Control release of biologically active compounds from multi-armed oligomers
First Claim
Patent Images
1. An oligomer or pharmaceutically acceptable salt thereof of formula I or II:
-
[R1—
O—
(Y)b—
C(O)CH2—
(X)a—
OC(O)]w—
R
I
[R2—
C(O)O—
(X1)a—
CH2C(O)—
(Y1)b—
O]w—
R
IIwherein;
R1—
O—
is a biologically active compound residue;
R2—
C(═
O)O—
is a biologically active compound residue;
X is selected from;
—
OC(═
O)CH2—
(inverse glycolic acid moiety), —
OC(═
O)CH(CH3)—
(inverse lactic acid moiety), —
OC(═
O)CH2OCH2CH2—
(inverse dioxanone acid moiety), —
OC(═
O)CH2CH2CH2CH2CH2—
(inverse caprolactone acid moiety), —
OC(═
O)(CH2)y—
, or —
OC(═
O)CH2(OCH2CH2)z—
;
X1 is selected from;
—
CH2C(═
O)O—
(glycolic acid moiety), —
CH(CH3)C(═
O)O—
(lactic acid moiety), —
CH2CH2OCH2C(═
O)O—
(dioxanone acid moiety), —
CH2CH2CH2CH2CH2C(═
O)O—
(caprolactone acid moiety), —
(CH2)yC(═
O)O—
, or —
(CH2CH2O)nCH2C(═
O)O—
;
Y is selected from;
—
C(═
O)CH2O—
(glycolic ester moiety), —
C(═
O)CH(CH3)O—
(lactic ester moiety), —
C(═
O)CH2OCH2CH2O—
(dioxanone ester moiety), —
C(═
O)CH2CH2CH2CH2CH2O—
(caprolactone ester moiety), —
C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;
Y1 is selected from;
—
OCH2C(═
O)—
(inverse glycolic ester moiety), —
OCH(CH3)C(═
O)—
(inverse lactic ester moiety), —
OCH2CH2OCH2C(═
O)—
(inverse dioxanone ester moiety), —
OCH2CH2CH2CH2CH2C(═
O)—
(inverse caprolactone ester moiety), —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;
R is a di-, tri, tetra-, penta- or hexaradical derived from C2-25 alkyl, aryl, or aryl-(C1-6alkyl)1-3-, wherein from 1-3 of the CH2 groups within the alkyl chain are optionally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH2 groups within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom;
or R is the backbone of a polymer or copolymer bearing carboxylic acid and/or hydroxyl functional groups, where the average molecular weight of the polymer or copolymer is between 500 to 5000 and wherein w is an integer from about 6 to about 50;
each a and b is independently an integer from about 1 to about 10;
each m, n, y, and z is independently an integer from about 2 to about 24; and
w is an integer from about 2 to about 6.
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Abstract
The present invention relates to the discovery of biodegradable multi-armed oligomers wherein the end groups of these oligomers have been functionalized with biologically active molecules. The resultant multi-armed oligomers end-functionalized with biologically active molecules have a controllable degradation profile. The hydrolytic degradation of oligomers of the present invention releases the biologically active compound as such with no change in native chemical structure.
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Citations
38 Claims
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1. An oligomer or pharmaceutically acceptable salt thereof of formula I or II:
-
[R1—
O—
(Y)b—
C(O)CH2—
(X)a—
OC(O)]w—
R
I
[R2—
C(O)O—
(X1)a—
CH2C(O)—
(Y1)b—
O]w—
R
IIwherein; R1—
O—
is a biologically active compound residue;R2—
C(═
O)O—
is a biologically active compound residue;X is selected from;
—
OC(═
O)CH2—
(inverse glycolic acid moiety), —
OC(═
O)CH(CH3)—
(inverse lactic acid moiety), —
OC(═
O)CH2OCH2CH2—
(inverse dioxanone acid moiety), —
OC(═
O)CH2CH2CH2CH2CH2—
(inverse caprolactone acid moiety), —
OC(═
O)(CH2)y—
, or —
OC(═
O)CH2(OCH2CH2)z—
;X1 is selected from;
—
CH2C(═
O)O—
(glycolic acid moiety), —
CH(CH3)C(═
O)O—
(lactic acid moiety), —
CH2CH2OCH2C(═
O)O—
(dioxanone acid moiety), —
CH2CH2CH2CH2CH2C(═
O)O—
(caprolactone acid moiety), —
(CH2)yC(═
O)O—
, or —
(CH2CH2O)nCH2C(═
O)O—
;Y is selected from;
—
C(═
O)CH2O—
(glycolic ester moiety), —
C(═
O)CH(CH3)O—
(lactic ester moiety), —
C(═
O)CH2OCH2CH2O—
(dioxanone ester moiety), —
C(═
O)CH2CH2CH2CH2CH2O—
(caprolactone ester moiety), —
C(═
O)(CH2)mO—
, or —
C(═
O)CH2—
O—
(CH2CH2O)n—
;Y1 is selected from;
—
OCH2C(═
O)—
(inverse glycolic ester moiety), —
OCH(CH3)C(═
O)—
(inverse lactic ester moiety), —
OCH2CH2OCH2C(═
O)—
(inverse dioxanone ester moiety), —
OCH2CH2CH2CH2CH2C(═
O)—
(inverse caprolactone ester moiety), —
O(CH2)mC(═
O)—
, or —
O(CH2CH2O)nOCH2C(═
O)—
;R is a di-, tri, tetra-, penta- or hexaradical derived from C2-25 alkyl, aryl, or aryl-(C1-6alkyl)1-3-, wherein from 1-3 of the CH2 groups within the alkyl chain are optionally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH2 groups within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom;
