U.S. patent application number 11/906765 was filed with the patent office on 2008-07-03 for stent coated with a sustained-release drug delivery and method for use thereof.
This patent application is currently assigned to Psivida Inc.. Invention is credited to Paul Ashton, Jianbing Chen.
Application Number | 20080161907 11/906765 |
Document ID | / |
Family ID | 26983411 |
Filed Date | 2008-07-03 |
United States Patent
Application |
20080161907 |
Kind Code |
A1 |
Chen; Jianbing ; et
al. |
July 3, 2008 |
Stent coated with a sustained-release drug delivery and method for
use thereof
Abstract
An intraluminal medical device comprises a stent having a
coating applied to at least part of an interior surface, an
exterior surface, or both. The coating comprises a sustained
release formulation of a combination of pharmaceutical compounds
dispersed within a biologically tolerated polymer composition. The
choice of the combination of pharmaceutical compounds are intended
to reduce neointimal hyperplasia restenosis.
Inventors: |
Chen; Jianbing; (Belmont,
MA) ; Ashton; Paul; (Boston, MA) |
Correspondence
Address: |
ROPES & GRAY LLP
PATENT DOCKETING 39/41, ONE INTERNATIONAL PLACE
BOSTON
MA
02110-2624
US
|
Assignee: |
Psivida Inc.
Watertown
MA
|
Family ID: |
26983411 |
Appl. No.: |
11/906765 |
Filed: |
October 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10245840 |
Sep 17, 2002 |
7279175 |
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11906765 |
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60322428 |
Sep 17, 2001 |
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60372761 |
Apr 15, 2002 |
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Current U.S.
Class: |
623/1.42 ;
424/423; 427/2.25; 623/1.46 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61K 9/7007 20130101; A61K 9/0024 20130101; A61K 47/32 20130101;
A61L 2300/222 20130101; A61K 31/513 20130101; A61L 2300/45
20130101; A61L 17/005 20130101; A61P 29/00 20180101; A61K 47/34
20130101; A61L 2300/41 20130101; A61L 2300/606 20130101; A61P 37/02
20180101; A61L 2300/602 20130101; A61L 29/16 20130101; A61L 31/10
20130101; A61P 31/04 20180101; A61L 31/16 20130101; A61P 43/00
20180101 |
Class at
Publication: |
623/1.42 ;
623/1.46; 424/423; 427/2.25 |
International
Class: |
A61L 33/04 20060101
A61L033/04; A61F 2/82 20060101 A61F002/82 |
Claims
1. A medical device comprising: (a) a substrate having a surface;
and (b) a coating adhered to the surface, said coating comprising a
polymer matrix including an anti-neoplastic nucleoside analog, or
prodrug thereof, dispersed or dissolved therein.
2. The device of claim 1, wherein the nucleoside analog is a
pyrimidine analog.
3. The device of claim 2, wherein the pyrimidine analog is selected
from the group consisting of 5-fluorouracil (5FU),
5'-deoxyfluorouridine, fluorouridine, 2'-deoxyfluorouridine,
fluorocytosine, trifluoro-methyl-2'-deoxyuridine, arabinosyl
cytosine, cyclocytidine, 5-aza-2'-deoxycytidine,
arabinosyl-5-azacytosine, 6-azacytidine,
N-phosphonoacetyl-L-asparticacid (PALA), pyrazofurin, 6-azauridine,
azaribine, thymidine, and 3-deazauridine.
4. The device of claim 2, wherein the pyrimidine analog is a
5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog.
5. The device of claim 1, wherein the nucleoside analog is
5-fluorouracil (5FU) or a prodrug thereof.
6. A medical device comprising: (a) a substrate having a surface;
and (b) a coating adhered to the surface, said coating comprising a
polymer matrix including a steroid, or prodrug thereof, dispersed
or dissolved therein, which steroid has a solubility less than 0.1
mg/mL in water at 25.degree. C.
7. The device of claim 6, wherein the steroid is a
corticosteroid.
8. The device of claim 6, wherein the steroid is triamcinolone or a
prodrug thereof.
9. The device of claim 6 or 7, wherein the steroid has a solubility
less than 0.01 mg/mL in water at 25.degree. C., dispersed or
dissolved therein.
10. The device of claim 6 or 7, wherein the steroid has a logP
value at least 0.5 logP units more than the logP value for
dexamethasone.
11. (canceled)
12. A medical device comprising: (a) a substrate having a surface;
and, (b) a coating adhered to the surface, said coating comprising
a polymer matrix having a low solubility prodrug dispersed therein,
wherein said low solubility prodrug is represented by the general
formula of A::B, in which A represents a drug moiety having a
therapeutically active form for producing a clinical response in a
patient; :: represents an ionic bond between A and B that
dissociates under physiological conditions to generate said
therapeutically active form of A; and B represents a moiety which,
when ionically bonded to A, results in the prodrug having a lower
solubility than the therapeutically active form of A.
13. The device of claim 12, wherein the solubility of the
therapeutically active form of A in water is greater than 1 mg/mL
and the solubility of the prodrug in water at 25.degree. C. is less
than 1 mg/mL.
14. The device of claim 12, which provides sustained release of the
therapeutically active form of A for a period of at least 24 hours,
and, over the period of release, the concentration of the prodrug
eluting from polymer is less than 10% of the concentration of the
therapeutically active form of A.
15. The device of claim 12, wherein the therapeutically active form
of A has a logP value at least 1 logp unit less than the logP value
of the prodrug.
16. The device of claim 12, wherein the solubility of the prodrug
is less than 100 .mu.g/ml in water at 25.degree. C.
17. The device of claim 12, wherein B is a hydrophobic aliphatic
moiety.
18. The device of claim 12, wherein B is a drug moiety having a
therapeutically active form generated upon cleavage of said linker
L or dissociation of said ionic bond.
19. The device of claim 18, wherein A and B are the same drug
moiety.
20. The device of claim 16, wherein A and B are different drug
moieties.
21. The device of claim 12, wherein B, after cleavage from the
prodrug, is a biologically or pharmacologically inert moiety.
22. The device of claim 12, wherein A is selected from immune
response modifiers, anti-proliferatives, anti-mitotic agents,
anti-platelet agents, platinum coordination complexes, hormones,
anticoagulants, fibrinolytic agents, anti-secretory agents,
anti-migratory agents, immunosuppressives, angiogenic agents,
angiotensin receptor blockers, nitric oxide donors, antisense
oligionucleotides and combinations thereof, cell cycle inhibitors,
corticosteroids, angiostatic steroids, anti-parasitic drugs,
anti-glaucoma drugs, antibiotics, differentiation modulators,
antiviral drugs, anticancer drugs and antiinflammatory drugs.
23. The device of claim 12, wherein B is selected from immune
response modifiers, anti-proliferatives, anti-mitotic agents,
anti-platelet agents, platinum coordination complexes, hormones,
anticoagulants, fibrinolytic agents, anti-secretory agents,
anti-migratory agents, immunosuppressives, angiogenic agents,
angiotensin receptor blockers, nitric oxide donors, antisense
oligionucleotides and combinations thereof, cell cycle inhibitors,
corticosteroids, angiostatic steroids, anti-parasitic drugs,
anti-glaucoma drugs, antibiotics, differentiation modulators,
antiviral drugs, anticancer drugs, and antiinflammatory drugs.
24. The device of claim 12, wherein A is an antineoplastic agent
and B is an antiinflammatory agent.
25. The device of claim 12, wherein at least one of A or B is an
antineoplastic agent.
26. The device of claim 24, wherein said antineoplastic agent is
selected from the group consisting of anthracyclines, vinca
alkaloids, purine analogs, pyrimidine analogs, inhibitors of
pyrimidine biosynthesis, and alkylating agents.
27. The device of claim 24, wherein said antineoplastic agent is
selected from the group consisting of 5-fluorouracil (5FU),
5'-deoxy-5-fluorouridine5-fluorouridine, 2'-deoxy-5-fluorouridine,
fluorocytosine, 5-trifluoromethyl-2'-deoxyuridine, arabinoxyl
cytosine, cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl
5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid,
pyrazofurin, 6-azauridine, azaribine, and 3-deazauridine.
28. The device of claim 24, wherein said antineoplastic agent is
selected from the group consisting of cladribine, 6-mercaptopurine,
pentostatin, 6-thioguanine, and fludarabin phosphate.
29. The device of claim 24, wherein said antineoplastic agent is a
pyrimidine analog.
30. The device of claim 28, wherein said pyrimidine analog is
selected from the group consisting of arabinosyl cytosine,
cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine and
6-azacytidine.
31. The device of claim 29, wherein the pyrimidine analog is
selected from the group consisting of 5-fluorouracil (5FU),
5'-deoxyfluorouridine, fluorouridine, 2'-deoxyfluorouridine,
fluorocytosine, trifluoro-methyl-2'-deoxyuridine, arabinosyl
cytosine, cyclocytidine, 5-aza-2'-deoxycytidine,
arabinosyl-5-azacytosine, 6-azacytidine,
N-phosphonoacetyl-L-asparticacid (PALA), pyrazofurin, 6-azauridine,
azaribine, thymidine and 3-deazauridine.
32. The device of claim 28, wherein the pyrimidine analog is a
5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog.
33. The device of claim 32, wherein the nucleoside analog is
5-fluorouracil (5FU) or a prodrug thereof.
34. The device of claim 12 or 24, wherein at least one of A or B is
steroid.
35. The device of claim 34, wherein the steroid is a
corticosteroid.
36. The device of claim 34, wherein the steroid has a solubility
less than 0.1 mg/mL in water at 25.degree. C., dispersed or
dissolved therein.
37. The device of claim 34, wherein the steroid has a logP value at
least 0.5 logP units more than the logP value for
dexamethasone.
38. The device of claim 34, wherein the steroid is triamcinolone or
a prodrug thereof.
39. The device of claim 12, wherein A is a fluorinated pyrimidine
and B is a corticosteroid.
40. The device of claim 12, wherein A is 5-fluorouracil and B is
triamcinolone acetonide.
41. The device of claim 12, wherein the linkage L is hydrolyzed in
bodily fluid.
42. The device of claim 41, wherein the linkage L includes one or
more hydrolyzable groups selected from the group consisting of an
ester, an amide, a carbamate, a carbonate, a cyclic ketal, a
thioester, a thioamide, a thiocarbamate, a thiocarbonate, a
xanthate and a phosphate ester.
43. The device of claim 12, wherein the linkage L is enzymatically
cleaved.
44. The device of any of claims 1, 2 or 12, wherein the polymer is
non-bioerodible.
45. The device of claim 44, wherein the non-bioerodible polymer is
selected from polyurethane, polysilicone, poly(ethylene-co-vinyl
acetate), polyvinyl alcohol, and derivatives and copolymers
thereof.
46. The device of claim 1, 2 or 12, wherein the polymer is
bioerodible.
47. The device of claim 46, wherein the bioerodible polymer is
selected from polyanhydride, polylactic acid, polyglycolic acid,
polyorthoester, polyalkylcyanoacrylate and derivatives and
copolymers thereof.
48. The device of claim 1, 2 or 12, wherein the substrate is a
surgical implement selected from a screw, a plate, a washer, a
suture, a prosthesis anchor, a tack, a staple, an electrical lead,
a valve, a membrane, an anastomosis device, a vertegral disk, a
bone pin, a suture anchor, a hemostatic barrier, a clamp, a clip, a
vascular implant, a tissue adhesive or sealant, a tissue scaffold,
a bone substitute, an intraluminal device and a vascular
support.
49. The device of claim 1, 2 or 12, selected from the group
consisting of catheters, implantable vascular access ports, blood
storage bags, blood tubing, central venous catheters, arterial
catheters, vascular grafts, intraaortic balloon pumps, heart
valves, cardiovascular sutures, artificial hearts, a pacemaker,
ventricular assist pumps, extracorporeal devices, blood filters,
hemodialysis units, hemoperfusion units, plasmapheresis units,
filters adapted for deployment in a blood vessel, intraocular
lenses, shunts for hydrocephalus, dialysis grafts, colostomy bag
attachment devices, ear drainage tubes, leads for pace makers and
implantable defibrillators, and osteointegrated orthopedic
devices.
