U.S. patent application number 16/338962 was filed with the patent office on 2021-01-14 for implantable devices for drug delivery with reduced burst release.
This patent application is currently assigned to Titan Pharmaceuticals, Inc.. The applicant listed for this patent is Titan Pharmaceuticals, Inc.. Invention is credited to Sunil R. BHONSLE, Rajesh A. PATEL, Sunil SREEDHARAN.
Application Number | 20210007973 16/338962 |
Document ID | / |
Family ID | 1000005149691 |
Filed Date | 2021-01-14 |
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United States Patent
Application |
20210007973 |
Kind Code |
A1 |
PATEL; Rajesh A. ; et
al. |
January 14, 2021 |
IMPLANTABLE DEVICES FOR DRUG DELIVERY WITH REDUCED BURST
RELEASE
Abstract
The invention provides implantable drug delivery devices
comprising a core comprising a polymer (or polymer blend) and one
or more drugs or pharmaceutical substances, and an outer shell
comprising a polymer (or polymer blend) and one or more porogen
materials. The invention reduces burst release of drug.
Pharmaceuticals such as triiodothyronine (T3) or ropinirole can be
delivered by the devices.
Inventors: |
PATEL; Rajesh A.; (Redwood
City, CA) ; SREEDHARAN; Sunil; (South San Francisco,
CA) ; BHONSLE; Sunil R.; (Oakland, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Titan Pharmaceuticals, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Titan Pharmaceuticals, Inc.
South San Francisco
CA
|
Family ID: |
1000005149691 |
Appl. No.: |
16/338962 |
Filed: |
October 5, 2017 |
PCT Filed: |
October 5, 2017 |
PCT NO: |
PCT/US2017/055432 |
371 Date: |
April 2, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62404643 |
Oct 5, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4045 20130101;
A61K 31/4458 20130101; B29K 2023/083 20130101; B29K 2001/08
20130101; B29K 2995/006 20130101; A61K 9/0024 20130101; A61K 31/506
20130101; A61K 31/485 20130101; A61K 9/4833 20130101; B29C 48/21
20190201; A61K 9/4808 20130101; A61K 9/4816 20130101; A61K 31/197
20130101; B29C 48/06 20190201; A61K 38/26 20130101; B29K 2105/0035
20130101; B29L 2031/753 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/48 20060101 A61K009/48; A61K 31/197 20060101
A61K031/197; A61K 31/4045 20060101 A61K031/4045; A61K 31/506
20060101 A61K031/506; A61K 31/4458 20060101 A61K031/4458; A61K
38/26 20060101 A61K038/26; A61K 31/485 20060101 A61K031/485 |
Claims
1. An implantable device for delivery of a pharmaceutical substance
comprising: a core comprising a first polymeric material and a core
pharmaceutical substance; and a shell comprising a second polymeric
material and a porogen material; wherein the implantable device has
reduced burst release as compared to a comparison device made
entirely of the first polymeric material and the core
pharmaceutical substance.
2. The implantable device of claim 1, wherein the shell is a
non-medicated layer.
3. The implantable device of claim 1, wherein the shell further
comprises a shell pharmaceutical substance.
4. The implantable device of any one of claims 1-3, wherein the
shell comprises about 1 wt % to about 80 wt % porogen material.
5. The implantable device of any one of claims 1-4, wherein the
porogen material comprises particles and at least about 90% of the
particles have a longest dimension between about 1 micrometer and
about 50 micrometers.
6. The implantable device of any one of claims 1-5, wherein the
porogen material comprises particles with an average longest
dimension between about 1 micrometer and about 50 micrometers.
7. The implantable device of any one of claims 1-6, wherein the
porogen material comprises particles and at least about 90% of the
particles have a mean dimension that varies by 10% or less from the
average of the mean dimension of the particles.
8. The implantable device of any one of claims 1-7, wherein the
porogen material comprises a bioerodible material.
9. The implantable device of any one of claims 1-7, wherein the
porogen material comprises a non-bioerodible material.
10. The implantable device of any one of claims 1-7, wherein the
porogen material comprises a material selected from the group
consisting of an alkyl cellulose, a hydroxyalkyl cellulose,
ethylcellulose, methylcellulose, hydroxymethylcellulose, a fatty
acid, stearic acid, palmitic acid, myristic acid, linoleic acid, a
biocompatible salt, sodium chloride, calcium chloride, and sodium
phosphate.
11. The implantable device of any one of claims 1-7, wherein the
porogen material comprises ethyl cellulose.
12. The implantable device of any one of claims 1-11, wherein the
porogen material dissolves or dissociates from the shell upon
washing the implantable device.
13. The implantable device of any one of claims 1-12, wherein the
first polymeric material or the second polymeric material comprises
a bioerodible material.
14. The implantable device of any one of claims 1-12, wherein the
first polymeric material or the second polymeric material comprises
a non-bioerodible material.
15. The implantable device of any one of claims 1-12, wherein the
first polymeric material comprises one or more materials selected
from the group consisting of polybutylene terephthalate,
polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
16. The implantable device of claim 15, wherein the first polymeric
material comprises ethylene-vinyl acetate.
17. The implantable device of any one of claims 1-12, 15, and 16,
wherein the second polymeric material comprises one or more
materials selected from the group consisting of polybutylene
terephthalate, polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
18. The implantable device of claim 17, wherein the second
polymeric material comprises ethylene-vinyl acetate.
19. The implantable device of any one of claims 1-18, wherein the
implantable device is rod-shaped.
20. The implantable device of claim 19, wherein the implantable
device has a diameter of about 1 mm to about 8 mm.
21. The implantable device of claim 19 or 20, wherein the
implantable device has a length of about 10 mm to about 80 mm.
22. The implantable device of any one of claims 19-21, wherein the
implantable device is capped at one end of the implantable
device.
23. The implantable device of any one of claims 19-22, wherein the
implantable device is capped at both ends of the implantable
device.
24. The implantable device of any one of claims 1-23, wherein the
core pharmaceutical substance comprises one or more substances
selected from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), a combination of L-thyroxine
(T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole, tenofovir,
emtricitabine, a combination of tenofovir and emtricitabine,
bosentan, methylphenidate, liraglutide, doxycycline, proguanil,
atovaquone, a combination of proguanil and atovaquone, and
nalmefene.
25. The implantable device of any one of claims 1-24, wherein the
core pharmaceutical substance comprises ropinirole or
triiodothyronine.
26. The implantable device of any one of claims 1-25, wherein the
core pharmaceutical substance comprises about 1 wt % to about 80 wt
% of the core.
27. The implantable device of any one of claims 3-26, wherein the
shell pharmaceutical substance comprises one or more substances
selected from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), a combination of L-thyroxine
(T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole, tenofovir,
emtricitabine, a combination of tenofovir and emtricitabine,
bosentan, methylphenidate, liraglutide, doxycycline, proguanil,
atovaquone, a combination of proguanil and atovaquone, and
nalmefene.
28. The implantable device of any one of claims 3-27, wherein the
shell pharmaceutical substance comprises ropinirole or
triiodothyronine.
29. The implantable device of any one of claims 3-28, wherein the
shell pharmaceutical substance comprises about 1 wt % to about 40
wt % of the outer layer.
30. The implantable device of any one of claims 3-29, further
comprising a reinforcing member inside the core.
31. A method of forming an implantable device comprising: extruding
a first composition to form a core, the first composition
comprising a first polymeric material and a core pharmaceutical
substance; and coating the core with a second composition to form a
shell, the second composition comprising a second polymeric
material and a porogen material.
32. A method of forming an implantable device comprising:
co-extruding a first composition and a second composition, where
the first composition is extruded to form a core, the first
composition comprising a first polymeric material and a core
pharmaceutical substance; and the co-extruded second composition
forming a shell around the core, the second composition comprising
a second polymeric material and a porogen material.
33. The method of claim 31 or claim 32, wherein the first
composition is formed by combining the first polymeric material
with the core pharmaceutical substance.
34. The method of any one of claims 31-33, wherein the second
composition is formed by combining the second polymeric material
with the porogen material.
35. The method of any one of claims 31-34, further comprising
washing the implantable device.
36. The method of claim 35, wherein the implantable device is
washed in ethanol, water, or a mixture of ethanol and water.
37. The method of claim 35 or claim 36, wherein washing the device
dissolves the porogen material or dissociates the porogen material
from the implantable device to form a plurality of pores in the
shell.
38. The method of any one of claims 31-37, wherein the second
composition is a non-medicated material.
39. The method of any one of claims 31-38, wherein the second
composition further comprises a shell pharmaceutical substance.
40. The method of any one of claims 31-39, wherein the second
composition comprises about 1 wt % to about 80 wt % porogen
materials.
41. The method of any one of claims 31-40, wherein the porogen
materials comprise spherical particles and at least about 90% of
the spherical particles have a diameter between about 1 micrometer
and about 50 micrometers.
42. The method of any one of claims 31-41, wherein the porogen
materials comprise spherical particles with a mean diameter between
about 1 micrometer and about 50 micrometers.
43. The method of any one of claims 31-42, wherein the porogen
materials comprise spherical particles and at least about 90% of
the spherical particles have a diameter that varies by 10% or less
from a mean diameter.
44. The method of any one of claims 31-43, wherein the porogen
materials comprise a bioerodible material.
45. The method of any one of claims 31-43, wherein the porogen
materials comprise a non-bioerodible material.
46. The method of any one of claims 31-43, wherein the porogen
comprises a material selected from the group consisting of an alkyl
cellulose, a hydroxyalkyl cellulose, ethylcellulose,
methylcellulose, hydroxymethylcellulose, a fatty acid, stearic
acid, palmitic acid, myristic acid, linoleic acid, a biocompatible
salt, sodium chloride, calcium chloride, and sodium phosphate.
47. The method of claim 46, wherein the porogen materials comprise
ethyl cellulose.
48. The method of any one of claims 31-47, wherein the first
polymeric material or the second polymeric material comprises a
bioerodible material.
49. The method of any one of claims 31-47, wherein the first
polymeric material or the second polymeric material comprises a
non-bioerodible material.
50. The method of any one of claims 31-47, wherein the first
polymeric material comprises one or more materials selected from
the group consisting of polybutylene terephthalate, polycarbonate,
polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
51. The method of claim 50, wherein the first polymeric material
comprises ethylene-vinyl acetate.
52. The method of any one of claim 31-47, 50, or 51, wherein the
second polymeric material comprises one or more materials selected
from the group consisting of polybutylene terephthalate,
polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
53. The method of claim 52, wherein the second polymeric material
comprises ethylene-vinyl acetate.
54. The method of any one of claims 31-53, wherein the implantable
device is rod-shaped.
55. The method of any one of claims 31-54, wherein the implantable
device has a diameter of about 1 mm to about 8 mm.
56. The method of any one of claims 31-55, wherein the implantable
device has a length of about 10 mm to about 80 mm.
57. The method of any one of claims 31-56, further comprising
capping the implantable device at one end of the implantable
device.
58. The method of any one of claims 31-57, further comprising
capping the implantable device at both ends of the implantable
device.
59. The method of any one of claims 31-58, wherein the core
pharmaceutical substance comprises one or more substances selected
from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), a combination of L-thyroxine
(T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole, tenofovir,
emtricitabine, a combination of tenofovir and emtricitabine,
bosentan, methylphenidate, liraglutide, doxycycline, proguanil,
atovaquone, a combination of proguanil and atovaquone, and
nalmefene.
60. The method of any one of claims 31-59, wherein the core
pharmaceutical substance comprises ropinirole or
triiodothyronine.
61. The method of any one of claims 31-60, wherein the core
pharmaceutical substance comprises about 1 wt % to about 80 wt % of
the first composition.
62. The method of any one of claims 38-61, wherein the shell
pharmaceutical substance comprises one or more substances selected
from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), a combination of L-thyroxine
(T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole, tenofovir,
emtricitabine, a combination of tenofovir and emtricitabine,
bosentan, methylphenidate, liraglutide, doxycycline, proguanil,
atovaquone, a combination of proguanil and atovaquone, and
nalmefene.
63. The method of any one of claims 38-62, wherein the shell
pharmaceutical substance comprises ropinirole or
triiodothyronine.
64. The method of any one of claims 38-63, wherein the shell
pharmaceutical substance comprises about 1 wt % to about 40 wt % of
the second composition.
65. A method of treating a disease in a subject comprising
implanting into the subject the implantable device according to any
one of claims 1-30.
66. A method of treating hypothyroidism, metabolic syndrome,
hyperlipidemia, or obesity in a subject, comprising implanting into
the subject the implantable device according to any one of claim
1-23, 26, 29, or 30, wherein the core pharmaceutical substance
comprises L-thyroxine (T.sub.4), L-triiodothyronine (T.sub.3), or a
combination of L-thyroxine (T.sub.4) and L-triiodothyronine
(T.sub.3).
67. A method of providing pre-exposure prophylaxis of HIV or
prophylaxis of retroviral acquisition in a subject, comprising
implanting into the subject the implantable device according to any
one of claim 1-23, 26, 29, or 30, wherein the core pharmaceutical
substance comprises tenofovir, emtricitabine, or a combination of
tenofovir and emtricitabine.
68. A method of treating HIV infection or retroviral infection in a
subject, comprising implanting into the subject the implantable
device according to any one of claim 1-23, 26, 29, or 30, wherein
the core pharmaceutical substance comprises tenofovir,
emtricitabine, or a combination of tenofovir and emtricitabine.
69. A method of providing prophylaxis against malaria in a subject,
comprising implanting into the subject the implantable device
according to any one of claim 1-23, 26, 29, or 30, wherein the core
pharmaceutical substance comprises doxycycline, atovaquone,
proguanil, or a combination of atovaquone and proguanil.
70. A method of treating Parkinson's disease in a subject,
comprising implanting into the subject the implantable device
according to any one of claim 1-23, 26, 29, or 30, wherein the core
pharmaceutical substance comprises ropinirole.
71. A method of treating restless leg syndrome in a subject,
comprising implanting into the subject the implantable device
according to any one of claim 1-23, 26, 29, or 30, wherein the core
pharmaceutical substance comprises ropinirole.
72. A method of treating pulmonary arterial hypertension in a
subject, comprising implanting into the subject the implantable
device according to any one of claim 1-23, 26, 29, or 30, wherein
the core pharmaceutical substance comprises bosentan.
73. A method of treating attention deficit/hyperactivity disorder
in a subject, comprising implanting into the subject the
implantable device according to any one of claim 1-23, 26, 29, or
30, wherein the core pharmaceutical substance comprises
methylphenidate.
74. A method of treating type 2 diabetes in a subject, comprising
implanting into the subject the implantable device according to any
one of claim 1-23, 26, 29, or 30, wherein the core pharmaceutical
substance comprises liraglutide.
75. A method of treating obesity in a subject, comprising
implanting into the subject the implantable device according to any
one of claim 1-23, 26, 29, or 30, wherein the core pharmaceutical
substance comprises liraglutide.
76. A method of treating alcoholism or alcohol addiction in a
subject, comprising implanting into the subject the implantable
device according to any one of claim 1-23, 26, 29, or 30, wherein
the core pharmaceutical substance comprises nalmefene.
77. The method of any one of claims 65-76, wherein the implantable
device releases an average of about 10 .mu.g to about 150 .mu.g of
the core pharmaceutical substance per day for the first 30 days
when implanted in the subject.
78. The method of any one of claims 65-77, wherein the implantable
device releases the core pharmaceutical substance when implanted in
the subject with a daily variance of less than about 10% from the
daily average release for the first 30 days.
79. The method of any one of claims 65-78 wherein the implantable
device releases the core pharmaceutical substance when implanted in
the subject with an initial burst at least 50% lower than the
initial burst from a comparison implant without the shell.
80. The method of any one of claims 65-78, wherein the implantable
device releases the core pharmaceutical substance when implanted in
the subject with an initial burst at least 50% lower than the
initial burst from a comparison implant where the shell is replaced
with additional core material.
81. The method of any one of claims 65-80, wherein the implantable
device is implanted subdermally in the subject.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims priority benefit of U.S.
Provisional Patent Application No. 62/404,643 filed Oct. 5, 2016.
The entire contents of that application are hereby incorporated by
reference herein.
TECHNICAL FIELD
[0002] The invention provides devices which can be implanted into a
patient for release of pharmaceutical substances, such as
triiodothyronine, over long periods of time, with reduced, minimal,
or no burst release.
