U.S. patent application number 10/815481 was filed with the patent office on 2005-02-10 for implantable polymeric device for sustained release of dopamine agonist.
Invention is credited to Bucalo, Louis R., Costantini, Lauren, Kleppner, Sofie, Patel, Rajesh A..
Application Number | 20050031667 10/815481 |
Document ID | / |
Family ID | 33159641 |
Filed Date | 2005-02-10 |
United States Patent
Application |
20050031667 |
Kind Code |
A1 |
Patel, Rajesh A. ; et
al. |
February 10, 2005 |
Implantable polymeric device for sustained release of dopamine
agonist
Abstract
The present invention provides compositions, methods, and kits
for treatment of Parkinson's disease and other conditions for which
treatment with a dopamine agonist is therapeutically beneficial.
The invention provides a biocompatible nonerodible polymeric device
which releases dopamine agonist continuously with generally linear
release kinetics for extended periods of time. Dopamine agonist is
released through pores that open to the surface of the polymeric
matrix in which it is encapsulated. The device may be administered
subcutaneously to an individual in need of continuous treatment
with dopamine agonist.
Inventors: |
Patel, Rajesh A.; (Redwood
City, CA) ; Bucalo, Louis R.; (Miami Beach, FL)
; Costantini, Lauren; (San Francisco, CA) ;
Kleppner, Sofie; (Burlingame, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
33159641 |
Appl. No.: |
10/815481 |
Filed: |
March 31, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60459315 |
Mar 31, 2003 |
|
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Current U.S.
Class: |
424/426 ;
514/295 |
Current CPC
Class: |
A61L 2300/20 20130101;
A61P 25/14 20180101; A61P 25/00 20180101; A61P 15/00 20180101; A61L
2420/04 20130101; A61L 2300/62 20130101; A61P 15/10 20180101; A61K
31/485 20130101; A61L 31/16 20130101; A61K 9/146 20130101; A61L
31/125 20130101; A61L 31/048 20130101; A61P 29/00 20180101; A61K
31/428 20130101; A61L 2300/602 20130101; A61L 31/10 20130101; A61K
9/1635 20130101; A61K 31/48 20130101; A61L 31/048 20130101; A61P
25/16 20180101; A61P 43/00 20180101; C08L 31/04 20130101; A61K
31/4045 20130101; A61L 2300/606 20130101; A61K 9/0024 20130101;
A61L 31/146 20130101; A61K 31/198 20130101; A61L 2300/40 20130101;
A61K 31/381 20130101; A61L 2300/41 20130101 |
Class at
Publication: |
424/426 ;
514/295 |
International
Class: |
A61F 002/00 |
Claims
We claim:
1. An implantable device for administration of a dopamine agonist
to a mammal in need thereof, comprising a dopamine agonist and a
biocompatible, nonerodible polymeric matrix, wherein said dopamine
agonist is encapsulated within said matrix, and wherein when said
implantable device is implanted subcutaneously in said mammal, said
dopamine agonist is continuously released in vivo over a sustained
period of time through pores that open to the surface of said
matrix at a rate that results in a plasma level of at least about
0.01 ng/ml at steady state.
2. An implantable device according to claim 1, wherein the
polymeric matrix comprises ethylene vinyl acetate copolymer
(EVA).
3. An implantable device according to claim 2, wherein said EVA
comprises about 33% vinyl acetate.
4. An implantable device according to claim 1, comprising about 10
to about 85% dopamine agonist.
5. An implantable device according to claim 4, wherein said
dopamine agonist is selected from the group consisting of
apomorphine, lisuride, pergolide, bromocriptine, pramipexole,
ropinerole, and rotigotine.
6. An implantable device according to claim 5, wherein said
dopamine agonist is apomorphine.
7. An implantable device according to claim 1, wherein the
sustained period of time is at least about 3 months.
8. An implantable device according to claim 1, wherein the
implantable device is produced by an extrusion process.
9. An implantable device according to claim 8, comprising
dimensions of about 2 to about 3 mm in diameter and about 2 to
about 3 cm in length.
10. An implantable device according to claim 9, wherein said
implantable device releases about 0.1 to about 10 mg of dopamine
agonist per day in vitro at steady state.
11. An implantable device according to claim 1, further comprising
an anti-inflammatory agent encapsulated within said matrix.
12. An implantable device according to claim 11, wherein said
anti-inflammatory agent is a steroid.
13. An implantable device according to claim 11, wherein said
anti-inflammatory agent is a nonsteroidal anti-inflammatory drug
("NSAID").
14. An implantable device according to claim 11, wherein said
anti-inflammatory agent is an antihistamine.
15. An implantable device according to claim 1, further comprising
an antioxidant encapsulated within said matrix.
16. An implantable device for administration of a dopamine agonist
to a mammal in need thereof, comprising a dopamine agonist and a
biocompatible, nonerodible polymeric matrix, wherein said dopamine
agonist is encapsulated within said matrix, and wherein when said
implantable device is subcutaneously implanted in a mammal, said
dopamine agonist is continuously released in vivo over a sustained
period of time through pores that open to the surface of said
matrix at a rate of at least about 0.1 mg of dopamine agonist per
day at steady state.
17. An implantable device according to claim 16, wherein the
polymeric matrix comprises EVA.
18. An implantable device according to claim 17, wherein said EVA
comprises 33% vinyl acetate.
19. An implantable device according to claim 16, comprising about
10 to about 85% dopamine agonist.
20. An implantable device according to claim 16, wherein said
dopamine agonist is selected from the group consisting of
apomorphine, lisuride, pergolide, bromocriptine, pramipexole,
ropinerole, and rotigotine.
21. An implantable device according to claim 20, wherein said
dopamine agonist is apomorphine.
22. An implantable device according to claim 16, wherein the
sustained period of time is at least about 3 months.
23. An implantable device according to claim 16, wherein the
implantable device is produced by an extrusion process.
