Balloon Catheter for Treating Stenosis of Body Passages and for Preventing Threatening Restenosis

• US 20110160698A1
• Filed: 02/09/2011
• Published: 06/30/2011
• Est. Priority Date: 07/03/2007
• Status: Active Grant

• Current Assignee: Hemoteq AG (Freudenberg & Company KG)
• Original Assignee: Hemoteq AG (Freudenberg & Company KG)
• Inventors: Faust, Volker, Hoffmann, Erika, Von Holst, Armin, Schreiber, Helmut, Hoffmann, Michael, Horres, Roland
• Granted Patent: US 9,192,697 B2
• Time in Patent Office: Days
• US Class Current: 604/509
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/80 characterised by a special chemical form
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61M 2025/1031 Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
• CPC Class Codes: A61M 2025/1075 having a balloon composed of several layers, e.g. by coating or embedding
• CPC Class Codes: A61M 25/1029 Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril

Abstract

The present invention is directed to a method for coating catheter balloons with a defined amount of a pharmacologically active agent, wherein the coating method uses a coating device having a volume measuring device for releasing a measurable amount of a coating solution by means of a dispensing device specifically onto the surface of the catheter balloon.

Claims

1. A catheter balloon coated with at least one active substance and at least one citrate ester.

2. A catheter balloon according to claim 1, wherein the citrate ester is tributyl citrate, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, or a mixture thereof.

