Patent Application
20110160647
The present disclosure relates to active drug eluting balloon apparatus useful for medical treatments. More specifically, the active medicament eluting balloon includes an ultrasonic means to facilitate the active release of the medicament from the balloon and into the treated vessel wall.
The first procedure to treat blocked coronary arteries was coronary artery bypass graft surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used to bypass the diseased segment of coronary artery. In 1977, Andreas Grüntzig introduced percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty, in which a catheter was introduced through a peripheral artery and a balloon expanded to dilate the narrowed segment of artery.
As equipment and techniques improved, the use of PTCA rapidly increased, and by the mid-1980s, PTCA and CABG were being performed at equivalent rates. Balloon angioplasty was generally effective and safe, but restenosis was frequent, occurring in ˜30-40% of cases, usually, within the first year after dilation. In ˜3% of balloon angioplasty cases, failure of the dilation and acute or threatened closure of the coronary artery (often because of dissection) prompted emergency CABG.
Dotter and Melvin Judkins had suggested using prosthetic devices inside arteries (in the leg) to maintain blood flow after dilation as early as 1964. In 1986, Fuel and Sigwart implanted the first coronary stent in a human patient. Several trials in the 1990s showed the superiority of stent placement over balloon angioplasty. Restenosis was reduced because the stent acted as a scaffold to hold open the dilated segment of artery; acute closure of the coronary artery (and the requirement for emergency CABG) was reduced, because the stent precluded acute closure allowing repaired dissections of the arterial wall to heal. By 1999, stents were used in 84% of percutaneous coronary interventions (i.e., those done via a catheter, and not by open-chest surgery.)
Early difficulties with coronary stents included a risk of early thrombosis (clotting) resulting in occlusion of the stent. Coating stainless steel stents with other substances such as platinum or gold were evaluated but, ultimately, did not eliminate this problem. High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug-therapy using aspirin and another inhibitor of platelet aggregation (usually ticlopidine or clopidogrel) nearly eliminated this risk of early stent thrombosis.
Though it occurred less frequently than with balloon angioplasty or other techniques, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth. To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall. While initial efforts were unsuccessful, it was shown in 2001 that the release (elution) of drugs with certain specific physicochemical properties from the stent can achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects [8]. As currently used in clinical practice, “drug-eluting” stents refers to metal stents which elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent restenosis.
Many prior deployable medical devices have used bioactive medicaments with polymeric and other coatings/binding agents on the surfaces of deployable devices so that the bioactive medicaments (e.g. Paclitaxel, Sirolimus (Rapamycin), Tacrolimus, Everolimus and Zotarolimus) will be passively released over time after the medical device has been deployed. Polymeric coatings can hold bioactive medicaments onto the surface of deployable medical devices during deployment of the medical device within a treatment segment of an artery and passively released over time. This occurs because the polymeric coating degrades over time allowing the bioactive medicament to diffuse into the bloodstream or tissue. However uses of passive polymeric coatings are not without problems.
Drug eluting stents that have bioactive medicaments with or without a polymeric coating have been known to have long term chronic complications. This might be due to the long term release of the medicament and/or due to the fact that the stent is an irritant implant within the tissue. It has been hypothesized that the medicaments precludes endothelialization of the stent which triggers thrombus formation. Recent reports have indicated that there may be an increased risk of late stent thrombosis with the use of drug-eluting stents, as compared with bare-metal stents.
Non-implanted percutaneous transluminal coronary angioplasty (PTCA) balloons catheters can be coated with Paclitaxel, Sirolimus (Rapamycin), Tacrolimus, Everolimus and Zotarolimus but due to the passive release need to have long inflation times. They can also have contra-indicated ischemic plots, proximal lesions/left main coronary artery and the loss of drug eluting material off the device during delivery can exhibit a high degree of washout (release of medicament into non-targeted areas, primarily non-diseased sections of artery) which can be greater than 80%. Weeping catheters/balloons can also have long inflation times with a high degree of washout which can be greater than 95%.
The polymer system used to encapsulate the medicament is of paramount importance. It must ensure that the medicament is not lost in the bloodstream (washout) during transport of the catheter through the human arterial system to the target lesion site in the coronary arteries. In devices without an active dispersing mechanism the coating must not be overly robust as to preclude drug delivery at the intended target site. This requires a fine balance where the coating is sufficiently robust to avoid drug washout during transit but is not overly robust so that the drug can be delivered at the intended targeted site. This need to balance the properties of the polymer coating remains problematic and, to date, results from drug eluting balloons have been disappointing in clinical testing.