24. An implantable device according to claim 16, further comprising
an anti-inflammatory agent encapsulated within said matrix.
25. An implantable device according to claim 24, wherein said
anti-inflammatory agent is a steroid.
26. An implantable device according to claim 24, wherein said
anti-inflammatory agent is a NSAID.
27. An implantable device according to claim 24, wherein said
anti-inflammatory agent is an antihistamine.
28. An implantable device according to claim 18, further comprising
an antioxidant encapsulated within said matrix.
29. A method for administration of a dopamine agonist to a mammal
in need thereof, the method comprising administering at least one
implantable device subcutaneously, wherein each of said at least
one implantable devices comprises a dopamine agonist encapsulated
within a biocompatible, nonerodible polymeric matrix, wherein said
dopamine agonist is continuously released in vivo from each of said
at least one implantable devices over a sustained period of time
through pores that open to the surface of said matrix at a rate
that results in a plasma level of at least about 0.01 ng/ml at
steady state.
30. A method according to claim 29, wherein said at least one
implantable device comprises a multiplicity of individual
implantable devices, and wherein the combination of said
implantable devices continuously releases dopamine agonist in vivo
over a sustained period of time at a rate that results in a plasma
level of at least about 0.05 ng/ml at steady state.
31. A method according to claim 29, wherein the polymeric matrix
comprises EVA.
32. A method according to claim 31, wherein said EVA comprises
about 33% vinyl acetate.
33. A method according to claim 29, wherein each of said at least
one implantable devices comprises at about 10 to about 85% dopamine
agonist.
34. A method according to claim 33, wherein said dopamine agonist
is selected from the group consisting of apomorphine, lisuride,
pergolide, bromocriptine, pramipexole, ropinerole, and
rotigotine.
35. A method according to claim 34, wherein said dopamine agonist
is apomorphine.
36. A method according to claim 29, wherein said mammal has
Parkinson's disease.
37. A method according to claim 29, wherein said mammal has toxin-
or disease-induced parkinsonism.
38. A method according to claim 29, wherein said mammal has a
condition selected from the group consisting of erectile
dysfunction and restless leg syndrome.
39. A method according to claim 29, wherein the sustained period of
time is at least about 3 months.
40. A method according to claim 29, wherein each of said at least
one implantable devices is produced by an extrusion process.
41. A method according to claim 40, wherein each implantable device
comprises dimensions of about 2 to about 3 mm in diameter and about
2 to about 3 cm in length.
42. A method according to claim 41, wherein each implantable device
releases at least about 0.1 mg of dopamine agonist per day in
vitro.
43. A method according to claim 29, wherein each of said at least
one implantable devices is subcutaneously implanted at a site
selected from the group consisting of the upper arm, the back, and
the abdomen.
44. A method according to claim 29, further comprising
administration of an anti-inflammatory agent.
45. A method according to claim 44, wherein said anti-inflammatory
agent is encapsulated in at least one of said at least one
implantable devices.
46. A method according to claim 44, wherein said anti-inflammatory
agent is encapsulated within a biocompatible, nonerodible polymeric
matrix that does not comprise said dopamine agonist, and wherein
said method comprises administration of said polymeric matrix
comprising said anti-inflammatory agent subcutaneously.
47. A method according to claim 44, wherein said anti-inflammatory
agent is administered via a route selected from the group
consisting of local injection, systemic injection, subcutaneous
injection, and oral administration.
48. A method according to claim 44, wherein said at least one
implantable devices further comprises an antioxidant.
49. A kit comprising at least one implantable device comprising a
dopamine agonist encapsulated within a biocompatible, nonerodible
polymeric matrix, wherein when said at least one implantable device
is implanted subcutaneously in a mammal, said dopamine agonist is
continuously released in vivo from each of said at least one
implantable devices over a sustained period of time through pores
that open to the surface of said matrix at a rate that results in a
plasma level of at least about 0.01 ng/ml at steady state and
instructions for use in a method of administration of a dopamine
agonist to a mammal in need thereof.
50. A kit according to claim 49, wherein said at least one
implantable device comprises a multiplicity of individual
implantable devices, and wherein when the combination of said
implantable devices is implanted subcutaneously in a mammal, said
implantable devices continuously release dopamine agonist in vivo
over a sustained period of time at a rate that results in a plasma
level of at least about 0.05 ng/ml at steady state.
51. A kit according to claim 49, wherein said implantable device
releases dopamine agonist at a rate of at least about 0.1 mg per
day in vitro.
52. A kit according to claim 49, wherein each of said implantable
devices comprises EVA.
53. A kit according to claim 52, wherein said EVA comprises about
33% vinyl acetate.
54. A kit according to claim 49, wherein each of said implantable
devices comprises about 10 to about 85% dopamine agonist.
55. A kit according to claim 54, wherein said dopamine agonist is
selected from the group consisting of apomorphine, lisuride,
pergolide, bromocriptine, pramipexole, ropinerole, and
rotigotine.
56. A kit according to claim 55, wherein said dopamine agonist is
apomorphine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application No. 60/459,315, filed on Mar. 31, 2003, which is
incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The invention provides a nonbioerodible, polymeric device
for subcutaneous implantation and sustained release of dopamine
agonist for treatment of Parkinson's disease and other conditions
for which administration of a dopamine agonist is therapeutically
beneficial.
BACKGROUND OF THE INVENTION
[0003] Parkinson's disease, a progressive neurodegenerative
disorder, is characterized by loss of neurons that synthesize and
release dopamine. This loss of dopaminergic neurons manifests
itself in symptoms such as rigidity, resting tremors (shaking),
poverty of movement (akinesia), slowness of movement
(bradykinesis), and changes in gait and posture. Treatment of
Parkinson's disease generally is based on therapeutic
administration of substances that can compensate for the lack of
dopaminergic neurotransmission due to the loss of
dopamine-secreting neurons. A classic treatment regime includes
chronic oral administration of levodopa, which is decarboxylated in
the brain to form dopamine. Often, after several years of treatment
with levodopa, abnormalities emerge, including involuntary
movements during the "on" phase of clinical improvement and
re-emergence of Parkinson's-type symptoms during "off" phases.