50. The device of claim 1, 24, or 12, which is a vascular
stent.
51. The device of claim 50, which is an expandable stent, and said
coating is flexible to accommodate compressed and expanded states
of said expandable stent.
52. The device of claim 1, 2 or 12, wherein the weight of the
coating attributable to the drug is in the range of about 0.05 mg
to about 10 mg of drug per cm2 of the surface coated with said
polymer matrix.
53. The device of claim 1, 2 or 12, wherein the coating has a
thickness in the range of 5 micrometers to 100 micrometers The
device of claim 1, 2, 11 or 12, wherein drug is present in an
amount between 5% and 70% by weight of the coating.
54. The device of claim 1, 2 or 12, wherein drug is present in an
amount between 5% and 70% by weight of the coating.
55. A stent having at least a portion which is insertable or
implantable into the body of a patient, wherein the portion has a
surface which is adapted for exposure to body tissue and wherein at
least a part of the surface is covered with a coating for releasing
at least one biologically active material, the coating comprising a
polymer matrix having an antineoplastic nucleoside analog, or
prodrug thereof, dispersed or dissolved therein.
56. A stent having at least a portion which is insertable or
implantable into the body of a patient, wherein the portion has a
surface which is adapted for exposure to body tissue and wherein at
least a part of the surface is covered with a coating for releasing
at least one biologically active material, the coating comprising a
polymer matrix having a steroid dispersed or dissolved therein,
which steroid has a solubility less than 0.1 mg/mL in water at
25.degree. C.
57. (canceled)
58. A stent having at least a portion which is insertable or
implantable into the body of a patient, wherein the portion has a
surface which is adapted for exposure to body tissue and wherein at
least a part of the surface is covered with a coating for releasing
at least one biologically active material, the coating comprising a
polymer matrix having a low solubility prodrug dispersed therein,
wherein said low solubility prodrug is represented by the general
formula of A::B, in which A represents a drug moiety having a
therapeutically active form for producing a clinical response in a
patient; :: represents an ionic bond between A and B that
dissociates under physiological conditions to generate said
therapeutically active form of A; and B represents a moiety which,
when ionically bonded to A, results in the prodrug having a lower
solubility than the therapeutically active form of A.
59. An intraluminal medical device coated with a sustained release
system comprising a biologically tolerated polymer and a
low-solubility prodrug dispersed in the polymer, said device having
an interior surface and an exterior surface; said device having
said system applied to at least a part of the interior surface, the
exterior surface, or both.
60. A method for treating an intraluminal tissue of a patient, the
method comprising the steps of: (a) providing a stent having an
interior surface and an exterior surface, said stent having a
coating on at least a part of the interior surface, the exterior
surface, or both; said coating comprising a low-solubility
pharmaceutical prodrug dissolved or dispersed in a
biologically-tolerated polymer; (b) positioning the stent at an
appropriate intraluminal tissue site; and (c) deploying the
stent.
61. A medical device comprising: (a) a substrate having a surface;
(b) a pharmaceutically active agent dispersed adjacent to said
surface; and (c) a polymer matrix encapsulating said
pharmaceutically active agent; wherein said matrix further
comprises a semi-permeable lattice having intermittent pores with
cross sectional area sufficient to restrict the passage of moiety A
but to allow the passage of moiety B.
62. The device of claim 61, wherein said lattice is
bioerodible.
63. The device of claim 61, which provides sustained release of
moiety A for a period of at least 24 hours, and, over the period of
release, the concentration of moiety A in fluid outside the polymer
is less than 10% of the concentration of moiety B in said
fluid.
64. The device of claim 61, wherein the substrate is a surgical
implement selected from a screw, a plate, a washer, a suture, a
prosthesis anchor, a tack, a staple, an electrical lead, a valve, a
membrane, an anastomosis device, a vertegral disk, a bone pin, a
suture anchor, a hemostatic barrier, a clamp, a clip, a vascular
implant, a tissue adhesive or sealant, a tissue scaffold, a bone
substitute, an intraluminal device and a vascular support.
65. The device of claim 61, selected from the group consisting of
catheters, implantable vascular access ports, blood storage bags,
blood tubing, central venous catheters, arterial catheters,
vascular grafts, intraaortic balloon pumps, heart valves,
cardiovascular sutures, artificial hearts, a pacemaker, ventricular
assist pumps, extracorporeal devices, blood filters, hemodialysis
units, hemoperfusion units, plasmapheresis units, filters adapted
for deployment in a blood vessel, intraocular lenses, shunts for
hydrocephalus, dialysis grafts, colostomy bag attachment devices,
ear drainage tubes, leads for pace makers and implantable
defibrillators, and osteointegrated orthopedic devices.
66. The device of claim 61, which is a vascular stent.
67. A coating for a medical device comprising a polymer matrix and
a prodrug, dispersed in the polymer, having a general formula of
A-L-B in which A represents a drug moiety having a therapeutically
active form for producing a clinical response in a patient; L
represents a covalent linker linking A and B to form a prodrug,
said linker being cleaved under physiological conditions to
generate said therapeutically active form of A; and B represents a
moiety which, when linked to A, results in the prodrug having a
lower solubility than the therapeutically active form of A; wherein
the solubility of therapeutically active form of A in water is
greater than 1 mg/ml and the solubility of the prodrug in water is
less than 1 mg/ml.
68. A coating for a medical device comprising a polymer matrix and
a prodrug, dispersed in the polymer, having a general formula of
A::B in which A represents a drug moiety having a therapeutically
active form for producing a clinical response in a patient; ::
represents a ionic bond between A and B that dissociates under
physiological conditions to generate said therapeutically active
form of A; B represents a moiety which, when ionically bonded to A,
results in the prodrug having a lower solubility than the
therapeutically active form of A; and wherein the solubility of
therapeutically active form of A in water is greater than 1 mg/ml
and the solubility of the prodrug in water is less than 1
mg/ml.
69. A coating for a medical device comprising a polymer matrix and
a prodrug, dispersed in the polymer, having a general formula of
A-L-B in which A represents a drug moiety having a therapeutically
active form for producing a clinical response in a patient; ::
represents a ionic bond between A and B that dissociates under
physiological conditions to generate said therapeutically active
form of A; B represents a moiety which, when ionically bonded to A,
results in the prodrug having a lower solubility than the
therapeutically active form of A; and wherein the solubility of
therapeutically active form of A in water is greater than 1 mg/ml
and the solubility of the prodrug in water is less than 1
mg/ml.
70. A coating for a medical device comprising a polymer matrix and
a prodrug, dispersed in the polymer, having a general formula of
A::B in which A represents a drug moiety having a therapeutically
active form for producing a clinical response in a patient; ::
represents a ionic bond between A and B that dissociates under
physiological conditions to generate said therapeutically active
form of A; B represents a moiety which, when ionically bonded to A,
results in the prodrug having a lower solubility than the
therapeutically active form of A; and wherein, when disposed in
biological fluid, said sustained release formulation provides
sustained release of the therapeutically active form of A for a
period of at least 24 hours, and, over the period of release, the
concentration of the prodrug in fluid outside the polymer is less
than 10% of the concentration of the therapeutically active form of
A.
71. The coating of any one of claims 67-70, wherein A and B are the
same drug moiety.
72. The coating of any one of claims 67-70, wherein A and B are
different drug moieties.
73. The coating of any one of claims 67-70, wherein B, after
cleavage from the prodrug, is a biologically inert moiety.
74. The coating of any one of claims 67-70, wherein A is selected
from immune response modifiers, anti-proliferatives, anti-mitotic
agents, anti-platelet agents, platinum coordination complexes,
hormones, anticoagulants, fibrinolytic agents, anti-secretory
agents, anti-migratory agents, immunosuppressives, angiogenic
agents, angiotensin receptor blockers, nitric oxide donors,
antisense oligionucleotides and combinations thereof, cell cycle
inhibitors, corticosteroids, angiostatic steroids, anti-parasitic
drugs, anti-glaucoma drugs, antibiotics, differentiation
modulators, antiviral drugs, anticancer drugs, and
anti-inflammatory drugs.
75. The coating of any one of claims 67-70, wherein B is selected
from immune response modifiers, anti-proliferatives, anti-mitotic
agents, anti-platelet agents, platinum coordination complexes,
hormones, anticoagulants, fibrinolytic agents, anti-secretory
agents, anti-migratory agents, immunosuppressives, angiogenic
agents, angiotensin receptor blockers, nitric oxide donors,
antisense oligonucleotides and combinations thereof, cell cycle
inhibitors, corticosteroids, angiostatic steroids, anti-parasitic
drugs, anti-glaucoma drugs, antibiotics, differentiation
modulators, antiviral drugs, anticancer drugs, and
anti-inflammatory drugs.
76. The coating of any one of claims 67-70, wherein the duration of
release of the therapeutically active form of A from the polymer
matrix is at least 24 hours.
77. The coating of any one of claims 67-70, wherein A is
5-fluorouracil (5FU) and B is a steroid.
78. The coating of any one of claims 67-70, wherein at least one of
A or B is an antineoplastic agent.
79. The coating of any one of claims 67-70, wherein said
antineoplastic agent selected from the group consisting of
anthracyclines, vinca alkaloids, purine analogs, pyrimidine
analogs, inhibitors of pyrimidine biosynthesis, and alkylating
agents.
80. The coating of any one of claims 67-70, wherein said
antineoplastic drug is a fluorinated pyrimidine.
81. The coating of any one of claims 67-70, wherein said
antineoplastic drug is selected from the group consisting of
5-fluorouracil (5FU), 5'-deoxy-5-fluorouridine5-fluorouridine,
2'-deoxy-5-fluorouridine, fluorocytosine,
5-trifluoromethyl-2'-deoxyuridine, arabinoxyl cytosine,
cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine,
6-azacytidine, N-phosphonoacetyl-L-aspartic acid, pyrazofurin,
6-azauridine, azaribine, and 3-deazauridine.
82. The coating of any one of claims 67-70, wherein said
antineoplastic drug is a pyrimidine nucleoside analog selected from
the group consisting of arabinosyl cytosine, cyclocytidine,
5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine, and
6-azacytidine.
83. The coating of any one of claims 67-70, wherein said
antineoplastic drug is selected from the group consisting of
cladribine, 6-mercaptopurine, pentostatin, 6-thioguanine, and
fludarabin phosphate.
84. The coating of any one of claims 67-70, wherein the
therapeutically active form of A is 5-fluorouracil.
85. The coating of any one of claims 67-70, wherein at least one of
A or B is an anti-inflammatory agent.
86. The coating of claim 85, wherein said anti-inflammatory agent
is a non-steroidal antiinflammatory.
87. The coating of claim 85, wherein said anti-inflammatory agent
is a glucocorticoid.
88. The coating of claim 87, wherein said glucocorticoid is
selected from the group consisting of aclometasone, beclomethasone,
betamethasone, budesonide, clobetasol, clobetasone, cortisone,
desonide, desoximetasone, diflorosane, fiumethasone, flunisolide,
fluocinolone acetonide, fluocinolone, fluocortolone, fluprednidene,
flurandrenolide, fluticasone, hydrocortisone, methylprednisolone
aceponate, mometasone furdate, prednisolone, prednisone and
rofleponide.
89. The coating of any one of claims 67-70, wherein the
therapeutically active form of B is selected from fluocinolone
acetonide, triamcinolone acetonide, diclofenac, and naproxen.
90. The coating of any one of claims 67-70, wherein the prodrug, in
its linked form, has an ED.sub.50 for producing said clinical
response at least 10 times greater than the ED.sub.50 of the
therapeutically active form of A.
91. The coating of any one of claims 67-70, wherein the polymer is
non-bioerodible.
92. The coating of any one of claims 67-70, wherein the polymer is
bioerodible.
93. The coating of any one of claims 67-70, wherein A is
5-fluorouracil (5FU) or triamcinolone (TA).
