Title:  Drug delivery via therapeutic hydrogels

United States Patent:  6,132,765

Assignee:  Uroteq Inc. (Ontario, CA)

Filed:  April 15, 1997

The present invention is directed to a vehicle for effecting drug delivery from a solid substrate. Hydrogels loaded with liposomal therapeutic agents such as antibiotics are covalently bonded to the surface of substrates such as in-dwelling medical devices, such as implants, catheters, and the like. The present invention is particularly useful in the treatment and prevention of biofilm mediated infection often associated with the use of in-dwelling medical devices.

SUMMARY OF THE INVENTION

The present invention avails the use of antibiotic-loaded liposomes sequestered within a biocompatible hydrogel retained on the surface of the biomedical device, e.g. catheter. Liposomes, microspheres, nanospheres, biodegradable polymers, and other systems are excellent drug delivery vehicles; and the methods of preparation and drug loading procedures for liposomes and the others are well-known in the art. Liposomes can store both apolar and polar compounds via interactions with the biocompatible and biodegradable lipid bilayer, or compartmentation within the aqueous core, respectively.

A method for producing a biofilm-resistant surface might involve the binding of antibiotic-containing liposomes directly to the surface. Theoretical calculations however, indicate that if a surface was saturated with drug-carrying liposomes, only about 150 ng of the antibiotic ciprofloxacin could be localized per square centimeter of surface. Nanogram quantities of ciprofloxacin are unlikely to provide protection from microbes over substantial periods of time, e.g. several days or more. We have devised a means to effectively exploit the space above the catheter's surface to significantly increase the surface area concentration of bound liposomal antibiotic. Specific formulation of the liposome bilayer allows for drug release over a period ranging from days to weeks. See, e.g., R. Nicholov, V. DiTizio, and F. DiCosmo, "Interaction of paclitaxel with phospholipid bilayers," J. Lipo. Res., 5, 503-522 (1995). M. S. Webb, T. O. Harasym, D. Masin, M. B. Bally, and L. D. Mayer, "Sphingomyelin-cholesterol liposomes significantly enhance the pharmokinetic and therapeutic properties of vincristine in murine and human tumour models," Br. J. Cancer, 72, 896-904 (1995). Furthermore, the biocompatibility of liposomes ensures that they will be safely degraded and assimilated by the host after their supply of drug is exhausted after six days or more.

The method of the present invention provides for co-valently attaching liposomes to a substrate such as a catheter, or other liquid-flow conduit, or other device, such as a wound dressing. The method exploits the surface area of the device as well as the volume occupied by the hydrogel matrix bonded to the surface. The volume of gel matrix can accommodate large quantities of drug-loaded liposomes, microspheres, nanospheres, or other drug carrier and consequently, relatively high doses of a therapeutic drug can be deposited at specific sites. The hydrogel matrix is biocompatible and biodegradable (i.e. does not release potentially toxic degradation products), and will ensure protection of the liposomes from membrane-disrupting shear forces that are encountered during handling and insertion of the device, and from rapid degradation of the liposome in vivo. The containment of the liposomes within the gel matrix also creates an opportunity to control drug diffusion rates, thereby affording long-term drug efflux.

Thus, the present invention includes a method for loading efficacious quantities of a liposomal therapeutic agent on a medical device by mixing said liposomal therapeutic agent with a hydrogel, and covalently binding said hydrogel to a preformed polymeric surface of a medical device. By pre-formed polymeric surface is meant that the polymeric material used in fabricating the medical device is formed or manufactured in advance of the covalent attachment of the hydrogel. As discussed more fully below, covalent attachment of the hydrogel to the polymeric material can be effected through the use of a bifunctional linker molecule, preferably one comprising an azide functional group. Preferably, the pre-formed polymeric surface is a silicone rubber.

One such embodiment is a silicone catheter loaded with a co-valently bonded polyethylene glycol-gelatin matrix containing a liposomal antibiotic-carrier coating to control catheter-related infections, such as bacteriuria and septicemia. Medical devices where the coating can be used include catheters, wound closures, surgical dressings, temporary orthopedic implants and others.

The liposomal hydrogel of the present invention includes a variety of hydrogel drug combinations. Generally, the selection or pairing of the hydrogel and drug is determined only by the desired application and relevant indication. That is, any active agent that can be compounded into liposomes, microspheres, nanospheres, or other suitable encapsulation vehicle can be confined within the hydrogel matrices of the present invention to create the therapeutic hydrogels of the present invention. Those hydrogels can then be affixed to a substrate such as the surface of a catheter or other in-dwelling liquid conduit, or the substrate or matrix of a wound closure or wound dressing material.

One embodiment of the present invention involves the deposition and co-valent attachment of a polyethylene glycol-gelatin matrix layer to the surface of in-dwelling biomedical implants (e.g. catheters, stents, intravenous tubes, dialysis tubes, orthopedic implants, surgical sponges and wound dressings, etc.) and the sequestration or covalent attachment of liposomes to the constituents of the matrix. The liposomes contain a therapeutic. The matrix thus constitutes a vehicle for the containment of high concentrations of therapeutic agent such as one or more antibiotics, hormones, steroids, growth factors, antihistamines, colony stimulating factors, interleukins, and the like, and/or combinations thereof. The therapeutic hydrogels of the present invention can be used in the management of tissue and biomaterial associated infection. The matrix can be a hydrogel (e.g., gelatin, pectin, etc.), a protein (e.g. collagen, hemoglobin, etc.), or other adjuvant. Preferably, the matrix will have some structural integrity as by cross-linking or similar structural support to impart resistance to shear forces resulting from insertion of the device.

