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Details for Patent: 6,221,367

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Details for Patent: 6,221,367

Title: 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.
Inventor(s): Milstein; Sam J. (Larchmont, NY), Leone-Bay; Andrea (Ridgefield, CT), Sarubbi; Donald J. (Carmel, NY), Leipold; Harry (Elmsford, NY)
Assignee: Emisphere Technologies, Inc. (Tarrytown, NY)
Filing Date:Sep 29, 1997
Application Number:08/939,939
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 .DELTA.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.

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.

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

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 .DELTA.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.

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.

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

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 .DELTA.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.

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.

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