94. A medical device comprising: (a) a substrate having a porous
surface; and (b) a pharmaceutically active agent carried by said
surface; (c) a polymer matrix encapsulating said pharmaceutically
active agent; wherein said matrix further comprises a
semi-permeable lattice having intermittent pores with cross
sectional area sufficient to restrict the passage of moiety A but
to allow the passage of moiety B.
95. The device of claim 94, wherein said lattice is
bioerodible.
96. The device of claim 94, which provides sustained release of
moiety A for a period of at least 24 hours, and, over the period of
release, the concentration of moiety A in fluid outside the polymer
is less than 10% of the concentration of moiety B in said
fluid.
97. The device of claim 94, wherein the substrate is a surgical
implement selected from a screw, a plate, a washer, a suture, a
prosthesis anchor, a tack, a staple, an electrical lead, a valve, a
membrane, an anastomosis device, a vertegral disk, a bone pin, a
suture anchor, a hemostatic barrier, a clamp, a clip, a vascular
implant, a tissue adhesive or sealant, a tissue scaffold, a bone
substitute, an intraluminal device and a vascular support.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Nos. 60/322,428, filed Sep. 17, 2001 and 60/372,761,
filed Apr. 15, 2002, the specifications of each of which are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention generally relates to an improved
intraluminal medical device and to a method for treating tissues.
More particularly, the present invention relates to a stent coated
with a sustained-release drug delivery system for supporting and
reinforcing an enlarged vessel, the system having a therapeutically
beneficial advantage of reducing the incidence, recurrence, or
both, of restenosis.
BACKGROUND OF THE INVENTION
[0003] A stent is a generally longitudinal tubular device formed of
biocompatible material, preferably a metallic or plastic material.
Stents are useful in the treatment of stenosis, strictures or
aneurysms in body vessels, such as blood vessels. It is well-known
to employ a stent for the treatment of diseases of various body
vessels. The device is implanted either as a "permanent stent"
within the vessel to reinforce collapsing, partially occluded,
weakened or abnormally dilated sections of the vessel or as a
"temporary stent" for providing therapeutic treatment to the
diseased vessel. Stents are typically employed after angioplasty of
a blood vessel to prevent restenosis of the diseased vessel. Stents
may be useful in other body vessels, such as the urinary tract and
the bile duct.
[0004] A typical stent includes an open flexible configuration. The
stent configuration allows the stent to be configured in a radially
compressed state for intraluminal catheter insertion into an
appropriate site. Once properly positioned within the lumen of a
damaged vessel, the stent is radially expanded to support and
reinforce the vessel. Radial expansion of the stent may be
accomplished by an inflatable balloon attached to the catheter, or
the stent may be of the self-expanding type that will radially
expand once deployed. An example of a suitable stent is disclosed
in U.S. Pat. No. 4,733,665, which is incorporated herein by
reference in its entirety.
[0005] Stents find various uses in surgical procedures. For
instance, stents are widely used in angioplasty. Angioplasty
involves insertion of a balloon-tipped catheter into an artery at
the site of a partially obstructive atherosclerotic lesion.
Inflation of the balloon can rupture the intima and media,
dramatically dilating the vessel and relieving the obstruction.
About 20 to 30% of obstructions reocclude in a few days or weeks,
but most can be redilated successfully. Use of stents significantly
reduces the reocclusion rate. Repeat angiography one year after
angioplasty reveals an apparently normal lumen in about 30% of
vessels on which the procedure has been performed.
[0006] Angioplasty is an alternative to bypass surgery in a patient
with suitable anatomic lesions. The risk is comparable with that of
surgery. Mortality is 1 to 3%; myocardial infarction rate is 3 to
5%; emergency bypass for intimal dissection with recurrent
obstruction is required in <3%; and the initial success rate is
85 to 93% in experienced hands.
[0007] Stents are also used in percutaneous endovascular therapy.
Many new treatments for vascular disease (occlusions and aneurysms)
avoid open surgery. These treatments may be performed by
interventional radiologists, vascular surgeons, or cardiologists.
The primary approach is percutaneous translumninal angioplasty
(PTA), whereby a small high-pressure balloon is used to open an
obstructed vessel. However, because of the high recurrence rate of
obstruction, alternative methods may be necessary.
[0008] A stent, such as a metallic mesh-like tube, is generally
inserted into a vessel at an obstructed site. As stents can be very
strong, they tend to keep vessels open much better than balloons
alone. Moreover, the recurrence rate of obstruction is reportedly
lower when stents are used. Stents work well in larger arteries
with high flow, such as iliac and renal vessels. They work less
well in smaller arteries, and in vessels in which the occlusions
are long. Stents for carotid disease are being studied.
[0009] There are at least two known causes of post-operative
restenosis--elastic recoil, wherein the vessel contracts due to the
natural elasticity of the vessel walls, and neointimal hyperplasia,
wherein medial cells proliferate in response to immune system
triggers. Stents have proven useful in reducing the incidence
and/or severity of post-operative elastic recoil restenosis, as
they resist the tendency of blood vessels to restenose after
removal of the balloon. Stents have proven less useful for
treatment of neointimal hyperplasia, which arises out of a complex
immune response to expanding and fracturing the atherosclerotic
plaque. In the case of neointimal hyperplasia, the initial
expansion and fracture of the atherosclerotic lesion initiates
inflammation, which gives rise to a complex cascade of cellular
events that activates the immune system, which in turn gives rise
to the release of cytokines that stimulate cell multiplication in
the smooth muscle layers of the vessel media. This cell stimulation
eventually causes the vessel to restenose.
[0010] Various approaches to the problem of neointimal hyperplasia
have been attempted. Among these approaches are: subsequent stent
placement, debulking, repeat angioplasty, and laser treatment.
Another recent approach has been to coat the stent with an
immunosuppressant or a chemotherapeutic drug. Immunosuppressant
drugs, such as rapamycin, target cells in the G1 phase, preventing
initiation of DNA synthesis. Chemotherapeutic drugs, such as
paclitaxel (Taxol--Bristol-Myers Squibb) and other taxane
derivatives, act on cells in the M phase, by preventing
deconstruction of microtubules, thereby interrupting cell division.
While these approaches present some promise, they also suffer
certain limitations, such as the tendency for rapamycin and taxanes
to quickly disperse from the stent site, thereby both limiting the
drugs' effective duration in proximity to the stent and also
risking undesirable systemic toxic effects.
[0011] There is therefor a need for an improved stent that will
provide sustained-release of pharmaceutically active compounds,
such as immunosuppressant, antiproliferative, chemotherapeutic, and
anti-inflammatory drugs, at or near the site of stent implantation
that alleviates or avoids the problem of rapid depletion of drug
from the stent site. There is also a need for an improved drug that
may be employed in such a stent.
[0012] There is furthermore a need for an improved stent that will
provide sustained-release of pharmaceutically active compounds,
such as immunosuppressant, chemotherapeutic, and antiinflammatory
drugs, at or near the site of stent implantation that does not
suffer the drawbacks of causing systemic toxic effects of the
immunosuppressant, chemotherapeutic, and antiinflammatory drugs.
There is also a need for an improved drug that may be employed in
such a stent.
SUMMARY OF THE INVENTION
[0013] The foregoing and other needs are provided by embodiments
according to the present invention, which provide a
sustained-release drug delivery system.
[0014] In certain embodiments, the system comprises: two or more
pharmaceutical agents (a "drug combination") dissolved or dispersed
in a biologically tolerated polymer to form a coating on a medical
device in which sustained release of the pharmaceutical agents
occurs, e.g., for at least a few days, and preferably for more than
15, 30, 45 or even 60 days. In preferred embodiments, the
pharmaceutical agents are provided in low-solubility form, such as
in the form of a homo- or hetero-codrug, as a prodrug, through the
use of particular salts, as a lyophilate from an organic solvent,
etc. In other embodiments, the drugs are rendered in sustained
release form by virtue of their mixture with the polymer for
forming the coating. The sustained release may achieve the release
in a number of different ways: a) constant release with time, (b)
release rate diminishing with time, c) burst release, and d) pulsed
release where all of the active material is released suddenly at a
certain time. The skilled artisan would readily appreciate that
such sustained release formulations may be designed by regulating
the rate of dissolution, the rate of permeability, or the swelling
rates, which in turn may be controlled by controlling the pH,
moisture and temperature of the environment, and chemical
properties of the polymeric matrix, such as for example its size,
shape and thickness.
[0015] For example, in certain embodiments, the polymer matrix may
be comprised of a semipermeable membrane with pores of sufficient
size to allow for the selective release of the pharmaceutical
agents. In such cases, the matrix may be rendered more permeable to
agents of a smaller molecular weight. This system may be
particularly suitable where the pharmaceutical agent has high
solubility in the physiological fluid.
[0016] An example of such a system includes a medical device
comprising a substrate having a surface and a pharmaceutically
active agent dispersed adjacent to said surface, wherein said
pharmaceutically active agent comprises at least two moieties
mixed, dispersed, or bonded together, said at least two moieties
comprising A and B with A having a molecular weight greater than B;
and a polymer matrix encapsulating said pharmaceutically active
agent; said matrix further comprises a semi-permeable lattice
having intermittent pores with cross sectional area sufficient to
restrict the passage of moiety A but to allow the passage of moiety
B. In yet another embodiment, the system includes a medical device
comprising a substrate having a surface and a pharmaceutically
active agent dispersed adjacent to said surface, wherein said
pharmaceutically active agent comprises at least two moieties
mixed, dispersed, or bonded together, said at least two moieties
comprising A and B wherein A has a solubility that is at least 50
times, 25 times, 20 times, 15 times, 10 times, 5 times, 2 times
more than the solubility of B in physiological solvents.
[0017] In yet another embodiment, the system comprises a single
pharmaceutical agent dissolved or dispersed in a biologically
tolerated polymer to form a coating on a medical device in which
sustained release of the pharmaceutical agent occurs, e.g., for at
least a few days, and preferably for more than 15, 30, 45 or even
60 days. In preferred embodiments, the sustained release profile of
the pharmaceutical agent is modulated so as to provide sustained
release of the pharmaceutical agent over a period of days such as
for example, over a period of a few days, and preferably for more
than 15, 30, 45 or even 60 days. Examples of such pharmaceutical
agents include within their scope without limitation the drug can
be an anticoagulant, such as an anti-inflammatory agents,
anti-neoplastic agents, heparin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, protaglandin inhibitors, platelet
inhibitors, or tick anti-platelet peptide. The pharmaceutical agent
can also be a promoter of vascular cell growth, such as a growth
factor receptor antagonists, transcriptional activator or
translational promoter. Alternatively, the pharmaceutical agent can
be an inhibitor of vascular cell growth, such as a growth factor
inhibitor, growth factor receptor antagonists, transcriptional
repressor or translational repressor, antisense DNA, antisense RNA,
replication inhibitor, inhibitory antibodies, antibodies directed
against growth factors, and bifunctional molecules. The
pharmaceutical agent can also be a cholesterol-lowering agent, a
vasodilating agent, and agents which interfere with endogenous
vasoactive mechanisms. Other examples of drugs can include,
anti-platelet or fibrinolytic agents, anti-allergic agents,
anti-rejection agents, anti-microbial or anti-bacterial or
anti-viral agents, hormones, vasoactive substances, anti-invasive
factors, anti-cancer agents, antibodies and lymphokines,
anti-angiogenic agents, radioactive agents and gene therapy agents,
among others. The pharmaceutical agents may be loaded as in
its/their original commercial form, or together with polymer or
protein carriers, as described herein to achieve delayed and/or
consistent release.
[0018] In a preferred embodiment, the pharmaceutical agent may be
an anti-neoplastic agent such as for example 5-fluorouracil, and
its rate of release from the device may be varied as described
herein, i.e. by regulating the rate of dissolution, the rate of
permeability, or the swelling rates, which in turn may be
controlled by controlling the pH, moisture and temperature of the
environment, and chemical properties of the polymeric matrix, such
as for example its size, shape and thickness. In another
embodiment, the 5-fluorouracil may be mixed, dispersed or bonded to
another chemical moiety that may reduce its solubility. In yet
other embodiments, the 5-fluorouracil may be diffused as a function
of the size of the polymeric matrix pores. The matrix diffusion
embodiment thus facilitates the delivery by coated device of single
drug that ordinarily have high solubility in physiological
fluids.