BACKGROUND OF THE INVENTION
[0003] Many patients require long-term, regular dosing with drugs
or pharmaceutical substances. Effective treatment often
necessitates the ingestion of one or more tablets per day for
extended periods of time. For example, patients who undergo
thyroidectomy, a common treatment for thyroid cancer, must take
oral thyroxine tablets for the rest of their lifetime. Typically,
patients take levothyroxine (T.sub.4), which is converted in vivo
into triiodothyronine (T.sub.3). Both T.sub.4 and T.sub.3 regulate
a wide variety of metabolic pathways in humans, including the basal
metabolic rate.
[0004] Several problems can arise during long-term administration
of drugs taken orally or by other routes requiring frequent
administration. Compliance with an extended dosing regimen can
often be inconvenient or difficult. For example, patients with
impaired cognitive function (due to Alzheimer's disease or other
disorders) may not be able to self-administer drugs reliably,
requiring a caregiver to ensure that medications are taken
properly. Furthermore, enteral drug delivery is sometimes poorly
tolerated or prohibited in patients with particular indications.
Frequent or periodic administration, such as would occur with daily
oral and sublingual delivery, can result in blood concentrations of
drug peaking quickly after initial administration, then dropping
steeply before the next administration.
[0005] Implantable devices used for drug delivery can overcome
several problems with oral, sublingual, or intravenous
administration of drugs. These devices can produce long-term,
continuous delivery of drugs, ensure compliance independent of the
patient, maintain stable blood levels of medication, and reduce the
likelihood of accidental use, abuse, or diversion for sale.
Continuous release of a compound in vivo over an extended duration
may be achieved via implantation of a device containing the
compound encapsulated in a polymeric matrix. Examples of
implantable polymeric devices for continuous drug release are
described in, e.g., U.S. Pat. Nos. 4,883,666; 5,114,719; and
5,601,835. Patel et al. U.S. Patent Application Publication Nos.
2004/0033250, 2007/0275031, and 2008/0026031, and Kleppner et al.
2006 J. Pharm. Pharmacol. 58:295-302 describe an implantable device
comprising buprenorphine blended with ethylene vinyl acetate (EVA
copolymer). Patel et al. U.S. Patent Application Publication No.
2005/0031668 describes an implantable polymeric device for
sustained release of nalmefene. Patel et al. U.S. Patent
Application Publication No. 2005/0031667 describes an implantable
polymeric device for sustained release of dopamine agonists.
Additional drug delivery devices include stents coated with
compositions comprising drugs. Various devices and coatings are
described in U.S. Pat. No. 6,506,437 to Harish; U.S. Pat. No.
7,364,748 to Claude and U.S. Pat. No. 7,384,660 to Hossainy. U.S.
Pat. No. 3,625,214 describes a drug-delivery device for prolonged
drug delivery, fabricated in a spiral or "jellyroll" fashion. U.S.
Pat. No. 3,926,188 describes a three-layer laminate drug dispenser
comprising a core lamina of a crystalline drug of low water
solubility dispersed in a polymer matrix, interposed between outer
laminas made of a drug release rate controlling polymer. U.S.
Pat.No. 5,683,719 describes a controlled release composition
comprising an extruded core of active material and excipients, the
core being coated in a water insoluble coating.
[0006] One difficulty encountered with virtually all sustained drug
formulations, including implants, is burst release. Burst release
is a high release of drug when the formulation is first
administered which is higher than the desired release rate, and
which can cause deleterious pharmacological effects resulting from
excessive levels of drug. This is particularly undesirable for
systems, such as implants, that release thyroid hormones, as
dangerous cardiac complications may occur. There is thus a need to
reduce or eliminate burst release in controlled-release systems for
delivery of pharmaceutical substances, including thyroid hormones
such as T.sub.3.
BRIEF SUMMARY OF THE INVENTION
[0007] The invention provides implantable drug delivery devices
comprising a core comprising a polymer (or polymer blend) and one
or more drugs or pharmaceutical substances, and an outer shell
comprising a polymer (or polymer blend) and one or more porogen
materials. The shell can optionally additionally comprise one or
more drugs or pharmaceutical substances. Surrounding the
drug-containing core with a porogen-containing shell can reduce the
burst release often observed with sustained release formulations.
Use of a porogen material having a narrow size distribution, and
the resulting narrow size distribution of the pores left in the
shell after removal of the porogen, also allows better control and
tuning of the release rate of the drug from the core.
[0008] In some embodiments, the invention provides an implantable
device for delivery of a pharmaceutical substance comprising a core
comprising a first polymeric material and a core pharmaceutical
substance; and a shell comprising a second polymeric material and a
porogen material. The shell can lack a pharmaceutical substance, or
alternatively the shell can further comprise a pharmaceutical
substance (referred to as a "shell pharmaceutical substance"). The
shell can comprise about 1 wt % to about 80 wt % porogen material.
In some embodiments, the porogen material comprises spherical
particles and at least about 90% of the spherical particles have a
diameter between about 1 micrometer and about 50 micrometers. In
some embodiments, the porogen material comprises spherical
particles with a mean diameter between about 1 micrometer and about
50 micrometers. In some embodiments, the porogen material comprises
spherical particles and at least about 90% of the spherical
particles have a diameter that varies by 10% or less from a mean
diameter.
[0009] The porogen material can comprise a bioerodible material.
The porogen material can comprise a non-bioerodible material. The
porogen material can comprise a material selected from the group
consisting of an alkyl cellulose, a hydroxyalkyl cellulose,
ethylcellulose, methylcellulose, hydroxymethylcellulose, a fatty
acid, stearic acid, palmitic acid, myristic acid, linoleic acid, a
biocompatible salt, sodium chloride, calcium chloride, and sodium
phosphate; in some embodiments, the porogen material comprises
ethyl cellulose. In some embodiments, the porogen material
dissolves or dissociates from the shell upon washing the
implantable device.
[0010] The first polymeric material or the second polymeric
material can comprise a bioerodible material. The first polymeric
material or the second polymeric material can comprise a
non-bioerodible material. The first polymeric material can comprise
one or more materials selected from the group consisting of
polybutylene terephthalate, polycarbonate, polyester, polyether
ether ketone, polyethylene-co-tetrafluoroethylene,
polymethylmethacrylate, polyolefin, polypropylene, polysulfones,
polytetrafluoroethylene, polyurethane, polyvinylchloride,
polyvinylidene fluoride, silicone, ABS resins, acrylic polymers and
copolymers, acrylonitrile-styrene copolymers, alkyd resins,
ethylene-vinyl acetate copolymers, copolymers of vinyl monomers
with each other and olefins, ethylene-methyl methacrylate
copolymers, epoxy resins, ethylene vinyl alcohol copolymer
(commonly known by the generic name EVOH or by the trade name
EVAL), poly(glyceryl sebacate), poly(glycolic acid-co-trimethylene
carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0011] The second polymeric material can comprise one or more
materials selected from the group consisting of polybutylene
terephthalate, polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0012] The first polymeric material can comprise ethylene-vinyl
acetate. The second polymeric material can comprise ethylene-vinyl
acetate. In one embodiment, both the first polymeric material and
the second polymeric material comprise ethylene-vinyl acetate
[0013] The implantable device can be rod-shaped. In some
embodiments, the implantable device has a diameter of about 1 mm to
about 8 mm. In some embodiments, the implantable device has a
length of about 10 mm to about 80 mm. In some embodiments, the
implantable device is capped at one end of the implantable device.
In some embodiments, the implantable device is capped at both ends
of the implantable device.
[0014] The core pharmaceutical substance can comprise one or more
substances selected from the group consisting of L-thyroxine
(T.sub.4), L-triiodothyronine (T.sub.3), a combination of
L-thyroxine (T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole,
tenofovir, emtricitabine, a combination of tenofovir and
emtricitabine, bosentan, methylphenidate, liraglutide, atovaquone,
proguanil, a combination of atovaquone and proguanil, and
nalmefene. In some embodiments, the core pharmaceutical substance
comprises triiodothyronine. In some embodiments, the core
pharmaceutical substance comprises ropinirole. The core
pharmaceutical substance can comprise about 1 wt % to about 80 wt %
of the core.
[0015] The shell pharmaceutical substance can comprise one or more
substances selected from the group consisting of L-thyroxine
(T.sub.4), L-triiodothyronine (T.sub.3), a combination of
L-thyroxine (T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole,
tenofovir, emtricitabine, a combination of tenofovir and
emtricitabine, bosentan, methylphenidate, liraglutide, atovaquone,
proguanil, a combination of atovaquone and proguanil, and
nalmefene. In some embodiments, the shell pharmaceutical substance
comprises triiodothyronine. In some embodiments, the shell
pharmaceutical substance comprises ropinirole. The shell
pharmaceutical substance can comprise about 1 wt % to about 40 wt %
of the shell.
[0016] The core pharmaceutical substance and the shell
pharmaceutical substance (when present) can be the same
pharmaceutical substance, such as triiodothyronine or ropinirole.
The core pharmaceutical substance and the shell pharmaceutical
substance (when present) can be different pharmaceutical
substances.
[0017] In some embodiments, the implantable device further
comprises a reinforcing member inside the core.
[0018] The invention further provides methods of forming the
implantable device, comprising extruding a first composition to
form a core, the first composition comprising a first polymeric
material and a core pharmaceutical substance; and coating the core
with second composition to form a shell, the second composition
comprising a second polymeric material and a porogen material. The
first composition can be formed by combining the first polymeric
material with the core pharmaceutical substance. The second
composition can be formed by combining the second polymeric
material with the porogen material.
[0019] The invention further provides methods of forming an
implantable device comprising co-extruding a first composition and
a second composition, where the first composition is extruded to
form a core, the first composition comprising a first polymeric
material and a core pharmaceutical substance; and the co-extruded
second composition forming a shell around the core, the second
composition comprising a second polymeric material and a porogen
material. The first composition can be formed by combining the
first polymeric material with the core pharmaceutical substance.
The second composition can be formed by combining the second
polymeric material with the porogen material.
[0020] In some embodiments of the methods, the method further
comprises washing the implantable device. The implantable device
can be washed with ethanol, water, or a mixture of ethanol and
water. Washing the device can dissolve the porogen material, or
dissociate the porogen material, from the implantable device to
form a plurality of pores in the shell.
[0021] In any of the implants or methods disclosed herein, the
second composition can be a non-medicated material, or the second
composition can further comprise a shell pharmaceutical
substance.
[0022] In any of the implants or methods disclosed herein, the
second composition can comprise about 1 wt % to about 40 wt %
porogen material. In some embodiments, the porogen material
comprises spherical particles and at least about 90% of the
spherical particles have a diameter between about 1 micrometer and
about 50 micrometers. In some embodiments, the porogen material
comprises spherical particles with a mean diameter between about 1
micrometer and about 50 micrometers. In some embodiments, the
porogen material comprises spherical particles and at least about
90% of the spherical particles have a diameter that varies by 10%
or less from a mean diameter.
[0023] In any of the implants or methods disclosed herein, the
porogen material comprises particles and the longest dimension of
at least about 90% of the particles is between about 1 micrometer
and about 50 micrometers. In some embodiments, the porogen material
comprises particles and the average longest dimension of the
particles is between about 1 micrometer and about 50 micrometers.
In some embodiments, the porogen material comprises particles and
the longest dimension of at least about 90% of the particles varies
by 10% or less from the average longest dimension of the
particles.
[0024] In any of the implants or methods disclosed herein, the
porogen material comprises particles and the mean dimension of at
least about 90% of the particles is between about 1 micrometer and
about 50 micrometers, where the mean dimension of the particles is
the mean of the longest dimension of the particles and the shortest
dimension of the particles. In some embodiments, the porogen
material comprises particles and the mean dimension of the
particles is between about 1 micrometer and about 50 micrometers.
In some embodiments, the porogen material comprises particles and
the mean dimension of at least about 90% of the particles varies by
10% or less from the average of the mean dimension of the
particles.
[0025] In any of the implants or methods disclosed herein, the
porogen material can comprise a bioerodible material, or the
porogen material can comprise a non-bioerodible material. The
porogen can comprise a material selected from the group consisting
of an alkyl cellulose, a hydroxyalkyl cellulose, ethylcellulose,
methylcellulose, hydroxymethylcellulose, a fatty acid, stearic
acid, palmitic acid, myristic acid, linoleic acid, a biocompatible
salt, sodium chloride, calcium chloride, and sodium phosphate. The
porogen material can comprise ethyl cellulose.
[0026] In any of the implants or methods disclosed herein, the
first polymeric material or the second polymeric material can
comprise a bioerodible material. In any of the implants or methods
disclosed herein, the first polymeric material or the second
polymeric material can comprise a non-bioerodible material.
[0027] In any of the implants or methods disclosed herein, the
first polymeric material can comprise one or more materials
selected from the group consisting of polybutylene terephthalate,
polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0028] In any of the implants or methods disclosed herein, the
second polymeric material can comprise one or more materials
selected from the group consisting of polybutylene terephthalate,
polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0029] In any of the implants or methods disclosed herein, the
first polymeric material can comprise ethylene-vinyl acetate. In
any of the implants or methods disclosed herein, the second
polymeric material can comprise ethylene-vinyl acetate. In any of
the implants or methods disclosed herein, first polymeric material
can comprise ethylene-vinyl acetate and the second polymeric
material can comprise ethylene-vinyl acetate.
[0030] In any of the implants or methods disclosed herein, the
implantable device can be rod-shaped. In any of the implants or
methods disclosed herein, the implantable device can have a
diameter of about 1 mm to about 8 mm. In any of the implants or
methods disclosed herein, the implantable device can have a length
of about 10 mm to about 80 mm.
[0031] Any of the implants or methods disclosed herein can further
comprise capping the implantable device at one end of the
implantable device. Any of the implants or methods disclosed herein
can further comprise capping the implantable device at both ends of
the implantable device.
[0032] In any of the implants or methods disclosed herein, the core
pharmaceutical substance can comprise one or more substances
selected from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), a combination of L-thyroxine
(T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole, tenofovir,
emtricitabine, a combination of tenofovir and emtricitabine,
bosentan, methylphenidate, liraglutide, atovaquone, proguanil, a
combination of atovaquone and proguanil, and nalmefene. In any of
the implants or methods disclosed herein, the core pharmaceutical
substance can comprise triiodothyronine. In any of the implants or
methods disclosed herein, the core pharmaceutical substance can
comprise ropinirole. The core pharmaceutical substance can comprise
about 1 wt % to about 80 wt % of the first composition.
[0033] In any of the implants or methods disclosed herein, the
shell pharmaceutical substance can comprise one or more substances
selected from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), a combination of L-thyroxine
(T.sub.4) and L-triiodothyronine (T.sub.3), ropinirole, tenofovir,
emtricitabine, a combination of tenofovir and emtricitabine,
bosentan, methylphenidate, liraglutide, atovaquone, proguanil, a
combination of atovaquone and proguanil, and nalmefene. In any of
the implants or methods disclosed herein, the shell pharmaceutical
substance can comprise triiodothyronine. In any of the implants or
methods disclosed herein, the shell pharmaceutical substance can
comprise ropinirole. The shell pharmaceutical substance can
comprise about 1 wt % to about 40 wt % of the second
composition.
[0034] In some embodiments, the invention provides methods of
treating a disease in a subject, comprising implanting into the
subject any of the implantable devices disclosed herein. The
disease can be hypothyroidism, Parkinson's disease, restless leg
syndrome (RLS), HIV infection, retroviral infection, pulmonary
arterial hypertension, attention deficit/hyperactivity disorder,
type 2 diabetes, metabolic syndrome, hyperlipidemia, obesity,
malaria, alcoholism, or alcohol addiction.
[0035] In some embodiments, the invention provides any of the
implantable devices disclosed herein for use in the treatment of a
disease. The disease can be hypothyroidism, Parkinson's disease,
restless leg syndrome (RLS), HIV infection, retroviral infection,
pulmonary arterial hypertension, attention deficit/hyperactivity
disorder, type 2 diabetes, metabolic syndrome, hyperlipidemia,
obesity, malaria, alcoholism, or alcohol addiction.
[0036] In some embodiments, the invention provides for use of any
of the implantable devices disclosed herein for treatment of a
disease. The disease can be hypothyroidism, Parkinson's disease,
restless leg syndrome (RLS), HIV infection, retroviral infection,
pulmonary arterial hypertension, attention deficit/hyperactivity
disorder, type 2 diabetes, metabolic syndrome, hyperlipidemia,
obesity, malaria, alcoholism, or alcohol addiction.
