CN1856329A - Inherently radiopaque polymeric products for embolotherapy - Google Patents

Abstract

Preferred embodiments relate to compositions of intrinsically radiopaque, biocompatible, bioresorbable polymer microparticles and methods of embolizing body lumens using them.

Description

Intrinsically radiopaque polymeric products for embolization

related application

Pursuant to U.S.C. Chapter 35, Section 119(e), this application claims priority to U.S. Provisional Application No. 60/601,677, filed August 13, 2004, and U.S. Provisional Application No. 60/505,951, filed September 25, 2003. The disclosures of both applications are incorporated herein by reference.

field of invention

Preferred embodiments of the invention relate to intrinsically radiopaque, biocompatible, bioresorbable polymer microparticles and methods of embolizing body lumens using them.

background

Embolization devices and agents include metal embolic rings, gel foams, bioglues, oils, alcohols, or particulate polymeric embolic agents used, for example, to control bleeding, prevent blood loss before or during surgical procedures, limit or block the impact of tumors and Blood supply to vascular malformations, eg, for uterine fibroids, tumors (ie, chemoembolization), hemorrhages (eg, trauma with hemorrhage), and arteriovenous malformations, fistulas, and aneurysms. The most commonly used are embolic rings and microparticles.

Conventional embolic coils are typically coiled strips of wire that are constrained within a linear configuration as they are delivered through a vascular catheter. They are pre-formed in a geometrically "crimped" state, to which they return after exiting the delivery catheter. Although there are many different designs and procedural variations with metal coils (see, for example, U.S. Patent Nos. 6,358,228 and 6,117,157); however, metal coils are all designed to take advantage of the first response, the hemodynamic response due to physical blockage in blood flow Induced blood clots, and in some cases for additional reactions, blood clots caused by the body's biological response to the coil material, where the therapeutic purpose of blocking blood flow is achieved by forming a blood clot in or around the metal coil.

While metallic coils possess some favorable physicomechanical properties, such as intrinsic radiopacity and shape memory (i.e., recovery to a preformed crimped state after deployment), the use of metal coils is associated with a number of disadvantages, including, inter alia, chronic tissue Injury, tissue proliferation, vascular occlusion, and permanent incorporation into tissue at the deployment site.

Metal-free options include liquid and particulate embolic agents. However, these also have significant disadvantages. Liquid embolic agents are generally divided into precipitating and active systems. In the former case, the polymer is solvated in a biologically acceptable solvent dispersed by vascular delivery, allowing the polymer to precipitate in situ (see, eg, US Pat. No. 5,851,508). Such agents may not settle quickly enough, allowing the unsolidified (sticky) polymer plug to migrate and embolize the unintended embolized tissue. This is especially important in arteriovenous malformations, where material readily enters the venous system and causes significant pulmonary embolism. Another disadvantage is the use of solvents such as dimethyl sulfoxide to transport the precipitated polymer.

Active embolic agents are mainly various cyanoacrylate chemical systems. An example of an FDA approved system is Cordis' TRUFILL ^(R) cyanoacrylate plug. Here, a liquid monomer and/or oligomeric cyanoacrylate mixture is introduced into the blood vessel site via a catheter, where the polymerization is initiated by the water available in the blood. Unfortunately, if released for too long, the cyanoacrylate sticky can bind the catheter tip to tissue with serious consequences. A second problem is that bioresorbable degradation products from these materials include formaldehyde, a toxic chemical.

Microparticle therapy Embolus consists of microparticles of different sizes, geometries and compositions. Schwarz et al., J. Biomater., 25(21), 5209-15(2004) disclosed that degradable hydroxy-ethylacrylate (HEA) microspheres had been synthesized and passed animal experiments, but they have not been commercialized yet. Microparticles for clinical use are usually suspended in radiopaque contrast fluid and released through vascular catheters by syringe injection. The three most commonly used particulate embolic agents today are GELFOAM ^(R) (absorbable gelatin microparticles from Pharmacia & Upjohn), polyvinyl alcohol (PVA) foam, and tripryl gelatin microspheres (EMBOSPHERE ^(R ) from Biosphere Medical). Unlike metal rings, these emboli are not inherently radiopaque. Indeed, placement visualization relies on inferences from fluoroscopic flow analysis at the time of embolization. There is no direct way to visualize the actual particles once they enter the body. Moreover, with PVA and EMBOSPHERE, the material may remain in the patient's body for a lifetime, increasing the risk of biorejection. With GELFOA M, there may be tissue rejection of this animal-derived agent.