[0019] Where the drug combination is provided in the form of a
co-drug, certain preferred embodiments of the coating will result
in a ratio of eluted active monomers to co-drug of greater than
10:1 (e.g., less than 10 percent co-drug eluting from coating) and
even more preferably greater than 20:1, 50:1 or even 100:1.
[0020] In certain embodiments, the subject medical device is an
intraluminal medical device, e.g., a stent, comprising: a coating
comprising a biologically tolerated polymer and a low-solubility
pharmaceutical agent dissolved or dispersed in the polymer; and a
stent, said stent having an interior surface and an exterior
surface; said stent having said coating applied to at least a part
of the interior surface, the exterior surface, or both.
[0021] While exemplary embodiments of the invention will be
described with respect to the treatment of restenosis and related
complications following percutaneous transluminal coronary
angioplasty, it is important to note that the local delivery of
drug/drug combinations may be utilized to treat a wide variety of
conditions utilizing any number of medical devices, or to enhance
the function and/or life of the device. For example, intraocular
lenses, placed to restore vision after cataract surgery is often
compromised by the formation of a secondary cataract. The latter is
often a result of cellular overgrowth on the lens surface and can
be potentially minimized by combining a drug or drugs with the
device. Other medical devices which often fail due to tissue
in-growth or accumulation of proteinaceous material in, on and
around the device, such as shunts for hydrocephalus, dialysis
grafts, colostomy bag attachment devices, ear drainage tubes, leads
for pace makers and implantable defibrillators can also benefit
from the device-drug combination approach.
[0022] Devices which serve to improve the structure and function of
tissue or organ may also show benefits when combined with the
appropriate agent or agents. For example, improved osteointegration
of orthopedic devices to enhance stabilization of the implanted
device could potentially be achieved by combining it with agents
such as bone morphogenic protein. Similarly other surgical devices,
sutures, staples, anastomosis devices, vertebral disks, bone pins,
suture anchors, hemostatic barriers, clamps, screws, plates, clips,
vascular implants, tissue adhesives and sealants, tissue scaffolds,
various types of dressings, bone substitutes, intraluminal devices,
and vascular supports could also provide enhanced patient benefit
using this drug-device combination approach. Essentially, any type
of medical device may be coated in some fashion with a drug or drug
combination which enhances treatment over use of the singular use
of the device or pharmaceutical agent.
[0023] Yet another aspect of the invention provides a method for
treating an intraluminal tissue of a patient, the method comprising
the steps of: (a) providing a stent having an interior surface and
an exterior surface, said stent having a coating on at least a part
of the interior surface, the exterior surface, or both; said
coating comprising a low-solubility pharmaceutical agent dissolved
or dispersed in a biologically-tolerated polymer; (b) positioning
the stent at an appropriate intraluminal tissue site; and (c)
deploying the stent. In such embodiments, the drug combinations and
delivery devices of the present invention may be utilized to
effectively prevent and treat vascular disease, and in particular,
vascular disease caused by injury.
[0024] The subject devices can be used to deliver such
pharmaceutical agents as: antiproliferative/antimitotic agents
including natural products such as vinca alkaloids (i.e.
vinblastine, vincristine, and vinorelbine), paclitaxel,
epidipodophyllotoxins (i.e. etoposide, teniposide), antibiotics
(dactinomycin (actinomycin D) daunorubicin, doxorubicin and
idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin
(mithramycin) and mitomycin, enzymes (L-asparaginase which
systemically metabolizes L-asparagine and deprives cells which do
not have the capacity to synthesize their own asparagine);
antiplatelet agents; antiproliferative/antimitotic alkylating
agents such as nitrogen mustards (mechlorethamine, cyclophosphamide
and analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs,
streptozocin), trazenes-dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid
analogs (methotrexate), pyrimidine analogs (fluorouracil,
floxuridine, and cytarabine), purine analogs and related inhibitors
(mercaptopurine, thioguanine, pentostatin and
2-chlorodeoxyadenosine (cladribine)); platinum coordination
complexes (cisplatin, carboplatin), procarbazine, hydroxyurea,
mitotane, aminoglutethimide; hormones (i.e., estrogen);
anticoagulants (heparin, synthetic heparin salts and other
inhibitors of thrombin); fibrinolytic agents (such as tissue
plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory;
antisecretory (breveldin); antiinflammatory: such as adrenocortical
steroids (cortisol, cortisone, fludrocortisone, prednisone,
prednisolone, 6U-methylprednisolone, triamcinolone, betamethasone,
and dexamethasone), non-steroidal agents (salicylic acid
derivatives, i.e., aspirin; para-aminophenol derivatives, i.e.,
acetominophen; indole and indene acetic acids (indomethacin,
sulindaC7 and etodalac), heteroaryl acetic acids (tolmetin,
diclofenac, and ketorolac), arylpropionic acids (ibuprofen and
derivatives), anthranilic acids (mefenamic acid, and meclofenamic
acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and
oxyphenthatrazone), nabumetone, gold compounds (auranofin,
aurothioglucose, gold sodium thiomalate); immunosuppressives
(cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin),
azathioprine, mycophenolate mofetil); angiogenic agents: vascular
endothelial growth factor (VEGF), fibroblast growth factor (FGF);
angiotensin receptor blocker; nitric oxide donors; anti-sense
oligionucleotides and combinations thereof; cell cycle inhibitors,
motor inhibitors, and growth factor signal transduction kinase
inhibitors.
[0025] Additional advantages of the present invention will become
readily apparent to those skilled in the art from the following
detailed description, and the appended drawings wherein only a
preferred embodiment of the invention is shown and described by way
of illustration of the best mode contemplated for carrying out the
invention. As will be realized, the present invention is capable of
other and different embodiments, and its several details are
capable of modifications in various respects, all without departing
from the scope of the present invention. Accordingly, the drawings
and description are to be regarded as illustrative in nature, and
not as restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The following description of the embodiment of the present
invention can be better understood when read in conjunction with
the following drawings, in which like reference numerals are
employed throughout to designate similar features, wherein:
[0027] FIG. 1 is a side plan view of a non-deployed stent according
to the present invention.
[0028] FIG. 2 is a side plan view of a deployed stent according to
the present invention.
[0029] FIG. 3 is a release profile of TC-112 from PVA-coated glass
slides into pH 7.4 buffer.
[0030] FIG. 4 is a release profile of TC-112 from silicone-coated
glass plates into pH 7.4 buffer.
[0031] FIG. 5 is a release profile of 5-Fluororuracil (5FU) and
triamcinolone acetonide (TA) from coated inserts.
[0032] FIG. 6 is a release profile of 5-fluorouracil (5FU) and
triamcinolone acetonide (TA) from coated inserts.
[0033] FIG. 7 illustrates the release pattern in vitro for a high
dose coated stent.
[0034] FIG. 8 shows the comparative drug release profiles between
explanted stents and non-implanted stents.
[0035] FIG. 9 shows the release rate from stents that were coated
with a mixture of TA and 5FU in a mole-ratio of 1 to 1 without
chemical linkage.
[0036] FIGS. 10A and 10B are graphs showing the effect of gamma
irradiation and plasma treatment on drug release. Group B: with
plasma treatment, with gamma irradiation. Group C: no plasma
treatment, with gamma irradiation. Group D: with plasma treatment,
no gamma irradiation. Group F: no plasma, no gamma irradiation.
DETAILED DESCRIPTION OF THE INVENTION
[0037] In certain embodiments, the present invention provides an
intraluminal medical device for implantation into a lumen of a
blood vessel, in particular adjacent an intraluminal lesion such as
an atherosclerotic lesion, for maintaining patency of the vessel.
In particular the present invention provides an elongate radially
expandable tubular stent having an interior luminal surface and an
opposite exterior surface extending along a longitudinal stent
axis, the stent having a coating on at least a portion of the
interior or exterior surface thereof. The local delivery of drug
combinations from a stent has the following advantages; namely, the
prevention of vessel recoil and remodeling through the scaffolding
action of the stent and the prevention of multiple components of
neointimal hyperplasia or restenosis as well as a reduction in
inflammation and thrombosis. This local administration of drugs to
stented coronary arteries may also have additional therapeutic
benefit. For example, higher tissue concentrations of the drugs may
be achieved utilizing local delivery, rather than systemic
administration. In addition, reduced systemic toxicity may be
achieved utilizing local delivery rather than systemic
administration while maintaining higher tissue concentrations. Also
in utilizing local delivery from a stent rather than systemic
administration, a single procedure may suffice with better patient
compliance. An additional benefit of combination drug therapy may
be to reduce the dose of each of the therapeutic drugs, agents or
compounds, thereby limiting their toxicity, while still achieving a
reduction in restenosis, inflammation and thrombosis. Local
stent-based therapy is therefore a means of improving the
therapeutic ratio (efficacy/toxicity) of anti-restenosis,
antiinflammatory, anti-thrombotic drugs, agents or compounds.
[0038] There are a multiplicity of different stents that may be
utilized following percutaneous transluminal coronary angioplasty.
Although any number of stents may be utilized in accordance with
the present invention, for simplicity, a limited number of stents
will be described in exemplary embodiments of the present
invention. The skilled artisan will recognize that any number of
stents may be utilized in connection with the present invention. In
addition, as stated above, other medical devices may be
utilized.
[0039] A stent is commonly used as a tubular structure left inside
the lumen of a duct to relieve an obstruction. Commonly, stents are
inserted into the lumen in a non-expanded form and are then
expanded autonomously, or with the aid of a second device in situ.
A typical method of expansion occurs through the use of a
catheter-mounted angioplasty balloon which is inflated within the
stenosed vessel or body passageway in order to shear and disrupt
the obstructions associated with the wall components of the vessel
and to obtain an enlarged lumen.
[0040] The stents of the present invention may be fabricated
utilizing any number of methods. For example, the stent may be
fabricated from a hollow or formed stainless steel tube that may be
machined using lasers, electric discharge milling, chemical etching
or other means. The stent is inserted into the body and placed at
the desired site in an unexpanded form. In one exemplary
embodiment, expansion may be effected in a blood vessel by a
balloon catheter, where the final diameter of the stent is a
function of the diameter of the balloon catheter used.
[0041] It should be appreciated that a stent in accordance with the
present invention may be embodied in a shape-memory material,
including, for example, an appropriate alloy of nickel and titanium
or stainless steel.
[0042] Structures formed from stainless steel may be made
self-expanding by configuring the stainless steel in a
predetermined manner, for example, by twisting it into a braided
configuration. In this embodiment after the stent has been formed
it may be compressed so as to occupy a space sufficiently small as
to permit its insertion in a blood vessel or other tissue by
insertion means, wherein the insertion means include a suitable
catheter, or flexible rod.
[0043] On emerging from the catheter, the stent may be configured
to expand into the desired configuration where the expansion is
automatic or triggered by a change in pressure, temperature or
electrical stimulation.
[0044] Regardless of the design of the stent, it is preferable to
have the drug combination dosage applied with enough specificity
and a sufficient concentration to provide an effective dosage in
the lesion area. In this regard, the "reservoir size" in the
coating is preferably sized to adequately apply the drug
combination dosage at the desired location and in the desired
amount.
[0045] In an alternate exemplary embodiment, the entire inner and
outer surface of the stent may be coated with drug/drug
combinations in therapeutic dosage amounts. It is, however,
important to note that the coating techniques may vary depending on
the drug combinations. Also, the coating techniques may vary
depending on the material comprising the stent or other
intraluminal medical device.
[0046] An embodiment of an intraluminal device (stent) according to
the present invention is depicted in FIGS. 1 and 2.
