One aspect of the present invention relates to a method of temporarily embolizing a blood vessel using a hydrolytically degradable crosslinked hydrogel as an embolus. In certain embodiments, the hydrolytically degradable crosslinked hydrogel substantially hydrolyzes only at about physiological pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel is stable at low pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel comprises a marker molecule, such as a dye, radiopaque, or an MRI-visible compound. It is to be understood that both the foregoing general description and the following detailed description are exemplary, and are intended to provide further explanation of the invention as claimed.

Description of the Invention

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a method of temporarily embolizing a blood vessel using a hydrolytically degradable crosslinked hydrogel as an embolus. In certain embodiments, the hydrolytically degradable crosslinked hydrogel substantially hydrolyzes only at about physiological pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel is stable at low pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel comprises a marker molecule, such as a dye, radiopaque, or an MRI-visible compound. It is to be understood that both the foregoing general description and the following detailed description are exemplary, and are intended to provide further explanation of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described more fully with reference to the accompanying examples, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

One aspect of the present invention relates to a method of temporarily embolizing a blood vessel using a hydrolytically degradable crosslinked hydrogel as an embolus. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel is stable at high pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel is stable at low pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel comprises a marker molecule, such as a dye, radiopaque, or an MRI-visible compound.

Embolization

Embolization is a process wherein a material is injected into a blood vessel to at least partially fill or plug the blood vessel and/or encourage clot formation so that blood flow through the vessel is reduced or stopped (See also Background of the Invention). Embolization of a blood vessel can be useful for a variety of medical reasons, including preventing or controlling bleeding due to lesions (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, and bleeding associated with an aneurysm), or to ablate diseased tissue (e.g., tumors, vascular malformations, hemorragic processes, etc.) by cutting off blood supply. Embolization may also be used to prevent blood loss during or immediately following surgery. Embolization of tumors may be performed preoperatively to shrink tumor size; to aid in the visualization of a tumor; and to minimize or prevent blood loss related to surgical procedures.

In other words, embolization is useful in a broad spectrum of clinical situations. Embolization can be particularly effective in hemorrhage, regardless of whether the etiology is trauma, tumor, epistaxis, postoperative hemorrhage, or GI hemorrhage. It can be performed anywhere in the body that a catheter can be placed, including the intracranial vasculature, head and neck, thorax, abdomen, pelvis, and extremities. With the availability of coaxial microcatheters, highly selective embolizations can be performed. In most patients, embolization for hemorrhage is preferable to surgical alternatives.

Emobilization may be used in treating skin, head, or neck tumors, tumors of the uterus or fallopian tubes, liver or kidney tumors, endometriosis, fibroids, etc. Particularly, embolization has been used for arteriovenous malformation of the pelvis, kidney, liver, spine and brain. Uterine artery embolization has been used for the treatment of fibroids; renal artery embolization has been used for the treatment of renal angiomyolipomas and renal cell carcinoma; intracranial embolization has been used for the treatment of cerebral and intracranial aneurysms, neuroendocrine metastases, intracranial dural arteriovenous fistula and patent ductus arteriosus. Other examples of specific embolization procedures include hepatic artery embolization and pulmonary artery embolization. Examples of such procedures are described, e.g., in Mourikis D., Chatziioannou A., Antoniou A., Kehagias D., Gikas D., Vlahous L., "Selective Arterial Embolization in the Management of Symptomatic Renal Angiomyolipomas (AMLs)," European Journal of Radiology 32(3):153-9, 1999 Dec.; Kalman D. Varenhorst E., "The Role of Arterial Embolization in Renal Cell Carcinoma," Scandinavian Journal of Urology & Nephrology, 33(3):162-70, 1999 Jun.; Lee W., Kim T S., Chung J W., Han J K., Kim S H., Park J H., "Renal Angiomyolipoma: Embolotherapy with a Mixture of Alcohol and Iodized Oil," Journal of Vascular & Interventional Radiology, 9(2):255-61, 1998 March-April; Layelle I., Flandroy P., Trotteur G., Dondelinger R F., "Arterial Embolization of Bone Metastases: is it Worthwhile?" Journal Belge de Radiologie, 81(5):223Oct. 5, 1998; Berman, M F., Hartmann A., Mast H., Sciacca R R., Mohr J P., PileSpellman J., Young W L., "Determinants of Resource Utilization in the Treatment of Brain Arteriovenous Malformations," Ajnr: American Journal of Neuroradiology, 20(10):2004-Nov.-Dec. 8, 1999 ; Shi H B., Suh D C., Lee H K., Lim S M., Kim D H., Choi C G., Lee C S., Rhim S C., "Preoperative Transarterial Embolization of Spinal Tumor: Embolization Techniques and Results," Ajnr: American Journal of Neuroradiology, 20(10):2009-Nov-Dec.15, 1999 ; Nagino M., Kamiya J., Kanai M., Uesaka K., Sano T., Yamamoto H., Hayakawa N., Nimura Y., "Right Trisegment Portal Vein Embolization for Biliary Tract Carcinoma: Technique and Clinical Utility," Surgery, 127(2):155-60,Feb. 2000; Mitsuzaki K., Yamashita Y., Utsunomiva D., Sumi S., Ogata I., Takahashi M., Kawakami S., Ueda S., "Balloon-Occluded Retrograde Transvenous Embolization of a Pelvic Arteriovenous Malformation," Cardiovascular & Interventional Radiology 22(6):518-Nov-Dec. 20, 1999.

