Disclosed are novel compositions for embolizing blood vessels which are particularly suited for treating vascular lesions via catheter delivery.

Description of the Invention

SUMMARY OF THE INVENTION

This invention is directed to the novel and unexpected discovery that the use of embolic compositions comprising a viscosity of at least about 150 cSt at 40.degree. C. provides for the in vivo formation of a solid, non-migratory mass which mass is substantially contiguous in shape.

Without being limited to any theory, it is now believed that embolic compositions having such a high viscosity permit more rapid and consistent solidification in vivo thereby rendering the solid mass formed non-migratory and substantially contiguous in shape. It is further believed that the rapid and consistent solidification in vivo arises at least in part from the high viscosity of these compositions which renders migration from the ejection port of the catheter at the vascular site more difficult.

Accordingly, in one of its composition aspects, this invention is directed to a composition comprising a biocompatible polymer, a biocompatible contrast agent, and a biocompatible solvent which solubilizes said biocompatible polymer

wherein sufficient amounts of said polymer are employed in said composition such that, upon delivery to a vascular site, a polymer precipitate forms which embolizes said vascular site; and

further wherein the viscosity of said composition is at least about 150 cSt at 40.degree. C.

In another of its composition aspects, this invention is directed to a composition comprising:

(a) a biocompatible polymer at a concentration of from about 2 to 50 weight percent;

(b) a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent; and

(c) a biocompatible solvent from about 10 to 88 weight percent

wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition; and

further wherein the composition has a viscosity of at least about 150 and more preferably at least about 200 cSt at 40.degree. C.

Preferably in this particular composition, the concentration of the polymer ranges from 6 to 50 weight percent and more preferably 8 to 30 weight percent.

In another of its composition aspects, this invention is directed to a composition comprising:

(a) a biocompatible polymer at a concentration of from about 12 to 50 weight percent;

(b) a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent; and

(c) a biocompatible solvent from about 10 to 78 weight percent

wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition and

further wherein the composition has a viscosity of at least about 150, preferably at least about 200 and more preferably at least 500 cSt at 40.degree. C.

Preferably the viscosity ranges from about 200 to 40,000 cSt at 40.degree. C., more preferably from about 500 to 40,000 cSt at 40.degree. C. In another embodiment, the viscosity ranges from about 500 to 5000 cSt at 40.degree. C.

In one of its method aspects, this invention is directed to a method for enhancing the formation of a solid, non-migratory coherent mass at a selected vascular site of a mammal which method comprises:

(a) placing a delivery device having an ejection port at a selected vascular site in a mammal;

(b) delivering through the ejection port of the delivery device a composition comprising a biocompatible polymer, a biocompatible solvent and optionally a contrast agent wherein the viscosity of the composition is at least about 150 cSt at 40.degree. C.

Preferably the composition delivered in (b) above comprises a biocompatible polymer, a biocompatible contrast agent and a biocompatible solvent which solubilizes the biocompatible polymer wherein the weight percents of the biocompatible polymer, contrast agent and biocompatible solvent are based on the total weight of the complete composition; further wherein sufficient amounts of said polymer are employed in said composition such that, upon delivery to a vascular site, a polymer precipitate forms which embolizes said vascular site; and still further wherein the viscosity of said composition is at least about 150 cSt at 40.degree. C.

More preferably, the composition delivered in (b) above comprises a a biocompatible polymer at a concentration of from about 2 to 50 weight percent, a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent, and a biocompatible solvent from about 10 to 88 weight percent wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition and further wherein the composition has a viscosity of at least about 150 and more preferably at least about 200 cSt at 40.degree. C.

Optionally, prior to the delivering aspect of (b) above, blood flow through the vascular site can be attenuated by insertion of a blood flow attenuating device immediately upstream the ejection port. Such a blood flow attenuating device is preferably an inflatable microballoon which permits both normal and attenuated blood flow depending upon whether the microballoon is deflated or inflated.

