U.S. patent application number 11/236977 was filed with the patent office on 2006-04-27 for solubilizing a drug for use in a coating.
This patent application is currently assigned to ATRIUM MEDICAL CORPORATION. Invention is credited to Joseph Ferraro, Steve A. Herweck, Theodore Karwoski, Roger Labrecque, Paul Martakos, Geoffrey Moodie, Lisa Rogers.
Application Number | 20060088596 11/236977 |
Document ID | / |
Family ID | 36119235 |
Filed Date | 2006-04-27 |
United States Patent
Application |
20060088596 |
Kind Code |
A1 |
Labrecque; Roger ; et
al. |
April 27, 2006 |
Solubilizing a drug for use in a coating
Abstract
A method for the provision of a coating on an implantable
medical device results in a medical device having a bio-absorbable
coating. The coating includes a bio-absorbable carrier component.
In addition to the bio-absorbable carrier component, a dissolved
therapeutic agent component can also be provided. The coated
medical device is implantable in a patient to effect controlled
delivery of the coating, including the dissolved therapeutic agent,
to the patient.
Inventors: |
Labrecque; Roger;
(Londonderry, NH) ; Moodie; Geoffrey; (Hudson,
NH) ; Rogers; Lisa; (Londonderry, NH) ;
Ferraro; Joseph; (Londonderry, NH) ; Karwoski;
Theodore; (Hollis, NH) ; Herweck; Steve A.;
(Nashua, NH) ; Martakos; Paul; (Pelham,
NH) |
Correspondence
Address: |
LAHIVE & COCKFIELD
28 STATE STREET
BOSTON
MA
02109
US
|
Assignee: |
ATRIUM MEDICAL CORPORATION
Hudson
NH
|
Family ID: |
36119235 |
Appl. No.: |
11/236977 |
Filed: |
September 28, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60613745 |
Sep 28, 2004 |
|
|
|
Current U.S.
Class: |
424/472 ;
427/2.14 |
Current CPC
Class: |
A61L 31/16 20130101;
A61P 35/00 20180101; A61L 31/10 20130101; A61L 2300/416 20130101;
A61P 7/02 20180101; A61M 25/0009 20130101; A61K 47/22 20130101;
A61K 47/44 20130101; A61L 2300/428 20130101; A61K 47/10 20130101;
A61L 31/08 20130101; A61F 2250/0067 20130101; A61L 31/148 20130101;
A61F 2/86 20130101; A61F 2/82 20130101; A61L 2300/606 20130101;
A61P 3/00 20180101; A61L 2300/802 20130101; A61M 25/0045 20130101;
A61P 29/00 20180101; A61L 2300/22 20130101; A61L 2300/45 20130101;
A61L 2420/02 20130101 |
Class at
Publication: |
424/472 ;
427/002.14 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 9/24 20060101 A61K009/24; B05D 3/00 20060101
B05D003/00 |
Claims
1. A method of dissolving an amount of one or more therapeutic
agents in a bio-absorbable carrier component and a vitamin E
compound, the method comprising the steps of: (a) identifying said
therapeutic agent and an amount thereof to be dissolved; (b)
selecting a solvent based on the identified therapeutic agent; (c)
dissolving the identified amount of the therapeutic agent in said
solvent to form a first mixture; (d) determining a ratio of the
vitamin E compound and the bio-absorbable carrier component; (e)
mixing the vitamin E compound and the bio-absorbable carrier
component to form a second mixture; (f) combining the first mixture
with the second mixture to form a homogeneous solution; and (g)
removing the solvent from the homogeneous solution such that the
therapeutic agent remains dissolved in the bio-absorbable carrier
component and the vitamin E.
2. The method of claim 1, wherein the vitamin E compound comprises
one or more of alpha-tocopherol, beta-tocopherol, delta-tocopherol,
gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol,
delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate,
beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherol
acetate, alpha-tocotrienol acetate, beta-tocotrienol acetate,
delta-tocotrienol acetate, gamma-tocotrienol acetate,
alpha-tocopherol succinate, beta-tocopherol succinate,
gamma-tocopherol succinate, delta-tocopherol succinate,
alpha-tocotrienol succinate, beta-tocotrienol succinate,
delta-tocotrienol succinate, gamma-tocotrienol succinate, vitamin E
TPGS, mixed tocopherols, derivatives, analogs and pharmaceutically
acceptable salts thereof.
3. The method of claim 1, wherein the bio-absorbable carrier
component comprises a naturally occurring oil, fish oil fatty
acids, fatty acid esters, free fatty acids or a combination
thereof.
4. The method of claim 3, wherein the naturally occurring oil
comprises fish oil.
5. The method of claim 1, wherein the bio-absorbable carrier
component is modified from its naturally occurring state of
increased viscosity in the form of a cross-linked gel.
6. The method of claim 3, wherein the fish oil fatty acids comprise
one or more of arachidic acid, gadoleic acid, arachidonic acid,
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or
derivatives, analogs and pharmaceutically acceptable salts
thereof.
7. The method of claim 3, wherein the free fatty acids comprise one
or more of butyric acid, caproic acid, caprylic acid, capric acid,
lauric acid, myristic acid, palmitic acid, palmitoleic acid,
stearic acid, oleic acid, vaccenic acid, linoleic acid,
alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic
acid, lignoceric acid, analogs and pharmaceutically acceptable
salts thereof.
8. The method of claim 1, wherein the therapeutic agent comprises
an antioxidant, an anti-inflammatory, and anti-coagulant, a drug to
alter lipid metabolism, an anti-proliferative, an anti-neoplastic,
an anti-fibrotic, an immunosuppressive, a tissue growth stimulant,
a functional protein/factor delivery agent, an anti-infective
agent, an imaging agent, an anesthetic, a chemotherapeutic agent, a
tissue absorption enhancer, an anti-adhesion agent, a germicide, an
antiseptic, a proteoglycan, a GAG, a gene or polynucleotide naked
or in association with a delivery agent, an analgesic,
anti-migratory agents, pro-healing agents, ECM/protein production
inhibitors, a polysaccharide (heparin), or a combination
thereof.
9. The method of claim 1, wherein the therapeutic agent comprises
one or more of rapamycin, melatonin, paclitaxel, cerivastatin,
cilostazol, fluvastatin, lovastatin, pravastatin or derivatives,
prodrugs, analogs and pharmaceutically acceptable salts
thereof.
10. The method of claim 1, wherein the solvent comprises
C.sub.2-C.sub.6 alkanols, 2-ethoxyethanol, ethanol, isopropanol,
butanol, benzyl alcohol, ethylene glycol, propylene glycol,
butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, 2-pyrrolidone, 2-piperidone,
2-caprolactam, N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; ethyl acetate, methyl acetate, butyl acetate,
ethylene glycol diethyl ether, ethylene glycol dimethyl ether,
propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactorne and isomers thereof, .beta.-butyrolactone
and isomers thereof; water, dimethylsulfoxide, benzyl benzoate,
ethyl lactate, acetone, methylethyl ketone, dimethylsolfone,
tetrahydrofuran, decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane
or a combination thereof.
11. The method of claim 1, wherein the first mixture and the second
mixture can be created independently and interchangeably first,
second or substantially simultaneously.
12. The method of claim 1, wherein the bio-absorbable carrier
component further comprises a compatibilizer, a preservative or a
combination thereof.
13. The method of preparing a coating for a medical device, wherein
the coating comprises an amount of one or more therapeutic agents
dissolved in a bio-absorbable carrier component and a vitamin E
compound, the method comprising the steps of: (a) identifying said
therapeutic agent and an amount thereof to be dissolved; (b)
selecting a solvent based on the identified therapeutic agent; (c)
dissolving the identified amount of the therapeutic agent in said
solvent to form a first mixture; (d) determining a ratio of the
vitamin E compound and the bio-absorbable carrier component; (e)
mixing the vitamin E compound and the bio-absorbable carrier
component to form a second mixture; (f) combining the first mixture
with the second mixture to form a homogeneous solution; and (g)
removing the solvent from the homogeneous solution such that the
therapeutic agent remains dissolved in the bio-absorbable carrier
component and the vitamin E.
14. The method of claim 13, wherein the vitamin E compound
comprises one or more of alpha-tocopherol, beta-tocopherol,
delta-tocopherol, gamma-tocopherol, alpha-tocotrienol,
beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol,
alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol
acetate, delta-tocopherol acetate, alpha-tocotrienol acetate,
beta-tocotrienol acetate, delta-tocotrienol acetate,
gamma-tocotrienol acetate, alpha-tocopherol succinate,
beta-tocopherol succinate, gamma-tocopherol succinate,
delta-tocopherol succinate, alpha-tocotrienol succinate,
beta-tocotrienol succinate, delta-tocotrienol succinate,
gamma-tocotrienol succinate, vitamin E TPGS, mixed tocopherols,
derivatives, analogs and pharmaceutically acceptable salts
thereof.
15. The method of claim 13, wherein the bio-absorbable carrier
component comprises a naturally occurring oil, fish oil fatty
acids, fatty acid esters, free fatty acids or a combination
thereof.
16. The method of claim 15, wherein the naturally occurring oil
comprises fish oil.
17. The method of claim 13, wherein the bio-absorbable carrier
component is modified from its naturally occurring state to one of
increased viscosity in the form of a cross-linked gel.
18. The method of claim 17, wherein the modification of the
bio-absorbable carrier component from its naturally occurring state
to the state of increased viscosity occurs prior to the formation
of the coating for the device.
19. The method of claim 15, wherein the fish oil fatty acids
comprise one or more of arachidic acid, gadoleic acid, arachidonic
acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or
derivatives, analogs and pharmaceutically acceptable salts
thereof.
20. The method of claim 15, wherein the free fatty acids comprise
one or more of butyric acid, caproic acid, caprylic acid, capric
acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid,
stearic acid, oleic acid, vaccenic acid, linoleic acid,
alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic
acid, lignoceric acid, analogs and pharmaceutically acceptable
salts thereof.
21. The method of claim 13, wherein the therapeutic agent comprises
an antioxidant, an anti-inflammatory, and anti-coagulant, a drug to
alter lipid metabolism, an anti-proliferative, an anti-neoplastic,
an anti-fibrotic, an immunosuppressive, a tissue growth stimulant,
a functional protein/factor delivery agent, an anti-infective
agent, an imaging agent, an anesthetic, a chemotherapeutic agent, a
tissue absorption enhancer, an anti-adhesion agent, a germicide, an
antiseptic, a proteoglycan, a GAG, a gene or polynucleotide naked
or in association with a delivery agent, an analgesic,
anti-migratory agents, pro-healing agents, ECM/protein production
inhibitors, a polysaccharide (heparin), or a combination
thereof.
22. The method of claim 13, wherein the therapeutic agent comprises
one or more of rapamycin, melatonin, paclitaxel, cerivastatin,
cilostazol, fluvastatin, lovastatin, pravastatin or derivatives,
prodrugs, analogs and pharmaceutically acceptable salts
thereof.
23. The method of claim 13, wherein the solvent comprises comprises
C.sub.2-C.sub.6 alkanols, 2-ethoxyethanol, ethanol, isopropanol,
butanol, benzyl alcohol, ethylene glycol, propylene glycol,
butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, 2-pyrrolidone, 2-piperidone,
2-caprolactam, N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; ethyl acetate, methyl acetate, butyl acetate,
ethylene glycol diethyl ether, ethylene glycol dimethyl ether,
propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactorne and isomers thereof, .beta.-butyrolactone
and isomers thereof, water, dimethylsulfoxide, benzyl benzoate,
ethyl lactate, acetone, methylethyl ketone, dimethylsolfone,
tetrahydrofuran, decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane,
or a combination thereof.
24. The method of claim 13, wherein the first mixture and the
second mixture can be created independently and interchangeably
first, second or substantially simultaneously.
25. The method of claim 13, wherein the bio-absorbable carrier
component further comprises a compatibilizer, a preservative or a
combination thereof.
26. A coating for a medical device comprising an amount of one or
more therapeutic agents dissolved in a bio-absorbable carrier
component and a vitamin E compound.
27. The coating of claim 26, wherein the vitamin E compound
comprises one or more of alpha-tocopherol, beta-tocopherol,
delta-tocopherol, gamma-tocopherol, alpha-tocotrienol,
beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol,
alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol
acetate, delta-tocopherol acetate, alpha-tocotrienol acetate,
beta-tocotrienol acetate, delta-tocotrienol acetate,
gamma-tocotrienol acetate, alpha-tocopherol succinate,
beta-tocopherol succinate, gamma-tocopherol succinate,
delta-tocopherol succinate, alpha-tocotrienol succinate,
beta-tocotrienol succinate, delta-tocotrienol succinate,
gamma-tocotrienol succinate, vitamin E TPGS, mixed tocopherols,
derivatives, analogs and pharmaceutically acceptable salts
thereof.
28. The coating of claim 26, wherein the bio-absorbable carrier
component comprises a naturally occurring oil, fish oil fatty
acids, fatty acid esters, free fatty acids or a combination
thereof.
29. The coating of claim 28, wherein the naturally occurring oil
comprises fish oil.
30. The coating of claim 26, wherein the bio-absorbable carrier
component is modified from its naturally occurring state to one of
increased viscosity in the form of a cross-linked gel.
31. The coating of claim 30, wherein the modification of the
bio-absorbable carrier component from its naturally occurring state
to the state of increased viscosity occurs prior to the formation
of the coating for the device.
32. The coating of claim 28, wherein the fish oil fatty acids
comprise one or more of arachidic acid, gadoleic acid, arachidonic
acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or
derivatives, analogs and pharmaceutically acceptable salts
thereof.
33. The coating of claim 28, wherein the free fatty acids comprise
one or more of butyric acid, caproic acid, caprylic acid, capric
acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid,
stearic acid, oleic acid, vaccenic acid, linoleic acid,
alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic
acid, lignoceric acid, analogs and pharmaceutically acceptable
salts thereof.
34. The coating of claim 26, wherein the therapeutic agent
comprises one or more of an antioxidant, an anti-inflammatory, and
anti-coagulant, a drug to alter lipid metabolism, an
anti-proliferative, an anti-neoplastic, an anti-fibrotic, an
immunosuppressive, a tissue growth stimulant, a functional
protein/factor delivery agent, an anti-infective agent, an imaging
agent, an anesthetic, a chemotherapeutic agent, a tissue absorption
enhancer, an anti-adhesion agent, a germicide, an antiseptic, a
proteoglycan, a GAG, a gene or polynucleotide naked or in
association with a delivery agent, an analgesic, anti-migratory
agents, pro-healing agents, ECM/protein production inhibitors, a
polysaccharide (heparin), or derivatives, prodrugs, analogs and
pharmaceutically acceptable salts thereof.
