Method for delivery of smooth muscle cell inhibitors

• US 5,171,217 A
• Filed: 02/28/1991
• Issued: 12/15/1992
• Est. Priority Date: 02/28/1991
• Status: Expired due to Fees

• Current Assignee: ADVANCED RESEARCH & TECHNOLOGY INSTITUTE
• Original Assignee: Indiana University Foundation
• Inventors: Hathaway, David R., March, Keith L., Wilensky, Robert L.
• Primary Examiner(s): Yasko, John D.
• Assistant Examiner(s): CERMAK, ADAM
• Application Number:
  US07/662,194
• Time in Patent Office: 656 Days
• Field of Search: 604/28, 604/48, 604/49, 604/51-53, 604/54, 604/55, 604/93, 604/265, 604/266, 604/269, 128/897, 128/898, 424/450
• US Class Current: 604/507
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

A method and composition for delivering a drug to an affected intramural site for sustained release in conjunction with or following balloon catheter procedures, such as angioplasty. The drug, carried by microparticles of a physiologically-compatible, biodegradable polymer is injected under directed pressure into the wall of a body vessel in the region of the affected site.

Claims

1. A method for delivering a drug to an affected intramural site for sustained release comprising:

injecting a smooth muscle cell inhibitor under directed pressure into the wall of a body vessel in the region of the affected intramural site, said drug being carried by microparticles of a physiologically-compatible, biodegradable polymer.

2. The method of claim 1 in which the smooth muscle cell inhibitor is selected from the group of:

A. Agents that modulate intracellular Ca²⁺ or Ca²⁺ -binding proteins

B. Receptor blockers for contractile agonists

C. Inhibitors of the sodium/hydrogen antiporter

D. Protease inhibitors

E. Nitrovasodilators

F. Phosphodiesterase inhibitors

G. Phenothiazines

H. Growth factor receptor antagonists

I. Anti-mitotic agents

J. Immunosuppressive agents

K. Antisense oligonucleotides and

L. Protein kinase inhibitors,

and the polymer is selected from the group of biodegradable polylactic acid, polyglycolic acid and polyanhydride-base polymers.

3. The method of claim 2 in which the smooth muscle cell inhibitor is selected from the group of:

A. Agents that modulate intracellular Ca²⁺ or Ca²⁺ -binding proteins, said agents being selected from the group of

a) L-type Ca²⁺ channel blockers,

b) T-type Ca²⁺ channel blockers,

c) calmodulin antagonists,

d) inhibitors of the sodium/calcium antiporter,

e) inhibitors of the ryanodine receptor, and

f) inhibitors of the IP₃ receptor;

B. Receptor blockers for contractile agonists, in which the receptor blockers are selected from the group of α

-adrenergic blocking agents, angiotensin II receptor antagonists and receptor antagonists for histamine, serotonin and endothelin;

C. Inhibitors of the sodium/hydrogen antiporter, in which the inhibitors are selected from the group of amiloride and its derivatives;

D. Inhibitors of protease, serine protease, metalloendoproteases and aspartyl protease, and thiol protease inhibitors selected from the group of benzyloxycarbonyl-leu-norleucinal (calpeptin) and acetyl-leu-leu-norleucinal;

E. Nitrovasodilators, wherein the nitrovasodilator is isosorbide dinitrate;

F. Phosphodiesterase inhibitors, wherein the phosphodiesterase inhibitor is isobutyl methylxanthine;

G. Phenothiazines, wherein the phenothiazine is amytriptyline;

H. Growth factor receptor antagonists for platelet-derived growth factor (PDGF), epidermal growth factor, interleukins, transforming growth factors alpha and beta, and acidic or basic fibroblast growth factors;

I. Anti-mitotic agents selected from the group of colchicine, anthracyclines and other antibiotics, folate antagonists and other anti-metabolites, vinca alkaloids, nitrosoureas, DNA alkylating agents, purine antagonists and analogs, pyrimidine antagonists and analogs, and alkyl sulfonates;

J. Immunosuppressive agents selected from the group of adrenocorticosteroids and cyclosporine;

K. Antisense oligonucleotides including sequences complementary to portions of PDGF or other growth factors;

L. Protein kinase inhibitors for tyrosine kinases, protein kinase C, myosin light chain kinase, Ca²⁺ /calmodulin kinase II and casein kinase II;

and the polymer is selected from the group of biodegradable polylactic acid, polyglycolic acid and polyanhydride-base polymers.