For example, particulate embolic agents can be used to restrict or block blood supply, such as in the treatment of tumors and vascular malformations, such as in the treatment of uterine fibroids, cancerous tumors (i.e. chemoembolization), bleeding (e.g. trauma with bleeding) and arteriovenous malformations, fistulas and aneurysms. Routine use usually involves delivery through a guide catheter.

Biocompatible, bioresorbable particulate embolic agents have the potential advantage of being transient. Effective removal of particulate foreign matter restores the tissue to its natural state over time.

Radiopaque particulate embolic agents have the potential particular advantage of being visualized during or after embolization procedures. During the procedure, visualization of the microparticles allows physicians to precisely deliver them to the target vessel or tissue. That is, doctors will be able to ensure that the particles do not settle in unintended locations. This level of control will greatly increase the safety and efficacy of embolization therapy. Once the radiopaque microparticles are implanted, the procedure for tracking can be limited to non-invasive methods, such as pure radiography. For example a tumor can be tracked in size as the radiopaque embolic portion will converge as the mass/volume decreases over time.

It should be noted that biocompatible embolic microparticles are currently on the market. In fact, bioresorbable, biocompatible embolic agents are available in the form of GELFOAM ^(R) . However, it should be noted that due to the animal origin of this material, there is a potential rejection. Furthermore, GELFOAM ^(R) is not FDA-approved for this application.

Attempts have been made to produce more biocompatible degradable embolic microparticles. Likewise, investigational radiopaque embolic agents have been prepared and their potential efficacy tested in animals. In all cases it is necessary to add external agents such as iodinated contrast agents or metals or their salts (eg tungsten, barium sulphate, etc.) or to render the non-bioresorbable composition intrinsically radiopaque by halogenation.

To date, however, no biocompatible, bioresorbable, inherently radiopaque microparticles have been conceived or attempted for embolization therapy. Thus, there remains an important unmet need to develop biocompatible, bioresorbable, intrinsically radiopaque microparticles for embolic therapy that also allow for repeated treatments of the same site while preventing or alleviating existing or The aforementioned disadvantages of contemplated particulate embolic agents.

Thus, there remains a significant unmet need for the development of bioresorbable, radiopaque embolic agents in which the polymeric materials used to formulate these agents possess desirable metallic properties (e.g., radiopacity) while preventing or mitigating the use of The aforementioned disadvantages are accompanied by one of metal rings or liquid and particulate emboli.

Summary of the invention

According to a preferred embodiment of the present invention an embolization therapy product is disclosed. Embolotherapy products include particulate formulations comprising a biocompatible, bioresorbable polymer and optionally stereoisomers thereof, wherein the polymer contains a sufficient number of halogen atoms to render the embolotherapy product intrinsically non-toxic. radiolucent. In some preferred embodiments, the polymer comprises a homopolymer, a heteropolymer, or a mixture thereof.

In a preferred embodiment of the embolization therapy product, the polymer contains one or more units described by formula I:

Wherein X=1 or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4;

Where f is between 0 and less than 1; g is between 0 and 1 (including 0 and 1); and f+g is between 0 and 1 (including 0 and 1);

where A is any of the following:

wherein _R is independently H or an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N;

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N;

wherein B is an aliphatic linear or branched diol or poly(alkylene glycol) unit; and

Wherein R and _R can be independently selected from:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a; wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n; wherein a and n are independently between 0 and 8 (inclusive); J ₁ and J ₂ are independently Br or I; and for R ₂ , Q contains a free carboxylic acid group, and for R, Q are selected from hydrogen and carboxylic acid esters and amides, wherein said esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds .

In variations on this embodiment of formula I, R and _R can be selected from:

wherein R _in each R is independently an alkyl group of from 1 to about ₁₈ carbon atoms containing 0 to 5 heteroatoms selected from O and N, and _R in each R is H;

wherein j and m are independently integers from 1 to 8 inclusive; and

wherein Z is independently O or S.

