JP2008086785A - New embolizing compositions - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide new compositions for embolizing blood vessels, especially suitable for treating blood vessel lesion by catheter delivery. <P>SOLUTION: This composition includes a cellulose diacetate polymer, a biocompatible solvent and a water insoluble contrasting agent having the average particle size of under about 10 μm. In another embodiment, cellulose diacetate polymer in the composition is displaced with biocompatible pre-polymer. In the composition, the biocompatible polymer is contained by about 2.5 wt.% to about 8.0 wt.%, and the water insoluble biocompatible contrast agent is contained by about 10 wt.% to about 40 wt.%. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

Background of the Invention
FIELD OF THE INVENTION The present invention relates to a novel composition for vascular embolization that is particularly suitable for treating vascular lesions by catheter delivery of the composition. In particular, the composition of the present invention comprises a biocompatible water-insoluble contrast agent characterized by having a biocompatible polymer, a biocompatible solvent and an average particle size of about 10 μm or less.

Publications cited references below are cited in this application as superscript numbers.
¹ Mandai et al., “Direct embolization of aneurysms with cellulose acetate polymer”, J. Neurosurg., 77: 497-500 (1992).
² Kinugasa et al., “Direct embolization of aneurysms with cellulose acetate polymer” J. Neurosurg., 77: 501-507 (1992).
³ Toxicology of Casarett and Doull, edited by Amdur et al., PergamonPress, New York, 661-664 (1975)
⁴ US patent application Ser. No. 08 / 507,863, filed Jul. 27, 1995, to Greff et al.
⁵ US patent application Ser. No. 08 / 508,248 filed Jul. 27, 1995, to “Greff et al., Cellulose Diacetate Composition for Vascular Embolization”
⁶ Kinugasa et al., "Early treatment of subarachnoid hemorrhage after preventing rupture of aneurysm", J. Ne-urosurg., 83: 34-41 (1995)
⁷ Kinugasa et al., “Prophylactic embolization to prevent new bleeding and delay aneurysm surgery”, Neurosurg., 36: 661 (1995)
⁸ Taki et al., "Selection and combination of different endovascular techniques in the treatment of giant aneurysms", J. Neurosurg., 77: 37-42 (1992).
⁹ US patent application Ser. No. 08 / 655,822 to Evans et al., “Novel Composition for Vascular Embolization,” filed May 31, 1996.
¹⁰ Castaneda-Zuniga et al., Interventional Radiology, Vascular Embolotherapy, Part 1, 1: 9-32, Williams & Wilkins, Publishers (1992)
¹¹ U.S. Pat. No. 3,527,224 issued to Rabinowitz et al. On 9/8/70, "Method of surgically joining tissues together"
¹² U.S. Pat. No. 3,591,676 for "surgical adhesive composition" issued on 7/6/71 of Hawkins et al.
¹³ US Patent Application No. 08 / 655,987, filed May 31, 1996, filed on May 31, 1996 as Evans et al.
¹⁴ US patent application Ser. No. 08 / 656,394 on “Reversible sterilization of female mammals” filed on May 31, 1996 as Attorney Document No. 018413-014 of Evans et al.

  All of the above documents are incorporated herein by reference in their entirety to the same extent as if each individual document was shown in detail and individually as if included in the present specification as is.

Description of the Prior Art Vascular embolization is for a variety of purposes including treatment of tumors, lesions such as aneurysms, arteriovenous malformations (AVM), arteriovenous fistulas (AVF), uncontrolled bleeding, etc. Done.

  Vascular embolization is preferably performed by a catheter technique that allows selective placement of the catheter at the vascular site to be embolized. In this regard, recent advances in catheter technology as well as angiography allow for neurovascular interventions, including the treatment of otherwise inoperable lesions. Specifically, the development of microcatheters and guidewires that can provide access to vessels as small as lmm in diameter enables endovascular treatment of many lesions.

Endovascular treatment regimes allow doctors to visualize the delivery of the composition to the vascular site using conventional techniques such as fluoroscopy ^1-8 (Patent Documents 1, 2, Non-Patent Documents 1-6) Preferably includes the use of a water-insoluble radiopac contrast agent in the embolization composition. Furthermore, the use of water-insoluble contrast agents is beneficial during post-treatment procedures, for example, to visualize embolized masses during surgery, or to monitor symptoms and / or for re-treatment purposes. Visualization is particularly necessary when using catheter delivery techniques to ensure that both the composition is delivered to the intended vascular site and the required amount of composition is delivered. The latter requirement is particularly important for the treatment of aneurysms that are intended to satisfy only the aneurysm sac and leave the adjacent blood vessels unaffected. Thus, in such treatment, the amount of embolizing composition delivered is chosen so that it substantially fills only the aneurysm sac but does not flow out. If less than this amount of embolization composition is delivered to the aneurysm sac, the patient is left with an active aneurysm, which in some cases may be more dangerous than an untreated aneurysm. If more embolization composition is delivered than this amount, the composition will flow into the adjacent blood vessel, which may then embolize the vessel as well as the aneurysm. If the affected blood vessel is in or reaches an important living organ such as the brain, permanent damage due to blood flow arrest will occur.

