U.S. patent application number 13/383810 was filed with the patent office on 2012-05-24 for therapeutic methods using controlled delivery devices having zero order kinetics.
This patent application is currently assigned to Board of Regents, The Univerity of Texas System. Invention is credited to Phillip Bowman, Paul S. Ho, Zhiquan Luo, Ashish Rastogi, Salomon S. Stavchansky, Zhuoijie Wu.
Application Number | 20120130300 13/383810 |
Document ID | / |
Family ID | 43450181 |
Filed Date | 2012-05-24 |
United States Patent
Application |
20120130300 |
Kind Code |
A1 |
Stavchansky; Salomon S. ; et
al. |
May 24, 2012 |
Therapeutic Methods Using Controlled Delivery Devices Having Zero
Order Kinetics
Abstract
An injectable or implantable medical device having orifice(s) on
the surface that release an active agent with zero-order release
kinetics is described herein. The device is a hollow matrix of any
size or shape, which can be made from both metal and non-metal
surfaces. The device comprises of a reservoir capable of releasing
at least one therapeutic, diagnostic, or prophylactic agent via the
orifices to the desired anatomical site. The developed device, due
to its composite structure, has the ability to combine several
release mechanisms, leading to zero-order release kinetics for most
of the time. The composition provides zero-order kinetics, in part,
because the diffusion rate of the drug from the device is slow
which enables sink conditions. Hence, no back transfer or build up
of drug occurs at anytime. Polymers are not required for controlled
release.
Inventors: |
Stavchansky; Salomon S.;
(Austin, TX) ; Bowman; Phillip; (San Antonio,
TX) ; Ho; Paul S.; (Austin, TX) ; Rastogi;
Ashish; (San Antonio, TX) ; Luo; Zhiquan;
(Chandler, AZ) ; Wu; Zhuoijie; (Austin,
TX) |
Assignee: |
Board of Regents, The Univerity of
Texas System
Austin
TX
|
Family ID: |
43450181 |
Appl. No.: |
13/383810 |
Filed: |
July 14, 2010 |
PCT Filed: |
July 14, 2010 |
PCT NO: |
PCT/US10/42029 |
371 Date: |
February 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61225352 |
Jul 14, 2009 |
|
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61225309 |
Jul 14, 2009 |
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Current U.S.
Class: |
604/8 ; 216/39;
264/400; 424/130.1; 424/484; 424/485; 424/486; 424/488; 424/94.1;
514/1.1; 514/169; 514/23; 514/44R; 514/558; 514/9.7; 604/93.01 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 25/08 20180101; A61P 35/00 20180101; A61P 11/00 20180101; A61F
2310/00017 20130101; A61P 9/00 20180101; A61P 25/00 20180101; A61B
5/076 20130101; A61B 5/686 20130101; A61P 31/10 20180101; A61L
17/005 20130101; A61F 2/91 20130101; A61M 25/0017 20130101; A61M
27/002 20130101; A61P 25/18 20180101; A61F 2/915 20130101; A61P
1/04 20180101; A61P 25/14 20180101; A61F 2310/00179 20130101; A61P
9/10 20180101; A61B 17/06166 20130101; A61L 29/16 20130101; A61M
25/001 20130101; A61F 2230/0054 20130101; A61M 25/0043 20130101;
A61F 2220/005 20130101; A61F 2250/0068 20130101; A61P 9/12
20180101; A61L 31/16 20130101; A61M 2025/0057 20130101; A61L
2300/43 20130101; A61F 2/0063 20130101; A61P 37/08 20180101; A61B
5/4839 20130101; A61F 2230/0013 20130101; A61L 31/06 20130101; A61P
25/24 20180101; A61F 2240/001 20130101; A61F 2310/00329 20130101;
A61P 27/02 20180101; A61P 3/10 20180101; A61F 2250/0002 20130101;
A61P 7/02 20180101; A61P 29/00 20180101; A61F 2/06 20130101; A61L
27/54 20130101; A61L 2300/602 20130101; A61B 2560/0219 20130101;
A61F 2/24 20130101; A61F 2/82 20130101; A61K 31/573 20130101; A61B
90/30 20160201; A61F 9/0017 20130101; A61P 21/02 20180101 |
Class at
Publication: |
604/8 ; 424/484;
424/485; 424/486; 424/488; 514/1.1; 514/44.R; 514/23; 514/558;
514/169; 424/130.1; 514/9.7; 424/94.1; 216/39; 264/400;
604/93.01 |
International
Class: |
A61M 1/00 20060101
A61M001/00; A61K 38/00 20060101 A61K038/00; A61K 31/7088 20060101
A61K031/7088; A61K 31/70 20060101 A61K031/70; A61K 31/20 20060101
A61K031/20; A61P 29/00 20060101 A61P029/00; A61P 37/08 20060101
A61P037/08; A61P 25/00 20060101 A61P025/00; A61K 31/56 20060101
A61K031/56; A61P 11/00 20060101 A61P011/00; A61P 25/18 20060101
A61P025/18; A61P 9/12 20060101 A61P009/12; A61P 21/02 20060101
A61P021/02; A61P 25/24 20060101 A61P025/24; A61P 25/14 20060101
A61P025/14; A61P 3/10 20060101 A61P003/10; A61P 1/04 20060101
A61P001/04; A61P 35/00 20060101 A61P035/00; A61K 39/395 20060101
A61K039/395; A61K 38/22 20060101 A61K038/22; A61K 38/43 20060101
A61K038/43; B44C 1/22 20060101 B44C001/22; B29C 67/00 20060101
B29C067/00; A61M 5/00 20060101 A61M005/00; A61K 9/00 20060101
A61K009/00 |
Claims
1. A device for delivery of one or more active agents comprising:
an impermeable, biocompatible housing matrix enclosing a supply of
one or more active agents, wherein the matrix comprises one or more
passageways that extend from a surface of the housing to the supply
of the one or more active agents wherein the passageways provide
for release of the active agents with zero order release
kinetics.
2. The device of claim 1, wherein the matrix is at least one of
nonbiodegradable, biodegradable, nonbioresorbable, bioresorbable or
a combination or modification thereof, wherein the one or more
active agents is in a dosage form selected from the group
consisting of a solid dosage form, a liquid dosage form, a
semi-solid dosage, a powder, or a hydrogel with or without the use
of a polymer, wherein the polymer is a natural polymer, a synthetic
polymer or a combination thereof.
3.-4. (canceled)
5. The method of claim 2, wherein the natural polymer is selected
from the group consisting of anionic polymers, alginic acid,
pectin, carrageenan, chondroitin sulfate, dextran sulfate, cationic
polymers, chitosan, polylysine, amphipathic polymers, collagen,
carboxymethyl chitin, fibrin, and neutral polymers, dextran,
agarose, pullulan, and combinations and modifications thereof.
6. The method of claim 4, wherein the synthetic polymer is selected
from the group consisting of poly (vinyl alcohol), poly (ethylene
oxide), poly (vinyl pyrrolidone), poly (N-isopropylacrylamide),
poly-(caprolactone), poly(hydroxybutyrate), HEMA
(hydroxyethylmethacrylate), PMMA (poly(methyl methacrylate), PEMA
(poly(ethyl methacrylate), PAAm (polyacrylamide), cyclodextrin, and
combinations and modifications thereof.
7. The device of claim 1, wherein the housing matrix is selected
from the group consisting of a polymer, a rubber, a metal, a
mineral, a ceramic or a glass, wherein the passageway is selected
from the group consisting of a hole, a perforation, a channel, an
orifice, an aperture, a bore or combinations thereof, and wherein
the active agent is selected from the group consisting of a
therapeutic drug, a vitamin, a mineral, a saccharide, a lipid, a
nucleic acid, a protein, a peptide, and combinations thereof.
8.-9. (canceled)
10. The device of claim 9, wherein the therapeutic drug is selected
from the group consisting of an analgesic agent, an
antiinflammatory agent, an antihistaminic agent, an antiallergic
agent, a central nervous system drug, an antipyretic agent, a
respiratory agent, a steroid, a local anesthetic, a sympathomimetic
agent, an antihypertensive agent, an antipsychotic agent, a calcium
antagonist, a muscle relaxant, a vitamin, a cholinergic agonist, an
antidepressant, an antispasmodic agent, a mydriatic agent, an
anti-diabetic agent, an anorectic agent, an antiulcerative agent,
an anti-tumor agent or combinations modifications thereof and,
wherein the proteins are selected from the group consisting of an
immunoglobulin or fragments thereof, a hormone, an enzyme, a
cytokine, a biomolecule, and combinations and modifications
thereof.
11. (canceled)
12. The device of claim 1, wherein the device comprises a
geometrical shape selected from the group consisting of a cuboid, a
cube, a sphere, a cone, an oval, and a cylinder.
13. The device of claim 1, wherein the device may optionally be
attached to a medical device or a microelectronic circuit, wherein
the microelectronic circuit comprises at least one of a sensor, a
transmitter, a receiver, a transceiver, a switch, a power supply or
a light.
14. The device of claim 13, wherein the medical device is selected
from the group consisting of a stent, an urinary catheter, an
intravascular catheter, a dialysis shunt, a wound drain tube, a
skin suture, a vascular graft, an implantable mesh, an intraocular
device, an eye buckle, a heart valve, and combinations and
modifications thereof.
15. The device of claim 1, wherein the passageways range from 5
nanometers-1 centimeter, 100 nanometers-100 microns, 1 micron-50
microns, 10-30 microns, 15-25 microns or 20 microns.
16. The device of claim 1, wherein the device is coated with a
coating that prevents release of the one or more active agents
until the coating is removed, which then causes release of the one
or more active agents at a substantially constant rate.
17.-24. (canceled)
25. A drug delivery device comprising a surface configured for a
controlled release of a drug supply to a body organ, a tissue, a
lumen, a blood vessel, wherein the drug release is maintained at a
substantially constant rate, thereby resulting in zero order
release kinetics, wherein the device encompasses the drug
supply.
26. The device of claim 25, wherein the surface comprises one or
more passageways comprising a hole, a perforation, a channel, an
orifice, an aperture, a bore, or combinations thereof, wherein the
passageway extends from the surface of the device to the drug
supply.
27. The device of claim 25, wherein the device has a geometrical
shape selected from the group consisting of a cuboid, a cube, a
sphere, a cone, an oval, and a cylinder.
28. The device of claim 25, wherein the device may optionally be
coated by a polymer, wherein the polymer is selected from the group
consisting of polysaccharides, proteins, poly(ethylene glycol),
poly(methacrylates), poly(ethylene-co-vinyl acetate),
poly(DL-lactide), poly(glycolide), copolymers of lactide and
glycolide, polyanhydride copolymers, and combinations and
modifications thereof.
29. The device of claim 25, wherein the device comprises a
biocompatible material selected from the group consisting of a
polymer, a metal, a mineral, a ceramic, a glass, and combinations
and modifications thereof.
30. (canceled)
31. The device of claim 25, wherein the device further comprises a
housing impermeable to the drug supply and bodily fluids.
32. The device of claim 25, wherein said device further comprises
at least one end having an outlet port, wherein the drug release
occurs through said outlet port.
33. The device of claim 25, wherein a number and a size of at least
one passageway modulates a rate and an extent of release of the
drug.
34. (canceled)
35. The device of claim 25, wherein the rate and the extent of drug
release is dependent on one or more parameters selected from the
group consisting of drug solubility, device dimensions, passageway
dimensions, and drug density and wherein the drug release rate is
manipulated by changing a parameter selected from the group
consisting of one or more holes on the surface, diameter of the
holes, distance between the holes, diameter of the tube, length of
the tube, solubility of the drug, and the amount of drug
supply.
36. (canceled)
37. The device of claim 25, wherein the passageway has a diameter
ranging approximately between 5 nanometers-1 centimeter, 100
nanometers-100 microns, 1 micron-50 microns, 10-30 microns, 15-25
microns or 20 microns.
38. The device of claim 25, wherein the drug supply is selected
from a drug depot or a drug reservoir comprising a solid, a liquid,
a semi-solid, and a suspension.
39. The device of claim 25, wherein the drug is a member of a
biopharmaceutical classification system (BCS) class selected from
the group consisting of Class I (High permeability, High
solubility); Class II (Low solubility, Low Permeability); Class III
(High Solubility, Low Permeability), and Class IV (Low solubility,
Low permeability).
40-41. (canceled)
42. The device of claim 25, wherein the device is attached to a
medical device, wherein the medical device is a stent.
43. A method for fabricating a controlled release delivery system
for providing a unidirectional release one or more active agents
with zero order release kinetics, wherein the active agents are
selected from the group consisting of a drug, a diagnostic agent, a
therapeutic agent, a prophylactic agent or combinations thereof
comprising the steps of: providing a silicon-wafer substrate
comprising a trench; placing a non-planar polyimide housing
comprising a hollow core within the trench; etching one or more
passageways extending from the housing surface into the hollow
core, wherein the etching is done by reactive ion etching, laser
ablation or any other suitable technique; and loading an active
agent supply comprising a drug depot or reservoir by a method
selected from the group consisting of capillary action, dipping,
injecting, and pressure loading using positive or negative
pressures.
44. The method of claim 43, further comprising the optional step of
coating the housing with a polymer, wherein the polymer is selected
from the group consisting of polysaccharides, proteins,
poly(ethylene glycol), poly(methacrylates), poly(ethylene-co-vinyl
acetate), poly(DL-lactide), poly(glycolide), copolymers of lactide
and glycolide, polyanhydride copolymers, and combinations and
modifications thereof.
45. (canceled)
Description
TECHNICAL FIELD OF THE INVENTION
[0001] This invention relates to delivering therapeutic agents and
methods of using a therapeutic agent delivery device that is
capable of delivering a diagnostic, therapeutic, and/or
prophylactic agents. Optionally, the delivery device may monitor
bodily fluid analytes by incorporation of microelectronics.
Additionally, the method creates a device that can provide for the
release of the agent from the device that is unidirectional and at
a controlled desirable rate. For example, the agent may include,
but is not limited to, drugs, proteins, peptides, biomarkers,
bioanalytes, and/or genetic material.
BACKGROUND ART
[0002] A number of implantable drug delivery devices have been
suggested to be capable of delivering the drug to the body lumen.
One universal advantage to implanted drug delivery devices is
related to the local administration of a drug that inherently
improves efficacy and decreases side effects, when compared to
other routes of administration such as oral, rectal, topical, or
systemic.
[0003] Nonetheless, a problem with the known implantable drug
delivery devices is that the delivery rate cannot be controlled
during all operational phases of the devices (i.e., drug delivery
rates may change thereby resulting in, for example, first order
delivery kinetics or second order delivery kinetics). Such problems
result in a drug delivery device that administers drugs in an
unpredictable pattern, thereby resulting in poor therapeutic
benefit.
[0004] For example, a popular drug delivery device is a drug
eluting stent. Stents are mesh-like steel or plastic tubes that are
used to open up a clogged atherosclerotic coronary artery or a
blood vessel undergoing stenosis. A drug may be attached onto, or
impregnated into, the stent that is believed to prevent re-clogging
or restenosis a blood vessel. However, the initial release of the
drug may be very rapid releasing 20-40% of the total drug in a
single day. Such high concentrations of the drug have been reported
to result in cytotoxicity at the targeted site.
[0005] As a result of these problems, there is a need for a drug
delivery device, which can be optimized to deliver any therapeutic,
diagnostic, or prophylactic agent for any time period up to several
years maintaining a controlled and desired rate.
SUMMARY OF THE INVENTION
[0006] This invention relates to methods of making a therapeutic
agent delivery device that is capable of delivering a diagnostic,
therapeutic, and/or prophylactic agent to a desired targeted site.
Optionally, the delivery device may monitor bodily fluid analytes.
Additionally, the method creates a device that can provide for the
release of the agent from the device is unidirectional and at a
controlled and desirable rate. For example, the agent may include,
but is not limited to, drugs, proteins, peptides, biomarkers,
bioanalytes, and/or genetic material.
[0007] The present invention provides a device for delivery of one
or more active agents comprising an impermeable, biocompatible
housing matrix enclosing a supply of one or more active agents,
wherein the matrix comprises one or more passageways that extend
from a surface of the housing to the supply of the one or more
active agents wherein the passageways provide for release of the
active agents with zero order release kinetics. In one aspect the
matrix is at least one of nonbiodegradable, biodegradable,
nonbioresorbable, bioresorbable or a combination or modification
thereof. In another aspect the one or more active agents is in a
dosage form selected from the group consisting of a solid dosage
form, a liquid dosage form, a semi-solid dosage, a powder, or a
hydrogel with or without the use of a polymer. In another aspect
the polymer is a natural polymer, a synthetic polymer or a
combination thereof. In yet another aspect the natural polymer is
selected from the group consisting of anionic polymers, alginic
acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate,
cationic polymers, chitosan, polylysine, amphipathic polymers,
collagen, carboxymethyl chitin, fibrin, and neutral polymers,
dextran, agarose, pullulan, and combinations and modifications
thereof and the synthetic polymer is selected from the group
consisting of poly (vinyl alcohol), poly (ethylene oxide), poly
(vinyl pyrrolidone), poly (N-isopropylacrylamide),
poly-(caprolactone), poly(hydroxybutyrate), HEMA
(hydroxyethylmethacrylate), PMMA (poly(methyl methacrylate), PEMA
(poly(ethyl methacrylate), PAAm (polyacrylaqmide), cyclodextrin,
and combinations and modifications thereof.
[0008] In other aspects the housing matrix is selected from the
group consisting of a polymer, a rubber, a metal, a mineral, a
ceramic, or a glass. In another aspect the passageway is selected
from the group consisting of a hole, a perforation, a channel, an
orifice, an aperture, a bore, or combinations thereof. In another
aspect the active agent is selected from the group consisting of a
therapeutic drug, a vitamin, a mineral, a saccharide, a lipid, a
nucleic acid, a protein, a peptide, and combinations thereof. In
yet another aspect the therapeutic drug is selected from the group
consisting of an analgesic agent, an antiinflammatory agent, an
antihistaminic agent, an antiallergic agent, a central nervous
system drug, an antipyretic agent, a respiratory agent, a steroid,
a local anesthetic, a sympathomimetic agent, an antihypertensive
agent, an antipsychotic agent, a calcium antagonist, a muscle
relaxant, a vitamin, a cholinergic agonist, an antidepressant, an
antispasmodic agent, a mydriatic agent, an anti-diabetic agent, an
anorectic agent, an antiulcerative agent, an anti-tumor agent, or
combinations modifications thereof. The proteins used in the
present invention are selected from the group consisting of an
immunoglobulin or fragments thereof, a hormone, an enzyme, a
cytokine, a biomolecule, and combinations and modifications
thereof.
[0009] In one aspect device comprises a geometrical shape selected
from the group consisting of a cuboid, a cube, a sphere, a cone, an
oval, and a cylinder. In another aspect the device may optionally
be attached to a medical device or a microelectronic circuit,
wherein the microelectronic circuit comprises at least one of a
sensor, a transmitter, a receiver, a transceiver, a switch, a power
supply, or a light. Some non-limiting examples of medical devices
that can be used in the present invention are selected from the
group consisting of a stent, an urinary catheter, an intravascular
catheter, a dialysis shunt, a wound drain tube, a skin suture, a
vascular graft, an implantable mesh, an intraocular device, an eye
buckle, a heart valve, and combinations and modifications thereof.