In another preferred embodiment of the embolization therapy product, the polymer may contain one or more units described by formula II:

wherein X of each polymer unit is independently Br or I, Y is between 1 and 4 inclusive and R is up to ₁₈ carbon atoms and 0 to 8 heteroatoms selected from O and N Alkyl, aryl or alkaryl.

In variations on polymers of Formula II, all X groups may be ortho oriented and Y may be 1 or 2. In another variation, _R4 is alkyl.

In another variation, the structure of _R4 is:

wherein R of each unit is independently alkyl, aryl, or alkaryl containing up to 18 carbon atoms and 0 _to 8 heteroatoms selected from O and N; and R _{and R} are each independently selected from from hydrogen and alkyl having up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N.

In another variation of R of formula _II , at least one _unit of R contains a pendant _COOR group, wherein in each occurrence of it, the subunit _R is independently hydrogen or contains O An alkyl group of from 1 to about 18 carbon atoms having up to 5 heteroatoms selected from O and N.

In another variation of _R4 of Formula II, _R9 independently has the following structure:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a, wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n, wherein a and n are independently between 0 and 8 (inclusive); and J _{and J} are independently Br or I; and Q is selected from hydrogen, free carboxylic acid groups, and carboxylic acids Esters and amides, wherein said esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds. In another variation of _R4 of Formula II, _R9 independently has the following structure:

wherein R is _an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and R _is independently hydrogen Or an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N.

In another variation of _R4 of Formula II, _R9 independently has the following structure:

wherein j and m are independently integers from 1 to 8 inclusive, and _R are independently hydrogen or from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N alkyl.

In some embodiments of the embolotherapy products of the present invention, the polymer may be copolymerized with the poly(C ₁ -C ₄ alkylene glycol). Preferably, the poly(C ₁ -C ₄ alkylene glycol) comprises less than about 75 weight percent. More preferably, the poly(alkylene glycol) is poly(ethylene glycol).

In another variation of the polymers disclosed herein, from about 0.01% to about 0.99% of the polymer units contain pendant -COOH groups.

In another variation of formula II, _R4 can be aryl or alkaryl. Preferably, R ₄ aryl or alkaryl is selected so that the polymer units are diphenols.

In another preferred embodiment of the embolization therapy product, the polymer may contain one or more units described by formula III:

Wherein X of each polymer unit is independently Br or I, Y1 and Y2 are each independently between 0 and 4 (including 0 and 4), and Y1+Y2 of each unit is independently between 1 and 8 ( 1 and 8 are included), and _R of each polymer unit is independently an alkyl, aryl, or alkaryl group containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N.

In a preferred variation of formula III, all X groups are ortho-oriented. Preferably, Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4.

In another variation of formula III, at least one unit of _R2 may contain a pendant _COOR1 group, wherein in each unit where the _COOR1 group is present, the subunit _R1 is independently hydrogen or contains 0 to 5 An alkyl group of from 1 to about 18 carbon atoms of heteroatoms selected from O and N.

In another variation of formula III, R _{independently} has the following structure:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a, wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n, wherein a and n are independently between 0 and 8 (inclusive); and J _{and J} are independently Br or I; and Q is selected from hydrogen, free carboxylic acid groups, and carboxylic acids Esters and amides, wherein said esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds. In another variation of formula III, R _{independently} has the following structure:

wherein R is _an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and R _is independently hydrogen Or an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N.

In another variation of formula III, R _{independently} has the following structure:

wherein j and m are independently integers from 1 to 8 inclusive, and _R are independently hydrogen or from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N alkyl.

In a preferred variation of formula III, from about 0.01% to about 0.99% of the polymer units contain pendant COOH groups. Preferably, the polymer is copolymerized with up to 75% by weight of poly(C ₁ -C ₄ alkylene glycol). More preferably, the poly(C ₁ -C ₄ alkylene glycol) is poly(ethylene glycol).

