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Details for Patent: 6,348,207

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Details for Patent: 6,348,207

Title: Orally deliverable supramolecular complex
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.
Inventor(s): Milstein; Sam J. (Larchmont, NY), Barantsevitch; Evgueni (New Rochelle, NY), Leone-Bay; Andrea (Ridgefield, CT), Wang; Nai Fang (Long Island City, NY), Sarubbi; Donald J. (Bronxville, NY), Santiago; Noemi B (Hawthorne, NY)
Assignee: Emisiphere Technologies, Inc. (Tarrytown, NY)
Filing Date:Sep 30, 1997
Application Number:08/941,609
Claims:1. A method for delivering, by the oral 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, an d 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 orally 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 is in an amount effective for oral delivery of said biologically active agent; and

(c) orally 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 .DELTA.G 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 mucoopolysaccharide, 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

wherein R is C.sub.1 to C.sub.24 alkyl, C.sub.2 to C.sub.24 alkenyl, C.sub.3 to C.sub.10 cycloalkyl, C.sub.3 to C.sub.10 cycloalkenyl, phenyl, naphthyl, (C.sub.1 to C.sub.10 alkyl)phenyl, (C.sub.2 to C.sub.10 alkenyl)phenyl, (C.sub.1 to C.sub.10 alkyl)naphthyl, (C.sub.2 to C.sub.10 alkenyl)naphthyl, phenyl(C.sub.1 to C.sub.10 alkyl), phenyl(C.sub.2 to C.sub.10 alkenyl), naphthyl(C.sub.1 to C.sub.10 alkyl) and naphthyl(C.sub.2 to C.sub.10 alkenyl);

R being optionally substituted with C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.1 to C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.1, C.sub.3 to C.sub.10 cycloalkyl, C.sub.3 to C.sub.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.sub.1 to C.sub.10 alkyl)aryl, aryl(C.sub.1 to C.sub.10)alkyl, or any combination thereof;

R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

R.sup.1 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.2 to C.sub.4 alkenyl; or

a salt thereof.

13. A method for preparing an orally 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 orally 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 is in an amount effective for oral delivery of said biologically active agent.

14. A method as defined in claim 13, wherein said intermediate state has .DELTA.G 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 i s 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

wherein R is C.sub.1 to C.sub.24 alkyl, C.sub.2 to C.sub.24 alkenyl, C.sub.1 to C.sub.10 cycloalkyl, C.sub.3 to C.sub.10 cycloalkenyl, phenyl, naphthyl, (C.sub.1 to C.sub.10 alkyl)phenyl, (C.sub.2 to C.sub.10 alkenyl)phenyl, (C.sub.1 to C.sub.10 alkyl)naphthyl, (C.sub.2 to C.sub.10 alkenyl)naphthyl, phenyl(C.sub.1 to C.sub.10 alkyl), phenyl(C.sub.2 to C.sub.10 alkenyl), naphthyl(C.sub.1 to C.sub.10 alkyl) and naphthyl(C.sub.2 to C.sub.10 alkenyl);

R being optionally substituted with C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.1 to C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.1, C.sub.3 to C.sub.10 cycloalkyl, C.sub.3 to C.sub.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.sub.1 to C.sub.10 alkyl)aryl, aryl(C.sub.1 to C.sub.10)alkyl, or any combination thereof;

R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

R.sup.1 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.2 to C.sub.4 alkenyl; or

a salt thereof.

23. 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;

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 oral 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 23, 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

wherein R is C.sub.1 to C.sub.24 alkyl, C.sub.2 to C.sub.24 alkenyl, C.sub.3 to C.sub.10 cycloalkyl, C.sub.3 to C.sub.10 cycloalkenyl, phenyl, naphthyl, (C.sub.1 to C.sub.10 alkyl)phenyl, (C.sub.2 to C.sub.10 alkenyl)phenyl, (C.sub.1 to C.sub.10 alkyl)naphthyl, (C.sub.2 to C.sub.10 alkenyl)naphthyl, phenyl(C.sub.1 to C.sub.10 alkyl), phenyl(C.sub.2 to C.sub.10 alkenyl), naphthyl(C.sub.1 to C.sub.10 alkyl) and naphthyl(C.sub.2 to C.sub.10 alkenyl);

R being optionally substituted with C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.1 to C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.1, C.sub.3 to C.sub.10 cycloalkyl, C.sub.3 to C.sub.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.sub.1 to C.sub.10 alkyl)aryl, aryl(C.sub.1 to C.sub.10)alkyl, or any combination thereof;

R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

R.sup.1 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.2 to C.sub.4 alkenyl; or

a salt thereof.

32. An orally deliverable 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 delivered by the oral 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 orally 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 oral 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 oral 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, said perturbant being present in an amount effective for oral 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. An orally deliverable composition comprising a mimetic of the orally deliverable composition prepared by the method of claim 13.
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