In yet another aspect the passageways range from 5 nanometers-1
centimeter, 100 nanometers-100 microns, 1 micron-50 microns, 10-30
microns, 15-25 microns or 20 microns. In a related aspect the
device is coated with a coating that prevents release of the one or
more active agents until the coating is removed, which then causes
release of the one or more active agents at a substantially
constant rate.
[0010] Another embodiment of the instant invention discloses a
controlled release delivery system for providing a unidirectional
release one or more active agents, comprising: (i) an impermeable
housing matrix comprising an outlet port and encompassing an active
agent supply, wherein the housing matrix is selected from the group
consisting of a polymer, a metal, a mineral, a ceramic, or a glass,
and the active agent supply comprises the one or more active agents
selected from the group consisting of a diagnostic agent, a
therapeutic agent, a prophylactic agent, a nutritional agent, or
combinations thereof, (ii) a polymer coating encapsulating the
impermeable housing matrix, wherein the polymer coating is at least
one of biocompatible, biodegradable, bioresorbable or a combination
thereof, and (iii) one or more passageways selected to provide zero
order release kinetics that comprise at least one of a hole, a
perforation, a channel, an orifice, an aperture, a bore, or
combinations thereof, wherein the passageway extends from a surface
of the polymer coating to the active agent supply. In one aspect
the polymer coating is selected from the group consisting of
polysaccharides, proteins, poly(ethylene glycol),
poly(methacrylates), poly(ethylene-co-vinyl acetate),
poly(DL-lactide), poly(glycolide), copolymers of lactide and
glycolide, polyanhydride copolymers, and combinations and
modifications thereof.
[0011] In another aspect the passageways range from 5 nanometers-1
centimeter, 100 nanometers-100 microns, 1 micron-50 microns, 10-30
microns, 15-25 microns or 20 microns. In another aspect the
therapeutic agent or the prophylactic agent is selected from the
group consisting of a drug, a protein, a peptide, a biomarker, a
bioanalyte, a genetic material, and combinations and modifications
thereof. In yet another aspect the drug is selected from the group
consisting of an analgesic agent, an antiinflammatory agent, an
antihistaminic agent, an antiallergic agent, a central nervous
system drug, an antipyretic agent, a respiratory agent, a steroid,
a local anesthetic, a sympathomimetic agent, an antihypertensive
agent, an antipsychotic agent, a calcium antagonist, a muscle
relaxant, a vitamin, a cholinergic agonist, an antidepressant, an
antispasmodic agent, a mydriatic agent, an antidiabetic agent, an
anorectic agent, an antiulcerative agent, an antitumor agent, and
combinations or modifications thereof.
[0012] In one aspect the proteins are selected from the group
consisting of an immunoglobulin, an antibody, a hormone, an enzyme,
a cytokine, a biomolecule, and combinations and modifications
thereof. In another aspect the system comprises a geometrical
shape, wherein the said geometrical shape is selected from the
group consisting of a cuboid, a cube, a sphere, a cone, an oval,
and a cylinder. In yet another aspect the system may optionally be
attached to a stent or a microelectronic sensor circuit, wherein
the sensor comprises a transmitter.
[0013] Yet another embodiment of the instant invention relates to a
drug delivery device comprising a surface configured for a
controlled release of a drug supply to a body organ, a tissue, a
lumen, a blood vessel, wherein the drug release is maintained at a
substantially constant rate, thereby resulting in zero order
release kinetics, wherein the device encompasses the drug supply.
In one aspect the surface comprises one or more passageways
comprising a hole, a perforation, a channel, an orifice, an
aperture, a bore, or combinations thereof, wherein the passageway
extends from the surface of the device to the drug supply. In
another aspect the device has a geometrical shape selected from the
group consisting of a cuboid, a cube, a sphere, a cone, an oval,
and a cylinder. In yet another aspect the device may optionally be
coated by a polymer, wherein the polymer is selected from the group
consisting of polysaccharides, proteins, poly(ethylene glycol),
poly(methacrylates), poly(ethylene-co-vinyl acetate),
poly(DL-lactide), poly(glycolide), copolymers of lactide and
glycolide, polyanhydride copolymers, and combinations and
modifications thereof.
[0014] The device as described hereinabove comprises a
biocompatible material selected from the group consisting of a
polymer, a metal, a mineral, a ceramic, a glass, and combinations
and modifications thereof. In one aspect the drug supply is loaded
by a method selected from the group consisting of capillary action,
dipping, injecting, and pressure loading using positive or negative
pressures. In another aspect the device further comprises a housing
impermeable to the drug supply and bodily fluids and further
comprises at least one end having an outlet port, wherein the drug
release occurs through said outlet port. In yet another aspect a
number and a size of at least one passageway modulates a rate and
an extent of release of the drug. In one aspect the device releases
the drug supply into the body lumen for a time period ranging from
days to several years, wherein the rate and the extent of drug
release is dependent on one or more parameters selected from the
group consisting of drug solubility, device dimensions, passageway
dimensions, and drug density. The drug release rate by the device
of the instant invention is manipulated by changing a parameter
selected from the group consisting of one or more holes on the
surface, diameter of the holes, distance between the holes,
diameter of the tube, length of the tube, solubility of the drug,
and the amount of drug supply.
[0015] In one aspect of the device described hereinabove the
passageway has a diameter ranging approximately between 5
nanometers-1 centimeter, 100 nanometers-100 microns, 1 micron-50
microns, 10-30 microns, 15-25 microns or 20 microns. In another
aspect the drug supply is selected from a drug depot or a drug
reservoir comprising a solid, a liquid, a semi-solid, and a
suspension. In yet another aspect the drug is a member of a
biopharmaceutical classification system (BCS) class selected from
the group consisting of Class I (High permeability, High
solubility); Class II (Low solubility, Low Permeability); Class III
(High Solubility, Low Permeability), and Class IV (Low solubility,
Low permeability).
[0016] The device of the instant invention is configured for
long-term administration in a biological organism by a method
selected from the group consisting of implantation, insertion, and
injection. In one aspect the device comprises one or more units and
is attached to a medical device, wherein the medical device is a
stent.
[0017] In one embodiment, the present invention contemplates a
method comprising: a) providing; i) a substrate comprising a
trench; and ii) a non-planar housing comprising a hollow core; b)
placing the housing within the trench; and c) etching a passageway
extending from the housing surface into the hollow core. In one
embodiment, the substrate comprises a silicon wafer. In one
embodiment, the trench comprises vertical sidewalls. In one
embodiment, the trench comprises a groove structure with sidewalls.
In one embodiment, the etching comprises reactive ion etching. In
one embodiment, the etched passageway comprises a micro-hole. In
one embodiment, the micro-hole has a diameter ranging from a
fraction of a micron to hundreds of microns. In one embodiment, the
housing comprises polyimide.
[0018] In one embodiment the present invention describes a method
for fabricating a controlled release delivery system for providing
a unidirectional release one or more active agents with zero order
release kinetics, wherein the active agents are selected from the
group consisting of a drug, a diagnostic agent, a therapeutic
agent, a prophylactic agent or combinations thereof comprising the
steps of: (i) providing a silicon-wafer substrate comprising a
trench; (ii) placing a non-planar polyimide housing comprising a
hollow core within the trench; (iii) etching one or more
passageways extending from the housing surface into the hollow
core, wherein the etching is done by reactive ion etching, laser
ablation or any other suitable technique; and (iv) loading an
active agent supply comprising a drug depot or reservoir by a
method selected from the group consisting of capillary action,
dipping, injecting, and pressure loading using positive or negative
pressures. The method as described hereinabove further comprises
the optional step of coating the housing with a polymer, wherein
the polymer is selected from the group consisting of
polysaccharides, proteins, poly(ethylene glycol),
poly(methacrylates), poly(ethylene-co-vinyl acetate),
poly(DL-lactide), poly(glycolide), copolymers of lactide and
glycolide, polyanhydride copolymers, and combinations and
modifications thereof. In one aspect of the method of the present
invention the passageways comprise micro-holes having diameters
ranging from 5 nanometers-1 centimeter, 100 nanometers-100 microns,
1 micron-50 microns, 10-30 microns, 15-25 microns or 20
microns.
[0019] In one embodiment, the present invention contemplates a
process of fabrication of micro-hole structures on non-planar
substrates or miniature structures, comprising: a) a non-planar
micro-structure or miniature substrate made of metal or non-metal,
b) a non-planar micro-structure or miniature substrate of varying
shapes, including cylindrical tubes and varying dimensions from
tens of microns to centimeters, and c) fabrication of micro-holes
on the surface of the micro-structure or the substrate. In one
embodiment, the micro-holes comprise a range of sizes, from a
fraction of a micron to hundreds of microns. In one embodiment, the
non-planar micro-structure or the miniature substrate comprise
different shapes depending on the application, including circular,
rectangular, triangular, elliptical, and square. In one embodiment,
the micro-structure is placed into a support structure with
built-in trenches or grooves to hold the non-planar
micro-structure. In one embodiment, the micro-structures and its
support structure can be incorporated into another complex
structure, such as a micro-chip, an integrated microelectronic
circuit, and a micro-electrical mechanical system (MEMS). In one
embodiment, the structures can be integrated with other systems
such as medical, bio-material and STENT. In one embodiment, the
trenches or grooves in the support structure can have a "V" shape,
a "U" shape or other shapes of interest to hold the non-planar
microstructure. In one embodiment, the support structure is
fabricated on a silicon wafer or other materials, depending on the
application of the micro-structure. In one embodiment, the
non-planar substrates can be inserted into the trenches of the
support structure using adhesives, such as photo-resist, to attach
the micro-structure to the trench of the support structure. In one
embodiment, the micro-structure described hereinabove can be cut
into segments with varying lengths.
DESCRIPTION OF THE DRAWINGS
[0020] A more complete understanding of embodiments of the
disclosure will be apparent from the detailed description taken in
conjunction with the accompanying drawings in which:
[0021] FIG. 1 is a tubular drug delivery device having an inner
lumen that serves as drug reservoir and surface perforations that
enable drug release from the device;
[0022] FIG. 2 is a cross-sectional view of the drug filled drug
delivery device in contact with an anatomical site;
[0023] FIG. 3 is a carrier, for example, a stent structure to which
the drug delivery device could be attached;
[0024] FIG. 4 is an example illustrating attachment of the drug
delivery device to the carrier of FIG. 3;
[0025] FIG. 5 is a singular adhesive patch attached with several
drug delivery tubes for combination therapy;
[0026] FIG. 6 is a graph illustrating cumulative zero order release
of crystal violet from three types of drug delivery device that
differ in the number of surface perforations;
[0027] FIG. 7 is a graph illustrating cumulative percentage of
crystal violet released from three types of drug delivery device
that differ in the number of surface perforations;
[0028] FIG. 8 is a graph illustrating the linearity of drug release
from the drug delivery device in proportion to the number of
holes;
[0029] FIG. 9 is a cumulative percentage of crystal violet released
from one open end of the drug delivery device with no
perforations;
[0030] FIG. 10 is a schematic of a mold showing the trenches and
the through holes;
[0031] FIGS. 11A-11D shows a process flow chart for fabricating a
silicon mold;
[0032] FIG. 12A-12F illustrates one embodiment of a method for
fabricating "U" or "V" shaped trenches on a silicon wafer. All
images show cross-sectional views;
[0033] FIGS. 13A-13C shows a plain view of a silicon mold
fabricated using the process shown in FIG. 11: FIG. 13A is the top
side of the mold; FIG. 13B is the backside of the mold; FIG. 13C is
a single window structure;
[0034] FIGS. 13D-13E shows several steps to fabricate one
embodiment of an impermeable therapeutic drug delivery device: FIG.
13D presents a scanning electron microscopic image of a "U" shaped
trench pattern; FIG. 13E presents an optical microscopic image of a
circular passageway through a polyimide tube made by
photolithographic technique;
[0035] FIGS. 14A and 14B is a schematic of a process flow for
etching holes on tubes with the help of a silicon mold;
[0036] FIGS. 15A-15E shows one embodiment of a schematic for the
process flow fabricating micro-holes on a polymer tube, all images
show cross-sectional views;
[0037] FIG. 16 is a stent structure whose struts can be built using
the perforated drug delivery device;
[0038] FIG. 17 is drug delivery device in different sizes with no
perforations and only one end open for drug release;
[0039] FIG. 18 is a photograph of drug release via the perforations
on the drug delivery device into the dissolution medium;
[0040] FIG. 19 is a graph illustrating cumulative zero order
release of crystal violet from three types of drug delivery device
of FIG. 17; and
[0041] FIG. 20 is a graph comparing the daily drug release from the
drug delivery devices of FIG. 17.
DESCRIPTION OF THE INVENTION
[0042] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts that can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0043] To facilitate the understanding of this invention, a number
of terms are defined below. Terms defined herein have meanings as
commonly understood by a person of ordinary skill in the areas
relevant to the present invention. Terms such as "a", "an" and
"the" are not intended to refer to only a singular entity, but
include the general class of which a specific example may be used
for illustration. The terminology herein is used to describe
specific embodiments of the invention, but their usage does not
delimit the invention, except as outlined in the claims.
[0044] Before any embodiments of the invention are described in
detail, it is to be understood that the invention is not limited in
its application to the details of construction and the arrangement
of components set forth in the following description. The invention
is capable of other embodiments and of being practiced or of being
carried out in various ways. Also it is to be understood that the
phraseology and terminology used herein is for the purpose of
description and should not be regarded as limiting. The use of
"including," "comprising," or "having" and variations thereof
herein is meant to encompass the items listed thereafter and
equivalents thereof, as well as additional items.
[0045] As used herein the term "mold" refers to a solid support
used to hold a substrate or material and to transfer a shape to the
substrate. The substrate may have different desired shapes and
sizes prior to being placed in the mold, or the mold may partially
or completely reshape the substrate. The substrate is either
placed, physically shaped, or poured into the mold to transfer a
particular and/or contemplated opening, shape, structure or
component by one or more techniques including but not limited to
lithography, imprinting, thermal and pressure molding, laser
ablation, etching (e.g., reactive ion etching), ion milling, and
other microfabrication techniques. The term includes both
stationary molds for processing a batch and moveable molds for
continuous casting.
[0046] The term "therapeutic agent delivery device" or "unit" as
used herein, refers to any device having a housing comprising an
impermeable matrix material encompassing a therapeutic agent filled
hollow core. The device may be constructed such that the
impermeable matrix material contains at least one passageway
capable of releasing the encompassed drug wherein the ends of the
device is plugged using a bioglue (i.e., for example, a
albumin-glutaraldehyde composition). Alternatively, the device may
be constructed such that the hollow core comprises an open end
(i.e., for example, an outlet port) wherein the housing is devoid
of passageways.
[0047] The term "housing" as used herein, refers to any impermeable
matrix material, of any shape or size, encompassing a hollow core
that is capable of supporting the formation of at least one
passageway. For example, the housing may be in the shape of a
cylinder and comprise from one to three passageways extending
between the housing surface and the encompassed hollow core.
[0048] The term "hollow core" as used herein, refers to any open
space encompassed by a housing, configured to contain a therapeutic
agent supply composition and/or formulation.
[0049] The term "passageway" or "channel` as used herein, refers to
any means by which a drug molecule is transported from the hollow
core, through and out of the housing. Such means may include but
are not limited to, an aperture, orifice, bore, channel outlet, or
hole. The number and size of the "passageway" may be selected to
tailor make the rate and extent of release of the agents. For
example, the diameter of a passageway may range from several
nanometers to several centimeters. Preferably, the diameter of a
passageway ranges between approximately 1 nanometers-1 centimeter.
More preferably, the diameter of a passageway ranges between
approximately 100 nanometers-750 microns. Even more preferably, the
diameter of a passageway ranges between approximately 5 microns
(i.e., micrometers)-500 microns (i.e., micrometers). Preferably,
the diameter of a passageway ranges between approximately 20
microns-100 microns.
[0050] The term "outlet port" as used herein, refers to any open
end of a hollow core.
[0051] The term "therapeutic agent" as used herein, refers to any
pharmacologically active substance capable of being administered
which achieves a desired effect. Such agents can be synthetic or
naturally occurring, non-peptide, proteins or peptides,
oligonucleotides or nucleotides, polysaccharides or sugars.
[0052] The term "administered" or "administering" a therapeutic
agent, as used herein, refers to any method of providing an agent
to a patient such that the agent has its intended effect on the
patient. For example, administering may include but not limited to,
local tissue administration (i.e., for example, via a drug delivery
device), oral ingestion, transdermal patch, topical, inhalation,
suppository etc.
[0053] The term "therapeutic agent supply" as used herein, refers
to any drug depot or reservoir in a form including, but not limited
to, a solid composition, a hydrogel, a colloid, a suspension,
solution, or powder that is placed within a hollow core.
[0054] The term "drug" as used herein, refers to any
therapeutically or prophylactically active agent, wherein the agent
obtains a desired diagnostic, physiological, or pharmacological
effect. For example, a drug may include, but is not limited to, any
compound, composition of matter, or mixture thereof that may be
natural or synthetic, organic or inorganic molecule or mixture
thereof which may be used as a therapeutic, prophylactic, or
diagnostic agent. Some examples include but are not limited to
chemotherapeutic agents such as 5-fluorouracil, paclitaxel,
sirolimus, adriamycin, and related compounds; antifungal agents
such as fluconazole and related compounds; anti-viral agents such
as trisodium phosphomonoformate, trifluorothymidine, acyclovir and
related compounds; cell transport/mobility impending agents such as
colchicine, vincristine, cytochalasin B and related compounds;
antiglaucoma drugs such as beta blockers: timolol, betaxolol,
atenolol, an related compounds; peptides and proteins such as
insulin, growth hormones, insulin related growth factors, enzymes,
and other compounds; steroids such as dexamethasone, prednisone,
prednisolone, estradiol. ethinyl estradiol, and similar compounds;
antihypertensives, anticonvulsants, blood glucose lowering agents,
diuretics, painkillers, blood thinning agents, anesthetics,
antibiotics, antihistaminics, immunosuppressants, anti-inflammatory
agents, anti-oxidants, in vivo diagnostic agents (e.g., contrast
agents), sugars, vitamins, toxin antidotes, and molecules developed
by gene therapy.
[0055] The term "bodily fluid" as used herein refers to any
liquid-like or semi-solid composition derived from an organism
including but not limited to blood, serum, urine, gastric, and
digestive juices, tears, saliva, stool, semen, and interstitial
fluids derived from tumored tissues.
[0056] The term "analyte" as used herein, refers to any compound
within a body fluid including, but not limited to, a small organic
molecule, a mineral, an inorganic ion, a protein, or a hormone.
[0057] The term "biopharmaceutical classification system" or "BCS"
as used herein, refers to a scientific classification framework for
drug substances based on their aqueous solubility and intestinal
permeability (U.S. Dept. Health & Human Services, Food and Drug
Administration Center for Drug Evaluation and Research (CDER)
August 2000).
[0058] The term "permeability" as used herein, refers to any
material that permits liquids or gases to pass through. The term
"impermeable" as used herein, refers to any material that does not
permit liquids or gases to pass through.
[0059] The term "solubility" as used herein, refers to the amount
of a substance that will dissolve in a given amount of another
substance. Typically solubility is expressed as the number of parts
by weight dissolved by 100 parts of solvent at a specified
temperature and pressure or as percent by weight or by volume.
