Hyperbranched polymeric micelles for encapsulation and delivery of hydrophobic molecules

• US 20030170202A1
• Filed: 12/18/2002
• Published: 09/11/2003
• Est. Priority Date: 04/23/1999
• Status: Abandoned Application

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Uhrich, Kathryn E.
• Application Number:
  US10/323,699
• Publication Number:
  US 20030170202A1
• Time in Patent Office: Days
• US Class Current: 424/78.38
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: C08G 83/005 Hyperbranched macromolecules
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: G03C 1/04 with macromolecular additives; with layer-forming substances
• CPC Class Codes: G03C 5/3056 Macromolecular additives G03C5/261 takes precedence

Abstract

Polymeric micelles for encapsulation of hydrophobic molecules are provided. Methods and formulations for delivering hydrophobic molecules to a host via these micelles are also provided. Methods of stabilizing liposomes or lipid based formulations by addition of polymeric micelles are also provided.

Claims

1. A polymer having a structure selected from the group consisting of:

R(—

O—

R₁), and R(—

NH—

R₁)_x

wherein R(—

O—

)_x is a polyol moiety and R(—

NH)_x is a polyamine moiety, with x being between 2 and 10, inclusive, and each R₁ independently has the structure;

wherein

 

is a divalent amino acid moiety with R₂ being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0;

wherein

 

is a divalent dicarboxylic acid moiety in which R₃ is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about 10 hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with from 3 to about 24 carbon atom carboxylic acids; and

wherein R₄ is a poly(alkylene oxide) having the structure;

R₅—

(R₆—

O—

)_a—

R₆-Q-

with R₅ being selected from the group consisting of 1 to 40 carbon atom alkyl groups, —

OH, —

OR₇, —

NH₂, —

NHR₇, —

NHR₇R₈, —

C—

OH, —

C—

OR₇, —

C—

O—

C—

R₇, —

C—

NH₂, —

C—

NHR₇ and —

C—

NR₇R₈;

R₆, R₇ and R₈ being independently selected from the group consisting of 2 to 40 carbon atom, straight-chain or branched alkylene groups;

Q being a divalent linkage moiety; and

a being between 2 and 110, inclusive;

with the proviso that when y is 0 and R is a 1,1,1-tris(hydroxyphenyl)ethane moiety, the divalent dicarboxylic acid moiety is not an acylated mucic acid moiety.

2. The polymer of claim 1, wherein x is 3 or 4.

3. The polymer of claim 2, having the structure R(—

NH—

R₁)_x, wherein R(—

NH—

)_x a polyamine moiety.

4. The polymer of claim 2, having the structure R(—

O—

R₁)_x, wherein R(—

O—

)_x is a polyol moiety.

5. The polymer of claim 4, wherein said polyol moiety is an aromatic polyol moiety.

6. The polymer of claim 5, wherein said polyol moiety is a 1,1,1-tris(hydroxyphenyl)ethane moiety.

7. The polymer of claim 1, wherein every hydroxyl group of said divalent dicarboxylic acid moiety is acylated with a 6 to 24 carbon atom carboxylic acid group.

8. The polymer of claim 7, wherein y is 0.

9. The polymer of claim 7, wherein said divalent dicarboxylic acid mucic acid moiety is a mucic acid moiety.

10. The polymer of claim 4, wherein said polyol moiety is an aliphatic or cycloaliphatic polyol moiety.

11. The polymer of claim 4, wherein said polyol moiety is a cyclic crown ether or cyclodextrin moiety.

12. The polymer of claim 1, wherein said poly(alkylene oxide) is a methoxy-terminated poly(ethylene glycol) and Q is —

NH—

.

13. The polymer of claim 1, wherein Q is —

O—

, or forms an anhydride linkage.

36. A method of stabilizing a liposome or lipid-based formulation comprising adding to the liposome or lipid-based formulation a polymer of claim 1.