In many instances, embolization procedures begin with diagnostic angiography to identify the source of bleeding. For example, in epistaxis, angiography of the external carotid artery with attention to the internal maxillary artery can be helpful. In pelvic fractures, the internal iliac arteries are examined angiographically. Selective and superselective angiography is more sensitive in finding the source of bleeding than are nonselective studies. Consequently, clinical suspicion and the results of other imaging studies, such as contrast-enhanced CT and radionuclide scans with Technetium Tc 99m-labeled RBCs, are important in guiding angiographic examination. In intra-abdominal bleeding, such as after complex trauma, CT scan may identify the site of acute bleeding, because acute bleeding often demonstrates higher density (Hounsfield units) than older blood; this is termed the "sentinel clot sign."

Hemorrhage may be identified by active extravasation of contrast outside of the confines of the vessel lumen. The angiographic appearance depends on the rate and location of bleeding. The extravasating contrast medium may flow towards the dependent part of the viscus; in the bowel, the extravasated contrast may outline the mucosa. When the bleeding site and artery have been identified on the initial angiogram, a catheter, often a 3F microcatheter, is placed as selectively as possible into the bleeding artery to confirm the bleeding and to stop it with embolization.

Coils have historically been the agent of choice for embolization. Coils are available in a variety of shapes and sizes; the largest coils measure 15 mm in diameter when deployed. Such a coil would be large enough to fill the common iliac artery, for instance. Once microcatheter technology (3F or smaller) became available, microcoils were developed to embolize increasingly smaller vessels. Microcoils assume a deployment diameter as small as 1 mm. In addition, some coils are straight when deployed; thus, the coil has the same diameter as the wire from which it is made (the term "straight coil" is a misnomer). The advantages of coils include their high radiopacity and that they can be deployed with high accuracy.

Particulate embolic agents are also useful in embolization. For example, acute hemorrhage may be treated using particulate embolic agents, including those comprised of polyvinyl alcohol (PVA), Embosphere Microsphere.TM. (see U.S. Pat. Nos. 5,648,100; and 5,635,215), and an absorbable gelatin sponge (Gelfoam). These agents are mixed with an iodine-contrast agent for fluoroscopic visualization and injected through a catheter or microcatheter. PVA is available in particle sizes ranging from 50-2000 micrometers, while Embospheres are available in particle sizes from 40-1200 micrometers. An appropriate range of particle size must be chosen based on the size of the vessels to be occluded. The smaller the particles, the more distal the embolization, and the greater the likelihood of tissue necrosis.

As noted above, gelfoam has also been used as a temporary occlusive agent; however, it can incite an inflammatory response, contributing to permanent thrombosis. Once injected, gelfoam induces a thrombogenic reaction, occluding the vessel. However, once occluded, thrombolytic enzymes degrade the clot and gelfoam, recanalizing the occluded vessel over a period of days to weeks. Gelfoam can be useful in trauma where a temporary occlusion is desired while either surgical repair of the injury is undertaken or the body's natural healing processes repair the damage. Gelfoam is available as either a sponge, which can be cut into pieces or from which a slurry can be made, or as powdered particles that average approximately 50 micrometers in diameter.

An embolizing agent is usually delivered using a catheter. The catheter delivering the embolizing agent composition may be a small diameter medical catheter. The particular catheter employed is not critical, provided that the catheter components and the embolizing agent are mutually compatible. In this regard, polyethylene catheter components can be useful. Other materials compatible with the embolizing agent composition may include fluoropolymers and silicone.

Once a catheter is in place, an embolizing agent composition containing microparticles is injected through the catheter slowly, typically with the assistance of X-ray or flouroscopic guidance. The particles should be of sufficient size that they do not remain mobile in the body. If the particles are too small, they can be engulfed by the body's white blood cells and carried to distant organs or be carried away in the microvasculature and travel until they reach a site of greater constriction. In preferred embodiments of the methods of the present invention, the embolic microparticies have a transverse cross-sectional dimension between 50 and 3,000 micrometers.