In another preferred embodiment of the embolization therapy product, the polymer may contain one or more units described by formula IV:

Wherein each X is independently I or Br, Y1 and Y2 of each diphenol unit are independently between 0 and 4 (including 0 and 4), and Y1+Y2 of each diphenol unit is between 1 and 8 room (including 1 and 8);

Each R and _R2 is independently an alkyl, aryl, or alkaryl group containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N, wherein _R2 also contains pendant carboxylic acid groups ;

where A is:

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N;

P is about 75% or less poly(C ₁ -C ₄ alkylene glycol) units by weight; f is between 0 and less than 1, and g is between 0 and 1 (inclusive) ; and f+g is between 0 and 1 (including 0 and 1).

In a preferred variation of formula IV, P is about 50% by weight or less poly(ethylene glycol). More preferably, P is about 30% by weight or less poly(ethylene glycol).

In other preferred variations of formula IV, both R and _R2 contain pendant _COOR1 groups; wherein for R, the subunit _R1 is independently from 1 to 5 containing 0 to 5 heteroatoms selected from O and N an alkyl group of about 18 carbon atoms; and wherein for R ₂ , the subunit R ₁ is a hydrogen atom.

In other preferred variations of Formula IV, each R and R _{independently} have the following structure:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a, wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n, wherein a and n are independently between 0 and 8 (inclusive); and J _{and J} are independently Br or I; and Q _of R contains a free carboxylic acid group, and each Q for each R is independently selected from hydrogen, carboxylic acid esters and amides, wherein the esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and biologically and pharmaceutically active compounds esters and amides. In other preferred variations of Formula IV, each _R independently has the following structure:

wherein R is _an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and _R is hydrogen.

In other preferred variations of Formula IV, each _R independently has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and R ₁ is hydrogen. Preferably, each carboxylate or amide of R is an ethyl or butyl ester or amide.

In other preferred variations of formula IV, A is a -C(=O)- group. In another preferred variation of formula III, A is:

Wherein R ₃ is C ₄ -C ₁₂ alkyl, C ₈ -C ₁₄ aryl or C ₈ -C ₁₄ alkaryl. Preferably, _R3 is chosen so that A becomes part of the naturally occurring metabolite dicarboxylic acid. More preferably, _R3 is a moiety selected from _-CH2 -C(=O)-, _{-CH2- CH2} -C(=O)-, -CH=CH- and ( _-CH2- ) _z , Wherein z is an integer from 1 to 8 (including 1 and 8).

In other preferred variants of formula IV, all X groups are ortho-oriented. Preferably, Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4.

In other preferred variations of formula IV, each halogen is iodine.

In other preferred variations of formula IV, f is greater than 0.1 to about 0.3. Preferably, f is greater than 0.2 to about 0.25.

In other preferred variations of Formula IV, the poly(C ₁ -C ₄ alkylene glycol) fraction is less than about 25 wt%.

In other preferred variations of formula IV, g is greater than 0.1 to about 0.35. More preferably, g is greater than 0.2 to about 0.3.

In another preferred embodiment of the embolization therapy product, the polymer may contain one or more units described by formula V:

wherein each x is independently iodine or bromine; each y is independently between 0 and 4 (inclusive), and the total number of ring-substituted iodine and bromine is between 1 and 8 (inclusive) ); each R _{and R} is independently an alkyl, aryl _, or alkaryl group containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N, and R also includes side carboxy acid group;

where A is:

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 5 heteroatoms selected from O and N;

P is less than about 75 weight percent poly(C ₁ -C ₄ alkylene glycol) units by weight;

f ranges from greater than 0 to less than 1; g is between 0 and 1 inclusive; and f+g is between 0 and 1 inclusive.

Preferably, P is a poly(ethylene glycol) unit.

In a preferred variation of formula V, each R ₄ and R ₆ of the polymer contains a pendant -COOR ₁ group, wherein for each R ₆ , each subunit R ₁ independently contains 0 to 5 An alkyl group of from 1 to about 18 carbon atoms of a heteroatom selected from O and N, and for each R ₄ , each subgroup R ₁ is a hydrogen atom.

In other preferred variations of formula V, each of R _{and R} of the polymer is:

wherein _R is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and for each R ₆ , Each subunit R ₁ is independently an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N, and for each R ₄ , each subunit R ₁ is A hydrogen atom.