[0037] In some embodiments, the invention provides for use of
L-thyroxine (T.sub.4), L-triiodothyronine (T.sub.3), or a
combination of L-thyroxine (T.sub.4) and L-triiodothyronine
(T.sub.3) for the manufacture of any of the implantable devices
described herein for the treatment of hypothyroidism, metabolic
syndrome, hyperlipidemia, or obesity; use of ropinirole for the
manufacture of any of the implantable devices described herein for
the treatment of Parkinson's disease or restless leg syndrome; use
of tenofovir, emtricitabine, or a combination of tenofovir and
emtricitabine for the manufacture of any of the implantable devices
described herein for the treatment of HIV infection, retroviral
infection, or prophylaxis against HIV infection or retroviral
infection; use of bosentan for the manufacture of any of the
implantable devices described herein for the treatment of pulmonary
arterial hypertension; use of methylphenidate for the manufacture
of any of the implantable devices described herein for the
treatment of attention deficit/hyperactivity disorder; use of
liraglutide for the manufacture of any of the implantable devices
described herein for the treatment of type 2 diabetes or obesity;
use of doxycycline, atovaquone, proguanil, or a combination of
atovaquone and proguanil for the manufacture of any of the
implantable devices described herein for the treatment of malaria,
or for prophylaxis against malaria; or use of nalmefene for the
manufacture of any of the implantable devices described herein for
the treatment of alcoholism or alcohol addiction.
[0038] In some embodiments, the invention provides methods of
providing pre-exposure prophylaxis of HIV or prophylaxis of
retroviral acquisition, comprising implanting into the subject any
of the implantable devices disclosed herein.
[0039] The implantable device can release an average of about 10
.mu.g to about 150 .mu.g of the core pharmaceutical substance per
day for the first 30 days when implanted in the subject. The
implantable device can release the core pharmaceutical substance
when implanted in the subject with a daily variance of less than
about 10% from the daily average release for the first 30 days.
[0040] The implantable device, when implanted in a subject, can
release the core pharmaceutical substance with an initial burst at
least 50% lower than the initial burst from a comparison implant
without the shell. The initial burst period for comparison can be
the first hour after implantation, the first six hours after
implantation, the first 12 hours after implantation, the first 24
hours after implantation, the first 48 hours after implantation,
the first three days after implantation, the first four days after
implantation, the first five days after implantation, the first six
days after implantation, the first seven days after implantation,
the first eight days after implantation, the first nine days after
implantation, or the first ten days after implantation. In one
embodiment, a comparison implant without the shell is an implant
which has only the medicated core of the core-shell implant, and no
shell. Thus, for example, in FIG. 1, a comparison implant without
the shell would simply have the outer shell removed. In another
embodiment, a comparison implant without the shell is an implant
where, instead of having a core and a shell, the entire comparison
implant is made of the material that forms the core with the same
dimensions as the core-shell implant. Thus, for example, in FIG. 1,
a comparison implant without the shell would have the outer shell
replaced with additional core material containing core
pharmaceutical substance, such that the comparison implant has the
same dimensions as the implant of the invention, but is uniformly
made of core material, including core pharmaceutical substance.
[0041] In any of the embodiments described herein, the core
pharmaceutical substance can be present in the form of a salt,
solvate, or hydrate of the active substance.
[0042] In another aspect, the implantable device provides a
steady-state level, an approximately constant level, or an
essentially constant level of pharmaceutical substance or drug in
the blood of the patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] FIG. 1 shows a drawing of one embodiment of an implant of
the invention, with about 30% to about 60% porogen filler in the
outer shell (the balance of the shell is made of ethylene-vinyl
acetate) and about 60% T.sub.3 in the core (the balance of the core
is made of ethylene-vinyl acetate). The drawing is not to
scale.
[0044] FIG. 1A shows a drawing of a cross-section 110 of an implant
of the invention. The drawing is not to scale.
[0045] FIG. 2A shows T.sub.3 plasma levels (ng/dL) in dogs with
T.sub.3 implants having 30% ethylcellulose porogen in the shell and
60% T.sub.3 in the core.
[0046] FIG. 2B shows an expanded version of days 215 to 225 from
FIG. 2A.
[0047] FIG. 3 shows T.sub.4 plasma levels (mcg/dL) in dogs before
and after removal of T.sub.3 implants having 30% ethylcellulose
porogen in the shell and 60% T.sub.3 in the core.
[0048] FIG. 4A shows T.sub.4 plasma levels (mcg/dL) in control dogs
after removal of placebo (non-T.sub.3 containing) implants.
[0049] FIG. 4B shows T.sub.3 plasma levels (ng/dL) in control dogs
after removal of placebo (non-T.sub.3 containing) implants.
[0050] FIG. 4C shows TSH plasma levels in control dogs after
removal of placebo (non-T.sub.3 containing) implants.
[0051] FIG. 5 shows T.sub.3 plasma levels (ng/dL) in dogs with a
stepwise dose increase in T.sub.3 implants having 60%
ethylcellulose porogen in the shell and 60% T.sub.3 in the core,
followed by the removal of all T3 implants.
[0052] FIG. 6 shows T.sub.4 plasma levels (mcg/dL) in dogs with a
stepwise dose increase in T.sub.3 implants having 60%
ethylcellulose porogen in the shell and 60% T.sub.3 in the core,
followed by the removal of all T3 implants.
[0053] FIG. 7 shows T.sub.3 plasma levels (ng/dL) in
thyroidectomized rats versus normal rats, respectively bearing
T.sub.3 implants having 60% ethylcellulose porogen in the shell and
60% T.sub.3 in the core. The data for normal rats in FIG. 7 is also
shown in FIG. 12A and FIG. 12B, using different units.
[0054] FIG. 8 shows LDL levels in dogs before and after removal of
T.sub.3 implants having 30% ethylcellulose porogen in the shell and
60% T.sub.3 in the core.
[0055] FIG. 9 shows triglyceride levels in dogs before and after
removal of T.sub.3 implants having 30% ethylcellulose porogen in
the shell and 60% T.sub.3 in the core.
[0056] FIG. 10 shows HDL levels in dogs before and after removal of
T.sub.3 implants having 30% ethylcellulose porogen in the shell and
60% T.sub.3 in the core.
[0057] FIG. 11 shows mean observed body weight over time of dogs
with T.sub.3 implants having 30% ethylcellulose porogen in the
shell and 60% T.sub.3 in the core versus the predicted body weight
over time of untreated dogs.
[0058] FIG. 12A shows the reduction of burst release upon initial
implantation of a drug-containing core/porogen shell implant, as
compared to an implant where both the core and the shell contain
drug. A linear scale is used for the Y-axis, which uses units of
ng/mL. The data for the drug-containing core/porogen shell implant
is also shown in FIG. 7 using different units.
[0059] FIG. 12B shows the same data as FIG. 12A, using a
logarithmic scale for the Y-axis (ng/mL). The data for the
drug-containing core/porogen shell implant is also shown in FIG. 7
using different units.
[0060] FIG. 13A shows the reduction of burst release upon initial
implantation of a ropinirole-containing core/porogen shell implant,
as compared to the core of the implant without the shell. A linear
scale is used for the Y-axis, which uses units of ng/mL.
[0061] FIG. 13B shows the same data as FIG. 13A, using a
logarithmic scale for the Y-axis (ng/mL).
[0062] FIG. 14 shows environmental scanning electron micrographs of
washed EVA sheets viewed from the top (upper row, panels A1, B1,
and C1) and cross-sectional (lower row, panels A2, B2, and C2)
perspectives, showing voids (pores) after washing. Panels A1 and A2
used citric acid as porogen. Panels B1 and B2 used benzoic acid as
a porogen. Panels C1 and C2 used a different preparation of benzoic
acid as a porogen. Each panel shows an approximately 685
micrometer-wide view of the samples.
DETAILED DESCRIPTION OF THE INVENTION
[0063] The invention provides implantable devices for long-term
sustained drug delivery. In one embodiment, the devices have
reduced burst release upon implantation. The devices comprise:
[0064] 1) a core comprising a polymer (or mixture of polymers)
blended with a drug or pharmaceutical substance (or multiple drugs
or pharmaceutical substances), and
[0065] 2) a shell comprising a polymer (or mixture of polymers)
blended with a porogen. The shell optionally also comprises a drug
or pharmaceutical substance (or multiple drugs or pharmaceutical
substances).
[0066] In one embodiment, the porogen is included in the device
when implanted into a patient. After implantation into the patient,
the porogen in the shell dissolves, leaving pores in the shell
polymer. Interstitial fluid can then access the core, resulting in
elution of drug into the interstitial fluid and eventually into the
systemic circulation.
[0067] In another embodiment, the porogen is removed from the
device prior to implantation. After implantation into the patient,
interstitial fluid can access the core, resulting in dissolution of
drug and diffusion through the resulting pores into the
interstitial fluid and eventually into the systemic circulation
[0068] The invention also provides methods for providing sustained
drug release and for treating diseases and disorders using the
devices of the invention, and kits useful in the methods of the
invention.
Definitions and General Descriptions
[0069] "Drug" and "pharmaceutical substance" are equivalent terms
and are used interchangeably, and encompasses any substance
intended for therapeutic, diagnostic, or nutritional use in a
patient, individual, or subject in need thereof. "Drugs" and
"pharmaceutical substance" include, but are not limited to,
diagnostic agents, therapeutic agents, hormones, nutrients,
vitamins, and minerals.
[0070] A porogen is a first material which is embedded or mixed
into a second material, which can be removed (for example, by
dissolution, diffusion, or degradation) from the second material.
The removal of the porogen results in the creation of pores in the
second material.
[0071] "Biocompatible," when used to describe a material or system,
indicates that the material or system does not provoke an adverse
reaction, or causes only minimal, tolerable adverse reactions, when
in contact with an organism, such as a human.
[0072] A "patient," "individual," or "subject" refers to a mammal,
preferably a human, an agricultural animal such as a cow, pig,
goat, or sheep, or a domestic animal such as a dog or cat. In a
preferred embodiment, a patient, individual, or subject is a
human.
[0073] "Treating" a disease or disorder with the devices and
methods disclosed herein is defined as administering one or more of
the devices disclosed herein to a patient in need thereof, with or
without additional agents, in order to reduce or eliminate either
the disease or disorder, or one or more symptoms of the disease or
disorder, or to retard the progression of the disease or disorder
or of one or more symptoms of the disease or disorder, or to reduce
the severity of the disease or disorder or of one or more symptoms
of the disease or disorder. "Suppression" of a disease or disorder
with the devices and methods disclosed herein is defined as
administering one or more of the devices disclosed herein to a
patient in need thereof, with or without additional agents, in
order to inhibit the clinical manifestation of the disease or
disorder, or to inhibit the manifestation of adverse symptoms of
the disease or disorder. The distinction between treatment and
suppression is that treatment occurs after adverse symptoms of the
disease or disorder are manifest in a patient, while suppression
occurs before adverse symptoms of the disease or disorder are
manifest in a patient. Suppression may be partial, substantially
total, or total. Because some diseases or disorders are inherited,
genetic screening can be used to identify patients at risk of the
disease or disorder. The devices and methods of the invention can
then be used to treat asymptomatic patients at risk of developing
the clinical symptoms of the disease or disorder, in order to
suppress the appearance of any adverse symptoms.
[0074] "Therapeutic use" of the devices disclosed herein is defined
as using one or more of the devices disclosed herein to treat a
disease or disorder, as defined above. A "therapeutically effective
amount" of a drug or a therapeutic agent is an amount of the drug
or agent, which, when administered to a patient, is sufficient to
reduce or eliminate either a disease or disorder or one or more
symptoms of a disease or disorder, or to retard the progression of
a disease or disorder or of one or more symptoms of a disease or
disorder, or to reduce the severity of a disease or disorder or of
one or more symptoms of a disease or disorder. A therapeutically
effective amount can be administered to a patient as a single dose,
or can be divided and administered as multiple doses.
[0075] "Prophylactic use" of the devices disclosed herein is
defined as using one or more of the devices disclosed herein to
suppress a disease or disorder, as defined above. A
"prophylactically effective amount" of a drug or therapeutic agent
is an amount of the drug or agent, which, when administered to a
patient, is sufficient to suppress the clinical manifestation of a
disease or disorder, or to suppress the manifestation of adverse
symptoms of a disease or disorder. A prophylactically effective
amount can be administered to a patient as a single dose, or can be
divided and administered as multiple doses.
[0076] "Blood level" as used herein refers to the concentration of
a drug, therapeutic agent, hormone, metabolite, or other substance
in the blood of a subject. A blood level can be measured in whole
blood, blood serum, or blood plasma, as per standard clinical
laboratory practice for the substance to be assayed.
[0077] As used herein, the singular forms "a", "an", and "the"
include plural references unless indicated otherwise or the context
clearly dictates otherwise.
[0078] When numerical values are expressed herein using the term
"about" or the term "approximately," it is understood that both the
value specified, as well as values reasonably close to the value
specified, are included. For example, the description "about
50.degree. C." or "approximately 50.degree. C." includes both the
disclosure of 50.degree. C. itself, as well as values close to
50.degree. C. Thus, the phrases "about X" or "approximately X"
include a description of the value X itself. If a range is
indicated, such as "approximately 50.degree. C. to 60.degree. C."
or "about 50.degree. C. to 60.degree. C," it is understood that
both the values specified by the endpoints are included, and that
values close to each endpoint or both endpoints are included for
each endpoint or both endpoints; that is, "approximately 50.degree.
C. to 60.degree. C." (or "about 50.degree. C. to 60.degree. C.") is
equivalent to reciting both "50.degree. C. to 60.degree. C." and
"approximately 50.degree. C. to approximately 60.degree. C." (or
"about 50.degree. C. to 60.degree. C").
[0079] With respect to numerical ranges disclosed in the present
description, any disclosed upper limit for a component may be
combined with any disclosed lower limit for that component to
provide a range (provided that the upper limit is greater than the
lower limit with which it is to be combined). Each of these
combinations of disclosed upper and lower limits are explicitly
envisaged herein. For example, if ranges for the amount of a
particular component are given as 10% to 30%, 10% to 12%, and 15%
to 20%, the ranges 10% to 20% and 15% to 30% are also envisaged,
whereas the combination of a 15% lower limit and a 12% upper limit
is not possible and hence is not envisaged.
[0080] Unless otherwise specified, percentages of ingredients in
compositions are expressed as weight percent, or weight/weight
percent. It is understood that reference to relative weight
percentages in a composition assumes that the combined total weight
percentages of all components in the composition add up to 100. It
is further understood that relative weight percentages of one or
more components may be adjusted upwards or downwards such that the
weight percent of the components in the composition combine to a
total of 100, provided that the weight percent of any particular
component does not fall outside the limits of the range specified
for that component.
[0081] Some embodiments described herein are recited as
"comprising" or "comprises" with respect to their various elements.
In alternative embodiments, those elements can be recited with the
transitional phrase "consisting essentially of" or "consists
essentially of" as applied to those elements. In further
alternative embodiments, those elements can be recited with the
transitional phrase "consisting of" or "consists of" as applied to
those elements. Thus, for example, if a composition or method is
disclosed herein as comprising A and B, the alternative embodiment
for that composition or method of "consisting essentially of A and
B" and the alternative embodiment for that composition or method of
"consisting of A and B" are also considered to have been disclosed
herein. Likewise, embodiments recited as "consisting essentially
of" or "consisting of" with respect to their various elements can
also be recited as "comprising" as applied to those elements.
Finally, embodiments recited as "consisting essentially of" with
respect to their various elements can also be recited as
"consisting of" as applied to those elements, and embodiments
recited as "consisting of" with respect to their various elements
can also be recited as "consisting essentially of" as applied to
those elements.
[0082] When a device, composition, or system is described as
"consisting essentially of" the listed elements, the device,
composition, or system contains the elements expressly listed, and
may contain other elements which do not materially affect the
condition being treated (for compositions for treating conditions),
or the properties of the described device or system. However, the
device, composition, or system either does not contain any other
elements which do materially affect the condition being treated
other than those elements expressly listed (for compositions for
treating systems) or does not contain any other elements which do
materially affect the properties of the device or system; or, if
the device, composition, or system does contain extra elements
other than those listed which may materially affect the condition
being treated or the properties of the system, the device,
composition or system does not contain a sufficient concentration
or amount of those extra elements to materially affect the
condition being treated by the composition or the properties of the
device or system. When a method is described as "consisting
essentially of" the listed steps, the method contains the steps
listed, and may contain other steps that do not materially affect
the condition being treated by the method or the properties of the
device or system produced by or used by the method, but the method
does not contain any other steps which materially affect the
condition being treated by the method or the device or system
produced or used other than those steps expressly listed.