  When delivered by a catheter, the embolization composition preferably includes a biocompatible solvent, a biocompatible polymer, and a water-insoluble contrast agent. The biocompatible solvent is miscible or soluble in blood or other body fluids and solubilizes the biocompatible polymer during delivery. The biocompatible polymer is selected to be soluble in the biocompatible solvent but insoluble in blood or other body fluids. The water-insoluble contrast agent is suspended in the composition and, as described above, allows the physician to visualize the catheter delivery of the composition by fluoroscopy. After contact with blood or other bodily fluids, the biocompatible solvent disappears from the embolization composition, after which the biocompatible polymer precipitates in the presence of a water-insoluble contrast agent and embolizes the blood vessel.

  In practice, however, this operational complexity has been found, including the fact that the fluoroscopic visualization of these compositions is often inconsistent during catheter delivery. Such discrepancies resulted in underfilling or overfilling of the vascular gap and inevitably resulted in unsatisfactory results.

Efforts have been made to improve the fluoroscopic visualization consistency of these compositions, but such efforts have been hampered by a lack of clear understanding of the underlying cause of the problem. In view of the above, there continues to be a desire to enhance fluoroscopic visualization of polymer compositions used to embolize vascular sites.
US patent application Ser. No. 08 / 507,863, filed Jul. 27, 1995, to Greff et al. US patent application Ser. No. 08 / 508,248 filed Jul. 27, 1995 to Greff et al. For “cellulose diacetate composition for vascular embolization” Mandai et al., “Direct embolization of aneurysms with cellulose acetate polymer”, J. Neurosurg., 77: 497-500 (1992). Kinugasa et al., “Direct embolization of aneurysms with cellulose acetate polymer” J. Neurosurg., 77: 501-507 (1992). Toxicology of Casarett and Doull, edited by Amdur et al., PergamonPress, New York, 661-664 (1975) Kinugasa et al., "Early treatment of subarachnoid hemorrhage after preventing rupture of aneurysm", J. Ne-urosurg., 83: 34-41 (1995) Kinugasa et al., “Prophylactic embolization to prevent new bleeding and delay aneurysm surgery”, Neurosurg., 36: 661 (1995) Taki et al., "Selection and combination of different endovascular techniques in the treatment of giant aneurysms", J. Neurosurg., 77: 37-42 (1992).

SUMMARY OF THE INVENTION The present invention relates to a new and unexpected discovery that the particle size of a water-insoluble contrast agent is important in obtaining an embolizing composition that can be consistently visualized during catheter delivery of the composition. Specifically, it has been found that fluoroscopic visualization of an embolization composition can be consistently obtained by using a water-insoluble contrast agent having an average particle size of about 10 μm or less.

  While not being limited by any theory, during catheter delivery of an embolization composition having an average particle size greater than 10 μm, some of the contrast agent may contain, for example, water from the suspension before and / or during catheter delivery. It is believed that they are not maintained in the embolizing composition delivered to the vascular site due to sedimentation of insoluble contrast agent, adherence of large particle size contrast agent to the wall of the catheter delivery system, and the like. Furthermore, the narrow passage of the catheter delivery system paired with a delivery protocol that requires the contrast agent to be maintained in suspension for an extended period of time is thought to exacerbate this situation. In any event, we believe that this failure to maintain a minimal amount of contrast in the injected embolization composition is what results in inconsistent fluoroscopic visualization during catheter delivery. Think.

Thus, in one of its compositional aspects, the present invention provides (a) from about 2.5% to about 8.0% by weight of a biocompatible polymer,
(B) about 10% to about 40% water-insoluble, biocompatible contrast agent having an average particle size of about 10 μm or less, and (c) about 52% to about 87.5% biocompatibility. Solvent (% by weight of polymer, contrast agent and biocompatible solvent is based on the total weight of all compositions)
Relates to a composition comprising

In one method aspect, the invention provides (a) from about 2.5% to about 8.0% by weight of a biocompatible polymer,
(B) about 10% to about 40% by weight of a water-insoluble, biocompatible contrast agent having an average particle size of about 10 pm or less;
(C) about 52 wt.% To about 87.5 wt.% Biocompatible solvent (wt% of polymer, contrast agent and biocompatible solvent is based on the total weight of all compositions)
A method of embolizing a blood vessel by delivering a composition comprising a catheter to the blood vessel under conditions that produce a precipitate that embolizes the blood vessel.