The embolizing agent composition can be introduced directly into critical blood vessels or they may be introduced upstream of target vessels. The amount of embolizing microparticles introduced during an embolization procedure will be an amount sufficient to cause embolization, e.g., to reduce or stop blood flow through the target vessels. The amount of embolizing agent composition delivered can vary depending on, e.g., the total of the vasculature to be embolized, and the concentration and size of the microparticles. Adjustment of such factors is within the skill of the ordinary artisan in the embolizing art.

After embolization, another arteriogram may be performed to confirm the completion of the procedure. Arterial flow will still be present to some extent to healthy body tissue proximal to the embolization, while flow to the diseased or targeted tissue is blocked. The procedure can take approximately 1 to 1 1/2 hours. As a result of the restricted blood flow, the diseased or targeted tissue begins to shrink.

Selected Clinical Applications of Embolization

As discussed above, embolization typically is performed using angiographic techniques with guidance and monitoring, e.g., fluoroscopic or X-ray guidance, to deliver an embolizing agent to vessels or arteries. Further, a vasodilator (e.g., adenosine) may be administered to the patient beforehand, simultaneously, or subsequently, to facilitate the procedure.

Importantly, while portions of the subsequent description include language relating to specific clinical applications of embolization, all types of embolization processes are considered to be within the contemplation of the methods of the present invention. Specifically, one of skill in the medical or embolizing art will understand and appreciate how microparticles of hydrolytically degradable hydrogels as described herein can be used in various embolization processes by guiding a delivery mechanism to a desired vascular body site, and delivering an amount of the microparticles to the site, to cause restriction, occlusion, filling, or plugging of one or more desired vessels and reduction or stoppage of blood flow through the vessels. Factors that might be considered, controlled, or adjusted for, in applying the process to any particular embolization process might include the chosen composition of the microparticles (e.g., to account for imaging, tracking, and detection of a radiopaque particle substrate); the amount of microparticles delivered to the body site; the method of delivery, including the particular equipment (e.g., catheter) used and the method and route used to place the dispensing end of the catheter at the desired body site, etc. Each of these factors will be appreciated by one of ordinary skill, and can be readily dealt with to apply the described methods to innumerable embolization processes.

A. Head and Neck

In the head and neck, embolotherapy most often is performed for epistaxis and traumatic hemorrhage. Otorhinolaryngologists differentiate anterior and posterior epistaxis on anatomic and clinical bases. Epistaxis results from a number of causes, including environmental factors such as temperature and humidity, infection, allergies, trauma, tumors, and chemical irritants. An advantage of embolization over surgical ligation is the more selective blockade of smaller branches. By embolizing just the bleeding branch, normal blood flow to the remainder of the internal maxillary distribution is retained. Complications of embolization may include the reflux of embolization material outside the intended area of embolization, which, in the worst case, may result in stroke or blindness. Embolization has been proven more effective than arterial ligation. Although embolization has a higher rate of minor complications, no difference in the rate of major complications was found. For traumatic hemorrhage, the technique of embolization is the same as for epistaxis. Because of the size of the arteries in the head and neck, microcatheters are often required.

B. Thorax

In the thorax, the two main indications for embolization in relation to hemorrhage are: (1) pulmonary arteriovenous malformations (PAVM); and (2) hemoptysis. PAVMs usually are congenital lesions, although they may occur after surgery or trauma. The congenital form is typically associated with hereditary hemorrhagic telangiectasia, also termed Rendu-Osler-Weber syndrome. There is a genetic predisposition to this condition. PAVMs can be single or multiple, and if large enough, can result in a physiologic right-to-left cardiac shunt. Clinical manifestations of the shunt include cyanosis and polycythemia. Stroke and brain abscesses can result from paradoxical embolism. PAVMs also may hemorrhage, which results in hemoptysis.

Treatment options for PAVMs include surgery and transcatheter therapy. The treatment objective is to relieve the symptoms of dyspnea and fatigue associated with the right-to-left shunt. In addition, if the patient suffers from paradoxical embolism, treatment prevents further episodes. As a result of the less invasive nature of the procedure and excellent technical success rate, embolization currently is considered the treatment of choice for PAVM, whether single or multiple. Embolotherapy is the clear treatment of choice for PAVMs.

Bronchial artery embolization is performed in patients with massive hemoptysis, defined as 500 cm.sup.3 of hemoptysis within a 24-hour period. Etiologies vary and include bronchiectasis, cystic fibrosis, neoplasm, sarcoidosis, tuberculosis, and other infections. Untreated, massive hemoptysis carries a high mortality rate. Death most often results from asphyxiation rather than exsanguination. Medical and surgical treatments for massive hemoptysis usually are ineffective, with mortality rates ranging from 35-100%. Embolization has an initial success rate of 95%, with less morbidity and mortality than surgical resection. Consequently, transcatheter embolization has become the therapy of choice for massive hemoptysis, with surgical resection currently reserved for failed embolization or for recurrent massive hemoptysis following multiple prior embolizations.

