A system for delivering solute to a target location within a mammalian body, the system including a medical device, a thermosensitive cellulose gel structure over the medical device, and a biologically active solute within said gel structure. The gel structure deswells and expels the biologically active solute with an increase in gel temperature. The invention includes a method of delivering solute to a target location, where the method includes the steps of providing a thermosensitive cellulose gel structure, wherein the gel structure is loaded with a solute; positioning the loaded gel structure to the target location; and increasing the temperature of the loaded gel structure.

Description of the Invention

SUMMARY OF THE INVENTION

In one aspect, the present invention includes a system for delivering solute to a target location within a mammalian body, the system comprising a medical device, a thermosensitive cellulose gel structure over the medical device, and a solute within the gel structure. In one embodiment, the gel deswells and expels the solute with an increase in gel temperature.

In another aspect, the present invention includes a method of delivering solute to a target location, the method comprising the steps of providing a thermosensitive cellulose gel structure, wherein the gel structure is loaded with a solute, positioning the loaded gel structure to the target location, and increasing the temperature of the loaded gel structure from an initial temperature to a temperature higher than the initial temperature. In one embodiment, the step of increasing the temperature of the loaded gel structure results in the deswelling of the gel, thus releasing the solute. In a further embodiment, the target location is located within a mammalian body, the substrate is a medical device, the solute is a biologically active solute, and the step of increasing the temperature of the loaded gel structure is accomplished by exposing the loaded gel structure to body temperature or an external fluid.

DETAILED DESCRIPTION

The present invention includes a temperature controlled solute delivery system comprising at least one thermosensitive cellulose gel structure. The present invention is described with specific reference to cellulose ether gels, which are the preferred cellulose gels of the present invention. The inventors have found that it is possible to use such gels in solute delivery systems wherein a solute is impregnated into a gel while in its low temperature, expanded state, and is then released from the gel when the gel is placed into its high temperature, deswelled state. Although typical thermosensitive gels are generally known to shrink when they are heated, the inventors have found that they do not exhibit similar solute release properties. For example, solute-loaded PNIPA gels substantially trap solute within the gel when they shrink, whereas the inventors have surprisingly found that solute-loaded thermosensitive cellulose gels release solute when they shrink. This is due to the fact that previously reported thermosensitive gels become impermeable to solute as they shrink, whereas the gels of the present invention remain permeable even when they shrink. Therefore, in contrast to previously reported thermosensitive gels, the gels of the present invention release solute upon shrinking in a sustained, convective release pulse such that substantially all of the loaded solute is released in a relatively short period of time. Moreover, the release of solute from shrinking gels is generally significantly faster than for non-shrinking gels.

As used herein, "cellulose ether gel" includes any crosslinked thermosensitive hydrogel formed by the partial or complete etherification of the hydroxyl groups in a cellulose molecule. Such gels include, for example, hydroxypropyl cellulose ("HPC") gels, hydroxypropylmethyl cellulose ("HPMC") gels, ethylhydroxyethyl cellulose ("EHEC") gels, carboxymethyl cellulose ("CMC") gels, hydroxyethyl cellulose ("HEC") gels., methyl cellulose ("MC") gels, ethyl cellulose ("EC") gels, propyl cellulose ("PC") gels, butyl cellulose ("BC") gels, and the like and blends thereof. These gels are physically or chemically crosslinked. Preferred crosslinkers for these gels include, for example, divinylsulfone ("DVS") and polyethylene glycol vinylene sulfone ("PEG-VS.sub.2").

The temperature control solute delivery systems of the present invention are of particular benefit to medical device applications such as, for example, balloon angioplasty units. While the present invention may be described with specific reference to use with a balloon catheter, the present invention is suitable for use with any medical device where the localized delivery of biologically active solute is desired.

Currently, the two principle forms of intervention for coronary artery disease are coronary artery bypass surgery and balloon angioplasty. Balloon angioplasty uses fluid pressure to expand a flexible balloon which is catheter-delivered to the site of an atherosclerotic lesion. The force generated by the expanding balloon expands the blocked lumen and compresses the blockage. Although balloon angioplasty provides increased blood flow in an obstructed lumen, the procedure often damages the surrounding arterial wall tissue. The biological response to this damage is a healing process, called restenosis, that often results in a renarrowing of the artery.

A preferred method for addressing restenosis is the localized delivery of biologically active solutes to the damaged tissue. This localized approach is attractive because doses that are higher than those achievable by systemic delivery are obtained. As a result, potential problems associated with biologically active solutes, such as toxicity, are minimized. Furthermore, biologically active solutes that are expensive or difficult to obtain, such as genetic modifiers, are used in an efficient manner. By way of the solute delivery system of the present invention, biologically active solutes are used as solutes in thermosensitive hydrogels to obtain such localized drug delivery.

The biologically active solutes used in the present invention include, for example, pharmaceutically active compounds, proteins, oligonucleotides, genes, DNA compacting agents, gene/vector systems, nucleic acids, and viral, liposomes and cationic polymers that are selected from a number of types depending on the desired application. For example, biologically active solutes include anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, and mesalamine; antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; anti-coagulants such as D-Phe-Pro-Arg chloromethyl keton, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin anticodies, anti-platelet receptor antibodies, aspirin, protaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides; vascular cell growth promotors such as growth factor inhibitors, growth factor receptor antagonistss, transcriptional activators, and translational promoters; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, antisense DNA, antisense RNA, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; and agents which interfere with endogeneus vascoactive mechanisms. These and other compounds are added to the gel using similar methods and routinely tested as set forth in the specification. Any modifications are routinely made by one skilled in the art.