[0060] The term "controlled release" as used herein, refers to a
predictable dissolution of a therapeutic agent supply that may be
described by mathematical relationships. For example, a controlled
release may follow zero order kinetics.
[0061] The term "zero-order kinetics" as used herein, refers to a
constant controlled release of a therapeutic agent wherein the
release rate that does not change during the dissolution of a
therapeutic drug supply (i.e., the release rate maintains linearity
throughout the dissolution of the drug supply).
[0062] The term "substantially constant rate" as used herein,
refers to a zero order kinetic release of a therapeutic agent
wherein a regression coefficient is at least 0.90 (i.e., for
example, R.sup.2)
[0063] The term "long-term administration" as used herein, refers
to any therapeutic agent that is given to a patient or subject at
greater than a single dose equivalent. For example, such
administration may comprise multiple doses on a single day or a
single dose over several days. Alternatively, such administration
may comprise a continuous substantially constant rate over the time
period comprising hours, days, week or years.
[0064] The term "geometrical shape" as used herein, refers to any
custom designed composition that is formulated for implantation
into a specific anatomical site of a biological organism. For
example, such compositions may include but are not limited to, a
cuboid, a cube, a sphere, a cone, an oval, or a cylinder. In
particular, a cube is shaped having six sides of equal area whereas
a cuboid in the broadest sense includes, but is not limited to,
polygonal, rhombus, trapezoid, rectangular, and square
cross-sectional shapes with substantially squared or rounded
corners and with perpendicular or angled sides.
[0065] The term "loading" or "loaded" as used herein, refers to the
placement of a therapeutic agent supply within the hollow core of a
drug delivery device. On the other hand, a device may be provided
that is "preloaded" with a therapeutic agent supply,
[0066] The term "body lumen" as used herein, refers to any cavity
of a tubular body organ (i.e., for example, the interior of a blood
vessel).
[0067] The term "biocompatible" as used herein, refers to any
material does not elicit a substantial detrimental response in the
host. There is always concern, when a foreign object is introduced
into a living body, that the object will induce an immune reaction,
such as an inflammatory response that will have negative effects on
the host. In the context of this invention, biocompatibility is
evaluated according to the application for which it was designed:
for example; an implanted medical device (i.e., for example, an
impermeable therapeutic agent delivery device) is regarded as
biocompatible with the internal tissues of the body. Preferably,
biocompatible materials include, but are not limited to,
biodegradable and biostable materials.
[0068] The term "biodegradable" as used herein, refers to any
material that can be acted upon biochemically by living cells or
organisms, or processes thereof, including water, and broken down
into lower molecular weight products such that the molecular
structure has been altered.
[0069] The term "bioresabsorbable" as used herein, refers to any
material that is assimilated into or across bodily tissues. The
bioresorption process may utilize both biodegradation and/or
bioerosin.
[0070] The term "non-biodegradable" as used herein, refers to any
material that cannot be acted upon biochemically by living cells or
organisms, or processes thereof, including water
[0071] The term "non-bioreabsorbable" as used herein, refers to any
material that cannot be assimilated into or across bodily tissues.
The term "medical device" as used herein, refers broadly to any
apparatus used in relation to a medical procedure and/or therapy.
Specifically, any apparatus that contacts a patient during and/or
after a medical procedure or therapy is contemplated herein as a
medical device. Similarly, any apparatus that administers a
compound or drug to a patient during or after a medical procedure
and/or therapy is contemplated herein as a medical device. Such
devices are usually implanted and may include, but are not limited
to, urinary and intravascular catheters, dialysis shunts, wound
drain tubes, skin sutures, vascular grafts and implantable meshes,
intraocular devices, implantable drug delivery systems (i.e., for
example, a stent or eye buckle) and heart valves, and the like. A
medical device is "coated" when a medium (i.e., for example a
polymer) comprising a therapeutic agent becomes attached to the
surface of the medical device. This attachment may be permanent or
temporary. When temporary, the attachment may result in a
controlled release of a drug.
[0072] The term "attached" as used herein, refers to any
interaction between a medium (or carrier) and a drug. Attachment
may be reversible or irreversible. Such attachment includes, but is
not limited to, covalent bonding, ionic bonding, Van der Waals
forces or friction, and the like. A drug is attached to a medium
(or carrier) if it is impregnated, incorporated, coated, in
suspension with, in solution with, mixed with, etc.
[0073] The term "anatomical site" as used herein refers to any
internal or external, deep or superficial body cavity, lumen,
tissue, or organ of a mammalian organism. Some examples of
anatomical sites where the medical device can be placed includes,
but is not limited to, eyes, toenails, fingernails, epidermis
(i.e., for example, skin), nasal cavity, gastro intestinal tract,
valves, veins, and arteries such as coronary arteries, renal
arteries, aorta, cerebral arteries, including for example, a
cerebral arterial wall.
[0074] The terms "reduce," "inhibit," "diminish," "suppress,"
"decrease," "prevent" and grammatical equivalents (including
"lower," "smaller," etc.) when in reference to the expression of
any symptom in an untreated patient relative to a treated patient,
mean that the quantity and/or magnitude of the symptoms in the
treated patient is lower than in the untreated patient by any
amount that is recognized as clinically relevant by any medically
trained personnel. In one embodiment, the quantity and/or magnitude
of the symptoms in the treated patient is at least 10% lower than,
preferably, at least 25% lower than, more preferably at least 50%
lower than, still more preferably at least 75% lower than, and/or
most preferably at least 90% lower than the quantity and/or
magnitude of the symptoms in the untreated patient.
[0075] The term "patient" as used herein, is a human or animal and
need not be hospitalized. For example, out-patients, persons in
nursing homes are patients. A patient may comprise any age of a
human or non-human animal and therefore includes both adult and
juveniles (i.e., children). It is not intended that the term
"patient" connote a need for medical treatment, therefore, a
patient may voluntarily or involuntarily be part of experimentation
whether clinical or in support of basic science studies.
[0076] The term "effective amount" as used herein, refers to a
particular amount of a pharmaceutical composition comprising a
therapeutic agent that achieves a clinically beneficial result
(i.e., for example, a reduction of symptoms). Toxicity and
therapeutic efficacy of such compositions can be determined by
standard pharmaceutical procedures in cell cultures or experimental
animals, e.g., for determining the LD.sub.50 (the dose lethal to
50% of the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio between toxic
and therapeutic effects is the therapeutic index, and it can be
expressed as the ratio LD.sub.50/ED.sub.50. Compounds that exhibit
large therapeutic indices are preferred. The data obtained from
these cell culture assays and additional animal studies can be used
in formulating a range of dosage for human use. The dosage of such
compounds lies preferably within a range of circulating
concentrations that include the ED.sub.50 with little or no
toxicity. The dosage varies within this range depending upon the
dosage form employed, sensitivity of the patient, and the route of
administration.
[0077] The term "derived from" as used herein, refers to the source
of a compound or sequence. In one respect, a compound or sequence
may be derived from an organism or particular species. In another
respect, a compound or sequence may be derived from a larger
complex or sequence.
[0078] The term "pharmaceutically" or "pharmacologically
acceptable" as used herein, refer to molecular entities and
compositions that for use in humans and other mammals that have
been approved by a drug and medical device regulating authority or
are under clinical development and have acceptable risk to benefit
ratio.
[0079] The term, "pharmaceutically acceptable carrier", as used
herein, includes any and all solvents, or a dispersion medium
including, but not limited to, water, ethanol, polyol (for example,
glycerol, propylene glycol, and liquid polyethylene glycol, and the
like), suitable mixtures thereof, and vegetable oils, coatings,
isotonic and absorption delaying agents, liposome, commercially
available cleansers, and the like. Supplementary bioactive
ingredients also can be incorporated into such carriers.
[0080] The term "formulation" as used herein, refers to any
composition comprising a therapeutic agent intended for
administration to a patient and/or subject. For example, a
formulation may include, but not be limited to, a solid, a powder,
a semisolid, or a gel.
[0081] This invention relates to methods of making a therapeutic
agent delivery device, which is capable of delivering a diagnostic,
therapeutic, and/or prophylactic agent to a desired targeted site.
Optionally, the delivery device may monitor bodily fluid analytes.
Additionally, the method creates a device that can provide for the
release of the agent from the device is unidirectional and at a
controlled desirable rate. For example, the agent may include, but
is not limited to, drugs, proteins, peptides, biomarkers,
bioanalytes, and/or genetic material.
[0082] Miniature substrates, such as polymer micro-tubes, are
finding increasing industrial and bio-medical applications. In many
cases, the miniature substrates need further processing to
fabricate specific structures to complete the desired devices. One
example is to fabricate micro-holes on the surfaces of polymer
tubes to form flexible drug release devices.
[0083] The method of laser ablation is commonly used to fabricate
micro-holes on polymer tubes. It is a fast one-step process without
using chemicals. However, the fabrication process is serial where
the holes are made one by one limiting it to a low throughput
manufacturing. For certain applications, a single device may
require a large number of micro-holes on a tube. In this case, the
manufacturing cost would be very high if the sequential laser
ablation method is used.
[0084] To overcome the disadvantages of laser ablation, the present
invention discloses a technology based on parallel processing to
fabricate micro-holes on tubes employing lithography and reactive
ion etching techniques. Such a parallel processing method is fast
and low-cost and is well suited for mass production. In addition,
the method has the potential to integrate electrical or electronic
sensors and devices to control the drug delivery devices. However,
the photo-resist and masking material used in the fabrication
process may contaminate the tubes. The baking step used in
photo-lithography and the chemicals used to clean the tubes after
etching may change the properties of the polymer as well. It would
be difficult to use this method to fabricate device structure using
chemically unstable polymeric materials, e.g., bio-degradable
tubes. Furthermore, due to the nonplanar surface of the tubes, the
mask used for lithographic patterning may not protect tubes well
during the etching process. As a result, cracks can develop on the
tube surface, reducing the manufacturing yield. Since the method is
based on a multi-step process: mask film deposition,
photo-lithography, etching etc. to fabricate the device, an
extensive facility equipped with the proper manufacturing tools is
required, making the manufacturing method expensive.
[0085] The present invention discloses another method, which
retains the efficient approach of parallel processing but
incorporates a simple molding method to form the micro-holes on
flexible polymer tubes, including bio-degradable tubes. The process
is fast, efficient, and low cost.
[0086] Although it is not necessary to understand the mechanism of
an invention, it is believed that such a delivery device will
eliminate the need for repeated dosing of a medicament thereby
improving patient compliance. It is further believed that such a
device would also decrease patient side effect risk, prolonged and
unnecessary pain, and expense for many long term therapeutic
regimens.
[0087] The instant invention uses a mold to fabricate
micro-structures on miniature substrates such as micro-tubes.
Trenches on the mold can hold tubes for convenient handling. The
mold also has predefined configurations of through-hole structures
from the backside. These predefined through-hole structures can be
transferred to the desired positions on tubes in a single step of
etching without any alignment and further manipulation. The mold
can be reused for many batches. It is more efficient than laser
ablation because it can process many tubes and fabricate many
structures simultaneously. The process is simple and runs in a
parallel manner. It is simpler than the micro-fabrication technique
disclosed in U.S. Provisional Patent No. 61/225,352 because it
requires no expensive processing steps, such as lithography,
multiple thin film deposition and etching.
[0088] This invention simplifies significantly the process to
fabricate microstructures on miniature substrates such as
micro-tubes. Once the mold is formed, the fabrication process can
be done in a single step. Except the parts exposed to the through
holes of the mold, tubes under processing is intact. So the tubes
are free of etching-induced cracks. Because it is a chemical-free
process, it avoids any possible chemical contamination. It can also
be easily applied to chemically unstable materials, e.g.,
bio-degradable tubes which are difficult to process by conventional
micro-fabrication techniques without degrading the material
properties of the tubes.
[0089] The disclosed invention combines the advantages of both
laser ablation and micro-fabrication. Compared to laser ablation,
which is a serial process, the parallel nature of the present
method enables a fast throughput thus reduces the manufacturing
cost for mass production. The predefined structures on the mold
make it free from any alignments and complex optics manipulating.
Compared to the micro-fabrication technique disclosed in U.S.
Provisional Patent No. 61/225,352 which is a multi-step process, it
is a single-step process. This greatly shortens the manufacturing
time and reduces both the material cost and investment on capital
equipment. This crack-free process also improves the yield.
Furthermore, the topside of the mold can also work as a template
similar to the one in U.S. Provisional Patent No. 61/225,352. In
another word, both sides of a tube can be processed by the mold
technology disclosed herein. The polymer tubes or other substrates
where the micro-holes are formed on can be integrated with
microelectronics circuits and MEMS structures to form integrated
devices for monitoring and controlled release of chemical agents or
medications.
[0090] The present invention offers several advantages over
existing drug delivery devices. One such advantage is to achieve
zero order release kinetics without an initial burst effect such as
is found in current designs that are known in the art. In its most
basic form, the invention relates to a medical device, which acts
as a housing containing drug reservoir, and means for facilitating
release of drug from the drug reservoir to an anatomical site. The
device enables a mechanism in which the drug is released at equal
increments from the reservoir per unit time.
[0091] One feature of the invention comprises simplicity of design
and prolonged duration drug release capability up to, and
including, several years. Further, drug release may be
unidirectional is not subject to back transfer or build up of the
drug as long as sink conditions are maintained. Although it is not
necessary to understand the mechanism of an invention, it is
believed that such a delivery device will eliminate the need for
repeated dosing of a medicament thereby improving patient
compliance. It is further believed that such a device would also
decrease patient side effect risk, prolonged and unnecessary pain,
and expense for many long term therapeutic regimens. In any drug
treatment, it is desired to deliver a pharmaceutical agent directly
at the targeted site for a sufficient duration in order to produce
a required beneficial effect. Since the advent of time, man has
sought means to find better cure. Oral, topical and inhalation are
commonly used modes of drug administration. Modern era has
witnessed development of alternate routes such as, systemic,
intravitreal, and pulmonary delivery of drugs. However, age
problems and disadvantages are associated with these conventional
methods that restrict their effectiveness.
[0092] In most instances, drugs administered via these conventional
routes result in the appearance of various deleterious side
effects. For example, some drugs that are administered orally may
not be properly absorbed through the stomach wall; may be degraded
by the gastrointestinal tract; or may irritate the stomach causing
an unwanted side effect. For example, insulin, which is a protein
based drug, cannot be given orally since it would be degraded by
proteolytic enzymes and therefore, must be given by injection.
Further, Intravenous Ganciclovir (GCV) is effective in treatment of
cytomegalovirus (CMV) retinitis in AIDS patients but 30-50%
patients experience bone marrow toxicity resulting in neutropenia
(neutrophil count <1000). Although an intravitreal
administration of 200-400 .mu.g/day of GCV twice a week has
decreased the instances of neutropenia, this regimen requires
repeated dosing thereby causing extreme discomfort to patients.
[0093] Some conventional routes of administration are problematic
in maintaining a constant therapeutic level. For example, a drug
concentration may either reach a toxic level or alternatively it
may decrease as the drug is either metabolized (i.e., for example,
by the liver) or eliminated (i.e., for example, by the kidney).
Frequently, the drug levels may drop below the therapeutic levels
and a second dose is needed.
[0094] One way to overcome this problem is to deliver drugs
locally, that is, directly at the desired physiological site. A
number of implantable drug delivery devices have been suggested to
be capable of delivering a drug to a body lumen. One advantage of
implanted drug delivery devices is related to local administration
of a drug. Although it is not necessary to understand the mechanism
of an invention, it is believed that local administration
inherently improves efficacy and decreases side effects, as
compared to other routes of administration such as oral, rectal,
topical, or systemic. Nonetheless, one problem with the known
implantable drug delivery devices is that the delivery rate cannot
be controlled during all operational phases of the devices (i.e.,
for example, drug delivery rates may change thereby resulting in
first order delivery kinetics or second order delivery
kinetics).
[0095] Such problems result in a drug delivery device that
administers drugs in an unpredictable pattern, thereby resulting in
poor therapeutic benefit. For example, one popular drug delivery
device is a drug eluting stent. Stents are mesh-like steel or
plastic tubes that are used to open up a clogged atherosclerotic
coronary artery or a blood vessel undergoing stenosis. A drug may
be attached onto, or impregnated into, the stent that is believed
to prevent re-clogging or restenosis a blood vessel. However, the
initial release of the drug from a stent may be very rapid, thereby
releasing 20-40% of the total drug in a single day. Such high
concentrations of the drug have been reported to result in
cytotoxicity at the targeted site. To maintain constant levels, a
drug should be released from the delivery system at a rate which
does not change with time (i.e., for example, zero order kinetics).
In many systems however, the release rate is proportional to time
(i.e., first order) or the square root of time (sometimes referred
to as Fickian release kinetics).
[0096] A zero order drug controlled release system offers many
advantages: i) Drug levels are continuously maintained at a
desirable therapeutic range; ii) Adverse effects are reduced by
targeting delivery to a specific site and avoiding distribution to
unwanted tissues; iii) Dose of drug is decreased while mean
residence time is increased; iv) Number of doses is decreased; v)
Less invasive dosing decreases patient trauma and improves patient
compliance; and vi) An inert and impermeable device protects the
drug in the hostile environment.
[0097] Several implantable drug delivery systems have been reported
which are capable of administering drugs at zero order rates. One
of the earliest zero order devices was developed as an ocular
insert as described in U.S. Pat. No. 3,618,604. The device was
described as a sealed container having the drug in an anterior
chamber. The device was capable of continuously releasing
pilocarpine at a predetermined rate of 20-40 .mu.g/hour for seven
days for treating glaucoma. The ocular pressure level and pupil
diameter were maintained throughout the 24-hour period of Ocusert
placement. Nonetheless, as described in U.S. Pat. No. 4,014,335
certain problems have been identified with such devices such as the
difficulty in sealing the margins to form a container. In addition,
stresses and strains introduced into the membrane walls from
deformation during manufacturing of the devices may cause the
reservoir to rupture and leak.
[0098] Another such device, as described in U.S. Pat. No. 5,660,848
comprises a subdermal implant for uses as a contraceptive. This
device was described as a central drug core; an intermediate
polymeric layer controlling the rate of diffusion of drug; and the
outer polymeric layer extending outwards from the intermediate
layer. The device described in U.S. Pat. No. 5,660,848 does have
problems. For example, the macroscopic size of the device releases
significant amounts of the drug, progesterone, into the circulation
causing problems of weight gain and vision loss in a small
percentage of treated patients.
[0099] Osmotic minipumps have been reported as capable of providing
zero-order drug release. One such device as described in U.S. Pat.
No. 3,993,073 has a reservoir, which is formed of a drug carrier
permeable to the passage of the drug and in which the drug has
limited solubility. The wall is formed in at least a part of a drug
release rate controlling material also permeable to the passage of
the drug, but the rate of passage of the drug through the wall is
lower than the rate passage of the drug through the drug carrier so
that drug release by the wall is the drug release rate controlling
step for releasing drug from the drug delivery device. Most of the
osmotic pump devices are developed in form of a tablet or capsule,
which can deliver drug up to a few hours or days and are not
suitable for diseased conditions wherein, a constant amount of drug
needs to be delivered for months and/or years.
[0100] Another minipump device, as described in U.S. Pat. Nos.