Thus, the present invention provides a medical device having a polymeric substrate; a matrix material covalently bound to said substrate; and a liposomal therapeutic agent confined within said matrix material. The matrix material can be a hydrogel, a protein, or other suitable adjuvant. The matrix material will preferably be a cross-linked material. One example is gelatin cross-linked with polyethylene glycol as by reacting gelatin with bis-(amine)-PEG.

Matrix material can be covalently bound to a substrate by a variety of means. For example, a protein such as gelatin can be derivatized with a bifunctional linker molecule such as 4-azido-2,3,5,6-tetrafluorobenzoic acid. That is, the carbonyl carbon of the benzoic acid group can be made to react with a free amine of a protein to form an amide; the azido functionality can be made to react with a methylene carbon of the silicone rubber. In this manner, the matrix material is covalently bonded to the substrate.

The therapeutic hydrogels of the present invention serve as support material for a variety of liposomal therapeutics. Any therapeutic agent suitable for encapsulation in a liposome, microsphere, nanosphere or the like can be utilized in the present invention. For example, therapeutic agents useful in the present invention include antibiotics, antihistamines, hormones, steroids, therapeutic proteins, and the like.

It will be appreciated by those of ordinary skill in the art that the desired concentration of active agent within a hydrogel loaded on a substrate will vary depending upon the characteristics of the chosen active agent. For example, as between an antibiotic and a therapeutic protein, the required concentration of antibiotic, which are generally active in the microgram range, will likely be higher than the concentration of a therapeutic protein, many of which are active in the nanogram range. Other standard dosing criteria will also be considered in selecting the concentration ranges of active agent loaded onto the substrate in accordance with standard practice in the art.

A preferred embodiment of the present invention is a gelatin hydrogel cross-linked with polyethylene glycol (PEG); and dispersed within the hydrogel is a liposomal antibiotic such as ciprofloxacin. Ciprofloxacin has been shown to exhibit good activity against a broad spectrum of bacteria, particularly those associated with urinary tract infections.

Such embodiments provide dramatically improved in-dwelling medical devices. Medical devices of the present invention can be loaded with as much as 1000 .mu.g/cm² ciprofloxacin. Preferred embodiments have about 10-300 .mu.g/cm² ; and still more preferred embodiments have about 25-200 .mu.g/cm². Thus, the present invention avails long-term, slow release of an anti-infective active agent from an in-dwelling medical device; and dramatically reduces the frequency with which such in-dwelling medical devices must be removed and replaced.

The PEG-gelatin-liposome mixture can be effectively applied to the surface of a silicone Foley catheter that has been pre-treated with phenylazido-modified gelatin. Methods for immobilization of photoreactive gelatin on the catheter's surface are presented herein. Use of silicone devices is not a limiting feature, as any such polymeric device can be treated to harbor a hydrogel in which liposomes, or other drug carriers are sequestered.

More specifically, the present invention provides a method for associating substantial quantities of antibiotic-releasing liposomes with a silicone Foley catheter through their inclusion in a surface-coating of PEG-gelatin hydrogel covalently linked to the silicone surface, and the antibiotic was released to the surrounding area over a period of greater than five days. Modifications of the technique should allow it to be applied to other medical devices as well, such as, intraperitoneal catheters, joint and vascular prostheses, and reconstructive implants. An attractive feature of this system is the possibility of sustained release of compounds having a range of chemical properties, such as antibiotics, enzymes, growth factors, human hormones, anticoagulants, etc. Also, the surface characteristics of the PEG-gelatin hydrogel will improve biocompatibility of the device as hydrogel-coated catheters tend to minimize the inflammation associated with the presence of any foreign object in the body. J. N. Nacey and B. Delahunt, "Toxicity study of first and second generation hydrogel-coated latex urinary catheters," Br. J. Urol, 67:314-316 (1991). The inclusion of gelatin in our hydrogel system will lead to its eventual degradation in vivo leaving a co-valently-bonded surface layer of AFB-gelatin that should be relatively resistant to further protease digestion. T. Okada and Y. Ikada, "In vitro and in vivo digestion of collagen covalently immobilized onto the silicone surface," J. Biomed. Mater. Res., 26:1569-1581 (1992). It is possible that the remaining layers of gelatin will facilitate better integration of the catheter with the surrounding tissue.

The liposomal matrix materials of the present invention can be used to prevent or treat patients at risk of or suffering from biofilm mediated infection or other forms of infection associated with in-dwelling medical devices, wound closures, and the like. The method comprises inserting into a patient a medical device of the present invention, said medical device comprising a substrate, as for example, a silicone rubber substrate, and covalently bound to said substrate is a hydrogel within which is dispersed a liposomal therapeutic material such as an antibiotic. Likewise, the method comprises replacing infected medical devices with the medical devices of the present invention.

Claim 1 of 18 Claims

What is claimed is:

1. A medical device comprising:

a. a polymeric liquid conduit having an external surface;

b. a gelatin hydrogel matrix material; and

c. a therapeutic agent encapsulated in a liposome and confined within said matrix material,

wherein said matrix material is affixed to the external surface of said polymeric liquid conduit by a plurality of covalent bonds.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.