Patent Application
20210386979
The inventions described below relate to the field of treatment of vascular disease, and more specifically to the field of drug eluting balloons for the treatment of restenosis.
Our prior U.S. Pat. No. 8,696,644, entitled Balloon Catheter Systems For Delivery Of Dry Drug Delivery Vesicles To A Vessel In The Body, described a drug eluting balloon catheter system well-suited for the delivery of a suspension of nanoparticles, in particular rapamycin loaded micelles, to blood vessels of a patient to treat various vascular diseases.
The devices and methods described below provide for improved administration of a suspension of nanoparticles through the wall of a drug eluting balloon. The system includes a catheter with a drug eluting balloon with a perforated wall with numerous pores, and a reservoir of nanoparticles in an aqueous solution disposed within the balloon or in fluid communication with the balloon. The particles may comprise drug loaded micelles, where the micelles are provided in the size range of 40 to 250 nm generally (0.040 μm to 0.250 μm), and the pores of the balloon wall are configured to allow passage of the micelles with a minimum of disruption. The pores are conical, with the diameter of the pore at the inside of the balloon wall smaller than the diameter of the pores at the outside of the balloon wall. The devices and method may be used in conjunction with balloon angioplasty to treat a lesion in a blood vessel to prevent restenosis after angioplasty, in conjunction with stent placement to open a blood vessel obstructed by a lesion to prevent restenosis after stent placement, or it may be used to treat a lesion in a blood vessel without concurrent use of angioplasty or concurrent placement of a stent.
The micelles may be loaded with rapamycin or other therapeutic agents such as rapamycin analogs, ABT-578, zotarolimus, everolimus, biolimus A9, deforolimus (also referred to as ridaforolimus), temsirolimus, tacrolimus, pimcrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitors, tubulusin, A3 agonists, CB2 agonists, 17-AAG, Hsp90 antagonists, tyrphostins, cathepsin S inhibitors, paclitaxel, corticosteroids, glucocorticoids, dexamethasone, ceramides, dimethyl sphingosine, ether-linked diglycerides, ether-linked phosphatidic acids, sphinganines, estrogens, taxol, taxol analogs, actinomycin D, prostaglandins, vitamin A, probucol, Batimastat, Statins, Trapidil, mitomycin C and Cytochalasin B.
The nanoparticles used in this system and method described above should have a diameter in the range of 40 to 250 nm generally, and in the range of 60 to 120 nm when comprising micelles formulated from the tri-block copolymer mentioned above (PLGA-PEG-PLGA), as determined by dynamic light scattering techniques. This size will result in a balance of efficient penetration of the micelles into the artery walls and sufficient space within the micelles to encapsulate a suitable amount of rapamycin or other therapeutic substance. Use of tri-block polymers such as PLGA-PEG-PLGA will provide micelles in the desired size range. The ratio of micelle diameter to the first diameter is preferably in the range of 0.08 to 1 (approximately 1 to 12) to 0.005 to 1 (1 to 200), more preferably about 1 to 20. The systems and methods described above can be employed to deliver other small drug delivery vesicles or delivery vessels in addition to micelles, such as nanoparticles and liposomes.