[0004] Apomorphine, an effective agonist at both dopamine receptors
in the nervous system, has been used for treatment of Parkinson's
disease in patients that have become resistant to or have developed
adverse side effects with associated with chronic levodopa therapy.
Typically, due to its short duration of effectiveness, apomorphine
is administered by repeated subcutaneous injections or continuous
parenteral infusion via a pump. These means of administration are
inconvenient, in the case of subcutaneous injection, and
technically difficult, in the case of pump administration,
especially for Parkinson's patients whose dexterity is impaired due
to the disease itself and the movements associated with chronic
levodopa treatment. Apomorphine may also be administered
transdermally (U.S. Pat. No. 5,562,917), intranasally (U.S. Pat.
No. 5,756,483), as a topically-applied gel (U.S. Pat. No.
5,939,094), or sublingually (U.S. Pat. No. 5,994,363). None of
these methods permits continuous administration over long periods
of time.
[0005] Dopamine agonists have also been used for treatment of
parkinsonism which results from central nervous system injury by
toxin exposure or a disease condition such as encephalitis,
erectile dysfunction, restless leg syndrome, and
hyperprolactinemia.
[0006] There is a need for an improved means of administration that
would permit continuous dosing of dopamine agonists over an
extended period of time of several months or longer, without the
adverse side effects associated with peaks and troughs in plasma
levels due to discontinuous dosing, or reliance on cumbersome
mechanical equipment such as a pump.
BRIEF SUMMARY OF THE INVENTION
[0007] The invention provides compositions (i.e., implantable
polymeric devices), methods, and kits for administration of one or
more dopamine agonists to a mammal in need thereof.
[0008] In one aspect, the invention provides an implantable device
for administration of a dopamine agonist to a mammal in need
thereof. The implantable device includes at least one dopamine
agonist encapsulated in a biocompatible, nonerodible polymeric
matrix. After subcutaneous implantation in a mammal, an implantable
device of the invention releases dopamine agonist continuously in
vivo through pores that open to the surface of the matrix at a rate
that results in a plasma level of at least about 0.001, 0.005,
0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10 ng/ml in various
embodiments. In some embodiments, an implantable device of the
invention includes ethylene vinyl acetate (EVA) as a biocompatible,
nonerodible polymer for formation of the polymeric matrix. In
various embodiments, the vinyl acetate content of EVA used for
preparation of the polymeric matrix is often about 2 to about 40,
more often about 10 to about 35, most often about 30 to about 35%.
In some embodiments, the vinyl acetate content is about 33%. An
implantable device of the invention includes about 10 to about 85%
dopamine agonist. In some embodiments, the dopamine agonist is
apomorphine, lisuride, pergolide, bromocriptine, pramipexole,
ropinerole, or rotigotine. In one embodiment, the dopamine agonist
is apomorphine. The dopamine agonist is generally at least a
dopamine D2 receptor agonist, but may also be an agonist for the D1
and/or D3 dopamine receptors. Implantable devices often release
dopamine agonist continuously in vivo for at least about 3, 6, 9,
12, 15, 18, 21, or 24 months. In some embodiments, implantable
devices of the invention are produced using an extrusion process,
sometimes producing devices with dimensions of about 2 to about 3
mm in diameter and about 2 to about 3 cm in length, although other
shapes and sizes are contemplated and are within the skill of the
art. Often, an implantable device of the invention releases
dopamine agonist at a rate of at least about 0.1 to about 10 mg/day
at steady state in vitro or in vivo. In various embodiments, the
implantable devices release dopamine agonist at a rate of at least
about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/day
in vitro or in vivo. In some embodiments, a dopamine-containing
implantable device may further include an anti-inflammatory agent,
for example a steroid, a nonsteroidal anti-inflammatory drug
("NSAID"), or an antihistamine, and/or an antioxidant within the
polymeric matrix.
[0009] In another aspect, the invention provides a method for
administration of a dopamine agonist to a mammal in need thereof.
Methods of the invention include subcutaneous administration of at
least one implantable device as described above. In some
embodiments, the methods include subcutaneous implantation of a
multiplicity of the devices. In methods of the invention, the
device or devices release dopamine agonist at a steady state level
that is therapeutically effective for treatment of a condition for
which administration of a dopamine agonist is therapeutically
beneficial, for example, Parkinson's disease, toxin- or
disease-induced parkinsonism, erectile dysfunction, restless leg
syndrome, or hyperprolactinemia. In some embodiments, the dopamine
agonist is apomorphine, lisuride, pregolide, bromocriptine,
pramipexole, ropinerole, or rotigotine. In one embodiment, the
dopamine agonist is apomorphine. Typically, each device, or the
combination of a multiplicity of devices, continuously releases at
least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07,
0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10,
25, 50, or 100 ng of dopamine agonist per ml of plasma at steady
state. Generally, each device releases at least about 0.1 mg of
dopamine agonist per day in vitro. In various embodiments, one or a
multiplicity of devices is subcutaneously implanted in an
individual, for example, on the upper arm, the back, and/or the
abdomen.
[0010] In some embodiments, one or more anti-inflammatory agents
are coadministered along with dopamine agonist. The
anti-inflammatory agent may be encapsulated within the same
polymeric device as dopamine agonist or in a separate polymeric
device that does not contain dopamine agonist, or may be
administered via a different route, such as orally or via
injection, either simultaneously with implantation of the dopamine
agonist-containing devices or at a different time, or on a
different schedule such as for example multiple dosing of an oral
or injectable formulation. In various embodiments, the
anti-inflammatory agent may be a steroid, a NSAID, and/or an
antihistamine. In some embodiments, an antioxidant is incorporated
into the dopamine agonist-containing polymeric device and is
coadministered along with dopamine agonist. In some embodiments,
the methods of the invention include administration of another
substance in conjunction with administration of dopamine agonist
via an implanted polymeric device of the invention. Such substances
include, but are not limited to, levodopa, dopamine agonists,
catechol-O-methyltranserase inhibitors, or monoamine oxidase
inhibitors, administered orally or intravenously.