In another embodiment, the biocompatible polymer composition can be replaced with a biocompatible prepolymer composition comprising a biocompatible prepolymer. In this embodiment, the present invention provides (a) a biocompatible prepolymer,
(B) relates to a composition comprising a biocompatible water-insoluble contrast agent having an average particle size of about 10 μm or less, and (c) optionally a biocompatible solvent.

In addition, the present invention also provides (a) a biocompatible prepolymer,
(B) A biocompatible water-insoluble contrast agent having an average particle size of about 10 μm or less, and (c) a method for embolizing a blood vessel site by delivering a composition containing a biocompatible solvent to a blood vessel with a catheter if necessary. The delivery relates to an embolization method in which the prepolymer is polymerized in situ in the presence of a water-insoluble contrast agent at the blood vessel site, thereby embolizing the blood vessel.
In a preferred embodiment, the water insoluble, biocompatible contrast agent is selected from the group consisting of barium sulfate, tantalum powder and tantalum oxide. In yet another preferred embodiment, the biocompatible solvent is dimethyl sulfoxide (DMSO), ethanol or acetone.

In one of the kit aspects, the present invention provides (a) a polymer composition comprising a biocompatible polymer, a biocompatible solvent and a biocompatible, water-insoluble contrast agent having an average particle size of about 10 μm or less, and (b) The present invention relates to a kit of parts including a catheter.

In another kit aspect, the present invention provides a prepolymer composition comprising (a) a biocompatible prepolymer, a biocompatible, water-insoluble contrast agent having an average particle size of about 10 μm or less, and optionally a biocompatible solvent. And (b) a kit of parts including a catheter.
In a preferred embodiment, the kit further comprises a microballoon catheter for reducing or stopping blood flow.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel vascular embolization composition that is particularly suitable for treating vascular lesions by catheter delivery of the composition.
Prior to describing the invention in further detail, the following terms will first be defined.

  The term “embolization” means that a substance is injected into a blood vessel, which, for example, in the case of an aneurysm, fills or clogs the aneurysm sac and / or promotes clot formation, resulting in an aneurysm. Represents the process by which blood flow to the ceases, and in the case of AVM and AVF, a plug or blood clot is formed to regulate / retransmit blood flow to allow proper tissue perfusion. Therefore, vascular embolization is important to prevent / control bleeding due to lesions (eg, organ bleeding, gastrointestinal bleeding, vascular bleeding, and bleeding associated with aneurysms). In addition, embolization can be used to remove diseased tissue (eg, a tumor, etc.) by interrupting the blood supply.

The term “biocompatible polymer” is the amount used, is non-toxic when used inside a patient, is chemically inert, and substantially non-immunogenic, and blood Represents a polymer that is substantially insoluble in Suitable biocompatible polymers include, for example, cellulose acetate ^2,6-7 (including cellulose diacetate ⁵ ), ethylene vinyl alcohol copolymer ^4,8 , hydrogel (eg, acrylic), polyacrylonitrile, polyvinyl acetate, cellulose acetate Butyrate, nitrocellulose, urethane / carbonate copolymer, styrene / maleic acid copolymer, and mixtures ⁹ thereof. Also, the biocompatible polymer is preferably non-inflammatory when used in situ.
The particular biocompatible polymer used is not critical and is selected with respect to the viscosity of the resulting polymer solution, the solubility of the biocompatible polymer in the biocompatible solvent, and the like. Such factors are known to those skilled in the art.

  Preferred biocompatible polymers include cellulose diacetate and ethylene vinyl alcohol copolymers. Cellulose diacetate polymers are commercially available or can be prepared by art recognized procedures. In a preferred embodiment, the number average molecular weight of the cellulose diacetate composition is from about 25,000 to about 100,000, more preferably from about 50,000 to about 75,000, more preferably from about 58,000 to about 64,000, as determined by gel permeation chromatography. is there. The weight average molecular weight of the cellulose diacetate composition is preferably from about 50,000 to 200,000, more preferably from about 100,000 to about 180,000 as determined by gel permeation chromatography. As will be apparent to those skilled in the art, a cellulose diacetate polymer having a low molecular weight will impart a low viscosity to the composition compared to a high molecular weight polymer, assuming all other factors are equal. Therefore, adjustment of the viscosity of the composition can be easily achieved by simply adjusting the molecular weight of the polymer composition.