35. The coating of claim 26, wherein the therapeutic agent
comprises one or more of rapamycin, melatonin, paclitaxel,
cerivastatin, cilostazol, fluvastatin, lovastatin, pravastatin or
derivatives, prodrugs, analogs and pharmaceutically acceptable
salts thereof.
36. The coating of claim 26, wherein the coating further comprises
a compatibilizer, a preservative or a combination thereof.
37. The coating of claim 26, wherein the vitamin E compound and the
bio-absorbable carrier component are present in about 70% of the
vitamin E compound and about 30% of the bio-absorbable carrier
component.
38. The coating of claim 37, wherein the bio-absorbable carrier
component comprises fish oil.
39. The coating of claim 37, wherein the bio-absorbable carrier
component is modified from its naturally occurring state to one of
increased viscosity in the form of a cross-linked gel.
40. The coating of claim 26, wherein the vitamin E compound and the
bio-absorbable carrier component are present in about 50% of the
vitamin E compound and about 50% of bio-absorbable carrier
component.
41. The coating of claim 40, wherein the bio-absorbable carrier
component comprises fish oil in combination with a free fatty
acid.
42. The coating of claim 41, wherein the free fatty acid is oleic
acid.
43. The coating of claim 26, wherein the coating is
non-polymeric.
44. The coating of claim 26, wherein the coating inhibits
restenosis.
45. The coating of claim 26, wherein the coating inhibits
neointimal growth.
46. The coating of claim 26, wherein the coating promotes
endothelialization.
47. A method of making a coated medical device comprising the steps
of: providing the medical device; and coating the medical device;
wherein the coating comprises an amount of one or more therapeutic
agents dissolved in a solvent, a bio-absorbable carrier component
and a vitamin E compound such that the coated medical device is
implantable in a subject to effect delivery of the one or more
therapeutic agents to a subject.
48. The method of claim 47, wherein the coating further comprises a
compatibilizer, a preservative or a combination thereof.
49. The method of claim 47, wherein the vitamin E compound
comprises one or more of alpha-tocopherol, beta-tocopherol,
delta-tocopherol, gamma-tocopherol, alpha-tocotrienol,
beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol,
alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol
acetate, delta-tocopherol acetate, alpha-tocotrienol acetate,
beta-tocotrienol acetate, delta-tocotrienol acetate,
gamma-tocotrienol acetate, alpha-tocopherol succinate,
beta-tocopherol succinate, gamma-tocopherol succinate,
delta-tocopherol succinate, alpha-tocotrienol succinate,
beta-tocotrienol succinate, delta-tocotrienol succinate,
gamma-tocotrienol succinate, vitamin E TPGS, mixed tocopherols,
derivatives, analogs and pharmaceutically acceptable salts
thereof.
50. The method of claim 47, wherein the bio-absorbable carrier
component comprises a naturally occurring oil, fish oil fatty
acids, fatty acid esters, free fatty acids or a combination
thereof.
51. The method of claim 50, wherein the naturally occurring oil
comprises fish oil.
52. The method of claim 47, wherein the bio-absorbable carrier
component is modified from its naturally occurring state to one of
increased viscosity in the form of a cross-linked gel.
53. The method of claim 52, wherein the modification of the
bio-absorbable carrier component from its naturally occurring state
to the state of increased viscosity occurs prior to the formation
of the coating for the device.
54. The method of claim 50, wherein the fish oil fatty acids
comprise one or more of arachidic acid, gadoleic acid, arachidonic
acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or
derivatives, analogs and pharmaceutically acceptable salts
thereof.
55. The method of claim 50, wherein the free fatty acids comprise
one or more of butyric acid, caproic acid, caprylic acid, capric
acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid,
stearic acid, oleic acid, vaccenic acid, linoleic acid,
alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic
acid, lignoceric acid, analogs and pharmaceutically acceptable
salts thereof.
56. The method of claim 47, wherein the therapeutic agent comprises
one or more of an antioxidant, an anti-inflammatory, and
anti-coagulant, a drug to alter lipid metabolism, an
anti-proliferative, an anti-neoplastic, an anti-fibrotic, an
immunosuppressive, a tissue growth stimulant, a functional
protein/factor delivery agent, an anti-infective agent, an imaging
agent, an anesthetic, a chemotherapeutic agent, a tissue absorption
enhancer, an anti-adhesion agent, a germicide, an antiseptic, a
proteoglycan, a GAG, a gene or polynucleotide naked or in
association with a delivery agent, an analgesic, anti-migratory
agents, pro-healing agents, ECM/protein production inhibitors, a
polysaccharide (heparin), or derivatives, prodrugs, analogs and
pharmaceutically acceptable salts thereof.
57. The method of claim 47, wherein the therapeutic agent comprises
one or more of rapamycin, melatonin, paclitaxel, cerivastatin,
cilostazol, fluvastatin, lovastatin, pravastatin or derivatives,
prodrugs, analogs and pharmaceutically acceptable salts
thereof.
58. The method of claim 47, wherein the solvent comprises
C.sub.2-C.sub.6 alkanols, 2-ethoxyethanol, ethanol, isopropanol,
butanol, benzyl alcohol, ethylene glycol, propylene glycol,
butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, 2-pyrrolidone, 2-piperidone,
2-caprolactam, N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; ethyl acetate, methyl acetate, butyl acetate,
ethylene glycol diethyl ether, ethylene glycol dimethyl ether,
propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactorne and isomers thereof, .beta.-butyrolactone
and isomers thereof; water, dimethylsulfoxide, benzyl benzoate,
ethyl lactate, acetone, methylethyl ketone, dimethylsolfone,
tetrahydrofuran, decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane,
or a combination thereof.
59. The method of claim 47, wherein the coating inhibits
restenosis.
60. The method of claim 47, wherein the coating inhibits neointimal
growth.
61. The method of claim 47, wherein the coating promotes
endothelialization.
62. The method of claim 47, wherein the coating is
non-polymeric.
63. The method of claim 47, wherein the medical device comprises a
stent.
64. The method of claim 63, wherein the stent is formed of a
substance selected from the group consisting of stainless steel,
Nitinol alloy, nickel alloy, titanium alloy, cobalt-chromium alloy,
tantalum, magnesium, ceramics, metals, plastics and polymers.
65. The method of claim 47, further comprising providing a
pre-treatment between the medical device and the coating, wherein
the pre-treatment improves consistency and conformability and
enhances the adhesion of the coating.
66. The method of claim 65, wherein the pre-treatment is
bio-absorbable.
67. The method of claim 65, wherein the pre-treatment comprises at
least one of a bio-absorbable carrier component.
68. The method of claim 67, wherein the pre-treatment comprises
fish oil.
69. The method of claim 65, wherein the pre-treatment comprises a
therapeutic agent.
70. The method of claim 67, wherein the pre-treatment is modified
from its naturally occurring state to one of increased viscosity in
the form of a cross-linked gel.
71. The method of claim 47, further comprising preparing the
coating prior to application to the medical device, the method
comprising the steps of: (a) identifying said therapeutic agent and
an amount thereof to be dissolved; (b) selecting a solvent based on
the identified therapeutic agent; (c) dissolving the identified
amount of the therapeutic agent in said solvent to form a first
mixture; (d) determining a ratio of the vitamin E compound and the
bio-absorbable carrier component; (e) mixing the vitamin E compound
and the bio-absorbable carrier component to form a second mixture;
and (f) combining the first mixture with the second mixture to form
a homogeneous solution.
72. The method of claim 71, further comprising the step of removing
the solvent after applying the coating to the medical device.
73. The method of claim 71, wherein the first mixture and the
second mixture can be created independently and interchangeably
first, second, or substantially simultaneously.
74. The method of claim 47, wherein applying the coating comprises
at least one of dipping the medical device in the coating, spraying
the coating on the medical device, painting the coating on the
medical device, wiping the coating on the medical device, printing
the coating on the device, applying the coating with an applicator
and electrostatically applying the coating to the medical
device.
75. The method of claim 47, further comprising curing the coating
on the medical device.
76. The method of claim 74, wherein curing comprises applying at
least one of heat, UV light, a reactive oil, a reactive gas, a
plasma treatment, or pressure in combination with a reactive
gas.
77. The method of claim 47, further comprising sterilizing the
coating and the medical device.
78. The method of claim 77, wherein sterilizing comprises
sterilizing using at least one of ethylene oxide, gamma radiation,
e-beam, steam, gas plasma, and vaporized hydrogen peroxide
(VHP).
79. A coated medical device comprising: a coating having an amount
of one or more therapeutic agents, a bio-compatible carrier
component and a vitamin E compound such that the medical device is
implantable in a subject to effect delivery of the one or more
therapeutic agents to said subject.
80. The device of claim 79, wherein the coating further comprises a
compatibilizer, a preservative or a combination thereof.
81. The device of claim 79, wherein the vitamin E compound
comprises one or more of alpha-tocopherol, beta-tocopherol,
delta-tocopherol, gamma-tocopherol, alpha-tocotrienol,
beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol,
alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol
acetate, delta-tocopherol acetate, alpha-tocotrienol acetate,
beta-tocotrienol acetate, delta-tocotrienol acetate,
gamma-tocotrienol acetate, alpha-tocopherol succinate,
beta-tocopherol succinate, gamma-tocopherol succinate,
delta-tocopherol succinate, alpha-tocotrienol succinate,
beta-tocotrienol succinate, delta-tocotrienol succinate,
gamma-tocotrienol succinate, vitamin E TGPS, mixed tocopherols,
derivatives, analogs and pharmaceutically acceptable salts
thereof.
82. The device of claim 79, wherein the bio-absorbable carrier
component comprises a naturally occurring oil, fish oil fatty
acids, fatty acid esters, free fatty acids or a combination
thereof.
83. The device of claim 82, wherein the naturally occurring oil
comprises fish oil.
84. The device of claim 79, wherein the bio-absorbable carrier
component is modified from its naturally occurring state to one of
increased viscosity in the form of a cross-linked gel.
85. The device of claim 84, wherein the modification of the
bio-absorbable carrier component from its naturally occurring state
to the state of increased viscosity occurs prior to the formation
of the coating for the device.
86. The device of claim 82, wherein the fish oil fatty acids
comprise one or more of arachidic acid, gadoleic acid, arachidonic
acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or
derivatives, analogs and pharmaceutically acceptable salts
thereof.
87. The device of claim 82, wherein the free fatty acids comprise
one or more of butyric acid, caproic acid, caprylic acid, capric
acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid,
stearic acid, oleic acid, vaccenic acid, linoleic acid,
alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic
acid, lignoceric acid, analogs and pharmaceutically acceptable
salts thereof.
88. The device of claim 79, wherein the therapeutic agent comprises
one or more of an antioxidant, an anti-inflammatory, and
anti-coagulant, a drug to alter lipid metabolism, an
anti-proliferative, an anti-neoplastic, an anti-fibrotic, an
immunosuppressive, a tissue growth stimulant, a functional
protein/factor delivery agent, an anti-infective agent, an imaging
agent, an anesthetic, a chemotherapeutic agent, a tissue absorption
enhancer, an anti-adhesion agent, a germicide, an antiseptic, a
proteoglycan, a GAG, a gene or polynucleotide naked or in
association with a delivery agent, an analgesic, anti-migratory
agents, pro-healing agents, ECM/protein production inhibitors, a
polysaccharide (heparin), or derivatives, prodrugs, analogs and
pharmaceutically acceptable salts thereof.
89. The device of claim 79, wherein the therapeutic agent comprises
one or more of rapamycin, melatonin, paclitaxel, cerivastatin,
cilostazol, fluvastatin, lovastatin, pravastatin or derivatives,
prodrugs, analogs and pharmaceutically acceptable salts
thereof.
90. The device of claim 79, wherein the coating inhibits
restenosis.
91. The device of claim 79, wherein the coating is
non-polymeric.
92. The device of claim 79, wherein the coating inhibits
neo-intimal growth.
93. The device of claim 79, wherein the coating promotes
endothelialization.
94. The device of claim 79, wherein the medical device comprises a
stent.
95. The device of claim 94, wherein the stent is formed of a
substance selected from the group consisting of stainless steel,
Nitinol alloy, nickel alloy, titanium alloy, cobalt-chromium alloy,
tantalum, magnesium, ceramics, metals, plastics and polymers.
Description
RELATED APPLICATIONS
[0001] This application claims priority to, and the benefit of,
co-pending U.S. Provisional Application No. 60/613,745, Sep. 28,
2004, for all subject matter common to both applications. The
disclosure of said provisional application is hereby incorporated
herein by reference in its entirety. This application also relates
to co-pending U.S. patent application Ser. No. 11/______ (Attorney
Docket No. ATA-426), filed concurrently with this application on
Sep. 28, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to coatings and preparations
of coatings for medical devices for the delivery of one or more
biologically active agents, and more particularly, the present
invention relates to coatings capable of containing one or more
biologically active components.
BACKGROUND OF THE INVENTION
[0003] Percutaneous transluminal coronary angioplasty (PTCA), also
known as balloon angioplasty, is a technique widely used for
treating intravascular diseases, such as atherosclerosis, and other
vascular occlusions. PTCA involves the use of a balloon-tipped
catheter inserted directly into the arteries and vessels of a
subject until the occluded site is reached, whereupon the balloon
is expanded. The inflation of the balloon forces the lumen open,
allowing blood flow to be restored. However, while PTCA is
effective in the short-term, approximately 30-50% of all cases of
balloon angioplasty alone require follow-up angioplasty due to
restenosis, or re-narrowing of the blood vessel or artery.
[0004] Restenosis is caused by three pathogenic factors: elastic
recoil of the artery, late-stage remodeling of the artery and
hyperproliferation of the smooth muscle cells of the artery. This
hyperproliferation, called neointimal hyperplasia, occurs as a
result of the body's natural response to the arterial injury caused
by the PTCA procedure. Upon the deployment of the balloon catheter,
small tears develop in the artery wall triggering an inflammatory
response. Growth factors and cytokines produced during the
inflammatory response activate smooth muscle cell proliferation and
migration, which can form an obstructing neointima, which, in turn,
leads to decreased blood flow through the artery.