The contrast agent is either a water soluble contrast agent or a water insoluble contrast agent. Preferably, the water insoluble contrast agent is a biocompatible material selected from the group consisting of barium sulfate, tantalum powder and tantalum oxide.

In still a further preferred embodiment, the biocompatible solvent is dimethylsulfoxide (DMSO), ethanol, ethyl lactate or acetone.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to novel compositions for embolizing blood vessels which are particularly suited for treating vascular lesions via catheter delivery of the composition.

However, prior to discussing this invention in further detail, the following terms will first be defined:

The term "embolizing" refers to a process wherein a material is injected into a blood vessel which, in the case of, for example, aneurysms, fills or plugs the aneurysm sac and/or encourages clot formation so that blood flow into the aneurysm ceases, in the case of high flow AVM's forms a plug or clot to control/reroute blood flow to permit proper tissue perfusion, and, in the case of a vascular site, fills the vascular site to prevent blood flow there through. Embolization of the blood vessel is, therefore, important in preventing/controlling bleeding due to lesions (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding as well as bleeding associated with an aneurysm). In addition, embolization can be used to ablate diseased tissue (e.g., tumors, etc.) by cutting off its blood supply.

The term "biocompatible polymer" refers to polymers which, in the amounts employed, are non-toxic and substantially non-immunogenic when used internally in the patient and which are substantially insoluble in the body fluid of the mammal. The biocompatible polymer can be either biodegradable or, preferably, non-biodegradable.

Biodegradable polymers are disclosed in the art. For example, Dunn, et al..sup.10 discloses the following examples of biodegradable polymers: linear-chain polymers such as polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers and combinations thereof. Other biodegradable polymers include, for example, gelatin, collagen, etc.

Suitable non-biodegradable biocompatible polymers include, by way of example, cellulose acetates.sup.2,6-7 (including cellulose diacetate.sup.5), ethylene vinyl alcohol copolymers.sup.4,8, hydrogels (e.g., acrylics), polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, and mixtures thereof.sup.9.

Preferably, the biocompatible polymer employed does not cause an adverse inflammatory reaction when employed in vivo. The particular biocompatible polymer employed is selected relative to the viscosity of the resulting polymer solution, the solubility of the biocompatible polymer in the biocompatible solvent, and the like. For example, the selected biocompatible polymer should be soluble in the amounts employed in the selected biocompatible solvent and the resulting composition should have a viscosity suitable for in vivo delivery by the methods of this invention.

Preferred biocompatible polymers include cellulose diacetate and ethylene vinyl alcohol copolymer. Cellulose diacetate polymers are either commercially available or can be prepared by art recognized procedures. In a preferred embodiment, the number average molecular weight, as determined by gel permeation chromatography, of the cellulose diacetate composition is from about 25,000 to about 100,000 more preferably from about 50,000 to about 75,000 and still more preferably from about 58,000 to 64,000. The weight average molecular weight of the cellulose diacetate composition, as determined by gel permeation chromatography, is preferably from about 50,000 to 200,000 and more preferably from about 100,000 to about 180,000. As is apparent to one skilled in the art, with all other factors being equal, cellulose diacetate polymers having a lower molecular weight will impart a lower viscosity to the composition as compared to higher molecular weight polymers. Accordingly, adjustment of the viscosity of the composition can be readily achieved by merely adjusting the molecular weight of the polymer composition.

Ethylene vinyl alcohol copolymers comprise residues of both ethylene and vinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent) of additional monomers can be included in the polymer structure or grafted thereon provided such additional monomers do not alter the properties of the composition. Such additional monomers include, by way of example only, maleic anhydride, styrene, propylene, acrylic acid, vinyl acetate and the like.

