Amphiphilic star-like macromolecules for drug delivery

• US 20040198641A1
• Filed: 01/09/2004
• Published: 10/07/2004
• Est. Priority Date: 07/12/2001
• Status: Active Grant

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Uhrich, Kathryn E., Tian, Lu
• Granted Patent: US 7,262,221 B2
• Time in Patent Office: Days
• US Class Current: 562/512
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention provides polymeric compounds that can form micelles in solutions. These compounds have a hydrophobic, core that is coupled to a plurality of hydrophilic moieties.

Claims

1. A compound having formula (I):

R¹—

((R²)_a—

(R³)_b—

(R⁴)_c—

(R⁵)_d—

(R⁶)_e)_n 

 

(I)

wherein R¹ is a core comprising a polyol or polyacid;

each R² independently is a divalent or polyvalent group having the formula —

X¹—

R⁸—

(X^1a)_g—

, wherein X¹ and X^1a are independently —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent, and each R⁸ is independently —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-;

a is 0 or an integer from 1 to about 10; and

g is an integer from 1 to about 6;

each R³ independently is a divalent dicarboxylic acid moiety having the formula —

C(═

O)—

R⁹—

C(═

O)—

, wherein R⁹ is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about 10 hydroxy groups, wherein one or more of the hydroxy groups of the dicarboxylic acid are acylated with an acid residue; and

b is an integer from 1 to about 10;

each R⁴ independently is a divalent or polyvalent group having the formula —

X²—

R¹⁰—

(X^2a)_h—

, wherein X² is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent;

X^2a is —

C(═

O)—

, —

C(═

S)—

, —

O, —

S—

, or —

N(R⁷)— and

R¹⁰ is —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-; and

c is 0 or an integer from 1 to about 10; and

h is an integer from 1 to 6;

each R⁵ independently is a group having the formula;

—

R¹²—

(R¹¹)_f—

R¹²—

X³—

wherein R¹¹ is a sugar moiety;

or a poly(alkylene oxide) or poly(alkylene imine) group having the formula —

(—

X⁴—

R¹³)—

;

wherein R¹³ is —

(C_2-40)alkylene- or branched —

(C_3-40)alkylene-;

wherein each R¹³ is independently —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent;

each X⁴ is independently —

O—

, or —

N(R⁷)—

; and

f is an integer from about 2 to about 150; and

d is from 1 to about 6,

each R¹² is independently a bond, —

(C_1-40)alkylene- or branched —

(C_1-40)alkylene-groups, wherein each R¹² is optionally substituted with one or more (e.g., 1, 2, or

     3) functional group; and

X⁴ is —

O—

, —

S—

, or —

N(R⁷)—

;

wherein n is from 2 to 12;

provided that a and b are not both zero;

wherein each R⁷ is independently selected from the group consisting of hydrogen, and C_(1-40)alkyl group, where the alkyl group can be a straight-chain or branched group; and

R^a and R^b are each independently hydrogen (C_1-8)alkyl, aryl, aryl(C_1-8)alkylene; and

R⁶ is hydrogen, are —

OH, —

OR^a, —

NR^aR^b, —

CO₂H, —

SO₃H (sulfo), —

CH₂—

OH, —

CH₂—

OR^a, —

CH₂—

O—

CH₂—

R^a—

CH₂—

NR^aR^b or a targeting moiety;

provided that at least one R⁶ group is a targeting moiety; and

e is from 1 to about 6.

5. The compound of any one of claims 14, wherein R² has the formula:

6. The compound of any one of claims 1-5, wherein R² has the formula:

7. The compound of any one of claims 1-6, wherein R² has the formula:

8. The compound of any one of claims 1-7, wherein the R¹-R² combination has the formula:

9. The compound of any one of claims 1-8, wherein R³ has the formula

10. The compound of any one of claims 1-9, wherein R³ is

11. The compound of any one of claims 1-10, wherein R¹⁶ is an alkanoyl group having from about 6 to about 18 carbon atoms.