[0011] In another aspect, the invention provides a kit for use in a
method of administration of a dopamine agonist to a mammal in need
thereof. Kits of the invention include at least one implantable
device that includes dopamine agonist encapsulated in a
biocompatible, nonerodible polymeric matrix, as described above,
and instructions for use. In some embodiments, kits of the
invention include a multiplicity of individual dopamine
agonist-containing implantable devices.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 depicts in vitro release of apomorphine over time.
FIG. 1 shows the average cumulative release of apomorphine HCl
("ApoH") from implants loaded with 50%, 60%, or 70% ApoH and washed
for 30 minutes (FIG. 1A), 60 minutes (FIG. 1B), or 120 minutes
(FIG. 1C) in ethanol.
[0013] FIG. 2 depicts in vitro release of ApoH and loratidine
("LA") over time from an implant loaded with 49% ApoH and 21%
LA.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The invention provides a biocompatible, nonerodible
polymeric device, which permits controlled, sustained release of
one or more dopamine agonists over extended periods of time when
implanted subcutaneously in an individual in need of treatment.
[0015] Continuous release of a compound in vivo over an extended
duration may be achieved via implantation of a device containing
the compound encapsulated, i.e., dispersed, in a nonerodible
polymeric matrix. Examples of implantable, nonerodible 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. Implantation of the
device and extended release of dopamine agonist improves compliance
with dosing regimens, eliminating the need for repeated injections,
ingestion of pills or tablets, or manipulations associated with a
mechanical diffusion pump. An implantable, sustained-release device
according to the present invention also permits achievement of more
constant blood levels of dopamine agonist than injectable or oral
dosage forms, thereby permitting lower dosing levels than
conventional means of administration, minimizing side effects, and
improving therapeutic effectiveness.
[0016] Devices of the invention include one or more non-bioerodible
polymers. Such polymers release compounds at linear rates for
extended time periods of several months or longer, in contrast to
bioerodible polymers, which do not exhibit linear release kinetics
due to formation of channels in the matrix as it erodes, resulting
in increased release rates over time. The present invention
includes a biocompatible, nonerodible polymer that exhibits
generally linear release kinetics for dopamine agonist in vivo,
after an initial burst.
[0017] Implantable Polymeric Devices
[0018] The invention includes implantable devices for treatment of
Parkinson's disease or other conditions for which administration of
a dopamine agonists is therapeutically beneficial. Devices of the
invention include one or more dopamine agonists encapsulated in a
polymeric, nonerodible matrix.
[0019] "Dopamine agonist" as used herein refers to a compound which
is capable of binding to one or more dopamine receptor subgroups,
resulting in beneficial therapeutic effect in an individual treated
with the agonist. The dopamine agonists described herein typically
are agonists for at least the D2 subgroup of dopamine receptors,
and may also be agonists for D1 and/or D3 receptors. In various
embodiments, an implantable device of the invention includes
apomorphine, lisuride, pergolide, bromocriptine, pramipexole,
ropinerole, or rotigotine, or a combination or two or more of these
dopamine agonists. In one embodiment, the implantable device
includes apomorphine. "Apomorphine" refers to apomorphine and
pharmaceutically acceptable salts thereof, such as for example,
apomorphine HCl ("ApoH").
[0020] Incorporation of dopamine agonist into the polymeric matrix
causes the formation of a series of interconnecting channels and
pores that are accessible to the surface for release of the drug.
When implanted subcutaneously, devices of the invention
continuously release dopamine agonist for an extended period of
time with a pseudo or near zero order release rate. After an
initial burst following implantation, release rates are typically
within about 10-20% of the steady state average.
[0021] As used herein, "nonerodible matrix" refers to a polymeric
carrier that is sufficiently resistant to chemical and/or physical
destruction by the environment of use such that the matrix remains
essentially intact throughout the release period. The polymer is
generally hydrophobic so that it retains its integrity for a
suitable period of time when placed in an aqueous environment, such
as the body of a mammal, and stable enough to be stored for an
extended period before use. The ideal polymer must also be strong,
yet flexible enough so that it does not crumble or fragment during
use. Nonerodible matrices remain intact in vivo for extended
periods of time, typically months or years. Drug molecules
encapsulated in the matrix are released over time via diffusion
through channels and pores in a sustained and predictable manner.
The release rate can be altered by modifying the percent drug
loading, porosity of the matrix, structure of the implantable
device, or hydrophobicity of the matrix, or by adding a hydrophobic
coating to the exterior of the implantable device.
[0022] Where appropriate, a coating that is impermeable to the drug
is placed over at least a portion of the device to further regulate
the rate of release. For example, a coating of a nonerodible
polymeric material, e.g., EVA, or a coating of a nonerodible
polymeric material with a lower drug loading than the remainder of
the implantable device, may be used. Such a coating may be formed,
for example, by co-extrusion with the device.
[0023] Typically, ethylene vinyl acetate copolymer (EVA) is used as
the polymeric matrix, but other nonerodible materials may be used.
Examples of other suitable materials include silicone, hydrogels
such as crosslinked poly(vinyl alcohol) and poly(hydroxy
ethylmethacrylate), acyl substituted cellulose acetates and alkyl
derivatives thereof, partially and completely hydrolyzed
alkylene-vinyl acetate copolymers, unplasticized polyvinyl
chloride, crosslinked homo- and copolymers of polyvinyl acetate,
crosslinked polyesters of acrylic acid and/or methacrylic acid,
polyvinyl alkyl ethers, polyvinyl fluoride, polycarbonate,
polyurethane, polyamide, polysulphones, styrene acrylonitrile
copolymers, crosslinked poly(ethylene oxide), poly(alkylenes),
poly(vinyl imidazole), poly(esters), poly(ethylene terephthalate),
polyphosphazenes, and chlorosulphonated polyolefines, and
combinations thereof.