Polynucleotide sequences useful in practice of the invention include DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of therapeutic polynucleotides include anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The polynucleotides of the invention can also code for therapeutic polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic polypeptides include as a primary example, those polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body. In addition, the polypeptides or proteins that can be incorporated in the gels, or whose DNA can be incorporated, include without limitation, angiogenic factors including acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor .alpha. and .beta., platelet-derived enotheial growth factor, platelet derived growth factor, tumor necrosis factor .alpha., hepatocyte growth factor and insulin like growth factor; growth factors; cell cycle inhibitors including CD inhibitors; thymidine kinase ("TK") and other agents useful for interfering with cell proliferation, including agents for treating malignancies.

Referring now to FIGS. 1a-1c (see Original Patent), an embodiment for the localized delivery of biologically active solute to a predetermined location within the body is described. The solute administration method shown in FIGS. 1a-1c illustrates the use of the present invention in conjunction with an angioplasty process. A catheter device 100 comprises a body 103 having a balloon 104 attached at its distal end. The balloon is formed of any suitable material such as vinyl polymers such as polyethylene; polyesters such as polyethylene terephthalate; polyamides such as nylon; polyolefins and copolymers thereof (e.g., Selar, Pebax, Surlyn, Hytrel, etc.). The balloon is optionally a perfusion balloon, which allows blood to perfuse the catheter to prevent ischemia during delivery. The balloon 104 on the body 103 includes a coating 106 of thermosensitive cellulose ether gel. As shown in FIG. 1a, a solution 108 comprising a biologically active solute is impregnated into the gel coating 106 with the balloon in its substantially deflated state prior to insertion into the patient. During the impregnation of the biologically active solute, the gel is held at a temperature lower than the gel transition temperature such that it is in an expanded state. Alternatively, the biologically active solute may be directly incorporated into the gel coating 106 using organic solvents or during synthesis of the gel.

After the biologically active solute is absorbed or incorporated into the gel, the device 100 is inserted into a body lumen 102 and positioned at a target location, such as an occlusion due to a deposition of plaque 105 on the lumen wall tissue 109. The device 100 is moved along the vessel to position the balloon 104 at the occlusion site, as shown in FIG. 1c. The lumen may be, for example, a narrow, tortuous opening through which the catheter is passed by torquing or other known techniques. As shown in FIG. 1c, the balloon 104 is inflated to provide close contact between the drug-impregnated gel coating 106 and the surrounding plaque and tissue.

Once positioned to the target location, the temperature of the gel coating 106 is increased above its transition temperature by any suitable technique such as, for example, exposure to a warm external fluid such as saline solution or by heating the saline internally with a thermal balloon, as is known in the art. Alternatively, in the case of short arterial delivery times, the gel transition temperature is below body temperature such that no external heating means is necessary. The increase in temperature above the transition temperature results in the deswelling of the gel coating 106, which in turn results in the accelerated release of the biologically active solute from the coating 106.

Referring to the embodiment of the invention illustrated in FIG. 2 (see Original Patent), the balloon portion 104 of catheter body 103 is optionally covered by a protective sheath 107 while the instrument 100 is inserted into a body lumen 102 and positioned at a target location. As the coated balloon 104 is positioned at occluded site 105, the protective sheath 107 is drawn back to expose the balloon 104. Alternatively, the sheath remains stationary while the catheter moves the coated balloon forward into the occluded region. The sheath 107 protects the coating and inhibits premature release of the biologically active solute. Such a sheath is particularly advantageous when the transition temperature of the gel coating 106 is less than body temperature, or when the biologically active solute(s) to be delivered is (are) highly toxic. In such cases, an advantage of a shrinking gel over a non-shrinking gel is the accelerated solute release rate, thus minimizing the required time for localized drug delivery.

Although FIGS. 1 and 2 (see Original Patent) illustrate the application of the present invention to an angioplasty process, the present invention is also used to administer biologically active solutes to target locations where there is no occlusive formation. Moreover, the present invention is not limited to use on balloon angioplasty devices, but is applicable to a variety of medical devices such as, for example, catheters, stents, blood filters, implants, artificial heart valves, oral dosage forms, suppositories and the like. Such medical devices may comprise metallic, polymer, or ceramic materials.

In one embodiment, the gel of the present invention is applied to a medical device that comprises a stent. As known in the art, stents are tubular support structures that are implanted inside tubular organs, blood vessels or other tubular body conduits. In the present invention, the stent is partially or completely coated with the solute-loaded hydrogel. The stent used with the present invention is of any suitable design, and is either self-expanding or balloon-expandable. The stent is made of any suitable metallic (e.g., stainless steel, nitinol, tantalum, etc.) or polymeric (e.g., polyethylene terephthalate, polyacetal, polylactic acid, polyethylene oxide--polybutylene terephthalate copolymer, etc.) material. The stent material, gel, and biologically active solute are selected to be compatible with each other. The gel is applied to the stent by any suitable method such as, for example, spraying the gel onto the stent or immersing the stent in the gel.
 

Claim 1 of 12 Claims

1. A method of delivering solute to a target location, the method comprising the steps of: providing at least one cellulose; providing a substrate, wherein said substrate comprises a polymer material; providing functional groups on said polymer material; adding a crosslinking material to said cellulose, wherein said crosslinking material reacts with said cellulose and said functional groups and thereby forms a cellulose ether gel and attaches said cellulose ether gel to the substrate to form a cellulose ether gel structure; loading said cellulose gel structure with a solute; positioning said loaded gel structure to said target location; and increasing the temperature of said loaded gel structure from an initial temperature to a temperature at or above the transition temperature of said gel.

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