Pressure applied by the inflator to the reservoir may be two to twenty atmospheres (203 kPa to 2027 kPa), and the inflator is preferably operated to apply 6 to 16 atmospheres (608 kPa to 1621 kPa) of pressure, more preferably 6 to 12 (608 kPa to 1216 kPa) atmospheres of pressure. With suspended micelle formulation in the suspension chamber, and holes sized and dimensioned as above, application of 12 atmospheres (1216 kPa) for 60 seconds will deliver the entire 1 ml of the suspended micelle formulation through the catheter and balloon wall. The pressure may be varied over the course of administration, for example, by applying pressure in the range of 6-8 atmospheres (608 kPa to 811 kPa) for about 20 seconds, and increasing pressure to 12 to 18 (1216 kPa to 1823 kPa) atmospheres for another 20 to 40 seconds (for an average of 12-14 atmospheres (1216 kPa to 1418 kPa) over the course of administration). The parameters may be adjusted to deliver 0.2 to 0.75 ml of suspension over the course of 10 to 120 seconds, preferably about 20 to 60 seconds, for flow rates of 0.0033 to 0.0375 ml/sec (preferred in the coronary arteries) or 0.0005 to 0.038 ml/sec (preferred in the peripheral arteries, out of the balloon for uptake by the surrounding blood vessel wall. The flow rate per pore is preferably in the range of range of 0.0001 to 0.00003 mL/sec/hole for coronary and 0.0001 to 0.00001 for peripheral arteries. These low flow rates help keep the balloon inflated so that it continues to exert opening force on the surrounding artery and maintains good contact with artery walls. Preferably, the total volume delivered is 0.2 ml to 0.75 ml. The dosage of drug or therapeutic agent actually delivered can thus be controlled and predetermined with some certainty by controlling the amount of drug or therapeutic agent in the micelle formulation disposed in the micelle storage chamber. For example, if it is desired to deliver 2 mg of rapamycin to a diseased portion of a blood vessel, the micelle reservoir containing 2 or 3 mg of rapamycin can be stored in the micelle storage chamber, reconstituting the micelles with fluid to achieve a concentration of 2 mg/ml (that is, 1 ml if the micelle storage chamber contains 2 mg total rapamycin), withdrawing 1 ml of fluid into the coiled tube suspension chamber, and forcing the entire 1 ml through the catheter and balloon into the blood vessel walls.
The ratio of the average particle size to the total pore area (on the at the inside surface of the balloon wall) may be controlled, to achieve a balance of internal balloon pressure needed to force compliance of the blood vessel to the balloon for angioplasty, flow rate of the suspension from the balloon to encourage uptake of the suspended micelles into surrounding vascular walls and avoid loss of the suspension in the blood stream. The total pore area may range from about 900 to about 30,000 microns (942 μm2 (for example, 100 holes at 3 micron average diameter) to 25,120 μm2 (1000 holes at 8 micron average diameter)). A very small ratio of average micelle particle diameter to inner wall total pore area in the range of 0.0000016 to 1 on the low side and 0.0008 to 1 on the large side will allow the suspension to be administered at high pressure, sufficient for angioplasty, while providing flow through the pores sufficient to treat the area with the loaded therapeutic agent. For example, with an average pore diameter of 5 microns (about 20.7 square microns) and a configuration of 200 total holes, the total pore area is 4142 μm2 (4.142 million square nanometers), a particle size of 0.250 μm (250 nm), the ratio of particle size to total pore area on the inside wall would be 0.00006 to 1.
In use, the method of treating a diseased blood vessel includes inserting the balloon of the balloon catheter system into the blood vessel and forcing the suspension of nanoparticles into the balloon and through the pores to a blood vessel wall, using the inflator to apply pressure to the reservoir at high pressure, to force the suspension of nanoparticles into the balloon, and through the walls of the balloon. With pores configured as shown in
To ensure that the entire length of a lesion is treated with the application of the therapeutic agent, the balloon used for the method is preferably longer than the lesion to be treated, such that the porous region of the balloon 16 (the region perforated with the numerous pores 7) is longer than the lesion. To ensure that the balloon is sufficiently long to cover the lesion and extend beyond the region, a surgeon performing the method may first determine the length of the lesion, and choose and insert a balloon with a porous region of sufficient length to extends along the entirety of the lesion and also extends both distally and proximally of the lesion, and operate the system to force the suspension of nanoparticles into the into the balloon and through the pores to the blood vessel wall along the entirety of the lesion and portions of the blood vessel wall extending both distally and proximally of the lesion. Alternately, several balloons shorter than the lesion, or several applications of a single balloon shorter that the lesion, may be used in the method.
While the preferred embodiments of the devices and methods have been described in reference to the environment in which they were developed, they are merely illustrative of the principles of the inventions. The elements of the various embodiments may be incorporated into each of the other species to obtain the benefits of those elements in combination with such other species, and the various beneficial features may be employed in embodiments alone or in combination with each other. Other embodiments and configurations may be devised without departing from the spirit of the inventions and the scope of the appended claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2019/053267 | 9/26/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62741421 | Oct 2018 | US |