C. Abdomen and Pelvis

Many indications for embolization in the abdomen and pelvis exist. For embolization of hemorrhage, the most common indication is acute GI hemorrhage. Solid organ injury, usually to the liver and spleen, can readily be treated with embolization. Other indications exist, such as gynecologic/obstetric-related hemorrhage and pelvic ring fractures.

Once the source of bleeding is identified, an appropriate embolization procedure can be planned. The technique for embolization is different for upper GI bleeding and lower GI bleeding. The vascular supply in the UGI tract is so richly collateralized that relatively nonselective embolizations can be performed without risk of infarcting the underlying organs. Conversely, the LGI tract has less collateral supply, which necessitates more selective embolizations.

Outside the GI tract, there are organ specific considerations when performing embolizations in the abdomen. For instance, the liver has a dual blood supply, with 75% of the total supply from the portal vein and 25% from the hepatic artery. The hepatic artery invariably is responsible for hemorrhage resulting from trauma due to its higher blood pressure compared to the portal vein. Therefore, all embolizations in the liver are performed in the hepatic artery and not in the portal vein. Because of the dual blood supply, occlusion of large branches of the hepatic artery can be performed without risk of necrosis.

In contrast, embolizations of the spleen always should be performed as distally as possible. Occlusion of the splenic artery can result in splenic necrosis and the possibility of a splenic abscess postembolization. If occlusion of the entire splenic artery is contemplated for traumatic hemorrhage, total splenectomy instead of embolization or total splenectomy postembolization should be performed.

Further indications for hemorrhage embolization in the abdomen and pelvis include postpartum, postcesarean, and postoperative bleeding. Differential diagnoses for postpartum bleeding include laceration of the vaginal wall, abnormal placentation, retained products of conception, and uterine rupture. Conservative measures for treating postpartum bleeding include vaginal packing, dilatation and curettage to remove retained products, IV and intramuscular medications (eg, oxytocin, prostaglandins), and uterine massage. When conservative methods fail, embolization is a safe and effective procedure for controlling pelvic hemorrhage, avoids surgical risks, preserves fertility, and shortens hospital stays.

Finally, embolization of the internal iliac arteries is valuable in patients with hemodynamically unstable pelvic fractures. Protocols for trauma include treatment of associated soft-tissue injury first, followed by stabilization of the pelvic ring. Patients with persistent hemodynamic instability are candidates for embolization. As in other clinical settings, angiography is used to identify the source of hemorrhage, and a selective embolization is performed.

Embolizing Agent Compositions

According to the invention, the embolizing agent composition comprises a combination of microparticles and a biocompatible carrier. In certain embodiments, the embolizing agent composition is injectable. The embolizing agent composition can preferably comprise a contrast-enhancing agent which can be tracked and monitored by known methods, including radiography and fluoroscopy. The contrast-enhancing agent can be any material capable of enhancing contrast in a desired imaging modality (e.g., magnetic resonance, X-ray (e.g., CT), ultrasound, magnetotomography, electrical impedance imaging, light imaging (e.g. confocal microscopy and fluorescence imaging) and nuclear imaging (e.g. scintigraphy, SPECT and PET)), and is preferably capable of being substantially immobilized within the particles, e.g., included in the microparticles as part of a carbon coating or as part of a particle substrate. Contrast-enhancing agents are well known in the arts of embolization and similar medical practices, with any of a variety of such contrast-enhancing agents being suitable for use according to the methods of the invention.

Preferred embodiments of the invention can include a contrast-enhancing agent that is radiopaque in nature, in particular, a radiopaque material which exhibits permanent radiopacity, as many metals or metal oxides do. Permanent radiopacity is unlike some other contrast-enhancing agents or radiopaque materials used in embolization or similar medical applications which biodegrade or otherwise lose their effectiveness (radiopacity) over a certain period, e.g., days or weeks, such as 7 to 14 days. (See, e.g., PCT/GB98/02621). Advantage is that permanent radiopaque materials can be monitored or tracked for as long as they remain in the body, whereas other non-permanent contrast-enhancing agents or radiopaque materials have a limited time during which they may be detected and tracked.

The contrast-enhancing agent may be incorporated into the microparticle as part of the particle substrate. In one sense, a contrast-enhancing agent can be added to a material that is not detectable, e.g., not radiopaque, to make that material detectable. The contrast-enhancing agent may be provided in any such portion of a microparticle by known methods. According to a preferred mode of the invention, a permanent radiopaque material, such as a metal or metal oxide, can be incorporated into a hydrolytically degradable crosslinked hydrogel. The particle substrates themselves are permanently radiopaque, and can be individually and permanently detected and tracked following deposition into the body.