[0083] This disclosure provides several embodiments. It is
contemplated that any features from any embodiment can be combined
with any features from any other embodiment where possible. In this
fashion, hybrid configurations of the disclosed features are within
the scope of the present invention.
Device Structure and Manufacture
Physical Parameters of Devices of the Invention
[0084] In some embodiments the devices of the invention are
rod-shaped or generally rod-shaped, and are about 0.5 cm to 10 cm
in length, such as from about 1 cm to about 6 cm in length, or from
about 1 cm to about 5 cm in length, or about 1 cm to about 4 cm in
length, or about 1 cm to 3 cm in length, or about 1.5 cm to 3.5 cm
in length, or about 2 cm to 4 cm in length, or about 2 cm to about
3 cm in length, or about 2 cm to about 5 cm in length, or about 2
cm to about 6 cm in length, or about 3 cm to about 5 cm in length,
or about 3 cm to about 6 cm in length, or about 4 cm to about 5 cm
in length, or about 4 cm to about 6 cm in length, or about 2.6 cm
in length. In some embodiments, the devices are rod-shaped or
generally rod-shaped, and are about 3 cm to about 5 cm in length,
or about 3.5 cm to about 4.5 cm, or about 4 cm. In some
embodiments, the devices are rod-shaped or generally rod-shaped,
and are about 5 cm to about 7 cm in length, or about 5.5 cm to
about 6.5 cm, or about 6 cm.
[0085] In one embodiment, the devices are rod-shaped or generally
rod-shaped, and are about 1 to about 3 mm in diameter, referring to
the overall diameter of the device (that is, including both core
and shell). In some embodiments, the devices are rod-shaped or
generally rod-shaped, and comprise dimensions of about 0.5 to about
7 mm in diameter, or about 2 to about 5 mm in diameter, or about 2
to about 3 mm in diameter, or about 2.4 mm in diameter, or about 3
mm in diameter. In some embodiments, the devices are rod-shaped or
generally rod-shaped, and comprise dimensions of about 2.4 mm in
total diameter and about 2.6 cm in total length.
[0086] The core and shell can vary independently in thickness. FIG.
1A shows a cross section 110 of one embodiment of an implant with a
shell 120 surrounding a core 130. The diameter of the core is
indicated by the arrow labeled 132, while the thickness of the
shell is indicated by the arrow labeled 122. It should be noted
that the overall diameter of the implant device, indicated by the
arrow labeled 112, is the diameter of the core 132 plus twice the
thickness of the shell 122. In one embodiment, the core
independently has a diameter between about 0.25 mm to about 6.75 mm
and the shell independently has a thickness between about 0.125 mm
to about 3.375 mm, with the proviso that the sum of the diameter of
the core and twice the thickness of the shell is less than or equal
to about 7 mm (that is, the total diameter of the implantable
device is less than or equal to about 7 mm). In one embodiment, the
core independently has a diameter between about 0.25 mm to about 4
mm and the shell independently has a thickness between about 0.125
mm to about 2 mm, with the proviso that the sum of the diameter of
the core and twice the thickness of the shell is less than or equal
to about 7 mm. In one embodiment, the core independently has a
diameter between about 1 mm to about 4 mm and the shell
independently has a thickness between about 0.125 mm to about 2 mm,
with the proviso that the sum of the diameter of the core and twice
the thickness of the shell is less than or equal to about 7 mm. In
one embodiment, the core independently has a diameter between about
2 mm to about 4 mm and the shell independently has a thickness
between about 0.125 mm to about 0.625 mm, with the proviso that the
sum of the diameter of the core and twice the thickness of the
shell is less than or equal to about 7 mm (in this embodiment, the
sum of the diameter of the core and twice the thickness of the
shell cannot exceed about 5.25 mm). In a preferred embodiment, the
core independently has a diameter of about 2.5 mm to about 3 mm,
such as 2.75 mm, and the shell independently has a thickness of
about 0.3 mm to about 0.5 mm, such as about 0.375 mm. (In the
embodiment where the core has a diameter of 2.75 mm and the shell
has a thickness of about 0.375 mm, the total diameter of the
implant is about {2.75 mm+(2.times.0.375 mm)}=3.5 mm.)
[0087] For rod-shaped devices, a reinforcing member can be
incorporated into the core. Such a reinforcing member can be
incorporated by co-extrusion of a polymer substance within the
drug-containing core, which will then form a third portion of the
device, having a reinforcing member, a drug-containing core
containing or surrounding the reinforcing member, and the
porogen-containing shell. The reinforcing member can comprise a
polymer with good mechanical strength and resilience, such as pure
ethylene-vinyl acetate. The reinforcing member can be a metal wire
made of a biocompatible metal, such as gold, copper, aluminum, or
stainless steel.
[0088] Producing rod-shaped devices by co-extrusion, followed by
cutting the extruded rod, results in a cylinder-shaped rod. The two
ends of the cylinder (the bases of the cylinder) will have an
exposed core region. In order to prevent elution of drug from the
exposed core region at either end of the device, one or both ends
of the device can be capped with a capping material. The capping
material can be a polymer, such as ethylene-vinyl acetate,
silicone, or an erodible polymer. The capping material can be 1 mm
thick, 2 mm thick, or 3 mm thick. The capping material can be
impermeable to the core pharmaceutical substance, which serves to
prevent elution of core pharmaceutical substance from the ends of
the device. The capping material can be permeable to the core
pharmaceutical substance, which serves to regulate elution of core
pharmaceutical substance from the ends of the device.
Chemical Composition of Devices of the Invention
[0089] CORE: the core of the device comprises polymer and drug. In
one embodiment, the core comprises about 40% to about 80% drug,
such as T.sub.3, or about 45% to about 75% drug, such as T.sub.3,
or about 50% to about 70% drug, such as T.sub.3, or about 55% to
about 65% drug, such as T.sub.3, or about 60% drug, such as
T.sub.3. The balance of the core is made up of polymer; a preferred
polymer is ethylene-vinyl acetate (EVA). EVA blends can have about
60% to about 75% ethylene content and about 40% to about 25% vinyl
acetate content. A preferred EVA blend has about 33% vinyl acetate
content.
[0090] SHELL: the shell of the device comprises polymer and a
porogen. A preferred porogen is ethylcellulose. In one embodiment,
the shell contains about 1% to about 80% porogen, such as
ethylcellulose, or about 1% to about 40% porogen, such as
ethylcellulose, or about 30% to about 80% porogen, such as
ethylcellulose, or about 5% to about 25% porogen, such as
ethylcellulose, or about 5% to about 15% porogen, such as
ethylcellulose, or about 25% to about 50% porogen, such as
ethylcellulose, or about 30% to about 60% porogen, such as
ethylcellulose, or about 35% to about 55% porogen, such as
ethylcellulose, or about 40% to about 50% porogen, such as
ethylcellulose, or about 30% to about 40% porogen, such as
ethylcellulose, or about 50% to about 60% porogen, such as
ethylcellulose. The balance of the shell is made up of polymer. In
one embodiment, the same polymer is used for the shell as is used
for the core, such as EVA, such as EVA with about 33% vinyl
acetate. In another embodiment, a different polymer is used for the
shell than the polymer used for the core.
[0091] Additional preferred porogens are citric acid and benzoic
acid, or salts of citric acid or benzoic acid, such as sodium and
potassium salts. Citric acid and benzoic acid are particularly
useful as shell porogens in an implant with an EVA shell, or an
implant with an EVA shell and an EVA core. Citric acid and benzoic
acid are inexpensive, commonly available in USP/NF grades, and can
be readily identified by their ultraviolet absorbance signatures
during routine HPLC analysis. Benzoic acid has particularly strong
characteristic absorptions at 227 (=.lamda..sub.max) and 275 nm. In
one embodiment, the shell contains about 1% to about 80% porogen,
such as benzoic acid, a benzoic acid salt, citric acid, or a citric
acid salt, or about 1% to about 40% porogen, such as benzoic acid,
a benzoic acid salt, citric acid, or a citric acid salt, or about
30% to about 80% porogen, such as benzoic acid, a benzoic acid
salt, citric acid, or a citric acid salt, or about 5% to about 25%
porogen, such as benzoic acid, a benzoic acid salt, citric acid, or
a citric acid salt, or about 5% to about 15% porogen, such as
benzoic acid, a benzoic acid salt, citric acid, or a citric acid
salt, or about 25% to about 50% porogen, such as benzoic acid, a
benzoic acid salt, citric acid, or a citric acid salt, or about 30%
to about 60% porogen, such as benzoic acid, a benzoic acid salt,
citric acid, or a citric acid salt, or about 35% to about 55%
porogen, such as benzoic acid, a benzoic acid salt, citric acid, or
a citric acid salt, or about 40% to about 50% porogen, such as
benzoic acid, a benzoic acid salt, citric acid, or a citric acid
salt, or about 30% to about 40% porogen, such as benzoic acid, a
benzoic acid salt, citric acid, or a citric acid salt, or about 50%
to about 60% porogen, such as benzoic acid, a benzoic acid salt,
citric acid, or a citric acid salt, or about 60% to about 70%
porogen, such as benzoic acid, a benzoic acid salt, citric acid, or
a citric acid salt, or about 50% to about 70% porogen, such as
benzoic acid, a benzoic acid salt, citric acid, or a citric acid
salt, or about 50% to about 80% porogen, such as benzoic acid, a
benzoic acid salt, citric acid, or a citric acid salt. The balance
of the shell is made up of polymer. In one embodiment, the same
polymer is used for the shell as is used for the core, such as EVA,
such as EVA with about 33% vinyl acetate. In another embodiment, a
different polymer is used for the shell than the polymer used for
the core.
[0092] Benzoic acid is alcohol-soluble, and can be readily removed
from the porogenic shells. Benzoic acid is also currently approved
by the United States Food and Drug Administration for topical,
oral, rectal, vaginal, intramuscular, and intravenous routes of
administration. Relative to citric acid, benzoic acid is less
corrosive toward metal processing equipment. In addition, benzoic
acid has a melting point of 120.degree. C., and can serve as a
surface glidant for the compounded polymer-porogen extrudate as it
passes through a heated nozzle.
[0093] In some embodiments of the invention, the devices
additionally comprise a radiopaque substance. The radiopaque
substance is preferably opaque to X-ray radiation. The radiopaque
substance aids in precisely locating the implant in a non-invasive
manner, for example, in an X-ray or CT scan. The radiopaque
substance can be located in the core, in the shell, or in both the
core and the shell. Barium sulfate is a preferred radiopaque
substance. Other radiopaque substances which can be used include,
but are not limited to, zirconium oxide, bismuth oxide, bismuth
salts, and calcium tungstate.
[0094] In some embodiments of the invention, the devices
additionally comprise a substance which is detectable by magnetic
resonance imaging, for use in locating the implant during an MRI
scan. The substance detectable by magnetic resonance imaging can be
located in the core, in the shell, or in both the core and the
shell.
[0095] In some embodiments of the invention, the devices
additionally comprise both a radiopaque substance and a substance
which is detectable by magnetic resonance imaging. The substance
detectable by magnetic resonance imaging can be located in the
core, in the shell, or in both the core and the shell, and the
radiopaque substance can be located in the core, in the shell, or
in both the core and the shell.
Reduction of Burst Release Using Devices of the Invention
[0096] Burst release from the devices of the invention is reduced
compared to previously used devices; see FIG. 12A, FIG. 12B, FIG.
13A, and FIG. 13B for examples of reduction of burst release. The
devices of the invention can be prepared with varying percentages
of porogen and varying sizes of porogen to adjust the reduction of
burst release as compared to devices without porogen. In some
embodiments, burst release is reduced by at least about three
orders of magnitude. In some embodiments, burst release is reduced
by up to about three orders of magnitude. In some embodiments,
burst release is reduced by about two to about three orders of
magnitude. In some embodiments, burst release is reduced by at
least about two orders of magnitude. In some embodiments, burst
release is reduced by up to about two orders of magnitude. In some
embodiments, burst release is reduced by about two orders of
magnitude. In some embodiments, burst release is reduced by about
one to about two orders of magnitude. In some embodiments, burst
release is reduced by at least about one order of magnitude. In
some embodiments, burst release is reduced by up to about one order
of magnitude. In some embodiments, burst release is reduced by
about one order of magnitude. In some embodiments, burst release is
reduced by about 50%.
[0097] The initial period over which burst release is measured for
comparison can be the first hour after implantation, the first six
hours after implantation, the first 12 hours after implantation,
the first 24 hours after implantation, the first 48 hours after
implantation, the first three days after implantation, the first
four days after implantation, the first five days after
implantation, the first six days after implantation, the first
seven days after implantation, the first eight days after
implantation, the first nine days after implantation, or the first
ten days after implantation.
Pharmaceutical Substance and Drugs for Use in Devices
[0098] A variety of pharmaceutical substances and drugs can be used
in the devices of the invention. In one embodiment, the
pharmaceutical substance or drug in the core comprises a substance
selected from the group consisting of L-thyroxine (T.sub.4),
L-triiodothyronine (T.sub.3), or a combination thereof. In one
embodiment, the pharmaceutical substance or drug in the core
comprises L-triiodothyronine (T.sub.3). In one embodiment, the
pharmaceutical substance or drug in the core comprises L-thyroxine
(T.sub.4). In one embodiment, the pharmaceutical substance or drug
in the core comprises a combination of L-thyroxine (T.sub.4) and
L-triiodothyronine (T.sub.3).
[0099] In one embodiment, the pharmaceutical substance or drug in
the core can comprise ropinirole. In one embodiment, the
pharmaceutical substance or drug in the core can comprise
tenofovir. In one embodiment, the pharmaceutical substance or drug
in the core can comprise emtricitabine. In one embodiment, the
pharmaceutical substance or drug in the core can comprise a
combination of tenofovir and emtricitabine. In one embodiment, the
pharmaceutical substance or drug in the core can comprise bosentan.
In one embodiment, the pharmaceutical substance or drug in the core
can comprise methylphenidate. In one embodiment, the pharmaceutical
substance or drug in the core can comprise liraglutide. In one
embodiment, the pharmaceutical substance or drug in the core can
comprise atovaquone, proguanil, or a combination of atovaquone and
proguanil. In one embodiment, the pharmaceutical substance or drug
in the core can comprise nalmefene.
[0100] In one embodiment, the pharmaceutical substance or drug in
the core can comprise doxycycline, atovaquone, proguanil, or a
combination of atovaquone and proguanil.
[0101] Any of the pharmaceutical substances or drugs that can be
used in the core can also be used as shell pharmaceutical
substances in implants and methods that have a shell pharmaceutical
substance.
[0102] Any of the pharmaceutical substances or drugs described
herein can be used in their non-salt form, or as a salt of the
pharmaceutical substance or drug. Any of the pharmaceutical
substances or drugs described herein can be used in their
non-solvate or non-hydrate form, or as a solvate or hydrate of the
pharmaceutical substance or drug.
Diseases Treatable with Devices of the Invention
[0103] The devices of the invention can be used in methods of
treatment of various diseases. Such diseases include
hypothyroidism, metabolic syndrome, hyperlipidemia, and obesity
(using devices comprising T.sub.3, T.sub.4, or a combination of
T.sub.3 and T.sub.4), Parkinson's disease (using devices comprising
ropinirole), restless leg syndrome (RLS) (using devices comprising
ropinirole), pre-exposure prophylaxis of HIV or other retroviral
acquisition or the treatment of HIV and other retroviral infection
(using devices comprising tenofovir, emtricitabine, or a
combination of tenofovir and emtricitabine); pulmonary arterial
hypertension (using devices comprising bosentan), attention
deficit/hyperactivity disorder (using devices comprising
methylphenidate), and type 2 diabetes (using devices comprising
liraglutide). The devices of the invention can also be used for
treating obesity and for weight loss (using devices comprising
liraglutide). The devices of the invention can also be used for
treating malaria, or for prophylaxis against malaria (using devices
comprising doxycycline, atovaquone, proguanil, or a combination of
atovaquone and proguanil). The devices of the invention can also be
used for treating alcoholism or alcohol addiction (using devices
comprising nalmefene).