or R is the backbone of a polymer or copolymer bearing carboxylic acid and/or hydroxyl functional groups, where the average molecular weight of the polymer or copolymer is between 500 to 5000 and wherein w is an integer from about 6 to about 50;each a and b is independently an integer from about 1 to about 10; each m, n, y, and z is independently an integer from about 2 to about 24; and w is an integer from about 2 to about 6. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
-
-
13. An oligomer of claim 1, wherein —
- (Y1)b—
O]wR is;
- (Y1)b—
-
14. An oligomer of claim 1, wherein —
- (X)a—
OC(═
O)]w—
R is;
- (X)a—
-
15. An oligomer of claim 1, wherein —
- CH2C(═
O)—
(Y1)b—
O]wR) is;
- CH2C(═
-
16. An oligomer of claim 1, wherein R1—
- O—
is selected from chalcones, hydroxy-benzoic acid, dihydroxy-benzoic acid, indoles, acetophenones, benzophenones, catechins, flavonoids, coumarins, hydroquinone, naproxen, acetaminophen, and acetylsalicylic acid.
- O—
-
17. A cosmetic composition, comprising at least one compound of claim 1 and a cosmetic ingredient.
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18. A pharmaceutical composition, comprising at least one compound of claim 1 and a pharmaceutically acceptable excipient.
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19. A pharmaceutical composition of claim 18, wherein the composition is suitable for administration via a route selected from oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal.
-
20. A pharmaceutical composition of claim 18, wherein the phenolic residue of formula I or II is derived from a phenolic compound with antimicrobial properties.
-
21. A pharmaceutical composition of claim 20, further comprising:
- an antimicrobial agent.
-
22. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with anti-inflammatory properties.
-
23. A pharmaceutical composition of claim 22, further comprising:
- anti-inflammatory agent.
-
24. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with pain-reducing properties.
-
25. A pharmaceutical composition of claim 24, further comprising:
- a pain reducing agent.
-
26. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with antioxidant properties.
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27. A pharmaceutical composition of claim 26, further comprising:
- an antioxidant agent.
-
28. A suture coating, comprising:
- at least one oligomer of claim 1.
-
29. An antimicrobial agent, comprising:
- at least one oligomer of claim 1, wherein the biologically active compound has an antimicrobial effect.
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30. A therapeutic method for treating a disease in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.
-
31. A therapeutic method for producing an analgesic effect in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active compound has an analgesic effect.
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32. A therapeutic method for treating cancer in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active compound has an anti-cancer effect.
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33. A therapeutic method for producing an anti-inflammatory effect in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active compound has anti-inflammatory effect.
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34. A therapeutic method for producing an anti-bacterial effect in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active compound has anti-bacterial effect.
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35. A therapeutic method for producing an anti-fungal effect in a patient, comprising:
- administering to a patient in need of such therapy an effective amount of at least one oligomer of claim 1 wherein the biologically active compound has an anti-fungal effect.
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36. A therapeutic method for producing an immunosuppressive effect in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active compound has an immunosuppressive effect.
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37. A therapeutic method for producing an anti-thrombotic effect in a patient, comprising:
- administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1, wherein the biologically active compound has anti-thrombotic effect.
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38. A therapeutic method for treating psoriasis, or inflammatory bowel disease in a patient, comprising:
- administering to a patient in need of such therapy, an effective mount of at least one oligomer of claim 1, wherein the biologically active compound has an anti-psoriasis or anti-inflammatory bowel disease effect.
Specification