14. A hydrophobic molecule encapsulated in a polymer, said polymer having a structure selected from the group consisting of:

R(—

O—

R₁)_x and R(—

NH—

R₁)_x

wherein R(—

O—

)_x is a polyol moiety and R(—

NH—

)_x is a polyamine moiety, with x being between 2 and 10, inclusive, and each R₁ independently has the structure;

wherein

 

is a divalent amino acid moiety with R₂ being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0;

wherein

 

is a divalent dicarboxylic acid moiety in which R₃ is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with from 3 to about 24 carbon atom carboxylic acids; and

wherein R₄ is a poly(alkylene oxide) having the structure;

R₅—

(—

R₆—

O—

)_a—

R₆-Q

with R₅ being selected from the group consisting of 1 to 40 carbon atom alkyl groups, —

OH, —

OR₇, —

NH₂, —

NHR₇, —

NHR₇R₈, —

C—

OH, —

C—

OR₇, —

C—

O—

C—

R₇, —

C—

NH₂, —

C—

NHR₇, and —

C—

NR₇R₈;

R₆, R₇ and R₈ being independently selected from the group consisting of 2 to 40 carbon atom, straight-chain or branched alkylene groups;

Q being a divalent linkage moiety; and

a being between 2 and 110, inclusive;

with the proviso that when y is 0 and R is a 1,1,1-tris (hydroxyphenyl)ethane moiety, the divalent dicarboxylic acid moiety is not a mucic acid moiety acylated with carboxylic acids having less than 6 carbon atoms.

15. The encapsulate of claim 14, wherein said hydrophobic molecule has biological or pharmaceutical activity.

16. The encapsulate of claim 14, wherein said hydrophobic molecule is a fragrance, dye, protein or vitamin.

17. The encapsulate of claim 14, having the structure R(—

O—

R₁)_x, wherein R(—

O—

)_x, is a polyol moiety.

18. The encapsulate of claim 17, wherein said polyol moiety is a 1,1,1-tris(hydroxyphenyl)ethane moiety.

19. The encapsulate of claim 17, wherein all of said hydroxyl groups of said dicarboxylic acid moiety are acylated with carboxylic acids having from 6 to 24 carbon atoms.

20. The encapsulate of claim 19, wherein y is 0.

21. The encapsulate of claim 19, wherein said divalent dicarboxylic acid moiety is a mucic acid moiety.

22. The encapsulate of claim 14, wherein said poly(alkylene oxide) is a methoxy-terminated poly(ethylene glycol) and Q is —

NH—

.

23. A formulation comprising the encapsulate of claim 14 and an acceptable vehicle.

24. The formulation of claim 23 wherein the accetable vehicle comprises an aqueous solution, suspension, dispersion, emollient, lotion, cream, salve, balm or ointment.

25. The formulation of claim 23, wherein the concentration of said encapsulate in said formulation is between about 10⁻

10 M and 10⁶ M.

26. The formulation of claim 25, wherein said encapsulate concentration is between about 10⁻

8 M and about 10⁶ M.

27. The formulation of claim 23, wherein the hydrophobic molecule of the encapsulate has biological or pharmaceutical activity.

28. The formulation of claim 23, wherein the hydrophobic molecule of the encapsulate is a dye, fragrance, protein, or vitamin.

29. A method of delivering a hydrophobic molecule to a host comprising administering to the host an encapsulate of claim 14.

30. The method of claim 29 wherein the host is an animal and the encapsulate is administered orally, subcutaneously, intramuscularly, intraperitoneally or intravenously.

31. The method of claim 29, wherein the encapsulate is administered topically to the host.

32. The method of claim 29 wherein the hydrophobic molecule of the encapsulate is biologically or pharmaceutically active.

33. The method of claim 29 wherein the hydrophobic molecule of the encapsulate is a dye, fragrance, protein or vitamin and the encapsulate is administered topically.

34. A transdermal device for the controlled release of a biologically or pharmaceutically active agent to the skin or mucosa of an animal, said device comprising a laminate of:

(a) a reservoir layer having a first surface and a second surface, and having the encapsulate of claim 15 incorporated therein;

(b) a backing layer having an inner surface and an outer surface, wherein said second surface of said reservoir layer and said inner surface of said backing layer are laminated together so that said encapsulate cannot permeate from said second surface of said reservoir layer through said outer surface of said backing layer; and

(c) a pressure sensitive adhesive layer coated on said first surface of said reservoir layer or said inner surface of said backing layer for affixing said laminate to said skin or mucosa of said host, so that said encapsulate is capable of being continuously released from said first surface of said reservoir layer thereto.

35. The device of claim 34, wherein said backing layer comprises one or more layers of an occlusive material.