WO2010028047A1

WO2010028047A1 - Erodible embolization material

Info

Publication number: WO2010028047A1
Application number: PCT/US2009/055736
Authority: WO
Inventors: Dennis J. Delap; Cleve Koehler
Original assignee: Cook Incorporated
Priority date: 2008-09-02
Filing date: 2009-09-02
Publication date: 2010-03-11

Abstract

A chemo-embolization agent for treating diffuse diseases in a targeted tissue vessel of a patient and a process thereof is presented. This chemo-embolization agent comprises an inner core of a chemotherapy drug having a diameter less than a predetermined size for the opening in the targeted tissue vessel; and an outer sphere of an embolization material encompassing the inner core and having an initial diameter to occlude the initial opening in the targeted tissue vessel. During the treatment of the disease, the outer sphere of embolization material erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent into the opening in the targeted tissue vessel. The inner core of chemotherapy drug disperses into the targeted tissue vessel after becoming exposed by the erosion of the embolization material of the outer sphere.

Description

ERODIBLE EMBOLIZATION MATERIAL

BACKGROUND OF THE INVENTION

[0001] This application claims the priority benefit of U.S. Provisional Application

Serial No. 61/093,505, filed on September 2, 2008 entitled "ERODIBLE EMBOLIZATION MATERIAL," the entire contents of which are incorporated herein by reference.

FIELD

[0002] This invention relates to embolization, as well as to the treatment of diffuse diseases and localized tumor destruction.

BACKGROUND

[0003] Diffuse diseases (e.g., malignant metastatic melanoma, etc.) that can be present in various body systems, such as the lymph nodes, are difficult to treat using conventional drug therapy or chemotherapy techniques. Conventional techniques typically include the surgical resection or removal of the affected tissue. These techniques can be ineffective due to the disease being present in adjacent tissue or other organs. In this case, it is possible that the disease may reemerge after surgical procedures are deemed initially successful.

[0004] Chemo-embolization is a technique that has been successful in treating well-defined cancerous tumors. This technique involves the use of an embolization material to deliver a concentrated dosage of a chemotherapy drug to a tumor with subsequent surgical removal of the resulting malignant tumor. The advantage of this technique lies in the fact that it provides a synergistic effect of embolization and local chemotherapy. The chemoembolization materials used in this technique are considered "permanent" in that activity is extended for a substantial length of time, thereby, ensuring tissue morbidity. For example, Gelfoam™ (Pfizer, New York) is known to have a two-week effective embolization time. [0005] It would be advantageous to the medical industry to utilize an embolization technique to treat diffuse diseases in addition to well defined tumors. Thus there is a need in the industry to develop a material and devise a method for applying a chemo-embolization technique for use with tissues that have a minimal amount or even an unquantifiable amount of a disease.

SUMMARY

[0006] The present invention generally provides a chemo-embolization agent for treating diffuse diseases in a targeted tissue vessel of a patient or for localized tumor destruction. In one embodiment, the chemo-embolization agent comprises an inner core of a chemotherapy drug having a diameter less than a predetermined size for the opening in the targeted tissue vessel and an outer sphere of an embolization material encompassing the inner core. The outer sphere has an initial diameter that occludes the initial opening in the targeted tissue vessel. During the treatment of the disease, the outer sphere of embolization material erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent into the opening of the targeted tissue vessel. The inner core of chemotherapy drug disperses into the targeted tissue vessel after becoming exposed by the erosion of the embolization material of the outer sphere.

[0007] In one embodiment of the present invention, the targeted tissue vessels may have an unquantifiable amount of disease. These targeted tissue vessels may be fluid-transfer vessels, including but not limited to vascular or lymphatic vessels. Although these vessels may be located elsewhere, they preferably are located in either liver or kidney tissue.