6,217,895 and 6,375,972B1, comprises a sustained release device for
the eye. This device is described as an inner core or reservoir
including an effective agent; an impermeable tube which encloses
the reservoir, at three sides; and a permeable membrane at the
fourth side through which drug release takes place. The device is
few hundred microns in dimensions and produces linear release.
However, one drawback of the membrane based reservoir system is
that the choice of the membrane is restricted by the solubility and
diffusion coefficient of the drug. Consequently, a different
membrane is required for each drug.
[0101] The problem of device size is extremely important in the
design of devices as it dictates the variety of anatomical sites
where it can be placed. A macro-sized device may be suitable for
implantation in or near vertebrae but it may not be suitable for
placement in an eye. Larger devices may also involve complex
surgery both during implantation and removal. Furthermore, a larger
device may also result in longer healing and recovery periods or
device rejection by the body. Over the years, the dimensions of
implantable drug delivery devices have decreased and the duration
of release has increased. These reductions in size have improved
immunological responses, biocompatibility, and reduced side effects
associated with earlier devices. Hence, there remains a need for
drug delivery device which can be optimized to deliver any
therapeutic, diagnostic, or prophylactic agent for any time period
up to several years maintaining a controlled and desired rate.
[0102] In some embodiment, the present invention contemplates
methods and devices which comprise an injectable and/or implantable
medical device having at least one orifice on the surface. Although
it is not necessary to understand the mechanism of an invention, it
is believed that the devices can be used to obtain a desired local
or systemic physiological or pharmacological effect in mammals,
e.g., humans. In one embodiment, the device comprises a hollow
matrix of any size or shape, which can be made from materials
including, but not limited to, metals and/or non metals. In one
embodiment, the device comprises a reservoir capable of releasing
at least one therapeutic, diagnostic, and/or prophylactic agent via
the orifices to the desired anatomical site. In one embodiment, a
perforated matrix can either be used individually, or as a set,
which in turn can be either built as part of a device or mounted on
a medical device, including, but not limited to, a stent. Although
it is not necessary to understand the mechanism of an invention, it
is believed that the presently contemplated device, due to its
composite structure, has an ability to combine several release
mechanisms, leading to controllable zero-order release kinetics.
For example, such drug release may be dependent on factors
including, but not limited to, drug solubility, dimensions of the
matrix and orifice, and/or density of drug(s) loaded inside the
device. It is further believed that, the composition provides
zero-order kinetics, in part, because the diffusion rate of the
drug from the device is slow which enables sink conditions. Hence,
no back transfer or build up of drug occurs at anytime. Polymers
are not required for controlled release.
[0103] I. Drug Release Kinetics: Over recent years, drug
release/dissolution from solid pharmaceutical dosage forms has been
of increasing interest. For example, whenever a new solid dosage
form is developed or produced, drug dissolution studies are
performed to determine the release characteristics (i.e., for
example, kinetics) of the formulation. Sometimes, mathematic models
are derived from a theoretical analysis of the observed kinetics.
Usually, however, a theoretical concept is not applicable and
empirical equations are applied instead. For example, drug
dissolution from solid dosage forms has been described by kinetic
models in which the dissolved amount of drug (Q) is a function of
the test time, t or Q=f (t). Some analytical definitions of the
Q(t) function are commonly used, including, but not limited to,
zero-order, first-order, Hixson-Crowell, Weibull, Higuchi,
Baker-Lonsdale, Korsmeyer-Peppas and Hopfenberg models. Other
release parameters, such as dissolution time (tx %), assay time (tx
min), dissolution efficacy (ED), difference factor (f1), similarity
factor (f2) and Rescigno index (xi1 and xi2) can be used to
characterize drug dissolution/release profiles.
[0104] Much effort has been expended to develop zero-order drug
release kinetics for various pharmaceutical drug formulations. Some
having skill in the art believe that linear drug release provides a
more stable therapeutic drug level over time and therefore provides
a more predictable clinical response. Ideal drug delivery process
would, therefore, be expected to exhibit zero-order kinetics.
However, in practice, most conventional drug delivery processes
follow first-order kinetics. Nonetheless, some mathematical models
have determined that certain polymer shapes of drug micro-carriers
that may support near zero-order release. Such mathematical models
may be derived from the Carslaw and Jaeger equation of conduction
of heat that models the relationship between carrier geometry shape
and drug concentration. It has been suggested that by reducing the
k value (i.e., for example, a ratio of volume of the fluid to that
of the sphere) gives a near zero-order kinetics drug delivery
response for most micro carrier geometry shapes that are roughly
spherical in shape. On the other hand, tetrahedron shapes exhibits
the best mathematical fit and tablets exhibit the worst
mathematical fit. Ng et al., "Optimization of Nanoparticle Drug
Micro Carrier on the Pharmacokinetics of Drug Release: A
Preliminary Study" J Med Syst. 32:85-92 (2008).
[0105] Nonetheless, a tablet formulation with a zero-order drug
release profile has been reported that is based on a balanced blend
of three matrix ingredients. Specifically, matrices comprising
Polyox.RTM., Carbopol.RTM., and lactose were evaluated for their
effect on the release rate of theophylline. The tablets were
prepared by direct compression and were subjected to an in vitro
dissolution study. A balanced blend of these matrix ingredients
could be used to attain a zero-order release profile. El-Malah et
al., "D-Optimal Mixture Design: Optimization of Ternary Matrix
Blends for Controlled Zero-Order Drug Release from Oral Dosage
Forms" Drug Dev Ind Pharm. 32:1207-18 (2006). Other polymer based
matrices have been produced that support zero-order delivery of the
highly soluble drug alfuzosin hydrochloride. These matrices were
reported to contain polyethylene oxide (PEO),
hydroxypropylmethylcellulose (HPMC), sodium bicarbonate, citric
acid and polyvinyl pyrrolidone. These drug release kinetics, matrix
swelling and subsequent erosion during dissolution was suggested as
suitable for a gastro-retentive drug delivery system in the
proximal small intestine. Liu et al., "Zero-Order Delivery of a
Highly Soluble, Low Dose Drug Alfuzosin Hydrochloride Via
Gastro-Retentive System" Int J Pharm 348:27-34 (2008).
[0106] Zero-order extended release formulations have also been
reported. For example, a gliclazide extended-release formulation
was created using two hydrophilic polymers: HPMC K 15M and sodium
alginate as retardant. Further, the effects of HPMC, lactose, and
sodium alginate concentrations were studied for their effects on
the gliclazide release rate. The drug release percent at 3, 6, 9
and 12 h were restricted to 20-30, 45-55, 70-80 and 90-100%,
respectively. The mechanism of drug release from these
extended-release matrix tablets was followed by a zero-order
release pattern. Jin et al., "Optimization of Extended Zero-Order
Release Gliclazide Tablets Using D-Optimal Mixture Design" Yakugaku
Zasshi 128: 1475-1483 (2008). An alternative extended release
gliclazide tablet formulation was tested that had a central
composite design with pH-dependent matrix forming polymers
keltone-HVCR and eudragit-EPO. These tablets were evaluated for
hardness, percent drug release after 1 hr, percent drug release
after 6 hr, diffusion exponent and time required for 50% of drug
release. One formulation, containing 8 mg of keltone-HVCR and 14.10
mg of eudragit-EPO, provides a sufficient hardness (>4.5 kg/cm2)
and exhibited zero-order release properties. Vijayalakshmi et al.,
"Development of Extended Zero-Order Release Gliclazide Tablets by
Central Composite Design" Drug Dev Ind Pharm. 34:33-45 (2008).
Glipizide hydrophilic sustained-release matrices have also been
evaluated for in vitro/in vivo correlations (IVIVC) in the presence
of a range of formulation/manufacturing changes. The effect of
polymeric blends of ethyl cellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500,
and lactose on in vitro release profiles were studied and fitted to
various release kinetics models. An IVIVC was established by
comparing the pharmacokinetic parameters of M-24 and Glytop-2.5 SR
formulations after single oral dose studies on white albino
rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24
(xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed zero-order
glipizide release. A Kopcha model analysis revealed that the
xanthan gum has a determinative effect on the zero-order release
profile. These data suggest that proper selection of
rate-controlling polymers with release rate modifier excipients may
determine overall release profile, duration and mechanism from
directly compressed matrices. Sankalia et al., "Drug Release and
Swelling Kinetics of Directly Compressed Glipizide
Sustained-Release Matrices: Establishment of Level A IVIVC" J
Control Release 129:49-58 (2008).
[0107] Osmotic minipumps have been reported as capable of providing
zero-order drug release. For example, a monolithic osmotic pump
tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN)
was evaluated for variations in tablet formulations such as, size
and location of the delivery orifice, membrane variables, and pH
value of the dissolution medium on 5-ISMN release from MOTS. These
results demonstrated that the tablet core played a role in MOTS
function, and membrane variables could also affect the 5-ISMN
release rate. The optimal formulation of 5-ISMN MOTS was determined
by a uniform design. Furthermore, the log pharmacokinetics and
relative bioavailability of the test formulation (5-ISMN MOTS) have
been compared with the reference formulation (Imdur(R): 60
mg/tablet, a sustained release, SR, tablet system) following an
oral single dose of 60 mg given to each of six Beagle dogs. The
mean drug fraction absorbed by each dog was calculated by the
Wagner-Nelson technique. The results showed that drug concentration
in plasma could be maintained more stable and longer after the
administration of 5-ISMN MOTS as compared with the matrix tablets
of Imdur(R), and a level A "in vitro/in vivo correlation" was
observed between the percentage released in vitro and percentage
absorbed in vivo. It was concluded that 5-ISMN MOTS is more
feasible for a long-acting preparation than 5-ISMN SR tablet system
as once-a-day treatment, and it is very simple in preparation, and
can release 5-ISMN at the rate of approximately zero order for the
combination of hydroxypropyl-methyl cellulose as retardant and NaCl
as osmogent. Duan et al., "Development of Monolithic Osmotic Pump
Tablet System for Isosorbide-5-Mononitrate Delivery and Evaluation
of it In Vitro and In Vivo" Drug Dev Ind Pharm 31:1-9 (2008).
Nonetheless, osmotic minipumps rely upon passage of analytes across
semipermeable membranes that encompass a drug solution.
Consequently, osmotic minipumps do not support zero order release
kinetics using impermeable housing matrix materials.
[0108] II. Impermeable Drug Delivery Devices: Some embodiments of
the present invention offer several advantages over existing drug
delivery devices. One such advantage is to achieve stable zero
order release kinetics without an initial burst effect such as is
found in previously reported devices (supra). Although it is not
necessary to understand the mechanism of an invention, it is
believed that an impermeable housing encompassing a therapeutic
agent supply plays a role in providing stable zero order release
kinetics. Although it is not necessary to understand the mechanism
of an invention, it is believed that a composition comprising a
solid therapeutic agent supply plays a role in providing stable
zero order release kinetics.
[0109] In one embodiment, the present invention contemplates a
medical device comprising an impermeable housing encompassing a
therapeutic agent (i.e., for example, a drug) supply (i.e., for
example, a reservoir or depot). Some embodiments may also comprise
at least one passageway or outlet port, thereby facilitating
release of drug from the drug reservoir to an anatomical site. The
device enables a mechanism in which the drug is released from the
reservoir at equal increments per unit time (i.e., for example, a
stable controlled desired release rate and/or zero order release
kinetics). This capability allows embodiment of the present
invention to release drugs for prolonged durations extending from
several hours to several years.
[0110] Thus, the presently contemplated device presents an improved
medical device, which maintains its physical and chemical integrity
in both the environments of use and in the presence of agent during
the controlled and continuous dispensing of agent over a prolonged
period of time. Additionally, due to composite design of the
device, there is no need of any coating or polymers for controlled
release of agents.
[0111] In one embodiment, the device may comprise a single housing,
wherein the housing encompasses an agent supply comprising at least
two therapeutic agents. In one embodiment, the device releases a
first drug at a first release rate. In one embodiment, the device
releases a second drug at a second release rate. Although it is not
necessary to understand the mechanism of an invention, it is
believed that the first and second agents are released at different
rates because of differential solubility relative to the agent
supply.
[0112] In one embodiment, the device may comprise at least two
housings. In one embodiment, the first housing comprises large
diameter passageways. In one embodiment, the second housing
comprises small diameter passageways. In one embodiment, the first
housing encompasses a first agent supply that is released at a
first rate. In one embodiment, the second housing encompasses a
second agent supply that is released at a second rate. Although it
is not necessary to understand the mechanism of an invention, it is
believed that the first agent is released at a faster rate than the
second agent.
[0113] A. The Impermeable Housing: In some embodiments, the device
housing comprises an impermeable composition, thereby providing
unidirectional release. Although it is not necessary to understand
the mechanism of an invention, it is believed that as long as the
therapeutic agent supply does not disintegrate (i.e., for example,
"sink conditions" are maintained), the device agent release
function will not be compromised by agent back-transfer or build up
of the agent within the passageways and/or outlet port.
[0114] The impermeable housing that encompasses a therapeutic agent
supply with which the delivery device is made includes, but is not
limited to, naturally occurring or synthetic materials that are
biologically compatible with body fluids and tissues and are
essentially insoluble and impermeable to the body fluid with which
it will come in contact with. For example, these materials include,
but are not limited to, glass, metal, ceramics, minerals, and
polymers such as polyimides, polyamides, polyvinyl acetate,
crosslinked polyvinyl alcohol, cross-linked polyvinyl butyrate,
ethylene ethylacrylate, copolymer, polyethyl hexylacrylate,
polyvinyl chloride, natural rubber, Teflon.RTM., plastisized soft
nylon, and silicone rubbers.
[0115] In one embodiment, the present invention contemplates a
composition comprising a therapeutic agent supply, wherein the
composition is impermeable to the passage of analytes that surround
and/or encompass the agent supply. In one embodiment, the agent
supply is in a form selected from the group consisting of a depot
and/or reservoir. In one embodiment, the composition comprises a
hollow cylindrical tube comprising at least one passageway on the
surface of the composition. In one embodiment, the agent supply
moves out of the reservoir through the hole at zero order. In one
embodiment, the composition comprises at least one end that may be
open or plugged using a biocompatible glue which may include, but
is not limited to, cyanoacrylates, BIOGLUE.RTM., epoxy resins,
silastics, TEFLON.RTM., or polyimide adhesives.
[0116] In one embodiment, the present invention contemplates a
method comprising releasing a therapeutic agent through the ends of
the hollow core (i.e., for example, a cylindrical hollow tube)
without any holes on the housing surface. In another embodiment,
one of the ends is plugged using a biocompatible glue which may
include, but is not limited to, cyanoacrylates, BIOGLUE.RTM., epoxy
resins, silastics, TEFLON.RTM., and polyimide adhesives.
[0117] B. The Therapeutic Agent Supply: In one embodiment, the
present invention contemplates an impermeable therapeutic agent
delivery device comprising a housing, wherein the housing
encompasses a therapeutic agent supply. In one embodiment, the
therapeutic agent supply comprises a solid. In one embodiment, the
therapeutic agent supply comprises a semi-solid.
[0118] In one embodiment, the present invention contemplates a
method of filling an impermeable therapeutic drug delivery device
comprising a housing, wherein the housing is filled with a drug
solution. In one embodiment, the method further comprises
evaporating the solution to create a solid therapeutic agent
supply. In one embodiment, the solid therapeutic agent supply
comprises a powder. In one embodiment, the method further comprises
evaporating the solution to create a semi-solid therapeutic agent
supply. In one embodiment, the semi-solid agent supply comprises a
gel. In one embodiment, the semi-solid agent supply comprises a
hydrogel. In one embodiment, the semi-solid agent supply comprises
a colloid.
[0119] The therapeutic agent enclosed in the impermeable matrix may
include, but not limited to, ocular agents, anti-neoplastic and/or
anti-mitotic agents, steroidal and non-steroidal anti-inflammatory
agents, opioid analgesics and antagonists, anti-cholinergic drugs,
adrenergic drugs, anti-adrenergic drugs, local anesthetics,
respiratory system drugs, hormones and related drugs,
anti-epileptic drugs, anti-parkinsonism drugs, drugs used in mental
illness, cardiovascular drugs, and anti-microbial drugs.
[0120] Examples of such ocular agents for treatment of ocular
diseases such as dry eye syndrome (DES), uveitis, and age related
macular degeneration may include, but is not limited cyclosporine
derivatives; doxycycline-induced protease inhibition; mucin
secretion stimulants; adenosine receptor agonists; chloride channel
stimulators; anti-TNF agents such as infliximab, adalimumab, and
etanercept, anti-interleukin therapy such as daclizumab, and
anakinra; interleukin 2 (IL-2) receptor antagonist, vascular
endothelial growth factor (VEGF) inhibitors such as pegaptanib,
ranibizumab, bevacizumab; and nuclear factor kappa B (NF-kB)
inhibitors.
[0121] Examples of such antineoplastics and/or antimitotics may
include, but not limited to paclitaxel, docetaxel, doxorubicin
hydrochloride, methotrexate, azathioprine, vincristine,
vinbiastine, and fluorouracil.
[0122] Examples of such steroidal and non-steroidal
anti-inflammatory agents may include, but not limited to
prednisone, dexamethasone, hydrocortisone, estradiol,
triamcinolone, mometasone, fluticasone, clobetasol, and
non-steroidal anti-inflammatories, such as, for example,
acetaminophen, ibuprofen, naproxen, adalimumab and sulindac.
[0123] Examples of such opioid analgesic may include, but not
limited to morphine, codeine, thebaine, papaverine, noscapine.
Examples of such opiod antagonist include naloxone and
naltrexone.
[0124] Examples of such anti-cholinergic drugs may include, but not
limited to atropine (e.g., for ophthalmic use as a cycloplegic;
mydriatic), scopolamine (e.g., for ophthalmic use as in uveitis,
iritis, and iridocyclitis), propantheline bromide (e.g., for
treatment of enuresis).
[0125] Examples of such adrenergic drugs include, but not limited
to noradrenaline, ephedrine, dopamine, phenylepherine, adrenaline,
ephedrine, dobutamine, isoprenaline, adrenaline, isoprenaline,
ephedrine, salbutamol, salbutamol, terbutaline, and nylidrine.
[0126] Examples of such anti-adrenergic drugs include, but not
limited to phentolamine, tolazoline, prazosin, propanolol, timolol,
oxprenolol, atenolol, oxprenolol, and alprenolol.
[0127] Examples of such local anesthetics include, but not limited
to lidocaine, cocaine, tetracaine, benoxinate, benzocaine,
butylaminobenzoate, and oxethazine.
[0128] Examples of such respiratory systems drugs include, but not
limited to anti-tussives such as codeine, morphine, noscapine,
oxeladin, and carbetapentane; antihistamines such as promethazine,
diphenhydramine, chlorpheniramine; anti-asthmatic such as
adrenaline, ephedrine, salbutamol, terbutaline, theophylline,
atropine methonitrate, ketotifen, nedocromil, prednisolone,
beclomethasone, and budesonide.
[0129] Examples of hormones and related drugs may include but not
limited to propylthiouracil, carbimazole, cortisol, prednisolone,
paramethasone, betamethasone, ethinyl estradiol,
diethylstilbestrol, calcitonin, vitamin D, calcitriol. Examples of
anti-epileptic drugs may include but not limited to phenobarbitone,
primidone, phenytoin, mephenytoin, carbamazepine; trimethadione,
cloanazepam, diazepam.