Exemplary Polymers for Use in Devices
[0104] As noted above, a preferred polymer for use in both the core
and shell of the implants is ethylene vinyl acetate (EVA). However,
other polymers can be used in the invention. As used herein, a
"polymer" or "polymeric material" means a macromolecule comprising
repeating monomer units or co-monomer units. The polymer may be
bioerodible or non-bioerodible. The polymer may be a homopolymer,
copolymer, terpolymer, or may contain more than three monomers. The
polymer is preferably biocompatible.
[0105] Exemplary polymers that can be used for making devices of
the invention include: acrylics, agarose, alginate, and
combinations, cellulose ethers, collagen, copolymers containing
poly(ethylene glycol) and polybutylene terephthalate segments
(PEG/PBT) (PolyActive(.TM.)), copolymers of poly(lactic) and
glycolic acid, copolymers thereof with poly(ethylene glycol),
derivatives and mixtures thereof, dextran, dextrose, elastin,
epoxides, ethylene vinyl acetate (EVA copolymer), fluoropolymers,
gelatin, hydroxypropylmethylcellulose, maleic anhydride copolymers,
methyl cellulose and ethyl cellulose, non-water soluble cellulose
acetate, non-water soluble chitosan, non-water soluble hydroxyethyl
cellulose, non-water soluble hydroxypropyl cellulose, peptides,
PLLA-poly-glycolic acid (PGA) copolymer (also known as
poly-L-lactic acid-co-glycolic acid, or PLGA), poly (L-lactic
acid), poly(2-ethoxyethyl methacrylate), poly(2-hydroxyethyl
methacrylate), poly(2-methoxyethyl acrylate), poly(2-methoxyethyl
methacrylate), poly(acrylamide), poly(alginic acid), poly(amino
acids), poly(anhydrides), poly(aspartic acid), poly(benzyl
glutamate), poly(beta-hydroxybutyrate), poly(caprolactone),
poly(D,L-lactic acid), poly(D,L-lactide)(PLA),
poly(D,L-lactide-co-caprolactone)(PLA/PCL) and
poly(glycolide-co-caprolactone) (PGA/PCL),
poly(D,L-lactide-co-glycolide) (PLA/PGA), poly(etherurethane urea),
poly(ethyl glutamate-co-glutamic acid), poly(ethylene carbonate),
poly(ethylene glycol), poly(ethylene-co-vinyl alcohol),
poly(glutamic acid), poly(glutamic acid-co-ethyl glutamate),
poly(glycolic acid), poly(glycolide-co-trimethylene carbonate)
(PGA/PTMC), poly(hydroxypropyl methacrylamide), poly(imino
carbonates), poly(leucine), poly(leucine-co-hydroxyethyl
glutamine), poly(L-lactide-co-D,L-lactide) (PLLA/PLA),
poly(L-lactide-co-glycolide)(PLLA/PGA), poly(lysine), poly(ortho
esters), poly(orthoesters), poly(oxaamides), poly(oxaesters),
poly(phosphate ester), poly(phosphazene), poly(phospho esters),
poly(phosphoesters), poly(propylene carbonate), poly(propylene
glycol), poly(pyrrole), poly(tert-butyloxy-carbonylmethyl
glutamate), poly(tetramethylene glycol), poly(trimethylene
carbonate), poly(ureas), poly(urethanes), poly(urethane-ureas),
poly(vinyl alcohol), poly(vinyl alcohol-co-vinyl acetate), high
molecular weight poly(vinylpyrrolidone) (PVP), poly[97.5%
dimethyl-trimethylene carbonate)-co-(2.5% trimethylene carbonate)],
polyacrylic acid, polyalkylene oxides, polyamides, polycaprolactone
(PCL) poly-(hydroxybutyrate-co-hydroxyvalerate) copolymer (PHBV),
polycaprolactone (PCL), polycaprolactone co-butylacrylate,
polydepsipeptides, polydioxanone (PDS), polyesters, polyethylene
glycol, polyethylene oxide (PEO), polyethylene terephthalate (PET),
polyglycolic acid and copolymers and mixtures thereof such as
poly(L-lactide) (PLLA), polyglycolic acid[polyglycolide (PGA)],
polyhydroxybutyrate (PHBT) and copolymers of polyhydroxybutyrate,
polyiminocarbonates, polylactic acid, polymethacrylic acid,
polyolefins, polyphosphazene polymers, polypropylene fumarate,
polysaccharides such as hyaluronic acid, polytetrafluoroethylene
(PTFE Teflon(R)), polyurethanes, silicones, tyrosine-derived
polyarylates, tyrosine-derived polycarbonates, tyrosine-derived
polyiminocarbonates, tyrosine-derived polyphosphonates, urethanes,
and combinations, derivatives and mixtures thereof.
[0106] Exemplary erodible or bioerodible polymers that can be used
for making devices of the invention include erodible or bioerodible
forms of polyamide, aliphatic polycarbonates,
polyalkylcyanoacrylate, polyalkylene oxalates, polyanhydride,
polycarboxylic acid, polyester, poly(hydroxybutyrate), polyimide,
poly(iminocarbonate), polycaprolactone (PCL), poly-D,L-lactic acid
(DL-PLA), polydioxanone, poly(glycolic acid), poly-L-lactic acid
(L-PLA), poly-L-lactic acid-co-glycolic acid (PLGA),
polyorthoester, polyphosphazenes, and polyphosphoester,
poly(trimethylene carbonate), and derivatives and mixtures thereof.
The polymer may also be formed from a material selected from the
group consisting of cellulose ester, polybutylene terephthalate,
polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
and derivatives and combinations thereof.
[0107] Additional representative examples of the polymer for use in
the invention include, but are not limited to, ABS resins, acrylic
polymers and copolymers, acrylonitrile-styrene copolymers, alkyd
resins, and carboxymethyl cellulose, and ethylene-vinyl acetate
copolymers, cellophane, cellulose butyrate, cellulose acetate
butyrate, cellulose acetate, cellulose ethers, cellulose nitrate,
cellulose propionate, copolymers of vinyl monomers with each other
and olefins, ethylene-methyl methacrylate copolymers, epoxy resins,
ethylene vinyl alcohol copolymer (commonly known by the generic
name EVOH or by the trade name EVAL), poly(glyceryl sebacate),
poly(glycolic acid-co-trimethylene carbonate),
poly(hydroxybutyrate-co-valerate), poly(hydroxyvalerate),
poly(lactide-co-glycolide), poly(propylene fumarate),
poly(trimethylene carbonate), polyacrylonitrile, polyamides, such
as Nylon 66 and polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as
polyvinyl acetate, polyvinyl ethers, such as polyvinyl methyl
ether, polyvinylidene halides, such as vinylidene fluoride based
homo- or co-polymer under the trade name Solef(.TM.) or
Kynar(.TM.), for example, polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, such as polyvinyl chloride,
copolymers of these polymers with poly(ethylene glycol) (PEG), or
combinations thereof.
[0108] In some embodiments, the polymer can be copolymers of
poly(lactic) and glycolic acid, poly(anhydrides), poly(D,L-lactic
acid), poly(D,L-lactide), poly(D,L-lactide-co-glycolide),
poly(ethylene carbonate), poly(glycolic acid), poly(glycolide),
poly(L-lactic acid), poly(L-lactide), poly(L-lactide-co-glycolide),
poly(ortho esters), poly(oxaamides), poly(oxaesters),
poly(phosphazenes), poly(phospho esters), poly(phosphoesters),
poly(propylene carbonate), poly(trimethylene carbonate),
poly(tyrosine derived carbonates), poly(tyrosine derived
iminocarbonates), poly(tyrosine derived arylates), copolymers of
these polymers with poly(ethylene glycol) (PEG), or combinations
thereof.
[0109] Examples of non-bioerodible polymers useful in the present
invention include poly(ethylene-co-vinyl acetate) (EVA),
polyvinylalcohol and polyurethanes, such as polycarbonate-based
polyurethanes.
[0110] As previously noted, a preferred polymer for both the core
and the shell of the devices of the invention is ethyl vinyl
acetate (EVA).
[0111] The devices can comprise a single type of polymer or a
mixture of two or more polymers. A mixture of two polymers may
modulate the release rate of the drug. It is desirable that an
effective therapeutic amount of the drug be released from a device
of the invention for a reasonably long period of time. U.S. Pat.
No. 6,258,121 to Yang et al. disclosed a method of altering the
release rate by blending two polymers with differing release rates
and incorporating them into a single layer; this technique can also
aid in reducing burst release of drug upon implant.
Exemplary Porogens
[0112] Examples of porogens which can be used in the shell can
include alkyl celluloses and hydroxyalkyl celluloses, such as
ethylcellulose, methylcellulose, and hydroxymethylcellulose; fatty
acids such as stearic acid, palmitic acid, myristic acid, and
linoleic acid; biocompatible salts, such as sodium chloride,
calcium chloride, or sodium phosphate; and soluble polymers such as
low molecular weight polyvinylpyrollidone (PVP). Porogen particles
are preferably used in a tight size distribution to enable control
over the size of the pores. The mean diameter of the porogens used
can be between about 1 micrometer and about 300 micrometers. In
some embodiments, the mean diameter of the porogens is greater than
the thickness of the shell. In some embodiments, the mean diameter
of the porogens is about equal to the thickness of the shell. In
some embodiments, the mean diameter of the porogens is less than
the thickness of the shell. In some embodiments, the mean diameter
of the porogens is less than about 75% of the thickness of the
shell. In some embodiments, the mean diameter of the porogens is
less than about 50% of the thickness of the shell. In some
embodiments, the mean diameter of the porogens is less than about
25% of the thickness of the shell.
[0113] The porogens (porogenic materials) function to create pores
in the shell of the implantable device, and in preferred
embodiments, are not pharmaceutically active substances or drugs.
In alternate preferred embodiments, porogens (porogenic materials)
are not pharmaceutically active substances or drugs for the disease
or condition which the implantable device is intended to treat.
Thus, for example, when the porogen is citric acid, the implantable
device is not intended to treat a disease or condition for which
citric acid is useful for treatment.
[0114] In some embodiments, the porogen material comprises
spherical particles or approximately spherical particles, and at
least about 90% of the particles have a diameter between about 1
micrometer and about 50 micrometers. In some embodiments, the
porogen material comprises spherical particles or approximately
spherical particles, with a mean diameter between about 1
micrometer and about 50 micrometers. In some embodiments, the
porogen material comprises spherical particles or approximately
spherical particles, and at least about 90% of the particles have a
diameter that varies by about 10% or less from a mean diameter.
[0115] In some embodiments, the porogen material comprises
particles and the longest dimension of at least about 90% of the
particles is between about 1 micrometer and about 50 micrometers.
In some embodiments, the porogen material comprises particles and
the longest dimension of the particles is between about 1
micrometer and about 50 micrometers. In some embodiments, the
porogen material comprises particles and the longest dimension of
at least about 90% of the particles varies by 10% or less from the
average longest dimension of the particles.
[0116] In some embodiments, the porogen material comprises
particles and the mean dimension of at least about 90% of the
particles is between about 1 micrometer and about 50 micrometers,
where the mean dimension of the particles is the mean of the
longest dimension of the particles and the shortest dimension of
the particles. In some embodiments, the porogen material comprises
particles and the mean dimension of the particles is between about
1 micrometer and about 50 micrometers. In some embodiments, the
porogen material comprises particles and the mean dimension of at
least about 90% of the particles varies by 10% or less from the
average of the mean dimension of the particles.
[0117] The mean diameter of the porogen particles, such as
spherical particles or approximately spherical particles, can be
between about 1 micrometer and about 300 micrometers. In one
embodiment, at least about 90% of the particles have a diameter
that varies by about 10% or less from a mean diameter, where the
mean diameter is between about 1 micrometer and about 300
micrometers. In one embodiment, at least about 90% of the particles
have a diameter that varies by about 10% or less from a mean
diameter, where the mean diameter is between about 1 micrometer and
about 200 micrometers. In one embodiment, at least about 90% of the
particles have a diameter that varies by about 10% or less from a
mean diameter, where the mean diameter is between about 1
micrometer and about 100 micrometers. In one embodiment, at least
about 90% of the particles have a diameter that varies by about 10%
or less from a mean diameter, where the mean diameter is between
about 1 micrometer and about 50 micrometers. In one embodiment, at
least about 90% of the particles have a diameter that varies by
about 10% or less from a mean diameter, where the mean diameter is
between about 1 micrometer and about 30 micrometers. In one
embodiment, at least about 90% of the particles have a diameter
that varies by about 10% or less from a mean diameter, where the
mean diameter is between about 1 micrometer and about 25
micrometers. In one embodiment, at least about 90% of the particles
have a diameter that varies by about 10% or less from a mean
diameter, where the mean diameter is between about 1 micrometer and
about 20 micrometers. In one embodiment, at least about 90% of the
particles have a diameter that varies by about 10% or less from a
mean diameter, where the mean diameter is between about 1
micrometer and about 10 micrometers. In one embodiment, at least
about 90% of the particles have a diameter that varies by about 10%
or less from a mean diameter, where the mean diameter is between
about 1 micrometer and about 5 micrometers.
[0118] In one embodiment, at least about 75% of the particles have
a diameter less than about 300 micrometers. In one embodiment, at
least about 75% of the particles have a diameter less than about
200 micrometers. In one embodiment, at least about 75% of the
particles have a diameter less than about 100 micrometers. In one
embodiment, at least about 75% of the particles have a diameter
less than about 50 micrometers. In one embodiment, at least about
75% of the particles have a diameter less than about 30
micrometers. In one embodiment, at least about 75% of the particles
have a diameter less than about 25 micrometers. In one embodiment,
at least about 75% of the particles have a diameter less than about
20 micrometers. In one embodiment, at least about 75% of the
particles have a diameter less than about 10 micrometers. In one
embodiment, at least about 75% of the particles have a diameter
less than about 5 micrometers.
[0119] In one embodiment, at least about 90% of the particles have
a diameter less than about 300 micrometers. In one embodiment, at
least about 90% of the particles have a diameter less than about
200 micrometers. In one embodiment, at least about 90% of the
particles have a diameter less than about 100 micrometers. In one
embodiment, at least about 90% of the particles have a diameter
less than about 50 micrometers. In one embodiment, at least about
90% of the particles have a diameter less than about 30
micrometers. In one embodiment, at least about 90% of the particles
have a diameter less than about 25 micrometers. In one embodiment,
at least about 90% of the particles have a diameter less than about
20 micrometers. In one embodiment, at least about 90% of the
particles have a diameter less than about 10 micrometers. In one
embodiment, at least about 90% of the particles have a diameter
less than about 5 micrometers.
[0120] For particles which are non-spherical or irregularly shaped,
such as needle-type particles, the particles can be characterized
by their longest dimension. The mean longest dimension of the
porogens can be between about 1 micrometer and about 300
micrometers. In one embodiment, at least about 90% of the particles
have a longest dimension that varies by about 10% or less from a
mean longest dimension, where the mean longest dimension is between
about 1 micrometer and about 300 micrometers. In one embodiment, at
least about 90% of the particles have a longest dimension that
varies by about 10% or less from a mean longest dimension, where
the mean longest dimension is between about 1 micrometer and about
200 micrometers. In one embodiment, at least about 90% of the
particles have a longest dimension that varies by about 10% or less
from a mean longest dimension, where the mean longest dimension is
between about 1 micrometer and about 100 micrometers. In one
embodiment, at least about 90% of the particles have a longest
dimension that varies by about 10% or less from a mean longest
dimension, where the mean longest dimension is between about 1
micrometer and about 50 micrometers. In one embodiment, at least
about 90% of the particles have a longest dimension that varies by
about 10% or less from a mean longest dimension, where the mean
longest dimension is between about 1 micrometer and about 30
micrometers. In one embodiment, at least about 90% of the particles
have a longest dimension that varies by about 10% or less from a
mean longest dimension, where the mean longest dimension is between
about 1 micrometer and about 25 micrometers. In one embodiment, at
least about 90% of the particles have a longest dimension that
varies by about 10% or less from a mean longest dimension, where
the mean longest dimension is between about 1 micrometer and about
20 micrometers. In one embodiment, at least about 90% of the
particles have a longest dimension that varies by about 10% or less
from a mean longest dimension, where the mean longest dimension is
between about 1 micrometer and about 10 micrometers. In one
embodiment, at least about 90% of the particles have a longest
dimension that varies by about 10% or less from a mean longest
dimension, where the mean longest dimension is between about 1
micrometer and about 5 micrometers.