  The ethylene vinyl alcohol copolymer contains residues of both ethylene monomers and vinyl alcohol monomers. A small amount (eg, less than 5 mol%) of additional monomer may be included in the polymer structure or grafted thereto. Provided that such additional monomers do not change the embolization properties of the composition. Examples of such additional monomers include maleic anhydride, styrene, propylene, acrylic acid, vinyl acetate and the like.

  Ethylene vinyl alcohol copolymers are commercially available or can be prepared by art recognized procedures. The ethylene vinyl alcohol copolymer composition is selected such that a solution of 6 wt% ethylene vinyl alcohol copolymer, 35 wt% tantalum contrast agent in DMSO has a viscosity of less than 60 centipoise at 20 ° C. As will be apparent to those skilled in the art, if all other factors are equal, a copolymer having a low molecular weight will impart a lower viscosity to the composition as compared to a high molecular weight copolymer. Therefore, adjustment of the viscosity of the composition as required for catheter delivery can be easily achieved by simply adjusting the molecular weight of the copolymer composition.

  Also, as is apparent, the ratio of ethylene to vinyl alcohol in the copolymer affects the overall hydrophobicity / hydrophilicity of the composition, which in turn is a relative water solubility / water insolubility of the composition as well as aqueous solutions (eg, Affects the rate of precipitation of the copolymer in the blood). In a particularly preferred embodiment, the copolymer used herein comprises from about 25 mole percent to about 60 mole percent ethylene and from about 40 mole percent to about 75 mole percent vinyl alcohol. These compositions provide the necessary precipitation rate suitable for use in embolizing blood vessels.

  The term “water-insoluble contrast agent” refers to a radiopaque material that can be monitored during injection into a mammalian subject, eg, by radiography (ie, having a water solubility of less than 0.01 mg / ml at 20 ° C.). Examples of water insoluble contrast agents include tantalum, tantalum oxide and barium sulfate, which are commercially available in a form suitable for in vivo use. Methods for preparing such water-insoluble biocompatible contrast agents having an average particle size of about 10 μm or less are described below. Other water-insoluble contrast agents include gold, tungsten and platinum.

  The term “biocompatible solvent” refers to an organic substance that is liquid at least at the body temperature of a mammal, in which the biocompatible polymer is soluble and substantially non-toxic in the amounts used. Suitable biocompatible solvents include, for example, dimethyl sulfoxide, analogs / homologs of dimethyl sulfoxide, ethanol, acetone, and the like. Also, aqueous mixtures with biocompatible solvents can be used provided that the amount of water used is small enough that the dissolved polymer precipitates after contact with blood. The biocompatible solvent is preferably dimethyl sulfoxide.

  The term “encapsulation” as used with contrast agents encapsulated in a polymer precipitate means that the capsule does not imply physical confinement of the contrast agent within the precipitate so that it encapsulates the drug. Rather, the term is used to mean that a single aggregated precipitate is formed that does not separate into individual components.

The term “biocompatible prepolymer” is a polymer that is polymerized in situ to form a polymer and is non-toxic, chemically inert when used inside a patient in the amount used, and Represents a substance that is substantially non-immunogenic and substantially insoluble in blood. Suitable biocompatible prepolymers include, for example, cyanoacrylate ^10,11,12 , hydroxyethyl methacrylate, silicon prepolymer, and the like. The prepolymer may be a monomer or reactive oligomer ¹² . Also, the biocompatible prepolymer is preferably non-inflammatory when used in situ.

Composition The polymer composition or prepolymer composition used in the method of the present invention is prepared by conventional methods whereby each of the ingredients is added until the total composition is substantially uniform. Are mixed together.

  For example, a polymer composition can be prepared by adding a sufficient amount of a biocompatible polymer to a biocompatible solvent to obtain an effective concentration for the polymer composition. The polymer composition will comprise from about 2.5% to about 8.0%, more preferably from about 4% to about 5.2% by weight of the biocompatible polymer composition, based on the total weight of the polymer composition. If desired, gentle heating and agitation can be used, for example, to effect dissolution of the biocompatible polymer in the biocompatible solvent at 50 ° C. for 12 hours.

