U.S. patent application number 10/045688 was filed with the patent office on 2002-08-22 for drug delivery via conformal film.
Invention is credited to Larson, Eugene A., Larson, Marian L..
Application Number | 20020115985 10/045688 |
Document ID | / |
Family ID | 22899973 |
Filed Date | 2002-08-22 |
United States Patent
Application |
20020115985 |
Kind Code |
A1 |
Larson, Marian L. ; et
al. |
August 22, 2002 |
Drug delivery via conformal film
Abstract
A drug delivery conformal film system according to the present
invention is adapted to be compounded and applied, by medical
personnel at the point of use, to a medical device such as a
cardiovascular and urology stent, pacemaker, vascular graft, suture
ring of mechanical heart valve, implantable infusion port,
implantable drug delivery pump, orthopedic hardware and appliance,
and, neurological stimulating device. The drug delivery conformal
film consists of one of three in vivo biocompatible; biodegradable,
bio-erodable or bioabsorbable embodiments: (1) cross-linked sodium
alginate, (2) UV photo-active polymer, or, (3) hydrogels. An
implantable medical device such as the stent or suture ring of a
mechanical artificial heart valve is coated with an in vivo
biocompatible; biodegradable or bioerodable or bioabsorbable
solution comprising a polymer and containing a drug, the solution
is cross-linked or cured to form a film on the device immediately
prior to placement in the body. When the coated device is
introduced into the body, the drug contained in the coating is
released in a local region. The invention provides a point of use
in vivo drug delivery system whereby the drug and its concentration
can be selected by medical personnel immediately prior to
implantation of the medical device.
Inventors: |
Larson, Marian L.; (Newport
Beach, CA) ; Larson, Eugene A.; (Lummi Island,
WA) |
Correspondence
Address: |
Robert L. McDowell
1170 Jackson Heights Drive
Webster
NY
14580
US
|
Family ID: |
22899973 |
Appl. No.: |
10/045688 |
Filed: |
October 29, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10045688 |
Oct 29, 2001 |
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09238946 |
Jan 27, 1999 |
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6309380 |
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Current U.S.
Class: |
604/890.1 ;
604/288.01 |
Current CPC
Class: |
A61K 9/7015 20130101;
A61K 9/0024 20130101; A61L 2300/606 20130101; A61L 31/16
20130101 |
Class at
Publication: |
604/890.1 ;
604/288.01 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. An implantable drug-delivering medical device for implantation
into a recipient, said device comprising: an implantable medical
device, a film adhered to said device, said film comprising an in
vivo biocompatible and biodegradable or bioabsorbable or
bioerodable polymer, said film further comprising a desired dosage
amount of one or more predetermined drugs, wherein the desired
dosage amount of said one or more predetermined drugs is selected
based on particular dosage requirements of said recipient and
wherein said film is adhered to said medical device immediately
prior to implantation of said medical device into said
recipient.
2. The device of claim 1 wherein said polymer comprises
alginates.
3. The device of claim 2 wherein said alginates comprise sodium
alginate.
4. The device of claim 3 wherein said sodium alginate is present in
the range of about 1 wt. % to about 8 wt. % and has a molecular
weight in the range of 12,000 to 190,000.
5. The device of claim 1 wherein said polymer comprises
hydrogels.
6. The device of claim 1 wherein said implantable medical device
comprises a stent.
7. The device of claim 1 wherein said implantable medical device
comprises at least one of pacemaker, vascular graft, suture ring,
implantable infusion port, implantable drug delivery pump,
orthopedic hardware and appliances, and, neurological stimulating
device.
8. The device of claim 1 wherein said film is sterile.
9. The device of claim 1 wherein said film is formed in the
presence of a cross-linking agent.
10. The device of claim 9 wherein said cross-linking agent
comprises at least one of calcium chloride, CaSO.sub.4, MgCl,
MgSO.sub.4, and barium compounds.
11. The device of claim 10 wherein said cross-linking agent
comprises calcium chloride.
12. The device of claim 1 wherein said film exhibits elasticity in
an amount greater than 200%.
13. The device of claim 1 wherein said film is adhered to said
device in a uniform thickness or in a non-uniform thickness.