[0008] In another embodiment of the present invention, the outer sphere of embolization material erodes at a predetermined rate that is predictable and controllable. This predetermined rate of erosion results in substantial erosion of the outer sphere in a timeframe of about 30 seconds to 24 hours. In addition, the outer sphere of embolization material erodes at a similar rate when in contact with the vessel walls or when in contact with a fluid located in the vessels. After erosion, any existing fragments of the embolization material are smaller than the size expected to cause a stroke or any other type of complication in the patient.

[0009] The outer sphere of embolization material may further comprise a therapeutic material, such as a chemotherapy agent, among others. This chemotherapy agent may be any agent known to one skilled in the art of cancer treatment. One example of such a chemotherapy agent is paclitaxel. The therapeutic material may be substantially similar in composition to the chemotherapy drug of the inner core.

[0010] The diameter of the outer sphere of embolization material is typically less than about 100 micrometers, while the diameter of the inner core of a chemotherapy drug is less than about 40 micrometers. The embolization material of the outer sphere and the chemotherapy drug of the inner core may be selected from any embolization material and chemotherapy drug known to one skilled in the art. [0011] It is another aspect of the present invention to provide a procedure for treating diffuse diseases in targeted tissue vessels of a patient. This procedure comprises the steps of introducing to the targeted tissue vessel, a chemo-embolization agent having an inner core of a chemotherapy drug and an outer sphere of an erodible embolization material, to deliver the chemo-embolization agent to the targeted tissue vessel so that the targeted tissue vessel is occluded in the initial portions thereof; eroding the outer sphere of embolization material at a predetermined rate to enhance penetration into the targeted tissue vessel and to expose the inner core; and dispersing the chemotherapy drug into the targeted tissue vessel when the inner core becomes substantially exposed.

[0012] The step of eroding the outer sphere of embolization material occurs at a similar rate whether the material is in contact with the vessel walls or with the fluids present in the vessels. During this step, the erosion of the outer sphere of embolizaton material may release a substantial concentration of a chemotherapy agent or therapeutic material near the targeted tissue vessels. [0013] In another embodiment, the present invention provides a chemo- embolization agent for treating diffuse diseases in targeted tissue vessels and for localized tumor destruction in a patient. The chemo-embolization agent comprises an inner core comprising at least one of a chemotherapy drug having a diameter less than a predetermined size for the opening in a targeted tissue vessel and a diameter less than a predetermined size for the opening in the targeted tissue vessel. The chemo- embolization agent further comprises an outer sphere of an embolization material encompassing the inner core and has an initial diameter to occlude the initial opening in the targeted tissue vessel. The outer sphere of embolization material erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent into the opening in the targeted tissue vessel. The inner core of chemotherapy drug disperses into the targeted tissue vessel after becoming exposed by the erosion of the embolization material of the outer sphere.

[0014] Further areas of applicability will become apparent from the description provided herein. It should be understood that the description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure in any way.

[0016] Figure 1 is a cross-sectional view of an erodible chemo-embolization agent according to one embodiment of the present invention.

[0017] Figure 2 is a cross-sectional view depicting the erosion of the outer sphere of the chemo-embolization agent shown in Figure 1 that allows for enhanced penetration of the agent into the targeted vessel.

[0018] Figure 3 is a schematic view of a method for treating a patient with a chemo-embolization agent in accordance with one example of the present invention. DETAILED DESCRIPTION

[0019] The following description is merely exemplary in nature and is in no way intended to limit the present disclosure or its application or uses. It should be understood that throughout the description and drawings, corresponding reference numerals indicate like or corresponding parts and features.

[0020] Embodiments of the present invention generally provide a chemo- embolization agent for treating diffuse diseases in a targeted tissue vessel of a patient. Referring to Figure 1 , the chemo-embolization agent (1 ) preferably comprises an inner core (10) of a chemotherapy drug that has a diameter less than a predetermined size for the initial opening in a targeted tissue vessel (15) and an outer sphere (5) of an embolization material that encompasses the inner core (10) and has an initial diameter that will occlude the initial opening (20) in the targeted tissue vessel (15). The outer sphere (5) may be comprised of a single layer or multiple layers that are different or similar in composition. In this embodiment, the outer sphere (5) of embolization material erodes at a predetermined rate, which enhances penetration of the chemo- embolization agent (1 ) into the opening of the targeted tissue vessel. Upon becoming exposed by the erosion of the embolization material of the outer sphere (5), the inner core (10) of chemotherapy drug preferably disperses rapidly into the targeted tissue vessel (15) within a matter of seconds to hours without obstructing subsequent blood flow.