Ethylene vinyl alcohol copolymers are either commercially available or can be prepared by art recognized procedures. As is apparent to one skilled in the art, with all other facts being equal, copolymers having a lower molecular weight will impart a lower viscosity to the composition as compared to higher molecular weight copolymers. Accordingly, adjustment of the viscosity of the composition as necessary for catheter delivery can be readily achieved by merely adjusting the molecular weight of the copolymer composition.

As is also apparent, the ratio of ethylene to vinyl alcohol in the copolymer affects the overall hydrophobicity/hydrophilicity of the composition which, in turn, affects the relative water solubility/insolubility of the composition as well as the rate of precipitation of the copolymer in an aqueous environment (e.g., blood or tissue). In a particularly preferred embodiment, the copolymers employed herein comprise a mole percent of ethylene of from about 25 to about 60 and a mole percent of vinyl alcohol of from about 40 to about 75. These compositions provide for requisite precipitation rates suitable for use in the methods described therein.

The term "contrast agent" refers to a biocompatible radiopaque material capable of being monitored during injection into a mammalian subject by, for example, radiography. The contrast agent can be either water soluble or water insoluble.

Examples of water soluble contrast agents include metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine. Examples of water insoluble contrast agents include tantalum, tantalum oxide, and barium sulfate, each of which is commercially available in the proper form for in vivo use including a preferred particle size of about 10 .mu.m or less. Other water insoluble contrast agents include gold, tungsten, and platinum powders.

Preferably, the contrast agent is water insoluble (i.e., has a water solubility of less than 0.01 mg/ml at 20.degree. C.).

The term "biocompatible solvent" refers to an organic material liquid at least at body temperature of the mammal in which the biocompatible polymer is soluble and, in the amounts used, is substantially non-toxic. Suitable biocompatible solvents include, by way of example, ethyl lactate, dimethylsulfoxide, analogues/homologues of dimethylsulfoxide, ethanol, acetone, and the like. Aqueous mixtures with the biocompatible solvent can also be employed provided that the amount of water employed is sufficiently small that the dissolved polymer precipitates upon contact with the blood. Preferably, the biocompatible solvent is dimethylsulfoxide.

The term "encapsulation" as used relative to the contrast agent being encapsulated in the polymer precipitate is not meant to infer any physical entrapment of the contrast agent within the precipitate much as a capsule encapsulates a medicament. Rather, this term is used to mean that an integral coherent precipitate forms which does not separate into individual components.

The term "migration distance" refers to the linear (confluent) distance the solid precipitate forms when 0.1 mL of a composition described herein is injected into an optically clear tube using the test method of Example 3 below. In this example, the migration distance is measured along the length of the precipitation formed as illustrated in FIGS. 1 and 2 (see Original Patent).

The term "proximate the ejection port" means that the solid coherent mass initially forms at or within about 5 mm of the ejection port. Preferably the solid coherent mass forms within about 3 mm and more preferably within about 1 mm of the ejection port.

Compositions

The polymer compositions employed in this invention are prepared by conventional methods whereby each of the components is added and the resulting composition mixed together until the overall composition is substantially homogeneous.

For example, these compositions can be prepared by adding sufficient amounts of the biocompatible polymer to the biocompatible solvent to achieve the effective concentration for the polymer composition. Preferably, the polymer composition will comprise from about 2 to about 50 weight percent of the biocompatible polymer composition based on the total weight of the polymer composition and more preferably from about 12 to about 50 weight percent. If necessary, gentle heating and stirring can be used to effect dissolution of the biocompatible polymer into the biocompatible solvent, e.g., 12 hours at 50.degree. C. for EVOH being dissolved in DMSO.

The viscosity of the composition is controlled either by the amount of polymer employed and/or its molecular weight. For example, high viscosity compositions which employ low concentrations of polymer can be achieved by use of very high molecular weight biocompatible polymers (e.g., average molecular weight greater than 250,000). Such factors are well known in the art. In any event, the compositions described herein have a viscosity of at least about 150 cSt at 40.degree. C. and preferably at least about 200 cSt at 40.degree. C.