[0130] Examples of anti-parkinsonism drugs may include but not
limited to, levodopa, bromocriptine, lisuride, apomorphine,
carbidopa, benserazide, amantadine, deprenyl, trihexyphenidyl, and
biperiden. Examples of drugs used in mental illness may include but
not limited to, antipsychotics such as chlorpromazine,
thioridiazine, haloperdol, droperidol, chlorprothixene,
thiothixene; antianxiety drugs such as diazepam, lorazepam,
alprazolam, propanolol, and anti-depressants such as phenelzine,
tranylcypromine, deprenyl, and moclobimide.
[0131] Examples of cardiovascular drugs may include but not limited
to, cardiac glycosides such as digitoxin, digoxin; anti-arrhythmic
drugs such as quinidine, procainamide, propafenone, lidocaine,
propanolol, verapamil, diltiazem; anti-anginal and ani-ischaemic
drugs such as nitrogylcerine, isosorbide dinitrate;
anti-hypertensives such as captopril, enalapril, thiazides,
furosemide, spironolactone; anti-restenosis drugs such as
pclitaxel, rapamycin, zotarolimus, and tacrolimus.
[0132] Examples of anti-microbial drugs may include but not limited
to, antibacterial such as penicillins, aminoglycosides, and
erythromycin; antifungal such as griseofulvin, ketoconazole;
antiviral such as acyclovir, amantadine, antiprotozoal such as
chloroquine, metronidazole; anthelmintic such as mebendazole,
piperazine, and niclosamide.
[0133] Examples of such drugs undergoing clinical trials may
include but not limited to, treatment of conditions such as
prostate cancer (e.g., toremifene citrate, acapodene, flutamide,
combination of docetaxel and estramustine, denosumab); brain tumors
(e.g., karenitecin, topotecan) and eye diseases (e.g.,
valganciclovir for treatment of patients with CMV retinitis and
AIDS; Celecoxib to treat macular degeneration).
[0134] C. The Release Passageways: In one embodiment, the delivery
device comprises an impermeable matrix which has at least one
passageway. Although it is not necessary to understand the
mechanism of an invention, it is believed that the release of an
agent is driven by diffusion and occurs through these passageways.
For example, a hollow cylindrical tube is filled with the drug
solution, which after evaporation of solvent changes to solid form.
The ends of the tubes are sealed with a bioglue such that the
passageways remain the only escape route for the drug. When the
device comes in contact with the bodily fluid, the difference in
concentrations of the drug inside and outside of the device causes
the drug to diffuse into the bodily fluid having zero-order
kinetics.
[0135] In one embodiment, the present invention contemplates a
controlled release delivery device comprising a therapeutic agent
supply, wherein the agent supply comprises a therapeutically
effective amount of at least one agent effective in obtaining a
diagnostic effect or effective in obtaining a desired physiological
or pharmacological effect. In one embodiment, the delivery device
comprises an impermeable housing.
[0136] In one embodiment, the present invention contemplates a
stable controlled release delivery device configured to provide
long-term therapeutic agent delivery. In one embodiment, the
diameter the passageways range from the nanometer scale to the
centimeter scale. In one embodiment, the diameter of the
passageways range from approximately 5 nanometers-1 centimeter. In
one embodiment, the diameter of the passageways range from
approximately 100 nanometers-100 microns. In one embodiment, the
diameter of the passageways range from approximately 1 micron-50
microns. In one embodiment, the diameter of the passageways range
from approximately 10-30 microns. In one embodiment, the diameter
of the passageways range from approximately 15-25 microns. In one
embodiment, the diameter of the passageways are approximately 20
microns. The data presented herein show that release kinetics from
a drug delivery device of the present invention having dimensions
of approximately 20 mm long with a 125 micron inside diameter
comprising 30 micron diameter passageways can be extrapolated to
support long term stable controlled agent release for: i)
approximately forty-three (43) years using a single passageway
embodiment; ii) approximately twenty-two (22) years using double
passageway embodiment; or iii) approximately fifteen (15) years
using a triple passageway embodiment. See, FIG. 7.
[0137] A comparison of the release data from Examples II, IV, and
VI shows that by increasing the number of similarly sized holes on
a device, the agent release rate is a function of number of holes.
Hence, an additive pattern in amount of drug released is observed.
For example, the amount crystal violet released from a triple
passageway impermeable delivery device and a double passageway
impermeable device are approximately, three-fold and two-fold the
amount released from a single passageway impermeable device,
respectively, as shown in FIGS. 6-8.
[0138] D. The Release Outlet Ports: In another embodiment, the
housing comprises a hollow core (i.e., for example, a cylindrical
hollow tube) having at least one outlet port at the end of the
core, but does not have any passageways on the housing surface
(e.g., surface passageways). One end of the housing is sealed with
a bioglue such that the other end is the only escape route for the
therapeutic agent. On contact with a bodily fluid, the agent
diffuses out having zero-order kinetics. Any biocompatible adhesive
may be used to seal and plug unused outlet port(s) at the end of
the tubes including, but is not limited to, mussel glue, frog glue,
cyanoacrylates, TEFLON.RTM. adhesive, polyimide adhesive, bioglue
containing albumin and glutaraldehyde or similar compounds,
silastic, epoxy resins and other commonly known glues and
adhesives.
[0139] In one embodiment, the present invention contemplates a
stable controlled release delivery device comprising at least one
outlet port configured to provide long-term therapeutic agent
delivery. In one embodiment, the diameter of the outlet port range
from approximately 1-100 microns. In one embodiment, the diameter
of the outlet port range from approximately 10-75 microns. In one
embodiment, the diameter of the outlet port range from
approximately 25-50 microns. In one embodiment, the diameter of the
outlet port are approximately 30 microns. The data presented herein
show that release kinetic from a drug delivery device of the
present invention having dimensions of approximately 20 mm long
with a 125 micro inside diameter comprising a 30 micron outlet port
can be extrapolated to support long term stable controlled agent
release for approximately two (2) years (FIG. 9).
[0140] A comparison of the crystal violet release data of Examples
IX and II indicates that as the passageway diameter size increases,
the release rate increases to an amount approximate to the square
of ratio of the two radii (i.e., for example,
{R.sub.1/R.sub.2}.sup.2).
[0141] E. Medical Device Attachments: In some embodiments, the
device can be incorporated (i.e., for example, attached) as part of
any other drug delivery system including, but not limited to, bare
metal stents, drug eluting stents, transdermal patches, retinal
implants, cochlear implants, renal implants, grafts and
transplants. In other embodiments, the device can be used as part
of any medical procedure including, but not limited to, mechanical
thrombectomy for treatment of stroke, drug eluting implants for
cancer therapy, drug delivery device to deliver insulin, gene
implant therapy, brain implants to reduce and prevent damage from
Alzheimer's, Parkinson's syndrome, or epilepsia, and delivery of
cholinesterase inhibitors, antiretroviral agents, and
immunosuppressants to treat autoimmune disorders such as myasthenia
gravis, and AIDS. Although it is not necessary to understand the
mechanism of an invention, it is believed that optimizing
therapeutic agent release from a device of the present invention
utilize parameters including, but not limited to, the route of
administration, targeted diseased condition, or desired release
rate provide guidances as to the type of drug loaded, the amount of
drug loaded, dimensions of the device, and dimensions and number of
holes on the device surface.
[0142] In one embodiment, the present invention contemplates an
impermeable drug delivery device attached to a stent. In one
embodiment, the stent comprises a nondegradable polymer. In one
embodiment, the non-degradable polymer stent may be selected from
the group comprising Cypher Select.RTM. (sirolimus eluting, Cordis
Johnson & Johnson) Taxus Liberti.RTM. (paclitaxel eluting,
Boston Scientific) Endeavor.RTM. (zotarolimus eluting, Medtronic)
ZoMaxx.RTM. (zotarolimus eluting, Abbott) Apollo.RTM. (paclitaxel
eluting, InTek) Xience.RTM. (everolimus eluting, Abbott) or
Promus.RTM. (everolimus eluting, Boston Scientific). In one
embodiment, the stent comprises a degradable polymer. In one
embodiment, the degradable polymer stent may be selected from the
group comprising BioMatrix.RTM. (biolimus eluting, Biosensors)
Infinnium.RTM. (paclitaxel eluting, SMT) Nobori.RTM. (biolimus
eluting, Terumo) Champion.RTM. (everolimus eluting, Guidant), and
CoStar.RTM. (paclitaxel eluting, Johnson & Johnson).
[0143] Despite the commercial availability, these drug eluting
stents were designed and tested before the discovery of LST and its
implications. Consequently, most FDA approved stents are still
questionable for their long term usage. Hence, against the backdrop
of these new complications, some embodiments of the present
invention comprise therapeutic agent delivery devices that do not
require a polymer to control agent release. Although it is not
necessary to understand the mechanism of an invention, it is
believed that such a device should be capable of delivering a
combination of drugs at concentrations sufficient to inhibit
restenosis without delaying the healing of the stent or inducing
post-implantation complications including, but not limited to, LST
or restenosis.
[0144] F. Microelectronic Integration: In one embodiment, the
present invention contemplates an impermeable therapeutic agent
delivery device, wherein the core, housing or other substrates can
be integrated with microelectronics circuits and
microelectromechanical systems (MEMS) structures. In one
embodiment, the microelectronic circuit comprises a sensor. In one
embodiment, the sensor comprises an analyte sensor. In one
embodiment, the sensor comprises a transmitter, wherein the
transmitter signal is received by a remote detector. In one
embodiment, the analyte may be selected from the group including,
but not limited to, an inorganic ion, a small organic molecule, a
protein, a steroid hormone. In one embodiment, the protein
comprises an insulin protein. In one embodiment, the device
comprises an integrated solid circuit capable of monitoring and
controlling the release of chemical agents or medications. In one
embodiment, the device comprises an integrated solid circuit
capable of monitoring body analytes and controlling the release of
chemical agents or medications.
[0145] III. Preparation and Loading of a Therapeutic Agent Supply:
In one embodiment, the present invention contemplates a method for
loading a therapeutic agent supply comprising a drug delivery
device and a therapeutic agent composition. In one embodiment, the
composition comprises a solid. In one embodiment, the composition
comprises a semi-solid. In one embodiment, the solid comprises a
polymer matrix. In one embodiment, the semi-solid comprises a
semi-solid. In one embodiment, the solid comprises a powder. In one
embodiment, the loading means may be selected from the group
comprising capillary (see, Example I), dipping, injecting, using
positive or negative pressure, or other commonly known drug loading
methods.
[0146] IV. Delivery Device Fabrication: In one embodiment, the
present invention contemplates a process for fabricating a
therapeutic device comprising micro-holes on non-planar substrates
including, but not limited to, cylindrical polymer tubes.
[0147] In one embodiment, the present invention contemplates a
process for fabrication of micro-holes on non-planar surfaces. In
one embodiment, a micro-hole can be formed on a wide range of
non-planar substrates, metal or non-metal, and with varying shapes,
including cylindrical tubes. Depending on the application, a
micro-hole can vary in size including, but not limited to, a
fraction of a micron to hundreds of microns in diameter. In one
embodiment, the present invention contemplates a fabrication
process comprising photo-lithography and reactive ion etching. In
another embodiment, the present invention contemplates a
fabrication process using a mold. Devices containing micro-holes
fabricated by the present invention can be used for a wide range of
applications including, but not limited to, medical, bio-material,
including implantable medical devices and controlled drug delivery
systems. In one embodiment, the method is capable of fabricating
micro-hole structures comprising complex geometries on non-planar
substrates such as the micro electromechanical systems (MEMS) and
microelectronics devices for a wide range of applications.
[0148] A. Background: The technology to fabricate micro-structures
on planar silicon wafers is well developed and has led to the use
of planar integrated circuits in everyday electrical and electronic
devices. Planar technology can be extended to fabricate MEMS and
nanotechnology devices for a wide range of applications in medicine
and bio-materials. Nonetheless, planar microfabrication technology
has many disadvantages when attempting to fabricate devices on
non-planar substrates including, but not limited to, a cylindrical
polymer tube.
[0149] For example, one common current method to fabricate
micro-holes on a cylindrical tube is by laser ablation. Laser
ablation is a serial process which is time consuming and difficult
to be used for mass production. The laser ablation method has a
number of limitations: i) the diameter of the micro-hole is
normally larger than 15 microns; ii) it is difficult to control
micro-hold shape; iii) it is difficult to control micro-hole depth;
and iv) laser beam usually damages the material around the
micro-hole.
[0150] Micro-structures or micro-devices on non-planar substrates
can potentially be used for a wide range of applications for the
pharmaceutical industry. The present invention describes a process
of micro-fabrication to create micro-structures and micro-devices
on non-planar substrates. The micro-structure fabricated by the
disclosed method can be integrated into a support structure to form
complex devices for a wide range of applications. In some
embodiments, the present invention contemplates a process for
fabricating micro-structures, and/or microdevices comprising
micro-holes, wherein the microdevices comprise non-planar surfaces,
comprising: 1) fabricating at least one trench on a planar
substrate, such as a silicon wafer, to hold a micro-structure with
a non-planar substrate such as a polymer tube; 2) fabricating a
micro-hole on non-planar substrates using a combination of
lithography, e.g., photolithography, reactive ion etching and/or
chemical etching; 3) a non-planar substrate comprising either a
metal or a non-metal having varying shapes capable of being placed
into a planar support structure including, but not limited to, a
silicon wafer trench: 4) micro-holes varying in size from a
fraction of a micron to hundreds of microns, and 5) micro-holes
varying in shape including, but not limited to, circular,
rectangular, triangular, elliptical and square.
[0151] B. Delivery Device Fabrication Methods: The technologies to
fabricate micro-structures on planar silicon wafers have been
previously reported. But it is difficult to fabricate on non-planar
substrate, including, but not limited to, a cylindrical polymer
tube. Current methods to fabricate micro-holes on a cylindrical
tube are usually performed by laser ablation. Laser ablation is a
serial process which is time consuming and difficult to adopt for
mass production. The micro-holes fabricated by laser ablation
normally have diameters larger than 15 microns and it is difficult
to control the shape and depth of the micro-hole. In addition,
laser beam usually burns and damages the material around the
micro-holes, which is not desirable for many medical
applications.
[0152] The present invention contemplates a process for fabrication
of passageways on non-planar surfaces. The passageway can be formed
on a wide range of substrates, metal or non-metal, and shapes, such
as tubes, depending on the application. The passageway varies in
size from a fraction of a micron to hundreds of microns in diameter
and can have a variety of shapes. In one embodiment, the
fabrication process is based on lithography and reactive ion
etching technologies. In another embodiment, the process first
fabricate a mold consisting of a substrate with trenches and
through holes located in trenches, then a non-planar substrate is
placed in the mold to form micro-hole structures by etching. Such
devices containing the passageways of the present invention can be
used for a wide range of medical and bio-materials applications,
including the use for medical implantation and controlled drug
delivery.
[0153] The modified lithographic technique described herein has
many advantages over current techniques. For example, i) the
process is a parallel process and suitable for mass production; ii)
the process is associated with a lower cost; iii) the process
greatly improves the capabilities and control in producing holes of
non-circular shapes and varying sizes on non-planar surfaces; iv)
the process can be integrated with MEMS and solid circuit sensors
to form devices for a range of applications, including
microelectronics, medical delivery and bio-materials.
[0154] The present invention discloses a process for fabrication of
passageways on non-planar surfaces. Depending on the application,
the passageways can be formed on a wide range of substrates, metal
or non-metal, and with varying shapes including a tubular form. In
some embodiments, passageway varies in size from a fraction of a
micron (i.e., for example, approximately, 0.01 micron) to hundreds
of microns (i.e., for example, 900 microns) in diameter.
[0155] Some embodiments of the present invention provide advantages
over conventionally used microelectronic photolithographic
processing technologies. For example, conventional
photolithographic techniques are limited to planar surfaces, while
the present invention has described photolithographic fabrication
of non-planar surfaces (i.e., for example, metal or non-metal). In
one embodiment, the fabrication comprises the etching of
passageways (i.e., for example, micro-holes) on a non-planar
surface. In one embodiment, a special structural element (i.e., for
example, a trench pattern) is fabricated first on a silicon wafer
to hold the non-planar surface material. The planar substrate can
be any material other than a silicon wafer, depending on the
structure and the application of interest. Accordingly, the process
steps will have to be adjusted. Other trench structures with other
shapes can be fabricated if desired, depending on the shape of the
non-planar substrates.
[0156] This method provides significant advantages over current
technology that fabricates micro-holes on a non-planar surfaces
requiring laser ablation which is a time consuming serial process
and expensive. On the other hand, the present invention discloses a
process that can be performed in parallel and therefore is
well-suited for mass production. This invention also provides
another advantage by enabling the fabrication of a variety of
passageways on many non-planar surfaces simultaneously, thus
significantly reducing the manufacturing cost. In addition, the
lithographic technique makes it possible to form individual
passageways or a group of passageways having different sizes and
shapes including, but not limited to, circular, elliptical, square
and rectangular shapes.
[0157] FIG. 1 shows a top view of several embodiments of the
invention. In each embodiment, a therapeutic agent delivery device
1 comprising a hollow cylindrical tube 2 is depicted which may be
used as a reservoir for therapeutic agents (i.e., for example, a
drug). The surface of the device comprises a plurality of
passageways 3, wherein the holes on the device are equidistant from
each other and from the end of the tube. Upper drawing: A device
comprising a single passageway. Middle drawing: A device comprising
two passageways. Lower drawing: A device comprising three
passageways.
[0158] FIG. 2 shows a cross-sectional view of one embodiment of the
therapeutic agent delivery device during administration of the
agent. The device 1 comprises a hollow cylindrical tube 2 and is
filled with a diagnostic, therapeutic, or prophylactic agent 4
while being placed against an anatomical site 5. The device is
positioned to release the agent is directly to the targeted
anatomical site in an unidirectional manner through the passageways
3 (see arrows). FIG. 3 shows one embodiment of a carrier 6 to which
a therapeutic agent delivery device may be attached. FIG. 4 shows
one embodiment depicting five (5) therapeutic agent delivery
devices 1, comprising three passageways 3 each, attached to a stent
7. FIG. 5 shows one embodiment depicting three (3) therapeutic
agent delivery devices 1, comprising three (3) passageways 3 each,
attached to an adhesive patch 8.
[0159] FIG. 6 shows exemplary data of zero order release kinetics
of crystal violet (e.g., a dye, and anti-fungal agent) for
twenty-eight (28) days from three embodiments of the therapeutic
drug delivery device. Circles: A device with one surface passageway
(R.sup.2=0.9945). Squares: A device with two surface passageways
(R.sup.2=0.9998). Triangles: A device with three surface
passageways (R.sup.2=0.9998). FIG. 7 shows exemplary data of the
percentage of crystal violet (dye, antifungal-agent) released at
zero-order for twenty-eight (28) days from three different
embodiments of the therapeutic drug delivery device. Circles: A
device with one surface passageway (R.sup.2=0.9945). Squares: A
device with two surface passageways (R.sup.2=0.9999). Triangles: A
device with three surface passageways (R.sup.2=0.9998). FIG. 8
shows exemplary data demonstrating the linearity of cumulative
agent release between the three embodiments tested in FIGS. 6 and 7
after twenty-eight (28) days (R.sup.2=0.9962). Circle: A device
with one surface passageway. Square: A device with two surface
passageways. Triangles: A device with three surface passageways.