[0005] Prevention of occlusive thrombus after PTCA can be
accomplished by the administration of oral high-dose, systematic
anti-platelet drug therapy in combination with aspirin. This course
of action has been shown to limit early complications after PTCA by
approximately 35%; however, serious bleeding complications and
other side effects can occur. Additionally, an orally administered
drug may not achieve the desired effect in the area of the body in
which it is needed. Furthermore, success by oral medication depends
entirely on patient compliance.
[0006] Currently, the only long term approach to preventing
restenosis is by utilizing a medical device, such as a stent, as an
arterial structural support. While deployment of a stent after PTCA
effectively eliminates elastic recoil and counteracts arterial
remodeling, in-stent restenosis is still a serious problem due to
neointimal hyperplasia. Introduction and presence of the stent
itself can create regions of trauma in the artery, causing the same
inflammatory response as the PTCA procedure.
[0007] Stent-based drug delivery has been developed in an attempt
to prevent in-stent restenosis. Local delivery of one or more
therapeutic agents by the use of a drug-eluting stent shows promise
as a solution to the problems of both early and late complications
due to the PTCA procedure. A number of therapeutic agents have been
studied for use with stents including anticoagulants (heparin,
hirudin), anti-platelet agents (abciximab), anti-inflammatory drugs
(dexamethasone), anti-migratory agents (batimastat) and
anti-proliferative agents (sirolimus, paclitaxel, actinomycin
D).
[0008] Typically, the drug-eluting stent is coated with a polymeric
material. The polymer may improve the quality of the stent by
strengthening it or by smoothing the surface of the stent to
minimize damage to the endothelium. In addition, the polymer may
serve as the component used to adhere the therapeutic agent to the
stent itself. Furthermore, the polymer may serve as the vehicle for
local drug delivery, for example, by serving as a drug depot and/or
degrading such that the drug is released to the desired area. There
are substantial concerns, however, regarding the lack of
bio-compatibility of polymer stent coatings. An assortment of both
biodegradable and non-biodegradable polymers have been shown to
induce an inflammatory response within the coronary artery,
including neointimal thickening (see, for example, van der Giessen,
et al. Circulation 1996; 94:1690-1697; De Schreerder, et al
Atherosclerosis 1995; 114:105-114, incorporated herein by reference
in their entirety).
[0009] There is a need, then, to produce a drug-eluting stent
without a polymeric coating. However, a coating is needed to
replace the functions performed by the polymer. For example, a
coating is needed to dissolve the therapeutic agent, as well as
serve as the element to adhere the therapeutic agent to the stent.
In addition, the coating would also be the vehicle for local
delivery for the therapeutic agent.
[0010] U.S. Patent Application Publication No. 20030191179 is
directed to a method of administration of paclitaxel formulated
with a vitamin E derivative. The composition for delivery of
paclitaxel comprises paclitaxel, a solvent, and a pharmaceutically
acceptable, water-miscible solubilizer which has the general
structure of R.sub.1COOR.sub.2, R.sup.1CONR.sub.2 and
R.sup.1COR.sub.2, wherein R.sub.1 is a hydrophobic C.sub.3-C.sub.50
alkane, alkene or alkyne, and R.sub.2 is a hydrophilic moiety. The
publication indicates that the solubilizer can be an esterified
fatty acid or alpha-tocopherol polyethylene glycol succinate, which
is a water-miscible derivative of alpha-tocopherol.
[0011] PCT Application Publication No. WO 99/25336 is directed to a
method for preventing restenosis in a patient by administering a
prophylactically effective amount a composition of a tocotrienol or
a mixture of tocotrienols. The publication is additionally directed
to a method for preventing restenosis in a patient undergoing
arterial angioplasty by coating the external surface of the
angioplastic balloon with a composition containing tocotrienols.
These compositions are prepared by combining one or more
tocotrienols with an acceptable carrier. Suitable carriers include
glycols, parabens, glycerin, alcohols, petrolatum oils and waxes.
The '336 patent application treats the tocotrienols as the
therapeutic agent for treating restenosis that is contained within
a carrier component.
[0012] U.S. Patent Application Publication No. 20040156879 is
directed to a method of manufacturing oxidation resistant medical
implants and, in particular, antioxidant-doped medical devices
containing cross-linked polymers. The method includes doping
consolidated polyethylene, such as ultra-high molecular weight
polyethylene (UHMWPE), with anti-oxidants before, during or after
crosslinking the consolidated polyethylene. The patent application
indicates that the doping of the consolidated polyethylene can be
carried out by diffusion of an antioxidant. Suitable antioxidants
include alpha- and delta-tocopherols; propyl, octyl, or dedocyl
galates; lactic, citric, and tartaric acids and their salts;
orthophosphates, tocopherol acetate and vitamin E. The doping
method involves soaking the consolidated UHMWPE in the antioxidant
or in a solution of the antioxidant when the antioxidant is
dissolved in ethanol. The '879 patent application calls for the use
of a consolidated polyethylene in the preparation of the described
medical devices.
[0013] U.S. Pat. No. 6,833,004 is directed to a stent with a
biologically and physiologically active substance stably loaded
onto the stent main body such that the biologically and
physiologically active substance does not decompose or degrade,
but, once implanted, the biologically and physiologically active
substance undergoes sustained release. The stent includes a main
body with a sustained release coating made up of two layers: a
layer containing the biologically and physiologically active
substance and a polymer layer formed on top of the biologically and
physiologically active substance layer. If the biologically and
physiologically active substance is unable to adhere to the wire
member constituting the stent main body, then the layer containing
the biologically and physiologically active substance can be
supplemented with an additional component which will impart
tackiness to the biologically and physiologically active substance.
For example, if the biologically and physiologically active
substance is a fat soluble substance, the additional component is a
low molecular weight higher fatty acid having a molecular weight of
up to 1000, such as a fish oil, a vegetable oil or a fat soluble
vitamin such as vitamin A or vitamin E. The medical device in the
'004 patent is treated with a polymeric layer after the application
of the biologically and physiologically active substance, with or
without the additional component.
[0014] U.S. Pat. No. 6,117,911 is directed to the use of compounds
and different therapies for the prevention of vascular and
non-vascular pathologies. The '911 patent discusses the possibility
of using many different types of delivery methods for a therapeutic
agent or agents to prevent various vascular and non-vascular
pathologies. One such approach is described as providing a method
of preventing or treating a mammal having, or at risk of
developing, atherosclerosis, including administering an amount of a
combination of aspirin or an aspirinate and at least one omega-3
fatty acid, wherein said amount of omega-3 fatty acid is effective
to maintain or increase the level of TGF-beta so as to provide a
synergistic effect with a therapeutic compound to inhibit or reduce
vessel lumen diameter diminution. As such, the patent discusses
some of the therapeutic benefits of primarily systemic
administration of omega-3 fatty acids, such as those found in fish
oil, to affect TGF-beta levels when a therapeutic agent is combined
with aspirin or aspirinate. That is, the dose or concentration of
omega-3-fatty acid required to increase the level of TGF-beta is
significantly greater, requiring long term systemic delivery.
[0015] U.S. Patent Application No. 20030077310 is directed to
coated stents, methods of making coated stents and methods of using
coated stents, wherein the coating contains unreacted HMG-CoA
reductase inhibitor in combination with a carrier. The carrier can
either be polymeric or non-polymeric. When the carrier is
non-polymeric, it can be a C6 to C18 fatty acid, a bio-compatible
wax, oil or gel, or a mixture of one or more of a wax, an oil, a
gel, and a fatty acid. The non-polymeric liquid carrier can also be
a hydrophobic liquid, such as a C4-C36 fatty acid, for example,
oleic or stearic acid, or an oil, such as peanut oil, cottonseed
oil, mineral oil, or other low molecular weight oils (C4-C36).
[0016] U.S. Pat. No. 6,610,035 is directed to an implantable
medical device with a bi-layer lubricious coating. The first layer
consists of a hydrophilic polymeric hydrogel layer which can swell
or dissolve upon exposure to an aqueous environment. The second
layer of the coating comprises a hydrophobic coating, which can be
silicone based or a naturally occurring composition including olive
oil, paraffin oil, corn oil, sesame oil, fish oil, and vegetable
oil. The medical devices described by the '035 patent are treated
with a hydrophilic polymer gel prior to the addition of a
hydrophilic coating.
[0017] U.S. Patent Application No. 20030083740 is directed to a
method of forming liquid coatings for medical devices made from
biodegradable materials in liquid, low melting solid or wax forms
which further degrade upon implantation without producing harmful
fragments. The liquid coatings additionally can contain
biologically active compounds which are released upon degredation
of the coatings after implantation. The carrier component of the
coating composition can be hydrophobic, bio-compatible and either
polymeric or non-polymeric. Suitable non-polymeric carrier
components comprise vitamin E or its derivatives, oleic acid,
stearic acid, mineral oil, peanut oil, or cottonseed oil, alone or
in combination.
[0018] U.S. Pat. No. 6,610,068 is directed to a catheter device
with a guide member lumen filled with a lubricious material. The
method of filling the guide member lumen with a lubricious material
eliminates the need for flushing the catheter device before and
during surgical procedures and provides a lubricant for easy
maneuvering of the catheter over the guide member. The '068 patent
indicates that the lubricious material can include both hydrophobic
and hydrophilic materials. Specifically, the hydrophobic materials
can include silicone based lubricants, glycerine, olive oil,
cottonseed oil, peanut oil, fish oil, vegetable oil, sesame oil,
and vitamin E. Vitamin E, if used, can also act as an antioxidant.
The antioxidant capability of vitamin E improves the long term
stability of the lubricious coating.
[0019] PCT Application Publication No. WO 02/100455 is directed to
ozonated medical devices and methods of using ozone to prevent
complications from indwelling medical devices. The application
discusses having the ozone in gel or liquid form to coat the
medical device. The ozone can be dissolved in olive oil, or other
types of oil, to form a gel containing ozone bubbles, and the gel
applied to the medical device as a coating. The application later
asserts a preference for the gel or other coating formulation to be
composed so that the ozone is released over time. However, there is
no indication in the application as to how a slow controlled
release of ozone can be affected. There is no enablement to a long
term controlled release of ozone from the olive oil gel, however,
there is mention of use of biocompatible polymers to form the
coating that holds and releases the ozone. Other drugs are also
suggested for combination with the ozone for delivery to a targeted
location. The application later describes different application
methods for the coating, including casting, spraying, painting,
dipping, sponging, atomizing, smearing, impregnating, and
spreading.
[0020] A paper entitled "Evaluation of the Biocompatibility and
Drug Delivery Capabilities of Biological Oil Based Stent Coatings",
by Shengqiao Li of the Katholieke Universiteit Leuven (incorporated
herein by reference in its entirety), discusses the use of
biological oils as a coating for delivering drugs after being
applied to stents. Three different coatings were discussed, a glue
coating (cod liver oil mixed with 100% ethanol at a 1:1 ratio), a
vitamin E coating (97% vitamin E oil solution mixed with 100%
ethanol at a 1:1 ratio), and a glue+vitamin E coating (cod liver
oil and 97% vitamin E oil solution mixed with 100% ethanol at a 1:1
ratio). Bare stents and polymer coated stents, along with stents
having each of the above coatings, were implanted into test
subjects, and analyzed over a four week period. At the end of the
period, it was observed that the bare stents and polymer coated
stents resulted in some minor inflammation of the tissue. The main
finding of the study was that the glue coatings have a good
biocompatibility with coronary arteries, and that the glue coating
does not affect the degree of inflammation, thrombosis, and
neointimal proliferation after endovascular stenting compared with
the conventional stenting approach. A further hypothesis asserted
was that the oil coating provided lubrication to the stent, thus
decreasing the injury to the vascular wall.
[0021] The study went on to analyze the drug loading capacity of
biological oil based stent coatings. Balloon mounted bare stents
were dip-coated in a biological oil solution with the maximal
solubilizable amount of different drugs (a separate drug for each
trial), and compared with polymer coated, drug loaded, stents.
According to the release rate curves, there was a clear indication
that drug release was fast in the first 24 hours with more than 20%
of the drug released, for the oil based coatings. The release rate
after the first 24 hours was much slower, and continued for a
period up to about six weeks.
[0022] Another aspect of the study looked at the efficacy of drug
loaded biological stents to decrease inflammation and neointimal
hyperplasia in a porcine coronary stent model. In this part of the
study, glue or modified glue (biological oil) coated stainless
steel stents were loaded with different drugs. The result was that
the characteristics of the particular drug loaded onto the stent
were the major factor to the reduction of restenosis, and the
biological oil did not have a major impact on either causing or
reducing inflammation.
[0023] A further comment indicated that in the studies comparison
was made between biological oil based drug loaded stents and bare
stents to find differences in inflammation, injury, and
hyperplasia. Inflammation, injury, and neointimal hyperplasia
resulted in in-stent area stenosis. Any anti-inflammation observed
was the result of the particular drug loaded on the stent,
regardless of biological oil, or polymer, coating.
[0024] A paper entitled "Addition of Cytochalasin D to a
Biocompatible Oil Stent Coating Inhibits Intimal Hyperplasia in a
Porcine Coronary Model" by Koen J. Salu, et al (Coronary Artery
Disease 2003; 14:545-555, incorporated herein by reference in its
entirety) discusses the use of a natural oil as a stent coating and
the efficacy of using a therapeutic agent combined with the natural
oil coating for the prevention of restenosis. The study first
performed a histopathological evaluation of eicosapentaenoic acid
oil coated stents compared with bare, uncoated stents. A series of
stents coated in eicosapentaenoic acid oil and bare stents were
implanted into test subjects and were analyzed after 5 days and
again after 4 weeks. In all cases, there was an identical tissue
response between the bare stents and the eicosapentaenoic acid oil
coated stents. It was also found that the oil-coating did not
elicit a hyperproliferative or inflammatory response. The study
proposed that the lack of inflammation or hyperproliferation of the
coated stent was due to the properties of eicosapentaenoic acid,
which exerts anti-inflammatory effects and inhibit vascular smooth
muscle cell proliferation in vitro.
[0025] Another aspect of the study compared eicosapentaenoic acid
oil coated stents with stents coated with a therapeutic agent
solubilized in eicosapentaenoic acid oil. The therapeutic agent
examined was cytochalasin D, a lipophilic, cell-permeable fungal
metabolite that inhibits the polymerization of actin into
microfilaments. The results of this aspect of the study indicated
that the inclusion of the therapeutic agent led to 39% less intimal
hyperplasia and 38% less area stenosis when compared to the control
group.
