Controlled release of biologically active compounds

• US 8,802,147 B2
• Filed: 09/24/2013
• Issued: 08/12/2014
• Est. Priority Date: 08/30/2007
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao S
• Primary Examiner(s): Ahvazi, Bijan
• Assistant Examiner(s): WANG, CHUN CHENG
• Application Number:
  US14/034,867
• Publication Number:
  US 20140099370A1
• Time in Patent Office: 322 Days
• Field of Search: 424/486, 424/280.1, 424/78.37, 424/78.38, 524/599, 528/128, 528/271, 549/403, 560/60, 560/61, 560/230, 562/471
• US Class Current: 424/486
• CPC Class Codes: A61K 2800/10 General cosmetic use
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 8/85 Polyesters
• CPC Class Codes: A61K 8/88 Polyamides
• CPC Class Codes: A61L 17/105 Polyesters not covered by A61L17/12
• CPC Class Codes: A61L 17/12 Homopolymers or copolymers of glycolic acid or lactic acid
• CPC Class Codes: A61L 17/145 Coating
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: C07C 59/70 Ethers of hydroxy-acetic acid , e.g. substitutes on the ring
• CPC Class Codes: C07C 69/63 of saturated acids
• CPC Class Codes: C07C 69/736 the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 311/36 : not hydrogenated in the hetero ring, e.g. isoflavones
• CPC Class Codes: C08G 63/16 : Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 63/672 : Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 69/40 : Polyamides containing oxygen in the form of ether groups C08G69/12, C08G69/32 take precedence
• CPC Class Codes: C08G 69/44 : Polyester-amides
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 77/12 : Polyester-amides

Abstract

The present invention relates to biodegradable polymers (e.g., polyesters and polyester amides) derived from functionalized biologically active compounds that can provide site specific delivery of bioactive compounds upon biodegradation in a controlled manner.

Claims

1. A biodegradable polyamide ester of formula VIII or IX, or a pharmaceutically acceptable salt thereof:

(C)

—

[(X¹)_cO(O═

)C—

R₉—

C(═

O)O—

(Y¹)_d—

(Y²)_a—

CH₂(O═

)C—

NH—

R₁₀—

NH—

C(═

O)CH₂—

(X²)_b]_o—

 

 

VIII

wherein the polyamide ester of formula VIII is formed by condensation polymerization of monomers of formula Va and VII;

H—

(X¹)_c—

O(O═

)C—

R₉—

C(═

O)O—

(Y¹)_d—

H 

 

Va

R₁₁—

(Y²)_a—

CH₂(O═

)C—

NH—

R₁₀—

NH—

C(═

O)CH₂—

(X²)_b—

R₁₂ 

 

VII

(D)

—

[(X)_a—

O—

R₁—

O—

(Y)_b—

(Y²)_a—

CH₂(O═

)C—

NH—

R₁₀—

NH—

C(═

O)CH₂—

(X²)_b]_p—

 

 

IX

wherein the polyamide ester of formula IX is formed by condensation polymerization of monomers of formula I and VII;

H—

(X)_a—

O—

R₁—

O—

(Y)_b—

H 

 

I

R₁₁—

(Y²)_a—

CH₂(O═

)C—

NH—

R₁₀—

NH—

C(═

O)CH₂—

(X²)_b—

R₁₂ 

 

VII

wherein;

o and p are each independently an integer from about 5 to about 1000;

R₁ and R₉ are each independently the remaining portion of a biologically active compound;

R₁₀ is the remaining portion of a biologically active compound or non-biologically active compound;

R₁₁ and R₁₂ are each independently selected from Cl, F, Br, and I;

X, X¹ and X² are independently at each occurrence —

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—

;

Y, Y¹, and Y² are independently at each occurrence —

CH₂C(═

O)O—

(glycolic acid moiety), —

CH(CH₃)C(═

O)O—

(lactic acid moiety), —

CH₂CH₂OCH₂C(═

O)O—

(dioxanone moiety), —

CH₂CH₂CH₂CH₂CH₂C(═

O)O—

(caprolactone moiety), —

(CH₂)_yC(═

O)O—

, or —

(CH₂CH₂O)_zCH₂C(═

O)O—

;

each y and z is independently an integer from about 2 to about 24;

each a, b, c, and d is independently an integer from about 1 to about 6.