  A sufficient amount of contrast agent is then added to the biocompatible solvent to obtain an effective concentration for the complete composition. The composition will preferably contain from about 10% to about 40%, more preferably from about 20% to about 40%, more preferably 30% by weight of contrast agent. Since the contrast agent is not soluble in the biocompatible solvent, it is used to homogenize the suspension from which agitation is obtained. To facilitate suspension formation, the contrast agent particle size is preferably maintained at about 10 μm or less, more preferably from about 1 μm to about 5 μm (eg, an average size of about 2 μm). . In one preferred embodiment, the appropriate particle size of the contrast agent is prepared, for example, by fractionation. In such embodiments, 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 (anhydrous), preferably in a clean environment. Agitation of the resulting suspension, followed by sedimentation for about 40 seconds, allows large particles to settle quickly. Removal of the top portion of the organic liquid, followed by separation of the liquid from the particles, results in a reduction in particle size as confirmed by light microscopy. The process is repeated as necessary until the desired average particle size is reached.

  The particular order of addition of the components to the biocompatible solvent is not critical and stirring of the resulting suspension is performed as necessary to obtain composition uniformity. Mixing / stirring of the composition is preferably performed at ambient pressure and in an anhydrous atmosphere. The resulting composition is preferably heat sterilized and then stored in sealed brown bottles or vials until needed.

  Each of the polymers described herein are commercially available, but can also be prepared by methods known in the art. For example, the polymer is typically used by conventional techniques such as free radicals, heat, UV, gamma rays, or electron beams, optionally using a polymerization catalyst or polymerization initiator to obtain a polymer composition. Prepared by induced polymerization. The particular method of polymerization is not critical and the polymerization technique used does not form part of the present invention.

In order to maintain solubility in the biocompatible solvent, the polymers described herein are preferably not cross-linked.
The prepolymer composition can be prepared by adding a sufficient amount of contrast agent to a solution (eg, a liquid prepolymer) to obtain an effective concentration for the total polymer composition. The prepolymer composition will preferably contain from about 10% to about 40%, more preferably from about 20% to about 40%, more preferably about 30% by weight of contrast agent. If the contrast agent is not soluble in the biocompatible prepolymer composition, it is used to obtain a homogeneity of the suspension from which agitation is obtained. To enhance the production of the suspension, the contrast agent particle size is preferably maintained at about 10 μm or less, more preferably from about 1 μm to about 5 μm (eg, an average size of about 2 μm).

  If the prepolymer is a liquid (as is the case with polyurethane), the use of a biocompatible solvent is not absolutely necessary, but may be preferred to give the embolic composition an appropriate viscosity, etc. Absent. When used, the biocompatible solvent is preferably from about 30% to about 90%, more preferably from about 60% to about 80%, by weight based on the total weight of the prepolymer composition. It will contain a prepolymer composition. When a biocompatible solvent is used, the prepolymer composition typically comprises from about 10% to about 50% by weight of prepolymer, based on the total weight of the composition.

  In a particularly preferred embodiment, the prepolymer is preferably a cyanoacrylate used in the absence of a biocompatible solvent. When used in this manner, the cyanoacrylate adhesive is selected to have a viscosity of from about 5 centipoise to about 20 centipoise at 20 ° C.

  The particular order of addition of the ingredients is not critical and stirring of the resulting suspension is performed as necessary to obtain composition uniformity. Mixing / stirring of the composition is preferably performed at ambient pressure and in an anhydrous atmosphere. The resulting composition is preferably sterilized and then stored in sealed brown bottles or vials until needed.

Method The composition can then be used in a method of catheter assisted embolization of mammalian blood vessels. In such a method, a sufficient amount of this composition is introduced into the selected blood vessel by means of fluoroscopic catheter delivery, which results in embolization of the blood vessel after polymer precipitation or prepolymer polymerization. . The particular amount of embolizing composition used is dictated by the total volume of vasculature to be embolized, the polymer / prepolymer concentration in the composition, the rate of polymer precipitation (solid formation), and the like. Such factors are within the skill of those skilled in the art.
One particularly preferred method for catheter delivery of the embolization composition of the present invention to selected vascular sites is with a small diameter medical catheter. The particular catheter used is not critical provided that the polymer catheter component is compatible with the embolization composition (ie, the catheter component does not readily degrade in the embolization composition). In this regard, the use of polyethylene for the catheter component is preferred due to its inertness in the presence of the embolizing composition described herein. Other materials that are compatible with the embolization composition can be readily determined by those skilled in the art and include, for example, other polyolefins, fluoropolymers (eg, Teflon ^™ ), silicones, and the like.

  When delivered by a catheter, the injection rate partially dictates the form of precipitation at the vascular site. Specifically, a low injection rate of about 0.05-0.3 cc / min will give a granular or nodular form of precipitation that is particularly advantageous for site-specific embolization. This is because a precipitate forms mainly at the injection location. Conversely, a high injection rate of about 0.1-0.5 cc or more / several seconds (eg up to 10 seconds) gives a filamentous mass that projects downstream from the catheter tip, which provides embolizing agents deep in the vascular tree. Particularly advantageous. Such an operation is suitable for embolizing a tumor mass. However, too rapid injection of DMSO into the vascular site can cause vasospasm and should therefore be avoided and / or if convulsions occur, the use of anticonvulsants such as papaverine is used.