[0021] Referring to Figure 2, during the treatment of the disease, the outer sphere (5) of embolization material preferably erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent (1 ) further into the opening in the targeted tissue vessel (15) as depicted in Figures 2A, 2B, and 2C. In this embodiment, the inner core (10) of chemotherapy drug disperses into the targeted tissue vessel (15) after becoming exposed by substantial erosion of the embolization material of the outer sphere (5) as depicted in Figure 2D.

[0022] The tissue vessels (15) targeted by the use of the chemo-embolization material (1 ) may have a minimal or unquantifiable amount of disease. These targeted tissue vessels (15) may be fluid-transfer vessels, including but not limited to vascular or lymphatic vessels. The chemo-embolization material (1 ) preferably is used to treat vessels (15) located in either the tissue of the liver or kidney, however, such treatment may be used with vessels (15) located elsewhere.

[0023] In this embodiment, the outer sphere (5) of embolization material erodes at a predetermined rate that is predictable and controllable. By erosion, the embolization material may become disassembled, digested, or metabolized into smaller or dispersed molecules through the action of the surrounding environment present in the targeted tissues vessels. Eroded embolization material may form fragments that will continue to erode. These erodible fragments of embolization material are smaller than the size expected to cause a stroke or any other type of complication in the patient.

[0024] This predetermined rate of erosion results in substantial erosion of the outer sphere (5) in a timeframe of about 30 seconds to 24 hours. Upon substantial erosion of the outer sphere (5), the inner core (10) of chemotherapy drug is able to disperse into the targeted tissue vessel (15). The properties of the embolization material may be adjusted to be suitable for use with vascular, lymphatic, or other fluid- transfer vessels. In addition, the outer sphere (5) of embolization material may erode at a similar rate when in contact with the vessel (15) walls or when in contact with a fluid located in the vessels (15). Maintaining a similar rate of erosion during treatment assists in keeping the embolization effect substantially constant as the chemo- embolization agent progresses through smaller and smaller vessels. [0025] The outer sphere (5) of embolization material may further comprise a therapeutic material. Such therapeutic material may include chemotherapy agents, anti-thrombogenic agents, antioxidants, and agents that promote or inhibit clotting, among others. The therapeutic material may be either a solid or a liquid. The addition of this therapeutic material will allow the targeted area to have a high concentration of the material proximal to the chemo-embolization agent (1 ). Additionally, the embolization material can be impregnated with a chemotherapy drug, such as pacitaxel, among others, that can function as a therapeutic/chemotherapy substance while the chemo-embolization material is penetrating further into the targeted vessels. The therapeutic material may be substantially similar in composition to the chemotherapy drug of the inner core (10).

[0026] In this embodiment, the diameter of the outer sphere (5) of embolization material is typically less than about 100 micrometers, while the diameter of the inner core (10) of a chemotherapy drug is preferably less than about 40 micrometers. In comparison, liver tumor vasculature vessels have an opening on the order of about 40 to 80 micrometers, while normal healthy liver tissue has vascular vessels with openings between about 7 to 40 micrometers. Thus the outer sphere (5) of embolization material has a diameter that is slightly larger than the initial opening in the targeted vessels, while the inner core (10) of the chemotherapy drug has a diameter either the same or slightly smaller than the expected size of the opening in the targeted vessels. The exact size of the openings associated with other vascular or lymphatic tissue vessels may vary from the above description. Such variation is contemplated to be within the scope of the present invention.