2. A biodegradable polyamide ester of claim 1 having formula VIII or a pharmaceutically acceptable salt thereof:

—

[(X¹)_c—

O(O═

)C—

R₉—

C(═

O)O—

(Y¹)_d—

(Y²)_a—

CH₂(O═

)C—

NH—

R₁₀—

NH—

C(═

O)CH₂—

(X²)_b]_o—

 

 

VIII.

3. A biodegradable polyamide ester of claim 1 having formula IX or a pharmaceutically acceptable salt thereof:

—

[(X)_a—

O—

R₁—

O—

(Y)_b—

(Y²)_a—

CH₂(O═

)C—

NH—

R₁₀—

NH—

C(═

O)CH₂—

(X²)_b]_p—

 

 

IX.

4. A polyamide ester of claim 2, wherein the non-biologically active compound is a diamino compound selected from:

5. A polyamide ester of claim 3, wherein the non-biologically active compound is a diamino compound selected from:

6. A biodegradable monomer according to claim 1, wherein the monomer is selected from formula Va, and VII.

7. A composition comprising at least two different polymers, wherein each polymer is independently a polyamide ester according to claim 1.

8. A cosmetic composition comprising a cosmetic ingredient and at least one polymer polyamide ester according to claim 1.

9. An implantable medical device or coating comprising at least one polyamide ester according to claim 1.

10. An implantable medical device or coating of claim 9, wherein the polyamide ester has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, ether lactones, morpholinediones, and p-dioxanone.

11. An implantable medical device or coating of claim 9, wherein the device is a stent.

12. An implantable medical device or coating of claim 11, wherein the polyamide ester has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, ether lactones, morpholinediones, and p-dioxanone.

13. An implantable medical device or coating of claim 9, wherein the device is a scaffold for tissue engineer comprising a porous structure for the attachment and proliferation of cells.

14. An implantable medical device or coating of claim 13, wherein the polyamide ester has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, ether lactones, morpholinediones, and p-dioxanone.

15. A coating for a stent comprising at least one polyamide ester according to claim 1.

16. A stent coating of claim 15, wherein the polyamide ester has been further polymerized with a lactone monomer selected from glycolide, lactide, ε

-caprolactone, trimethylene carbonate, ether lactones, morpholinediones, and p-dioxanone.

17. A drug delivery system comprising at least one polyamide ester according to claim 1 physically admixed with a biologically or pharmacologically active agent.

18. A drug delivery system of claim 17, wherein the biologically or pharmacologically active agent is physically embedded or dispersed into the polyamide ester and the polyamide ester is in the form of a polymeric matrix.

19. A suture coating comprising at least one polyamide ester according to claim 1.

20. A suture comprising at least one polyamide ester according to claim 1.

21. An antimicrobial agent comprising at least one polyamide ester according to claim 1.

22. A method for treating a disease in a patient, comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

23. A method for producing an analgesic effect in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

24. A method for treating cancer in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

25. A method for producing an anti-inflammatory effect in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

26. A method for producing an anti-bacterial effect in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

27. A method for producing an anti-fungal effect in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

28. A method for producing an immunosuppressive effect in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

29. A method for producing an anti-thrombotic effect in an patient comprising administering to an animal in need of such therapy, an effective amount of at least one polymer polyamide ester to claim 1.

30. A method for treating psoriasis, inflammatory bowel disease, skin cancer, or a brain tumor in an patient, comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

31. A method for producing an anti-infective effect in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.

32. A therapeutic method for treating pain in a patient comprising administering to an animal in need of such therapy, an effective amount of at least one polyamide ester according to claim 1.