[0047] FIG. 1 shows a side plan view of a preferred elongate
radially expandable tubular stent 13 having a surface coated with a
sustained release drug delivery system in a non-deployed state. As
shown in FIG. 1, the stent 13 has its radially outer boundaries
14A, 14B at a non-deployed state. The interior luminal surface 15,
the exterior surface 16, or an entire surface of the stent 13 may
be coated with a sustained release drug delivery system or comprise
a sustained release drug delivery system. The interior luminal
surface 15 is to contact a body fluid, such as blood in a vascular
stenting procedure, while the exterior surface 16 is to contact
tissue when the stent 13 is deployed to support and enlarge the
biological vessel or duct.
[0048] In an alternate embodiment, an optional reinforcing wire 17
that connects two or more of the adjacent members or loops of the
stent structure 13 is used to lock-in and/or maintain the stent at
its expanded state when a stent is deployed. This reinforcing wire
17 may be made of a Nitinol or other high-strength material. A
Nitinol device is well known to have a preshape and a transition
temperature for said Nitinol device to revert to its preshape. One
method for treating an intraluminal tissue of a patient using a
surface coated stent 13 of the present invention comprises
collapsing the radially expandable tubular stent and retracting the
collapsed stent from a body of a patient. The operation for
collapsing a radially expandable tubular stent may be accomplished
by elevating the temperature so that the reinforcing wire 17 is
reversed to its straightened state or other appropriate state to
cause the stent 13 to collapse for removing said stent from the
body of a patient.
[0049] FIG. 2 shows an overall view of an elongate radially
expandable tubular stent 13 having a sustained release drug
delivery system coated stent surface at a deployed state. As shown
in FIG. 2, the stent 13 has its radially outer boundaries 24A, 24B
at a deployed state. The interior luminal surface 14, the exterior
surface 16, or an entire surface of the stent 13 may be coated or
may comprise the sustained release drug delivery system. The
interior luminal surface 15 is to contact a body fluid, such as
blood in a vascular stenting procedure, while the exterior surface
16 is to contact tissue when the stent 13 is deployed to support
and enlarge the biological vessel. The reinforcing wire 17 may be
used to maintain the expanded stent at its expanded state as a
permanent stent or as a temporary stent. In the case of the surface
coated stent 13 functioning as a temporary stent, the reinforcing
wire 17 may have the capability to cause collapsing of the expanded
stent.
[0050] The deployment of a stent can be accomplished by a balloon
on a delivery catheter or by self-expanding after a pre-stressed
stent is released from a delivery catheter. Delivery catheters and
methods for deployment of stents are well known to one who is
skilled in the art. The expandable stent 13 may be a
self-expandable stent, a balloon-expandable stent, or an
expandable-retractable stent. The expandable stent may be made of
memory coil, mesh material, and the like.
[0051] The intraluminal medical device comprises the sustained
release drug delivery coating. The inventive stent coating may be
applied to the stent via a conventional coating process, such as
impregnating coating, spray coating and dip coating.
[0052] In one embodiment, an intraluminal medical device comprises
an elongate radially expandable tubular stent having an interior
luminal surface and an opposite exterior surface extending along a
longitudinal stent axis. The stent may include a permanent
implantable stent, an implantable grafted stent, or a temporary
stent, wherein the temporary stent is defined as a stent that is
expandable inside a vessel and is thereafter retractable from the
vessel. The stent configuration may comprise a coil stent, a memory
coil stent, a Nitinol stent, a mesh stent, a scaffold stent, a
sleeve stent, a permeable stent, a stent having a temperature
sensor, a porous stent, and the like. The stent may be deployed
according to conventional methodology, such as by an inflatable
balloon catheter, by a self-deployment mechanism (after release
from a catheter), or by other appropriate means. The elongate
radially expandable tubular stent may be a grafted stent, wherein
the grafted stent is a composite device having a stent inside or
outside of a graft. The graft may be a vascular graft, such as an
ePTFE graft, a biological graft, or a woven graft. As appropriate,
the subject drugs (in monomeric or co-drug form) may be
incorporated into the grafted material.
[0053] The drug combinations may be incorporated onto or affixed to
the stent in a number of ways. In the exemplary embodiment, the
drug combination is directly incorporated into a polymeric matrix
and sprayed onto the outer surface of the stent. The drug
combination elutes from the polymeric matrix over time and enters
the surrounding tissue. The drug combination preferably remains on
the stent for at least three days up to approximately six months,
and more preferably between seven and thirty days.
[0054] Any number of non-erodible polymers may be utilized in
conjunction with the drug combination. Polymers that can be used
for coatings in this application can be absorbable or nonabsorbable
and must be biocompatible to minimize irritation to the vessel
wall. The polymer may be either biostable or bioabsorbable
depending on the desired rate of release or the desired degree of
polymer stability, but a bioabsorbable polymer is preferred since,
unlike biostable polymer, it will not be present long after
implantation to cause any adverse, chronic local response.
Furthermore, bioabsorbable polymers do not present the risk that
over extended periods of time there could be an adhesion loss
between the stent and coating caused by the stresses of the
biological environment that could dislodge the coating and
introduce further problems even after the stent is encapsulated in
tissue.
[0055] Suitable bioabsorbable polymers that could be used include
polymers selected from the group consisting of aliphatic
polyesters, poly(amino acids), copoly(ether-esters), polyalkylenes
oxalates, polyamides, poly(iminocarbonates), polyorthoesters,
polyoxaesters, polyamidoesters, polyoxaesters containing amido
groups, poly(anhydrides), polyphosphazenes, biomolecules and blends
thereof. For the purpose of this invention aliphatic polyesters
include homopolymers and copolymers of lactide (which includes
lactic acid d-, 1- and meso lactide), epsilon.-caprolactone,
glycolide (including glycolic acid), hydroxybutyrate,
hydroxyvalerate, para-dioxanone, trimethylene carbonate (and its
alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one,
6,6-dimethyl-1,4-dioxan-2-one and polymer blends thereof.
Poly(iminocarbonate) for the purpose of this invention include as
described by Kemnitzer and Kohn, in the Handbook of Biodegradable
Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic
Press, 1997, pages 251-272. Copoly(ether-esters) for the purpose of
this invention include those copolyester-ethers described in
Journal of Biomaterials Research, Vol. 22, pages 993-1009, 1988 by
Cohn and Younes and Cohn, Polymer Preprints (ACS Division of
Polymer Chemistry) Vol. 30(1), page 498, 1989 (e.g. PEO/PLA).
Polyalkylene oxalates for the purpose of this invention include
U.S. Pat. Nos. 4,208,511; 4,141,087; 4,130,639; 4,140,678;
4,105,034; and 4,205,399 (incorporated by reference herein).
Polyphosphazenes, co-, ter- and higher order mixed monomer based
polymers made from L-lactide, D,L-lactide, lactic acid, glycolide,
glycolic acid, para-dioxanone, trimethylene carbonate and
.epsilon.-caprolactone such as are described by Allcock in The
Encyclopedia of Polymer Science, Vol. 13, pages 31-41, Wiley
Intersciences, John Wiley & Sons, 1988 and by Vandorpe,
Schacht, Dejardin and Lemmouchi in the Handbook of Biodegradable
Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic
Press, 1997, pages 161-182 (which are hereby incorporated by
reference herein). Polyanhydrides from diacids of the form
HOOC--C.sub.6H.sub.4--O--(CH.sub.2).sub.n--O--C.sub.6H.sub.4--CO-
OH where m is an integer in the range of from 2 to 8 and copolymers
thereof with aliphatic alpha-omega diacids of up to 12 carbons.
Polyoxaesters polyoxaamides and polyoxaesters containing amines
and/or amido groups are described in one or more of the following
U.S. Pat. Nos. 5,464,929; 5,595,751; 5,597,579; 5,607,687;
5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213 and
5,700,583; (which are incorporated herein by reference).
Polyorthoesters such as those described by Heller in the Handbook
of Biodegradable Polymers, edited by Domb, Kost and Wisemen,
Hardwood Academic Press, 1997, pages 99-118 (hereby incorporated
herein by reference). Polymeric biomolecules for the purpose of
this invention include naturally occurring materials that may be
enzymatically degraded in the human body or are hydrolytically
unstable in the human body such as fibrin, fibrinogen, collagen,
elastin, and absorbable biocompatible polysaccharides such as
chitosan, starch, fatty acids (and esters thereof), glucoso-glycans
and hyaluronic acid.
[0056] Suitable biostable polymers with relatively low chronic
tissue response, such as polyurethanes, silicones,
poly(meth)acrylates, polyesters, polyalkyl oxides (polyethylene
oxide), polyvinyl alcohols, polyethylene glycols and polyvinyl
pyrrolidone, as well as, hydrogels such as those formed from
crosslinked polyvinyl pyrrolidinone and polyesters could also be
used. Other polymers could also be used if they can be dissolved,
cured or polymerized on the stent. These include polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers; acrylic
polymers (including methacrylate) and copolymers, vinyl halide
polymers and copolymers, such as polyvinyl chloride; polyvinyl
ethers, such as polyvinyl methyl ether; polyvinylidene halides such
as polyvinylidene fluoride and polyvinylidene chloride;
polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics such as
polystyrene; polyvinyl esters such as polyvinyl acetate; copolymers
of vinyl monomers with each other and olefins, such as
ethylene-methyl methacrylate copolymers, acrylonitrile-styrene
copolymers, ABS resins and ethylene-vinyl acetate copolymers;
polyamides, such as Nylon 66 and polycaprolactam; alkyd resins;
polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy
resins, polyurethanes; rayon; rayon-triacetate, cellulose,
cellulose acetate, cellulose acetate butyrate; cellophane;
cellulose nitrate; cellulose propionate; cellulose ethers (i.e.,
carboxymethyl cellulose and hydroxyalkyl celluloses); and
combinations thereof. Polyamides for the purpose of this
application would also include polyamides of the form
--NH--(CH.sub.2).sub.n--CO-- and
NH--(CH.sub.2).sub.n--NH--CO--(CH.sub.2).sub.y--CO, wherein n is
preferably an integer in from 6 to 13; x is an integer in the range
of form 6 to 12; and y is an integer in the range of from 4 to 16.
The list provided above is illustrative but not limiting.
[0057] In certain embodiments, the polymers used for coatings have
molecular weights high enough as to not be waxy or tacky. The
polymers preferably adhere to the stent and are readily deformable
after deposition on the stent as to be able to be displaced by
hemodynamic stresses. The polymers molecular weight be high enough
to provide sufficient toughness so that the polymers will not to be
rubbed off during handling or deployment of the stent and not crack
during expansion of the stent, though cracking can be avoided by
careful placement of the coating, e.g., on portions of the stent
which do not change shape between expanded and collapsed forms. The
melting point of the polymer used in the present invention should
have a melting temperature above 40.degree. C., preferably above
about 45.degree. C., more preferably above 50.degree. C. and most
preferably above 55.degree. C.
[0058] Coating may be formulated by mixing one or more of the
therapeutic agents with the coating polymers in a coating mixture.
The therapeutic agent may be present as a liquid, a finely divided
solid, or any other appropriate physical form. Optionally, the
mixture may include one or more additives, e.g., nontoxic auxiliary
substances such as diluents, carriers, excipients, stabilizers or
the like. Other suitable additives may be formulated with the
polymer and pharmaceutically active agent or compound. For example,
hydrophilic polymers selected from the previously described lists
of biocompatible film forming polymers may be added to a
biocompatible hydrophobic coating to modify the release profile (or
a hydrophobic polymer may be added to a hydrophilic coating to
modify the release profile). One example would be adding a
hydrophilic polymer selected from the group consisting of
polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol,
carboxylmethyl cellulose, hydroxymethyl cellulose and combination
thereof to an aliphatic polyester coating to modify the release
profile. Appropriate relative amounts can be determined by
monitoring the in vitro and/or in vivo release profiles for the
therapeutic agents.