[0027] The embolization material of the outer sphere (5) may be any embolization material known to one skilled in the art including but not limited to polyvinyl alcohol, tris-acryl gelatin microspheres, gelatin sponge microfibrillar collagen, ethoiodized oil, autologous materials, polyvinyl alcohol, celluloses, polyacrylic acids, polyacylamides, and alginates or mixtures thereof. The embolization material may be multi-component in that it can be comprised of a polymer solution and a gelling precursor.

[0028] The chemotherapy drug of the inner core (10) may be any drug known to one skilled in the art including but not limited to alkylating agents, antimetabolites, anthracyclines, plant alkaloids, antitumor antibiotics, taxanes, platinum derivatives, paclitaxel, L-asparaginase, hydroxyurea, thalidomide, and dactinomycin. The inner core may be ionically or covalently bonded to the embolization material of the outer sphere or held in place by entanglement, van der Waal forces, hydrogen bonding, or any other means known to one skilled in the art of particle encapsulation. The chemotherapy drug of the inner core (10) may be either a solid or a liquid. [0029] In one embodiment of the present invention, the chemo-embolization agent may be spherical in shape, although nonspherical shapes are similarly allowable. Such shaping of the chemo-embolization agent may occur during or after formation of the chemo-embolization agent using any process known to one skilled in the art, such as molding, compression, or agglomeration, among others.

[0030] In another embodiment, the inner core (10), outer core (5), or both may further comprise a radioopaque material. The radiopaque material may be discrete particles or a coating. The radiopaque material may be a polymer, ceramic, or a noble metal. Examples of noble metals include gold, platinum, iridium, palladium, or rhodium, or a mixture thereof. The radiopaque material provides enhanced fluoroscopy to more easily identify the location of the chemo-embolization agent (1 ) during delivery, [0031] It is another aspect of the present invention to provide a method for treating diffuse diseases in targeted tissue vessels (15) of a patient. Referring to Figure 3, this method comprises delivering (20) a chemo-embolization agent (1 ) to the targeted tissue vessel (15) so that the targeted tissue vessel (15) is occluded in the initial portions thereof. This may be accomplished by using a system comprising an introducer apparatus, such as a wire-catheter arrangement well known to one skilled in the art of medicine. In this embodiment, a wire-catheter arrangement includes using a hollow needle to pierce the patient's skin and enter the body tissue at an angle with respect thereto. A wire guide is then inserted into the hollow needle and is advanced percutaneously into the body tissue to the desired position for delivery of the chemo- embolization agent (1 ) to the targeted tissue vessels (15). The hollow needle is then pulled in a backward direction so as to be removed from the body tissue and from contact with the wire guide. Next, a catheter is advanced along the wire guide to the desired position.

[0032] The catheter has a distal end through which the chemo-embolization agent is delivered into the targeted tissue vessel (15). The catheter is preferably made of a soft, flexible material such as silicon or any other suitable material. Generally, the catheter also has a proximal end and a plastic adaptor to receive the chemo- embolization agent (1 ). The diameter of the catheter is based upon the size of the body tissue into which the catheter is inserted and the amount of chemo-embolization agent (1 ) to be delivered. The inner diameter of the catheter is larger than the diameter of the outer core (5) of the chemo-embolization agent (1 ) to allow delivery of the agent to the targeted tissue vessel (15).

[0033] In use, the chemo-embolization agent (1 ) may be placed in the catheter prior to insertion into the body tissue. The chemo-embolization agent (1 ) is then guided through the catheter preferably from the proximal end and distally beyond the distal end of the catheter to a location within the vascular tissue near or at the targeted tissue vessel (15).

[0034] The delivery assembly may further include a polytetrafluoroethylene

(PTFE) introducer sheath to assist the percutaneous introduction of the wire guide and the catheter in the body tissue. Of course, any other suitable material may be used for the sheath. The introducer sheath facilitates inserting the catheter percutaneously to a desired location in the body tissue and provides stability to the catheter at the desired location in the body tissue. For example, as the introducer sheath is held stationary within the vascular tissue of the liver, it adds stability to the catheter, as the catheter is advanced through the introducer sheath to a desired location in the vascular tissue. [0035] When the distal end of the catheter is at a location near the targeted tissue vessel (15), the chemo-embolization agent (1 ) is inserted into the catheter and is advanced coaxially through the catheter for delivery through the distal end of the catheter. In this configuration, a shaft or other mechanical means can be used to advance or push the chemo-embolization agent (1 ) from the proximal end through the catheter and exiting the distal end of the catheter at or near the targeted tissue vessel (15).

