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|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), 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:||Emisphere Technologies, Inc. (Hawthorne, NY)|
|Filing Date:||Oct 25, 1994|
|Claims:||1. A method for transporting a biologically active agent across a cellular membrane or a lipid bilayer, 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 transportable 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, and
said biologically active agent not forming a microsphere with said perturbant; and
(c) exposing said membrane or bilayer to said supramolecular complex, to transport said biologically active agent across said membrane or bilayer.
2. A method as defined in claim 1, further comprising
(d) 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.
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 is selected from the group consisting of
(a) a proteincid;
(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
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.
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