Ultrasound energy is a configurable modality that can create a variety of different bioeffects in tissue. Low frequency, below 1 MHz, pulsed ultrasound tends to produce mechanical impacts such as cell lyses, fractionation, cavitation, and microstream formation. High frequency continuous power delivery tended to produce thermal heating in tissue. Medical applications of therapeutic ultrasound include lithotripsy of renal stones, treatment of prostatic hyperplasia, prostate cancer and testicular tumors, ablation of uterine tumors and heart disease. In cardiology, the use of High Intensity Focused Ultrasound (HIFU) in a catheter based system was recently investigated in a FDA approved clinical trial for the treatment of atrial fibrillation.
As disclosed in (Circulation. 1997; 95:1360-1362 Paul G. Yock, MD; Peter J. Fitzgerald, MD, PhD, the potential for using therapeutic ultrasound to treat atherosclerosis and thrombosis has been appreciated for decades, but actual development efforts were slow to get under way. Catheter-based delivery systems for therapeutic ultrasound were first conceived and patented in the 1960s. Dedicated in vivo experimental work began in the early 1970s with the demonstration by Sobbe and colleagues that ultrasound delivered through a wire probe could be used to disrupt blood clots in animals. As with many other technologies in cardiology, however, it was the explosive growth of angioplasty in the 1980s that brought attention, funding, and real momentum to the development of therapeutic catheter ultrasound.
In the late 1980s, two groups, headed by Siegel and Rosenschein, began serious development efforts to address these issues. The resulting catheter designs have converged on some basic features. The current catheters from both groups are built around a solid-metal wave guide made of titanium or aluminum alloy. In the distal segment, which must be relatively flexible, the wire is either tapered or replaced by several thinner wire components. At the tip of the probe, there is a ball of larger diameter (1.2 to 1.7 mm), designed to increase energy delivery to the target. Proximal to this ball tip, the wire guide is ensheathed in plastic catheter. The catheters accept a standard guide wire in some version of a “rail” design and can be delivered through conventional guiding catheters. The proximal end of the ultrasound catheter is attached to an ultrasound transducer with a frequency of ≈20 kHz (compared with 20 to 30 MHz for intravascular ultrasound imaging transducers). The power at the transducer is 16 to 20 W, but because of loss of energy in the wave guide, the power actually delivered to the lesion is reduced by 50% or more.
These ultrasound catheters were designed to penetrate occlusions in arteries by vibrating a ball tip at the far distal end of the device against occlusive tissue. The action of the ball tip predisposing the device to puncture and cross the lesion. The effects of the ultrasound energy on normal arterial wall are now known to be to be relatively innocent under conditions simulating clinical use. Initial in vitro and animal studies raised concern about thermal effects, recording temperatures as high as 50° C. at the probe tip during continuous administration of ultrasound energy. This led to a number of strategies for temperature reduction, including saline flushing, use of pulsed instead of continuous ultrasound, and limited periods of sonication in a given treatment cycle (typically 30 or 60 seconds). With these modifications, the degree of heating has been reduced to <5° C., and histology studies have shown minimal evidence for thermal damage. One unanticipated and fascinating beneficial effect of catheter ultrasound is its ability to induce local vasodilation in the region of the probe tip. The in vitro studies of Fischell et al demonstrated ultrasound dose-dependent, endothelium-independent smooth muscle cell relaxation. These investigators suggested that ultrasound may promote a reversible disruption of the actin filament interaction in the contractile apparatus, leading to muscle cell relaxation. Initial studies of catheter-based ultrasound were performed in peripheral vessels in the late 1980s. In the first 45 patients reported by Siegel et al, 86% of completely occluded segments were recanalized using ultrasound. The ability of the ultrasound probe to induce local vasodilation (and to overcome spasm) was clearly demonstrated. There was no angiographic or clinical evidence of distal embolization. Restenosis, judged by ankle-brachial index, was 20%.
The first clinical application of therapeutic ultrasound in coronary arteries was reported by Siegel et al. in 1994. 44 procedures were clinically successful, with all but 1 using balloon angioplasty after the ultrasound treatment. In 7 of 44 cases, the ultrasound probe was not successful in crossing the lesion; however, in 9 other cases of complete occlusion, the probe was successful where conventional techniques had failed. The average residual stenosis after ultrasound treatment alone was 71%; after balloon dilation, this was further reduced to 34%. Although only 14 of the patients had completed a 6-month follow-up at the time of the report, the rate of revascularization was high enough (3 among these 14) to lead the authors to suggest that there may be “no major effect on restenosis” compared with standard catheter techniques. In the 7 patients with acute myocardial infarction, ultrasound treatment appeared to be successful in reducing thrombus burden.
Rosenschein et al. extend this experience with coronary ultrasound thrombolysis in their report on the first 15 patients in the feasibility phase of the ACUTE trial (Analysis of Coronary Ultrasound Thrombolysis Endpoints). Patients were treated in two stages: first with the ultrasound catheter and then with balloon angioplasty if required. The authors report that after they stabilized their technique in the first case, the remaining 14 applications of ultrasound were successful. Taken together, these findings suggest that the ultrasound catheter was effective in substantially reducing thrombus burden and, to an intermediate degree, relieving stenoses.