[0024] Implantable devices of the invention are typically
formulated with dopamine agonist loading of about 10% to about 85%.
Devices are often formulated as compositions that include a
polymeric matrix that includes EVA (33% acetate) and any of at
least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, or 80 to about
85%, or any of about 10 to about 20, about 20 to about 30, about 30
to about 40, about 40 to about 50, about 50 to about 60, about 60
to about 70, about 70 to about 80, or about 80 to about 85%
dopamine agonist by weight. Devices may be produced using an
extrusion process, wherein ground EVA is blended with dopamine
agonist, melted, and extruded into rod-shaped structures. Rods are
cut into individual implantable devices of the desired length,
packaged, and sterilized prior to use. Other methods for
encapsulating therapeutic compounds in implantable polymeric,
nonerodible matrices are well known to those of skill in the art.
Such methods include, for example, solvent casting (see, e.g., U.S.
Pat. Nos. 4,883,666, 5,114,719, and 5,601,835). A skilled artisan
would be able to readily determine an appropriate method of
preparing such an implantable device, depending on the shape, size,
drug loading, and release kinetics desired for a particular type of
patient or clinical indication.
[0025] Devices of the invention are suitable for sustained release
of dopamine agonist for treatment of idiopathic Parkinson's disease
or another condition for which administration of dopamine agonist
is therapeutically beneficial, such as, for example, toxin- or
disease-induced parkinsonism, erectile dysfunction, restless leg
syndrome, or hyperprolactinemia. As used herein, "sustained
release" refers to the release of dopamine agonist such that the
blood concentration remains within the therapeutic range but below
toxic levels for an extended duration. Devices of the invention
generally exhibit near zero-order pharmacokinetics in vivo, similar
to kinetics achieved with an IV drip, but without the need for
external medical equipment and personnel associated with
intravenous methods. Generally, after implantation, the devices
release therapeutically effective amounts of dopamine for periods
of several months up to one year or longer.
[0026] Multiple implantable devices may be used, or the size and
shape of the devices may be modified, to achieve a desired overall
dosage. Implantable devices are often about 0.5 to about 10, more
often about 1.5 to about 5, often about 2 to about 6, most often
about 2 to about 3 cm in length, and are often about 0.5 to about
7, more often about 1.5 to about 5, most often about 2 to about 3
mm in diameter. An implantable device of the invention may release
dopamine agonist in vitro or in vivo at a rate of about 0.01 to
about 10, about 0.1 to about 10, about 0.25 to about 5, or about 1
to about 3 mg/day in vitro or in vivo. The release rate of
implantable devices may also be modified by changing the vinyl
acetate content in the EVA polymer matrix. The vinyl acetate
content is often about 2 to about 40, more often about 10 to about
35, most often about 30 to about 35% by weight. In one embodiment,
the vinyl acetate content is about 33% by weight.
[0027] In certain embodiments, devices of the invention may include
other substances in addition to dopamine agonist to increase
effectiveness of treatment and/or reduce inflammation at the site
of administration, or to prevent oxidation of dopamine agonist(s).
For example, an anti-inflammatory agent, such as for example, a
steroid, examples of which include but are not limited to
dexamethasone, triamcinolone, betamethasone, clobetasol, cortisone,
hydrocortisone, or a pharmaceutically acceptable salt thereof, or a
nonsteroidal anti-inflammatory agent ("NSAID"), examples of which
include but are not limited to diclofenac potassium diclofenac
sodium, diclofenac sodium with misoprostol, diflunisal, etodolac,
fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam,
nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam,
sulindac, tolmetin, COX-2 inhibitors (e.g., celecoxib, rofecoxib,
valdecoxib), acetylated salicylates (e.g., aspirin), nonacetylated
salicylates (e.g., choline, magnesium, and sodium salicylates,
salicylate), and/or an antihistamine, examples of which include but
are not limited to loratadine ("LT"), astemizole, cetrizine
dihydrochloride, chlorpheniramine, dexochlorpheniramine,
diphenhydramine, mebhydrolin napadisylate, pheniramine maleate,
promethazine, or terfenadine, may be encapsulated within an implant
to prevent or reduce local inflammation at the site of
administration. Any of these agents, or a combination, may be
included in the same implant(s) as dopamine agonist or
alternatively, may be incorporated into one or more separate
implants that do not include dopamine agonist. An antioxidant,
e.g., ascorbic acid, sodium metabisulfite, glutathione, may be
included in the same implant as dopamine agonist to prevent or
reduce oxidation of dopamine agonist during preparation, storage,
and/or administration of the implant.
METHODS OF THE INVENTION
[0028] The invention provides methods for treatment of idiopathic
Parkinson's disease or toxin- or disease-induced parkinsonism, or
any other condition for which administration of a dopamine agonist
is therapeutically beneficial, e.g., erectile dysfunction, restless
leg syndrome, or hyperprolactinemia. "Parkinsonism" as used herein
includes conditions resulting from injury to the central nervous
system that cause an individual to exhibit symptoms similar to
those of Parkinson's disease. Parkinsonism may result, for example,
from toxin exposure, for example, carbon monoxide or manganese
poisoning or MPTP administration, or from a disease condition such
as encephalitis.
[0029] Methods of the invention include subcutaneous administration
of one or more polymeric implantable devices which each include one
or more dopamine agonists encapsulated within a biocompatible,
nonerodible polymeric matrix, e.g., EVA, and release of the
dopamine agonist(s) in a controlled manner over an extended period
of time through multiple pores that open to the surface of the
implantable device(s). Often, implantable devices are produced via
an extrusion process, as described above.