14. The device of claim 1 wherein said polymer comprises
polyethylene glycol or derivatives and copolymers of polyethylene
glycol.
15. The device of claim 5 wherein said hydrogels comprises a
mixture of polyethylene oxide and polyethylene glycol.
16. The device of claim 1 wherein said one or more predetermined
drugs are at least one of water soluble drugs and non-water soluble
drugs.
17. An implantable drug-delivering medical device for implantation
into a recipient, said device comprising: an implantable medical
device, a film adhered to said device, said film comprising sodium
alginate, said film further comprising a desired dosage amount of
one or more predetermined drugs, wherein the desired dosage amount
of said one or more predetermined drugs is selected based on
particular dosage requirements of said recipient and wherein said
film is adhered to said medical device immediately prior to
implantation of said medical device into said recipient.
18. The device of claim 17 wherein said implantable medical device
comprises a stent.
19. An implantable drug-delivering medical device for implantation
into a recipient, said device comprising: an implantable medical
device, a film adhered to said device, said film comprising sodium
alginate cross linked with calcium chloride, said film further
comprising a desired dosage amount of one or more predetermined
drugs, wherein the desired dosage amount of said one or more
predetermined drugs is selected based on particular dosage
requirements of said recipient and wherein said film is adhered to
said medical device immediately prior to implantation of said
medical device into said recipient.
20. The device of claim 19 wherein said film is lubricious.
Description
[0001] This application is a divisional of copending application
Ser. No. 09/238,946 filed Jan. 27, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to the local delivery of drugs
in vivo into the cardiovascular system and other body regions. In
particular, the present invention is directed to the local delivery
of drugs by applying a coating of a bioabsorbable/biodegradable or
inert, in vivo biocompatible conformal film, to an implantable
medical device.
BACKGROUND OF THE INVENTION
[0003] Angioplasty is a procedure that involves placing and
inflating a balloon catheter in the blood vessel in the area of
blockage, which breaks up the accumulated plaque and opens the
vessel. While this technique works well in the short term, current
literature indicates that 30 to 50% of all angioplasty operations
performed will need follow-up treatment within six months. This is
due to incomplete plaque removal and the formation of scar tissue
as a result of irritation of the blood vessel, known as restenosis.
Restenosis results in significant morbidity and mortality and often
necessitates further interventions such as repeat angioplasty,
coronary bypass, laser surgery or local drug delivery. There has
been a focused effort in the health-are industry over the last few
years to combat restenosis because repeat angioplasty or surgery is
expensive, inconvenient, and potentially life threatening.
[0004] Limitations of angioplasty long-term success include abrupt
closure (4.4-8.3%) and restenosis (chronic reclosure 30-50%) of the
vessel--both of which are associated with excessive vascular
injury.
[0005] Intravascular stenting (the placement of a supporting
structure within a blood vessel) has demonstrated moderate success
in addressing these issues. These devices provide structural
support to keep the vessel walls from closing and minimize the
problem of arterial blockage caused by plaque falling in to the
vessel after inflation.
[0006] Stents have been made using materials of varied composition.
U.S. Pat. No. 4,886,062 to Wiktor describes a stent made from low
memory metal such as a copper alloy, titanium, or gold. Current
stent designs tend to be thrombogenic (causing clot formation) and
immunologically stimulating (causing cell formation). Current metal
stent designs will not eliminate the restenosis problem. If
restenosis should recur, follow-up treatments such as laser surgery
or localized drug delivery using other angioplasty devices may be
required. A stent alone can not restrict hyperplasia of smooth
muscle cells, nor can it prevent restenosis or thrombus. Local
delivery of antithrombogenic drugs and those capable of restricting
hyperplasia of smooth muscle cells is desirable.
[0007] Drugs have been incorporated on or in a catheter or stent
during the manufacturing design to provide local delivery of drugs
to address restenosis, thrombus, and coagulation. U.S. Pat. Nos.
4,994,033 to Shockey et al.; 5,674,192 to Sahatian et al. and
5,545,208 to Wolff et al. disclose catheters comprising
absorbable/biodegradable polymers or hydrogels containing the
desired dosage of a drug. Stents incorporating drug delivery may be
found, for example, in U.S. Pat. Nos. 5,766,710 to Turnlund et al.;
5,769,883 to Buscemi et al.; 5,605,696 to Eury et al.; 5,500,013 to
Buscemi et al.; 5,551,954 to Buscemi et al. and 5,443,458 to
Eury.