Other catheters with different mechanisms for disrupting clots are being developed. The most extensively tested technique at this point is the “hydrolysis” approach, in which water jets break up thrombus and, in one design, create suction through a Venturi effect to help remove the particulate. The ultrasound catheters do have two potential advantages of uncertain importance: (1) they tend to prevent and even overcome spasm, and (2) ultrasound can be effective in ablating plaque as well as thrombus.
Initial experience suggests that there are at least some cases in which ultrasound may be more effective than conventional techniques for crossing complete occlusions. Ultrasound does have the ability to ablate fibrocalcific tissue, which is the major source of difficulty for the interventionist in dealing with old occlusions. Another fascinating potential application for ultrasound stems from its ability to enhance the compliance of a lesion. The in vitro studies of Demer et al. indicate that ultrasound treatment produces a large increase in lesion distensibility, presumably by disrupting fibrous elements and calcium within the plaque. It follows that there may be a role for ultrasound in heavily fibrocalcific lesions, particularly in the context of stenting. Pretreatment of these segments with ultrasound might allow for full expansion of stents at relatively low pressures, potentially reducing trauma to the vessel wall.
Despite improvements to device design there remains the lack of a satisfactory solution to treat recurrent restenosis, particularly in-stent restenosis, where it is desirable to re-open the artery without having to place a second stent (or more). Multiple stents placed at the same targeted lesion fare worse so there is a need to eliminate neointimal tissue formation without using a stent platform.
Hence, there is a need for a drug eluting medical device which has an expandable member coated with a bioactive medicament that is actively released, which overcomes the shortcomings of prior art devices.
The present disclosure relates to active drug eluting angioplasty balloon which utilizes ultrasonic energy to facilitate the release of the bioactive drug thereby avoids many of the drawbacks of prior art drug eluting devices.
The present invention is an angioplasty balloon catheter which is coated with a bioactive medicament, such as Paclitaxel, Sirolimus (Rapamycin), Tacrolimus, Everolimus and Zotarolimus or other cell proliferation drug in which the balloon capable of delivering sufficient, in vivo, ultrasonic energy for actively releasing the bioactive medicament within a stenosis of coronary arteries or other blood vessels in the human body. The present invention angioplasty balloon catheter may be excited to deliver ultrasonic energy in either the deflated or inflated state, or any state of partial inflation with a contrast fluid. Further, the present invention angioplasty balloon can also include one or more polymeric or other coatings below, over, or within the bioactive medicament.
The catheter has one lumen through which a guide wire may be passed for guiding the catheter to the site of stenosis. The catheter has another lumen for providing the pneumatic means or liquid contrast media to inflate and deflate the distal located angioplasty balloon. The catheter may have another lumen for the wires to electrically connect the proximal ultrasonic means to the distal ultrasonic means, although the wires can be included within the guide wire lumen, the inflation/deflation lumen, or integrated within the polymeric materials of the catheter.
The polymer coating is designed to remain intact during transport of the balloon catheter through the bloodstream until ultrasonic energy, estimated to range from 20,000 Hz to 10 MHz and with a preferable range from 200,000 to 1 MHz and less than 10 watts to cause it to break up and release the medicament(s).
According to the method of the invention, the catheter is guided to the site of arterial stenosis by means of a guiding catheter and a flexible guide wire. When the catheter has crossed the stenosis, the balloon may be inflated and the ultrasonic energy is initiated. The inflation of the balloon causes the vibrating surface of the balloon and the medicament/bioactive coating to remain in mechanical contact of the artery tissues and actively release the medicaments within the tissues. The ultrasound energy, and its driving parameters, optimally configured to drive medication into tissue while avoiding unwanted tissue heating and damage. Repeated inflations and deflations of the balloon allow for flushing of the ablated material by perfusion of blood.
Ultrasound energy has several unique properties that provide advantages in delivering energy to perform a function in the heart. First, ultrasound does not interact with blood. It passes through blood until it contacts tissue where it is absorbed. This property enables the energy to be used without heating blood that can lead to thrombus formation, a very important consideration in any procedure in the coronary arteries. This property is best exemplified in ultrasound imaging, where the blood is dark (lack of absorption) due to a lack of interaction and tissue is bright (ultrasound energy is absorbed). Second, ultrasound has a long established history of safe use in the human body. It is the preferred modality for imaging human fetus during pregnancy. Third, there is a growing body of scientific research suggest that ultrasound energy may be utilized to help drive medication into targeted areas of the body. In cancer research for example, local drug delivery is enhanced by the use of ultrasound energy that is intended to promote localized absorption of the drug into a specified targeted area.