[0030] In various embodiments, the method includes administration
of apomorphine, lisuride, pergolide, bromocriptine, pramipexole,
ropinerole, or rotigotine, or a combination or two or more of these
dopamine agonists. A combination of dopamine agonists may be
administered from the same implantable device(s) or may be
administered from separate implantable devices. In one embodiment,
the method includes administration of apomorphine.
[0031] Implantable devices are administered by subcutaneous
implantation to an individual in need of treatment with a dopamine
agonist. As used herein, "individual" refers to a mammal, such as a
human, in need of treatment for Parkinson's disease or
parkinsonism, or another condition for which dopamine
administration is therapeutically beneficial. Generally,
implantable devices are administered by subcutaneous implantation
at sites including, but not limited to, the upper arm, back, or
abdomen of an individual. Other suitable sites for administration
may be readily determined by a medical professional. Multiple
implantable devices may be administered to achieve a desired dosage
for treatment.
[0032] Typically, in a treatment method of the invention, an
implantable device or a multiplicity of devices is administered
that will release dopamine at a rate that will maintain a
therapeutically effective plasma level for an extended period of
time of at least about 3, 6, 9, 12, 15, 18, 21, or 24 months.
Often, the duration of implantation, with continuous release of
dopamine agonist, is from about 3 months to about 2 years, about 3
months to about 1 year, about 3 months to about 9 months, or about
3 months to about 6 months.
[0033] The desired dosage rate will depend upon factors such as the
underlying condition for which dopamine agonist is being
administered, and the physiology of a particular patient, but will
be readily ascertainable to physicians. Dopamine agonist is
desirably released from one or a multiplicity of implanted devices
at a rate that maintains plasma levels of the drug(s) at a
therapeutically effective level. Maintenance of dopamine agonist at
a fairly constant plasma level often permits dosing at a lower
level than with other therapies, such as oral administration.
[0034] As used herein, "therapeutically effective amount" or
"therapeutically effective level" refers to the amount of dopamine
agonist that will render a desired therapeutic outcome, e.g., a
level or amount effective to reduce symptoms of Parkinson's disease
and/or increase periods of therapeutic effectiveness ("on" periods)
for a patient undergoing chronic dopaminergic therapy for
idiopathic Parkinson's disease or toxin- or disease-induced
parkinsonism, or beneficial treatment, i.e., reduction or
alleviation of adverse or undesirable symptoms of a condition
treatable with a dopamine agonist, such as erectile dysfunction,
restless leg syndrome, or hyperprolactinemia. For treatment of
Parkinson's disease or parkinsonism, effectiveness is often
associated with reduction in "on"/"off" fluctuations associated
with a particular Parkinson's disease treatment regime, such as for
example, chronic levodopa administration. An amount that is
"therapeutically effective" for a particular patient may depend
upon such factors as a patient's age, weight, physiology, and/or
the particular symptoms or condition to be treated, and will be
ascertainable by a medical professional.
[0035] When multiple devices are administered, the combination of
the devices releases dopamine agonist at a rate that will achieve a
therapeutically effective plasma level. Often, a desirable
steady-state plasma level of dopamine agonist in methods of the
invention is in the range of about 0.005 to about 100 ng/ml, about
0.01 to about 100 ng/ml, about 0.05 to about 0.65 ng/ml, about 0.2
to about 0.65 ng/ml, about 0.2 to about 45 ng/ml, or about 1 to
about 20 ng/ml. In various embodiments, an implantable device of
the invention may release dopamine agonist in vivo at a rate that
results in a plasma level of at least about 0.001, 0.005, 0.01,
0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4,
0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10 ng/ml at steady state. A total
release rate from one or a multiplicity of implanted devices that
results in delivery of a therapeutically effective amount of
dopamine agonist on a daily basis is typically about 0.01 to about
10 mg/day, often about 0.25 to about 5 mg/day, sometimes about 1 to
about 3 mg/day, but may be modified depending upon the symptomology
involved and the particular patient being treated. For example, for
treatment of Parkinson's disease with apomorphine or another
dopamine agonist described herein, one or more implantable devices
may be used with a total release rate of about 0.01 to about 10
mg/day, about 0.25 to about 5 mg/day, or about 1 to about 3 mg/day
apomorphine.
[0036] It is anticipated that the implantable devices of the
invention will alleviate compliance difficulties, as described
above. In methods of the invention, long term continuous release of
dopamine agonist generally reduces or eliminates the peaks and
troughs of blood concentration associated with other formulations
such as oral or injectable dosage forms, which permits dosing at a
lower level than traditional treatment regimens. This often reduces
or alleviates adverse side effects associated with higher dosages,
for example, nausea, vomiting, orthostatic hypotension,
hallucinations, delirium, or dyskinesia.
[0037] In some methods of the invention, dopamine is administered
via an implantable device of the invention in conjunction with
another therapy. For example, for Parkinson's or parkinsonism,
dopamine agonist may be administered via implantable devices of the
invention in conjunction with levodopa, dopamine agonists,
catechol-O-methyltransferase (COMT) inhibitors, or monoamine
oxidase (MAO) inhibitors, administered orally or intravenously.
[0038] Some methods of the invention include coadministration of
another substance or substances in conjunction with dopamine
agonist. For example, an anti-inflammatory agent or agents, such as
a steroid, a NSAID, and/or an antihistamine, may be administered
via an implantable device, by local, systemic, or subcutaneous
injection, or orally, in conjunction with administration of
dopamine agonist in an implantable device of the invention, to
reduce or prevent inflammation caused by the agonist(s) at the site
of administration of the implant. When the anti-inflammatory
agent(s) is administered via an implantable device, it may be
included in the same implant as dopamine agonist or in a separate
implantable device. An implantable device may include one or more
of the anti-inflammatory agents described above. The amount of
anti-inflammatory agent administered is an amount expected to be
effective to reduce local inflammation associated with
administration of dopamine agonist in an implanted device of the
invention.