Some examples of radiopaque materials include paramagnetic materials (e.g. persistent free radicals or more preferably compounds, salts, and complexes of paramagnetic metal species, for example transition metal or lanthanide ions); heavy atom (i.e. atomic number of 37 or more) compounds, salts, or complexes (e.g. heavy metal compounds, iodinated compounds, etc.); radionuclide-containing compounds, salts, or complexes (e.g. salts, compounds or complexes of radioactive metal isotopes or radiodinated organic compounds); and superparamagentic particles (e.g. metal oxide or mixed oxide particles, particularly iron oxides). Preferred paramagnetic metals include Gd (III), Dy (III), Fe (II), Fe (III), Mn (III) and Ho (III), and paramagnetic Ni, Co and Eu species. Preferred heavy metals include Pb, Ba, Ag, Au, W, Cu, Bi and lanthanides such as Gd, etc.

The amount of contrast-enhancing agent included in a microparticle should be sufficient to allow detection of the microparticle as desired. Preferably, microparticles of the embolizing agent composition can comprise from about 10 to about 50 weight percent of contrast-enhancing agent, more preferably from about 20 to 40 weight percent contrastenhancing agent, and even more preferably about 30 weight percent contrast-enhancing agent. Optionally, some, i.e., only a portion, but not all microparticles used in a particular embolization procedure can include a contrast-enhancing agent. Microparticles that include a permanent radiopaque particle substrate can preferably have greater than 50 percent of their mass made up of the particle substrate.

As stated, the carrier can be any biocompatible fluid capable of delivering the microparticles to a desired site. Examples of suitable materials for a carrier can include saline, dextran, glycerol, polyethylene glycol, corn oil or safflower, or other polysaccharides or biocompatible organic polymers either singly or in combination. In use, the embolic agent composition can typically be injected in a fluid state, e.g., as a slurry, fluid suspension or emulsion, or as a gel, through a catheter, syringe needle, or cannula into a body site. When deposited into the blood stream, the carrier will disperse or be destroyed.

Hydrogels

As is known in the art, a hydrogel is a polymeric network formed by crosslinking one or more multifunctional backbone molecules or polymers. The resulting polymeric network is hydrophilic and swells in an aqueous environment thus forming a gel-like material, i.e., a hydrogel. Typically, a hydrogel comprises a backbone bonded to a crosslinking agent.

Hydrogels are characterized by their water-insolubility, hydrophilicity, high-water absorbability and swellable properties. The molecular components, units or segments of a hydrogel are characterized by a significant portion of hydrophilic components, units or segments, such as segments having ionic species or dissociable species, such as acids (e.g., carboxylic acids, phosphonic acids, sulfonic acids, sulfinic acids, phosphinic acids, etc.), bases (e.g., amine groups, proton accepting groups), or other groups that develop ionic properties when immersed in water (e.g., sulfonamides). Acryloyl groups (and to a lesser degree methacryloyl groups) and the class of acrylic polymers, polymer chains containing or terminated with oxyalkylene units (such as polyoxyethylene chains or polyoxyethylene/polyoxypropylene copolymer chains) are also well recognized as hydrophilic segments that may be present within hydrophilic polymers Certain preferred water insoluble polymeric compositions useful in the present invention are listed below, although the entire class of hydrogel materials known in the art may be used to varying degrees. The polymers set forth below and containing acid groups can be, as an option, partially or completely neutralized with alkali metal bases, either in the monomer or the polymer or both. While the list below contains many of the preferred polymers which may be used in hydrogels, the present invention is not limited to the use of just these polymers. Generally, polymers traditionally understood as hydrogels by those skilled in the art can also be used; for example: a) polyacrylic acid, polymethacrylic acid, polymaleic acid, copolymers thereof, and alkali metal and ammonium salts thereof; b) graft copolymers of starch and acrylic acid, starch and saponified acrylonitrile, starch and saponified ethyl acrylate, and acrylate-vinyl acetate copolymers saponified; c) polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl alkylether, polyethylene oxide, polyacrylamide, and copolymers thereof; d) copolymers of maleic anhydride and alkyl vinylethers; and e) saponified starch graft copolymers of acrylonitrile, acrylate esters, vinyl acetate, and starch graft copolymers of acrylic acid, methylacrylic acid, and maleic acid.

The above exemplary polymers are cross-linked either during polymerization or after the core is encapsulated. This cross-linking is achieved using hydrolytically degradable cross-linking agents by methods known to those skilled in the art. This cross-linking can be initiated in the presence of radiation or a chemical free radical initiator.