[0059] In one exemplary embodiment, which can be useful where the
drugs are provided as individual monomers rather than as co-drugs,
the polymeric matrix comprises two layers. The base layer comprises
a solution of poly(ethylene-covinylacetate) and
polybutylmethacrylate. The drug combination is incorporated into
this base layer. The outer layer comprises only
polybutylmethacrylate and acts as a diffusion barrier to prevent
the drug combination from eluting too quickly. The thickness of the
outer layer or top coat determines the rate at which the drug
combination elutes from the matrix. Essentially, the drug
combination elutes from the matrix by diffusion through the polymer
matrix. Polymers are permeable, thereby allowing solids, liquids
and gases to escape therefrom. The total thickness of the polymeric
matrix is in the range from about one micron to about twenty
microns or greater. It is important to note that primer layers and
metal surface treatments may be utilized before the polymeric
matrix is affixed to the medical device. For example, acid
cleaning, alkaline (base) cleaning, salinization and parylene
deposition may be used as part of the overall process described
below.
[0060] To further illustrate, a poly(ethylene-co-vinylacetate),
polybutylmethacrylate and drug combination solution may be
incorporated into or onto the stent in a number of ways. For
example, the solution may be sprayed onto the stent or the stent
may be dipped into the solution. Other methods include spin coating
and RF plasma polymerization. In one exemplary embodiment, the
solution is sprayed onto the stent and then allowed to dry. In
another exemplary embodiment, the solution may be electrically
charged to one polarity and the stent electrically changed to the
opposite polarity. In this manner, the solution and stent will be
attracted to one another. In using this type of spraying process,
waste may be reduced and more precise control over the thickness of
the coat may be achieved.
[0061] In another exemplary embodiment, the drug combination or
other therapeutic agent may be incorporated into a polyfluoro
copolymer comprising an amount of a first moiety selected from the
group consisting of polymerized vinylidenefluoride and polymerized
tetrafluoroethylene, and an amount of a second moiety other than
the first moiety and which is copolymerized with the first moiety,
thereby producing the polyfluoro copolymer, the second moiety being
capable of providing toughness or elastomeric properties to the
polyfluoro copolymer, wherein the relative amounts of the first
moiety and the second moiety are effective to provide the coating
and film produced therefrom with properties effective for use in
treating implantable medical devices.
[0062] In one embodiment according to the present invention, the
exterior surface of the expandable tubular stent of the
intraluminal medical device of the present invention comprises a
coating according to the present invention. The exterior surface of
a stent having a coating is the tissue-contacting surface and is
biocompatible. The "sustained release drug delivery system coated
surface" is synonymous with "coated surface", which surface is
coated, covered or impregnated with sustained release drug delivery
system according to the present invention.
[0063] In an alternate embodiment, the interior luminal surface or
entire surface (i.e., both interior and exterior surfaces) of the
elongate radially expandable tubular stent of the intraluminal
medical device of the present invention has the coated surface. The
interior luminal surface having the inventive sustained release
drug delivery system coating is also the fluid contacting surface,
and is biocompatible and blood compatible.
[0064] In certain embodiments, the device, e.g., a stent, may have
two or more coatings, each of which may include a different
pharmaceutically active agent. The coatings may be of the same or
different polymeric material. For example, a device may have a
first coating that has low permeability, and a second coating,
disposed on the first coating (which may or may not completely
cover the first coating) that has high permeability. The first
coating may include a drug, such as 5-FU, that has high solubility
in biological media, and the second coating may include a drug,
such as TA, that has low solubility in biological media. Arranged
in this way, the low-solubility agent, being in closer contact with
the external environment, may be delivered into the environment at
a rate similar to that of the high-solubility agent, the release of
which is impeded by the second coating, whereas if the two agents
were present in the same coating, the agent with the higher
solubility would be released more rapidly than the less soluble
agent.
[0065] In certain embodiments, the device, such as a stent, may be
coated with a non-polymeric coating, preferably a porous coating,
that includes (e.g., is impregnated with, or is admixed with) one
or more pharmaceutically active compounds. Such coatings may
include ceramic materials, organic materials substantially
insoluble in physiologic fluids, and other suitable coatings, as
will be understood by those of skill in the art. In certain other
embodiments, the surface of the device itself is porous, e.g., the
device may be formed of a porous material such as a ceramic or
specially fabricated polymeric material, or the device may be
formed in such a way that the surface achieves a porous character,
and the pharmaceutically active compound is carried in the pores of
the device's surface, thereby permitting gradual release of the
compound upon introduction into a biological environment. In
certain embodiments, the compound is 5-FU and/or TA. The surface of
the device may further be coated with a polymeric material, e.g.,
that modulates the release of the agent(s), that improves
biocompatibility, or otherwise improves the performance of the
device in the medical treatment.
[0066] Another aspect of the invention relates to a device having a
matrix, such as a fibrous matrix, such as a woven or non-woven
cloth, e.g., vascular gauze (such as a Gortex.RTM. gauze), in which
one or more pharmaceutically active compounds are disposed. In
certain embodiments, the matrix is disposed on a stent, either
wrapped around individual elements (e.g., wires) of the frame, or
enveloping the entire device.
[0067] U.S. Pat. No. 5,773,019, U.S. Pat. No. 6,001,386, and U.S.
Pat. No. 6,051,576 disclose implantable controlled-release devices
and drugs and are incorporated in their entireties herein by
reference. The inventive process for making a surface coated stent
includes deposition onto the stent of a coating by, for example,
dip coating or spray coating. In the case of coating one side of
the stent, only the surface to be coated is exposed to the dip or
spray. The treated surface may be all or part of an interior
luminal surface, an exterior surface, or both interior and exterior
surfaces of the intraluminal medical device. The stent may be made
of a porous material to enhance deposition or coating into a
plurality of micropores on or in the applicable stent surface,
wherein the microporous size is preferably about 100 microns or
less.
[0068] Problems associated with treating restinosis and neointimal
hyperplasia can be addressed by the choice of pharmaceutical agent
used to coat the stent. In certain preferred embodiments of the
present invention, the chosen pharmaceutical agent is a moiety of
low solubility and comprises at least two pharmaceutically active
compounds. The pharmaceutically active compounds can be the same or
different chemical species, and can be formed, as desired, in
equimolar or non-equimolar concentrations to provide optimal
treatment based on the relative activities and other
pharmaco-kinetic properties of the compounds. The drug combination,
particularly where co-drug formulations are used, may itself be
advantageously relatively insoluble in physiologic fluids, such as
blood and blood plasma, and has the property of regenerating any or
all of the pharmaceutically active compounds when dissolved in
physiologic fluids. In other words, to the extent that the
low-solubility agent dissolves in physiologic fluids, it is quickly
and efficiently converted into the constituent pharmaceutically
active compounds upon dissolution. The low-solubility of the
pharmaceutical agent thus insures persistence of the agent in the
vicinity of an intraluminal lesion. The quick conversion of the
low-solubility pharmaceutical agent into the constituent
pharmaceutically active compounds insures a steady, controlled,
dose of the pharmaceutically active compounds near the site of the
lesion to be treated.
[0069] Examples of a suitable first pharmaceutically active
compound include immune response modifiers such as cyclosporin A
and FK506, corticosteroids such as dexamethasone, fluocinolone
acetonide and triamcinolone acetonide, angiostatic steroids such as
trihydroxy steroids, antibiotics including ciprofloxacin,
differentiation modulators such as retinoids (e.g., trans-retinoic
acid, cis-retinoic acid and analogues),
anticancer/anti-proliferative agents such as 5-fluorouracil (5FU)
and carmustine (BCNU), and non-steroidal anti-inflammatory agents
such as naproxen, diclofenac, indomethacin and flurbiprofen.
[0070] In some embodiments according to the present invention, the
preferred first pharmaceutically active compound is 5FU.
##STR00001##
[0071] Examples of a suitable second pharmaceutically active
compound include immune response modifiers such as cyclosporin A
and FK 506, corticosteroids such as dexamethasone, fluocinolone
acetonide and triamcinolone acetonide, angiostatic steroids such as
trihydroxy steroids, antibiotics including ciprofloxacin,
differentiation modulators such as retinoids (e.g., trans-retinoic
acid, cis-retinoic acid and analogues),
anticancer/anti-proliferative agents such as 5FU and BCNU, and
non-steroidal anti-inflammatory agents such as naproxen,
diclofenac, indomethacin and flurbiprofen.
[0072] In some embodiments according to the present invention, the
second pharmaceutically active compound is selected from
fluocinolone acetonide, triamcinolone acetonide, diclofenac, and
naproxen.
##STR00002##
[0073] The low-solubility pharmaceutically active agent according
to the present invention may comprise further residues of
pharmaceutically active compounds. Such further pharmaceutically
active compounds include immune response modifiers such as
cyclosporin A and FK 506, corticosteroids such as dexamethasone,
fluocinolone acetonide and triamcinolone acetonide, angiostatic
steroids such as trihydroxy steroids, antibiotics including
ciprofloxacin, differentiation modulators such as retinoids (e.g.,
trans-retinoic acid, cis-retinoic acid and analogues),
anticancer/anti-proliferative agents such as 5FU and BCNU, and
non-steroidal antiinflammatory agents such as naproxen, diclofenac,
indomethacin and flurbiprofen.
[0074] In certain embodiments, the low-solubility pharmaceutical
agent comprises a moiety of at least two pharmaceutically active
compounds that can be covalently bonded, connected through a
linker, ionically combined, or combined as a mixture.
[0075] In some embodiments according to the present invention, the
first and second pharmaceutically active compounds are covalently
bonded directly to one another. Where the first and second
pharmaceutically active compounds are directly bonded to one
another by a covalent bond, the bond may be formed by forming a
suitable covalent linkage through an active group on each active
compound. For instance, an acid group on the first pharmaceutically
active compound may be condensed with an amine, an acid or an
alcohol on the second pharmaceutically active compound to form the
corresponding amide, anhydride or ester, respectively.
[0076] In addition to carboxylic acid groups, amine groups, and
hydroxyl groups, other suitable active groups for forming linkages
between pharmaceutically active moieties include sulfonyl groups,
sulfhydryl groups, and the haloic acid and acid anhydride
derivatives of carboxylic acids.
[0077] In other embodiments, the pharmaceutically active compounds
may be covalently linked to one another through an intermediate
linker. The linker advantageously possesses two active groups, one
of which is complementary to an active group on the first
pharmaceutically active compound, and the other of which is
complementary to an active group on the second pharmaceutically
active compound. For example, where the first and second
pharmaceutically active compounds both possess free hydroxyl
groups, the linker may suitably be a diacid, which will react with
both compounds to form a diether linkage between the two residues.
In addition to carboxylic acid groups, amine groups, and hydroxyl
groups, other suitable active groups for forming linkages between
pharmaceutically active moieties include sulfonyl groups,
sulfhydryl groups, and the haloic acid and acid anhydride
derivatives of carboxylic acids.
[0078] Suitable linkers are set forth in Table 1 below.
TABLE-US-00001 TABLE 1 First Pharmaceutically Second
Pharmaceutically Active Compound Active Active Compound Active
Group Group Suitable Linker Amine Amine Diacid Amine Hydroxy Diacid
Hydroxy Amine Diacid Hydroxy Hydroxy Diacid Acid Acid Diamine Acid
Hydroxy Amino acid, hydroxyalkyl acid sulfhydrylalkyl acid Acid
Amine Amino acid, hydroxyalkyl acid sulfhydrylalkyl acid
[0079] Suitable diacid linkers include oxalic, malonic, succinic,
glutaric, adipic, pimelic, suberic, azelaic, sebacic, maleic,
fumaric, tartaric, phthalic, isophthalic, and terephthalic acids.
While diacids are named, the skilled artisan will recognize that in
certain circumstances the corresponding acid halides or acid
anhydrides (either unilateral or bilateral) are preferred as linker
agents. A preferred anhydride is succinic anhydride. Another
preferred anhydride is maleic anhydride. Other anhydrides and/or
acid halides may be employed by the skilled artisan to good
effect.
[0080] Suitable amino acids include y-butyric acid, 2-aminoacetic
acid, 3-aminopropanoic acid, 4-aminobutanoic acid, 5-aminopentanoic
acid, 6-aminohexanoic acid, alanine, arginine, asparagine, aspartic
acid, cysteine, glutamic acid, glutamine, glycine, histidine,
isoleucine, leucine, lysine, methionine, phenylalanine, proline,
serine, threonine, tryptophan, tyrosine, and valine. Again, the
acid group of the suitable amino acids may be converted to the
anhydride or acid halide form prior to their use as linker
groups.