3. A catheter balloon according to claim 1, wherein the citrate ester has the formula:

4. A catheter balloon according to claim 3, wherein R, R′

, and R″

are independently selected from —

H, —

OH, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

O-cyclo-C₃H₅, —

OCH(CH₃)₂, —

OC(CH₃)₃, —

OC₄H₉, —

SH, —

SCH₃, —

SC₂H₅, —

NO₂, —

F, —

Cl, —

Br, —

I, COCH₃, —

COC₂H₅, —

COC₃H₇, —

CO-cyclo-C₃H₅, —

COCH(CH₃)₂, —

COOH, —

COOCH₃, —

COOC₂H₅, —

COOC₃H₇, —

COO-cyclo-C₃H₅, —

COOCH(CH₃)₂, —

OOC—

CH₃, —

OOC—

C₂H₅, —

OOC—

C₃H₇, —

OOC-cyclo-C₃H₅, —

OOC—

CH(CH₃)₂, —

CONH₂, —

CONHCH₃, —

CONHC₂H₅, —

CONHC₃H₇, —

CONH-cyclo-C₃H₅, —

CONH[CH(CH₃)₂], —

CON(CH₃)₂, —

CON(C₂H₅)₂, —

CON(C₃H₇)₂, —

CON(cyclo-C₃H₅)₂, —

CON[CH(CH₃)₂]₂, —

NHCOCH₃, —

NHCOC₂H₅, —

NHCOC₃H₇, —

NHCO-cyclo-C₃H₅, —

NHCO—

CH(CH₃)₂, —

NHCO—

OCH₃, —

NHCO—

OC₂H₅, —

NHCO—

OC₃H₇, —

NHCO—

O-cyclo-C₃H₅, —

NHCO—

OCH(CH₃)₂, —

NHCO—

OC(CH₃)₃, —

NH₂, —

NHCH₃, —

NHC₂H₅, —

NHC₃H₇, —

NH-cyclo-C₃H₅, —

NHCH(CH₃)₂, —

NHC(CH₃)₃, —

N(CH₃)₂, —

N(C₂H₅)₂, —

N(C₃H₇)₂, —

N(cyclo-C₃H₅)₂, —

N[CH(CH₃)₂]₂, —

SO₂CH₃, —

SO₂C₂H₅, —

SO₃H, —

SO₃CH₃, —

SO₃C₂H₅, —

OCF₃, —

OC₂F₅, —

NH—

CO—

NH₂, —

NH—

C(═

NH)—

NH₂, —

O—

CO—

NH₂, —

O—

CO—

NHCH₃, —

O—

CO—

N(CH₃)₂, —

O—

CO—

N(C₂H₅)₂, —

CH₂F, —

CHF₂, —

CF₃, —

CH₂Cl, —

CH₂Br, —

CH₂—

CH₂F, —

CH₂—

CF₃, —

CH₂—

CH₂Cl, —

CH₂—

CH₂Br, —

CH₃, —

C₂H₅, —

C₃H₇, —

CH(CH₃)₂, —

C(CH₃)₃, —

C₄H₉, —

CH₂—

CH(CH₃)₂, —

CH(CH₃)—

C₂H₅, —

O₅H₁₁, —

C₆H₁₃, —

C₇H₁₅, —

C₈H₁₇, -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-O₅H₉, -cyclo-C₆H₁₁, —

Ph, —

CH₂—

Ph, —

CH—

CH₂, —

CH₂—

CH═

CH₂, —

C(CH₃)═

CH₂, —

CH═

CH—

CH₃, —

C₂H₄—

CH═

CH₂, —

CH═

C(CH₃)₂, —

C≡

CH, —

C≡

C—

CH₃, —

CH₂—

C≡

CH.

5. A catheter balloon as in claim 1 wherein said active agent comprises an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, fungicidal and/or antithrombotic active agent.

6. A catheter balloon as in claim 1 wherein said active agent comprises rapamycin.

7. A catheter balloon as in claim 1 wherein said active agent comprises paclitaxel.

8. A catheter balloon having a coating comprising

an active substance which is an antiproliferative, immunosuppressive, anti-inflammatory, antimycotic and/or antithrombotic active agent,

in combination with at least one adjuvant which is a member of the group consisting of triethyl citrate, triethyl citrate acetylate, tributyl citrate, tributyl citrate acetylate, triacetin, benzoic acid benzyl ester, isopropyl myristate, isopropyl palmitate, 2-pyrrolidone, dibutyl phthalate, diethyl phthalate and diethanol amine.

9. A catheter balloon as in claim 8 wherein the active substance comprises rapamycin or a derivative thereof that binds to the mTOR binding site.

10. A catheter balloon as in claim 9 wherein the rapamycine derivative is biolimus or everolimus.

11. A catheter balloon as in claim 8 wherein the active substance comprises paclitaxel.

12. A catheter balloon as in claim 8 wherein said at least one adjuvant is a member of the group consisting of triethyl citrate, triethyl citrate acetylate, tributyl citrate and tributyl citrate acetylate, and mixtures thereof.

13. A method of treating a patient to prevent or lessen occurrence of restenosis at a vascular site, comprising

advancing a catheter having a balloon having a coating comprising an active substance which is an antiproliferative, immunosuppressive, anti-inflammatory, antimycotic and/or antithrombotic active agent, to a treatment site of a vessel wall and

inflating the balloon to contact the vessel wall and transfer at least some of the active substance to the vessel wall,

wherein the coating further comprises an adjuvant which is a member of the group consisting of triethyl citrate, triethyl citrate acetylate, tributyl citrate, tributyl citrate acetylate, triacetin, benzoic acid benzyl ester, isopropyl myristate, isopropyl palmitate, 2-pyrrolidone, dibutyl phthalate, diethyl phthalate and diethanol amine.

14. A method as in claim 13 wherein the active substance comprises rapamycin or a derivative thereof that binds to the mTOR binding site.

15. A method as in claim 14 wherein the rapamycine derivative is biolimus or everolimus.

16. A method as in claim 13 wherein the active substance comprises paclitaxel.

17. A method as in claim 13 wherein said at least one adjuvant is a member of the group consisting of triethyl citrate, triethyl citrate acetylate, tributyl citrate and tributyl citrate acetylate, and mixtures thereof.

18. A method of treating a patient to prevent or lessen occurrence of restenosis at a vascular site, comprising

advancing a catheter having a balloon having a coating comprising an active substance to a treatment site of a vessel wall and

inflating the balloon to contact the vessel wall and transfer at least some of the active substance to the vessel wall,

wherein the coating further comprises an adjuvant which is a citrate ester.