One of the many useful properties of hydrogels is their ability to absorb water and swell without dissolution of the matrix. As a hydrogel swells, the pore size of the hydrogel increases, enhancing uptake of aqueous solutions and the diffusion of entrapped compounds out of the hydrogel. These properties have allowed use of hydrogels as controlled drug release systems and as absorbent materials. However, the rate of swelling of dried hydrogels upon exposure to an aqueous solution is limited by diffusion of water into the glassy polymer matrix. Conventional dried hydrogels have relatively small pore sizes resulting in slow swelling and release or absorption of liquids. The size of the pores in the hydrogel can be a factor used in the selection of hydrogels with the appropriate properties for the specific vessel to be embolized in the practice of the present invention. The larger the pore size, the generally higher rate of initial swelling a hydrogel undergoes.

Among the many hydrogel polymers which are useful as matrix polymers include poly(hydroxyalkyl methacrylate)s of which poly-(2-hydroxyethyl methacrylate), poly(glyceryl methacrylate) and poly(hydroxypropyl methacrylate) are well-known and identified in the literature as (P-HEMA), (P-GMA) and (P-(HPMA), respectively. Other hydrogel polymers include poly(acrylamide), poly(methacrylamide), poly(N-vinyl-2-pyrrolidine), and poly(vinyl alcohol), hydroxypropyl guar, high molecular weight polypropylene glycol or polyethylene glycol, and the like.

Non-limiting examples of the unsaturated monomers used as a starting material include those polymerizable monomers known to be soluble in water, water/organic mixtures and organic solvents. Examples of these unsaturated monomer are: monomers containing an acid group, such as acrylic acid, beta-acryloyloxypropionic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, fumaric acid, itaconic acid, cinnamic acid, sorbic acid, 2-(meth)acryloylethane sulfonic acid, 2-(meth)acryloylpropane sulfonic acid, 2-(meth)acrylamido-2-methylpropane sulfonic acid, vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, vinyl phosphonic acid and 2-(meth)acryloyloxyethyl phosphate, and alkaline metal salts and alkaline earth metal salts, ammonium salts, and alkyl amine salts thereof; dialkyl amino alkyl(meth)acrylates, such as N,N-dimethylaminoethyl(meth)acrylate and N,N-dimethylaminopropyl(meth)acrylate, and quaternary compounds thereof (for example, a reaction product produced with alkylhalide, and a reaction product produced with dialkyl sulfuric acid); dialkyl amino hydroxyalkyl(meth)acrylates, and quaternary compounds thereof; N-alkyl vinyl pyridine halide; hydroxyalkyl(meth)acrylates, such as hydroxymethyl (meth)acrylate, 2-hydroxyethyl(meth)acrylate, and 2-hydroxypropyl (meth)acrylate; acrylamide, methacrylamide, N-ethyl (meth)acrylamide, N-propyl(meth)acrylamide, N-isopropyl(meth)acrylamide, N,N-dimethyl (meth)acrylamide, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, polyethylene glycol mono(meth)acrylate, vinylpyridine, N-vinylpyrrolidone, N-acryloyl piperidine, and N-acryloyl pyrrolidine; vinyl acetate; and alkyl (meth)acrylates, such as methyl (meth)acrylate, and ethyl (meth)acrylate. These monomers may be used individually, or in combination.

Among the aforementioned monomers, unsaturated monomers containing an acrylate moiety are preferred because the resulting water-absorbent resins have significantly improved water absorption characteristics. Preferred acrylate monomers include acrylic acids and water-soluble salts of acrylic acids. The water-soluble salts of acrylic acids include alkaline metal salts, alkaline earth metal salts, ammonium salts, hydroxy ammonium salts, amine salts and alkyl amine salts of acrylic acids having a neutralization rate within a range of from 30 mol % to 100 mol %, more preferably within a range of from 50 mol % to 99 mol %. Among the exemplified water-soluble salts, sodium salt and potassium salt are more preferred. These acrylate monomers may be used individually or in combination. When the unsaturated monomer contains an acrylate moiety as a chief constituent, the amount of monomers other than the acrylate monomer is preferably less than 40 weight percent, more preferably less than 30 weight percent, and most preferably less than 10 weight percent of the total hydrogel. By using monomers other than the acrylate monomer in the above-mentioned ratios, the water absorption characteristics of the resulting water-absorbent resin are further improved.

The backbones of the hydrogels used in the methods of the present invention are prepared from a mixture comprising a monomer, which has an active group available to react with the terminal reactive moieties of the hydrolytically degradable crosslinking agent to form covalent linkages. Moreover, the degradation products should also be substantially biocompatible as defined below. By "biocompatible" it is intended that the monomer used in the backbone will not substantially adversely affect the body and tissue of the living subject into which the embolic hydrogel is to be injected. More particularly, the material does not substantially adversely affect the growth and any other desired characteristics of the tissue surrounding the implanted embolus. It is also intended that the material used does not cause any substantially medically undesirable effect in any other parts of the living subject. Methods for assessing the biocompatibility of a material are well known.