a is a cross-sectional view of the one embodiment of the present invention in its intended environment as used in cooperation with an inflatable angioplasty balloon.
b is a cross-sectional view of another embodiment of the present invention in its intended environment as used in cooperation with an inflatable angioplasty balloon.
a is a cross-sectional view of the proximal section of the present invention catheter in combination with an active releasing medicament angioplasty balloon, as seen along line 6a-6a in
b is a cross-sectional view of the distal section of the present invention catheter in combination with an active delivery medicament angioplasty balloon, as seen along line 6b-6b in
a is a cross-section view of the active delivery medicament angioplasty balloon, as seen along line 7a-7a in
a is a cross-section view of the active delivery medicament angioplasty balloon with cutting edges, as seen along line 8a-8a in
a is a cross-section view of the active delivery medicament angioplasty balloon with cutting edges, as seen along line 9a-9a in
Generally, the catheter of the present invention comprises a multi-lumen tubular member having at least two lumens. The first lumen is used to accommodate a flexible guide wire and the second lumen forms a fluid path for a contrast fluid which serves to inflate or deflate the angioplasty balloon located at the distal end of the catheter (or a fixed guide wire design). A pair of wires may be in a third lumen, incorporated into one of the other lumens, or integrated within the catheter material whereby the wires provide electrical communication between the ultrasonic generator and the transducer.
The present invention is angioplasty balloon catheter which is coated with a bioactive medicament, such as Paclitaxel, Sirolimus (Rapamycin), Tacrolimus, Everolimus and Zotarolimus or other cell proliferation drug in which the balloon capable of delivering sufficient, in vivo, ultrasonic energy for actively releasing the bioactive medicament within a stenosis of coronary arteries or other blood vessels in the human body. The present invention angioplasty balloon catheter may be excited to deliver ultrasonic energy in either the deflated or inflated state, or any state of partial inflation with a contrast fluid. Further, the present invention angioplasty balloon can also include one or more polymeric or other coatings below, over, or within the bioactive medicament.
Referring initially to
As shown in
Referring now to
Referring now to
The guide wire 22 may be made of a suitable material such as stainless steel or other metallic materials. Any number of conventionally available guide wires may be chosen for insertion into the guide wire lumen. It is anticipated by the Applicants that a fixed wire design can be utilized with the present invention.
Turning now to
Also shown in FIG. 5., located at the distal end of the catheter 17 is the expandable balloon 10, 11 with the piezoelectric transducer 27 located within the proximal end of the balloon.
a is a cross-sectional view of the proximal section of the present invention catheter in combination with an active releasing medicament angioplasty balloon, as seen along line 6a-6a in
b is a cross-sectional view of the distal section of the present invention catheter in combination with an active delivery medicament angioplasty balloon, as seen along line 6b-6b in
a is a cross-section view of the active delivery medicament angioplasty balloon 10, as seen along line 7a-7a in
a is a cross-section view of the active delivery medicament angioplasty balloon 11 with cutting edges 15, as seen along line 8a-8a in
a is a cross-section view of the active delivery medicament angioplasty balloon 11 with cutting edges 15, as seen along line 9a-9a in
Provided below are some experiments used to support the present invention.
Balloon Material:
Experiment 1
PA—Polyamide, Nylon
PEBA—Pebax Nylon ether block copolymer
PET
PE
PU—Polyurethane
Hytrel
This experiment was performed just to get feel for the polymer as starting point and to learn.
Before leaving the lab, performed a quick visual inspection of the dipped balloons. The 4% solution dipped balloons had very low coverage. It looked as if the prepol was a net pattern with wet and un-wet spot forming the net pattern. The 10% solution formed a much better coverage and looked like about 80% coverage or better.
This was the first experience with the coated balloons. The adhesion properties were looked at as wall thickness of the coated balloons was measured with a blade micrometer and performed another visual.
In order to mimic drug delivery situation, balloons were coated first with 10% solution and then powdered salt was rolled on to the balloon.
The experiment was conducted to test the effectiveness of the coated balloons. The method used was to measure the electrical conductivity of the water in a beaker.
3. 150 ml beaker
4. 150 ml flask
5. Distilled water
7. Ultrasonic fogger—Alpine Corporation FG100
Following are the results:
2. Discussion: The results look promising. The release salt after the 2nd coating seems to show potential even with this coating material. Need to make more samples and test.
Dipped 8× samples in 10% solution and left 7 without the second coating in case we needed to change directions.
Made some observations on the 4 samples that were 2nd coated the day before.
General comments and thought for further work.
This application claims priority under 35 U.S.C. Section 119(e) to U.S. Provisional Application Ser. No. 61/291,348 filed on Dec. 30, 2009.
| Number | Date | Country | |
|---|---|---|---|
| 61291348 | Dec 2009 | US |