12. The compound of any one of claims 1-11, wherein R¹ has from about 2 carbons to about 20 carbons.

13. The compound of any one of claims 1-12, wherein R¹ has from about 3 carbons to about 12 carbons.

14. The compound of any one of claims 1-13, wherein the R¹ moeity has from about 4 carbons to about 10 carbons.

15. The compound of any one of claims 1-3 or 5-14, wherein R¹ is a cycloaliphatic polyol.

16. The compound of any one of claims 1-15, wherein R¹ is a polyacid having the formula

17. The compound of claim 16, where R¹⁵ is alkyl.

18. The compound of claim 17, where R¹⁵ is methyl, ethyl, or propyl.

19. The compound of claim 18, where R¹⁵ is methyl, or propyl.

20. The compound of any one of claims 1-16, wherein R¹ comprises a core having the formula:

21. The compound of any one of claims 1-20, wherein R² is —

C(═

O)—

CH₂—

CH₂—

S—

.

22. The compound of any one of claims 1-16 or 20-21, wherein the R¹-R² combination is pentaerythritol tetrakis(3-mercaptopropionate).

23. The compound of any of claims 1-16 or 20-22, wherein the R¹ moeity comprises from about 2 to about 20 hydroxy groups.

24. The compound of any one of claims 1-16 or 20-23, wherein the R¹ moeity comprises from about 2 to about 12 hydroxy groups.

25. The compound of any one of claims 1-16 or 20-24, wherein the R¹ moeity comprises from about 2 to about 10 hydroxy groups.

26. The compound of any one of claims 1-25, wherein the R¹ moeity is substituted with one or more carboxy groups.

27. The compound of any of claims 1-26, wherein the R¹ moeity is substituted with two carboxy groups.

28. The compound of any one of claims 1-27, wherein the R¹ moeity is substituted with one carboxy group.

29. The compound of any one of claims 1-28, wherein R⁴ has the formula:

30. The compound of any one of claims 1-29, wherein R⁵ has the formula:

—

R¹²—

(O—

R¹³)_f—

R¹²—

,

wherein R¹³ is a 1 to 20 carbon straight-chain or branched alkyl group,

wherein each R¹² is optionally substituted with one or more functional groups selected from the group consisting of —

OH, —

OR^a, —

NR^aR^b, —

CO₂H, —

SO₃H, —

CH₂OR^a, —

CH₂—

O—

CH₂—

R^a, —

CH₂CO₂H, —

CH₂SO₃H, —

O—

C(═

O)—

CH₂—

CH₂—

C(═

O)—

O—

or —

CH₂—

NR^aR^b;

Q is —

O—

, —

S—

, and —

NR^a—

; and

R¹² is a 1 to 10 carbon straight-chain or branched divalent alkylene group;

R^a and R^b are each independently hydrogen (C_1-6)alkyl, aryl, aryl(C_1-8)alkylene

f is an integer from 2 to 150, inclusive.

31. The compound of any one of claims 1-31, wherein the R is a polyethylene ether having between about 2 and about 110 alkylene oxide repeating units.

32. The compound of any one of claims 1-31, wherein the alkylene oxide units containing from 2 to about 10 carbon atoms and may be straight chained or branched.

33. The compound of any one of claims 1-31, wherein the alkylene oxide units contain from 2 to 4 carbon atoms and may be straight chained or branched.

34. The compound of any one of claims 1-31 wherein R⁵ is linked to R¹ through an ester, thioester, or amide linkage.

35. The compound of any one of claims 1-31 wherein R⁵ is linked to R¹ through an ester or amide linkage.

36. The compound of any one of claims 1-29, wherein R⁵ has the formula:

—

R¹²—

(N(R⁷)—

R¹³)_f—

R¹²—

,

wherein each R¹² and R¹³ are independently a 1 to 20 carbon straight-chain or branched alkyl group,

wherein each R¹² is optionally substituted with one or more functional groups selected from the group consisting of —