[0026] PCT Application Publication No. WO 03/039612 is directed to
an intraluminal device with a coating containing a therapeutic
agent. The publication describes coating an intraluminal device
with a therapeutic agent comprised of a matrix that sticks to the
intraluminal device. The matrix is formed of a bio-compatible oil
or fat, and can further include alpha-tocopherol. The publication
further indicates that an oil or fat adheres sufficiently strongly
to the intraluminal device so that most of the coating remains on
the intraluminal device when it is inserted in a body lumen. The
publication further states that the oil or fat slows the release of
the therapeutic agent, and also acts as an anti-inflammatory and a
lubricant. The publication goes on to indicate that the oil or fat
can be chemically modified, such as by the process of
hydrogenation, to increase their melting point. Alternatively,
synthetic oils could be manufactured as well. The oil or fat is
further noted to contain fatty acids.
[0027] The '612 publication provides additional detail concerning
the preferred oil or fat. It states that a lower melting point is
preferable, and a melting point of 0.degree. C. related to the oils
utilized in experiments. The lower melting point provides a fat in
the form of an oil rather than a wax or solid. It is further stated
that oils at room temperature can be hydrogenated to provide a more
stable coating and an increased melting point, or the oils can be
mixed with a solvent such as ethanol. Preferences were discussed
for the use of oils rather than waxes or solids, and the operations
performed on the fat or oil as described can be detrimental to the
therapeutic characteristics of some oils, especially
polyunsaturated oils containing omega-3 fatty acids.
[0028] The above-described references do refer to the use of oils
and fats as a drug delivery platform. There is indication that the
coatings described in the above references are bio-absorbable,
while also providing the release of biologically active components,
such as drugs. Additionally, many of the above-described patents
and patent applications require the use of a polymeric material,
which serves as either a base upon which a drug coating is applied,
a substance mixed in with the drug to form the coating, or a top
coating applied over a previously applied drug coating to control
the release of the drug. However, there is no realization of the
difficulty of using an oil having its own therapeutic
characteristics for the solubilization and release of a therapeutic
agent.
[0029] U.S. Pat. No. 6,761,903 is directed to pharmaceutical
compositions capable of solubilizing therapeutically effective
amounts of therapeutic agents. The patent discusses pharmaceutical
compositions having a carrier and a therapeutic agent, as well as
pharmaceutical composition comprising an oil soluble vitamin and a
carrier. The carrier for both pharmaceutical compositions includes
a triglyceride in combination with at least two surfactants,
wherein one of the surfactants is hydrophilic. Suitable
triglycerides include a number of oils, including fish oil, while
suitable surfactants include a variety of fatty acid ester
derivatives and polymers, transesterified products of oils and
alcohols, mono- and diglycerides, sterols, sterol derivatives,
polymer glycol alkyl ethers and alkyl phenols, sugar esters,
POE-POP block co-polymers, and ionic surfactants, such as the salts
of fatty acids and bile salts. The '903 patent further discusses
the use of oil-soluble vitamins for improving the solubility and
stability of therapeutic agents in the pharmaceutical compositions,
and that there may be improved absorption or permeability of the
therapeutic agents across an absorption barrier, such as a mucosal
membrane.
[0030] The above-referenced patent does describe the use of an oil
based pharmaceutical composition capable of solubilizing
therapeutic agents. However, the '903 patent always requires the
use of a hydrophilic surfactant and does not indicate the use of
the pharmaceutical compositions described for medical devices.
[0031] What is desired is a bio-absorbable delivery agent having
non-inflammatory and other therapeutically advantageous
characteristics that is able to dissolve at least one therapeutic
agent for the delivery of that therapeutic agent to body
tissue.
SUMMARY OF THE INVENTION
[0032] There is a need for a bio-absorbable coating for application
to an implantable medical device for therapeutic purposes. The
present invention is directed toward further solutions to address
this need.
[0033] In accordance with one embodiment of the present invention,
a method is provided for dissolving an amount of one or more
therapeutic agents in a bio-absorbable carrier component and a
vitamin E compound. Accordingly, the steps of the method for
dissolving an amount of one or more therapeutic agents can include:
(a) identifying said therapeutic agent and an amount thereof to be
dissolved; (b) selecting a solvent based on the identified
therapeutic agent; (c) dissolving the identified amount of the
therapeutic agent in said solvent to form a first mixture; (d)
determining a ratio of the vitamin E compound and the
bio-absorbable carrier component; (e) mixing the vitamin E compound
and the bio-absorbable carrier component to form a second mixture;
(f) combining the first mixture with the second mixture to form a
homogeneous solution; and (g) removing the solvent from the
homogeneous solution such that the therapeutic agent remains
dissolved in the bio-absorbable carrier component and the vitamin
E.
[0034] In accordance with one aspect of the present invention, a
method is provided for dissolving an amount of one or more
therapeutic agents in a bio-absorbable carrier component and a
vitamin E compound. Accordingly, the steps of the method for
dissolving an amount of one or more therapeutic agents can include:
(a) identifying said therapeutic agent and an amount thereof to be
dissolved; (b) determining a ratio of the vitamin E compound and
the bio-absorbable carrier component; and (c) dissolving the
identified amount of the therapeutic agent in the vitamin E
compound and the bio-absorbable carrier component to form a
homogenous mixture.
[0035] In accordance with one embodiment of the present invention,
a method is provided for preparing a coating for a medical device.
The coating can include an amount of one or more therapeutic agents
dissolved in a bio-absorbable carrier component and a vitamin E
compound. Accordingly, the steps of the method for preparing a
coating for a medical device can include: (a) identifying said
therapeutic agent and an amount thereof to be dissolved; (b)
selecting a solvent based on the identified therapeutic agent; (c)
dissolving the identified amount of the therapeutic agent in said
solvent to form a first mixture; (d) determining a ratio of the
vitamin E compound and the bio-absorbable carrier component; (e)
mixing the vitamin E compound and the bio-absorbable carrier
component to form a second mixture; (f) combining the first mixture
with the second mixture to form a homogeneous solution; and (g)
removing the solvent from the homogeneous solution such that the
therapeutic agent remains dissolved in the bio-absorbable carrier
component and the vitamin E.
[0036] In accordance with one aspect of the present invention, a
method is provided for preparing a coating for a medical device.
The coating can include an amount of one or more therapeutic agents
dissolved in a bio-absorbable carrier component and a vitamin E
compound. Accordingly, the steps of the method for preparing a
coating for a medical device can include: (a) identifying said
therapeutic agent and an amount thereof to be dissolved; (b)
determining a ratio of the vitamin E compound and the
bio-absorbable carrier component; and (c) dissolving the identified
amount of the therapeutic agent in the vitamin E compound and the
bio-absorbable carrier component to form a homogenous mixture.
[0037] In accordance with one aspect of the present invention, a
method of making a coated medical device is provided. Accordingly,
the steps of the method include providing the medical device and
coating the medical device. In one embodiment, the coating includes
an amount of one or more therapeutic agents dissolved in a solvent,
a bio-absorbable carrier component and a vitamin E compound such
that the coated medical device is implantable in a subject to
effect delivery of the one or more therapeutic agents to a subject.
Accordingly, the solvent can be a solvent compatible with the
coating, therapeutic agent, and intended use. In one embodiment,
the solvent can be ethanol, N-methyl-pyrrolidone or a combination
thereof. The coating may further include a compatibilizer, a
preservative or both. The method of making a coated medical device
can further involve preparing the coating prior to application to
the medical device. The steps of preparing the coating prior to the
application to the medical device include: (a) identifying said
therapeutic agent and an amount thereof to be dissolved; (b)
selecting a solvent based on the identified therapeutic agent; (c)
dissolving the identified amount of the therapeutic agent in said
solvent to form a first mixture; (d) determining a ratio of the
vitamin E compound and the bio-absorbable carrier component; (e)
mixing the vitamin E compound and the bio-absorbable carrier
component to form a second mixture; and (f) combining the first
mixture with the second mixture to form a homogeneous solution. As
above, the solvent can be a solvent compatible with the coating,
therapeutic agent, and intended use. In one embodiment, the solvent
can be ethanol, N-methylpyrrolidone or a combination thereof. In
one embodiment, a further step includes removing the solvent after
application of the coating to the medical device.
[0038] In accordance with one aspect of the present invention, a
method of making a coated medical device is provided. Accordingly,
the steps of the method include providing the medical device and
coating the medical device. In one embodiment, the coating includes
one or more therapeutic agents dissolved in a bio-absorbable
carrier component and a vitamin E compound. The method of making a
coated medical device can further involve preparing the coating
prior to application to the medical device. The steps of preparing
the coating prior to the application to the medical device include:
(a) identifying said therapeutic agent and an amount thereof to be
dissolved; (b) determining a ratio of the vitamin E compound and
the bio-absorbable carrier component; and (c) dissolving the
identified amount of the therapeutic agent in the vitamin E
compound and the bio-absorbable carrier component to form a
homogenous mixture.
[0039] In accordance with one aspect of the present invention, the
method of making a coated medical device further includes providing
a pre-treatment between the medical device and the coating. The
pre-treatment can improve consistency and conformability and
enhance the adhesion of the coating to the medical device. In one
embodiment, wherein the pre-treatment is bio-absorbable.
Accordingly, the pre-treatment can include at least one of a
bio-absorbable carrier component, for example, fish oil. The
bio-absorbable carrier component may be modified from its naturally
occurring state to one of increased viscosity in the form of a
cross-linked gel.
[0040] In accordance with one embodiment of the present invention,
a coated medical device is provided. The coated medical device
includes a coating having an amount of one or more therapeutic
agents, a bio-compatible carrier component and a vitamin E compound
such that the medical device is implantable in a subject to effect
delivery of the one or more therapeutic agents to said subject.
Accordingly, the medical device is implantable in a subject to
effect delivery of the one or more therapeutic agents to the
subject. The coated medical device may further include a
compatabilizer, a preservative or a combination thereof. In
accordance with another aspect of the present invention, the coated
medical device further includes a solvent, wherein the solvent is
selected based on the therapeutic agent. The solvent can be a
solvent compatible with the coating, therapeutic agent, and
intended use. In one embodiment, the solvent can be ethanol,
N-methyl-pyrrolidone or a combination thereof.
[0041] The coated medical device can include a pre-treatment
provided on the medical device having a bio-absorbable carrier
component and a coating disposed on top of the pre-treatment. The
pre-treatment can improve consistency and conformability and can
enhance the adhesion of the coating. In another embodiment, the
pre-treatment may comprise plasma, parylene, a hydrophobic polymer,
or a hydrophilic polymer. The coating disposed on top of the
pre-treatment can further include a second bio-absorbable carrier
component, a vitamin E compound and an amount of one or more
therapeutic agents. In various embodiments, the bio-absorbable
carrier component includes a naturally occurring oil, a fish oil
fatty acid, a free fatty acid, a fatty acid ester, a mono-, a di-
or a triglyceride, an oxidized triglyceride, a partially hydrolyzed
triglyceride or a combination thereof. In various embodiments, the
coated medical device is implantable in a subject to effect
delivery of one or more therapeutic agents to the subject. In
accordance with one aspect of the present invention, the coated
medical device further includes a compatabilizer, a preservative or
a combination thereof. In accordance with one aspect of the present
invention, the coated medical device further includes a solvent. In
various embodiments, the solvent is selected based on the
therapeutic agent. In various embodiments, the solvent can be a
solvent compatible with the coating, therapeutic agent, and
intended use. In one embodiment, the solvent can be ethanol,
N-methyl-pyrrolidone or a combination thereof.
[0042] In accordance with one aspect of the present invention, the
vitamin E compound can include one or more of alpha-tocopherol,
beta-tocopherol, delta-tocopherol, gamma-tocopherol,
alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol,
gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol
acetate, gamma-tocopherol acetate, delta-tocopherol acetate,
alpha-tocotrienol acetate, beta-tocotrienol acetate,
delta-tocotrienol acetate, gamma-tocotrienol acetate,
alpha-tocopherol succinate, beta-tocopherol succinate,
gamma-tocopherol succinate, delta-tocopherol succinate,
alpha-tocotrienol succinate, beta-tocotrienol succinate,
delta-tocotrienol succinate, gamma-tocotrienol succinate, vitamin E
TPGS, mixed tocopherols, derivatives, analogs and pharmaceutically
acceptable salts thereof. It should be noted that other
antioxidants can be used to fulfill the role of vitamin E in this
coating.
[0043] In accordance with one aspect of the present invention, the
bio-absorbable carrier component contains lipids. The
bio-absorbable carrier component can be a naturally occurring oil,
a fish oil fatty acid, a free fatty acid, a mono-, di- or
triglyceride, a fatty acid ester, an oxidized triglyceride, a
partially hydrolyzed triglyceride or a combination thereof. In one
embodiment, the bio-absorbable carrier component can be fish oil.
The bio-absorbable carrier component can be modified from its
naturally occurring state to a state of increased viscosity in the
form of a cross-linked gel. The bio-absorbable carrier component
can contain omega-3 fatty acids. In accordance with further aspects
of the present invention, the cross-linked gel is formed of an oil
or oil composition that is at least partially cured. The
cross-linked gel can be a biological oil that is at least partially
cured, including fish oil or other oils, including those oils
containing lipids and/or omega-3 fatty acids.
[0044] It should be noted that the term cross-linked gel, as
utilized herein with reference to the present invention, refers to
a gel that is non-polymeric and is derived from an oil composition
comprising molecules covalently cross-linked into a
three-dimensional network by one or more of ester, ether, peroxide,
and carbon-carbon bonds in a substantially random configuration. In
various preferred embodiments, the oil composition comprises a
fatty acid molecule, a glyceride, and combinations thereof.
[0045] Accordingly, the fish oil fatty acids includes one or more
of arachidic acid, gadoleic acid, arachidonic acid,
eicosapentaenoic acid, docosahexaenoic acid or derivatives, analogs
and pharmaceutically acceptable salts thereof. In various
embodiments, the free fatty acids include one or more of butyric
acid, caproic acid, caprylic acid, capric acid, lauric acid,
myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic
acid, vaccenic acid, linoleic acid, alpha-linolenic acid,
gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid,
analogs and pharmaceutically acceptable salts thereof.
[0046] In accordance with one aspect of the present invention, the
therapeutic agent can include an antioxidant, an anti-inflammatory,
an anti-coagulant, a drug to alter lipid metabolism, an
anti-proliferative, an anti-neoplastic, an anti-fibrotic, an
immunosuppressive, a tissue growth stimulant, a functional
protein/factor delivery agent, an anti-infective agent, an imaging
agent, an anesthetic, a chemotherapeutic agent, a tissue absorption
enhancer, an anti-adhesion agent, a germicide, an antiseptic, a
proteoglycan, a GAG, a gene or polynucleotide delivery agent, an
analgesic, a polysaccharide (heparin), or a combination thereof. In
various embodiments, the therapeutic agent can include one or more
of rapamycin, melatonin, paclitaxel, a protein kinase C inhibitor,
cerivastatin, cilostazol, fluvastatin, lovastatin, pravastatin or
derivatives, prodrugs, analogs and pharmaceutically acceptable
salts thereof.