Examples of hydrogel backbones suitable for use in the microparticles used in the methods of embolization of the present invention include, but are not limited to, optionally substituted poly(acrylamide), optionally substituted poly(acrylate), proteins, glycoproteins, phosphorylated proteins, acylated proteins, and chemically modified proteins, peptides, aminocarbohydrates, glycosaminoglycans, aminolipids, polyols, polythiols, polycarboxylic acids, polyamines, such as dilysine, poly(vinylamine) and polylysine, poly(ethylene glycol) amines, and pharmaceutical agents having at least two active groups. Preferred examples of a suitable backbone include, but are not limited to, poly(N-substituted acrylamide), poly(acrylamide), and poly(acrylate). The hydrolytically degradable crosslinking agent used in the hydrogels may be in a linear, branched or star form. In branched or star forms, three or more linear polymers are covalently crosslinked.

As will be apparent, because of the hydrolytically degradable linkages incorporated in the crosslinking agent, the hydrogels used in the methods of the present invention are hydrolytically degradable. Thus, the hydrogels used in the embolization methods of the present invention gradually break down or degrade in the body due to the hydrolysis of the hydrolytically degradable crosslinks. The degradation or breakdown of the embolic hydrogels in the body is gradual in nature and subject to control due to the hydrolytically degradable crosslinkers. The ability to control the rate of hydrolytic degradation of the embolic hydrogels turns on the composition of the polymeric backbone, the type of crosslinker use, and the number of crosslinks in a particular embolus.

Embolic Microparticles

Microspheres have been manufactured and used in vivo to occlude blood vessels in the treatment of arteriovascular malformation, fistulas and tumors (See U.S. Pat. No. 5,635,215; and Laurent et al., J. Am. Soc. Neuroiol, 17:533-540 (1996); and Beaujeux et al. J. Am. Soc. Neuroial, A:533-540 (1996)).

In general, microparticles for use in the present invention may have any shape, with microparticles which are spherical in shape being preferred. Microparticles for use in the present invention may have diameters ranging between about 10 .mu.m to about 5000 .mu.m. Preferably, microparticles for use in the present invention will have diameters ranging between 50 .mu.m and 3000 .mu.m. The microparticles for use in the present invention are flexible, such that they can easily pass into and through injection devices and small catheters without being permanently altered.

The microparticles for use in the present invention are also stable in suspension which allows the microparticles to be formulated and stored in suspension and injected with different liquids. More specifically, the hydrophilic nature of the microparticles permits placing them in suspension, and in particular, in the form of sterile and pyrogenic (pyrogen-free) injectable solutions, while avoiding the formation of aggregates or adhesion to the walls of storage containers and implantation devices, such as catheters, syringes, needles, and the like. Preferably, these injectable solutions contain microparticles distributed approximately in caliber segments ranging between about 10 .mu.m and about 5000 .mu.m.

Microparticles may be prepared by suspension polymerization, drop-by-drop polymerization or any other method known to the skilled artisan. The mode of microparticle preparation selected will usually depend upon the desired characteristics, such as microparticle diameter and chemical composition, for the resulting microparticles. The microparticles of the present invention can be made by standard methods of polymerization described in the art (See, e.g., E. Boschetti, Microspheres for Biochromatography and Biomedical Applications. Part I, Preparation of Microbands In: Microspheres, Microencapsulation and Liposomes, John Wiley & Sons, Arshady R., Ed., 1998, which is incorporated herein by reference). The microspheres of the invention may also be obtained by other methods of polymerization, such as those described in French Patent 2,378,808 and U.S. Pat. No. 5,648,100, each of which is incorporated herein by reference. In general, the polymerization of monomers in solution is carried out at a temperature ranging between about 0.degree. C. and about 100.degree. C., and between about 40.degree. C. and about 60.degree. C., in th presence of a polymerization reaction initiator.

