Claims
- 1. A method for preparing an orally administrable biologically active agent, said method comprising:
- exposing a biologically active agent, which can exist in (i) a native conformational state, (ii) a denatured conformational state. and (iii) an intermediate conformational state, to acomplexing perturbant to reversibly transform said biologically active agent to said intermediate state and to form a transportable suprarnolecular complex,
- said intermediate conformational state being reversible to said native state and said intermediate conformational state being between said native and denatured states,
- 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.
- 2. A method as defined in claim 1, wherien said intermediate state has .DELTA.G ranging from about -20 kcal/mole to about 20 kcal/moles.
- 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 method as defined in claim 1, wherein said perturbant is selected from the group consisting of
- (a) a proteinoid;
- (b) an acylated amino acid;
- (c) an acylated poly amino acid;
- (d) a sulfonated amino acid;
- (e) a sulfonated poly amino acid;
- (f) an acylated aldehyde of an amino acid;
- (g) an acylated ketone of an amino acid;
- (h) an acylated aldehyde of a poly amino acid;
- (i) an acylated ketone of a poly amino acid; and
- (j) a carboxylic acid having the formula
- R--CO.sub.2 H
- 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.
- 6. An oral delivery composition comprising a supramolecular complex comprising:
- (a) a biologically active agent in an intermediate conformational state non-covalently complexed with
- (b) a complexing perturbant having a molecular weight ranging from about 150 to about 600 and having at least one hydrophilic moiety and at least one hydrophobic moiety;
- said intermediate conformational state being reversible to a native state, said intermediate conformational state being between said native conformational state and a denatured conformational state of said biologically active agent, said composition not being a microsphere.
- 7. A method as defined in claim 6, 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.
- 8. A method as defined in claim 7 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.
- 9. A method as defined in claim 6, wherein said perturbant is selected from the group consisting of
- (a) a proteinoid;
- (b) an acylated amino acid;
- (c) an acylated poly amino acid;
- (d) a sulfonated amino acid;
- (e) a sulfonated poly amino acid;
- (f) an acylated aldehyde of an amino acid;
- (g) an acylated ketone of an amino acid;
- (h) an acylated aldehyde of a poly amino acid;
- (i) an acylated ketone of a poly amino acid; and
- (j) a carboxylic acid having the formula
- R--CO.sub.2 H
- 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.
- 10. A dosage unit form comprising
- (A) a composition as defined in claim 6; 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.
- 11. A method for preparing an agent which is transportable across a cellular membrane or a lipid-bilayer and which is bioavailable after crossing said membrane or bilayer, said method comprising
- exposing a biologically active agent, which can exist in (i) a native conformational state, (ii) a denatured conformational state, and (iii) an intermediate conformational state, to a complexing perturbant to reversibly transform said biologically active agent to said intermediate state and to form a transportable supramolecular complex,
- said intermediate conformational state being reversible to said native state and said intermediate conformational state being between said native and denatured states,
- 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; and
- (c) preparing a mimetic of said supramolecular complex.
- 12. A method as defined in claim 11, wherein said biologically active agent comprises a peptide and said mimetic comprises a peptide mimetic.
- 13. A method for preparing an agent which is transportable across a cellular membrane or a lipid-bilayer, and which is bioavailable after crossing said membrane or bilayer, said method comprising
- exposing a biologically active agent, which can exist in (i) a native conformational state, (ii) a denatured conformational state, and (iii) an intermediate conformational state, to a perturbant to reversibly transform said biologically active agent to said intermediate state, said intermediate conformational state being reversible to said native state and said intermediate conformational state being between said native and denatured states; and
- (c) preparing a mimetic of said intermediate state.
- 14. A method as defined in claim 13, wherein said perturbant comprises a pH changing agent, an ionic strength changing agent, or guanidine hydrochloride.
- 15. An oral delivery composition comprising a mimetic of the oral delivery composition prepared by the method of claim 1.