[0039] In some methods of the invention, an antioxidant may be
included in the dopamine agonist implant to prevent oxidation of
the dopamine agonist(s) during preparation, storage, and/or
administration of the implant. Generally, the amount of antioxidant
incorporated into the implant is an amount sufficient to prevent
oxidation of at least a portion, typically substantially all of the
dopamine agonist in the implant.
[0040] Methods of the invention may be used to treat any
subpopulation of Parkinson's disease patients, including, for
example, "de novo" patients, e.g, patients who have not previously
received treatment, "early stage" patients, e.g., patients who have
been treated for a short period of time with another therapy such
as levodopa administration but who are not exhibiting adverse side
effects from the other therapy, "late stage" patients, e.g.,
patients who are exhibiting side effects associated with chronic
treatment with another therapeutic substance such as levodopa, and
"fluctuators," e.g., patients for whom treatment with another
substance such as levodopa fluctuates in effectiveness in an
"on"/"off" manner.
[0041] Methods of the invention may be used, for example, to
decrease motor fluctuations and dyskinesias for treatment of "late
stage" patients with motor fluctuations. Continuous dosing via an
implantable device of the invention may decrease "off" time and
decrease dyskinesias. The methods may also be used, for example, to
prevent motor fluctuations and dyskinesias in "early stage"
patients who are undergoing pharmacologic therapy for the first
time. This group often received monotherapy with a dopamine
agonist. Administration via an implantable device of the invention
may allow continuous dopamine agonist receptor stimulation, thus
decreasing the risk of motor fluctuations and dyskinesias later in
treatment. The methods may also be used, for example, to prevent
motor fluctuations and dyskinesias in patients on dopamine agonist
monotherapy who require 1-dopa supplementation. Since it is
difficult to administer 1-dopa with linear dosing kinetics, and
motor complications often emerge when 1-dopa is administered,
continuous dosing via the implantable devices of the invention may
allow continuous dopamine agonist receptor stimulation and decrease
the risk of motor fluctuations and dyskinesias at this point in
treatment.
[0042] Kits
[0043] The invention also provides kits for use in treatment of
Parkinson's disease or another condition for which dopamine agonist
administration is therapeutically beneficial, as described above.
The kits contain at least one implantable, nonerodible device of
the type herein described, capable of delivering long-term
therapeutic levels of dopamine agonist, in suitable packaging,
along with instructions providing information to the user and/or
health care provider regarding subcutaneous implantation and use of
the system for treating a condition for which dopamine agonist
administration is therapeutically beneficial, such as, for example,
Parkinson's disease, toxin- or disease-induced parkinsonism,
erectile dysfunction, restless leg syndrome, or hyperprolactinemia.
Kits may also include literature discussing performance of the
implantable devices of the invention.
[0044] In various embodiment, kits of the invention may include
implantable devices that include apomorphine, lisuride, pergolide,
bromocriptine, pramipexole, ropinerole, or rotigotine, or
combinations of any of these dopamine agonists in the same or
separate polymeric implants. In one embodiment, a kit includes one
or more implantable devices that include encapsulated
apomorphine.
[0045] Kits may include a delivery system, i.e., one or a
multiplicity of implantable devices, capable of providing sustained
release of therapeutic levels of dopamine agonist, e.g., about
0.005 to about 100 ng/ml, about 0.01 to about 100 ng/ml, about 0.05
to about 0.65 ng/ml, about 0.2 to about 0.65 ng/ml, about 0.2 to
about 45 ng/ml, or about 1 to about 20 ng/ml, for at least about 3
months. Kits of the invention may include implantable devices each
capable of in vivo release of dopamine agonist such that a plasma
level of at least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05,
0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,
0.9, 1, 5, 10, 25, 45, or 100 ng/ml is achieved at steady state.
Kits of the invention may include a delivery system capable of
releasing about 0.1 to about 10, about 0.25 to about 5, or about 1
to about 3 mg/day dopamine agonist in vitro or in vivo.
[0046] The device(s) in a kit may include one or more substances in
addition to dopamine agonist, such as one or more an
anti-inflammatory agents, such as a steroid, NSAID, or
antihistamine, and/or an antioxidant.
[0047] In kits of the invention, an implantable device or devices
may be preloaded into an apparatus or apparatuses suitable for
subcutaneous implantation of the device(s) into a patient, such as,
for example, syringes or trocars.
EXAMPLES
[0048] The following examples are intended to illustrate but not
limit the invention.
Example 1
Materials and Methods
[0049] Materials
[0050] The following materials were used:
[0051] Apomorphine HCl, supplied by Hawkins, Inc.
[0052] Triamcinolone Acetonide, supplied by Spectrum
[0053] Glutathione, supplied by Aldrich, St. Louis, Mo.
[0054] Ethylene vinyl acetate copolymer, 33% vinyl acetate,
supplied by Southwest Research Institute, San Antonio, Tex.
[0055] Methanol, ChromAR HPLC Grade, supplied by Mallinckrodt, St.
Louis, Mo.
[0056] Acetonitrile, ChromAR HPLC Grade, supplied by Mallinckrodt,
St. Louis, Mo.
[0057] Trifluoro Acetic Acid, 99%, Spectrochemical grade, supplied
by Aldrich Chemicals, St. Louis, Mo.
[0058] Sodium Dodecyl Sulfate, 99%, supplied by EM Science
[0059] Ethanol, supplied by Mallinckrodt, St. Louis, Mo.
[0060] HPLC Assays
[0061] An HPLC method was used to determine the rate of in vitro
release of apomorphine HCl ("ApoH") or loratidine ("LA") from the
implants. Chromatography was performed using a Zorbax SB-C 18 (250
mm.times.4.6 mm) column and 60% 0.1 trifluoro acetic acid in water,
15% methanol, 25% acetonitrile as the mobile phase, and a flow rate
of 1 ml/min. The injection volume was 10 .mu.l. Detection was
accomplished by means of a UV/VIS detector at a wavelength of 270
nm. Instrument control and data acquisition were facilitated using
a Waters Millennium (V 2.15) software package. The external
calibration was obtained using ApoH or LA standard solutions.