19. A method as in claim 18 wherein the citrate ester has the formula:

20. A method as in claim 19, wherein R, R′

, and R″

are independently selected from —

H, —

OH, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

O-cyclo-C₃H₅, —

OCH(CH₃)₂, —

OC(CH₃)₃, —

OC₄H₉, —

SH, —

SCH₃, —

SC₂H₅, —

NO₂, —

F, —

Cl, —

Br, —

I, COCH₃, —

COC₂H₅, —

COC₃H₇, —

CO-cyclo-C₃H₅, —

COCH(CH₃)₂, —

COOH, —

COOCH₃, —

COOC₂H₅, —

COOC₃H₇, —

COO-cyclo-C₃H₅, —

COOCH(CH₃)₂, —

OOC—

CH₃, —

OOC—

CH_S, —

OOC—

C₃H₇, —

OOC-cyclo-C₃H₅, —

OOC—

CH(CH₃)₂, —

CONH₂, —

CONHCH₃, —

CONHC₂H₅, —

CONHC₃H₇, —

CONH-cyclo-C₃H₅, —

CONH[CH(CH₃)₂], —

CON(CH₃)₂, —

CON(C₂H₅)₂, —

CON(C₃H₇)₂, —

CON(cyclo-C₃H₅)₂, —

CON[CH(CH₃)₂]₂, —

NHCOCH₃, —

NHCOC₂H₅, —

NHCOC₃H₇, —

NHCO-cyclo-C₃H₅, —

NHCO—

CH(CH₃)₂, —

NHCO—

OCH₃, —

NHCO—

OC₂H₅, —

NHCO—

OC₃H₇, —

NHCO—

O-cyclo-C₃H₅, —

NHCO—

OCH(CH₃)₂, —

NHCO—

OC(CH₃)₃, —

NH₂, —

NHCH₃, —

NHC₂H₅, —

NHC₃H₇, —

NH-cyclo-C₃H₅, —

NHCH(CH₃)₂, —

NHC(CH₃)₃, —

N(CH₃)₂, —

N(C₂H₅)₂, —

N(C₃H₇)₂, —

N(cyclo-C₃H₅)₂, —

N[CH(CH₃)₂]₂, —

SO₂CH₃, —

SO₂C₂H₅, —

SO₃H, —

SO₃CH₃, —

SO₃C₂H₅, —

OCF₃, —

OC₂F₅, —

NH—

CO—

NH₂, —

NH—

C(═

NH)—

NH₂, —

O—

CO—

NH₂, —

O—

CO—

NHCH₃, —

O—

CO—

N(CH₃)₂, —

O—

CO—

N(C₂H₅)₂, —

CH₂F, —

CHF₂, —

CF₃, —

CH₂Cl, —

CH₂Br, —

CH₂—

CH₂F, —

CH₂—

CF₃, —

CH₂—

CH₂Cl, —

CH₂—

CH₂Br, —

CH₃, —

CH_S, —

C₃H₇, —

CH(CH₃)₂, —

C(CH₃)₃, —

C₄H₉, —

CH₂—

CH(CH₃)₂, —

CH(CH₃)—

C₂H₅, —

O₅H₁₁, —

C₆H₁₃, —

C₇H₁₅, —

C₈H₁₇, -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-O₅H₉, -cyclo-C₆H₁₁, —

Ph, —

CH₂—

Ph, —

CH═

CH₂, —

CH₂—

CH═

CH₂, —

C(CH₃)═

CH₂, —

CH═

CH—

CH₃, —

C₂H₄—

CH═

CH₂, —

CH═

C(CH₃)₂, —

C≡

CH, —

C≡

C—

CH₃, —

CH₂—

C≡

CH.

21. A method as in claim 18 wherein said active substance comprises an antiproliferative, immunosuppressive, anti-inflammatory, antimycotic and/or antithrombotic active agent.