[0121] In one embodiment, at least about 75% of the particles have
a longest dimension less than about 300 micrometers. In one
embodiment, at least about 75% of the particles have a longest
dimension less than about 200 micrometers. In one embodiment, at
least about 75% of the particles have a longest dimension less than
about 100 micrometers. In one embodiment, at least about 75% of the
particles have a longest dimension less than about 50 micrometers.
In one embodiment, at least about 75% of the particles have a
longest dimension less than about 30 micrometers. In one
embodiment, at least about 75% of the particles have a longest
dimension less than about 25 micrometers. In one embodiment, at
least about 75% of the particles have a longest dimension less than
about 20 micrometers. In one embodiment, at least about 75% of the
particles have a longest dimension less than about 10 micrometers.
In one embodiment, at least about 75% of the particles have a
longest dimension less than about 5 micrometers.
[0122] In one embodiment, at least about 90% of the particles have
a longest dimension less than about 300 micrometers. In one
embodiment, at least about 90% of the particles have a longest
dimension less than about 200 micrometers. In one embodiment, at
least about 90% of the particles have a longest dimension less than
about 100 micrometers. In one embodiment, at least about 90% of the
particles have a longest dimension less than about 50 micrometers.
In one embodiment, at least about 90% of the particles have a
longest dimension less than about 30 micrometers. In one
embodiment, at least about 90% of the particles have a longest
dimension less than about 25 micrometers. In one embodiment, at
least about 90% of the particles have a longest dimension less than
about 20 micrometers. In one embodiment, at least about 90% of the
particles have a longest dimension less than about 10 micrometers.
In one embodiment, at least about 90% of the particles have a
longest dimension less than about 5 micrometers.
[0123] For particles which are non-spherical or irregularly shaped,
such as needle-type particles, the particles can be also
characterized by the mean of their longest dimension and shortest
dimension ("mean of LD and SD"). The average mean of LD and SD of
the porogens can be between about 1 micrometer and about 300
micrometers. In one embodiment, at least about 90% of the particles
have a mean of LD and SD that varies by about 10% or less from an
average mean of LD and SD, where the average mean of LD and SD is
between about 1 micrometer and about 300 micrometers. In one
embodiment, at least about 90% of the particles have a mean of LD
and SD that varies by about 10% or less from an average mean of LD
and SD, where the average mean of LD and SD is between about 1
micrometer and about 200 micrometers. In one embodiment, at least
about 90% of the particles have a mean of LD and SD that varies by
about 10% or less from an average mean of LD and SD, where the
average mean of LD and SD is between about 1 micrometer and about
100 micrometers. In one embodiment, at least about 90% of the
particles have a mean of LD and SD that varies by about 10% or less
from an average mean of LD and SD, where the average mean of LD and
SD is between about 1 micrometer and about 50 micrometers. In one
embodiment, at least about 90% of the particles have a mean of LD
and SD that varies by about 10% or less from an average mean of LD
and SD, where the average mean of LD and SD is between about 1
micrometer and about 30 micrometers. In one embodiment, at least
about 90% of the particles have a mean of LD and SD that varies by
about 10% or less from an average mean of LD and SD, where the
average mean of LD and SD is between about 1 micrometer and about
25 micrometers. In one embodiment, at least about 90% of the
particles have a mean of LD and SD that varies by about 10% or less
from an average mean of LD and SD, where the average mean of LD and
SD is between about 1 micrometer and about 20 micrometers. In one
embodiment, at least about 90% of the particles have a mean of LD
and SD that varies by about 10% or less from an average mean of LD
and SD, where the average mean of LD and SD is between about 1
micrometer and about 10 micrometers. In one embodiment, at least
about 90% of the particles have a mean of LD and SD that varies by
about 10% or less from an average mean of LD and SD, where the
average mean of LD and SD is between about 1 micrometer and about 5
micrometers.
[0124] In one embodiment, at least about 75% of the particles have
a mean of LD and SD less than about 300 micrometers. In one
embodiment, at least about 75% of the particles have a mean of LD
and SD less than about 200 micrometers. In one embodiment, at least
about 75% of the particles have a mean of LD and SD less than about
100 micrometers. In one embodiment, at least about 75% of the
particles have a mean of LD and SD less than about 50 micrometers.
In one embodiment, at least about 75% of the particles have a mean
of LD and SD less than about 30 micrometers. In one embodiment, at
least about 75% of the particles have a mean of LD and SD less than
about 25 micrometers. In one embodiment, at least about 75% of the
particles have a mean of LD and SD less than about 20 micrometers.
In one embodiment, at least about 75% of the particles have a mean
of LD and SD less than about 10 micrometers. In one embodiment, at
least about 75% of the particles have a mean of LD and SD less than
about 5 micrometers.
[0125] In one embodiment, at least about 90% of the particles have
a mean of LD and SD less than about 300 micrometers. In one
embodiment, at least about 90% of the particles have a mean of LD
and SD less than about 200 micrometers. In one embodiment, at least
about 90% of the particles have a mean of LD and SD less than about
100 micrometers. In one embodiment, at least about 90% of the
particles have a mean of LD and SD less than about 50 micrometers.
In one embodiment, at least about 90% of the particles have a mean
of LD and SD less than about 30 micrometers. In one embodiment, at
least about 90% of the particles have a mean of LD and SD less than
about 25 micrometers. In one embodiment, at least about 90% of the
particles have a mean of LD and SD less than about 20 micrometers.
In one embodiment, at least about 90% of the particles have a mean
of LD and SD less than about 10 micrometers. In one embodiment, at
least about 90% of the particles have a mean of LD and SD less than
about 5 micrometers.
[0126] A single material can be used as the porogen used in the
shell. Alternatively, two or more different porogen materials can
be used.
Manufacture of Devices of the Invention
[0127] In some embodiments, the implantable devices of the
invention can be produced by co-extruding the drug-containing core
of the device and the porogen-containing shell. The drug substance
is reduced to fine particles by milling (e.g., ball-milling,
impact-milling), spray-drying, solvent precipitation, screening, or
other method or combination of methods known in the art to produce
fine particles. The drug can be combined with a polymer which is
also prepared as fine particles to form the mixture used to make
the drug-containing core. Likewise, the porogen-containing shell is
prepared by blending fine particles of polymer with particles of
porogen of the desired size. Each blended mixture is heated to a
temperature suitable for extrusion, such as the softening point of
the polymer. At this point, optionally and if necessary, either or
both of the softened mixtures can be homogenized. The mixtures are
then co-extruded, e.g., via Microtruder screw extruder, Model No.
RCP-025, Randcastle Extrusion Systems, Cedar Grove, N.J., or via
other extrusion devices known in the industry. The diameter of
extrusion, as well as temperature, pressure and other parameters
can be controlled as appropriate for each drug and polymer.
[0128] The extrudate can be extruded horizontally and collected for
further processing. The extrudate can be cut into desirable
lengths, e.g., from about 1 to about 3 cm. The extrudate can then
be washed in a solvent, such as a solvent which dissolves and
removes excess drug from the surface of the implant, or a solvent
which assists in sterilization. Washing with or immersing in
solvents which remove the porogen from the shell can also be used
if it is desired that the porogen be removed prior to implantation.
Examples of solvents which can be used for washing the implant
include water, saline, aqueous buffers, and alcohols such as
ethanol or isopropanol. Mixtures of water and alcohols can also be
used, such as ethanol-water mixtures. Preferable solvents are 100%
ethanol or water-ethanol mixtures. The implants can then be dried
and packaged.
[0129] Washing may be followed by drying to remove the solvent.
Drying is typically done between about 30.degree. C. and about
60.degree. C. for about 6 to about 24 hours, such as at about
40.degree. C. for about 12 hours.
[0130] Drying may be followed by packaging and sterilization.
Implants may be vacuum-packed in moisture barrier foil pouches,
heat-sealed and/or vacuum-sealed, and then sterilized using gamma
irradiation, such as about 20 to 30 kilograys, or about 25
kilograys, or about 2.5 to about 3.5 Megarad, or about 2.9 to about
3.1 Mrads, or about 3 Mrads.
Pharmacological Properties of Devices
Pharmacokinetics
[0131] The implants can provide an approximately constant blood
level. The level of drug delivery is preferably within the
therapeutic range of the drug, and lower than a level that might
cause toxicity. In one embodiment, devices of the invention can
comprise multiple drugs. In one embodiment, more than one
implantable device may be inserted into a patient to achieve a
desired level of drug concentration in the blood.
[0132] Total serum T.sub.3 (i.e., both free T.sub.3 and
protein-bound T.sub.3) in a normal adult human ranges from about
0.9 to about 2.7 nmol/L (about 60 to about 180 ng/dL) (Klee G. G.,
Clinical Chemistry 42(1):155 (1996)). Accordingly,
T.sub.3-containing implants of the invention can be administered to
a patient provide total T.sub.3 levels of about 0.9 to about 2.7
nmol/L (about 60 to about 180 ng/dL), or about 1.2 to about 2.7
nmol/L (about 80 to about 180 ng/dL). T.sub.3-containing implants
of the invention can be administered to a patient to result in a
thyroid-stimulating hormone blood level of about 0.34 to about 4.82
uIU/mL.
[0133] Devices of the invention may be designed to provide a
steady-state concentration of drug in the blood (e.g., in plasma or
serum). Devices of the invention may be designed such that the
resulting concentration of drug in the blood remains essentially
constant over extended periods of time. Devices of the invention
may be designed such that the resulting concentration of drug in
the blood remains approximately constant over extended periods of
time.
[0134] The release of drug from the devices of the invention is
dependent on the rate of dissolution and on passive diffusion
through the polymer matrix, and on other parameters.
[0135] Drug release rates are also affected by washing of the
implant prior to insertion into the patient. The implants may be
washed with a solvent such as water, ethanol, isopropanol, etc.
[0136] An "approximately constant blood level" refers to an
approximately constant level of drug over a period of time in the
blood of the subject or patient. As previously defined, "blood
level" refers to the concentration of a drug, hormone, metabolite,
or other substance in the blood of a subject, and can be measured
in whole blood, blood serum, or blood plasma, as per standard
clinical laboratory practice for the substance to be assayed. In
one embodiment, an approximately constant blood level of drug
varies by no more than about .+-.30% over a day, over a week, over
a month, over three months, over six months, or over nine months,
as compared to the mean or average blood level over that time
period. In another embodiment, an approximately constant level of
drug varies by no more than about .+-.20% over a day, over a week,
over a month, over three months, over six months, or over nine
months, as compared to the mean or average blood level over that
time period. In another embodiment, an approximately constant level
of drug varies by no more than about .+-.10% over a day, over a
week, over a month, over three months, over six months, or over
nine months, as compared to the mean or average blood level over
that time period. An "approximately constant release rate"
indicates that an approximately constant amount of the
pharmaceutical substance is released from a device of the invention
over a period of time, such as over a day, over a week, over a
month, over three months, over six months, or over nine months. In
some embodiments, the approximately constant release rate varies by
no more than about .+-.50%, about .+-.40%, about .+-.30%, about
.+-.20%, or about .+-.10% over the time period indicated, as
compared to the average or mean release. An approximately constant
release rate is preferred in order to achieve an approximately
constant blood level. By "essentially constant" is meant that for
about 95% of the extended period of time, the concentration of drug
in blood is within about three, about two, or preferably about one
standard deviation of the mean blood level. Measurements of the
blood level can be performed hourly, twice a day, daily, twice a
week, weekly, every two weeks, monthly, or at any other periodic
interval for determination of the mean blood levels. For example,
if the mean blood level of a drug sampled at weekly intervals is
2.0 ng/ml, and one standard deviation of the measurement is .+-.0.1
ng/ml, then blood levels that fall within about .+-.0.3 ng/ml,
about .+-.0.2 ng/ml, or preferably about .+-.0.1 ng/ml for about
95% of the measurements are considered essentially constant. By
"extended periods of time" is meant from a period of about 3 months
to a period of about 1 year, or longer, e.g., an extended period of
time can be about 3 months or at least about 3 months, about 4
months or at least about 4 months, about 5 months or at least about
5 months, about 6 months or at least about 6 months, about 9 months
or at least about 9 months, about 12 months or at least about 12
months, about 15 months or at least about 15 months, about 18
months or at least about 18 months, about 21 months or at least
about 21 months, about 24 months or at least about 24 months, or
more than about 24 months.
Insertion and Removal of Drug Delivery Device
[0137] Another aspect of this invention is a method for delivering
a pharmaceutical substance or drug to a patient in need thereof,
comprising the step of inserting a device or devices as disclosed
herein into the patient, wherein the pharmaceutical substance or
drug is released from the device or devices into the patient. In a
preferred method of this invention, devices of the invention are
administered by subdermal implantation. In various embodiments, the
devices are subdermally implanted at a site selected from a group
consisting of the upper arm, scapular region, the back, the leg and
the abdomen. Before implantation, the patient may be lightly
anesthetized, e.g., with isoflurane or other anesthetic known in
the art, and/or may have topical, transdermal, or subdermal
anesthetic applied at the site of implantation. A small incision
can be made through the skin and a trocar inserted subdermally,
then loaded with one implant. The stylet can be inserted to hold
the implant in place and the trocar carefully removed, leaving the
implant in the subdermal space. Each site can be sutured closed and
examined later. Complications such as skin irritation,
inflammation, infection or other site-specific adverse effects can
be monitored and treated, e.g., with antibiotics, as needed.
[0138] In various embodiments, devices of the invention can be left
in the body for up to one year or more. The period of sustained
release of drug into the body is thus from about 1 month to about 1
year, or longer, or from about 3 months to about 1 year or longer,
e.g., at least about 3 months, at least about 6 months, at least
about 9 months, at least about 12 months, at least about 15 months,
at least about 18 months, at least about 21 months, or at least
about 24 months or more. In some embodiments the devices can be
left in the body for more than 1 year. Implants may be removed from
the body at the end of the treatment period, through an incision,
e.g., a 3-mm incision, using forceps.
[0139] A second implant may, for example, be used to deliver a
pharmaceutical substance to counteract any adverse effects caused
by a drug released from a first implant.
[0140] Multiple implants may be inserted into a single patient to
regulate the delivery of a single drug, or to deliver several
drugs.
Exemplary Embodiments
[0141] The invention is further described by the following
embodiments. The features of each of the embodiments are combinable
with any of the other embodiments where appropriate and
practical.
[0142] Embodiment 1. An implantable device for delivery of a
pharmaceutical substance comprising a core comprising a first
polymeric material and a core pharmaceutical substance; and a shell
comprising a second polymeric material and a porogen material;
wherein the implantable device has reduced burst release as
compared to a comparison device made entirely of the first
polymeric material and the core pharmaceutical substance.
[0143] Embodiment 2. The implantable device of embodiment 1,
wherein the shell is a non-medicated layer.
[0144] Embodiment 3. The implantable device of embodiment 1,
wherein the shell further comprises a shell pharmaceutical
substance.
[0145] Embodiment 4. The implantable device of any one of
embodiments 1-3, wherein the shell comprises about 1 wt % to about
80 wt % porogen material.
[0146] Embodiment 5. The implantable device of any one of
embodiments 1-4, wherein the porogen material comprises spherical
particles and at least about 90% of the spherical particles have a
diameter between about 1 micrometer and about 50 micrometers.
[0147] Embodiment 6. The implantable device of any one of
embodiments 1-5, wherein the porogen material comprises spherical
particles with a mean diameter between about 1 micrometer and about
50 micrometers.
[0148] Embodiment 7. The implantable device of any one of
embodiments 1-6, wherein the porogen material comprises spherical
particles and at least about 90% of the spherical particles have a
diameter that varies by 10% or less from a mean diameter.
[0149] Embodiment 8. The implantable device of any one of
embodiments 1-7, wherein the porogen material comprises a
bioerodible material.
[0150] Embodiment 9. The implantable device of any one of
embodiments 1-7, wherein the porogen material comprises a
non-bioerodible material.
[0151] Embodiment 10. The implantable device of any one of
embodiments 1-7, wherein the porogen material comprises a material
selected from the group consisting of an alkyl cellulose, a
hydroxyalkyl cellulose, ethylcellulose, methylcellulose,
hydroxymethylcellulose, a fatty acid, stearic acid, palmitic acid,
myristic acid, linoleic acid, a biocompatible salt, sodium
chloride, calcium chloride, and sodium phosphate.
