Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-01-27
2001-10-30
Nguyen, Anhtuan T. (Department: 3734)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S028000, C604S265000, C128S898000
Reexamination Certificate
active
06309380
ABSTRACT:
FIELD OF THE INVENTION
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
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-care industry over the last few years to combat restenosis because repeat angioplasty or surgery is expensive, inconvenient, and potentially life threatening.
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.
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.
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.
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. No. 4,994,033 to Shockey et al.; U.S. Pat. No. 5,674,192 to Sahatjian et al. and U.S. Pat. No. 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. No. 5,766,710 to Tumiund et al.; U.S. Pat. No. 5,769,883 to Buscemi et al.; U.S. Pat. No. 5,605,696 to Eury et al.; U.S. Pat. No. 5,500,013 to Buscemi et al.; U.S. Pat. No. 5,551,954 to Buscemi et al. and U.S. Pat. No. 5,443,458 to Eury.
When drugs or biological modifiers are applied in conjunction with the manufacture of the device, there are several problems, for example:
1. sterilization: heat or ionizing radiation alters the composition of many drugs and biological modifiers;
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);
3. the drug dosage is not variable for specific patient needs; and,
4. a large inventory of devices is required to provide a range of drugs and therapies.
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.
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
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.
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
The present invention will now be discussed in detail with reference to the preferred embodiments. Unless otherwise stated, all percentages represent weight percent.
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).
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.
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 specializ
Larson Eugene A.
Larson Marian L.
McDowell Robert L.
Nguyen Anhtuan T.
Thompson Michael M
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