[0036] In another embodiment, the chemo-embolization agent (1 ) may be introduced into the patient through the use of a fluid delivery apparatus. Such a fluid delivery apparatus may include, but not be limited to, the use of a saline solution premixed with the chemo-embolization agent (1 ).

[0037] The method further comprises eroding (25) the outer sphere (5) of embolization material at a predetermined rate to enhance penetration into the targeted tissue vessel (15) and to expose the inner core (10). The step of eroding (25) the outer sphere (5) of embolization material occurs at a similar rate whether the material is in contact with the vessels' walls or with the fluids present in the vessels. During this step, the erosion of the outer sphere (5) of embolizaton material may release a substantial concentration of a chemotherapy or therapeutic liquid near or in the vicinity of the targeted tissue vessels.

[0038] The method further comprises dispersing (30) the inner core (10) of a chemotherapy drug into the targeted tissue vessel (15) when the inner core (10) becomes substantially exposed.

[0039] The effective concentration or dosage of the chemo-embolization agent can be determined and varied by the physician treating the patient. Such a decision should be based on the nature, location, and severity of the condition to be treated and the method selected to administer the agent. Any means known to one skilled in the art may be used to introduce an acceptable dosage of the chemo-embolization agent to the targeted tissue. A chemo-embolization agent of appropriate concentration may be used to for localized tumor destruction, as well as for treating diffuse diseases. [0040] A person skilled in the art will recognize from the previous description that modifications and changes can be made to the present disclosure without departing from the scope of the disclosure as defined in the following claims.

Claims

CLAIMSWhat is claimed is

1. A chemo-embolization agent for treating diffuse diseases in targeted tissue vessels and for localized tumor destruction in a patient, the chemo-embolization agent comprising: an inner core of a chemotherapy drug having a diameter less than a predetermined size for the opening in the targeted tissue vessel; and an outer sphere of an embolization material encompassing the inner core and having an initial diameter to occlude the initial opening in the targeted tissue vessel; wherein the outer sphere of embolization material erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent into the opening in the targeted tissue vessel; wherein the inner core of chemotherapy drug disperses into the targeted tissue vessel after becoming exposed by the erosion of the embolization material of the outer sphere.

2. The chemo-embolization agent of Claim 1 , wherein the predetermined rate at which the outer sphere of embolizaton material erodes is predictable and controllable.

3. The chemo-embolization agent of Claim 1 , wherein the targeted tissue vessels are fluid-transfer vessels.

4. The chemo-embolization agent of Claim 1 wherein the predetermined rate of erosion for the outer sphere of embolization material results in substantial erosion of the outer sphere in a timeframe of about 30 seconds to 24 hours.

5. The chemo-embolization agent of Claim 2, wherein the outer sphere of embolization material erodes at a similar rate when in contact with the vessel walls or when in contact with a fluid located in the vessels.

6. The chemo-embolization agent of Claim 4, wherein after erosion, any existing fragments of the embolization material are smaller than the size expected to cause a stroke or other type of complication in the patient.

7. The chemo-embolization agent of Claim 1 , wherein the outer sphere of embolization material further comprises a therapeutic material.

8. The chemo-embolization agent of Claim 7, wherein the therapeutic material is a chemotherapy agent.

9. The chemo-embolization agent of Claim 1 , wherein the diameter of the outer sphere of embolization material is less than about 100 micrometers and the diameter of the inner core of a chemotherapy drug is less than about 40 micrometers.

10. The chemo-embolization agent of Claim 1 , wherein the embolization material of the outer sphere is one selected from the group of polyvinyl alcohol, tris- acryl gelatin microspheres, gelatin sponge microfibrillar collagen, ethoiodized oil, autologous materials, polyvinyl alcohol, celluloses, polyacrylic acids, polyacylamides, and alginates or mixtures thereof.