[0062] Preparation of Implantable Devices
[0063] Implantable devices were prepared using an extrusion process
in a Microtruder device (Rancastle, RC-025-CF-RF). In order to
facilitate feeding into the extruder and to enable mixing of
apomorphine and other substances to be incorporated into the
implants, EVA was ground into smaller particle sizes prior to
extrusion. The extrusion process was performed under argon gas to
prevent oxidation of apomorphine. All blends of copolymer and
drug(s) were prepared by rolling in a 120 ml amber bottle for
approximately 10 minutes. The blend was then fed through the
Microtruder. Parameters that were used for extrusion of ApoH/EVA
implants are shown in Table 1, and parameters used for extrusion of
implants that included triancinolone ("TA"), glutathione ("GSH"),
and/or LA are shown in Table 2.
1TABLE 1 Parameters for Extrusions of APO/EVA Implants Formulations
Zone Temperature (.degree. F.) (Weight Percentage) 1 2 3 Die
APO/EVA 180 185 190 185 (50:50) APO/EVA 185 195 200 195 (60:40)
APO/EVA 215 230 240 250 (70:30)
[0064]
2TABLE 2 Parameters for Extrusions of APO/EVA/TA/GSH Implants
Formulations Zone Temperature (.degree. F.) (Weight Percentage) 1 2
3 Die APO/EVA 190 195 205 200 (60:40) APO/TA/EVA 215 230 240 248
(60:10:30) APO/TA/GSH/EVA 215 235 245 255 (60:8:2:30) APO/LA/EVA
215 226 232 230 (49:21:30)
[0065] All of the materials used during the extrusion process were
protected from light to prevent light-catalyzed oxidation. The
extruder was set to the required temperatures and allowed to reach
equilibrium. After the extruder reached equilibrium, approximately
15 grams of blend were extruded and cut into 18-inch rods. The
diameter was measured at 2.4 mm. The rods were then cut to the
desired implant length of 26 mm.
[0066] The implants were then washed by placing them on an aluminum
screen and immersing them in ethanol (approximately 50 ml per
implant). The implants were washed for approximately 30, 60, or 120
minutes in the ethanol bath. The washed implants were air dried for
10 minutes and oven dried at 40.degree. C. for 1 hour before drying
in a vacuum over for 24 hours at 30.degree. C. The implants were
packaged into 20 ml glass vials in the presence of argon gas,
sealed, and then sterilized by gamma irradiation.
Example 2
In Vitro Characterization of Extruded Implantable Devices
[0067] Extruded rods prepared as described above were characterized
for total drug load and for rate of drug release.
[0068] Assessment of Drug Loading
[0069] Implants prepared with 70% ApoH:30% EVA were cut into 2 mm
pieces, accurately weighed, and placed into 250 ml volumetric
flasks. Approximately 200 ml of methanol was added to each flask
and the solution was continuously stirred at room temperature until
the implants was dissolved. The solution was then assayed for drug
content.
[0070] The average ApoH content for unwashed, washed, and
sterilized rods was between 66.9 and 67.9% ApoH, corresponding to
95.6 to 97% recovery.
[0071] Assessment of Drug Release
[0072] Experiments were performed to determine the rate of
apomorphine released from the extruded rods. The medium for these
studies was 0.5% sodium dodecyl sulfate ("SDS"). Preweighed rods
were placed in 100 ml screw cap jars containing 50 ml of medium and
placed on an orbital shaker. The orbital shaker was housed in an
incubator maintained at 37.degree. C. Sampling was performed by
replacing the medium periodically. The samples obtained were
analyzed by HPLC.
[0073] FIG. 1 shows the release of apomorphine from implants that
have been loaded with 50, 60, or 70% apomorphine and that have been
washed for 30, 60, or 120 minutes. The in vitro release data
indicate that the implants released a high amount of apomorphine
during the first few days, then reached steady state between about
3 and 7 days. As the drug load increased, the rate of release ApoH
increased for implants washed up to one hour. The data from
implants washed for 2 hours showed no significant difference in
release rate for the different drug loading levels.
[0074] FIG. 2 shows the release of ApoH and LA from a 49% ApoH/21%
LA/EVA implant. Both ApoH and LA reached steady state release rates
within about 3 days.
Example 3
In Vivo Evaluation of Drug Loaded Implantable Devices
[0075] Four MPTP-lesioned, L-DOPA-nave cynomolgus monkeys were
administered three 2.4 mm diameter.times.2.6 cm length rod-shaped
implantable devices prepared as described above, each containing
33% vinyl acetate and loaded with 98 mg+10% apomorphine HCl (68.5%
apomorphine). Devices were implanted between the shoulder blades
using a trocar. For comparison, three additional MPTP-lesioned,
L-DOPA-nave monkeys received pulsatile daily subcutaneous
injections of apomorphine at a dosage of 0.2 mg/kg, which is the
minimally-effective dose to achieve "ON" status in the animal.
[0076] All of the monkeys that received apomorphine implants were
continuously in an "ON" state within one day after implantation,
with an average steady state apomorphine level of approximately
0.5-1.0 ng/ml achieved after an initial burst. In contrast, animals
that received pulsatile injections were "ON" for only approximately
90 minutes after each administration of apomorphine.
[0077] After 8.3 days (range 7-10) of daily apomorphine injections,
all animals in the pulsatile injection group developed dyskinesias.
However, in the implant group, no animal developed dyskinesia for
the duration of the treatment (up to six months). The apomorphine
EVA implants provided continuous plasma levels of apomorphine,
allowing for continuous stimulation of striatal dopaminergic
receptors without onset of dyskinesia, for the six month duration
of the evaluation.
[0078] 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, which is delineated by the appended claims.
[0079] All publications, patents, and patent applications cited
herein are hereby incorporated by reference in their entirety.
* * * * *