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Generated: September 22, 2017
| Title: | Diketopiperazine-based delivery systems |
| Abstract: | Compositions useful in the delivery of active agents are provided. These delivery compositions include (a) an active agent; and either (b)(1) a carrier of (i) at least one amino acid and (ii) at least one diketopiperazine or (b)(2) at least one mono-N-substituted, di-N-substituted, or unsubstituted diketopiperazine. Methods for preparing these compositions and administering these compositions are also provided. |
| Inventor(s): | Milstein; Sam J. (Larchmont, NY) |
| Assignee: | Emisphere Technologies, Inc. (Hawthorne, NY) |
| Filing Date: | Sep 29, 1994 |
| Application Number: | 08/315,200 |
| Claims: | 1. A delivery composition comprising: (a) an active agent; (b) a diketopiperazine having the formula: ##STR5## wherein R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.1 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.1 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), and naphthyl (C.sub.1 -C.sub.10 alkenyl); R.sup.1 or R.sup.2, or both R.sup.1 and R.sup.2, optionally, are independently substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl; R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 , optionally, are independently interrupted by oxygen, nitrogen, sulfur, or any combination thereof; said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, --OH, --SH, or CO.sub.2 R.sup.4 wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkenyl; and R.sup.1 and R.sup.2 are not both hydrogen; and (c) an enzyme inhibitor selected from the group consisting aprotinin, Bowman-Birk inhibiting actinonin, or any combination of the foregoing. 2. A delivery composition as defined in claim 1, comprising a microsphere. 3. A delivery composition as defined in claim 2, wherein said microsphere comprises a microcapsule. 4. A delivery composition as defined in claim 2, wherein said microsphere has a diameter of less than about 10 .mu.m. 5. A delivery composition as defined in claim 1, wherein said active agent comprises a fragrance. 6. A delivery composition as defined in claim 1, wherein said active agent comprises a biologically active agent. 7. A delivery composition as defined in claim 6, wherein said biologically active agent is selected from the group consisting of a peptide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination thereof. 8. The delivery composition 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 monoolonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or any combination of any of the foregoing. 9. A delivery composition as defined in claim 8, wherein said biologically-active agent is selected from the group consisting of an interferon, interleukin-II, insulin, heparin, calcitonin, oxytocin, vasopressin, cromolyn sodium, vancomycin, DFO, or any combination of any of the foregoing. 10. A delivery composition as defined in claim 1, wherein said diketopiperazine is derived from two .alpha.-amino acids. 11. A delivery composition as defined in claim 10, wherein said two .alpha.-amino acids from which said diketopiperazine is derived are independently selected from the group consisting of glutamic acid, aspartic acid, tyrosine, phenylalanine, and optical isomers thereof. 12. A delivery composition as defined in claim 10, wherein said two .alpha.-amino acids from which said diketopiperazine is derived are the same. 13. A delivery composition as defined in claim 10, wherein said diketopiperazine is prepared by the thermal condensation of said two .alpha.-amino acids from which said diketopiperazine is derived. 14. A pharmacological composition comprising: (a) at least one pharmacologically active agent; and (b) a diketopiperazine having the formula: ##STR6## wherein R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.1 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.1 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), and naphthyl (C.sub.1 -C.sub.10 alkenyl); R.sup.1 or R.sup.2, or both R.sup.1 and R.sup.2, optionally, are independently substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl; R.sup.1, R.sup.2, or R.sup.1 and R.sup.2, optionally, are independently interrupted by oxygen, nitrogen, sulfur, or any combination thereof; said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, --OH, --SH, or CO.sub.2 R.sup.4 wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkenyl; and R.sup.1 and R.sup.2 are not both hydrogen; and (c) an enzyme inhibitor selected from the group consisting aprotinin, Bowman-Birk inhibiting actinonin, or any combination of the foregoing. 15. A dosage unit form comprising: (A) a delivery 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. 16. A dosage unit form as defined in claim 14, comprising an oral dosage unit form. 17. A dosage unit form as defined in claim 15, selected from the group consisting of a tablet, a capsule, and a liquid. 18. A method for administering a biologically active agent to an animal in need of such agent, said method comprising administering orally to said animal, a composition as defined in claim 1. 19. A delivery composition comprising: (a) an active agent; (b) a diketopiperazine having the formula ##STR7## (c) an enzyme inhibitor selected from the group consisting aprotinin, Bowman-Birk inhibiting actinonin, or any combination of the foregoing. 20. A delivery composition as defined in claim 19, comprising a microsphere. 21. A delivery composition as defined in claim 20, wherein said microsphere comprises a microcapsule. 22. A delivery composition as defined in claim 20, wherein said microsphere has a diameter of less than about 10 .mu.m. 23. A delivery composition as defined in claim 19, wherein said active agent comprises a fragrance. 24. A delivery composition as defined in claim 19, wherein said active agent comprises a biologically active agent. 25. A delivery composition as defined in claim 24, wherein said biologically active agent is selected from the group consisting of a peptide, a muco-polysaccharide, a carbohydrate, a lipid, a pesticide, or any combination of any of the foregoing. 26. A delivery 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 interfer-on, interleukin-II, insulin, heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotro-pin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or any combination of any of the foregoing. 27. A delivery composition as defined in claim 26, wherein said biologically-active agent is selected from the group consisting of an interferon, interleukin-II, insulin, heparin, calcitonin, oxytocin, vasopressin, cromolyn sodium, vancomycin, DFO, or any combination of any of the foregoing. 28. A pharmacological composition comprising: (A) at least one pharmacologically active agent; (B) a carrier comprising a diketopiperazine having the formula: ##STR8## (c) an enzyme inhibitor selected from the group consisting aprotinin, Bowman-Birk inhibiting actinonin, or any combination of the foregoing. 29. A dosage unit form comprising: (A) a delivery composition as defined in claim 19; 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. 30. A dosage unit form as defined in claim 29, comprising an oral dosage unit form. 31. A dosage unit form as defined in claim 29, selected from the group consisting of a tablet, a capsule, and a liquid. 32. A method for administering a biologically active agent to an animal in need of such agent, said method comprising administering orally to said animal, a delivery composition as defined in claim 19. |
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