One particularly preferred method for catheter injection of the composition of the present invention is as follows.
1. In vivo microcatheter placement is confirmed by injection of water-soluble contrast agent.
2. The cap on the microcatheter luer hub is secured, and then the water-insoluble contrast agent in the composition is shaken vigorously and then allowed to settle well by dispersing it away.
Aspirate 0.8 cc sterile DMSO into a 3.1 cc syringe. Remove the cap from the microcatheter hub. DMSO 0.30cc is injected into a typical 150cm microcatheter. Remove syringe and overfill / wash luer hub with 0.3cc DMSO. Immediately place the cap on the microcatheter luer hub and secure to prevent backflow and mixing.
4. Again, shake the composition well to fully disperse the water-insoluble contrast agent. A 1 cc syringe is filled with the composition with a 21 gauge needle. Remove the cap from the microcatheter hub and fill the space in the hub with the remaining DMSO and immediately connect the composition syringe to the catheter hub to ensure that no air is present in the hub during the connection.
5. With the composition syringe facing up, creating a sharp interface boundary between DMSO and the embolization composition, gradually injecting the first 0.25cc over a period of 1 minute to replace the DMSO in the microcatheter, Dilute DMSO in blood.
6. Under fluoroscopy, the embolization composition should be visible at the distal portion of the microcatheter body. The syringe tip is lowered and the embolization composition is injected as needed in the clinical situation. Monitoring the volume of embolization composition injected to correspond to the volume of the vascular gap filled; and
7. After completing the embolization composition injection, gently aspirate with an embolization syringe to separate the catheter tip from the embolization composition mass. Wait a few seconds to release the syringe plunger and remove the microcatheter.

In this protocol, the dead space of a 150 cm microcatheter is about 0.32 cc.
In the case of an aneurysm, it is preferred that the mammal be rotated to place the aneurysm in a downward position to facilitate replacement of the aneurysm blood.
When introduced into a vascular site, the biocompatible solvent diffuses rapidly into the blood, producing a solid precipitate, which is a water-insoluble polymer with the contrast agent encapsulated therein. Without being limited to any theory, it is believed that initially, a soft gel-sponge solid precipitate is formed after contact with blood. This precipitate then restricts blood flow and traps red blood cells, thereby resulting in blood vessel clot embolization.

Utility The compositions described herein are useful for embolizing mammalian blood vessels, which in turn prevent / bleed bleeding (eg, organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with aneurysms) / It can be used to regulate or excise diseased tissue (eg, a tumor, etc.). Therefore, these compositions have application in human and other mammalian subjects in need of vascular embolization. In addition, these compositions can be used for reversible sterilization of mammalian patients as described in applications ¹³ , ¹⁴ filed concurrently by Evans et al.

In addition, these compositions can be used as carriers for compatible pharmaceutically active compounds, which are delivered in vivo for subsequent release. Examples of such compounds include antibiotics, anti-inflammatory agents, chemotherapeutic agents, and the like.
The following examples are presented to illustrate the invention and should not be considered as limiting thereof.

Unless otherwise stated, all temperatures are in degrees Celsius. In these examples and others, the following abbreviations have the following meanings.
cc = cubic centimeter
cm = centimeter
DMSO = dimethyl sulfoxide
EVOH = ethylene vinyl alcohol copolymer
g = grams
ID = inside diameter
in. = inch
min. = minute
mL = milliliter
mm = millimeter
OD = outer diameter
sec. = Second μm = micron

Example 1
The purpose of this example is that the amount of water-insoluble contrast delivered by a small diameter medical catheter correlates with the average particle size of the contrast when all other factors are kept constant. Is to demonstrate.
Specifically, two EVOH polymer compositions identical in all aspects except the average particle size were prepared as follows.

First composition
A) EVOH 8g,
B) 30 g tantalum with an average particle size of about 15 μm (narrow size distribution), and
C) DMSO 100 mL.
Second composition
A) EVOH 8g,
B) 30 g of tantalum with an average particle size of about 3 μm (narrow size distribution), and
C) DMSO 100 mL.
Each ingredient was mixed until uniform.