[0047] In accordance with one aspect of the present invention, the
coating can contain about 70% of a vitamin E compound and about 30%
of a bio-absorbable carrier component, for example, fish oil. In
one embodiment, bio-absorbable carrier component can be modified
from its naturally occurring state to a state of increased
viscosity in the form of a cross-linked gel. In another aspect of
the present invention, the coating can contain about 50% of a
vitamin E compound and about 50% of a bio-absorbable carrier
component. Accordingly, the bio-absorbable carrier component can
comprise a free fatty acid, for example, oleic acid.
[0048] In accordance with one aspect of the present invention, the
coating is non-polymeric. In accordance with one aspect of the
present invention the coating can inhibit restenosis and neointimal
growth. In accordance with one aspect of the present invention, the
coating can promote endothelialization. In accordance with one
aspect of the present invention, the coating is bio-absorbable.
[0049] In accordance with one aspect of the present invention, the
medical device can be a stent. In various embodiments, the stent is
formed of a substance selected from the group consisting of
stainless steel, Nitinol alloy, nickel alloy, titanium alloy,
cobalt-chromium alloy, tantalum, magnesium, ceramics, metals,
plastics, and polymers.
[0050] In accordance with one aspect of the present invention,
applying the coating to the medical device can include at least one
of dipping the medical device in the coating, spraying the coating
on the medical device, painting the coating on the medical device,
wiping the coating on the medical device, printing the coating on
the device, applying the coating with an applicator and
electrostatically applying the coating to the medical device. In
various embodiments, the method of making a coated medical device
further includes curing the coating on the medical device. Curing
can involve applying at least one of heat, UV light, chemical
cross-linker, or reactive gas to cure the coating. Curing with
respect to the present invention generally refers to thickening,
hardening, or drying of a material brought about by heat, UV, or
chemical means.
[0051] In various embodiments, the method of making a coated
medical device further includes sterilizing the coating and the
medical device. Sterilization can involve use of at least one of
ethylene oxide, gamma radiation, e-beam, steam, gas plasma, and
vaporized hydrogen peroxide (VHP).
[0052] In accordance with one aspect of the present invention, the
coated medical device further comprises hardening the
bio-absorbable carrier. In various embodiments, the further
comprising hardening the bio-absorbable carrier by mixing the
bio-absorbable carrier with reactive oils or oil compounds such as
mono, di or triglycerides, esters of fatty acids, free fatty acids,
partially oxidized or partially hydrolyzed triglycerides.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] The aforementioned features and advantages, and other
features and aspects of the present invention, will become better
understood with regard to the following description and
accompanying drawings, wherein:
[0054] FIG. 1 is a flow chart illustrating a method of dissolving a
therapeutic agent, in accordance with one embodiment of the present
invention;
[0055] FIG. 2 is a flow chart illustrating a method of making a
coating for a medical device, in accordance with one embodiment of
the present invention;
[0056] FIG. 3 is a diagrammatic illustration of a medical device,
according to one embodiment of the present invention;
[0057] FIG. 4 is a cross-sectional view of the medical device in
accordance with one aspect of the present invention;
[0058] FIG. 5 is a cross-sectional view of the medical device in
accordance with another aspect of the present invention;
[0059] FIG. 6 is a flow chart illustrating a method of making the
coated medical device of the present invention, in accordance with
one embodiment of the present invention;
[0060] FIG. 7 is a flow chart illustrating a variation of the
method of FIG. 6, in accordance with one embodiment of the present
invention;
[0061] FIG. 8 is a flow chart illustrating a variation of the
method of FIG. 6, in accordance with one embodiment of the present
invention; and
[0062] FIG. 9 is a diagrammatic illustration of a coated medical
device in accordance with one embodiment of the present
invention.
DETAILED DESCRIPTION
[0063] FIGS. 1 through 9, wherein like parts are designated by like
reference numerals throughout, illustrate examples of embodiments
of solubilizing a therapeutic agent and of embodiments of a coated
medical device according to the present invention. Although the
present invention will be described with reference to the example
embodiments illustrated in the figures, it should be understood
that many alternative forms can embody the present invention. One
of ordinary skill in the art will additionally appreciate different
ways to alter the parameters of the embodiments disclosed, such as
the size, shape, or type of elements or materials, in a manner
still in keeping with the spirit and scope of the present
invention.
[0064] FIG. 1 is a flowchart illustrating a method of the present
invention, in the form of dissolving a therapeutic agent in a
solvent, a vitamin E compound and a bio-absorbable carrier
component, in accordance with one embodiment of the present
invention. The term "bio-absorbable" as used herein generally
refers to having the property or characteristic of being able to
penetrate the tissue of a subject's body. In certain embodiments of
the present invention the bio-absorbable substance is soluble in
the phospholipid bi-layer of cells of body tissue, and therefore
impacts how the bio-absorbable substance penetrates into the cells.
In various embodiments, the bio-absorbable carrier can be
bio-compatible. The term "bio-compatible" refers to materials that
do not elicit a toxic or severe immunological response.
[0065] It should be noted that a bio-absorbable substance differs
from a biodegradable substance. Biodegradable is generally defined
as capable of being decomposed by biological agents, or capable of
being broken down by microorganisms or biological processes.
Biodegradation thus relates to the breaking down and distributing
of a substance through the subject's body, verses incorporation
into and/or utilization by the cells of the subject's body tissue.
Biodegradable substances can cause inflammatory response due to
either the parent substance or those formed during breakdown, and
they may or may not be absorbed by tissues.
[0066] In further detail, the term "bio-absorbable" generally
refers to having the property or characteristic of being able to
penetrate the tissues of a patient's body. In example embodiments
of the present invention, the bio-absorbable coating contains
lipids, many of which originate as triglycerides. It has previously
been demonstrated that triglyceride products such as partially
hydrolyzed triglycerides and fatty acid molecules can integrate
into cellular membranes and enhance the solubility of drugs into
the cell. Whole triglycerides are known not to enhance cellular
uptake as well as partially hydrolyzed triglycerides, because it is
difficult for whole triglycerides to cross cell membranes due to
their relatively large molecule size. Alpha-tocopherol can also
integrate into cellular membranes resulting in decreased membrane
fluidity and cellular uptake.
[0067] It is also known that damaged vessels undergo oxidative
stress. A coating containing an antioxidant such as
alpha-tocopherol may aid in preventing further damage by this
mechanism.
[0068] Referring again to FIG. 1, a method of dissolving a
therapeutic agent in a solvent, a vitamin E compound and a
bio-absorbable carrier component involves determining the
therapeutic agent to be dissolved (step 100). The therapeutic
agents suitable for use in the invention are not particularly
limited. The therapeutic agents can be hydrophilic, lipophilic,
amphiphilic or hydrophobic, and can be dissolved in the
bio-absorbable carrier, the solvent or the bio-absorbable carrier
and the solvent. The therapeutic agent can be any agent having
therapeutic value when administered to a subject, for example, a
mammal. The therapeutic agent component can take a number of
different forms including but not limited to anti-oxidants,
anti-inflammatory agents, anti-coagulant agents, drugs to alter
lipid metabolism, anti-proliferatives, anti-neoplastics, tissue
growth stimulants, analgesics, functional protein/factor delivery
agents, anti-infective agents, anti-imaging agents, anesthetic
agents, therapeutic agents, tissue absorption enhancers,
anti-adhesion agents, anti-migratory agents, pro-healing agents,
ECM/Protein production inhibitors, germicides, antiseptics,
proteoglycans, GAG's, gene delivery (polynucleotides),
polysaccharides (heparin), rapamycin, melatonin, paclitaxel, a
protein kinase C inhibitor, cerivastatin, cilostazol, fluvastatin,
lovastatin, pravastatin or derivatives, analogs, prodrugs and
pharmaceutically acceptable salts thereof, and any additional
desired therapeutic agents such as those listed in Table 1 below.
TABLE-US-00001 CLASS EXAMPLES Antioxidants Alpha-tocopherol,
lazaroid, probucol, phenolic antioxidant, resveretrol, AGI-1067,
vitamin E Antihypertensive Agents Diltiazem, nifedipine, verapamil
Antiinflammatory Agents Glucocorticoids (e.g. dexamethazone,
methylprednisolone), leflunomide, NSAIDS, ibuprofen, acetaminophen,
hydrocortizone acetate, hydrocortizone sodium phosphate,
macrophage-targeted bisphosphonates Growth Factor Angiopeptin,
trapidil, suramin Antagonists Antiplatelet Agents Aspirin,
dipyridamole, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors,
abcximab Anticoagulant Agents Bivalirudin, heparin (low molecular
weight and unfractionated), wafarin, hirudin, enoxaparin, citrate
Thrombolytic Agents Alteplase, reteplase, streptase, urokinase,
TPA, citrate Drugs to Alter Lipid Fluvastatin, colestipol,
lovastatin, atorvastatin, amlopidine Metabolism (e.g. statins) ACE
Inhibitors Elanapril, fosinopril, cilazapril Antihypertensive
Agents Prazosin, doxazosin Antiproliferatives and Cyclosporine,
cochicine, mitomycin C, sirolimus Antineoplastics micophenonolic
acid, rapamycin, everolimus, tacrolimus, paclitaxel, QP-2,
actinomycin, estradiols, dexamethasone, methatrexate, cilostazol,
prednisone, cyclosporine, doxorubicin, ranpirnas, troglitzon,
valsarten, pemirolast, C- MYC antisense, angiopeptin, vincristine,
PCNA ribozyme, 2-chloro-deoxyadenosine Tissue growth stimulants
Bone morphogeneic protein, fibroblast growth factor Promotion of
hollow Alcohol, surgical sealant polymers, polyvinyl particles, 2-
organ occlusion or octyl cyanoacrylate, hydrogels, collagen,
liposomes thrombosis Functional Protein/Factor Insulin, human
growth hormone, estradiols, nitric oxide, delivery endothelial
progenitor cell antibodies Second messenger Protein kinase
inhibitors targeting Angiogenic Angiopoetin, VEGF Anti-Angiogenic
Endostatin Inhibitation of Protein Halofuginone, prolyl hydroxylase
inhibitors, C-proteinase Synthesis/ECM formation inhibitors
Antiinfective Agents Penicillin, gentamycin, adriamycin, cefazolin,
amikacin, ceftazidime, tobramycin, levofloxacin, silver, copper,
hydroxyapatite, vancomycin, ciprofloxacin, rifampin, mupirocin,
RIP, kanamycin, brominated furonone, algae byproducts, bacitracin,
oxacillin, nafcillin, floxacillin, clindamycin, cephradin,
neomycin, methicillin, oxytetracycline hydrochloride, Selenium.
Gene Delivery Genes for nitric oxide synthase, human growth
hormone, antisense oligonucleotides Local Tissue perfusion Alcohol,
H2O, saline, fish oils, vegetable oils, liposomes Nitric oxide
Donor NCX 4016 - nitric oxide donor derivative of aspirin,
Derivatives SNAP Gases Nitric oxide, compound solutions Imaging
Agents Halogenated xanthenes, diatrizoate meglumine, diatrizoate
sodium Anesthetic Agents Lidocaine, benzocaine Descaling Agents
Nitric acid, acetic acid, hypochlorite Anti-Fibrotic Agents
Interferon gamma-1b, Interluekin-10
Immunosuppressive/Immunomodulatory Cyclosporine, rapamycin,
mycophenolate motefil, Agents leflunomide, tacrolimus, tranilast,
interferon gamma-1b, mizoribine Chemotherapeutic Agents
Doxorubicin, paclitaxel, tacrolimus, sirolimus, fludarabine,
ranpirnase Tissue Absorption Fish oil, squid oil, omega 3 fatty
acids, vegetable oils, Enhancers lipophilic and hydrophilic
solutions suitable for enhancing medication tissue absorption,
distribution and permeation Anti-Adhesion Agents Hyaluronic acid,
human plasma derived surgical sealants, and agents comprised of
hyaluronate and carboxymethylcellulose that are combined with
dimethylaminopropyl, ehtylcarbodimide, hydrochloride, PLA, PLGA
Ribonucleases Ranpirnase Germicides Betadine, iodine, sliver
nitrate, furan derivatives, nitrofurazone, benzalkonium chloride,
benzoic acid, salicylic acid, hypochlorites, peroxides,
thiosulfates, salicylanilide Antiseptics Selenium Analgesics
Bupivicaine, naproxen, ibuprofen, acetylsalicylic acid
[0069] Some specific examples of therapeutic agents useful in the
anti-restenosis realm include cerivastatin, cilostazol,
fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, a
rapamycin carbohydrate derivative (for example as described in US
Patent Application Publication 2004/0235762), a rapamycin
derivative (for example as described in U.S. Pat. No. 6,200,985),
everolimus, seco-rapamycin, seco-everolimus, and simvastatin.
[0070] Referring again to FIG. 1, the amount of the therapeutic
agent is then identified (step 105). The amount of the therapeutic
agent in the present invention, in one embodiment, can be an
effective amount. The term "effective amount" as used herein,
refers to that amount of a compound sufficient to result in
amelioration of symptoms, e.g., treatment, healing, prevention or
amelioration of the relevant medical condition, or an increase in
rate of treatment, healing, prevention or amelioration of such
conditions. When applied to an individual active ingredient,
administered alone, an effective amount refers to that ingredient
alone. When applied to a combination, an effective amount can refer
to combined amounts of the active ingredients that result in the
therapeutic effect, whether administered in combination, serially
or simultaneously. In various embodiments, where formulations
comprise two or more therapeutic agents, such formulations can be
described as an effective amount of compound A for indication A and
an effective amount of compound B for indication B, such
descriptions refer to amounts of A that have a therapeutic effect
for indication A, but not necessarily indication B, and amounts of
B that have a therapeutic effect for indication B, but not
necessarily indication A. In a further embodiment, one of the
therapeutic agents may have a synergistic effect on another
therapeutic agent in a combination of therapeutic agents. Moreover,
each therapeutic agent may have a synergistic effect on any other
therapeutic agent provided in the invention. As used herein,
"synergy" or "synergistic effect" refers to an enhancement of the
therapeutic properties of one or more therapeutic agents of the
invention. Furthermore two or more compounds may be administered
for the same or different indication with or without a true
synergism. In another embodiment, compound A can have an
enhancement effect on compound B and compound B can have an
enhancement effect on compound A. In another embodiment, A and B
may have no effect upon each other.