Sufficient amounts of the contrast agent can be added to the biocompatible solvent to achieve the effective concentration for the complete composition. Preferably, the composition will comprise from about 10 to about 40 weight percent of the contrast agent and more preferably from about 20 to about 40 weight percent and even more preferably about 30 weight percent. Insofar as water insoluble contrast agents are not soluble in the biocompatible solvent, stirring is employed to effect homogeneity of the resulting suspension for compositions employing such contrast agents.

In order to enhance formation of the suspension, the particle size of water insoluble contrast agents is preferably maintained at about 10 .mu.m or less and more preferably at from about 1 to about 5 .mu.m (e.g., an average size of about 2 .mu.m). In one preferred embodiment, the appropriate particle size of the contrast agent is prepared, for example, by fractionation. In such an embodiment, a water insoluble contrast agent such as tantalum having an average particle size of less than about 20 microns is added to an organic liquid such as ethanol (absolute) preferably in a clean environment. Agitation of the resulting suspension followed by settling for approximately 40 seconds permits the larger particles to settle faster. Removal of the upper portion of the organic liquid followed by separation of the liquid from the particles results in a reduction of the particle size which is confirmed under an optical microscope. The process is optionally repeated until a desired average particle size is reached.

The particular order of addition of components to the biocompatible solvent is not critical and stirring of the resulting solution or suspension is conducted as necessary to achieve homogeneity of the composition. Preferably, mixing/stirring of the composition is conducted under an anhydrous atmosphere at ambient pressure. The resulting composition is heat sterilized and then stored preferably in sealed bottles or vials until needed.

Each of the polymers recited herein is commercially available but can also be prepared by methods known in the art. For example, polymers are typically prepared by conventional techniques such as radical, thermal, UV, .gamma. irradiation, or electron beam induced polymerization employing, as necessary, a polymerization catalyst or initiator to provide for the polymer composition. The specific manner of polymerization is not critical and the polymerization techniques employed do not form a part of this invention.

In order to maintain solubility in the biocompatible solvent, the polymers described herein are preferably not cross-linked.

Methods

The compositions described above can then be employed in methods for the catheter assisted embolization of mammalian blood vessels. In such methods, a sufficient amount of this composition is introduced into the selected blood vessel via a catheter delivery means under fluoroscopy so that upon precipitation of the polymer, the blood vessel is embolized. The particular amount of embolic composition employed is dictated by the total volume of the vasculature to be embolized, the concentration of polymer in the composition, the rate of precipitation (solids formation) of the polymer, etc. Such factors are well within the skill of the art.

One particularly preferred method for catheter delivery of the embolic compositions of this invention to the selected vascular site is via a small diameter medical catheter connected to a threaded syringe. One example of a novel threaded syringe has a threaded plunger which is operable as a conventional syringe for aspiration of the embolic composition and then is used in a threaded manner for delivery of the embolic composition. The threaded syringe may also include a tactile or audible indication of delivery which allows clinician to monitor delivery of the embolic composition without looking at the syringe. The catheter for delivery of the embolic compositions preferably has a burst strength of 100 psi or greater, and more preferably 200 psi or greater, and still more preferably 1000 psi or greater. In order to prevent catheter burst, the threaded syringe may be provided with a force release mechanism which prevents the clinician from applying pressures above the catheter burst strength. As an alternative delivery means to the threaded syringe, a syringe pump may be used.

Preferably, in order to enhance the in vivo delivery of a uniform suspension of this composition, the composition is mixed at a temperature of above 40.degree. C. which ensures formation of a uniform suspension and then this heated composition is transferred while maintaining its temperature above room temperature and preferably above 40.degree. C. into the catheter for in vivo delivery.