[0081] Suitable diamines include 1,2-diaminoethane,
1,3-diaminopropane, 1,4-diaminobutane, 4,5-diaminopentane,
1,6-diaminohexane.
[0082] Suitable aminoalcohols include 2-hydroxy-1-aminoethane,
3-hydroxy-1-aminoethane, 4-hydroxy-1-aminobutane,
5-hydroxy-1-aminopentane, 6-hydroxy-1-aminohexane.
[0083] Suitable hydroxyalkyl acids include 2-hydroxyacetic acid,
3-hydroxypropanoic acid, 4-hydroxybutanoic acid, 5-hydroxypentanoic
acid, 5-hydroxyhexanoic acid.
[0084] The person having skill in the art will recognize that by
selecting first and second pharmaceutical moieties (and optionally
third, etc. pharmaceutical moieties) having suitable active groups,
and by matching them to suitable linkers, a broad palette of
inventive compounds may be prepared within the scope of the present
invention.
[0085] Exemplary preferred low-solubility pharmaceutically active
agents according to the present invention include 5FU covalently
bonded to fluocinolone acetonide, 5FU covalently bonded to
diclofenac, and 5FU covalently bonded to naproxen. Illustrative
examples include the following:
##STR00003##
[0086] In other embodiments, the first and second pharmaceutically
active compounds may be combined to form a salt. For instance, the
first pharmaceutically active compound may be an acid, and the
second pharmaceutically active compound may be a base, such as an
amine. As a specific example, the first pharmaceutically active
compound may be diclofenac or naproxen (acids), and the second
pharmaceutically active compound may be ciprofloxacin (a base). The
combination of diclofenac and ciprofloxacin would for instance form
the salt:
##STR00004##
[0087] In still other embodiments, the first and second
pharmaceutical active compounds may be combined as a mixture.
[0088] As used in regard to the low-solubility pharmaceutical
agent, the term "low-solubility" relates to the solubility of the
pharmaceutical agent in biological fluids, such as blood plasma,
lymphatic fluid, peritoneal fluid, etc. In general,
"low-solubility" means that the pharmaceutical agent is only very
slightly soluble in aqueous solutions having pH in the range of
about 5 to about 8, and in particular to physiologic solutions,
such as blood, blood plasma, etc. Some low-solubility agents
according to the present invention will have solubilities of less
than about 100 (.mu.g/ml, preferably less than about 20 .mu.g/ml,
more preferably less than about 15 .mu.g/ml, and more preferably,
less than about 10 .mu.g/ml. Solubility is in water at a
temperature of 25.degree. C. as measured by the procedures set
forth in the 1995 USP, unless otherwise stated. This includes
compounds which are slightly soluble (about 10 mg/ml to about 1
mg/ml), very slightly soluble (about 1 mg/ml to about 0.1 mg/ml)
and practically insoluble or insoluble compounds (less than about
0.1 mg/ml).
[0089] Inventive compounds are slowly dissolved in physiologic
fluids, but are relatively quickly dissociated into at least first
and second pharmaceutically active compounds upon dissolution in
physiologic fluids. In some embodiments the dissolution rate of the
inventive compounds is in the range of about 0.001 .mu.g/day to
about 10 .mu.g/day. In certain embodiments, the inventive compounds
have dissolution rates in the range of about 0.01 to about 1
.mu.g/day. In particular embodiments, the inventive compounds have
dissolution rates of about 0.1 .mu.g/day.
[0090] The low-solubility pharmaceutical agent is incorporated into
a biocompatable (i.e. biologically tolerated) polymer coating. In
some embodiments according to the present invention, the
low-solubility pharmaceutical agent is present as a plurality of
granules dispersed within the polymer coating. In such cases, it is
preferred that the low-solubility pharmaceutical agent be
relatively insoluble in the polymer coating, however the
low-solubility pharmaceutical agent may possess a finite solubility
coefficient with respect to the polymer coating and still be within
the scope of the present invention. In either case, the polymer
coating solubility of the low-solubility pharmaceutical agent
should be such that the agent will disperse throughout the polymer
coating, while remaining in substantially granular form.
[0091] In some embodiments according to the present invention, the
low-solubility pharmaceutical agent is dissolved within the polymer
coating. In such cases, it is preferred that the polymer coating be
a relatively non-polar or hydrophobic polymer which acts as a good
solvent for the relatively hydrophobic low-solubility
pharmaceutical agent. In such cases, the solubility of the
low-solubility pharmaceutical agent in the polymer coating should
be such that the agent will dissolve thoroughly in the polymer
coating, being distributed homogeneously throughout the polymer
coating.
[0092] In some embodiments according to the present invention, the
polymer is non-bioerodible. Examples of non-bioerodible polymers
useful in the present invention include poly(ethylene-co-vinyl
acetate) (EVA), polyvinylalcohol and polyurethanes, such as
polycarbonate-based polyurethanes. In other embodiments of the
present invention, the polymer is bioerodible. Examples of
bioerodible polymers useful in the present invention include
polyanhydride, polylactic acid, polyglycolic acid, polyorthoester,
polyalkylcyanoacrylate or derivatives and copolymers thereof. The
skilled artisan will recognize that the choice of bioerodibility or
non-bioerodibility of the polymer depends upon the final physical
form of the system, as described in greater detail below. Other
exemplary polymers include polysilicone and polymers derives from
hyaluronic acid. The skilled artisan will understand that the
polymer according to the present invention is prepared under
conditions suitable to impart permeability such that it is not the
principal rate determining factor in the release of the
low-solubility agent from the polymer.
[0093] Moreover, suitable polymers include naturally occurring
(collagen, hyaluronic acid) or synthetic materials that are
biologically compatible with bodily fluids and mammalian tissues,
and essentially insoluble in bodily fluids with which the polymer
will come in contact. In addition, the suitable polymers
essentially prevent interaction between the low-solubility agent
dispersed/suspended in the polymer and proteinaceous components in
the bodily fluid. The use of rapidly dissolving polymers or
polymers highly soluble in bodily fluid or which permit interaction
between the low-solubility agent and proteinaceous components are
to be avoided since dissolution of the polymer or interaction with
proteinaceous components would affect the constancy of drug
release. Other suitable polymers include polypropylene, polyester,
polyethylene vinyl acetate (EVA), polyethylene oxide (PEO),
polypropylene oxide, polycarboxylic acids, polyalkylacrylates,
cellulose ethers, polyalkyl-alkyacrylate copolymers,
polyester-polyurethane block copolymers, polyether-polyurethane
block copolymers, polydioxanone, poly-(.beta.-hydroxybutyrate),
polylactic acid (PLA), polycaprolactone, polyglycolic acid, and
PEO-PLA copolymers.
[0094] The coating of the present invention may be formed by mixing
one or more suitable monomers and a suitable low-solubility
pharmaceutical agent, then polymerizing the monomer to form the
polymer system. In this way, the agent is dissolved or dispersed in
the polymer. In other embodiments, the agent is mixed into a liquid
polymer or polymer dispersion and then the polymer is further
processed to form the inventive coating. Suitable further
processing includes crosslinking with suitable crosslinking agents,
further polymerization of the liquid polymer or polymer dispersion,
copolymerization with a suitable monomer, block copolymerization
with suitable polymer blocks, etc. The further processing traps the
drug in the polymer so that the drug is suspended or dispersed in
the polymer coating.
[0095] In some embodiments according to the present invention,
monomers for forming a polymer are combined with an inventive
low-solubility compound and are mixed to make a homogeneous
dispersion of the inventive compound in the monomer solution. The
dispersion is then applied to a stent according to a conventional
coating process, after which the crosslinking process is initiated
by a conventional initiator, such as UV light. In other embodiments
according to the present invention, a polymer composition is
combined with an inventive low-solubility compound to form a
dispersion. The dispersion is then applied to a stent and the
polymer is cross-linked to form a solid coating. In other
embodiments according to the present invention, a polymer and an
inventive low-solubility compound are combined with a suitable
solvent to form a dispersion, which is then applied to a stent in a
conventional fashion. The solvent is then removed by a conventional
process, such as heat evaporation, with the result that the polymer
and inventive low-solubility drug (together forming a
sustained-release drug delivery system) remain on the stent as a
coating.
[0096] An analogous process may be used where the inventive
low-solubility pharmaceutical compound is dissolved in the polymer
composition.
[0097] In some embodiments according to the invention, the system
comprises a polymer that is relatively rigid. In other embodiments,
the system comprises a polymer that is soft and malleable. In still
other embodiments, the system includes a polymer that has an
adhesive character. Hardness, elasticity, adhesive, and other
characteristics of the polymer may be varied as necessary.
[0098] In some embodiments according to the present invention, the
polymer is non-bioerodible, or is bioerodible only at a rate slower
than a dissolution rate of the low-solubility pharmaceutical agent,
and the diameter of the granules is such that when the coating is
applied to the stent, the granules' surfaces are exposed to the
ambient tissue. In such embodiments, dissolution of the
low-solubility pharmaceutical agent is proportional to the exposed
surface area of the granules.
[0099] In other embodiments according to the present invention, the
polymer coating is permeable to water in the surrounding tissue,
e.g. in blood plasma. In such cases, water solution may permeate
the polymer, thereby contacting the low-solubility pharmaceutical
agent. The rate of dissolution may be governed by a complex set of
variables, such as the polymer's permeability, the solubility of
the low-solubility pharmaceutical agent, the pH, ionic strength,
and protein composition, etc. of the physiologic fluid. In certain
embodiments, however the permeability may be adjusted so that the
rate of dissolution is governed primarily, or in some cases
practically entirely, by the solubility of the low-solubility
pharmaceutical agent in the ambient liquid phase. In still other
embodiments the pharmaceutical agent may have a high solubility in
the surrounding fluid. In such cases the matrix permeability may be
adjusted so that the rate of dissolution is governed primarily, or
in some cases practically entirely, by the permeability of the
polymer:
EXAMPLES
[0100] The present invention can be more fully understood with
reference to the following examples.
[0101] Agent TC-112 comprising a conjugate of 5-fluorouracil and
naproxen linked via a reversible covalent bond, and agent G.531.1,
comprising a conjugate of 5-fluorouracil and fluocinolone
acetonide, were prepared in accordance with the methods set forth
in U.S. Pat. No. 6,051,576. The structure of these compounds is
reproduced below.
##STR00005##
[0102] The following examples are intended to be illustrative of
the disclosed invention. The examples are non-limiting, and the
skilled artisan will recognize that other embodiments are within
the scope of the disclosed invention.
Example 1
[0103] To 20 gm of 10% (w/v) aqueous poly(vinyl alcohol) (PVA)
solution, 80.5 mg of agent TC-112 was dispersed. 5 pieces of glass
plates were then dipping coated with this TC-112/PVA suspension and
followed by air-drying. The coating and air-drying was repeated
four more times. At the end about 100 mg of TC-12/PVA was coated on
each glass plates. The coated glass plates were then heat treated
at 135.degree. C. for 5 hours. After cooling to room temperature,
the glass plates were individually placed in 20 ml of 0.1 M mol
phosphate buffer (pH 7.4, 37.degree. C.) for release test. Sample
was taken daily and entire release media were replaced with fresh
one at each sampling time. The drugs and TC-112 released in the
media were determined by reverse-phase HPLC. The half-life for
TC-112 in pH 7.4 buffer is 456 min, in serum is 14 min.
[0104] The results are shown in FIG. 3, which shows the total
cumulative release of TC-112 from PVA coated glass plates. The
slope of the curve demonstrates that TC-112 is released at 10
.mu.g/day. The data represent both intact and constituents
(5-fluorouracil and naproxen) of the compound TC-112.
Example 2
[0105] 12.0 gm of silicone part A (Med-6810A) were mixed with 1.2
gm of silicone part B (Med-6810B), and degassed in sonicator for 10
min, followed by water aspirator. 41.2 mg of (TC-112) were
dispersed in this degassed silicone, and degassed again. 0.2 gm of
the mixture was spread on one surface of a glass plate. The glass
plates (total 5) were then placed in oven and heated at 105.degree.