In the second composition, the average particle size of the contrast agent was prepared by fractionation, where tantalum having an average particle size of less than about 20 μm was added to ethanol (anhydrous) in a clean environment. The resulting suspension was stirred and then allowed to settle for about 40 seconds to quickly settle large particles. The top of the ethanol is removed, followed by separation of the liquid from the particles to obtain a reduction in particle size, which is confirmed by a microscope (Nikon Alpha Photo ^™ ). The process was repeated as necessary until an average particle size of 3 μm was reached.
Each of two identical catheters (polyolefin microcatheter, OD 0.036 in. XID 0.016 in., Dade space 0.45 cc) was flushed with 10 cc saline solution and then started with DMSO 0.3 cc. Two lcc syringes were filled with the first or second composition described above with a 21 gauge needle and connected to the Luer hub of the catheter. The distal tip of the catheter was submerged in warm tap water. Exactly 0.50 cc of each composition was poured into water over a period of 5 minutes.
Tantalum is black and the polymer composition is white otherwise. Therefore, the degree of tantalum contamination in the injected composition is visually monitored by measuring the color characteristics of each injected composition. In this case, the precipitate generated from each catheter is evaluated and the results of this evaluation are reported in Table I below.

Each precipitate was then visualized under fluoroscopy. The first precipitate with tantalum with an average particle size of 15 μm in the composition was barely visible while the second precipitate (tantalum with an average particle size of 3 μm in the composition) was prominent.
Subsequent experiments on similar compositions confirmed these results. Specifically, the first composition produced a white to gray precipitate at 5.0 and 2.0 minute injection times, while a 1.0 minute injection time produced a black precipitate.

  The above results show that a composition comprising a water-insoluble contrast agent having an average particle size greater than about 10 μm delivered sufficient contrast agent by catheter injection to be easily visualized when the composition is gradually injected. Prove that it was not retained in the composition. Rapid injection clearly minimizes sedimentation and / or other phenomena related to water insoluble contrast agents not being retained during precipitation. Conversely, the same composition with an average particle size of about 3 μm for the water-insoluble contrast agent produced acceptable results at all injection times.

  It is also contemplated that the embolizing compositions of the present invention have improved flow rates and less separation in the catheter compared to similar compositions comprising water insoluble contrast agents having an average particle size greater than 10 μm.

  It will be appreciated that the same procedure as described above can be used with compositions using liquid prepolymers.

  From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications that fall within the scope of the claims are intended to be included therein.

Claims (46)

