivery composition prepared by the method of    claim 50   .  
     
     
         75 . A method for delivering, by the intranasal route, a biologically active agent to a subject in need of said 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;    (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 between 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 intranasal delivery of said biologically active agent; and  
   (c) intranasally administering said supramolecular complex to said subject.    
     
     
         76 . A method as defined in    claim 75   , further comprising 
 (d) after said administering step, removing said perturbant from said supramolecular complex to transform said biologically active agent to said native state.    
     
     
         77 . A method as defined in    claim 76   , wherein step (d) comprises diluting said supramolecular complex.  
     
     
         78 . A method as defined in    claim 75   , wherein said intermediate state has a ΔG ranging from about −20 kcal/mole to about 20 kcal/moles relative to said native state.  
     
     
         79 . A method as defined in    claim 75   , wherein said biologically active agent is selected from the group consisting of a peptide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination of the foregoing.  
     
     
         80 . A method as defined in    claim 79   , 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.  
     
     
         81 . A method as defined in    claim 75   , wherein said perturbant comprises a proteinoid.  
     
     
         82 . A method as defined in    claim 75   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         83 . A method as defined in    claim 75   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         84 . A method as defined in    claim 75   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         85 . A method as defined in    claim 75   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         86 . A method as defined in    claim 75   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10 alkyl)phenyl, (C 2  to C 10 alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         87 . 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 administrable 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.  
   
     
     
         88 . A method as defined in    claim 87   , wherein said intermediate state has ΔG ranging from about −20 kcal/mole to about 20 kcal/moles relative to said native state.  
     
     
         89 . A method as defined in    claim 87   , 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.  
     
     
         90 . A method as defined in    claim 89   , 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.  
     
     
         91 . A method as defined in    claim 87   , wherein said perturbant comprises a proteinoid.  
     
     
         92 . A method as defined in    claim 87   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         93 . A method as defined in    claim 87   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         94 . A method as defined in    claim 87   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         95 . A method as defined in    claim 87   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         96 . A method as defined in    claim 87   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2  to C 10  alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10  )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         97 . 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 and said composition is not a microsphere; and said perturbant being present in an amount effective for intranasal delivery of said biologically active agent.  
   
     
     
         98 . A composition as defined in    claim 97   , 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.  
     
     
         99 . A composition as defined in    claim 98   , 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.  
     
     
         100 . A composition as defined in    claim 97   , wherein said perturbant comprises a proteinoid.  
     
     
         101 . A composition as defined in    claim 97   , wherein said perturbant is selected from the group consisting of an acylated amino acid and an acylated poly amino acid.  
     
     
         102 . A composition as defined in    claim 97   , wherein said perturbant is selected from the group consisting of a sulfonated amino acid and a sulfonated poly amino acid.  
     
     
         103 . A composition as defined in    claim 97   , wherein said perturbant is selected from the group consisting of an acylated aldehyde of an amino acid and an acylated aldehyde of a poly amino acid.  
     
     
         104 . A composition as defined in    claim 97   , wherein said perturbant is selected from the group consisting of an acylated ketone of an amino acid and an acylated ketone of a poly amino acid.  
     
     
         105 . A composition as defined in    claim 97   , wherein said perturbant comprises a carboxylic acid having the formula  
       R—CO 2 H  
       wherein 
 R is C 1  to C 24  alkyl, C 2  to C 24  alkenyl, C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, phenyl, naphthyl, (C 1  to C 10  alkyl)phenyl, (C 2 to C 10  alkenyl)phenyl, (C 1  to C 10  alkyl)naphthyl, (C 2  to C 10  alkenyl)naphthyl, phenyl(C 1  to C 10  alkyl), phenyl(C 2  to C 10  alkenyl), naphthyl(C 1  to C 10  alkyl) and naphthyl(C 2  to C 10  alkenyl);  
 R being optionally substituted with C 1  to C 10  alkyl, C 2  to C 10  alkenyl, C 1  to C 4  alkoxy, —OH, —SH, —CO 2 R 1 , C 3  to C 10  cycloalkyl, C 3  to C 10  cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more atoms of N, O, S or any combination thereof, aryl, (C 1  to C 10  alkyl)aryl, aryl(C 1  to C 10 )alkyl, or any combination thereof;  
 R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and  
 R 1  is hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; or  
 a salt thereof.  
 
     
     
         106 . A dosage unit form comprising: 
 (A) a composition as defined in    claim 97   ; 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.  
   
     
     
         107 . 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;    (b) exposing said biologically active agent to a complexing perturbant to reversibly transform said biologically active agent to said intermediate state and to form an intranasally administrable 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 said perturbant, and  
 said perturbant being present in an amount effective for intranasal delivery of said biologically active agent; and  
   (c) preparing a mimetic of said supramolecular complex.    
     
     
         108 . A method as defined in    claim 107   , wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.  
     
     
         109 . 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 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.    
     
     
         110 . A method as defined in    claim 109   , wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.  
     
     
         111 . An oral delivery composition comprising a mimetic of the oral delivery composition prepared by the method of    claim 87   .