Polymerization can be carried out in mass or in emulsion. In the case of a mass polymerization, the aqueous solution containing the different dissolved constituents and the initiator undergoes polymerization in an homogeneous medium. This makes it possible to access a lump of aqueous gel which can then be separated into microspheres, by passing, for example, through the mesh of a screen. Emulsion or suspension polymerization is a preferred method of preparation, since it makes it possible to access directly microspheres of a desired size. It can be conducted as follows: The aqueous solution containing the dissolved constituents (e.g., different monomers), is mixed by stirring, with a liquid organic phase which is not miscible in water, and optionally in the presence of an emulsifier. The rate of stirring is adjusted so as to obtain an aqueous phase emulsion in the organic phase forming drops of desired diameter. Polymerization is then started off by addition of the initiator. It is accompanied by an exothermic reaction and its development can then be followed by measuring the temperature of the reaction medium. It is possible to use as the organic phase vegetable or mineral oils, certain petroleum distillation products, chlorinated hydrocarbons or a mixture of these different solutions. Furthermore, when the polymerization initiator includes several components (redox system), it is possible to add one of them in the aqueous phase before emulsification. The microspheres thus obtained can then be recovered by cooling, decanting and filtration. They are then separated by size category and washed to eliminate any trace of secondary product.

Injected microparticles can generate some transient adverse reactions, such as local inflammation; therefore, the microparticles may contain or be injected with anti-inflammatory drugs, such as: salicylic acid derivatives including aspirin; para-aminophenol derivatives including acetaminophen; non-steroidal anti-inflammatory agents including indomethacin, sulindac, etodolac, tolmetin, diclodfenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin; anthranilic acids including mefenamic acid, meclofenamic acid; enolic acids such as piroxicam, tenoxicam, phenylbutazone, oxyphenthatrarone; and nabumetone. These anti-inflammatories are preferably adsorbed in the microparticle's network and released slowly over a relatively short period of time (e.g., a few days). The microparticles may also be used to release other specific drugs which can be incorporated within the microparticle network before injection into the patient. The drug may be released locally at the site of implantation over a short period of time to improve the overall treatment.

Incorporation of active molecules, such as drugs, into the microparticles of the present invention can be accomplished by mixing dry microparticles with solutions of said active molecules or drugs in an aqueous or hydro-organic solution. The microparticles swell by adsorbing the solutions and incorporate the active molecule of interest into the microparticle network. The active molecules will remain inside the microparticle due to an active mechanism of adsorption essentially based on ion exchange effect. The ability of various types of microparticles to adsorb drug molecules may be readily determined by the skilled artisan, and is dependent on the monomers present in the initial solution from which the microparticles are prepared.

Embolization Kits

The methods of the present invention may also be practiced using an embolization kit comprising a degradable crosslinked hydrogel microparticle. Such kits may contain the degradable crosslinked hydrogel microparticle in sterile lyophilized form, and may include a sterile container of an acceptable reconstitution liquid. Suitable reconstitution liquids are disclosed in Remington's Pharmaceutical Sciences and The United States Pharmacopia--The National Formulary. Such kits may alternatively contain a sterile container of a composition of the degradable crosslinked hydrogel microparticle of the invention. Such kits may also include, if desired, other conventional kit components, such as, for example, one or more carriers, one or more additional vials for mixing. Instructions, either as inserts or labels, indicating quantities of the degradable crosslinked hydrogel microparticles and carrier, guidelines for mixing these components, and protocols for administration may also be included in the kit. Sterilization of the containers and any materials included in the kit and lyophilization (also referred to as freeze-drying) of the degradable crosslinked hydrogel microparticles may be carried out using conventional sterilization and lyophilization methodologies known to those skilled in the art.

Lyophilization aids useful in the embolization kits include but are not limited to mannitol, lactose, sorbitol, dextran, Ficoll, and polyvinylpyrrolidine(PVP). Stabilization aids useful in the embolization kits include but are not limited to ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol. Bacteriostats useful in the embolization kits include but are not limited to benzyl alcohol, benzalkonium chloride, chlorobutanol, and methyl, propyl or butyl paraben. A component in an embolization kit can also serve more than one function. A reducing agent can also serve as a stabilization aid, a buffer can also serve as a transfer ligand, a lyophilization aid can also serve as a transfer, ancillary or co-ligand and so forth.

The predetermined amounts of each component of an embolization kit are determined by a variety of considerations that are in some cases specific for that component and in other cases dependent on the amount of another component or the presence and amount of an optional component. In general, the minimal amount of each component is used that will give the desired effect of the formulation. The desired effect of the formulation is that the end-user of the embolization kit may practice the embolization methods of the invention with a high degree of certainty that the subject will not be harmed.

The embolization kits also contain written instructions for the practicing end-user. These instructions may be affixed to one or more of the vials or to the container in which the vial or vials are packaged for shipping or may be a separate insert, termed the package insert.

Claim 1 of 63 Claims

1. A method of embolizing a vascular site in a mammal, comprising the step of: introducing into the vasculature of a mammal a microparticle comprising a hydrolytically degradable crosslinked hydrogel, thereby embolizing a vascular site of said mammal; wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound selected from the group consisting of a compound of formula 1 and a compound of formula 2; the compound of formula 1 is represented by -- see Original Patent.
 

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