4. A method for preventing restenosis following a procedure for vessel recanalization involving vascular injury comprising:

injecting a smooth muscle cell inhibitor for sustained release at the affected intramural site, said smooth muscle cell inhibitor being carried by microparticles of a physiologically-compatible, biodegradable polymer.

5. The method of claim 4 in which the smooth muscle cell inhibitor is selected from the group of:

A. Agents that modulate intracellular Ca²⁺ or Ca²⁺ -binding proteins

B. Receptor blockers for contractile agonists

C. Inhibitors of the sodium/hydrogen antiporter

D. Protease inhibitors

E. Nitrovasodilators

F. Phosphodiesterase inhibitors

G. Phenothiazines

H. Growth factor receptor antagonists

I. Anti-mitotic agents

J. Immunosuppressive agents

K. Antisense oligonucleotides, and

L. Protein Kinase inhibitors

and the polymer is selected from the group of biodegradable polylactic acid, polyglycolic acid and polyanhydride-base polymers.

6. The method of claim 5 in which the drug is selected from the group of

A. Agents that modulate intracellular Ca²⁺ or Ca²⁺ -binding proteins, said agents being selected from the group of

a) L-type Ca²⁺ channel blockers,

b) T-type Ca²⁺ channel blockers,

c) calmodulin antagonists,

d) inhibitors of the sodium/calcium antiporter,

e) inhibitors of the ryanodine receptor, and

f) inhibitors of the IP₃ receptor;

B. Receptor blockers for contractile agonists, in which the receptor blockers are selected from the group of α

-adrenergic blocking agents, angiotensin II receptor antagonists and receptor antagonists for histamine, serotonin and endothelin;

C. Inhibitors of the sodium/hydrogen antiporter, in which the inhibitors are selected from the group of amiloride and its derivatives;

D. Inhibitors of protease, serine protease, metalloendoproteases and aspartyl protease, and thiol protease inhibitors selected from the group of benzyloxycarbonyl-leu-norleucinal (calpeptin) and acetyl-leu-leu-norleucinal;

E. Nitrovasodilators, wherein the nitrovasodilator is isosorbide dinitrate;

E. Phosphodiesterase inhibitors, wherein the phosphodiesterase inhibitor is isobutyl methylxanthine;

G. Phenothiazines, wherein the phenothiazine is amytriptyline;

H. Growth factor receptor antagonists for platelet-derived growth factor (PDGF), epidermal growth factor, interleukins, transforming growth factors alpha and beta, and acidic or basic fibroblast growth factors;

I. Anti-mitotic agents selected from the group of colchicine, anthracyclines and other antibiotics, folate antagonists and other anti-metabolites, vinca alkaloids, nitrosoureas, DNA alkylating agents, purine antagonists and analogs, pyrimidine antagonists and analogs, and alkyl sulfonates;

J. Immunosuppressive agents selected from the group of adrenocorticosteroids and cyclosporine;

K. Antisense oligonucleotides including sequences complementary to portions of PDGF or other growth factors;

L. Protein kinase inhibitors for tyrosine kinases, protein kinase C, myosin light chain kinase, Ca²⁺ /calmodulin kinase II and casein kinase II;

and the polymer is selected from the group of biodegradable polylactic acid, polyglycolic acid and polyanhydride-base polymers.

7. The method of claim 6 in which the smooth muscle cell inhibitor is selected form the group of anti-mitotic agents, protease inhibitors and antisense oligonucleotides.