(A) a biocompatible polymer from about 2.5% to about 8.0% by weight;
(B) about 10% to about 40% water-insoluble, biocompatible contrast agent having an average particle size of about 10 μm or less, and (c) about 52% to about 87.5% biocompatibility. Solvent (% by weight of polymer, contrast agent and biocompatible solvent is based on the total weight of all compositions)
A composition comprising The composition according to claim 1, wherein the biocompatible solvent is selected from the group consisting of dimethyl sulfoxide, ethanol and acetone. The composition according to claim 2, wherein the biocompatible solvent is dimethyl sulfoxide. The composition according to claim 1, wherein the water-insoluble contrast agent is selected from the group consisting of tantalum, tantalum oxide, tungsten, and barium sulfate. The composition according to claim 3, wherein the contrast agent is tantalum. The biocompatible polymer comprises cellulose acetate, ethylene vinyl alcohol copolymer, hydrogel, polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, nitrocellulose, urethane / carbonate copolymer, styrene / maleic acid copolymer, and mixtures thereof. The composition according to claim 1, which is selected from the group. The composition of claim 6 wherein the biocompatible polymer is a copolymer of ethylene and vinyl alcohol. 8. The composition of claim 7, wherein the contrast agent has an average particle size of 1 to 10 microns. (A) a biocompatible polymer from about 2.5% to about 8.0% by weight;
(B) about 10% to about 40% water-insoluble, biocompatible contrast agent having an average particle size of about 10 μm or less, and (c) about 52% to about 87.5% biocompatibility. Solvent (% by weight of polymer, contrast agent and biocompatible solvent is based on the total weight of all compositions)
A method of embolizing a blood vessel by delivering a composition comprising a catheter to the blood vessel under conditions that produce a precipitate embolizing the blood vessel. The method of claim 9, wherein the biocompatible solvent is selected from the group consisting of dimethyl sulfoxide, ethanol and acetone. 11. The method according to claim 10, wherein the biocompatible solvent is DMSO. The method according to claim 9, wherein the water-insoluble contrast agent is selected from the group consisting of tantalum, tantalum oxide, tungsten and barium sulfate. The biocompatible polymer comprises cellulose acetate, ethylene vinyl alcohol copolymer, hydrogel, polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, nitrocellulose, urethane / carbonate copolymer, styrene / maleic acid copolymer, and mixtures thereof. 10. A method according to claim 9 selected from the group. The method of claim 9 wherein said biocompatible polymer is a copolymer of ethylene and vinyl alcohol. 15. The method of claim 14, wherein the contrast agent has an average particle size of 1 to 10 microns. (A) a biocompatible prepolymer,
(B) a composition comprising a water-insoluble biocompatible contrast agent having an average particle size of about 10 μm or less, and (c) a biocompatible solvent. 18. The composition according to claim 17, wherein the water-insoluble contrast agent is selected from the group consisting of tantalum, tantalum oxide, and barium sulfate. The composition according to claim 17, wherein the contrast agent is tantalum. 17. The composition of claim 16, wherein the biocompatible prepolymer is selected from the group consisting of cyanoacrylate, hydroxyethyl methacrylate, and silicone prepolymer. 20. The composition of claim 19, wherein the biocompatible prepolymer is cyanoacrylate. 21. The composition of claim 20, wherein the contrast agent has an average particle size of 1 micron to 10 microns. The composition according to claim 16, further comprising a biocompatible solvent. 23. The composition according to claim 22, wherein the biocompatible solvent is selected from the group consisting of dimethyl sulfoxide, acetone and ethanol. (A) a biocompatible prepolymer,
(B) A biocompatible water-insoluble contrast agent having an average particle size of about 10 μm or less, and (c) a method for embolizing a blood vessel site by delivering a composition containing a biocompatible solvent, if necessary, to a blood vessel by a catheter Wherein the delivery is performed under conditions where the prepolymer polymerizes in situ at the vascular site, thereby embolizing the blood vessel and further encapsulating the non-particulate drug in the polymer Forming method. 25. The method of claim 24, wherein the water-insoluble contrast agent is selected from the group consisting of tantalum, tantalum oxide, tungsten, and barium sulfate. 26. The method of claim 25, wherein the contrast agent is tantalum. 25. The method of claim 24, wherein the biocompatible prepolymer is selected from the group consisting of cyanoacrylate, hydroxyethyl methacrylate, and silicone prepolymer. 28. The method of claim 27, wherein the biocompatible prepolymer is cyanoacrylate. 26. The method of claim 25, wherein the contrast agent has an average particle size of 1 to 10 microns. 26. The method of claim 25, wherein the biocompatible solvent is selected from the group consisting of dimethyl sulfoxide, acetone and ethanol. (A) A kit of parts comprising a biocompatible polymer, a biocompatible solvent and a water-insoluble, biocompatible contrast agent having an average particle size of about 10 μm or less, and (b) a catheter. 32. The kit of parts according to claim 31, wherein said biocompatible solvent is selected from the group consisting of dimethyl sulfoxide, ethanol and acetone. 33. A kit of parts according to claim 32, wherein the biocompatible solvent is dimethyl sulfoxide. 32. The kit of parts according to claim 31, wherein the water-insoluble contrast agent is selected from the group consisting of tantalum, tantalum oxide, tungsten, and barium sulfate. The kit of parts according to claim 34, wherein said contrast agent is tantalum. The biocompatible polymer comprises cellulose acetate, ethylene vinyl alcohol copolymer, hydrogel, polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, nitrocellulose, urethane / carbonate copolymer, styrene / maleic acid copolymer, and mixtures thereof. 32. A kit of parts according to claim 31 selected from the group. The kit of parts according to claim 36, wherein said biocompatible polymer is a copolymer of ethylene and vinyl alcohol. 38. A kit of parts according to claim 37, wherein the contrast agent has an average particle size of 1 to 10 microns. 32. The kit of parts of claim 31, further comprising a microballoon catheter for reducing or stopping blood flow. (A) a biocompatible prepolymer, a water-insoluble biocompatible contrast agent having an average particle size of about 10 pm or less, and, optionally, a prepolymer composition comprising a biocompatible solvent, and (b) a component comprising a catheter Kit. 41. A kit of parts according to claim 40, wherein said water-insoluble contrast agent is selected from the group consisting of tantalum, tantalum oxide, tungsten and barium sulfate. 42. The kit of parts according to claim 41, wherein the contrast agent is tantalum. 41. The kit of parts of claim 40, wherein the biocompatible prepolymer is selected from the group consisting of cyanoacrylate, hydroxyethyl methacrylate, and silicone prepolymer. 44. A kit of parts according to claim 43, wherein said biocompatible prepolymer is cyanoacrylate. 41. The kit of parts of claim 40, wherein the contrast agent has an average particle size of 1 to 10 microns. 41. A kit of parts according to claim 40, further comprising a microballoon catheter for reducing or stopping blood flow.