11. The chemo-embolization agent of Claim 1 , wherein the chemotherapy drug of the inner core is one selected from the group of alkylating agents, antimetabolites, anthracyclines, plant alkaloids, antitumor antibiotics, taxanes, platinum derivatives, paclitaxel, L-asparaginase, hydroxyurea, thalidomide, and dactinomycin, or mixtures thereof.

12. The chemo-embolization agent of Claim 1 , wherein at least one of the inner core (10) and outer core (5) further comprises a radiopaque material.

13. A method for treating diffuse diseases in targeted tissue vessels of a patient, the procedure comprising the steps of: introducing to the targeted tissue vessel, a chemo-embolization agent having an inner core of a chemotherapy drug and an outer sphere of an erodible embolization material, to deliver the chemo-embolization agent to the targeted tissue vessel so that the targeted tissue vessel is occluded in the initial portions thereof; eroding the outer sphere of embolization material at a predetermined rate to enhance penetration into the targeted tissue vessel and to expose the inner core; and dispersing the chemotherapy drug into the targeted tissue vessel when the inner core becomes substantially exposed.

14. The method of Claim 13, wherein the step of eroding the outer sphere of embolization material releases a substantial concentration of a chemotherapy or therapeutic liquid near the targeted tissue vessels.

15. The method of Claim 13, wherein the step of eroding the outer sphere of embolization material occurs at a similar rate whether the material is in contact with the vessels' walls or with the fluids present in the vessels.

16. A delivery system for delivering a treatment for diffuse diseases to a targeted tissue vessel in a patient's body, the delivery system comprising: an introducer apparatus; and a chemo-embolization agent having an inner core of a chemotherapy drug whose diameter is less than the predetermined size of the opening in the targeted tissue vessel; and an outer sphere of an embolization material that encompasses the inner core and whose initial diameter occludes the initial opening in the targeted tissue vessel; wherein the outer sphere of embolization material erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent into the opening in the targeted tissue vessel and allowing the inner core of chemotherapy drug to disperse into the targeted tissue vessel after becoming substantially exposed by the erosion of the outer sphere.

17. The delivery system of Claim 16, wherein the introducer apparatus is a wire-catheter arrangement including a hollow needle to pierce the patient's body; a wire guide for insertion into the hollow needle with percutaneous advancement into the patient's body to the desired targeted tissue vessel allowing for the subsequent removal of the hollow needle; a catheter having a proximal and distal end advanced along the wire guide to the desired targeted tissue vessel allowing for removal of the wire guide; and a mechanical means to advance the chemo-embolization agent from the proximal end of the catheter through the distal end of the catheter into the targeted tissue vessel.

18. The delivery system of Claim 17, wherein the introducer apparatus further comprising an introducer sheath to assist in the percutaneous introduction of the wire guide and the catheter into the patient's body.

19. The delivery system of Claim 16, wherein the introducer apparatus is a fluid delivery apparatus.

20. The delivery system of Claim 19, wherein the fluid delivery apparatus introduces into a patient a saline solution premixed with a chemo-embolization agent.

21. A chemo-embolization agent for treating diffuse diseases in targeted tissue vessels and for localized tumor destruction in a patient, the chemo-embolization agent comprising: an inner core comprising at least one of a chemotherapy drug having a diameter less than a predetermined size for the opening in a targeted tissue vessel and a diameter less than a predetermined size for the opening in the targeted tissue vessel; and an outer sphere of an embolization material encompassing the inner core and having an initial diameter to occlude the initial opening in the targeted tissue vessel; wherein the outer sphere of embolization material erodes at a predetermined rate, enhancing penetration of the chemo-embolization agent into the opening in the targeted tissue vessel; wherein the inner core of chemotherapy drug disperses into the targeted tissue vessel after becoming exposed by the erosion of the embolization material of the outer sphere.