C. for 20 min. to cure. After removing from the oven and cooled to
room temperature, 0.2 gm of the mixture was spread on the other
uncoated surface of each glass plate. The coated glass plates were
then heat treated again at 105.degree. C. for 20 min. After cooling
to room temperature, the glass plates were individually placed in
20 ml of 0.1 M phosphate buffer (pH 7.4, 37.degree. C.) for release
test. Samples were taken daily, and the entire release media was
replaced with fresh media at each sampling time. The drugs
(5-fluorouracil and naproxen) and TC-112 released in the media were
determined by HPLC.
[0106] The total TC-112 release for silicone coating was calculated
as follows. The molecular weight of Naproxen is 230.3, and the
molecular weight for 5-Fluorouracil is 130.1, while the compound
TC-112 generated from these two drugs has a molecular weight of
372.4. To detect x mg of naproxen, this means that x*372.4/230.3 mg
of TC-112 was hydrolyzed. The total TC-112 released equals the sum
of TC-112 detected in the release media and the TC-112 hydrolyzed.
For example, up to day 6, 43.9 mg of naproxen is detected, this
means 71.0 (43.9*372.4/230.3) mg of was hydrolyzed, at the same
time, 51.4 mg of TC-112 is detected in buffer, therefore a total of
122.4 mg (51.4 plus 71.0) of TC-112 is released up to day 6.
[0107] The results are shown in FIG. 4, which shows the total
cumulative release of TC-112 from silicone coated glass plates. The
slope of the curve demonstrates that TC-112 is released at 13.3
.mu.g/day. Again, the data represent both intact and constituents
of the inventive compound. The similarity in the slopes
demonstrates that the polymers have little effect on the release of
the drug.
Example 3
[0108] A mixture of 3.3 gm Chronoflex C(65D) (Lot# CTB-G25B-1234)
dispersion containing 0.3 gm of Chronoflex C(65D) and 2.2 gm
Chronoflex C(55D) (Lot# CTB-121B-1265) dispersion containing 0.2 gm
of Chronoflex C (55D), both in dimethyl acetamide (DMAC) (1:10,
w/w) was prepared by mixing the two dispersions together. To this
mixture, 6.0 gm of tetrahydrofurane (HPLC grade) were added and
mixed. The final mixture was not a clear solution. Then 101.5 mg of
TC-32 was added and dissolved into the polymer solution.
[0109] Ten (10) HPLC inserts were then coated with the
polymer/TC-32 solution by dipping, which was then followed by
air-drying under ambient temperature. The coating and air-drying
process was repeated four (4) times (5 times total) until a total
of about 10 mg of polymer/CT-32 was applied to each insert. The
inserts were then placed in an oven at 80.degree. C. for two hour
to remove the residue of the solvent.
[0110] The inserts were placed individually in 20 ml of 0.1 m
phosphate buffer, pH 7.4, in glass tube and monitoring of the
release of compounds from the inserts at 37.degree. C. was begun.
Samples were taken daily, and the entire media was replaced with
fresh media at each sampling time. The drugs released in the media
were determined by HPLC. TC-32 is a compound comprising 5FU linked
to triamcinolone acetonide (TA). Because of the short half-life of
TC-32 in buffer, no TC-32 was detectable in the release media; only
amounts of parent drugs, 5FU and TA, could be determined. The
release profiles are displayed in FIG. 5.
Example 4
[0111] To 5.0 gm of stirred dimethyl acetamide (DMAC), 300 mg of
Chronoflex C(65D) (Lot# CTB-G25B-1234) and 200 mg of Chronoflex
C(55D) (Lot# CTB-121B-1265) were added. The polymer was slowly
dissolved in DMAC (about 4 hours). Then 5.0 gm of THF was added to
the polymer dispersion. The mixture was not a clear solution. Then
100.9 mg of TC-32 was added and dissolved in the mixture.
[0112] Three (3) Stents, supplied by Guidant Corp, were coated then
with the polymer/TC-32 solution by dipping and followed by
air-drying under ambient temperature. The coating and air-drying
process was repeated a few times till a total of about 2.0 mg of
polymer/TC-32 were applied to each stent. The coated stents were
air-dried under ambient temperature in a biological safety cabinet
over night. The stents were then vacuum dried at 80.degree. C. for
two hour to remove the residue of the solvent. Afterwards they were
placed individually in 5.0 ml of 0.1 m phosphate buffer, pH 7.4, in
glass tube and monitoring of the release of compounds from the
stents was at 37.degree. C. was begun. Samples were taken daily,
and the entire media was replaced with a fresh one at each sampling
time. The drugs released in the media were determined by HPLC. The
release profiles were shown in the FIG. 6. No TC-32 was detectable
in the release media.
[0113] The purpose of the above description and examples is to
illustrate some embodiments of the present invention without
implying any limitation. It will be apparent to those of skill in
the art that various modifications and variations may be made to
the systems, devices and methods of the present invention without
departing from the spirit or scope of the invention. All patents
and articles cited herein are specifically incorporated herein in
their entireties.
Example 5
[0114] Chronoflex C (65D, Lot# CTB-G25B-1234) was first dissolved
in tetrahydrofuran. Into this solution bioreversible conjugates of
5FU and TA were dissolved and the resulting solution spray coated
onto coronary Tetra stents produced by Guidant. After air-drying,
the coated stents were vacuum dried at 50.degree. C. for 2 hours to
remove solvent residue, and subject to plasma treatment and
gamma-irradiation. Two different levels of drug loading were
applied to stents: 80 .mu.g Low Dose (13%) and 600 .mu.g High Dose
(60%). The release rate was determined in vitro by placing the
coated stents (inflated with a dialation catheter: 3.0 mm balloon
size and 20 mm long) in 0.1M phosphate buffer (pH 7.4) at
37.degree. C. Samples of the buffer solution were periodically
removed for analysis by HPLC, and the buffer was replaced to avoid
any saturation effects.
[0115] The results shown in FIG. 7 illustrate the release pattern
in vitro for a High Dose coated stent. The pattern followed a
pseudo logarithmic pattern with approximately 70% being released in
10 weeks. A similar pattern is seen in both High Dose and Low Dose
loaded stents. TA and FU were released in an equimolar fashion at
all times during the experiments. No co-drugs of 5FU/TA were
detectable in the release media.
Example 6
[0116] Chronoflex C (65D, Lot# CTB-G25B-1234, 1.008 gm) was added
to 50.0 gm of tetrahydrofuran (THF). The mixture was stirred
overnight to dissolve the polymer. 5.0 gm of the polymer solution
was diluted with 10.0 gm of THF. 150.2 mg of a co-drug TC-32
(5-fluorouracil and triamcinolone acetonide) was added to the
polymer solution and dissolved. The coating solution was prepared
with 60% codrug loading. A 13% codrug loaded coating solution was
also prepared. Bare stents (Tetra, Guidant, Lot# 1092154, 13 mm
Tetra) were washed with isopropanol, air-dried, and spray coated
with the coating solution using a precision airbrush. The coating
was repeated until approximately 1.0 mg of total coating had been
applied to each stent. After air-drying, the coated stents were
vacuum dried at 50.degree. C. for 2 hours to remove solvent
residue, and subject to plasma treatment and gamma-irradiation.
[0117] Co-drug coated stents were tested in two groups. After
inflated with a dialation catheter (3.0 mm balloon size and 20 mm
long), Group One stents were placed individually into a glass tube
containing 5.0 ml of 0.1 M phosphate buffer (pH 7.4). Samples were
taken periodically and the concentration of co-drug in the buffer
was tested by HPLC. The entire release media was replaced after
each sample.
[0118] Group Two stents were placed in vivo. Three common swine had
TC-32 coated stents implanted into the left anterior descending
(LAD) coronary artery on study day 1. The stents were harvested on
study day 5 and then placed in 0.1 M phosphate buffer as describe
for Group One stents. The amount of each drug released into the
media was determined by HPLC. The intact codrug was not detectable
in release media.
[0119] The results are shown in FIG. 8, showing the comparative
drug release profiles between explanted stents and non-implanted
stents. The release patterns for both explanted and pre-implanted
stents indicate that in-vivo release may be predicted by in vitro
release patterns.
Example 7
[0120] Fourteen (14) domestic swine received a maximum of three (3)
stents deployed in any of the three-epicardial coronaries (LAD,
LCX, and RCA). Some animals were given only control stents,
comprising either Bare Metal Tetra Coronary Stent on Cross Sail Rx
balloon delivery system (Control), or PU Coated Tetra Coronary
Stent on Cross Sail Rx balloon delivery system (Control). Other
animals were given drug-coated stents either in Low Dose (80 .mu.g
TA+5FU (13%)) or High Dose (600 .mu.g TA+5FU (60%)). The stents
were implanted into arteries of the animals. Each stent was
advanced to the desired location in the artery, and was deployed
using an inflation device. The pressure of the inflation device was
chosen to achieve a balloon to artery ratio of 1.1-1.2:1.
[0121] After 28 days, arterial sections directly adjacent to the
stents were surgically excised and embedded in a methacrylate
resin. Histologic 5-.mu.m sections were cut and stained with
Verhoeff's elastin and Hematoxylin and Eosin stains, and the
thickness of each excised section was measured. The results are
shown in table for both High and Low Dose drug-coated stents. The
response at 28 days in both low-dose and high-dose experimental
groups shows a profound reduction in intimal thickness attributed
to the co-release of TA and 5FU3 from polymer coated Tetra
stents.
TABLE-US-00002 Bare Metal Polymer Low Dose High Dose Balloon:artery
1.07 .+-. 1.11 .+-. 0.07 1.13 .+-. 0.05 1.11 .+-. 0.08 ratio 0.05
Intimal Thickness 0.29 .+-. 0.36 .+-. 0.08 0.13 .+-. 0.01.sup..xi.
0.13 .+-. 0.04.sup..rho. (mm) 0.03 Medial area 1.39 .+-. 1.98 .+-.
0.41 0.96 .+-. 0.06.sup..sctn. 0.98 .+-. 0.07.sup..zeta. (mm.sup.2)
0.10 .sup..xi.P = 0.0008 Bare Metal vs Low Dose, p = 0.03 Polymer
vs. Low Dose .sup..sctn.p = 0.002 Bare Metal vs. Low Dose, p = 0.04
Polymer vs Low Dose .sup..rho.p = 0.02 Bare Metal vs. High Dose, p
= 0.07 Polymer vs. High Dose .sup..zeta.p = 0.01 Bare Metal vs High
Dose, p = 0.07 Polymer vs. High Dose
Example 8
[0122] Stents were coated with a mixture of TA and 5FU in a
mole-ratio of 1 to 1 without chemical linkage. The release rate was
determined in vitro by placing the coated stents in 0.1M phosphate
buffer (pH 7.4) at 37.degree. C. Samples of the buffer solution
were periodically removed for analysis by HPLC, and the buffer was
replaced to avoid any saturation effects.
[0123] The results are shown in FIG. 9. Because of the hydrophilic
nature of 5FU, this compound was released from the mixture coating
much faster than from the codrug coating. Within 4 weeks, more than
95% of total 5FU was released. TA release from the drug mixture
coating was much slower, with about 20% TA released over the first
6 weeks.
[0124] The 5FU/TA mixture in a polymer coating demonstrated
different release profiles compared to the codrug polymer coating.
However, this study indicates that use of a mixture of 5FU and TA
can be applied to a stent to achieve controlled release of a
desired active compound mixture.
Example 9
[0125] A polymer-coated stent was also tested to identify any
inherent release pattern attributable to the polymer. Following
plasma treatment and gamma-irradiation, the stents were inflated
with a dilatation catheter (3.0 mm balloon size, 20 mm long) and
placed individually into a glass tube containing 5.0 ml of 0.1 M
phosphate buffer (pH 7.4). Samples were taken periodically and the
entire release media was replaced after each sample. The amount of
each drug released into the media was determined by HPLC. The
intact codrug was not detectable in release media.
* * * * *