- 16. An oral delivery composition comprising a peptide mimetic of a peptidic biologically active agent having a native state, a denatured state, and an intermediate state conformationally between said native and denatured states, wherein said intermediate state is reversible to said native state.
- 17. The method as defined in claim 1, wherein said perturbant is selected from the group consisting of cyclohexanecarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, methylcyclohexanecarboxylic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, phenylpropanoic acid, adipic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, pentylcyclohexanoic acid, 2-cyclopentanehexanoic acid, cyclohexane pentanoic acid, hexanedioic acid, cyclohexanebutanoic acid, and (4-methylphenyl) cyclohexane acetic acid.
- 18. The oral delivery composition as defined in claim 6, wherein said perturbant is selected from the group consisting of cyclohexanecarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, methylcyclohexanecarboxylic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, phenylpropanoic acid, adipic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, pentylcyclohexanoic acid, 2-cyclopentanehexanoic acid, cyclohexane pentanoic acid, hexanedioic acid, cyclohexanebutanoic acid, and (4-methylphenyl) cyclohexane acetic acid.
- 19. The method as defined in claim 11, wherein said perturbant is selected from the group consisting of cyclohexanecarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, methylcyclohexanecarboxylic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, phenylpropanoic acid, adipic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, pentylcyclohexanoic acid, 2-cyclopentanehexanoic acid, cyclohexane pentanoic acid, hexanedioic acid, cyclohexanebutanoic acid, and (4-methylphenyl) cyclohexane acetic acid.
- 20. The method as defined in claim 13, wherein said perturbant is selected from the group consisting of cyclohexanecarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, methylcyclohexanecarboxylic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, phenylpropanoic acid, adipic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, pentylcyclohexanoic acid, 2-cyclopentanehexanoic acid, cyclohexane pentanoic acid, hexanedioic acid, cyclohexanebutanoic acid, and (4-methylphenyl) cyclohexane acetic acid.
Parent Case Info
This is a continuation of application Ser. No. 08/328,932, filed Oct. 25, 1994, now U.S. Pat. No. 5,714,167 which is a continuation-in-part of Ser. No. 08/051,019, filed Apr. 22, 1993, now U.S. Pat. No. 5,451,410; and a continuation-in-part of Ser. No. 08/168,776, filed Dec. 16, 1993, now U.S. Pat. No. 5,447,728; which is a continuation-in-part of Ser. No. 08/051,019, filed Apr. 22, 1993, now U.S. Pat. No. 5,451,410; and a continuation-in-part of Ser. No.08/143,571 filed Oct. 26, 1993, now abandoned; which is a continuation-in-part of Ser. No. 08/076,803, filed Jun. 14, 1993, which is a continuation-in-part of Ser. No. 08/920,346, filed Aug. 27, 1997, which is a continuation in part of Ser. No. 07/898,909, filed Jun. 15, 1992, now abandoned; and a continuation-in-part of PCT/US94/04560, filed Apr. 22, 1994; which is a continuation-in-part of Ser. No. 08/051,019, filed Apr. 22, 1993, now U.S. Pat. No. 5,451,410; and a continuation-in-part of Ser. No. 08/205,511, filed Mar. 2, 1994; and a continuation-in-part of Ser. No. 08/231,623, filed Apr. 22, 1994, now U.S. Pat. No. 5,544,200; and a continuation-in-part of Ser. No. 08/205,511, filed Mar. 2, 1994; and a continuation-in-part of Ser. No.08/231,623, filed Apr. 22, 1994; and a continuation-in-part of Ser. No. 08/315,200, filed Sep. 29, 1994; and a continuation-in-part of Ser. No. 08/316,404, filed Sep. 30, 1994.
US Referenced Citations (151)
Foreign Referenced Citations (1)
Number |
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1077842 |
Aug 1976 |
CAX |
Continuations (1)
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328932 |
Oct 1994 |
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Continuation in Parts (5)
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051019 |
Apr 1993 |
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076803 |
Jun 1993 |
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920346 |
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898909 |
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PCTUS9404560 |
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