8. The method of claim 7 in which the smooth muscle cell inhibitor is colchicine and biodegradable polymer is a copolymer of lactic acid and glycolic acid.

9. The method for preventing restenosis of a coronary artery recanalized by angioplasty comprising:

injecting a smooth muscle cell inhibitor for sustained release at the affected intramural site, said smooth muscle cell inhibitor being carried by microparticles of a physiologically-compatible, biodegradable polymer, said smooth muscle cell inhibitor being selected from the group of;

A. Agents that modulate intracellular Ca²⁺ or Ca²⁺ -binding proteins

B. Receptor blockers for contractile agonists

C. Inhibitors of the sodium/hydrogen antiporter

D. Protease inhibitors

E. Nitrovasodilators

F. Phosphodiesterase inhibitors

G. Phenothiazines

H. Growth factor receptor antagonists

I. Anti-mitotic agents

J. Immunosuppressive agents

K. Antisense oligonucleotides and

L. Protein kinase inhibitors,

and the polymer is selected from the group of biodegradable polylactic acid, polyglycolic acid and polyanhydride-base polymers.

10. The method of claim 9 in which the smooth muscle cell inhibitor is selected from the group of:

A. agents that modulate intracellular Ca²⁺ or Ca²⁺ -binding proteins, said agents being selected from the group of

a) L-type Ca²⁺ channel blockers,

b) T-type Ca²⁺ channel blockers,

c) calmodulin antagonists,

d) inhibitors of the sodium/calcium antiporter,

e) inhibitors of the ryanodine receptor, and

f) inhibitors of the IP₃ receptor;

B. Receptor blockers for contractile agonists, in which the receptor blockers are selected from the group of α

-adrenergic blocking agents, angiotensin II receptor antagonists and receptor antagonists for histamine, serotonin and endothelin;

C. Inhibitors of the sodium/hydrogen antiporter, in which the inhibitors are selected from the group of amiloride and its derivatives;

D. Inhibitors of protease, serine protease, metalloendoproteases and aspartyl protease, and thiol protease inhibitors selected from the group of benzyloxycarbonyl-leu-norleucinal (calpeptin) and acetyl-leu-leu-norleucinal;

E. Nitrovasodilators, wherein the nitrovasodilator is isosorbide dinitrate;

F. Phosphodiesterase inhibitors, wherein the phosphodiesterase inhibitor is isobutyl methylxanthine;

g. Phenothiazines, wherein the phenothiazine is amytriptyline;

H. Growth factor receptor antagonists for platelet-derived growth factor (PDGF), epidermal growth factor, interleukins, transforming growth factors alpha and beta, and acidic or basic fibroblast growth factors;

I. Anti-mitotic agents selected from the group of colchicine, anthracyclines and other antibiotics, folate antagonists and other anti-metabolites, vinca alkaloids, nitrosoureas, DNA alkylating agents, purine antagonists and analogs, pyrimidine antagonists and analogs, and alkyl sulfonates;

J. Immunosuppressive agents selected from the group of adrenocorticosteroids and cyclosporine;

K. Antisense oligonucleotides including sequences complementary to portions of PDGF or other growth factors;

L. Protein kinase inhibitors for tyrosine kinases, protein kinase C, myosin light chain kinase, Ca²⁺ /calmodulin kinase II and casein kinase II;

and the polymer is selected from the group of biodegradable polylactic acid, polyglycolic acid and polyanhydride-base polymers.

11. The method for preventing restenosis of a coronary artery recanalized by angioplasty comprising:

injecting a smooth muscle cell inhibitor selected from the group of anti-mitotic agents, protease inhibitors and antisense oligonucleotides into the arterial wall in the region of angioplasty for sustained release, said smooth muscle inhibitor being carried by microparticles of a biodegradable polymer selected from the group of polylactic acid, polyglycolic acid and polyanhydride-base polymers and copolymers.

12. The method of claim 11 in which the anti-mitotic agent is colchicine.

13. The method of claim 12 in which the polymer is a copolymer of lactic acid and glycolic acid.