Biodegradable Poly(Ester-Amide) And Poly(Amide) Coatings For Implantable Medical Devices With Enhanced Bioabsorption Times

• US 20100047319A1
• Filed: 08/21/2008
• Published: 02/25/2010
• Est. Priority Date: 08/21/2008
• Status: Abandoned Application

• Current Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories Incorporated)
• Original Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories Incorporated)
• Inventors: Hossainy, Syed F. A., Lim, Florencia, Ngo, Michael Huy, Trollsas, Mikael O.
• Application Number:
  US12/196,143
• Publication Number:
  US 20100047319A1
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08L 77/00 Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain of polyhydrazides C08L79/06; of polyamideimides or polyamide acids C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 77/12 Polyester-amides

Abstract

This invention is generally related to coating layers for implantable medical devices, such as drug delivery vascular stents, and methods of fabricating coated implantable medical devices. Specifically various embodiments of the present invention include methods of fabricating and modulating of coating layers to enhance bioabsorption. The coating layers include poly(ester-amide) and/or poly(amide) polymers.

Claims

1. A method of modulating the in vivo absorption rate of a coating on an implantable medical device comprising a poly(ester-amide) (PEA), a poly(amide) (PA) polymer, or a combination thereof, and a drug, the coating layer comprising a polymer phase and a dispersed drug phase, the method comprising:

a) causing faster and greater water ingress into the coating layer,

b) increasing fraction of interfacial area of the polymer with the dispersed drug phase, and/or

c) increasing the surface area of the coating layer or the interfacial area of the polymer phase with the dispersed drug phase;

wherein the coating layer completely degrades or substantially degrades within 12 months after implantation of the implantable medical device.

2. The method of claim 1, wherein the method modulates the in vivo absorption rate of a coating layer on an implantable medical device, and wherein the implantable medical device is a stent.

3. The method of claim 1, wherein the coating layer completely or substantially degrades within 6 months after implantation.

4. The method of claim 1, wherein the coating layer has degraded by about 50% at 3 months after implantation.

5. The method of claim 1, wherein causing faster and greater water ingress into the coating layer comprises adding a non-therapeutic soluble component to the coating layer.

6. The method of claim 1, wherein increasing the fraction of interfacial area of the polymer with the dispersed drug phase comprises using a drug to polymer ratio in the range of about 1:

1 to about 1;

7.

7. The method of claim 1, wherein increasing fraction of interfacial area of the polymer with the dispersed drug phase comprises using a soluble component to polymer ratio in the range of about 1:

1 to about 1;

7.

8. The method of claim 1, wherein increasing the surface area of the coating layer or the interfacial area of the polymer phase with the dispersed drug phase comprises applying the coating layer such that the domain size of the domains of the dispersed drug phase are between about 100 nm and about 2 μ

m.

9. The method of claim 1, wherein the method modulates a coating layer on an implantable medical device, and wherein the coating layer comprises a poly(ester-amide) polymer, a poly(amide) polymer, or a combination thereof, and a drug, and wherein the poly(ester-amide) or poly(amide) polymer is a polymer of the formula:

wherein;

i is an integer from 1 to 10, inclusive;

j is an integer from 0 to 10, inclusive;

k is an integer from 0 to 15, inclusive;

x_n is an integer from 0 to 100, inclusive;

y_m is an integer from 0 to 150, inclusive;

p is an integer from 2 to about 4500;

M_w is from about 10,000 to about 1,000,000 Da;

s_i is a number from 0 to 0.5, inclusive;

t_j is a number from 0 to 0.5, inclusive;

v_k is a number from 0 to 0.5, inclusive;

with the proviso that

Σ

_i s_i+Σ

_j t_j+Σ

_k v_k=1.0;

Σ

_i s_i=Σ

_j t_j+Σ

_k v_k=0.5;

Σ

_i s_i>

0;

Σ

_j t_j>

0 or Σ

_k v_k>

0;

each A_i has the chemical structure;

each B_j has the chemical structure

each C_k has the chemical structure;

wherein;

each R_bj, and R_bj′

are independently selected from the group consisting of hydrogen and (C1-C4)alkyl, wherein;

the alkyl group is optionally substituted with a moiety selected from the group consisting of —

OH, —

SH, —

SeH, —

C(O)OH, —

NHC(NH)NH₂,

phenyl and

one or more of R_bj and R_bj′

may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising —

CH₂CH₂CH₂—

;

each R_ai and each R_cj are independently selected from the group consisting of (C1-C12)alkyl, (C2-C12)alkenyl, (C3-C8)cycloalkyl, —

(CH₂CH₂O))_qCH₂CH₂—

wherein q is an integer from 1 to 10, inclusive, and

where z is 0, 1, or 2;

R_dk is selected from the group consisting of —

H, —

OH, —

O(C1-C20)alkyl, —

O(C1-C20)alkenyl and —

O(CH₂CH₂O)_wCH₂CH₂OR_ek, wherein;

w is an integer from 1 to 600, inclusive;

R_ek is selected from the group consisting of hydrogen, —

C(O)CH═

CH₂ and —

C(O)C(CH₃)═

CH₂; and

,

each R_ai corresponds to the i^th A_i group, each R_bj, R_bj′

, and R_cj corresponds to the j^th B_j group, and each R_dk and optionally R_ek correspond to the k^th C_k group.