[0008] When drugs or biological modifiers are applied in
conjunction with the manufacture of the device, there are several
problems, for example:
[0009] 1. sterilization: heat or ionizing radiation alters the
composition of many drugs and biological modifiers;
[0010] 2. the presence of a drug imposes a shorter shelf life
independent of the implantable medical device, and could require
special storage (i.e. refrigeration);
[0011] 3. the drug dosage is not variable for specific patient
needs; and,
[0012] 4. a large inventory of devices is required to provide a
range of drugs and therapies.
[0013] It is an object of the present invention to provide a drug
delivery system that overcomes the deficiencies associated with the
application of drugs in conjunction with the manufacture of the
device.
[0014] It is a further object of the present invention to provide a
procedure where the drug is applied to the device at the point of
use of the device.
SUMMARY OF THE INVENTION
[0015] The present invention is directed to a method of producing
an implantable drug-deliverable medical device. The method
comprises providing an implantable medical device, coating the
device with an in vivo biocompatible and biodegradable or
bioabsorbable or bioerodable liquid or gel solution containing a
polymer with the solution comprising a desired dosage amount of one
or more predetermined drugs. The solution is converted to a film
adhering to the medical device thereby forming the implantable
drug-deliverable medical device.
[0016] The present invention is also directed to a drug delivery
conformal film system adapted to be applied by medical personnel at
the point of use, to an implantable medical device such as
cardiovascular and urology stents, pacemakers, vascular grafts,
suture rings of mechanical heart valves, implantable injection or
infusion ports, implantable drug delivery pumps, orthopedic
hardware and appliances, and, neurological stimulating devices. The
drug delivery conformal film comprises one of three in vivo
biocompatible; biodegradable, bio-erodable or bio-inert
embodiments: (1) cross-linked sodium alginate, (2) UV photo-active
polymer, or, (3) hydrogels. A stent or other implantable medical
device such as the suture ring of a mechanical artificial heart
valve is coated with this biodegradable, bio-erodable or bio-inert
material containing a drug, cross-linked or cured, or otherwise
treated to form a film, immediately prior to placement in the body.
When the film-coated device is introduced into the body, the drug
contained in the film coating is released in a local region. The
invention provides a point of use in vivo drug delivery system
whereby the drug and its concentration can be selected by medical
personnel immediately prior to implantation of the medical
device.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The present invention will now be discussed in detail with
reference to the preferred embodiments. Unless otherwise stated,
all percentages represent weight percent.
[0018] Drugs or other biologically active materials incorporated
into the drug delivery conformal film system of the present
invention are intended to perform a variety of functions,
including, but not limited to: anti-clotting or anti-platelet
formation, and the prevention of smooth muscle cell growth on the
vessel wall. Drugs anticipated for delivery include antibiotics,
anticoagulants, tissue generation factor, and angiogenesis drugs.
Drugs also include, but are not limited to, anti-thrombogenic drugs
(heparin, PPACK, enoxaprin, aspirin, coumadin, hirudin, TPA,
urokinase, and streptokinase), anti-proliferative drugs (monoclonal
antibodies, heparin, angiopeptin, enxoaprin, methotrexate,
cisplatin, flourouracil, Adriamycin), antimetabolites, thromboxane
inhibitors, non-steroidal and steroidal anti-inflammatory drugs,
Beta and Calcium channel blockers, genetic materials (including DNA
and RNA fragments), and bioactive materials (such as fibronectin,
laminin, elastin, collagen, and intergrins).
[0019] As stated previously, the drug delivery conformal film of
the present invention comprises one of three in vivo biocompatible;
biodegradable, bio-erodable or bio-inert embodiments: (1)
cross-linked sodium alginate, (2) UV photo-active polymer, or, (3)
hydrogels, for example, thermal irreversible hydrogels. Of these
embodiments, cross-linked sodium alginate is preferred.