Specifically, a uniform suspension is achieved by mixing the compositions at a temperature above about 40.degree. C., preferably from above about 40.degree. C. to about 90.degree. C., and more preferably from about 50.degree. C. to about 70.degree. C. The particular temperature employed should be sufficiently high to ensure adequate mixing of the composition.

In a particularly preferred embodiment, the composition is heated for a period of time from at least about 3 to about 20 minutes and preferably from about 5-10 minutes to facilitate formation of a uniform suspension. In some cases, the formation of a uniform suspension requires that the heated composition be placed in a suitable mixer, e.g., vortex mixer, and is mixed until the suspension is homogeneous. In this case, after formation of the homogenous suspension via the mixer, the composition is preferably reheated to a temperature of from above about 40.degree. C. to about 90.degree. C. and preferably from about 50.degree. C. to about 70.degree. C. The specific temperature employed for heating is selected relative to the biocompatible solvent and biocompatible polymer employed. Such selections are well within the skill of the art.

In either case, the heated composition is then transferred preferably via a syringe and delivered into the catheter under conditions wherein the temperature of the composition is above room temperature and preferably above about 40.degree. C. In one preferred embodiment, the conditions which effect such transfer are rapid transfer (e.g., transfer occurs within 2 minutes of heating cessation) of the composition to the catheter.

Surprisingly, the heated composition maintains both a uniform suspension and ease of delivery during catheter injection into a vascular site in a mammal and, when ejected at the distal end of the catheter, there is no evidence of trauma to this site. See, for example, U.S. patent application Ser. No. 09/574,963, now U.S. Pat. No. 6,454,738, filed concurrently herewith and entitled "Methods for Delivering In Vivo Uniform Dispersed Embolic Compositions of High Viscosity" which application is incorporated herein by reference in its entirety.

The particular catheter employed is not critical provided that polymeric catheter components are compatible with the embolic composition (i.e., the catheter components will not readily degrade in the embolic composition). In this regard, it is preferred to use polyethylene in the catheter components because of its inertness in the presence of the embolic composition described herein. Other materials compatible with the embolic compositions can be readily determined by the skilled artisan and include, for example, other polyolefins, fluoropolymers (e.g., Teflon.TM.), silicone, etc.

When delivered by catheter, preferred delivery techniques include those set forth in U.S. Pat. No. 6,645,167, entitled "Methods for Embolizing Vascular Sites With an Embolizing Composition" which is incorporated herein by reference in its entirety.

In another embodiment, the catheter employs an interface device which connects to the syringe to create a blunt interface between a DMSO composition not containing either a biocompatible polymer or a contrast agent and the embolic composition described herein. Such devices are disclosed in U.S. Pat. No. 6,511,472 entitled "Interface Needle and Method for Creating a Blunt Interface Between Delivered Liquids" which is incorporated herein by reference in its entirety.

Utility

The compositions described herein are useful in embolizing mammalian blood vessels which, in turn, can be used to prevent/control bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm), to ablate diseased tissue (e.g., tumors, etc.), and to treat aneurysms and/or AVMs. Accordingly, these compositions find use in human and other mammalian subjects requiring embolization of blood vessels.

It is contemplated that these compositions can be employed as a carrier for a compatible pharmaceutically active compound wherein this compound is delivered in vivo for subsequent release. Such compounds include, by way of example only, antibiotics, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, and the like.
 

Claim 1 of 17 Claims

1. A composition capable of embolizing an aneurysm at a vascular site comprising: (a) a biocompatible polymer; (b) a biocompatible contrast agent wherein a sufficient amount of said contrast agent is employed in said composition to effect visualization in vivo; and (c) a biocompatible solvent which solubilizes said biocompatible polymer wherein a sufficient amount of said polymer are employed in said composition such that, upon delivery to a vascular site, a polymer precipitate forms which embolizes said vascular site; and further wherein the biocompatible polymer has a molecular weight sufficient to impart to the composition a viscosity of at least about 150 cSt at 40.degree. C.

____________________________________________
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.