In other preferred variations of formula V, each _{R subunit} of R of the polymer is ethyl or butyl.

In other preferred variations of formula V, A is a -C(=O)- group. Alternatively, A can be:

Wherein R ₃ is C ₄ -C ₁₂ alkyl, C ₈ -C ₁₄ aryl or C ₈ -C ₁₄ alkaryl.

In other preferred variations of formula V, _R3 is chosen so that A becomes part of the naturally occurring metabolite dicarboxylic acid.

In other preferred variations of formula V, R ₃ is selected from -CH ₂ -C(=O)-, -CH ₂ -CH ₂ -C(=O)-, -CH=CH- and (-CH ₂ - ) z, where z is an integer from 1 to 8 (inclusive).

In other preferred variants of formula V, all X groups are ortho-oriented and y is 2 or 3.

In other preferred variations of formula V, each X group is iodine.

In other preferred variations of Formula V, f is greater than 0.1 to about 0.3.

In other preferred variations of Formula V, g is greater than 0.1 to about 0.35.

In a preferred embodiment of the embolization product of the invention, a microparticle formulation may be formulated for administration by injection. The formulations contain polymeric particles selected from the group consisting of spherical particles, geometrically inhomogeneous particles, porous particles, hollow particles, solid particles, and particles having an excluded diameter of from about 10 microns to about 5,000 microns, and mixtures thereof .

Alternatively, the formulation may contain a polymeric hydrogel composition.

In a preferred embodiment of the embolotherapy product, the polymer may also contain an effective amount of at least one therapeutic agent. Preferably, said at least one therapeutic agent is selected from chemotherapeutic agents, non-steroidal anti-inflammatory agents or steroidal anti-inflammatory agents.

In another preferred embodiment of the embolization product, the polymer may also contain an effective amount of a magnetic resonance enhancer.

In a preferred embodiment of the embolization product, the polymer may also contain an effective amount of a radiopaque agent selected from iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten, and mixtures thereof.

In another preferred embodiment of the embolization product, the polymer may also contain a coating of a biocompatible, bioresorbable polymer suitable to facilitate the selected biological response. Preferably, the biological response is selected from the group consisting of thrombus formation, cell adhesion, cell proliferation, attraction of inflammatory cells and deposition of matrix proteins, inhibition of thrombus formation, inhibition of cell adhesion, inhibition of cell proliferation, inhibition of inflammatory cells and inhibition of deposition of matrix proteins or their The combination.

In another preferred embodiment of the embolization therapy product, the polymer may contain the formula I:

Wherein X=1 or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4;

Where f is between 0 and less than 1; g is between 0 and 1 (including 0 and 1); and f+g is between 0 and 1 (including 0 and 1);

Wherein R and _R can be independently selected from:

Wherein, for R ₂ , R ₁ is H, and for R, R ₁ is a long-chain aliphatic hydrocarbon;

Wherein j and m are independently integers from 1 to 8 (including 1 and 8);

wherein Z is independently O or S;

wherein A is selected from:

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; and

wherein B is an aliphatic linear or branched diol or poly(alkylene glycol) unit.

According to another preferred embodiment of the present invention a method of embolizing a body lumen is disclosed. The method comprises the step of introducing into a body cavity an effective amount of an embolization product comprising a formulation of microparticles comprising a biocompatible, bioresorbable polymer, wherein said polymer contains a sufficient number of halogen atoms to enable embolization. The product is inherently radiopaque.

Preferably, the step of introducing is accomplished by injection through a catheter or syringe.

In another preferred embodiment of the present invention, a method of treating varicose and/or spider veins is disclosed. The method comprises administering to said varicose vein and/or spider vein an effective amount of an embolization product comprising a microparticle formulation comprising a biocompatible, bioresorbable polymer, wherein said polymer Containing a sufficient number of halogen atoms makes the embolization product inherently radiopaque.

Preferably, the step of administering is accomplished by injection through a catheter or syringe.