OH, —

OR^a, —

NR^aR^b, —

CO₂H, —

SO₃H, —

CH₂—

ORa, —

CH₂—

O—

CH₂—

R^a, —

CH₂CO₂H, —

CH₂SO₃H, —

O—

C(═

O)—

CH₂—

CH₂—

C(═

O)—

O—

or —

CH₂—

NR^aR^b;

Q is —

O—

, —

S—

, and —

NR^a—

; and

R¹² is a 1 to 10 carbon straight-chain or branched divalent alkylene group;

R^a and R^b are each independently hydrogen (C_1-6)alkyl, aryl, aryl(C_1-8)alkylene

f is an integer from 2 to 150, inclusive.

37. The compound of any one of claims 1-29 or 36, wherein R⁵ is a polyethylene imine having between about 2 and about 110 repeating units.

38. The compound of any one of claims 1-29 or 36-37, wherein the polyethylene imine has units contain from 2 to about 10 carbon atoms.

39. The compound of any one of claims 1-38, wherein R⁶ is alkyl, aryl, biotin, streptavidin, sugar moieties, folic acid, amino acids or peptides.

40. The compound of any one of claims 1-39, wherein is the peptide Arg-Gly-Asp (R-G-D) or Tyr-Ile-Gly-Ser-Arg (Y-I-G-S—

R).

41. The compound of any one of claims 1-40, wherein R⁶ is biotin

42. The compound of any one of claims 1-41, wherein the acid residue comprises from about 2 to about 24 carbon atoms.

43. The compound of any one of claims 1-42, wherein the acid residue comprises from about 6 to about 18 carbon atoms.

44. The compound of claim 1 wherein the acid residue comprises caprylic, capric, lauric, myristic, myristoleic, palmitic, palmitoleic, stearic, oleic, linoleic, eleostearic, arachidic, behenic, erucic acid, or a mixture thereof.

45. The compound of any of claims 1-44, wherein the functional groups are —

OH, —

ORa, —

NRaRb, —

CO2H, —

SO3H (sulfo), —

CH2—

OH, —

CH2—

ORa, —

CH2-O-CH2-Ra, or —

CH2-NRaRb.

46. An encapsulate comprising a molecule surrounded or partially surrounded by at least one compound of formula (I), as described in any one of claims 1-45.

47. An encapsulate comprising a therapeutic agent surrounded or partially surrounded by at least one compound of formula (I), as described in any one of claims 1-45.

48. A composition comprising at least one compound of formula (I) as described in any one of claims 1-45 in a solvent.

49. The composition of claim 48, wherein the solvent comprises an organic solvent.

50. The composition of claim 48, wherein the solvent comprises water.

51. The composition of claim 48, wherein the solvent is water.

52. A method for preparing an encapsulate as described in claim 47, comprising combining at least one compound of formula (I), as described in any one of claims 1-45, and a molecule in a solvent;

and allowing the compound of formula (I) to aggregate around the molecule, to provide the encapsulate

53. A pharmaceutical composition comprising an encapsulate as described in claim 45;

and a pharmaceutically acceptable carrier.

54. A method for delivering a therapeutic agent to an animal in need of treatment with the agent comprising administering an encapsulate as described in claim 45 to the animal.

2. A compound having formula (I):

R¹—

((R²)_a—

(R³)_b—

(R⁴)_c—

(R⁵)_d—

(R⁶)_e)_n 

 

(I)

wherein R¹ is a core comprising a polyol or polyacid;

each R² independently is a divalent or polyvalent group having the formula —

X¹—

R⁸—

(X^1a)_g—

, wherein X¹ and X^1a are independently —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent, and each R⁸ is independently —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-;

a is an integer from 1 to about 10; and

g is an integer from 1 to about 6;

each R³ independently is a divalent dicarboxylic acid moiety having the formula —