[0071] Actual dosage levels of the active ingredients in a
therapeutic formulation of the present invention may be varied so
as to obtain an amount of the active ingredients which is effective
to achieve the desired therapeutic response without being
unacceptably toxic. The selected dosage level will depend upon a
variety of pharmacokinetic factors including the activity of the
particular therapeutic formulations of the present invention
employed, or the ester, salt or amide thereof, the route of
administration, the time of administration, the duration of
administration, the rate of excretion of the particular compounds
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compounds employed, and like factors well known in the medical
arts.
[0072] Some specific examples of therapeutic agents useful in the
anti-restenosis realm include cerivastatin, cilostazol,
fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, and
simvastatin. Depending on the type of therapeutic agent component
added to the coating, the resulting coating can be bio-absorbable
if the therapeutic agent is also bio-absorbable. As described in
the Summary of the Invention, the present invention relates to
coating for a medical device in which the coating is formed of
three primary components, the bio-absorbable carrier component, the
vitamin E compound and a therapeutic agent component. The
therapeutic agent component has some form of a therapeutic or
biological effect. The bio-absorbable carrier component can also
have a therapeutic or biological effect. It should again be noted
that the bio-absorbable carrier component is different from the
conventional bio-degradable substances utilized for similar
purposes. The bio-absorbable characteristic of the carrier
component enables the cells of the body tissue of a patient to
absorb the bio-absorbable carrier component itself, rather than
breaking down the carrier component into inflammatory by-products
and disbursing said by-products of the component for ultimate
elimination by the patient's body. Accordingly, anti-inflammatory
drug dosages to the patient do not need to be increased to
additionally compensate for inflammation caused by the carrier
component, as is otherwise required when using polymer-based
carriers that themselves cause inflammation
[0073] Referring again to FIG. 1, a solvent based on the
therapeutic agent can be selected (step 110). In various
embodiments, the solvent can be chosen based on the physical
properties of the therapeutic agent. One skilled in the art will be
able to determine the appropriate solvent to use. The solvent can
be a solvent or mixture of solvents and include solvents that are
generally acceptable for pharmaceutical use. Suitable solvents
include, for example: alcohols and polyols, such as C.sub.2-C.sub.6
alkanols, 2-ethoxyethanol, ethanol, isopropanol, butanol, benzyl
alcohol, ethylene glycol, propylene glycol, butanediols and isomers
thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol,
dimethyl isosorbide, polyethylene glycol, and polypropylene glycol;
amides, such as 2-pyrrolidone, 2-piperidone, 2-caprolactam,
N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; esters, such as ethyl acetate, methyl acetate,
butyl acetate, ethylene glycol diethyl ether, ethylene glycol
dimethyl ether, propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactorne and isomers thereof, .beta.-butyrolactone
and isomers thereof; and other solvents, such as water,
dimethylsulfoxide, benzyl benzoate, ethyl lactate, acetone,
methylethyl ketone, dimethylsolfone, tetrahydrofuran,
decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform,
dichloromethane.
[0074] The amount of solvent that can be included in compositions
of the present invention is not particularly limited. In accordance
with one embodiment of the present invention, the amount of the
therapeutic agent to be dissolved can be an amount up to the
maximum amount that can be dissolved in the solvent, vitamin E
compound and the bio-absorbable carrier component. The maximum
amount of the therapeutic agent that can be dissolved is readily
determined by simple mixing, as the presence of any non-dissolved
therapeutic agent is apparent after solvent removal on visual
inspection. In various embodiments, the amount of the therapeutic
agent will be less than the maximum that can be dissolved. Upon
administration to a subject of the therapeutic agent dissolved in
the bio-absorbable carrier and the solvent, the amount of the given
solvent can be limited to a pharmaceutically acceptable amount,
which can be readily determined by one of skill in the art. In
various aspects, it can be appropriate to include amounts of
solvents in excess of pharmaceutically acceptable amounts, with
excess solvent removed prior to providing the administration of the
composition using conventional techniques such as evaporation.
[0075] Referring again to FIG. 1, the therapeutic agent and a
solvent can be mixed together, for example, by vortexing,
sonicating, stirring, rolling, or shaking, to form a first mixture
(step 120).
[0076] Referring again to FIG. 1, the ratio of a vitamin E compound
and the bio-absorbable carrier component is then determined (step
130). One skilled in the art would be able to readily determine the
ratio by, for example, combining the therapeutic that is dissolved
in a solvent with various combinations of vitamin E and
bio-absorbable carrier components. The bio-absorbable carrier
component can include fish oil, fish oil mono, di and
triglycerides, free fatty acids, fatty acid esters, partially
oxidized oil, or hydrolyzed oil and any derivatives. After the
formulations are made the solvent is removed from the sample under
vacuum and the drug formulation is inspected under a microscope for
crystal formation. The level of soluble drug can be influenced by
such factors as vitamin E level, fish oil level, fatty acid ester
content, free fatty acid content, mono, di or triglyceride content,
presence of oxidation, or by hydrolysis byproducts of the oil. The
amount of soluble drug can also be effected by the solvent and/or
solvent loading that is used to load the drug into the
formulation.
[0077] Vitamin E describes a family of eight fat-soluble
antioxidants, the four tocopherols, alpha-, beta-, gamma- and
delta-(Formula I), and the four tocotrienols also alpha-, beta-,
gamma- and delta-(Formula II): TABLE-US-00002 (I) ##STR1## (II)
##STR2## Tocopherol Structure Tocotrienol Structure R.sup.5,
R.sup.7, R.sup.8 Alpha-tocopherol Alpha-tocotrienol R.sup.5R.sup.7,
R.sup.8 = CH.sub.3 Beta-tocopherol Beta-tocotrienol R.sup.5,
R.sup.8 = CH.sub.3; R.sup.7 = H Gamma-tocopherol Gamma-tocotrienol
R.sup.7, R.sup.8 = CH.sub.3; R.sup.5 = H Delta-tocopherol
Delta-tocotrienol R.sup.5, R.sup.7 = H; R.sup.8 = CH.sub.3
[0078] The term "vitamin E compound" as used herein generally
refers to any compound of the vitamin E family, including
derivatives, analogs, and pharmaceutically acceptable salts
thereof. The vitamin E compound and include, for example,
alpha-tocopherol, beta-tocopherol, delta-tocopherol,
gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol,
delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate,
beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherol
acetate, alpha-tocotrienol acetate, beta-tocotrienol acetate,
delta-tocotrienol acetate, gamma-tocotrienol acetate,
alpha-tocopherol succinate, beta-tocopherol succinate,
gamma-tocopherol succinate, delta-tocopherol succinate,
alpha-tocotrienol succinate, beta-tocotrienol succinate,
delta-tocotrienol succinate, gamma-tocotrienol succinate, Vitamin E
TPGS, derivatives, analogs, pharmaceutically acceptable salts and
mixtures thereof. Suitable vitamin E compound analogs can be, for
example, desmethyl-tocotrienol, didesmethyl-tocotrienol, P.sub.18
tocotrienol.TM., P.sub.25 tocotrienol, alpha-tocomonoenol. The
vitamin E compounds can be conveniently isolated from biological
materials or synthesized from commercially available starting
materials by techniques known to those skilled in the art. In
various embodiments, the vitamin E compounds can be in their
isomerically pure form or be present as mixtures of isomers. For
example, the vitamin E compounds can exist as the D-isomer, the
L-isomer, or the D,L-racemic mixture.
[0079] In one embodiment, other fat soluble vitamins can be used in
the invention. Suitable fat soluble vitamins include, for example,
vitamin A, vitamin D, vitamin K, and derivatives, pharmaceutically
acceptable salts, esters and amides thereof.
[0080] The term "bio-absorbable carrier component" as used herein
refers to a composition comprising a naturally occurring oil, fish
oil fatty acids, free fatty acids, fatty acid esters,
triglycerides, diglycerides, monoglycerides, partially hydrolyzed
oil, oxidized oil or a combination thereof. In one embodiment, the
naturally occurring oil is fish oil. Suitable fish oils can be
obtained, for example from a variety of fish and can include cod
liver oil, shark liver oil and fish body oils. In various
embodiments, the components of fish oil include triacylglycerol,
diacylglycerol, monoacylglycerol, phospholipids, sterylesters,
sterols, mixed tocopherols and free fatty acids. The quantities of
total lipids may vary between different fish oils. In various
embodiments, the fish oil is modified to a state of increased
viscosity. The modification of the fish oil and be accomplished by
techniques known to those skilled in the art.
[0081] The term "fatty acid" as used herein refers to compounds
comprising carbon, hydrogen and oxygen arranged as a carbon
skeleton with a carboxyl group at one end. Saturated fatty acids
have all hydrogens, thus have no double bonds. Monounsaturated
fatty acids have one double bond and polyunsaturated fatty acids
have more than one double bond. Examples of common fatty acids are
seen in Table 2. TABLE-US-00003 TABLE 2 # of Carbon # of Double
Common Name Atoms Bonds Scientific Name Sources Butyric acid 4 0
Butanoic acid Butterfat Caproic acid 6 0 Hexanoic acid Butterfat
Caprylic acid 8 0 Octanoic acid Coconut oil Capric acid 10 0
Decanoic acid Coconut oil Lauric acid 12 0 Dodecanoic acid Coconut
oil Myristic acid 14 0 Tetradecanoic acid Palm kernel oil Palmitic
acid 16 0 Hexadecanoic acid Palm oil Palmitoleic acid 16 1
9-hexadecenoic acid Animal fats Stearic acid 18 0 Octadecanoic acid
Animal fats Oleic acid 18 1 9-octadecenoic acid Olive oil Vaccenic
acid 18 1 11-octadecenoic acid Butterfat Linoleic acid 18 2
9,12-octadecadienoic Safflower oil acid Alpha-linoleic acid 18 3
9,12,15- Flaxseed octadecatrienoic acid Gamma-linoleic 18 3
6,9,12-octadecatrienoic Borage oil acid acid Arachidic acid 20 0
Eicosanoic acid Peanut oil, fish oil Gadoleic acid 20 1
9-eicosenoic acid Fish oil Arachidonic acid 20 4 5,8,11,14- Liver
fats eicosatetraenoic acid EPA 20 5 5,8,11,14,17- Fish oil
eicosapentaenoic acid Behenic acid 22 0 Docasanoic acid Rapeseed
oil Erucic acid 22 1 13-doxosenoic acid Rapeseed oil DHA 22 6
4,7,10,13,16,19- Fish oil docosahexaenoic acid Lignoceric acid 24 0
Tetraxosanoic acid Small amounts in most fats
[0082] Polyunsaturated fats can be further broken down into omega-3
fatty acids and omega-6 fatty acids. Omega-3 and omega-6 fatty
acids are also known as essential fatty acids because they are
important for maintaining good health, despite the fact that the
human body cannot make them on its own. As such, omega-3 and
omega-6 fatty acids must be obtained from external sources, such as
food. Omega-6 fatty acids can be characterized as linoleic acids,
gamma-linoleic acids and arachidonic acid. Omega-3 fatty acids can
be further characterized as eicosapentaenoic acid (EPA),
docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). Both EPA
and DHA are known to have anti-inflammatory effects and wound
healing effects within the human body.
[0083] As used herein, the term "fish oil fatty acids" refers to
those fatty acids which can be obtained from fish oil. Fish oil
fatty acids can include, but are not limited to, arachidic acid,
gadoleic acid, arachidonic acid, eicosapentaenoic acid,
docosahexaenoic acid, derivatives, analogs, pharmaceutically
acceptable salts, and combinations thereof.
[0084] As used herein, the term "free fatty acids" refers to those
fatty acids which are not bound to other molecules. Bound fatty
acids can be bound to compounds including, but not limited to,
glycerides, glycerophospatides, glycosyldiglycerides, sterol
esters, waxes, acylglycerols, cholesterol esters and
glycospingolipids. Free fatty acids can be derived from their bound
form by techniques well known in the art, such as saponification.
Suitable free fatty acids can include butyric acid, caproic acid,
caprylic acid, capric acid, lauric acid, myristic acid, palmitic
acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid,
linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic
acid, erucic acid, lignoceric acid, and derivatives, analogs and
pharmaceutically acceptable salts thereof. In various embodiments,
free fatty acids can also comprise fish oil fatty acids.
[0085] The ratio of the vitamin E compound to the bio-absorbable
carrier component can be determined by techniques known to those
skilled in the art. Accordingly, the bio-absorbable carrier can be
about 70% of a bio-absorbable carrier component and about 30% of a
vitamin E compound; about 70% of a vitamin E compound and about 30%
of a bio-absorbable carrier component; or about 50% of a vitamin E
compound and about 50% of a bio-absorbable carrier component.
[0086] Referring again to FIG. 1, the bio-absorbable carrier
component and the vitamin E compound or a combination thereof are
provided (step 130). In accordance with one aspect of the present
invention, the bio-absorbable carrier component and the vitamin E
compound can be mixed together, for example, by vortexing,
sonicating, stirring, rolling, or shaking, to form a second mixture
(step 140). Accordingly, the second mixture can be mixed first, the
first mixture can be mixed first, or the first mixture and the
second mixture can be mixed substantially simultaneously. The first
mixture and the second mixture can then be mixed (step 150) such
that the therapeutic agent is dissolved, or, if the therapeutic
agent was previously dissolved in the solvent, the therapeutic
agent remains dissolved. After mixing the first mixture and the
second mixture, the solvent is removed by techniques well known in
the art, for example, by vacuum, washing, heating, evaporation and
the like (step 160). Upon removal of the solvent, the resulting
solution can be inspected for presence of crystal formation by
techniques well known in the art (step 170). Suitable techniques
for inspection for the presense of crystal formation include, for
example, visual inspection, microscopic inspections, as well as
chemical analysis techniques such as scanning electron microscopy
(SEM), environmental scanning electron microscopy (ESEM),
differential scanning calorimetry (DSC) and atomic force microscopy
(AFM).
[0087] FIG. 2 is a flowchart illustrating a method of the present
invention, in the form preparing a coating for medical devices, in
accordance with one embodiment of the present invention. A
combination of the first mixture and the second mixture is provided
(step 200) and the solvent is removed (step 205), which forms the
coating for a medical device (step 210).