FIG. 9 shows exemplary data of zero order release kinetics of
crystal violet for five (5) days from one embodiment of the
therapeutic agent delivery device, wherein there are no holes on
the device surface, but has a single outlet port on one end of the
device (R.sup.2=0.9993).
[0160] In one embodiment, the process of forming micro-holes
requires first the fabrication of a mold consisting of a planar
substrate with trenches and through holes located in trenches as
illustrated in FIG. 10. The trenches can hold the miniature
substrates, such as polymer tubes. Then the whole assembly can be
flipped over and then etched from the backside to produce through
holes in the targets such as the wall of a biodegradable tube. In
this way, the planar substrate works as a mold. The mold can be
made from a variety of materials, including a silicon wafer, a
glass substrate, and a metal plate. The etching technique can be
chosen from a number of techniques including but not limited to
physical etching, chemical etching, reactive ion etching, laser
ablation, and cutting by plasma torches.
[0161] FIG. 10 shows a schematic drawing of a mold 1000 with
trenches 1002 and through holes 1004. Although the through holes
1004 shown in the figure are circular, they can be formed in other
shapes as desired.
[0162] In one embodiment, the mold can be fabricated on a silicon
wafer using micro-fabrication technology. An example of the process
flow is shown in FIG. 11A-11D where all figures are shown in a
cross-sectional view. To start, the silicon mold can be fabricated
on a double side polished wafer 1101. The fabrication process
begins with a deposition of masking layers 1103 and 1105 on the
topside and the backside of the wafer respectively, as shown in
FIG. 11A. Low stress silicon nitride formed by low pressure
chemical vapor deposition (LPCVD) is a preferred material for
masking layer 202 and 203. In FIG. 11B, a photolithography step is
applied to define an opening on the topside which is further
transferred through the silicon nitride layer by reactive ion
etching (RIE). Alignment marks are fabricated in this step but not
shown in the figure. Then a wet anisotropic etching using TMAH is
applied to etch a trench 1107 in the silicon wafer with a silicon
nitride layer as an etching mask. The trench sidewalls 1109 are
smooth planes which work as etch stop layers. The V-groove trench
1107 will be used to hold the tubes. After that, the second
photolithography step is applied to the backside of wafer to define
a window pattern which is aligned to the trench on the topside with
the help of alignment marks. RIE and wet anisotropic etching are
used again to transfer the window 1111 pattern into the silicon
wafer and expose the smooth planes 1113 as shown in FIG. 11C. In
FIG. 11D, the third lithography step is applied to define the hole
structure which is then etched into a through hole 1115 by RIE. An
optional step to harden the mold surface is to apply a silicon
nitride layer on the surface, which is not shown in the figure.
[0163] In one embodiment, the method comprises preparing a trench
structure on a planar substrate, such as a silicon wafer 10 (FIG.
12A). In one embodiment, a trench structure on the silicon wafer
was fabricated by a combination of photolithography and anisotropic
etching wherein a silicon dioxide layer 20 was deposited on a
silicon wafer 10, followed by the deposition of a chromium layer 30
by physical vapor deposition (FIG. 12B). The silicon dioxide 20 and
chromium 30 layers serve as etching mask layers for the subsequent
process steps. The silicon wafer can be either a (110, FIG. 12E) or
a (100, FIG. 12F) wafer, depending on the choice of "U" shaped or
"V" shaped trenches to be fabricated by wet anisotropic etching.
After spin-coating of a photo-resist 40 layer, a trench structure
50 was created by photolithography on the photo-resist layer 40 as
shown in FIG. 12C. The trench direction is aligned to the wafer
flat. Alignment marks 140 were also created in this step. See, FIG.
11A. The alignment marks were designed to position future patterns,
e.g., micro-holes, to the desired places of non-planar substrates,
such as polymer tubes, which would placed into trenches on the
silicon wafer. The trench structure was then transferred through
the chromium layer to the silicon oxide layer by reactive ion
etching (FIG. 12D). This was followed by a second reactive ion
etching step transferring the trench structure through the oxide
layer to the silicon substrate using the chromium layer as the
etching mask. This step produced the trench structures 60. The
final step to fabricate the trench structure was a wet anisotropic
etching step, which was used to remove the un-wanted silicon
materials. The processing sequence as described produced a "U"
shaped trench 70 in a (110) wafer, or a "V" shaped trench 80 in a
(100) wafer as shown in FIGS. 12E and 12F, respectively. The depth
and width of the trench structures can be controlled by the
geometry of the photo-mask and the anisotropic etching time. The
depth and width of trenches should be slightly larger than the
dimension of the non-planar substrate. The structures with the U
shape or the V shape trench can also be used as to form a mold. An
example of a V shape trench is shown in FIG. 11B.
[0164] FIGS. 13A-13C shows the plan view of the schematic silicon
mold fabricated following the process shown in FIGS. 11A-11D. FIG.
13A is the topside 1300 of the wafer with wafer flat 1302. As
shown, the design looks similar to that in FIG. 10 with trenches
1304 and through holes 1306. Two alignment marks 1308 and 1310 are
fabricated in this step as shown in FIG. 11A. FIG. 13B shows the
backside 1312 of the wafer. Window structures 1314 and through
holes 1306 are aligned with the trenches 1304 on the topside. The
window structures 1314 correspond to 1111 in FIG. 11C. FIG. 13C
shows an enlarged view of a single window structure 1312 in FIG.
13B. Four planes 1316 here correspond to 1113 in FIG. 11C and the
through holes 1306 in FIGS. 13A-13C correspond to the hole 1115 in
FIG. 11D.
[0165] FIG. 13D shows a scanning electron microscopy image of a "U"
shaped trench fabricated on a silicon wafer. The width and depth of
the trench is about 100 microns and 80 microns, respectively.
[0166] After the mold is fabricated, the fabrication of micro-holes
in the tubes is rather simple. As shown in FIG. 14A, first the
tubes 1402 are inserted into the trenches on the topside of the
mold. Adhesives may or may not be applied to part of the trenches
to hold the tubes in the trenches. Another substrate 1404 may also
be used to push tubes toward the bottom of the trenches. Then the
whole assembly is flipped over so that the backside of the mold is
facing up as shown in FIG. 14B. An etching step is performed to
transfer the through hole patterns of the mold to the tubes and
finally holes 1408 on tubes are obtained. In one embodiment,
reactive ion etching is used as indicated by the reactive plasma
1406.
[0167] The planar substrate can be any material other than a
silicon wafer, depending on the structure and the application of
interest. Accordingly, the process steps will have to be adjusted.
Other trench structures with other shapes can be fabricated if
desired, depending on the shape of the non-planar substrates.
[0168] In one embodiment, the fabrication of passageways, such as
micro-holes, on a non-planar substrate starts with inserting the
non-planar substrate into the trench structure of the supporting
substrates. In one embodiment, an adhesive is applied in the trench
to hold the non-planar substrate in place. In one embodiment, the
adhesive is a photo-resist. The assembly of the supporting
substrate with the non-planar substrate is then handled as a
conventional subject with a planar substrate for subsequent process
steps.
[0169] In one embodiment, the non-planar substrate is a polymer
tube 90 shown in FIGS. 15A-15E. In one embodiment, it was inserted
into a "U" shaped trench as shown in FIG. 15A. In one embodiment, a
masking layer 100 was deposited on the wafer as well as the surface
of the polymer tube 90, as shown in FIG. 15B. In one embodiment,
the masking layer 100 is a chromium layer. The alignment marks were
protected during the chromium deposition. This was followed with
spin-coating of a photo-resist layer 110 on top of the polymer tube
as shown in FIG. 15C. After careful alignment, micro-holes 120 were
fabricated following a sequence of steps: first, defining the
micro-holes using photolithography with a photo-resist layer 110.
Then the micro-hole structures were transferred through the
chromium layer 100 by reactive ion etching. Finally, a second
reactive ion etching step was applied to transfer the micro-hole
structure through the tube wall to yield fully penetrated
micro-holes 130 on the tube. FIG. 13D shows an optical microscopy
image of a polyimide tube with a hole of about 20 microns in
diameter fabricated by this method.
[0170] FIG. 16 illustrates a schematic of one embodiment of a
carrier comprising a skeleton of a bare metal stent. FIG. 17 shows
one another embodiment of a therapeutic agent delivery device with
different diameters that is 200 microns, 400 microns, and 600
microns. The device comprises of one outlet port 32 without any
passageways on the surface of the device. One end of the device 31
is sealed with a heat shrink tube or a biocompatible adhesive.
Upper drawing: A device with inside diameter of 200 microns. Middle
drawing: A device with inside diameter of 400 microns. Middle
drawing: A device with inside diameter of 600 microns.
[0171] FIG. 18 presents an exemplary photomicrograph showing
release of crystal violet 71 from a device 72 comprising two
passageways 73 into a phosphate buffered saline solution 74.
Release of drug from each hole is independent of the other. The
dimension of the tube is 1000 microns and the holes size is
approximately 400 microns. These bigger sized tubes and holes were
selected to visually observe the release mechanism, and are not
intended to limit the present invention. FIG. 19 shows exemplary
data of zero order release kinetics of crystal violet (e.g., a dye,
and anti-fungal agent) for twenty-eight (28) days from three
embodiments of the therapeutic drug delivery device. Circles: A
device with one outlet port and inside diameter of 200 microns
(R.sup.2=0.9667). Squares: A device with one outlet port and inside
diameter of 400 microns. Triangles: A device with one outlet port
and inside diameter of 600 microns (R.sup.2=0.9355). FIG. 20 shows
exemplary data comparing cumulative amount of crystal violet
released from the three groups (200 microns, 400 microns, and 600
microns) for seven days. The release rates follow a quadratic
relationship as is evident by the equations of line for each day,
which are in the form: y=ax.sup.2+bx+c, and their corresponding
R.sup.2 values which are close to 1.000. Hence, the rate of release
of drug is also proportional to the square of the radius, that
is,
M T .alpha. r 2 . ##EQU00001##
[0172] V. Therapeutic Applications: In one embodiment, the present
invention contemplates methods for treating medical conditions and
diseases. For example, such conditions may include, but are not
limited to, cardiovascular disease, cancer, diabetes, pain,
Parkinson's disease, epilepsy, or ocular diseases.
[0173] A. Cardiovascular Diseases: In one embodiment, the present
invention contemplates a method for treating a cardiovascular
disease. In one embodiment, the cardiovascular disease may include,
but not limited to, stenosis, restenosis, stroke, myocardial
infarction, congestive heart disease, high blood pressure, angina,
atherosclerosis, or thrombosis. In many cases, cardiovascular
diseases are treated with drug eluting stents (DES). While easily
inserted into specific cardiovascular vessels these DESs have
encountered significant biocompatibility problems.
[0174] 1. Clinical Problems Associated with Drug Eluting Stents:
Since their inception, DESs have significantly reduced the rate of
clinical restenosis as compared to bare metal stents (BMS) and
conventional balloon angioplasty. Moses et al., "Sirolimus-Eluting
Stents Versus Standard Stents in Patients with Stenosis in a Native
Coronary Artery" N Engl Med 349:1315-1323 (2003); and Park et al.,
"A Paclitaxel-Eluting Stent for the Prevention of Coronary
Restenosis" N Engl Med 348:1537-1545 (2003). An ideal drug eluting
stent has been suggested to possess characteristics including, but
not limited to: i) polymers allowing ideal drug release; ii) drugs
should inhibit vascular smooth cell proliferation and inflammation
and prevent restenosis; iii) the stent becomes part of the
vasculature to prevent any late inflammations/thrombosis; iv) the
stent allows collateral blood vessel circulation. Baffour et al.,
"Enhanced Angiogenesis and Growth of Collaterals by In Vivo
Administration of Recombinant Basic Fibroblast Growth Factor in
Rabbit Model of Acute Lower Limb Ischemia: Dose-Response Effect of
Basin Fibroblast Growth Factor" Vasc Surg 16:181-191 (1992); and
Geerts A M, "Colic I. Angiogenesis in Portal Hypertension:
Involvement in Increased Splenehnic Blood Flow and Collaterals?"
Acta Clin Belg 62:271-275 (2007). However, even before introduction
of the first commercial DES, potential problems were identified
that may arise due to "nonerodable thick polymer sleeve, very high
concentration of the active drug, extended release kinetics, loose
stent architecture, and inhomogeneous drug delivery". Virmani et
al., "Mechanism of Late In-Stent Restenosis After Implantation of
Paclitaxel Derivate-Eluting Polymer Stent System in Humans"
Circulation 106:2649-2651 (2002).
[0175] Studies have shown an increase in the rate of death and
myocardial infarction in patients following 18 months to 3 years
after stenting with CYPHER.RTM. and TAXUS.RTM.. Aziz et al., "Late
Stent Thrombosis Associated with Corona Aneurysm Formation After
Sirolimus-Eluting Stent Implantation" Invasive Cardiol 19:E96-8
(2007); Camenzind E., "Treatment of In-Stent Restenosis--Back to
the Future?" N Engl Med 355:2149-2151 (2006); Camenzind et al.,
"Stent Thrombosis Late After Implantation of First-Generation
Drug-Eluting Stents: a Cause for Concern" Circulation 15:1440-1455
(2007); and Pfisterer M E., "The BASKET-LATE-Study. Basel Stent
Cost-Effectiveness Trial--Late Thrombotic Events Trial" Herz 31:259
(2006). A statement issued by United States Food and Drug
Administration also identified adverse cardiac events in patients
treated with drug during stents. fda.gov/cdrlVnewslOgl406
(2007).
[0176] The reported problems are usually associated with late stent
thrombosis (LST) which blocks the arteries increases the risk of
myocardial infarction. Interestingly, it has been reported that
bare metal stents (BMS) have lower MACE rates as compared to DES.
Kim et al., "Stent-Related Cardiac Events After Non-Cardiac
Surgery: Drug-Eluting Stent Bare Metal Stent" lnt J Cardiol
123:353-354 (2008); Lagerqvist et al., "Long-Term Outcomes with
Drug-Eluting Stents Versus Bare-Metal Stents in Sweden" N Engl Med
356:1009-1019 (2007); and Steinberg et al., "Drug-Eluting Stent
Thrombosis Bare Metal Stent Restenosis Finding the Lesser of Two
Evils" Am Heart Hosp 5:151-154 (2007). However, the exact nature of
drug-eluting stent thrombosis is still unclear, for example, what
causes it, how often it occurs, under what circumstances it occurs,
or what the risk of occurrence is in a given patient.
[0177] 2. Late Stent Thrombosis (LST): Polymer coatings have been
named as one factor associated with the failure of DES. Under
mechanical stress such as during implantation of stents, polymer
coatings might crack leading to injury to arterial wall. Injury
activates platelet aggregation and blood clotting leading to LST.
Generally, it takes 28 days for the bare metal stent to become part
of the vasculature (endothelialization). Cracking of polymers may
also lead to drug dumping at the injured arterial site delaying the
healing of the stent. The incomplete endothelialized stent becomes
an attractive site for platelet adhesion increasing the probability
of LST. The drug overexposure also prevents collateral blood vessel
formation, thereby increasing the stress on the heart.
Alternatively, polymer hypersensitivity might incite inflammation
reactions. The occurrence of such allergic reactions has supportive
evidence such as a marked activation of inflammatory cells (i.e.,
for example, leucocytes) at the site of a stent. Li et al., "Is
Inflammation Contributor for Coronary Stent Restenosis?" Med
Hypotheses 68:945-951 (2007). Leukocytes have also been linked to
the formation of neointimal hyperplasia along with platelet
adhesion indicating the central role of inflammation in both
restenosis and LST. Golino et al., "Inhibition of Leukocyte and
Platelet Adhesion Reduces Neointimal Hyperplasia After Arterial
Injury" Thromb Haemost 77:783-788 (1997); Sainani et al., "The
Endothelial Leukocyte Adhesion Molecule. Role in Coronary Artery
Disease" Aeta Cardiol 60:501-507 (2005; Wang et al., "Enhanced
Leukocyte Adhesion to Interleukin-I Beta Stimulated Vascular Smooth
Muscle Cells is Mainly Through Intercellular Adhesion Molecule-l"
Cardiovasc Res 28:1808-1814 (1994).
[0178] 3. Restenosis: Restenosis is believed to result from
mechanisms including, but not limited to, inflammation or cell
proliferation at the site of injury in the stented artery. Drugs
such as paclitaxel and sirolimus are being currently used in drug
eluting stents to prevent scar tissue growth and neointima
formation. In general, these drugs were chosen for potency, and
general effects on suppressing cellular growth without targeting
the underlying vascular disease.
[0179] Restenosis is believed to result from injury to an arterial
wall during stent implantation and occurs within 6-12 months of the
procedure. In contrast, LST mainly occurs when the stent is not
able to endothelialize and usually occurs after 12 months of
stenting. Classic restenosis occurring with bare metal stents
(i.e., for example, non-drug coated) comprises progressive, instead
of rapid, symptoms and affects 25-30% of the treated patients. In
contrast, LST is believed to result of sudden formation of a blood
clot within the stent. Though LST is observed in only 1.5-5% of the
patients but morbidity and mortality rates are quite high, making
it more dangerous. Holmes D R, Jr., "Incidence of Late Stent
Thrombosis with Bare-Metal, Sirolimus, and Paclitaxel Stents" Rev
Cardiovasc Med 8(Suppl 1): S11-18 (2007).
[0180] A. Anti-Restenosis Drugs: Zotarolimus (formerly known as
ABT-578) is a sirolimus analogue having cytostatic properties.
Buellesfeld et al., ABT-578-eluting stents. The promising successor
of sirolimus- and paclitaxel-eluting stent concepts? Herz
29167-29170 (2004). Zotarolimus may be synthesized by substituting
the native hydroxyl group with the tetrazole ring at position 40 in
rapamycin. It is believed extremely lipophilic and a very low water
solubility, hence very little is released to the circulation.
Seabra-Gomes R., "Percutaneous Coronary Interventions with Drug
Eluting Stents for Diabetic Patients" Heart 2006; 92:410-419
(2006). Everolimus is synthesized from sirolimus by substituting a
--CH.sub.2OH group at position 40. Like sirolimus, everolimus also
inhibits mammalian target of rapamycin (mTOR). Experimental studies
have shown that oral everolimus also inhibits smooth muscle cell
proliferation and prevents neointimal thickening and
arteriosclerosis. Farb et al., "Oral Everolimus Inhibits In-Stent
Neointimal Growth" Circulation 106:2379-2384 (2002); Waksman et
al., "Optimal Dosing and Duration of Oral Everolimus to Inhibit
In-Stent Neointimal Growth in Rabbit Iliac Arteries" Cardio-vasc
Revasc Med 7:179-184 (2006). Everolimus has been reported to have a
better pharmacokinetic profile and bioavailability compared with
sirolimus. Patel et al., "Everolimus: Immunosuppressive Agent in
Transplantation" Expert Opin Pharmacother 7:1347-1355 (2006).
Everolimus has also been reported to absorb into tissues more
rapidly than sirolimus and may have a longer cellular residence
time and activity. Grube et al., "Everolimus for Stent-Based
Intracoronary Applications" Rev Cardiovasc Med 5(Suppl 2):S3-S8
(2004).