10. The method of claim 9, wherein for the polymer i=1, j=2, k=0, and

each of R_a1 is selected from the group consisting of —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉—

, and —

(CH₂)₁₀—

;

each of R_b1, R_b1′

, R_b2 and R_b2′

are the same, and are selected from the group consisting of —

(CH₂)—

(CH(CH₃)₂) and —

(CH₃);

R_c1 is selected from the group consisting of —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, and —

(CH₂)₈—

; and

R_c2 is selected from the group consisting of

where z is 0, 1, or 2.

11. A method of fabricating an implantable medical device coated with a bioabsorbable coating layer, the method comprising:

applying to an implantable medical device a coating layer comprising a poly(ester-amide) and/or a poly(amide) polymer, and a soluble component;

wherein the soluble component to polymer ratio is between 1;

1 to 1;

7; and

wherein the coating layer thickness is between about 2 μ

m and 10 μ

m; and

wherein the polymer in the coating layer, or the coating layer, is substantially absorbed or completely absorbed in vivo in 12 months or fewer after implantation.

12. The method of claim 11, wherein the coating layer comprises a drug.

13. The method of claim 11, wherein the coating layer comprises a non-therapeutic soluble component.

14. The method of claim 11, wherein the polymer is a random poly(ester amide) copolymer having the formula:

[(A₁-B₁)_x1|(A₁-B₂)_x2]_p(M_w, s₁, t₁, t₂)

wherein;

A₁ has the chemical structure;

each of B₁ and B₂ has the chemical structure

t₁ is between 0.125 and 0.375;

t₂=0.5−

t₁;

s1=0.5; and

p is an integer from 2 to about 4500;

wherein;

R_a1 is selected from the group consisting of —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉—

, and —

(CH₂)₁₀—

;

each of R_b1, R_b1′

, R_b2 and R_b2′

are the same, and are selected from the group consisting of —

(CH₂)—

(CH(CH₃)₂) and —

(CH₃);

R_c1 is selected from the group consisting of —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, and —

(CH₂)₈—

; and

R_c2 is selected from the group consisting of

where z is 0, 1, or 2.

15. A coating layer on a substrate, the coating layer comprising:

a drug and a poly(ester-amide) polymer and/or a poly(amide) polymer wherein the ratio of drug to polymer is from about 1;

3 to about 1;

5;

wherein the coating layer thickness on the substrate is between 2 μ

m to about 10 μ

m; and

wherein the polymer mass in the coating layer after 3 months is about 50% or less of the initial polymer mass in the coating layer wherein the reduction is due to in vivo absorption.

16. The coating layer of claim 15, wherein the polymer is a random poly(ester-amide) copolymer having the formula:

[(A₁-B₁)_x1|(A₁-B₂)_x2]_p(M_w, s₁, t₁, t₂)

wherein;

A₁ has the chemical structure;

each of B₁ and B₂ has the chemical structure

t₁ is between 0.125 and 0.375;

t₂=0.5−

t₁;

s1=0.5; and

p is an integer from 2 to about 4500;

wherein;

R_a1 is selected from the group consisting of —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉— and

—

(CH₂)₁₀—

;

each of R_b1 R_b1′

, R_b2 and R_b2′

are the same, and are selected from the group consisting of —

(CH₂)—

(CH(CH₃)₂) and —

(CH₃);

R_c1 is selected from the group consisting of —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, and —

(CH₂)₈—

; and

R_c2 is selected from the group consisting of

where z is 0, 1, or 2.

17. An implantable medical device comprising a coating layer of claim 16.

18. The device of claim 17 wherein the implantable medical device is a stent.

19. The coating layer of claim 16, wherein for the poly(ester-amide) polymer

R_a1 is —

(CH₂)₈—

;

R_b1, R_b1′

, R_b2 and R_b2′

are —

(CH₂)—

(CH(CH₃)₂);

R_c1 is —

(CH₂)₆—

; and

R_c2 is

21. The method of claim 19, wherein the soluble component comprises a drug.

22. The method of claim 19, wherein the soluble component comprises a nontherapeutic soluble component selected from the group consisting of poly(vinyl pyrrolidone), poly(ethylene glycol) (PEG), poly(propylene glycol), and combinations thereof.

20. A method of fabricating an implantable medical device coated with a bioabsorbable coating layer, the method comprising:

providing an implantable medical device;

applying to the implantable medical device a coating layer comprising a poly(ester-amide) and/or a poly(amide) polymer, and a soluble component;

wherein the soluble component to polymer ratio is between 1;

1 to 1;

7; and

wherein the coating layer thickness is between about 2 μ

m and 10 μ

m;

determining the in vivo bioabsorption time of the coating layer;

wherein if the in vivo bioabsorption time is too long;

increasing the ratio of soluble component to polymer,

decreasing the coating layer thickness, and/or

decreasing the domain size of the soluble component;

or if the in vivo bioabsorption time is too short;

decreasing the ratio of soluble component to polymer,

increasing the coating layer thickness, and/or

increasing the domain size of the soluble component.

23. The method of claim 20, wherein the polymer is a random poly(ester-amide) copolymer having the formula:

[(A₁-B₁)_x1|(A₁-B₂)_x2]_p(M_w, s₁, t₁, t₂)

wherein;

A₁ has the chemical structure;

each of B₁ and B₂ has the chemical structure

t₁ is between 0.125 and 0.375;

t₂=0.5−

t₁;

s1=0.5; and

p is an integer from 2 to about 4500;

wherein;

R_a1 is —

(CH₂)₈—

;

R_b1, R_b1′

, R_b2 and R_b2′

are —

(CH₂)—

(CH(CH₃)₂);

R_c1 is —

(CH₂)₆—

; and

R_c2 is