[0020] Sodium alginate is preferred because of its biocompatibility
and in vivo biodegradability, and cross-linking film forming
properties. A sterile and low endotoxin form of sodium alginate has
recently become available under product number K8P569 from
Monsanto, 800 N. Lindbargh Blvd. St. Louis, Mo., or under product
number UP MVG from Pro Nova, Strandveien 18, N-1324 Lysaker,
Norway. Very low endotoxin levels can be obtained in alginates by
use of a highly specialized purification process. Alginates in a
water gel form have the unique ability to form elastic films by
reaction with calcium salts and/or magnesium salts. Once
cross-linked, these films retain their shape and resist stress.
[0021] The preferred embodiment of the present invention is a
medical release drug delivery conformal film system comprised of
sterile, low endotoxin sodium alginate and sterile low-pyrogen
water which uses a solution of calcium chloride to achieve gelation
through cross-linking. The sodium alginates selected for this
invention have a Mannuronic acid content of approximately 58 to 62%
and a Guluronic acid content of approximately 42 to 38%. The
alginate films thus produced have known and acceptable long-term
biocompatibility and biodegradability in vivo and are manufactured
in such a manner and form that renders the film sterile and
biocompatible with human tissue, organs and body fluids. Sodium
alginate in purified form, such as Monsanto part number K8P569 and
ProNova part number UP MVG as a solution in water containing
acceptably low levels of pyrogens is the preferred composition that
demonstrates the desired in vivo biocompatibility and known in vivo
biodegradability.
[0022] Alginates, such as sodium alginate, form aqueous solutions
in either liquid or gel form. The addition of increasing amounts of
non-aqueous water-miscible solvents (i.e., glycols) to an alginate
solution increases the solubility of non-water-soluble compounds.
As the alginate solution in this invention is intended to serve as
a drug delivery film, non-water soluble drugs can be added to an
alginate solution prepared with up to 10% propylene glycol, or
other biocompatible solvents, substituted for water. Alternatively,
water and the particular glycol may be mixed prior to the addition
of the alginate. Furthermore, the drug may be added to the
water/glycol mixture prior to the addition of the alginate.
[0023] Sodium alginates gel by cross-linking between a pH range of
3 to 5. Calcium chloride has been selected for its low pH and in
vivo biocompatible characteristics to cross4ink the algin gel
creating a strong film. Alginates, when cross-linked with calcium
chloride form a biodegradable/bioabsorbable film that is lubricious
and thus provides a lubricating coating. This lubricious coating
can assist in the insertion of the medical device into the human
body.
[0024] Sodium alginate used in the embodiments of this invention
may also include Monsanto Keltone HVCR. A formulation was prepared
from the HVCR grade that represents the mannuronic acid and
guluronic acid content that will produce suitable solutions of
algin and is similar in characterizations to Monsanto part number
K8P569 and ProNova part number UP MVG which is the most preferred
alginate polymer of the invention. This solution has an acceptable
viscosity, film forming rheology and film mechanical properties,
and produces an in vivo biocompatible solution and film.
[0025] The alginate solution can be used to coat an implantable
medical device, at its point of use, whereby the high viscosity
alginate solution, to which a drug has been added, is rendered into
a film by dipping the coated device into calcium chloride. To
restrict the film to the exterior and perforations of a device, the
internal diameter of the device can be blocked off, for example
with a balloon, during the coating process. Over an extended period
of time, through its biodegradable characteristics, the film can
deliver a controlled amount of a drug that was added to the
alginate solution at the point of use, in known concentration over
such extended period of time. The drug may be delivered either
uniformly or nonuniformly depending on the uniformity of the
coating thickness.
[0026] For the following examples, non-sterile Monsanto alginate
part number HVCR was used whose properties are comparable to the
purified form Monsanto part number K8P569 alginate and ProNova part
number UP MVG.
[0027] In order to produce a biocompatible conformal film solution,
application of Good Manufacturing Procedures (GMP) and use of
sterile, low endotoxin sodium alginate and sterile, low endotoxin
10% calcium chloride solutions, are recommended to ensure raw
material and finished product quality.
[0028] In the preferred embodiment of this invention, sodium
alginate is mixed with sterile, low-pyrogen water, which is also
known as "water for injection," to form a solution. Sodium alginate
concentration amounts of about 1% to about 8% by weight and of
various molecular weights, in the range of 12,000 to 190,000 with a
preferred molecular weight of 120,000 to 190,000 can be used to
form a pourable solution tailored to Theological properties desired
for the application.