[0181] Biolimus A9 (Biosensors International, Singapore) is
reported as a highly lipophilic sirolimus analog. Biolimus has been
reported as well tolerated and effective having similar
immunosuppressive potency as sirolimus. However, it appears that
Biolimus A9 is more rapidly absorbed than sirolimus by the vessel
wall and enters smooth muscle cell membranes more readily, thereby
causing cell cycle arrest at G.sub.0. Costa et al., "Angiographic
Results of the First Human Experience with the Biolimus A9
Drug-Eluting Stent for De Coronary Lesions" Am Cardiol 98:443-446
(2006). Recently release data indicates that Biolimus A9 showed
significantly less neointimal formation as compared with
paclitaxel. Chevalier B., "NOBORI l: Part A Prospective, Randomized
Trial of Biolimus A9 and Paclitaxel-Eluting Stents: 9-Month
Clinical and Angiographic Follow-Up" Transcatheter Cardiovascular
Therapeutics Symposium (2006).
[0182] Tacrolimus (also FK-506, Fujimycin, Prograf) is a
hydrophobic macrolide immunosuppressant produced by Streptomyces
tsukubaensis. Goto et al., "Discovery of FK-506, Novel
Immunosuppressant Isolated from Streptomyces Tsukubaensis"
Transplant Proc 19:4-8 (1987). Tacrolimus is widely used to prevent
allograft rejection after organ transplantation. Although it is not
necessary to understand the mechanism of an invention, it is
believed that tacrolimus is a noncytotoxic T cell inhibitor, which
causes cell apoptosis following growth arrest in the G.sub.0 phase
of the cell cycle. Gottschalk et al., "Apoptosis in B lymphocytes:
the WEHI-231 perspective" Immunol Cell Biol 73:8-16 (1995). A
protein-engineered nanoparticle albumin bound paclitaxel
(nab-paclitaxel) is commercially available and may be useful for
the treatment of coronary and peripheral artery restenosis
(Coroxane.RTM., Abraxis Bioscience, Inc.). Coroxane.RTM., like its
oncology counterpart Abraxane.RTM., is a protein stabilized
emulsion that is believed to enhance the solubility of water
insoluble paclitaxel. The albumin formulation may also reduce
toxicities associated with a solubility enhancing excipient,
Cremophor EL.RTM.. Green et al., "Abraxane, Novel Cremophor-Free,
Albumin-Bound Particle Form of Paclitaxel for the Treatment of
Advanced Non-Small Cell Lung Cancer" Ann Oncol 17:1263-1268 (2006).
As a result, the solubility of paclitaxel is improved and the
non-drug related toxicities are eliminated. A Phase II clinical
study tested twenty three (23) patients randomized to one of four
doses (10, 30, 70, or 100 mg/m.sup.2), wherein doses between
approximately 10-30 mg/m.sup.2 were found to be safe and effective.
Margolis et al., "Systemic Nanoparticle Paclitaxel (Nab-Paclitaxel)
for In-Stent Restenosis (SNAPIST-I): First-In-Human Safety and Dose
Finding Study" Clin Cardiol 30:165-170 (2007).
[0183] Docetaxel is commercially available (Taxotere.RTM.,
Sanofi-Aventis) and approved as an anti-mitotic drug used for the
treatment of breast, ovarian and non-small cell lung cancer. Clarke
et al., "Clinical Pharmacokinetics of Docetaxel" Clin Pharmacokinet
36:99-114 (1999). Docetaxel is a semi-synthetic analogue of
paclitaxel and differs from paclitaxel at two positions in its
chemical structure. For example, docetaxel has a hydroxyl
functional group on carbon 10, whereas paclitaxel has an acetate
ester and a tert-butyl substitution exists on the phenylpropionate
side chain. The carbon 10 functional group change causes docetaxel
to be more lipid soluble than paclitaxel. Docetaxel is believed to
be a microtubule polymerizing agent, and may have improved
antiproliferative properties as compared to paclitaxel. Yasuda et
al., "Local Delivery of Low-Dose Docetaxel, Novel Microtubule
Polymerizing Agent, Reduces Neointimal Hyperplasia in Balloon
Injured Rabbit Iliac Artery Model" Cardiovasc Res 53:481-486
(2002). Docetaxel, however, has been associated with cytotoxicity,
which has been reported to occur in a dose-dependant manner.
Silvestrini et al., "In Vitro Cytotoxic Activity of Taxol and
Taxotere on Primary Cultures and Established Cell Lines of Human
Ovarian Cancer" Stem Cells 11:528-535 (1993). Docetaxel has the
potential as a therapeutic for preventing restenosis, but more
improvement is needed for better safety and efficacy.
[0184] Curcumin (diferuloylrnethane) is believed to be a
polyphenolic yellow pigment found in the Indian spice, tumeric (a
powdered rhizome of Curcurna longa Linn). Huang et al., "Inhibitory
Effects of Dietary Curcumin for Stomach, Duodenal, and Colon
Carcinogenesis in Mice" Cancer Res 54:5841-5847 (1994). Curcumin is
believed to exhibit various biological activities including, but
not limited to, anti-proliferative activity, anti-inflammatory,
antioxidant activity, wound healing ability, and anti-microbial
activity. Dorai et al., "Role of Chemopreventive Agents in Cancer
Therapy" Cancer Lett 215:129-140 (2004); Gupta et al., "Dietary
Antioxidant Curcumin Inhibits Microtubule Assembly Through Tubulin
Binding." FEBS J 273:5320-5332 (2006); and Ruby et al., "Antitumour
and Antioxidant Activity of Natural Curcuminoids" Cancer Lett
94:79-83 (1995). Although it is not necessary to understand the
mechanism of an invention, it is believed that at least two
mechanisms contribute to restenosis including, but not limited to,
proliferation of vascular smooth muscle cells and inflammation at
the site of injury. It is further believed that inflammation
reactions may be initiated by a build-up of reactive oxygen species
(i.e., for example, ROS, or free radicals) at an arterial site.
Like paclitaxel, curcumin inhibits cell proliferation by
stabilizing microtubule assembly through tubulin binding. In
addition, curcumin may reduce nitric oxide (NO) levels thereby
acting as a suitable antioxidant. Ukil et al., "Dos Curcumin, the
Major Component of Food Flavour Turmeric, Reduces Mucosal Injury in
Trinitrobenzene Sulphonic Acid-Induced Colitis" Br Pharmacol
139(2): 209-218 (2003). The natural healing powers of curcumin make
it an excellent candidate for treatment and prevention of
restenosis.
[0185] Resveratrol (trans-3, 4, 5-trihydroxystilbene). is believed
to be a phytoalexin found in grapes and other medicinal plants that
protects them against fungal infections. Docherty et al.,
"Resveratrol Selectively Inhibits Neisseria Gonorrhoea and
Neisseria Meningitidis" Antimicrob Chemother 47:243-244 (2001).
Resveratrol has been suggested as a possible answer for the
observed `French paradox`. The `French paradox` refers to the
observation that a high consumption of red wine is associated with
relatively low incidences of coronary heart diseases. Kopp P.,
"Resveratrol, Phytoestrogen Found in Red Wine: A Possible
Explanation for the Conundrum of the `French Paradox`?" Eur
Endocrinol 138:619-620 (1998). Additionally, resveratrol is also a
widely reported anti-fungal, anti-bacterial, anti-viral,
anti-oxidant, and an anti-inflammatory agent. de la Lastra et al.,
"Resveratrol as Antioxidant and Prooxidant Agent: Mechanisms and
Clinical Implications" Biochem Soc Trans 35:1156-1160 (2007);
Docherty et al., "Resveratrol Inhibition of Herpes Simplex Vires
Replication" Antiviral Res 43:145-155 (1999): Elmali et al.,
"Effects of Resveratrol in Inflammatory Arthritis" Inflammation
30:1-6 (2007); Kasdallah-Grissa et al., "Resveratrol, a Red Wine
Polyphenol, Attenuates Ethanol-Induced Oxidative Stress in Rat
Liver" Life Sci 80:1033-1039 (2007); and Rahman et al., "Regulation
of Inflammation and Redox Signaling by Dietary Polyphenols" Biochem
Pharmacol 72:1439-1452 (2006). Resveratrol is also believed to
block human platelet aggregation and vascular smooth muscle cell
proliferation inhibiting thrombosis and inducing apoptosis which
suggests its potential use against restenosis. Mnjoyan et al.,
"Profound Negative Regulatory Effects by Resveratrol Vascular
Smooth Muscle Cells: role of p53-p21 (WAF1/CIP I) pathway" Biochem
Biophys Res Commun 311:546-552 (2003); Olas et al., "Resveratrol, a
Phenolic Antioxidant with Effects on Blood Platelet Functions"
Platalets 16:251-260 (2005); Pace-Asciak et al., "The Red Wine
Phenolics Trans-Resveratrol and Quercetin Block Platelet
Aggregation and Eicosanoid Synthesis: Implications for Protection
Against Coronary Heart Disease" Clin Chim Acta 235:207-219 (1995).
Poussier et al., "Resveratrol Inhibits Vascular Smooth Muscle Cell
Proliferation and Induces Apoptosis" Vasc Surg 42:1190-1197
(2005).
[0186] B. Diabetes: In one embodiment, the present invention
contemplates a method for treating diabetes using an impermeable
therapeutic agent delivery device. In one embodiment, the delivery
device provides controlled release of the agent. In one embodiment,
the agent comprises insulin. In one embodiment, the device further
comprises a glucose sensor. In one embodiment, the glucose sensor
readout is transmitted to a remote detector. In one embodiment, the
device is implanted within a cardiovascular vessel. One advantage
of this method is that a diabetic patient receiving treatment using
a delivery device comprising a glucose sensor would not be required
to perform routine tests for blood sugar levels.
[0187] Diabetes is a chronic (lifelong) disease marked by high
levels of sugar in the blood. Insulin is a hormone produced by the
pancreas to control blood sugar. Diabetes can be caused by too
little insulin, resistance to insulin, or both. People with
diabetes have high blood sugar because: i) their pancreas does not
make enough insulin and/or ii) their muscle, fat, and liver cells
do not respond to insulin normally.
[0188] Type 1 diabetes is usually diagnosed in childhood. Many
patients are diagnosed when they are older than age 20. In this
disease, the body makes little or no insulin. Daily injections of
insulin are needed. The exact cause is unknown. Genetics, viruses,
and autoimmune problems may play a role. Type 2 diabetes is far
more common than type 1. It makes up most of diabetes cases. It
usually occurs in adulthood, but young people are increasingly
being diagnosed with this disease. The pancreas does not make
enough insulin to keep blood glucose levels normal, often because
the body does not respond well to insulin. Many people with type 2
diabetes do not know they have it, although it is a serious
condition. Type 2 diabetes is becoming more common due to
increasing obesity and failure to exercise. Gestational diabetes is
high blood glucose that develops at any time during pregnancy in a
woman who does not have diabetes.
[0189] There are many risk factors for type 2 diabetes including,
but not limited to, age over 45 years, family history, heart
disease, high blood cholesterol level, obesity, or lack of
exercise. Diabetic symptoms may include, but not be limited to,
blurry vision, excessive thirst, fatigue, frequent urination,
hunger, or unexplained weight loss
[0190] Examination and testing for diabetes usually begins with a
urine analysis to determine glucose and ketones levels. Diagnosing
diabetes may be determined by comparing the following factors: i)
fasting blood glucose level--diabetes is diagnosed if higher than
126 mg/dL on two occasions. Levels between 100 and 126 mg/dL are
referred to as impaired fasting glucose or pre-diabetes. These
levels are considered to be risk factors for type 2 diabetes and
its complications, ii) oral glucose tolerance test--diabetes is
diagnosed if glucose level is higher than 200 mg/dL after 2 hours.
(This test is used more for type 2 diabetes.), iii) random
(non-fasting) blood glucose level--diabetes is suspected if higher
than 200 mg/dL and accompanied by the classic diabetes symptoms of
increased thirst, urination, and fatigue. (This test must be
confirmed with a fasting blood glucose test.).
[0191] C. Epilepsy: In one embodiment, the present invention
contemplates a method for treating epilepsy using an impermeable
therapeutic agent delivery device. In one embodiment, the delivery
device provides controlled release of the agent. In one embodiment,
the agent comprises an anticonvulsant, wherein the anticonvulsant
suppresses brain cell firing rates. In one embodiment, the device
is implanted within a localized area of the brain that is suspected
of having localized cell damage.
[0192] Epilepsy is a brain disorder involving repeated seizures of
any type. Seizure disorders affect about 0.5% of the population.
Approximately 1.5-5.0% of the population may have a seizure in
their lifetime. Epilepsy can affect people of any age. Seizures are
episodes of disturbed brain function that cause changes in
attention or behavior. They are caused by abnormal excited
electrical signals in the brain. Sometimes seizures are related to
a temporary condition, such as exposure to drugs, withdrawal from
certain drugs, or abnormal levels of sodium or glucose in the
blood. In such cases, repeated seizures may not recur once the
underlying problem is corrected. In other cases, injury to the
brain (for example, stroke or head injury) causes brain tissue to
be abnormally excitable. In some people, an inherited abnormality
affects nerve cells in the brain, which leads to seizures. Some
seizures are idiopathic, which means the cause can not be
identified. Such seizures usually begin between ages 5 and 20, but
they can occur at any age. People with this condition have no other
neurological problems, but often have a family history of seizures
or epilepsy.
[0193] Disorders affecting the blood vessels, such as stroke and
TIA, are the most common cause of seizures after age 60.
Degenerative disorders such as senile dementia Alzheimer type can
also lead to seizures.
[0194] Some of the more common causes of seizures include but are
not limited to, developmental problems, metabolic abnormalities,
brain injury, tumors and brain lesions (such as hematomas), or
infections. The severity of symptoms can vary greatly, from simple
staring spells to loss of consciousness and violent convulsions.
For many patients, the event is the same thing over and over, while
some people have many different types of seizures that cause
different symptoms each time. The type of seizure a person has
depends on a variety of many things, such as the part of the brain
affected and the underlying cause of the seizure. An aura
consisting of a strange sensation (such as tingling, smell, or
emotional changes) occurs in some people prior to each seizure.
Seizures may occur repeatedly without explanation. Risk factors
include, but are not limited to, a family history of epilepsy, head
injury, or other condition that causes damage to the brain.
[0195] Epileptic seizures may fall under one of several
classifications including, generalized seizures (i.e., for example,
petit mal and grand mal), partial seizures (i.e., for example,
simple and complex).
[0196] The diagnosis of epilepsy and seizure disorders requires a
history of recurrent seizures of any type. A physical examination
(including a detailed neuromuscular examination) may be normal, or
it may show abnormal brain function related to specific areas of
the brain. For example, an electroencephalograph (EEG), a reading
of the electrical activity in the brain, may confirm the presence
of various types of seizures. It may, in some cases, indicate the
location of the lesion causing the seizure. EEGs can often be
normal in between seizures, so it may be necessary to do prolonged
EEG monitoring. Other tests may include various blood tests to rule
out other temporary and reversible causes of seizures, including,
but not limited to, a complete blood count, blood chemistry, blood
glucose, liver function, kidney function, infectious diseases, or
cerebrospinal fluid analysis.
[0197] Anti-convulsant oral drugs are normally prescribed to
control the seizures. As each individual's response to the drug
differs, the initial administration is carefully monitored and
titrated. The type of medicine used depends on seizure type, and
dosage may need to be adjusted from time to time. Some seizure
types respond well to one medication and may respond poorly (or
even be made worse) by others. Some medications need to be
monitored for side effects and blood levels.
[0198] Epilepsy that does not respond to the use of several
medications is called refractory epilepsy. Certain people with this
type of epilepsy may benefit from brain surgery to remove the
abnormal brain cells that are causing the seizures. Others may be
helped with a vagal nerve stimulator, which is implanted in the
chest. This stimulator can help reduce the number of seizures.
[0199] D. Macular Degeneration: In one embodiment, the present
invention contemplates a method for treating macular degeneration
using an impermeable therapeutic agent delivery device. In one
embodiment, the delivery device provides controlled release of the
agent. In one embodiment, the agent may be selected from the group
comprising Macugen.RTM., Avastin.RTM., Lucentis.RTM., or
Kenalog.RTM.. In one embodiment, the device is implanted within the
vitreous humor of the eye, such that the device is
free-floating.
[0200] Macular degeneration is a disorder that affects the macula
(the central part of the retina of the eye) causing decreased
vision and possible loss of central vision. The macula is the part
of the retina that allows the eye to see fine details at the center
of the field of vision. Degeneration results from a partial
breakdown of the retinal pigment epithelium (RPE). The RPE is the
insulating layer between the retina and the choroid (the layer of
blood vessels behind the retina). The RPE acts as a filter to
determine what nutrients reach the retina from the choroid. Many
components of blood are harmful to the retina and are kept away
from the retina by normal RPE.
[0201] Breakdown of the RPE interferes with the metabolism of the
retina, causing thinning of the retina (the "dry" phase of macular
degeneration). These harmful elements may also cause new blood
vessel to form and fluid to leak (the "wet" phase of macular
degeneration).
[0202] Macular degeneration results in the loss of central vision
only--peripheral fields usually stay normal. Although loss of
ability to read and drive may be caused by macular degeneration,
the disease does not lead to complete blindness. The disease
becomes increasingly common as people age over 50. By age 75,
almost 15% of people have this condition. Other risk factors are
family history, cigarette smoking, and being Caucasian.
[0203] In general, macular degeneration symptoms usually include,
but are not limited to, blurred, distorted, dim, or absent central
vision. Testing to evaluate retinal function may include, but is
not limited to, visual acuity, refraction test, pupillary reflex
response, slit lamp examination, retinal examination, fluorescein
angiography, Amsler grid, optical coherence tomography (OCT), a
test that creates a color picture of the macula or retina
[0204] While there is no specific treatment for dry macular
degeneration, dietary zinc supplements may slow the progression of
the disease. Alternatively, laser photocoagulation (i.e., for
example, laser surgery to stop the leaking in choroidal blood
vessels) may be useful in the early stages of the wet form of the
disease. It involves the use of a thermal laser, which burns the
abnormal, leaky blood vessels and stops them from spreading.
[0205] Photodynamic therapy may be used in conjunction with
verteporfin (Visudyne.RTM.), a light-sensitive medication that is
conventionally injected into a vein in the patient's arm. When a
non-thermal laser is shone into the eyes, verteporfin produces a
chemical reaction that destroys abnormal blood vessels. While the
treatment is temporary, it can be repeated without adverse
effect.
[0206] Other drugs used to treat the wet form of macular
degeneration include, but is not limited to, Macugen, Avastin,
Lucentis, and Kenalog. Conventional administration requires direct
injection into the eye at regular intervals.
[0207] E. Pain Management: In one embodiment, the present invention
contemplates a method for treating acute and/or chronic pain using
an impermeable therapeutic agent delivery device. In one
embodiment, the delivery device provides controlled release of the
agent. In one embodiment, the agent comprises an opioid. In one
embodiment, the device is implanted within a spinal disc, wherein
the disc is suspected of having localized nerve cell damage. Pain
is mediated by the peripheral and central nervous systems to
identify to a biological organism the source and severity of an
injury or illness. Pain may occur at many different intensities
having many different qualitative natures. For example, a pain may
be of a minimal intensity but having a stable nature.
Alternatively, a pain may be of a maximal intensity but having an
unstable nature (i.e., for example, throbbing). Further, the
apparent location of a particular pain may not accurately reflect
the actual source of the injury or illness (i.e., for example,
referred pain).