[0088] In accordance with one aspect of the present invention, a
coated medical device is provided. The medical devices of the
invention can be, for example, a catheter, a guidewire, a cannula,
a stent, a vascular or other graft, a cardiac pacemaker lead or
lead tip, a cardiac defibrillator lead or lead tip, a heart valve,
or an orthopedic device, appliance, implant, or replacement. In one
aspect, the medical device is a stent. The term "stent" refers to
what is known in the art as a metallic or polymeric cage-like
device that is used to hold bodily vessels, such as blood vessels,
open.
[0089] The device and methods of the present invention can be
useful in a wide variety of locations within a human or veterinary
patient, such as in the esophagus, trachea, colon, biliary tract,
urinary tract and vascular systems, including coronary vessels, as
well as for subdural and orthopedic devices, implants or
replacements. They can be advantageous for reliably delivering
suitable bioactive materials during or following an intravascular
procedure, and find particular use in preventing abrupt closure
and/or restenosis of a blood vessel. More particularly, they
permit, for example, the delivery of an effective amount of one or
more therapeutic agents to the region of a blood vessel which has
been opened by PTA. The coated medical devices of the invention can
be implantable in a subject. As used here, the term "subject"
includes animals (e.g., vertebrates, amphibians, fish), mammals
(e.g., cats, dogs, horses, pigs, cows, sheep, rodents, rabbits,
squirrels, bears), and primates (e.g., chimpanzees, gorillas, and
humans).
[0090] The device of the present invention can be formed of a
substance selected from the group consisting of stainless steel,
nickel, silver, platinum, gold, titanium, tantalum, iridium,
tungsten, Nitinol, inconel, Nitinol alloy, nickel alloy, titanium
alloy, cobalt-chromium alloy, magnesium, tantalum, ceramics,
metals, plastics, and polymers or the like.
[0091] FIG. 3 illustrates a stent 10 in accordance with one
embodiment of the present invention. The stent 10 is representative
of a medical device that is suitable for having a coating applied
thereon to effect a therapeutic result. The stent 10 is formed of a
series of interconnected struts 12 having gaps 14 formed
therebetween. The stent 10 is generally cylindrically shaped.
Accordingly, the stent 10 maintains an interior surface 16 and an
exterior surface 18.
[0092] One of ordinary skill in the art will appreciate that the
illustrative stent 10 is merely exemplary of a number of different
types of stents available in the industry. For example, the strut
12 structure can vary substantially. The material of the stent can
also vary from a metal, such as stainless steel, Nitinol, nickel,
and titanium alloys, to cobalt chromium alloy, ceramic, plastic,
and polymer type materials. One of ordinary skill in the art will
further appreciate that the present invention is not limited to use
on stents. Instead, the present invention has application on a wide
variety of medical devices. For purposes of clarity, the following
description will refer to a stent as the exemplar medical device.
The terms medical device and stent are interchangeable with regard
to the applicability of the present invention. Accordingly,
reference to one or another of the stent, or the medical device, is
not intended to unduly limit the invention to the specific
embodiment described.
[0093] FIG. 4 illustrates one example embodiment of the stent 10
having a coating 20 applied thereon in accordance with the present
invention. FIG. 5 is likewise an alternative embodiment of the
stent 10 having the coating 20 also applied thereon. The coating 20
is applied to the medical device, such as the stent 10, to provide
the stent 10 with different surface properties, and also to provide
a vehicle for therapeutic applications.
[0094] In FIG. 4, the coating 20 is applied on both the interior
surface 16 and the exterior surface 18 of the strut 12 forming the
stent 10. In other words, the coating 20 in FIG. 4 substantially
encapsulates the struts 12 of the stent 10. In FIG. 5, the coating
20 is applied only on the exterior surface 18 of the stent 10, and
not on the interior surface 16 of the stent 10. The coating 20 in
both configurations is the same coating; the difference is merely
the portion of the stent 10 that is covered by the coating 20. One
of ordinary skill in the art will appreciate that the coating 20 as
described throughout the description can be applied in both manners
shown in FIG. 4 and FIG. 5, in addition to other configurations
such as, partially covering select portions of the stent 10
structure. All such configurations are described by the coating 20
reference.
[0095] It should further be emphasized that the bio-absorbable
nature of the coating results in the coating 20 being absorbed over
time by the cells of the body tissue. The coating, or break down
products of the coating, will not induce an inflammatory response.
In short, the coating 20 is generally composed of fatty acids,
including in some instances omega-3 fatty acids bound to
trigycerides, and potentially also including a mixture of free
fatty acids and vitamin E. The triglycerides are broken down by
lipases (enzymes) which result in free fatty acids that can be
transported across cell membranes. Subsequently, fatty acid
metabolism by the cell occurs to metabolize any substances
originating with the coating. The bio-absorbable nature of the
coating of the present invention thus results in the coating being
absorbed, leaving only an underlying delivery or other medical
device structure. The bio-absorbable carrier component does not
induce a foreign body response. The modification of the oils from a
more liquid state to a more solid, but still flexible, physical
state is implemented through a curing process. Curing with respect
to the present invention generally refers to thickening, hardening,
or drying of a material brought about by heat, UV, or chemical
means. As the oils are cured, especially in the case of fatty
acid-based oils such as fish oil, cross-links form creating a gel.
As the curing process is performed over increasing time durations
and/or increasing temperature conditions and/or increasing UV
output, more cross-links form transitioning the gel from a
relatively liquid gel to a relatively solid-like, but still
flexible, gel structure.
[0096] The coatings for the medical device of the present invention
can include an amount of one or more therapeutic agents dissolved
in a bio-absorbable carrier component and a vitamin E compound. The
coating for the medical device can additionally include an amount
of one or more therapeutic agents dissolved in a bio-absorbable
carrier component, a vitamin E compound and a solvent. The coatings
of the invention can further contain a compatibilizer, a
preservative or both. As used herein, the term "compatibilizer"
refers to an added component of the coating that may prevent
crystal formation after the removal of solvent. Suitable
compatibilizers include, for example Vitamin E or its derivatives,
free fatty acids, fatty acid esters, partially oxidized
triglycerides, hydrolyzed triglycerides, therapeutic agents,
antioxidants, surfactants and any amphiphilic materials. The term
"preservative", as used herein, refers to an added component of the
coating that can prevent the deterioration of the therapeutic
agent, the coating or both. Suitable preservatives include, for
example, vitamin E or its derivatives, as well as antioxidant
materials.
[0097] Accordingly, the coatings of the invention are
non-polymeric. As used herein, the term "polymer" is a generic term
that is normally used by one of ordinary skill in the art to
describe a substantially long molecule formed by the chemical union
of five or more identical combining units called monomers. In most
cases, the number of monomers is quite large (3500 for pure
cellulose). See Hawley's Condensed Chemical Dictionary, page 900.
Prior attempts to create drug delivery platforms such as coatings
on stents primarily make use of polymer based coatings containing
one or more therapeutic agents. Regardless of how much of the
therapeutic agent would be most beneficial to the damaged tissue,
the polymer releases the therapeutic agent based on the properties
of the polymer coating. Accordingly, the effect of the coating is
substantially local at the surface of the tissue making contact
with the coating and the stent. In some instances, the effect of
the coating is further localized to the specific locations of stent
struts pressed against the tissue location being treated. These
prior approaches can create the potential for a localized toxic
effect. In addition, patients that received a polymer-based implant
must also follow a course of long term systemic anti-platelet
therapy, on a permanent basis, to offset the thrombogenic
properties of the non-absorbable polymer and the inflammatory
response thereto. A significant percentage of patients that receive
such implants are required to undergo additional medical
procedures, such as surgeries (whether related follow-up surgery or
non-related surgery) and are required to stop their anti-platelet
therapy. This can lead to a thrombotic event, such as stroke, which
can lead to death. Use of the inventive coating described herein
can negate the necessity of anti-platelet therapy, and the
corresponding related risks described, because there is no
thrombogenic polymer reaction to the coating.
[0098] Due to the lipophilic mechanism enabled by the
bio-absorbable coating 20 the uptake of the therapeutic agent is
facilitated by the delivery of the therapeutic agent to the cell
membrane by the bio-absorbable carrier component. Further, the
therapeutic agent is not freely released into the body fluids, but
rather, is delivered directly to the cells and tissue. In prior
configurations using polymer based coatings, the drugs were
released at a rate regardless of the reaction or need for the drug
on the part of the cells receiving the drug.
[0099] In addition, the bio-absorbable nature of the carrier
component and the resulting coating results in the coating 20 being
completely absorbed over time by the cells of the body tissue and
body fluids. The coating breaks down into sub-parts and substances
which do not induce an inflammatory response and are eventually
distributed through the body and, in some instances, disposed of by
the body, as is the case with biodegradable coatings. The
bio-absorbable nature of coating 20 of the present invention
results in the coating being absorbed, leaving only the stent
structure, or other medical device structure. There is no foreign
body response to the bio-absorbable carrier component.
[0100] Despite the action by the cells, the coating 20 of the
present invention can be further configured to release the
therapeutic agent component at a rate no faster than a selected
controlled release rate over a period of weeks to months. The
controlled release rate action is achieved by providing an
increased level of vitamin E in the mixture with the fish oil, to
create a more viscous, sticky coating substance that better adheres
and lasts for a longer duration on the implanted medical device.
The controlled release rate can include an initial burst of
release, followed by the sustained multi-week to multi-month period
of release. Correspondingly, with a greater amount of the
bio-absorbable carrier component relative to the level of vitamin
E, the controlled release rate can be increased. The fatty acids
can be found in the oil, and/or fatty acids such as myristic acid
or oleic acid can be added to the oil. Thus, the ratio of fatty
acids to alpha-tocopherol can be varied in the preparation of the
coating 20 to vary the subsequent release rate of the therapeutic
agent in a controlled and predictable manner.
[0101] In addition, the oil provides a lubricious surface against
the vessel walls. As the stent 10 having the coating 20 applied
thereon is implanted within a blood vessel, for example, there can
be some friction between the stent walls and the vessel walls. This
can be injurious to the vessel walls, and increase injury at the
diseased vessel location. The use of the naturally occurring oil,
such as fish oil, provides extra lubrication to the surface of the
stent 10, which reduces the initial injury. With less injury caused
by the stent, there is less of an inflammatory response and less
healing is required.
[0102] The coatings of the invention can inhibit restenosis,
induced either biologically or mechanically. Biologically induced
restenosis includes, but is not limited to injury attributed to
infectious disorders including endotoxins and herpes viruses such
as cytomegalovirus; metabolic disorders such as atherosclerosis;
and vascular injury resulting from hypothermia, and irradiation.
Mechanically induced restenosis includes, but is not limited to,
vascular injury caused by catheterization procedures or vascular
scraping procedures such as percutaneous transluminal coronary
angioplasty; vascular surgery; transplantation surgery; laser
treatment; and other invasive procedures which disrupt the
integrity of the vessel.
[0103] The coatings of the invention can additionally inhibit
neointimal growth. Neointimal growth refers to the migration and
proliferation of vascular smooth muscle (VSM) cells with subsequent
deposition of extracellular matrix components at the site of
injury. Neointimal growth can occur as the result of arterial
tissue injury caused by biological or mechanical origins. Injury
can cause an exaggerated or excessive healing response
characterized by excessive proliferation of the vascular smooth
muscle cells in the neointima and subsequent secretion of
extracellular matrix causing intimal hyperplasia that can often
result in stenosis of the artery. While the mechanism is complex,
the hyperplasia appears to result at least partly from
transformation of the smooth muscle cells from a quiescent,
contractile phenotype to a proliferative phenotype. If untreated
the proliferation of cells and secretion of extracellular matrix
can obstruct the vessel lumen.
[0104] The coatings of the invention can further promote
endothelialization. Endothelialization refers to both any process
of replacing the endothelium stripped by any biological or
mechanical process and any process of growing new endothelial cells
to cover an implanted medical device. The endothelialization can
involve ingrowth of the proximal or distal endothelium
longitudinally over the stent, from the lumen of the blood vessel
into which the stent is inserted. Endothelialization via this
method can result in endothelial cells lining the lumen of the
stented vessel. Stents can be treated or coated with drugs or other
substances which encourage endothelial growth and/or recruitment of
endothelial progenitor cells for example from the blood
circulation.
[0105] In the instance of an expanded PTFE vascular graft, covered
stent or stent graft the endothelialization can involve promoting
pannus ingrowth longitudinally into the device from the lumen of
the blood vessel into which the stent is inserted.
Endothelialization via this method can result in endothelial cells
lining the lumen of the device with few if any endothelial cells in
the porosity of the device. Endothelialization can also refer to
"transmural" or "transinterstitial" endothelialization, which can
involve promoting the ingrowth of capillaries and/or capillary
endothelial cells through the device wall and into the porosity.
Such endothelial cells originate in the microvasculature of
adjacent tissue external to the device, and grow through the device
wall, in part by virtue of its porosity. Under appropriate
conditions, the endothelial cells are able to grow through the
stent wall and colonize the stent lumen. Endothelialization can
further refer to "capillary endothelialization". The process of
capillary endothelialization can be distinguished by its sequential
cellular steps, including the initial attachment of endothelial
cells to the stent material, followed by their spreading, inward
migration, and optionally, proliferation. Accordingly,
endothelialization can additionally refer to all of these
processes. The term "endothelial cells" can refer to both mature
endothelial cells and endothelial progenitor cells.
[0106] In accordance with one aspect of the present invention, the
coatings can effect controlled delivery of the one or more
therapeutic agents. The phrases "controlled release" and "delivery
of the therapeutic agent is controlled" generally refers to the
release of a biologically active agent in a predictable manner over
the time period of several days, several weeks, or several months
as desired and predetermined upon formation of the biologically
active agent on the medical device from which it is being released.
Controlled release includes the provision of an initial burst of
release upon implantation, followed by the predictable release over
the aforementioned time period.
[0107] Furthermore, the step of applying a coating substance to
form a coating on the medical device such as the stent 10 can
include a number of different application methods. For example, the
stent 10 can be dipped into a liquid solution of the coating
substance. The coating substance can be sprayed onto the stent 10,
which results in application of the coating substance on the
exterior surface 18 of the stent 10 as shown in FIG. 5. Another
alternative application method is painting, using an applicator or
wiping the coating substance on to the stent 10, which also results
in the coating substance forming the coating 20 on the exterior
surface 18 as shown in FIG. 5. One of ordinary skill in the art
will appreciate that other methods, such as electrostatic adhesion
and inkjet application, and other application methods, can be
utilized to apply the coating substance to the medical device such
as the stent 10. Some application methods may be particular to the
coating substance and/or to the structure of the medical device
receiving the coating. Accordingly, the present invention is not
limited to the specific embodiment described herein, but is
intended to apply generally to the application of the coating
substance to the medical device, taking whatever precautions are
necessary to make the resulting coating maintain desired
characteristics.