[0029] Proper blending techniques are necessary to dissolve the
lyophilized sodium alginate in water. A high-shear mixer, which
creates vortex, is recommended. The mixing blade is placed off
center in the mixing container. The mixing blade is positioned near
the bottom of the solution to avoid introducing excessive air. The
lyophilized alginate is slowly sifted into the vortex. The
application of heat aids in dissolving the alginate powder. While
blending, slowly elevate the heat to 135 degrees Fahrenheit and mix
for approximately 30 minutes.
[0030] The following examples illustrate preferred compositions and
formulations that can be used to prepare solutions of alginate,
suitable for use in medical implant procedures.
[0031] Using the manufacturing procedures outlined above, two
solutions of alginate were prepared to determine its physical film
properties. The following examples were prepared:
EXAMPLE 1
[0032]
1 PART A PART B 8% Grade HVCR sodium alginate 10% Calcium Chloride
Solution 92% sterile low-pyrogen water
EXAMPLE 2
[0033]
2 PART A PART B 4% Grade HVCR sodium aiginate 10% Calcium Chloride
Solution 96% sterile low-pyrogen water
[0034] The most preferred formula for the embodiment of this
inventive device of an in vivo biodegradable conformal film system
is the formula used in Example 2 that utilizes 4% sodium alginate
(Part A).
[0035] Once the alginate polymer solution (in either liquid or gel
form) has been prepared by the addition of the polymer to the
initial liquid (e.g. water or water and propylene glycol), a drug
can be added at the point of use through mixing into the solution.
Alteratively, a drug may be added to the liquid to which the
polymer is then added to form the solution. A device is then dipped
into the solution, coating the device with the drug impregnated
solution. Alteratively, the solution may be painted or sprayed onto
the device. As previously stated, to restrict the film to the
exterior and perforations of a device, the internal diameter of the
device can be blocked off, for example with a balloon, during the
coating process. The device is then place into sterile,
pyrogen-free 10% calcium chloride (Part B) for up to ten minutes,
cross-linking the gel and forming a strong, elastic film.
[0036] In the above experiments, the elasticity of the film created
exceeded 200%. This elasticity makes the film ideal for implantable
devices that are expanded once placed at the desired location
(i.e., vascular stent).
[0037] The invention can be achieved using polymer systems other
than alginates such as polymer systems which are in vivo
biocompatible and biodegradable and cured with light, such as
ultraviolet, or simply dried to form a film. For example,
biodegradable PEG polymer (polyethylene glycol) or its derivatives
and copolymers that are cured by exposure to ultraviolet light at
the point of use may be utilized. Polymers of this nature are
commercially available, for example, from Shearwater Polymers of
Huntsville, Ala., and are supplied as dry powders that are water
soluble and can be mixed with sterile water, or other biocompatible
solvents, at the point of use. Bonding of a PEG polymer drug
bearing film to a device can be enhanced by the presence of an
amino group on the surface which anchors the conformal film.
[0038] The invention can also be achieved using
previously-mentioned hydrogels such as thermal irreversible
hydrogels that are in vivo biocompatible and biodegradable One
example is a PEO/PEG polymer (e.g. Pluronic manufactured by BASF)
combined with an alginate, such as sodium alginate, mixed with
water to form a solution and cross-linked by interaction with
calcium ions (e.g. immersion in 10% by weight calcium chloride).
Hydrogel containing films may exhibit less elasticity than the
cross-linked sodium alginate films discussed above. However, such
hydrogel films are well suited as coatings for devices that are
static or unexpanding, such as suture rings Although the preferred
cross-linking agent is calcium chloride, other soluble-substances
may be utilized. For example, calcium compounds, such as
CaSO.sub.4, magnesium compounds such as MgCl or MgSO.sub.4, or
barium compounds are also contemplated by the present invention for
use in cross-linking.
[0039] While the invention has been described with reference to
preferred embodiments it is to be understood that the invention is
not limited to the particulars thereof The present invention is
intended to include modifications which would be apparent to those
skilled in the art to which the subject matter pertains without
deviating from the spirit and scope of the appended claims.
* * * * *