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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. (Tarrytown, NY)|
|Filing Date:||Sep 30, 1997|
|Claims:||1. 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, and said composition not being a microsphere.
2. The composition of 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.
3. The composition of claim 2 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.
4. The composition of 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
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.
5. A dosage unit form comprising
(A) a composition as defined in claim 1; 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.
6. 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.