C(═

O)—

R⁹—

C(═

O)—

, wherein R⁹ is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about 10 hydroxy groups, wherein one or more of the hydroxy groups of the dicarboxylic acid are acylated with an acid residue; and

b is an integer from 1 to about 10;

each R⁴ independently is a divalent or polyvalent group having the formula —

X²—

R¹⁰—

(X^2a)_h—

, wherein X² is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent;

X^2a is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, or —

N(R⁷) and R¹⁰ is —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-; and

c is 0 or an integer from 1 to about 10; and

h is an integer from 1 to 6;

each R⁵ independently is a group having the formula;

—

R¹²—

(R¹¹)_f—

R¹²—

X³—

wherein R¹¹ is a sugar moiety;

or a poly(alkylene oxide) or poly(alkylene imine) group having the formula —

(—

X⁴—

R¹³)—

;

wherein R¹³ is —

(C_2-40)alkylene- or branched —

(C_3-40)alkylene-;

wherein each X³ is independently —

C(═

O)—

, —

C(═

S)—

, —

O, —

S—

, —

N(R⁷)—

or absent;

each X⁴ is independently —

O—

, or —

N(R⁷)—

; and

f is an integer from about 2 to about 150; and

d is from 1 to about 6;

each R¹² is independently a bond, —

(C_1-40)alkylene- or branched —

(C_1-10)alkylene-groups, wherein each R¹² is optionally substituted with one or more (e.g., 1, 2, or

     3) functional groups; and

X⁴ is —

O—

, —

S—

, or —

N(R⁷)—

;

wherein n is from 2 to 12;

provided that a and b are not both zero;

wherein each R⁷ is independently selected from the group consisting of hydrogen, and C_(1-40)alkyl group, where the alkyl group can be a straight-chain or branched group; and

R^a and R^b are each independently hydrogen (C_1-8)alkyl, aryl, aryl(C_1-8)alkylene; and

R⁶ is hydrogen, are —

OH, —

OR^a, —

NR^aR^b, —

CO₂H, —

SO₃H (sulfo), —

CH₂—

OH, —

CH₂OR^a, —

CH₂—

O—

CH₂—

R^a, —

CH₂—

NR^aR^b or a targeting moiety; and

e is from 1 to about 6.

3. A compound having formula (I):

R¹—

((R²)_a—

(R³)_b—

(R⁴)_c—

(R⁵)_d—

(R⁶)_e)_n 

 

(I)

wherein R¹ is a core comprising a polyol or polyacid;

each R² independently is a divalent or polyvalent group having the formula —

X¹—

R⁸—

(X^1a)_g—

, wherein X¹ and X^1a are independently —

C(═

O)—

, —

C(═

S)—

, O—

, —

S—

, —

N(R⁷)—

or absent, and each R⁸ is independently —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-;

a is 0 or an integer from 1 to about 10; and

g is an integer from 1 to about 6;

each R³ independently is a divalent dicarboxylic acid moiety having the formula —

C(═

O)—

R⁹—

C(═

O)—

, wherein R⁹ is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about 10 hydroxy groups, wherein one or more of the hydroxy groups of the dicarboxylic acid are acylated with an acid residue; and

b is an integer from 1 to about 10;

each R⁴ independently is a divalent or polyvalent group having the formula —

X²—

R¹⁰—

(X^2a)_h—

, wherein X² is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent;

X^2a is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, or —

N(R⁷)— and

R¹⁰ is —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-; and

c is 0 or an integer from 1 to about 10; and

h is an integer from 1 to 6;

each R⁵ independently is a group having the formula;

—

R¹²—

(R¹¹)_f—

R¹²—

X³—

wherein R¹¹ is a sugar moiety;

or a poly(alkylene oxide) or poly(alkylene imine) group having the formula —

(—

X⁴—

R¹³)—

;

wherein R¹³ is —

(C_2-40)alkylene- or branched —

(C_3-40)alkylene-;

wherein each X³ is independently —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent;

each X⁴ is independently —

O—

, or —

N(R⁷)—

; and

f is an integer from about 2 to about 150; and

d is from 1 to about 6;

each R¹² is independently a bond, —

(C_1-40)alkylene- or branched —

(C_1-40)alkylene-groups, wherein each R¹² is optionally substituted with one or more (e.g., 1, 2, or