[0152] Embodiment 11. The implantable device of any one of
embodiments 1-7, wherein the porogen material comprises ethyl
cellulose.
[0153] Embodiment 12. The implantable device of any one of
embodiments 1-11, wherein the porogen material dissolves or
dissociates from the shell upon washing the implantable device.
[0154] Embodiment 13. The implantable device of any one of
embodiments 1-12, wherein the first polymeric material or the
second polymeric material comprises a bioerodible material.
[0155] Embodiment 14. The implantable device of any one of
embodiments 1-12, wherein the first polymeric material or the
second polymeric material comprises a non-bioerodible material.
[0156] Embodiment 15. The implantable device of any one of
embodiments 1-12, wherein the first polymeric material comprises
one or more materials selected from the group consisting of
polybutylene terephthalate, polycarbonate, polyester, polyether
ether ketone, polyethylene-co-tetrafluoroethylene,
polymethylmethacrylate, polyolefin, polypropylene, polysulfones,
polytetrafluoroethylene, polyurethane, polyvinylchloride,
polyvinylidene fluoride, silicone, ABS resins, acrylic polymers and
copolymers, acrylonitrile-styrene copolymers, alkyd resins,
ethylene-vinyl acetate copolymers, copolymers of vinyl monomers
with each other and olefins, ethylene-methyl methacrylate
copolymers, epoxy resins, ethylene vinyl alcohol copolymer
(commonly known by the generic name EVOH or by the trade name
EVAL), poly(glyceryl sebacate), poly(glycolic acid-co-trimethylene
carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0157] Embodiment 16. The implantable device of embodiment 15,
wherein the first polymeric material comprises ethylene-vinyl
acetate.
[0158] Embodiment 17. The implantable device of any one of
embodiments 1-12, 15, and 16, wherein the second polymeric material
comprises one or more materials selected from the group consisting
of polybutylene terephthalate, polycarbonate, polyester, polyether
ether ketone, polyethylene-co-tetrafluoroethylene,
polymethylmethacrylate, polyolefin, polypropylene, polysulfones,
polytetrafluoroethylene, polyurethane, polyvinylchloride,
polyvinylidene fluoride, silicone, ABS resins, acrylic polymers and
copolymers, acrylonitrile-styrene copolymers, alkyd resins,
ethylene-vinyl acetate copolymers, copolymers of vinyl monomers
with each other and olefins, ethylene-methyl methacrylate
copolymers, epoxy resins, ethylene vinyl alcohol copolymer
(commonly known by the generic name EVOH or by the trade name
EVAL), poly(glyceryl sebacate), poly(glycolic acid-co-trimethylene
carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0159] Embodiment 18. The implantable device of embodiment 17,
wherein the second polymeric material comprises ethylene-vinyl
acetate.
[0160] Embodiment 19. The implantable device of any one of
embodiments 1-18, wherein the implantable device is rod-shaped.
[0161] Embodiment 20. The implantable device of embodiment 19,
wherein the implantable device has a diameter of about 1 mm to
about 8 mm.
[0162] Embodiment 21. The implantable device of embodiment 19 or
20, wherein the implantable device has a length of about 10 mm to
about 80 mm.
[0163] Embodiment 22. The implantable device of any one of
embodiments 19-21, wherein the implantable device is capped at one
end of the implantable device.
[0164] Embodiment 23. The implantable device of any one of
embodiments 19-22, wherein the implantable device is capped at both
ends of the implantable device.
[0165] Embodiment 24. The implantable device of any one of
embodiments 1-23, wherein the core pharmaceutical substance
comprises one or more substances selected from the group consisting
of L-thyroxine (T4), L-triiodothyronine (T3), a combination of
L-thyroxine (T4) and L-triiodothyronine (T3), ropinirole,
tenofovir, emtricitabine, a combination of tenofovir and
emtricitabine, bosentan, methylphenidate, and liraglutide.
[0166] Embodiment 25. The implantable device of any one of
embodiments 1-24, wherein the core pharmaceutical substance
comprises ropinirole or triiodothyronine.
[0167] Embodiment 26. The implantable device of any one of
embodiments 1-25, wherein the core pharmaceutical substance
comprises about 1 wt % to about 80 wt % of the core.
[0168] Embodiment 27. The implantable device of any one of
embodiments 3-26, wherein the shell pharmaceutical substance
comprises one or more substances selected from the group consisting
of L-thyroxine (T4), L-triiodothyronine (T3), a combination of
L-thyroxine (T4) and L-triiodothyronine (T3), ropinirole,
tenofovir, emtricitabine, a combination of tenofovir and
emtricitabine, bosentan, methylphenidate, and liraglutide.
[0169] Embodiment 28. The implantable device of any one of
embodiments 3-27, wherein the shell pharmaceutical substance
comprises ropinirole or triiodothyronine.
[0170] Embodiment 29. The implantable device of any one of
embodiments 3-28, wherein the shell pharmaceutical substance
comprises about 1 wt % to about 40 wt % of the outer layer.
[0171] Embodiment 30. The implantable device of any one of
embodiments 3-29, further comprising a reinforcing member inside
the core.
[0172] Embodiment 31. A method of forming an implantable device
comprising extruding a first composition to form a core, the first
composition comprising a first polymeric material and a core
pharmaceutical substance; and coating the core with second
composition to form a shell, the second composition comprising a
second polymeric material and a porogen material.
[0173] Embodiment 32. A method of forming an implantable device
comprising co-extruding a first composition and a second
composition, where the first composition is extruded to form a
core, the first composition comprising a first polymeric material
and a core pharmaceutical substance; and the co-extruded second
composition forming a shell around the core, the second composition
comprising a second polymeric material and a porogen material.
[0174] Embodiment 33. The method of embodiment 31 or embodiment 32,
wherein the first composition is formed by combining the first
polymeric material with the core pharmaceutical substance.
[0175] Embodiment 34. The method of any one of embodiments 31-33,
wherein the second composition is formed by combining the second
polymeric material with the porogen material.
[0176] Embodiment 35. The method of any one of embodiments 31-34,
further comprising washing the implantable device.
[0177] Embodiment 36. The method of embodiment 35, wherein the
implantable device is washed in ethanol, water, or a mixture of
ethanol and water.
[0178] Embodiment 37. The method of embodiment 35 or embodiment 36,
wherein washing the device dissolves the porogen material or
dissociates the porogen material from the implantable device to
form a plurality of pores in the shell.
[0179] Embodiment 38. The method of any one of embodiments 31-37,
wherein the second composition is a non-medicated material.
[0180] Embodiment 39. The method of any one of embodiments 31-38,
wherein the second composition further comprises a shell
pharmaceutical substance.
[0181] Embodiment 40. The method of any one of embodiments 31-39,
wherein the second composition comprises about 1 wt % to about 80
wt % porogen materials.
[0182] Embodiment 41. The method of any one of embodiments 31-40,
wherein the porogen materials comprise spherical particles and at
least about 90% of the spherical particles have a diameter between
about 1 micrometer and about 50 micrometers.
[0183] Embodiment 42. The method of any one of embodiments 31-41,
wherein the porogen materials comprise spherical particles with a
mean diameter between about 1 micrometer and about 50
micrometers.
[0184] Embodiment 43. The method of any one of embodiments 31-42,
wherein the porogen materials comprise spherical particles and at
least about 90% of the spherical particles have a diameter that
varies by 10% or less from a mean diameter.
[0185] Embodiment 44. The method of any one of embodiments 31-43,
wherein the porogen materials comprise a bioerodible material.
[0186] Embodiment 45. The method of any one of embodiments 31-43,
wherein the porogen materials comprise a non-bioerodible
material.
[0187] Embodiment 46. The method of any one of embodiments 31-43,
wherein the porogen comprises a material selected from the group
consisting of an alkyl cellulose, a hydroxyalkyl cellulose,
ethylcellulose, methylcellulose, hydroxymethylcellulose, a fatty
acid, stearic acid, palmitic acid, myristic acid, linoleic acid, a
biocompatible salt, sodium chloride, calcium chloride, and sodium
phosphate.
[0188] Embodiment 47. The method of embodiment 46, wherein the
porogen materials comprise ethyl cellulose.
[0189] Embodiment 48. The method of any one of embodiments 31-47,
wherein the first polymeric material or the second polymeric
material comprises a bioerodible material.
[0190] Embodiment 49. The method of any one of embodiments 31-47,
wherein the first polymeric material or the second polymeric
material comprises a non-bioerodible material.
[0191] Embodiment 50. The method of any one of embodiments 31-47,
wherein the first polymeric material comprises one or more
materials selected from the group consisting of polybutylene
terephthalate, polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0192] Embodiment 51. The method of embodiment 50, wherein the
first polymeric material comprises ethylene-vinyl acetate.
[0193] Embodiment 52. The method of any one of embodiments 31-47,
50, or 51, wherein the second polymeric material comprises one or
more materials selected from the group consisting of polybutylene
terephthalate, polycarbonate, polyester, polyether ether ketone,
polyethylene-co-tetrafluoroethylene, polymethylmethacrylate,
polyolefin, polypropylene, polysulfones, polytetrafluoroethylene,
polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone,
ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene
copolymers, alkyd resins, ethylene-vinyl acetate copolymers,
copolymers of vinyl monomers with each other and olefins,
ethylene-methyl methacrylate copolymers, epoxy resins, ethylene
vinyl alcohol copolymer (commonly known by the generic name EVOH or
by the trade name EVAL), poly(glyceryl sebacate), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(propylene
fumarate), poly(trimethylene carbonate), polyacrylonitrile,
polyamides, Nylon 66, polycaprolactam, polycarbonates,
polycyanoacrylates, polydioxanone, polyesters, polyethers,
polyimides, polyisobutylene and ethylene-alphaolefin copolymers,
polyoxymethylenes, polyphosphoester urethane, polyvinyl ketones,
polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl
acetate, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene
halides, vinylidene fluoride based homo- or copolymer, for example,
polyvinylidene fluoride (PVDF) or
poly(vinylidene-co-hexafluoropropylene) (PVDF-co-HFP) and
polyvinylidene chloride, rayon, rayon-triacetate, silicones, vinyl
halide polymers and copolymers, polyvinyl chloride, and copolymers
of these polymers with poly(ethylene glycol) (PEG).
[0194] Embodiment 53. The method of embodiment 52, wherein the
second polymeric material comprises ethylene-vinyl acetate.
[0195] Embodiment 54. The method of any one of embodiments 31-53,
wherein the implantable device is rod-shaped.
[0196] Embodiment 55. The method of any one of embodiments 31-54,
wherein the implantable device has a diameter of about 1 mm to
about 8 mm.
[0197] Embodiment 56. The method of any one of embodiments 31-55,
wherein the implantable device has a length of about 10 mm to about
80 mm.
[0198] Embodiment 57. The method of any one of embodiments 31-56,
further comprising capping the implantable device at one end of the
implantable device.
[0199] Embodiment 58. The method of any one of embodiments 31-57,
further comprising capping the implantable device at both ends of
the implantable device.
[0200] Embodiment 59. The method of any one of embodiments 31-58,
wherein the core pharmaceutical substance comprises one or more
substances selected from the group consisting of L-thyroxine (T4),
L-triiodothyronine (T3), a combination of L-thyroxine (T4) and
L-triiodothyronine (T3), ropinirole, tenofovir, emtricitabine, a
combination of tenofovir and emtricitabine, bosentan,
methylphenidate, and liraglutide.
[0201] Embodiment 60. The method of any one of embodiments 31-59,
wherein the core pharmaceutical substance comprises ropinirole or
triiodothyronine.
[0202] Embodiment 61. The method of any one of embodiments 31-60,
wherein the core pharmaceutical substance comprises about 1 wt % to
about 80 wt % of the first composition.
[0203] Embodiment 62. The method of any one of embodiments 38-61,
wherein the shell pharmaceutical substance comprises one or more
substances selected from the group consisting of L-thyroxine (T4),
L-triiodothyronine (T3), a combination of L-thyroxine (T4) and
L-triiodothyronine (T3), ropinirole, tenofovir, emtricitabine, a
combination of tenofovir and emtricitabine, bosentan,
methylphenidate, and liraglutide.
[0204] Embodiment 63. The method of any one of embodiments 38-62,
wherein the shell pharmaceutical substance comprises ropinirole or
triiodothyronine.
[0205] Embodiment 64. The method of any one of embodiments 38-63,
wherein the shell pharmaceutical substance comprises about 1 wt %
to about 40 wt % of the second composition.
[0206] Embodiment 65. A method of treating a disease in a subject
comprising implanting into the subject the implantable device
according to any one of embodiments 1-30.
[0207] Embodiment 66. The method of embodiment 65, wherein the
disease is hypothyroidism, Parkinson's disease, restless leg
syndrome (RLS), HIV infection, retroviral infection, pulmonary
arterial hypertension, attention deficit/hyperactivity disorder,
type 2 diabetes, or obesity.
[0208] Embodiment 67. A method of providing pre-exposure
prophylaxis of HIV or prophylaxis of retroviral acquisition,
comprising implanting into the subject the implantable device
according to any one of embodiments 1-30.
[0209] Embodiment 68. The method of any one of embodiments 65-67,
wherein the implantable device releases an average of about 10
.mu.g to about 150 .mu.g of the core pharmaceutical substance per
day for the first 30 days when implanted in the subject.
[0210] Embodiment 69. The method of any one of embodiments 64-68,
wherein the implantable device releases the core pharmaceutical
substance when implanted in the subject with a daily variance of
less than about 10% from the daily average release for the first 30
days.
[0211] Embodiment 70. The method of any one of embodiments 64-68,
wherein the implantable device releases the core pharmaceutical
substance when implanted in the subject with an initial burst at
least 50% lower than the initial burst from a comparison implant
without the shell.
[0212] Embodiment 71. The method of any one of embodiments 64-68,
wherein the implantable device releases the core pharmaceutical
substance when implanted in the subject with an initial burst at
least 50% lower than the initial burst from a comparison implant
where the shell is replaced with additional core material.
[0213] Embodiment A1. An implantable device for delivery of a
pharmaceutical substance comprising a core comprising a first
polymeric material and a core pharmaceutical substance; and a shell
comprising a second polymeric material and a porogen material.
[0214] Embodiment A2. The implantable device of embodiment A1,
wherein the core diameter is between about 0.5 mm to about 3.5 mm,
and the shell thickness is between about 0.25 mm to about 1.75 mm
thickness.
[0215] Embodiment A3. The implantable device of embodiment A1,
wherein the core diameter is between about 0.5 mm to about 3.5 mm,
and the shell thickness is between about 0.25 mm to about 1.75 mm
thickness, with the proviso that the sum of the core diameter plus
twice the thickness of the shell does not exceed about 4 mm.
[0216] Embodiment A4. The implantable device of any one of
embodiments A1-A3, wherein the core diameter is between about 1.5
mm to about 3 mm, and the shell thickness is between about 0.25 mm
to about 0.75 mm.
[0217] Embodiment A5. The implantable device of any one of
embodiments A1-A4, wherein the porogenic material comprises about
1% to about 80% of the shell.
[0218] Embodiment A6. The implantable device of any one of
embodiments A1-A4, wherein the porogenic material comprises about
5% to about 25% of the shell.
[0219] Embodiment A7. The implantable device of any one of
embodiments A1-A4, wherein the porogenic material comprises about
25% to about 50% of the shell.
[0220] Embodiment A8. The implantable device of any one of
embodiments A1-A4, wherein the porogenic material comprises about
50% to about 70% of the shell.
[0221] Embodiment A9. The implantable device of any one of
embodiments A1-A8, wherein the porogenic material is removed from
the device prior to implantation.
[0222] Embodiment A10. The implantable device of any one of
embodiments A1-A9, wherein the porogenic material comprises one or
more of ethyl cellulose, benzoic acid, a benzoic acid salt, citric
acid, or a citric acid salt.
[0223] Embodiment A11. The implantable device of any one of
embodiments A1-A10, wherein the porogenic material comprises ethyl
cellulose.
[0224] Embodiment A12. The implantable device of any one of
embodiments A1-A10, wherein the porogenic material comprises
benzoic acid.
[0225] Embodiment A13. The implantable device of any one of
embodiments A1-A10, wherein the porogenic material comprises a
benzoic acid salt.
[0226] Embodiment A14. The implantable device of any one of
embodiments A1-A10, wherein the porogenic material comprises citric
acid.