[0208] Pain may occur in almost any part of the body including, but
not limited to, abdomen, ankle, anus, back, bones, breast, ear,
elbow, eye, finger, foot, groin, head, heel, hip, joints, knee,
leg, muscles, neck, rib cage, shins, shoulder, flank, teeth, wrist,
or somatoform. Pain medicines are also called analgesics. Every
type of pain medicine has benefits and risks. Specific types of
pain may respond better to one kind of medication than to another
kind. Further, pain medications may also be patient-specific, where
a specific pain medication may work in one patient but be
ineffective in another. Over-the-counter (OTC) medications are good
for many types of pain. OTC medicines include, but are not limited
to, acetaminophen and nonsteroidal anti-inflammatory drugs.
Acetaminophen is a non-aspirin pain reliever. It can be used to
lower a fever and soothe headaches and other common aches and
pains. However, acetaminophen does not reduce swelling
(inflammation). This medicine is easier on the stomach than other
pain medications, and it is safer for children. It can, however, be
harmful to the liver if you take more than the recommended dose.
NSAIDs include aspirin, naproxen, and ibuprofen. These medicines
relieve pain, but they also reduce inflammation caused by injury,
arthritis, or fever. NSAIDs work by reducing the production of
hormone-like substances that cause pain.
[0209] Prescription medications may be needed for other types of
pain. COX-2 inhibitors are a type of prescription painkiller that
block an inflammation-promoting substance called COX-2. This class
of drugs was initially believed to work as well as traditional
NSAIDs, but with fewer stomach problems. However, numerous reports
of heart attacks and stroke have prompted the FDA to re-evaluate
the risks and benefits of the COX-2s. Patients should ask their
doctor whether a COX-2 drug is appropriate and safe for them.
Narcotic painkillers (i.e., for example, opioids) are very strong,
potentially habit-forming medicines used to treat severe pain. They
include, but are not limited to, morphine and codeine.
[0210] F. Parkinson's Disease: In one embodiment, the present
invention contemplates a method for treating Parkinson's disease
using an impermeable therapeutic agent delivery device. In one
embodiment, the delivery device provides controlled release of the
agent. In one embodiment, the agent comprises a dopamine agonist.
In one embodiment, the device is implanted within a substantia
nigra tissue, wherein the tissue is suspected of having localized
cell damage. In one embodiment, the tissue comprises transplanted
tissue. In one embodiment, the agent comprises a contrast agent,
wherein the agent facilitates high resolution, localized brain
imaging.
[0211] Parkinson's disease is a disorder of the brain that leads to
shaking (tremors) and difficulty with walking, movement, and
coordination. The disease affects approximately 2 of every 1,000
people and most often develops after age 50. It is one of the most
common neurologic disorders of the elderly. Sometimes Parkinson's
disease occurs in younger adults, but is rarely seen in children.
It affects both men and women. In some cases, Parkinson's disease
occurs within families, especially when it affects young people.
Most of the cases that occur at an older age have no known
cause.
[0212] Parkinson's disease occurs when the nerve cells in the part
of the brain that controls muscle movement (i.e., for example, the
substantia nigra) are gradually destroyed. The damage gets worse
with time. The exact reason that the cells of the brain waste away
is unknown. The disorder may affect one or both sides of the body,
with varying degrees of loss of function.
[0213] Nerve cells within the substantia nigra comprise dopamine as
a neurotransmitter. Damage in the area of the brain that controls
muscle movement causes a decrease in dopamine production. Too
little dopamine disturbs the balance between nerve-signaling
substances (transmitters). Without dopamine, the nerve cells cannot
properly send messages. This results in the loss of muscle
function.
[0214] Some people with Parkinson's disease become severely
depressed. This may be due to loss of dopamine in certain brain
areas involved with pleasure and mood. Lack of dopamine can also
affect motivation and the ability to make voluntary movements.
[0215] Early loss of mental capacities is uncommon. However,
persons with severe Parkinson's may have overall mental
deterioration (including dementia and hallucinations). Dementia can
also be a side effect of some of the medications used to treat the
disorder.
[0216] Symptoms of Parkinson's disease may include, but be limited
to, muscle rigidity, unstable, stooped, or slumped-over posture,
loss of balance, abnormal gait, slow movements, voluntary movement
initiation difficulty, walking initiation difficulty, standing
initiation difficulty, myalgia, shaking, tremors, facial expression
abnormalities, speech abnormalities, fine motor skill
abnormalities, frequent falls, decline in intellectual function
(may occur, can be severe), or gastrointestinal symptoms (i.e., for
example, constipation).
[0217] Diagnosis usually requires a professional subjective
evaluation of the expressed symptomology. Objective tests may be
used to rule out other disorders that cause similar symptoms in
order to perform a differential diagnosis.
[0218] Currently prescribed medications only control symptoms
primarily by increasing the levels of dopamine in the brain, and do
not provide any curative value. The specific type of medication,
the dose, the amount of time between doses, or the combination of
medications taken may need to be changed from time to time as
symptoms change. Many medications can cause severe side effects, so
monitoring and follow-up by the health care provider is
important.
[0219] Types of medication usually prescribed for Parkinson's
disease includes, but is not limited to, deprenyl, amantadine,
levodopa, carbidopa, entacapone, pramipexole, ropinirole,
rasagiline, or rotigotine. Additional medications to help reduce
symptoms or control side effects of primary treatment medications
include antihistamines, antidepressants, monoamine oxidase
inhibitors (MAOIs), and others.
[0220] Transplantation of adrenal gland tissue to the brain has
been attempted, with variable results. Such transplants are in an
attempt to improve the bioavailability of naturally produced
dopamine precursors that may help elevate dopamine levels.
[0221] G. Cancer: In one embodiment, the present invention
contemplates a method for treating cancer using an impermeable
therapeutic agent delivery device. In one embodiment, the delivery
device provides controlled release of the agent. In one embodiment,
the agent comprises an antiproliferative. In one embodiment, the
device is implanted within a tumor or in proximity therewith. In
one embodiment, the device is implanted within a cardiovascular
vessel.
[0222] Cancer is generally defined as an uncontrolled growth of
abnormal cells in the body. Cancerous cells may be either malignant
or benign. Cancer grows out of normal cells in the body and appears
to occur when the growth of cells in the body is out of control and
cells divide too rapidly. It can also occur when cells lose the
ability to undergo apoptosis.
[0223] There are many different kinds of cancers. Cancer can
develop in almost any organ or tissue, including, but not limited
to the lung, colon, breast, skin, bones, or nerve tissue. Specific
types of cancer may include but are not limited to, lung cancer,
brain cancer, cervical cancer, uterine cancer, liver cancer,
leukemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, kidney
cancer, ovarian cancer, skin cancer, testicular cancer, thyroid
cancer. There are multiple causes of cancers, including but not
limited to, radiation, sunlight, tobacco, viruses, chemicals,
poisonous mushrooms, or aflatoxins.
[0224] The three most common cancers in men in the United States
are prostate cancer, lung cancer, and colon cancer. The three most
frequently occurring cancers in women in the U.S. are breast, lung
and colon cancers. Certain cancers are more common in particular
geographic areas. For example, in Japan, there are many cases of
gastric cancer, while in the U.S. this type of cancer is relatively
rare. Differences in diet may play a role.
[0225] Symptoms of cancer depend on the type and location of the
tumor. For example, lung cancer can cause coughing, shortness of
breath, or chest pain, while colon cancer often causes diarrhea,
constipation, and blood in the stool. Some cancers may not have any
symptoms at all. In some cancers, such as gallbladder cancer,
symptoms often are not present until the disease has reached an
advanced stage. In general symptoms that are common with most
cancers include, but are not limited to, fever, chills, night
sweats, weight loss, loss of appetite, fatigue, or malaise.
[0226] Examination and tests to identify and/or diagnose cancers
vary based on the type and location of the tumor. Nonetheless,
common cancer tests include, but are not limited to, computer
tomography scanning, complete blood count, blood chemistries,
tissue biopsy, or X-ray radiography. Most cancer diagnoses are
confirmed by biopsy. Depending on the location of the tumor, the
biopsy may be a simple procedure or a serious operation. Most
patients with cancer undergo imaging scans to determine the exact
location of the tumor or tumors.
[0227] Cancer treatments also vary based on the type, stage and
location of a particular cancer and/or cancerous tumor. The stage
of a cancer refers to how much it has grown and whether the tumor
has spread from its original location. If the cancer is confined to
one location and has not spread, the goal for treatment would be
surgery and cure. This is often the case with skin cancers. If the
tumor has spread to local lymph nodes only, sometimes these can
also be removed. If all of the cancer cannot be removed with
surgery, the options for treatment include radiation, chemotherapy,
or both. Some cancers require a combination of surgery, radiation,
and chemotherapy.
[0228] H. Fungal Infections: In one embodiment, the present
invention contemplates a method for treating a fungus infection
using an impermeable therapeutic agent delivery device. In one
embodiment, the delivery device provides controlled release of the
agent. In one embodiment, the agent comprises an antifungal agent.
In one embodiment, the device is implanted underneath a toenail. In
one embodiment, the device is implanted underneath a fingernail. In
one embodiment, the device is implanted using a twenty-seven (27)
gauge needle.
[0229] The body normally hosts a variety of bacteria and fungi and
some species are useful to the body, while others result in
infection. Fungi can live on the dead tissues of the hair, nails,
and outer skin layers. Fungal infections may include, but are not
limited to, athlete's foot, jock itch, ringworm, or Tinea capitis.
Other fungal infections may also include yeast-like fungi such as
candida. Candida yeast infections include, but are not limited to,
cutaneous candidiasis, diaper rash, oral thrush, or genital
rashes.
[0230] In particular, fungal nail infections are most often seen in
adults and are often quite persistant and refractory to most
topical treatments. They often follow fungal infection of the feet.
Toenails are affected more often than fingernails. People who
frequent public swimming pools, gyms, or shower rooms--and people
who perspire a great deal--commonly have mold-like infections. The
fungi that cause them thrive in warm, moist areas.
[0231] Symptoms of a nail fungal infection include, but are not
limited to, brittleness, change in nail shape, crumbling of the
nail, debris trapped under the nail, discoloration, detachment,
loss of luster and shine, or thickening.
[0232] Over-the-counter creams and ointments generally do not help
treat this condition. Consequently, prescription antifungal
medicines may taken by mouth may help clear the fungus in about 50%
of patients. However, such medicines can cause side effects or may
interfere with other medications. Further, some of the oral
medications used to treat fungal infections of the nail can harm
the liver.
Example I
Manufacture of a Single Passageway Impermeable Delivery Device
[0233] This example describes the manufacture of one embodiment of
an impermeable zero order kinetic drug delivery device having a
single passageway.
[0234] Lengths of polyimide tubes were provided having a length of
20 mm and a diameter of 125 microns. At the centre of each tube, a
passageway with a diameter of 30 microns was made using standard
chemical procedures.
[0235] Seven (7) tubes having the optimal passageways were selected
and loaded with a concentrated solution of crystal violet in
ethanol by capillary method. The tubes were then allowed to stand
for 24 hours at room temperature to evaporate alcohol from the
tubes, such that the tube is tightly packed with a solid crystal
violet composition.
[0236] After taking an initial weight measurement, an average
amount of 126 micrograms of crystal violet was estimated inside the
tubes. The ends of the tubes were sealed with a bioglue and
dried.
Example II
Release Kinetics of a Single Passageway Impermeable Delivery
Device
[0237] This example describes one method that evaluates the release
of an agent from a single passageway impermeable delivery
device.
[0238] Single passageway tubes made according to Example I were
placed in microvials containing 0.26 ml of phosphate buffered
saline (0.01 M phosphate, pH 7.37). The vials were placed in a USP
Disintegration Apparatus having dip rate of 30-32 dips per minute.
The apparatus was connected to a waterbath maintained at 37.degree.
C. for the entire duration of study. The buffer was changed every
48 hours, sampled, and analyzed for the amount of crystal violet
released using a UV-Vis Spectrophotometer for 28 days.
[0239] A significant linearity of release of the crystal violet was
obtained from this single passageway device (see FIGS. 6 and 7).
Additionally, the percentage release when extrapolated to 100%
corresponds to the total duration of release of approximately 43
years.
Example III
Manufacture of a Double Passageway Impermeable Delivery Device
[0240] This example describes the manufacture of one embodiment of
an impermeable zero order kinetic drug delivery device having two
passageways.
[0241] Several drug delivery devices were constructed in accordance
with in Example I except that two passageways were made located
equidistant from the tube centre. The optimal seven (7) were
selected and loaded with crystal violet in accordance with Example
I.
Example IV
Release Kinetics of a Double Passageway Impermeable Delivery
Device
[0242] This example describes one method that evaluates the release
of an agent from a double passageway impermeable delivery
device.
[0243] The double passageway tubes made in accordance with Example
III were tested for crystal violet release in accordance with
Example II. Again, significant linear agent release was obtained
from the double passageway embodiment as seen in FIGS. 6 and 7.
Additionally, the percentage release when extrapolated to 100%
corresponds to the total duration of release of approximately 22
years.
Example V
Manufacture of a Triple Passageway Impermeable Delivery Device
[0244] This example describes the manufacture of one embodiment of
an impermeable zero order kinetic drug delivery device having three
passageways.
[0245] Several drug delivery devices were constructed in accordance
with Example I except that three passageways were made located
equidistant from each end of the tube. The optimal seven (7) were
selected and loaded with crystal violet in accordance with Example
I.
Example VI
Release Kinetics of a Triple Passageway Impermeable Delivery
Device
[0246] This example describes one method that evaluates the release
of an agent from a triple passageway impermeable delivery
device.
[0247] The triple passageway tubes made in accordance with Example
III were tested for crystal violet release in accordance with
Example II. Again, significant linear agent release was obtained
from the triple passageway embodiment (FIGS. 6 and 7).
Additionally, the percentage release when extrapolated to 100%
corresponds to the total duration of release of approximately 15
years.
Example VII
Comparative Release Linearity Between Single, Double, and Triple
Passageway Delivery Devices
[0248] This example compares the linearity data collected in
Example II, IV, and VI between the single, double, and triple
passageway delivery devices.
[0249] The data shows no differences in the linearity of release
rates amongst the single, double, and triple passageway devices.
This data suggests that each passageway releases the same amount of
agent over time regardless of the number of passageways present on
the surface of the device. In this experiment, the passageways in
each of the three groups have similar dimensions and only differ in
number of holes on the surface (FIG. 8).
Example VIII
Construction of a Single Outlet Port Impermeable Delivery
Device
[0250] This example describes the manufacture of one embodiment of
an impermeable zero order kinetic drug delivery device having a
single outlet port at the end of the device.
[0251] Seven (7) lengths of polyimide tubes were provided having a
length of 20 mm and a diameter of 125 microns. The tubes were then
loaded with a concentrated solution of crystal violet in ethanol by
capillary method. The tubes were then allowed to stand for 24 hours
at room temperature to evaporate alcohol from the tubes, such that
the tube is tightly packed with a solid crystal violet composition.
One end of the tube was sealed with a bioglue while the other end
was left open.
[0252] After taking an initial weight measurement, an average
amount of 126 micrograms of crystal violet was estimated inside the
tubes.
Example IX
Release Kinetics of an Outlet Port Impermeable Delivery Device
[0253] This example describes one method that evaluates the release
of an agent from a single outlet port impermeable delivery
device.
[0254] A drug delivery device made in accordance with Example VIII
was subjected to release studies as described in Example II. In
particular, the device did not have any surface passageways but
allowed to release from one open end. A significant linearity of
release of the crystal violet was obtained over a period of five
(5) days as shown in FIG. 9. The percentage release when
extrapolated to 100% corresponds to the total duration of release
of approximately 2 years.
Example X
Release Kinetics of an Outlet Port Impermeable Delivery Device
[0255] Drug delivery devices were made having one outlet port and
one sealed end. In particular, the device did not have any surface
passageways but allowed to release from one open end. Three
different variation of devices were prepared with different inside
diameters, as in 200, 400, and 600 microns. Four devices of each
type were subjected to release studies as described in Example I.
Single passageway tubes were placed in micro vials containing 3.0
ml of phosphate buffered saline (0.01 M phosphate, pH 7.37). The
vials were placed in an incubator maintained at 37.degree. C. for
the entire duration of study. The buffer was changed every 24
hours, sampled, and analyzed for the amount of crystal violet
released using a UV-Vis Spectrophotometer for seven (7) days. A
significant linearity of release of the crystal violet was obtained
over a period of seven (7) days (FIG. 17).
Example XI
Drug Loading of Prednisolone Suspension using Positive Pressure
[0256] An ethanolic suspension of prednisolone was prepared by
adding 200 mg of prednisolone to 0.5 ml ethanol. A 1 ml syringe,
which was attached to the touhy borst adapter, was filled with the
high density suspension. The polyimide tube (diameter=125 microns)
was screwed tightly to the other end of the adapter, and the
prednisolone suspension was injected into the tube. Afterwards, the
ethanol was evaporated by allowing the tubes to stand overnight.
The final weight was analyzed using TGA-7. A net amount of
87.58.+-.11.70 micrograms of prednisolone was loaded into the
tubes. The amount of drug loaded per unit length of the tube was
5.68.+-.0.65 micrograms/mm. The net amount of drug loaded indicates
content uniformity amongst all the tubes whereas, amount of drug
loaded per unit length indicates the homogeneity of drug
distribution inside the tube.
Example XII
Drug Loading of Powdered Crystal Violet
[0257] A group of polyimide tubes (diameter=1000 microns) were
manually loaded with crystal violet powder. The average amount of
crystal violet loaded per unit length in the groups was
5.31.+-.0.28 milligrams/cm.
[0258] Although the present invention has been described with
several embodiments, a myriad of changes, variations, alterations,
transformations, and modifications may be suggested to one skilled
in the art, and it is intended that the present disclosure
encompass such changes, variations, alterations, transformation,
and modifications as they fall within the scope of the appended
claims. It is contemplated that any embodiment discussed in this
specification can be implemented with respect to any method, kit,
reagent, or composition of the invention, and vice versa.
Furthermore, compositions of the invention can be used to achieve
methods of the invention.
[0259] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the claims. All publications and patent
applications mentioned in the specification are indicative of the
level of skill of those skilled in the art to which this invention
pertains. All publications and patent applications are herein
incorporated by reference to the same extent as if each individual
publication or patent application was specifically and individually
indicated to be incorporated by reference.
[0260] The use of the word "a" or "an" when used in conjunction
with the term "comprising" in the claims and/or the specification
may mean "one," but it is also consistent with the meaning of "one
or more," "at least one," and "one or more than one." The use of
the term "or" in the claims is used to mean "and/or" unless
explicitly indicated to refer to alternatives only or the
alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0261] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps.
[0262] The term "or combinations thereof" as used herein refers to
all permutations and combinations of the listed items preceding the
term. For example, "A, B, C, or combinations thereof" is intended
to include at least one of: A, B, C, AB, AC, BC, or ABC, and if
order is important in a particular context, also BA, CA, CB, CBA,
BCA, ACB, BAC, or CAB. Continuing with this example, expressly
included are combinations that contain repeats of one or more item
or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so
forth. The skilled artisan will understand that typically there is
no limit on the number of items or terms in any combination, unless
otherwise apparent from the context.
[0263] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. All such similar substitutes and modifications apparent
to those skilled in the art are deemed to be within the spirit,
scope and concept of the invention as defined by the appended
claims.
* * * * *