     3) functional groups; and

X⁴ is —

O—

, —

S—

, or —

N(R⁷)—

;

wherein n is from 2 to 12;

provided that a and b are not both zero;

wherein each R⁷ is independently selected from the group consisting of hydrogen, and C_(1-40)alkyl group, where the alkyl group can be a straight-chain or branched group; and

R^a and R^b are each independently hydrogen (C_1-8)alkyl, aryl, aryl(C_1-8)alkylene; and

R⁶ is hydrogen, are —

OH, —

OR^a, —

NR^aR^b, —

CO₂H, —

SO₃H (sulfo), —

CH₂—

OH, —

CH₂—

OR^a, —

CH₂—

O—

CH₂—

R^a, —

CH₂—

NR^aR^b or a targeting moiety; and

e is from 1 to about 6.

4. A compound having formula (I):

R¹—

((R²)_a—

(R³)_b—

(R⁴)_c—

(R⁵)_d—

(R⁶)_e)_n 

 

(I)

wherein R¹ is a core comprising a polyacid moiety having the formula

or a pentaerythritol polyol having the formula

wherein each R² independently is a divalent or polyvalent group having the formula —

X¹—

R⁸—

(X^1a)_g—

, wherein X¹ and X^1a are independently —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent, and each R⁸ is independently —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-;

a is 0 or an integer from 1 to about 10; and

g is an integer from 1 to about 6;

each R³ independently is a divalent dicarboxylic acid moiety having the formula —

C(═

O)—

R⁹—

C(═

O)—

, wherein R⁹ is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about 10 hydroxy groups, wherein one or more of the hydroxy groups of the dicarboxylic acid are acylated with an acid residue; and

b is an integer from 1 to about 10;

each R⁴ independently is a divalent or polyvalent group having the formula —

X²R¹⁰(X^2a)_h—

, wherein X² is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷)—

or absent;

X^2a is —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, or —

N(R⁷)— and

R10 is —

(C_1-8)alkylene-, branched —

(C_1-8)alkylene- or —

(C_6-10)aryl-; and

c is 0 or an integer from 1 to about 10; and

h is an integer from 1 to 6;

each R⁵ independently is a group having the formula;

—

R¹²—

(R¹¹)_f—

R¹²—

X³—

wherein R¹¹ is a sugar moiety;

or a poly(alkylene oxide) or poly(alkylene imine) group having the formula —

(—

X⁴—

R¹³)—

;

wherein R¹³ is —

(C_2-40)alkylene- or branched —

(C_3-40)alkylene-;

wherein each X³ is independently —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

S—

, —

N(R⁷_or absent;

each X⁴ is independently —

O—

, or —

N(R⁷)—

; and

f is an integer from about 2 to about 150; and

d is from 1 to about 6;

each R¹² is independently a bond, —

(C_1-40)alkylene- or branched —

(C_1-40)alkylene-groups, wherein each R¹² is optionally substituted with one or more (e.g., 1, 2, or

     3) functional groups; and

X⁴ is —

O—

, —

S—

, or —

N(R⁷)—

;

wherein n is from 2 to 12;

provided that a and b are not both zero;

wherein each R⁷ is independently selected from the group consisting of hydrogen, and C_(1-40)alkyl group, where the alkyl group can be a straight-chain or branched group; and

R^a and R^b are each independently hydrogen (C_1-8)alkyl, aryl, aryl(C_1-8)alkylene; and

R⁶ is hydrogen, are —

OH, —

OR^a, —

NR^aR^b, —

CO₂H, —

SO₃H (sulfo), —

CH₂—

OH, —

CH₂—

OR^a, —

CH₂—

O—

CH₂—

R^a, —

CH₂—

NR^aR^b or a targeting moiety; and

e is from 1 to about 6.