[0227] Embodiment A15. The implantable device of any one of
embodiments A1-A10, wherein the porogenic material comprises a
citric acid salt.
[0228] Embodiment A16. The implantable device of any one of
embodiments A1-A15, wherein the porogenic material has a longest
average dimension between about 5 micrometers and about 200
micrometers.
[0229] Embodiment A17. The implantable device of any one of
embodiments A1-A15, wherein the porogenic material has a longest
average dimension between about 10 micrometers and about 150
micrometers.
[0230] Embodiment A18. The implantable device of any one of
embodiments A1-A15, wherein the porogenic material has a longest
average dimension between about 5 micrometers and about 30
micrometers.
[0231] Embodiment A19. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
L-thyroxine (T4).
[0232] Embodiment A20. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
L-triiodothyronine (T3).
[0233] Embodiment A21. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is a
combination of L-thyroxine (T4) and L-triiodothyronine (T3).
[0234] Embodiment A22. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
ropinirole.
[0235] Embodiment A23. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
tenofovir.
[0236] Embodiment A24. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
emtricitabine.
[0237] Embodiment A25. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is a
combination of tenofovir and emtricitabine.
[0238] Embodiment A26. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
bosentan.
[0239] Embodiment A27. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
methylphenidate.
[0240] Embodiment A28. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
liraglutide.
[0241] Embodiment A29. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
doxycycline.
[0242] Embodiment A30. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
proguanil.
[0243] Embodiment A31. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
atovaquone.
[0244] Embodiment A32. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is a
combination of proguanil and atovaquone.
[0245] Embodiment A33. The implantable device of any one of
embodiments A1-A18, wherein the core pharmaceutical substance is
nalmefene.
[0246] Embodiment A34. The implantable device of any one of
embodiments A1-A33, wherein the core pharmaceutical substance
comprises about 1% to about 80% of the core.
[0247] Embodiment A35. The implantable device of any one of
embodiments A1-A33, wherein the core pharmaceutical substance
comprises about 10% to about 80% of the core.
[0248] Embodiment A36. The implantable device of any one of
embodiments A1-A33, wherein the core pharmaceutical substance
comprises about 30% to about 70% of the core.
[0249] Embodiment A37. The implantable device of any one of
embodiments A1-A33, wherein the core pharmaceutical substance
comprises about 50% to about 70% of the core.
[0250] Embodiment A38. The implantable device of any one of
embodiments A1-A37, wherein the first polymeric material is
ethylene vinyl acetate (EVA).
[0251] Embodiment A39. The implantable device of any one of
embodiments A1-A38, wherein the second polymeric material is
ethylene vinyl acetate (EVA).
[0252] Embodiment A40. The implantable device of any one of
embodiments A1-A39, wherein the implantable device releases the
core pharmaceutical substance when implanted in the subject with an
initial burst at least 50% lower than the initial burst from a
comparison implant without the shell.
[0253] Embodiment A41. The implantable device of any one of
embodiments A1-A39, wherein the implantable device releases the
core pharmaceutical substance when implanted in the subject with an
initial burst at least 50% lower than the initial burst from a
comparison implant where the shell is replaced with additional core
material comprising the first polymeric material and the core
pharmaceutical substance.
[0254] Embodiment A42. A method of forming an implantable device of
any one of embodiments A1-A41, comprising extruding a first
composition to form the core, the first composition comprising the
first polymeric material and the core pharmaceutical substance; and
coating the core with a second composition to form the shell, the
second composition comprising the second polymeric material and the
porogen material.
[0255] Embodiment A43. A method of forming an implantable device of
any one of embodiments A1-A41, comprising co-extruding a first
composition and a second composition, where the first composition
is extruded to form the core, the first composition comprising the
first polymeric material and the core pharmaceutical substance; and
the co-extruded second composition forming the shell around the
core, the second composition comprising the second polymeric
material and the porogen material.
[0256] Embodiment A44. The implantable device of any one of
embodiments 1-30 or embodiments A1-41, or the method of any one of
embodiments 31-71 or A42-43, wherein the porogenic material is not
a pharmaceutically active substance or a drug.
[0257] Embodiment A45. The implantable device of any one of
embodiments 1-30 or embodiments A1-41, or the method of any one of
embodiments 31-71 or A42-43, wherein the porogenic material is not
a pharmaceutically active substance or a drug for treating the
disease or condition which the device or method is intended to
treat.
EXAMPLES
[0258] The following examples are intended to illustrate the
invention, and are not intended to limit the invention to the
embodiments exemplified.
Example 1
Testing Implants in Canines
[0259] Implants were prepared by co-extrusion as described above
and tested in two groups of dogs, with a third group of dogs
serving as control. Each Group 1 dog (n=3) received three implants
(30% ethyl cellulose shell/60% T.sub.3 core; 26.times.2.4 mm; 75.8
mg T.sub.3), and were followed for about 8 months, including one
week after removal of the implants. Each Group 2 dog (n=3) received
three T.sub.3 implants (60% ethyl cellulose shell/60% T.sub.3 core)
on day 1, three additional T.sub.3 implants on day 87, and three
additional T.sub.3 implants on day 118, for a dose-escalation
study. The core of the T.sub.3 implants was about 2 mm in diameter,
and the shell thickness was about 0.2 mm (twice the shell thickness
is added to the core diameter to obtain the 2.4 mm diameter of the
T.sub.3 implants). Control dogs (n=3) received EVA-based implants
containing no thyroid hormones. The first implant was 4 cm in
length and 3 mm in diameter; subsequent implants were 6 cm in
length and 3 mm in diameter. Implants were washed with ethanol
prior to use. T.sub.3, T.sub.4, and TSH levels were tested by
immunoassay.
[0260] FIG. 2A shows T.sub.3 levels in Group 1 dogs. FIG. 2B shows
a close-up of T.sub.3 levels upon implant removal on Day 217.
T.sub.3 levels dropped after implants were removed and went back up
after 2 days.
[0261] FIG. 3 shows T.sub.4 levels upon Group 1 implant removal on
Day 217. T.sub.4 levels dropped briefly after implant removal and
then rose sharply to peak four days after removal (Day 221). Since
T.sub.4 is produced only endogenously and is suppressed when there
is exogenous T.sub.3, this result suggests that the implants were
releasing T.sub.3 until they were removed (.about.8 months) when
the dogs began to produce excess T.sub.4 in response to the drop in
T.sub.3.
[0262] FIG. 4A shows T.sub.4 levels upon non-T3 implant removal in
the control dogs. FIG. 4B shows T.sub.3 levels upon non-T3 implant
removal in the control dogs. FIG. 4C shows TSH levels upon non-T3
implant removal in the control dogs. No noticeable effect on
T.sub.3, TSH or T.sub.4 levels were observed after the control
non-T3 implants were removed.
[0263] FIG. 5 shows T.sub.3 levels in Group 2 dogs, implanted with
three T.sub.3 implants on each of Day 1, Day 87, and Day 118. After
each increase in the implantation dose, there was an initial peak
followed by steady state release of T.sub.3. After all 9 implants
were removed, T.sub.3 levels dropped sharply. FIG. 6 shows T.sub.4
levels in Group 2 dogs. T.sub.4 levels dropped after each increase
in T.sub.3 implant dose. After all 9 implants were removed, T.sub.4
levels rose up sharply. TSH levels also dropped with increasing
T.sub.3 implant dose, and rose after all implants were removed (not
shown)
[0264] T.sub.3, but not T.sub.4, has been reported to lower LDL and
triglycerides in hypothyroid human subjects in a study conducted by
the NIH. Celi et al. reported that substitution of L-T.sub.3 for
L-T.sub.4 at equivalent doses (relative to the pituitary) reduced
body weight and resulted in greater thyroid hormone action on lipid
metabolism (Celi et al., J. Clin. Endocrinol. Metab. (2011),
96(11):3466-74). Accordingly, a lipid panel was run on the Group 1
dogs. FIG. 8 shows LDL levels in Group 1 dogs. Mean LDL levels
briefly dropped after removal of the T3 implants, and then rose
sharply to peak by day 3 post-removal. FIG. 9 shows triglyceride
levels in Group 1 dogs. Mean triglyceride levels rose sharply and
peaked a day after the T.sub.3 implants were removed, then dropped
by day 2 and started to rise again. FIG. 10 shows HDL levels in
Group 1 dogs. Mean HDL levels were unaffected the first day after
the T.sub.3 implants were removed, and then dropped sharply by day
2 and went back up by day 3.
[0265] FIG. 11 shows mean body weight of Group 1 dogs. Mean body
weight over time in dogs receiving T3 implants trailed the
simulated normal body weight growth curve for beagle dogs derived
by the Gompertz equation (Helmsmuller et al. BMC Veterinary
Research 2013, 9:203):
m.sub.t=m.sub.maxexp(-exp.sup.[-(t-c)/b])
[0266] where m.sub.t is mass at time t, m.sub.max is mature body
mass, b is proportional to duration of growth, c is the age at
point of inflection (i.e., 36.8% of mature body mass) and t is age
in weeks. A few recorded mean body weights over time were also
obtained from the animal supplier (Ridglan Farms) who noted that
body weight values for some beagle dog ages carry the caveat that
"due to sales, there are fewer dogs to weigh as the age increases,"
which may account for the high variability in mean body weights
over time reported by Ridglan Farms.
Example 2
Testing T3 Implants in Thyroidectomized Rats
[0267] Administration of exogenous T.sub.3 results in a decrease in
production of endogenous T.sub.3 by the thyroid. In order to get
around the issue of endogenous T.sub.3 confounding the analysis of
T.sub.3 release from implants, a thyroidectomized rat model with
low background T.sub.3 was employed.
[0268] Each thyroidectomized rat (n=3) received one T.sub.3 implant
(60% Ethocel Shell/60% T.sub.3 Core; 40.times.3 mm) (ETHOCEL is a
registered trademark of the Dow Chemical Company, Midland, Mich.,
United States, for ethyl cellulose polymer). The results are shown
in FIG. 7, with comparison to normal rats. T.sub.3 release from
T.sub.3 implants in thyroidectomized rats parallel that seen for
these implants in normal rats. The assay upper limits of
quantitation were capped at 1200 ng/dL. Implants were washed with
ethanol prior to use.
[0269] The data for the normal rats receiving the 60% Ethocel
Shell/60% T.sub.3 Core implant is also shown in FIG. 12A and FIG.
12B, in comparison to normal rats receiving a 60% T.sub.3
Shell/Core implant.
Example 3
Ropinirole Implants in Dogs
[0270] Implants were prepared containing ropinirole. Implants with
no shell ("core-only" implant) were prepared with 60% ropinirole in
EVA, which were 2.4 mm in diameter and 26 mm in length. Two
different sets of implants with shells were prepared. One set of
shelled implants was prepared which was 40 mm long and 3 mm in
diameter, having the same 2.4-mm-diameter 60% ropinirole in EVA
core, and with a 0.3 mm-thick shell having 10% ETHOCEL in an EVA
shell (twice the shell thickness is added to the core diameter to
obtain the 3 mm diameter of these implants). The second set of
shelled implants was similar, but was 60 mm long instead of 40 mm
long. The implants were washed with ethanol prior to subdermal
implantation. Three groups of male beagle dogs were used, with
three dogs in each group. Three dogs received two implants each of
the no-shell, core-only implant; three dogs received two implants
each of the 40-mm-long implants with shell, and three dogs received
two implants each of the 60-mm-long implants with shell.
[0271] Plasma levels of ropinirole in the animals is shown in FIG.
13A (Y-axis in linear scale) and FIG. 13B (Y-axis in log scale).
Error bars indicate standard error of the mean (SEM). As can be
readily seen, the implants with no shell had significant burst
release, while the implants with porogen-containing shells had
burst release reduced by nearly an order of magnitude, and could be
considered as having no burst release. The implants with no shell
had a highly variable release over two months, while the resulting
plasma levels from the implants with porogen-containing shell had
much more consistent plasma levels extending for three months, and
had non-zero plasma levels at least as far out as 3.5 months.
Example 4
Benzoic Acid and Citric Acid as Shell Porogens
[0272] Citric acid and benzoic acid were spray dried from ethanol
solution (10% w/v solids) using a ProCepT model 4M8 system. The
citric acid was collected in a single fraction in about 65% yield,
while the benzoic acid was collected in two fractions with a total
yield of around 55%. The powders were characterized for particle
size and morphology using an Olympus BX60 optical microscope. The
spray drying operation resulted in fine, flowable powders for both
citric and benzoic acid. Overall, the citric acid exhibited a
smaller particle size (10-20 .mu.m) than the benzoic acid (30-150
.mu.m). The two preparations of benzoic acid differed primarily by
the preponderance of ribbon-like particles in the second fraction.
The citric acid powder blend was appreciably more dense than the
benzoic acid powder blends, and the latter required more careful
sweeping of the feeder hopper to promote conveyance. However, the
ultimate extrusion, molding, and physical handling characteristics
were similar between the blends.
[0273] The spray-dried powders were blended with milled EVA polymer
with a porogen loading of 60% by weight. Three separate blends were
prepared, respectively, containing citric acid, a first preparation
of benzoic acid, or a second preparation of benzoic acid. A total
of 10-15 g of each blend was prepared and extruded. Neat EVA was
used to purge the extruder between the citric and benzoic acid
runs.
[0274] The porogen formulations were extruded at a barrel
temperature setting of 85.+-.5.degree. C. The blended powders were
hand fed into the extruder. The molten product exited directly from
the extruder's 3 mm orifice (i.e., no external nozzle was applied),
and the extruded filaments were collected on a motorized conveyor
belt (Dorner 2200).
[0275] Extruded filaments were hand-cut into .about.5 cm segments
and pressed into sheets using a heated (100.degree. C.) Carver
hydraulic press equipped with aluminum shims (0.02'' thick). Both
sides of the sheets were protected with PET release film that was
removed after cooling. The sheets, nominally 0.45 mm thick, were
then cut into 2.times.2 cm square coupons. These were loaded into
jars and soaked overnight in absolute ethanol, which was added in a
proportion of 20 mL/g.
[0276] After soaking, the soak solution was drained, and the
coupons and containers were rinsed with fresh ethanol. After
rinsing, the coupons were dried under vacuum in their original
containers. Dry weights were recorded, and representative coupons
were sectioned for imaging in the Zeiss EVO-50 environmental
SEM.
[0277] The weight loss after drying of the extruded, pressed, and
washed EVA coupons indicated near-quantitative elimination of the
porogens (see Table 1), and the washed surfaces appeared free from
particulate. The observed variation in weight loss likely reflects
differences in the local the blend homogeneity.
TABLE-US-00001 TABLE 1 Weight loss behaviors for organic
acid-loaded EVA coupons. EVA/Benzoic EVA/Benzoic EVA/Citric Acid
(first Acid (second Acid preparation) preparation) Porogen Loading
as 60.0% 60.0% 60.0% Formulated by Weight Net Weight Before 5.211
3.683 4.788 Washing (g) Net Weight After 2.160 1.381 1.847 Wash
& Dry (g) Percent Weight Lost 58.5% 62.5% 61.4% to Washing
[0278] FIG. 14 shows environmental scanning electron micrographs of
washed EVA sheets viewed from the top (upper row, panels A1, B1,
and C1) and cross-sectional (lower row, panels A2, B2, and C2)
perspectives, showing voids (pores) after washing. Panels A1 and A2
used citric acid as porogen. Panels B1 and B2 used benzoic acid as
a porogen. Panels C1 and C2 used a different preparation of benzoic
acid as a porogen. Each panel shows an approximately 685
micrometer-wide view of the samples.
[0279] All three test groups exhibited highly interconnected
porosity following the extrusion, molding, and washing operations.
The surface pore distribution was more uniform for the benzoic acid
groups, while the cross-sectional pore size distribution was
smaller and more uniform throughout the citric acid sample. Given
the lower bulk density of the benzoic acid powder blends, more air
was likely introduced during the extrusion of those samples. No
distinguishing features were evident between the two different
benzoic acid samples following washing.
[0280] Although the foregoing invention has been described in some
detail by way of illustration and examples for purposes of clarity
of understanding, it will be apparent to those skilled in the art
that certain changes and modifications may be practiced without
departing from the spirit and scope of the invention. Therefore,
the description should not be construed as limiting the scope of
the invention.
[0281] All publications, patents, and patent applications cited
herein are hereby incorporated by reference in their entirety.
* * * * *