[0108] FIG. 6 illustrates one method of making the present
invention, in the form of the coated stent 10, in accordance with
one embodiment of the present invention. The process involves
providing a medical device, such as the stent 10 (step 600). A
coating, such as coating 20, is then applied to the medical device
(step 610). One of ordinary skill in the art will appreciate that
this basic method of application of a coating to a medical device
such as the stent 10 can have a number of different variations
falling within the process described. Depending on the particular
application, the stent 10 with the coating 20 applied thereon can
be implanted after the coating 20 is applied, or additional steps
such as curing and sterilization can be applied to further prepare
the stent 10 and coating 20. Furthermore, if the coating 20
includes a therapeutic agent that requires some form of activation
(such as UV light), such actions can be implemented
accordingly.
[0109] FIG. 7 is a flowchart illustrating one example
implementation of the method of FIG. 6. In accordance with the
steps illustrated in FIG. 7, the therapeutic agent desired for
delivery is identified (step 700) and the amount of said
therapeutic agent is identified (step 705). A solvent based on the
properties of the therapeutic agent is selected (step 710) and the
solvent and the therapeutic agent are mixed to provide a first
mixture (step 715). The ratio of the vitamin E compound and the
bio-absorbable carrier component is determined (step 720), and are
subsequently mixed to form a second mixture (step 725). The first
mixture and the second mixture are then combined to form a coating
for a medical device (step 730). The coating for the medical device
is applied to the medical device (step 735) and the solvent is
removed (step 740), or, alternatively, the solvent is removed (step
745) and the coating is applied to the medical device (step
750).
[0110] The coating for a medical device can be applied to the
medical device (step 735 and step 750) and can take place in a
manufacturing-type facility and subsequently shipped and/or stored
for later use. Alternatively, the coating 20 can be applied to the
stent 10 just prior to implantation in the patient. The process
utilized to prepare the stent 10 will vary according to the
particular embodiment desired. In the case of the coating 20 being
applied in a manufacturing-type facility, the stent 10 is provided
with the coating 20 and subsequently sterilized in accordance with
any of the methods provided herein, and/or any equivalents. The
stent 10 is then packaged in a sterile environment and shipped or
stored for later use. When use of the stent 10 is desired, the
stent is removed from the packaging and implanted in accordance
with its specific design.
[0111] In the instance of the coating being applied just prior to
implantation, the stent can be prepared in advance. The stent 10,
for example, can be sterilized and packaged in a sterile
environment for later use. When use of the stent 10 is desired, the
stent 10 is removed from the packaging, and the coating substance
is applied to result in the coating 20 resident on the stent 10.
The coating 20 can result from application of the coating substance
by, for example, the dipping, spraying, brushing, swabbing, wiping,
printing, using an applicator or painting methods.
[0112] The coated medical device is then sterilized using any
number of different sterilization processes (step 755).
Sterilization can involve the use of at least one of ethylene
oxide, gamma radiation, e-beam, steam, gas plasma, and vaporized
hydrogen peroxide (VHP).
[0113] One of ordinary skill in the art will appreciate that other
sterilization processes can also be applied, and that those listed
herein are merely examples of sterilization processes that result
in a sterilization of the coated stent, preferably without having a
detrimental effect on the coating 20.
[0114] In accordance with another embodiment of the present
invention a surface preparation or pre-treatment 22, as shown in
FIG. 9, is provided on a stent 10. More specifically and in
reference to the flowchart of FIG. 8, a pre-treatment substance is
first provided (step 800). The pre-treatment substance is applied
to a medical device, such as the stent 10, to prepare the medical
device surface for application of the coating (step 810). Suitable
pre-treatments include partially cured fish oil, plasma, parylene,
and hydrophobic or hydrophilic polymers. If desired, the
pre-treatment 22 is cured (step 820). Curing methods can include
processes such as application of UV light or application of heat or
curing by chemical means. A coating substance is then applied on
top of the pre-treatment 22 (step 830). The coated medical device
is then sterilized using any number of sterilization processes as
previously mentioned (step 840).
[0115] FIG. 9 illustrates the stent 10 having two coatings,
specifically, the pre-treatment 22 and the coating 20. The
pre-treatment 22 serves as a base or primer for the coating 20. The
coating 20 conforms and adheres better to the pre-treatment 22
verses directly to the stent 10, especially if the coating 20 is
not heat or UV cured. The pre-treatment can be formed of a number
of different materials or substances. In accordance with one
example embodiment of the present invention, the pre-treatment is
formed of a bio-absorbable substance, such as a naturally occurring
oil (e.g., fish oil). The bio-absorbable nature of the
pre-treatment 22 results in the pre-treatment 22 ultimately being
absorbed by the cells of the body tissue after the coating 20 has
been absorbed.
[0116] It has been previously mentioned that curing of substances
such as fish oil can reduce or eliminate some of the therapeutic
benefits of the omega-3 fatty acids, including anti-inflammatory
properties and healing properties. However, if the coating 20
contains the bio-absorbable carrier component in combination with a
vitamin E compound having the therapeutic benefits, the
pre-treatment 22 can be cured to better adhere the pre-treatment 22
to the stent 10, without losing the therapeutic benefits resident
in the subsequently applied coating 20. Furthermore, the cured
pre-treatment 22 provides better adhesion for the coating 20
relative to when the coating 20 is applied directly to the stent 10
surface. In addition, the pre-treatment 22, despite being cured,
remains bio-absorbable, like the coating 20. In addition, methods
can be used to enhance the curing process. These methods include,
for example, the addition of other reactive oils, such as linseed
oil, and the application of reactive gasses, such as oxygen,
fluorine, methane or propylene, plasma treatment, and pressure in
the presence of reactive gasses and the like.
[0117] The pre-treatment 22 can be applied to both the interior
surface 16 and the exterior surface 18 of the stent 10, if desired,
or to one or the other of the interior surface 16 and the exterior
surface 18. Furthermore, the pre-treatment 22 can be applied to
only portions of the surfaces 16 and 18, or to the entire surface,
if desired. In one embodiment, the pre-treatment can include a
therapeutic agent.
[0118] Various aspects and embodiments of the present invention are
further described by way of the following Examples. The Examples
are offered by way of illustration and not by way of
limitation.
EXAMPLE #1
[0119] A bio-absorbable carrier component in combination with a
vitamin E compound was made by mixing 1.5 grams of vitamin E and
3.5 grams of fish oil to form a base coating (30% vitamin E). A
sample was then prepared by first dissolving 28 mg of rapamycin in
529 mg of NMP (N-methyl-2-pyrrolidone). After the drug was fully
dissolved in the solvent, 502 mg of the 30% vitamin E/70% fish oil
base coat was added and the solution was vortexed until thoroughly
mixed. A drop of the coating was then placed on a microscope slide
and the sample was dried over night under vacuum in a bell jar.
This was the maximum level of drug loading (5.3%) attainable with
this formulation before crystals began to form after drying. A
bio-absorbable carrier component in combination with a vitamin E
compound was then made by mixing 3.5 grams of vitamin E and 1.5
grams of fish oil to form a base coating (70% vitamin E). A sample
was then prepared by first dissolving 110 mg of rapamycin in 244 mg
of NMP (n-Methyl-2-Pyrrolidone). After the drug was fully dissolved
in the solvent, 118 mg of the 70% vitamin E/30% fish oil base coat
was added and the solution was vortexed until thoroughly mixed. A
drop of the coating was then placed on a microscope slide and the
sample was dried over night under vacuum in a bell jar. This was
the maximum level of drug loading attainable with this formulation
due to solubility constraints of the solvent. Crystals did not form
after drying at any percentage below this level with this
formulation. The 30% vitamin E formulation has a maximum solubility
of just over 5% for the rapamycin and the 70% vitamin E formulation
has a maximum solubility of greater than 48%.
EXAMPLE #2
[0120] A bio-absorbable carrier component in combination with a
vitamin E compound was made by mixing 3.5 grams of Vitamin E and
1.5 grams of fish oil to form a base coating (70% vitamin E/30%
fish oil). A sample was then prepared by first dissolving 41 mg of
melatonin in 270 mg of NMP (N-methyl-2-pyrrolidone). After the drug
was fully dissolved in the solvent, 316 mg of the 70% vitamin E/30%
fish oil base coat was added and the solution was vortexed until
thoroughly mixed. A drop of the coating was then placed on a
microscope slide and the sample was dried over night under vacuum
in a bell jar. This was the maximum level of drug loading (11.5%)
attainable with this formulation before crystals began to form
after drying. A bio-absorbable carrier component in combination
with a vitamin E compound was then made by mixing 3.5 grams of
vitamin E and 1.5 grams of fish oil fatty acids (FOFA) to form a
base coating (70% vitamin E/30% FOFA). A sample was then prepared
by first dissolving 81.5 mg of melatonin in 120 mg of NMP
(N-methyl-2-pyrrolidone). After the drug was fully dissolved in the
solvent, 209 mg of the 70% vitamin E/30% FOFA base coat was added
and the solution was vortexed until thoroughly mixed. A drop of the
coating was then placed on a microscope slide and the sample was
dried over night under vacuum in a bell jar. This was the maximum
level of drug loading attainable (28%) with this formulation before
crystals began to form after drying. Crystals did not form after
drying at any percentage below this level with this formulation.
Melatonin formulated with 70% vitamin E and 30% fish oil
formulation has a maximum solubility of 11.5%. When a 70% vitamin E
and 30% fish oil fatty acid formulation is used with melatonin, the
maximum solubility increases to greater than 28%.
EXAMPLE #3
[0121] A bio-absorbable carrier component in combination with a
vitamin E compound was made by mixing 3.5 grams of vitamin E and
1.5 grams of fish oil to form a base coating (70% vitamin E/30%
fish oil). A sample was then prepared by first dissolving 8.4 mg of
paclitaxel in 153 mg of ethanol. After the drug was fully dissolved
in the solvent, 162.4 mg of the 70% vitamin E/30% fish oil base
coat was added and the solution was vortexed until thoroughly
mixed. A drop of the coating was then placed on a microscope slide
and the sample was dried over night under vacuum in a bell jar.
This was the maximum level of drug loading (4.9%) attainable with
this formulation before crystals began to form after drying. A
bio-absorbable carrier component in combination with a vitamin E
compound was then made by mixing 3.5 grams of vitamin E and 1.5
grams of fish oil to form a base coating (70% vitamin E/30% fish
oil). A sample was then prepared by first dissolving 8.4 mg of
paclitaxel in 153 mg of NMP (N-methyl-2-pyrrolidone). After the
drug was fully dissolved in the solvent, 162.4 mg of the 70%
vitamin E/30% fish oil base coat was added and the solution was
vortexed until thoroughly mixed. A drop of the coating was then
placed on a microscope slide and the sample was dried over night
under vacuum in a bell jar. This was the minimum level of drug
loading (4.9%) tested with this formulation and crystals formed
after drying. Loading paclitaxel at 4.9% by weight in a coating
using N-methyl-2-pyrrolidone, the drug is not totally dissolved.
Loading paclitaxel at 5% by weight in a coating using ethanol, the
drug is completely dissolved.
EXAMPLE #4
[0122] A bio-absorbable carrier component in combination with a
vitamin E compound was made by mixing 3.5 grams of vitamin E and
1.5 grams of fish oil to form a base coating (70% vitamin E/30%
fish oil). A sample was then prepared by first dissolving 23.7 mg
of melatonin in 213.7 mg of ethanol. After the drug was fully
dissolved in the solvent, 244.8 mg of the 70% vitamin E/30% fish
oil base coat was added and the solution was vortexed until
thoroughly mixed. A drop of the coating was then placed on a
microscope slide and the sample was dried over night under vacuum
in a bell jar. At this level of drug loading (9%) there were
crystals that formed in this formulation after drying. A
bio-absorbable carrier component in combination with a vitamin E
compound was then made by mixing 3.5 grams of vitamin E and 1.5
grams of fish oil to form a base coating (70% vitamin E/30% fish
Oil). A sample was then prepared by first dissolving 43.2 mg of
melatonin in 394.7 mg of NMP (N-methyl-2-pyrrolidone). After the
drug was fully dissolved in the solvent, 449.2 mg of the 70%
vitamin E/30% fish oil base coat was added and the solution was
vortexed until thoroughly mixed. A drop of the coating was then
placed on a microscope slide and the sample was dried over night
under vacuum in a bell jar. This was a similar level of drug
loading (9%) tested with this formulation and no crystals formed
after drying. Loading melatonin at 9% by weight in a 70% vitamin E
and 30% fish oil formulation using N-methyl-2-pyrrolidone, the drug
is totally dissolved. Loading melatonin at 9% by weight in a 70%
vitamin E and 30% fish oil using ethanol, the drug forms
crystals.
[0123] Numerous modifications and alternative embodiments of the
present invention will be apparent to those skilled in the art in
view of the foregoing description. Accordingly, this description is
to be construed as illustrative only and is for the purpose of
teaching those skilled in the art the best mode for carrying out
the present invention. Details of the structure may vary
substantially without departing from the spirit of the invention,
and exclusive use of all modifications that come within the scope
of the appended claims is reserved. It is intended that the present
invention be limited only to the extent required by the appended
claims and the applicable rules of law.
[0124] All literature and similar material cited in this
application, including, patents, patent applications, articles,
books, treatises, dissertations and web pages, regardless of the
format of such literature and similar materials, are expressly
incorporated by reference in their entirety. In the event that one
or more of the incorporated literature and similar materials
differs from or contradicts this application, including defined
terms, term usage, described techniques, or the like, this
application controls.
[0125] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described in any way.
[0126] While the present inventions have been described in
conjunction with various embodiments and examples, it is not
intended that the present teachings be limited to such embodiments
or examples. On the contrary, the present inventions encompass
various alternatives, modifications, and equivalents, as will be
appreciated by those of skill in the art.
[0127] The claims should not be read as limited to the described
order or elements unless stated to that effect. It should be
understood that various changes in form and detail may be made
without departing from the scope of the appended claims. Therefore,
all embodiments that come within the scope and spirit of the
following claims and equivalents thereto are claimed.
EQUIVALENTS
[0128] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of the present
invention and are covered by the following claims. The contents of
all references, patents, and patent applications cited throughout
this application are hereby incorporated by reference. The
appropriate components, processes, and methods of those patents,
applications and other documents may be selected for the present
invention and embodiments thereof.
* * * * *