Patent Application
20100268191
This invention relates to catheters for delivering drugs, pharmacological agents and the like in microcapsule form to a targeted region in a patient and for rupturing the microcapsules to locally release the agent.
The prior art and medical practitioners have long recognized the desirability to deliver drugs or other bioactive or pharmacologically active agents directly to a specific location in the body instead of by systemic delivery. Localized delivery is particularly desirable in vascular applications, for example, to deliver drugs adapted to prevent restenosis as may occur after a percutaneous catheter intervention (PCI) procedure such as angioplasty or stent placement. For example, one such technique is described in U.S. Pat. No. 5,102,402 (Dror) in which a coating of body-affecting chemicals in the form of microcapsules is applied to the exterior of a balloon of a balloon catheter. The coating releases from the balloon when the balloon is inflated into contact with and against a vascular lumen to be treated. Other approaches are described in U.S. Pat. No. 5,580,575 (Unger) and U.S. Pat. No. 7,358,226 (Dayton) that describe drug-carrying microcapsules that can be ruptured by ultrasound to release the drug. Drug-laden microcapsules also have been described as being delivered by direct injection, as in U.S. patent application publication number 2008/0069801 (Lee).
It would be desirable for the clinician to receive a simplified arrangement for delivering drug-carrying microcapsules or microcapsules to a targeted region and for releasing the drug at that region. The invention provides an alternate system for delivering biologically active materials in microcapsule form to a specific target location within a patient, such as a particular location within the vascular system. The invention may be practiced, for example, in connection with medications intended to prevent clotting or to deliver agents adapted to prevent restenosis following an angioplasty procedure. The invention is not limited, however, to post-angioplasty applications but may be adapted for use in other vascular or non-vascular applications in appropriate circumstances.
The system includes a delivery catheter having a shaft and a balloon on the distal end of the shaft with an inflation lumen extending through the shaft to communicate with the balloon to permit inflation and deflation. The balloon is porous, having a porous structure including numerous pores with a predetermined maximum effective pore size. A second, internal, non-porous balloon may be disposed, optionally, within the first, outer, porous balloon. The catheter is used together with frangible microcapsules containing the drug, pharmacological or biological agent, the microcapsules being carried in a biocompatible carrier fluid, i.e. in a suspension. The microcapsules are sized to have effective outer dimensions greater than the effective pore size of the balloon so that the microcapsules cannot, by free flow of the suspension, readily pass intact through the pores of the balloon. The materials from which the microcapsules and the balloon are formed are selected so that the microcapsules will deform or rupture sufficiently to release their contents under increased fluid pressure applied to the suspension or by mechanical compression between the outer balloon and the optional inner balloon. The released agent will then be entrained in the fluid that is expelled through the balloon pores. Individual microcapsules may obstruct the pores of the balloon such that, upon their rupture as the microcapsules are forced against the balloon pores, the agent will be ejected directly through the pores and outwardly of the balloon.
In a further embodiment the catheter balloon may be pre-loaded with microcapsules that protect and preserve the drug as well as to enhance the shelf life of the pre-loaded delivery catheter until the intended time of use. The microcapsules may be made from materials selected to be immune to the manufacturing processes, for example, to protect drugs or substances sensitive to sterilization.
The system is used by advancing the catheter to locate the balloon at the intended delivery site. With the balloon in position, inflation fluid (e.g., saline) or a suspension carrying the microcapsules is directed under pressure through the inflation lumen to inflate the balloon against the inner luminal wall of the vessel. The fluid pressure then is increased sufficiently to cause the microcapsules to rupture or deform sufficiently to release their contents, which will be entrained in fluid that is expelled outwardly of the balloon and against the luminal surface of the vessel. The microcapsules are formed from biodegradable materials so that remnants of the microcapsule shells that may be ejected through the pores may dissolve or otherwise break down in the body.
In the dual balloon embodiment of the invention, the outer balloon may be inflated with a microcapsule-carrying suspension to inflate the balloon against the inner luminal surface of the vessel, after which the inner balloon can be inflated to more uniformly redistribute the microcapsules between the balloons to cause more uniform release of the drug from the microcapsules and through the pores of the outer balloon. The inner balloon may be sized to contact an inner surface of the outer balloon to compress and rupture the microcapsules therebetween.
In the accompanying drawings:
Specific embodiments of the present invention are now described with reference to the figures, wherein like reference numbers indicate identical or functionally similar elements. The terms “distal” and “proximal” are used in the following description with respect to a position or direction relative to the treating clinician. “Distal” or “distally” are a position distant from or in a direction away from the clinician. “Proximal” and “proximally” are a position near or in a direction toward the clinician. As used in this specification, the term “drug,” is intended to include any and all biologically active materials usable for diagnosis or therapeutic treatment of the mammalian body. The terms “effective pore size” and “effective microcapsule size” are intended to refer to the relative dimensions of the pores or micropores in the balloon and the drug-carrying microcapsules. The term “fluid” is intended to include gases and liquids although it is preferable to use liquids when the invention is used in the circulatory system. The term “suspension” is intended to mean a mixture of microcapsules dispersed in a fluid.
The catheter shaft 10, fitting 13 and tails 20, 22 may be formed from any of a variety of materials for such components as are well known to those skilled in the art. Balloon 12 should be formed to have a relatively noncompliant construction and may be made, for example, from polyethylene terephthalate (PET), to exhibit little or no stretching when inflated under the pressures sufficient to deform the microcapsules sufficiently to release the drug. The balloon is inflatable, under a relatively low “nominal” pressure, to a nominal diameter at which the balloon will be in apposition with the inner luminal surface of the vessel to which the nominal size of the balloon is adapted. The degree of noncompliance should be selected to assure that the effective pore size of the balloon remains smaller than the effective microcapsule size throughout the range of balloon pressures necessary to release the drug. It should be understood, however, that other balloon materials may be employed provided they have the requisite degree of noncompliance, flexibility and strength sufficient to perform in the manner described herein.
The porous balloon 12 may be fabricated in accordance with U.S. Pat. No. 5,087,244 (Wolinsky), the disclosed processes and materials of which are hereby incorporated by reference in its entirety. Balloon 12 may have a single wall thickness ranging from 0.0002 inches to 0.002 inches. A balloon formed from PET may be fabricated to include a multiplicity of pores 24 that are substantially regularly spaced about a generally cylindrical wall portion 18 of the balloon. The pores 24 may be formed by a variety of techniques including material ablation by an electron beam or by a laser beam from an excimer laser having wavelengths of 248 or 308 nm. As taught in the Wolinsky '244 patent, the aggregate flow area defined by the pores 24 is selected so that under the general range of inflation pressures expected, the liquid flow through the holes will be very low, weeping in nature. The pores 24 should be dimensioned with respect to the microcapsules 26 so that the microcapsules cannot pass freely through the pores, as suggested diagrammatically in
Microcapsules for use in this invention may be made by any of a variety of well-known encapsulating processes using a variety of materials. Among these are those described in U.S. Pat. Nos. 3,516,846; 3,516,941; 3,996,156; 4,087,376; 4,409,156; 5,180,637 and 5,591,146, the disclosed processes and materials of which are hereby incorporated by reference in their entireties. By way of example only, microcapsule walls may be made from natural hydrophilic polymeric materials such as gelatin, gum Arabic, starch, carrageenan and zein; natural polymeric materials may be modified and include ethyl cellulose, carboxymethyl cellulose, shellac resin and nitrous cellulose as well as other polymers including polyvinyl alcohol, polyethylene, polystyrene, polyacrylamide, polyether, polyester, polybutadiene, silicone, epoxy and polyurethane. The materials contained in the microcapsules can be in a variety of forms including solutions, dispersions and gels. These and other materials and processes are described in the references incorporated above. The materials and fabricating processes may be varied and should be selected to produce the combination of microcapsules and balloon pores to cause the microcapsules to be mechanically ruptured sufficiently to cause release of the carried drug out of the balloon and against the vessel wall. As used in this specification the term “rupture” is intended to mean a condition at which the microcapsule has been deformed sufficiently to cause release of the drug from the microcapsule. The fluid pressure in the balloon at which the release may be affected from a particular combination of balloon and microcapsules may be referred to as “rupture pressure.”
Microcapsules 26 may be received by the clinician in various ways for use in the invention. For example, the microcapsules 26 may be received dry and pre-loaded within porous balloon 12. Alternatively, a vial containing either dry or suspended microcapsules may be received within package 28 or separately therefrom. Dry microcapsules may be mixed with suitable fluid either within balloon 12 or outside the catheter 5 to prepare a suspension for use as described herein. In accordance with the invention, microcapsules 26 may be stored, handled, mixed with fluids and/or injected into catheter 5 before finally being caused to rupture within balloon 12 and thereby release the contained drug or agent for ejection through pores 24.
Alternatively, the second balloon 32 has an outer diameter sized for being inflated into contact with an inner surface of the generally cylindrical wall portion 18 of the first balloon 12. First and second balloons 12, 32 are configured by size and material properties to be capable of rupturing microcapsules 26 by mechanically compressing the microcapsules between the first and second balloons in response to the inflation pressure within inner balloon 32, as illustrated in
It should be understood that the foregoing description of the invention is intended to be merely illustrative only and that other embodiments, modifications and equivalents within the scope of the invention may be apparent to those skilled in the art.