According to a preferred embodiment of the present invention, a method of promoting local release of a therapeutic agent to tissue is also disclosed. The method comprises the steps of: administering an embolization product to a blood vessel associated with the tissue in an amount sufficient to reduce blood flow to said tissue; and administering a therapeutic agent to the blood vessel alone or in combination with the embolization product so as to enhance localization of the therapeutic agent releasing; and repeating the steps of administering the embolotherapy product and the therapeutic agent after the first administration of the embolotherapy product has degraded sufficiently for the vessel to allow further administration. Embolization products useful in this method comprise formulations of microparticles comprising a biocompatible, bioresorbable polymer, wherein said polymer contains a sufficient number of halogen atoms to render the embolization product inherently radiopaque.

A method of retreating a body cavity is also disclosed. The method comprises the steps of: administering to a vascular region associated with said tissue an amount of a biocompatible, bioresorbable polymeric embolic therapy product sufficient to reduce blood flow to the tissue over a period of time; and at a later time Any products of embolization are administered to approximately the same area of the blood vessel as the tissue is to subject the tissue to retreatment or other form of reintervention.

In one embodiment of the embolotherapy product of the invention, the polymer comprises a non-naturally occurring bioresorbable intrinsic radiopaque polymer. In another variation, the polymer comprises a bioresorbable intrinsically radiopaque polymer comprising at least one amino acid.

Brief description of the drawings

Figures 1A-1C show x-ray images of a transplanted porcine kidney injected with a radiopaque polymeric embolic therapeutic composition according to a preferred embodiment.

Fig. 2 shows, according to the preferred embodiment, at 37 ℃, chemotherapy drug (paclitaxel (Paclitaxel)) sample in PBS containing Tween 20 from poly-DTE-carbonate coating (a kind of biocompatible polymer plug Dissolution in therapeutic coatings).

Figures 3a-b show an X-ray comparison of the apparent radiopacity exhibited by a radiopaque bioresorbable triiodinated tyrosine-derived polycarbonate film according to a preferred embodiment of the present invention. The optical density of the poly(I2DITE-co-20%PEG2k) carbonate film was comparable to that of human bone.

Best Mode for Carrying Out the Invention

According to preferred embodiments of the present invention bioresorbable, intrinsically radiopaque polymeric embolotherapy products are disclosed. They are useful, for example, in the treatment of tumors and vascular malformations, such as in the treatment of uterine fibroids, tumors (i.e., chemoembolization), bleeding (e.g., in trauma with ) and arteriovenous malformations, fistulas, and aneurysms. These embolic agents can also be delivered by other means, such as directly into the body via a syringe or other non-catheter vehicle to provide protection against spider veins (small unsightly or unwanted veins, close to the skin surface, tree-like veins) that appear on the legs and face Cosmetic treatment of branched or spider webs, red or blue) or even varicose veins (swollen and raised above the surface of the skin).

According to a preferred aspect of the invention, the embolization product may have at least some of the following properties: (a) sufficient radiopacity to allow visualization by conventional X-ray fluoroscopy; (b) sufficient particle compressibility, flowability and buoyancy to facilitate Drug delivery and function for embolization; (c) ideal surface properties or functionality can be tuned according to the needs of a range of applications (e.g. hemocompatibility or thrombus formation); (d) ideal biodegradation and bioresorption The spectrum can be tailored to the needs of a range of applications, including occlusion of the body lumen for varying lengths of time; (e) the ideal dwell time in the tissue body lumen so that any embolic products can later be used to re-treat blood vessels in approximately the same area and The tissue may allow other forms of retreatment such as surgery; (f) sufficient therapeutic amount to promote the desired biological and/or physiological effect and/or (g) sufficiently biocompatible, bioresorbable coating to promote Biological and/or physiological effects on the need to embolize a body lumen. A body cavity as used herein designates a vascular lumen or vessel (ie, arteries and/or veins of any size) containing the circulatory system of an organism.

According to one aspect of the present invention, the embolization product provided is a biocompatible, bioresorbable polymer particle formulation, wherein said polymer has a sufficient number of halogen atoms to render the embolization product visible under conventional x-ray fluoroscopy. development.

Preferred embodiments of the present invention relate to compositions and methods for embolization or occlusion of body lumens, preferably blood vessels, by the introduction of biocompatible, bioresorbable particulate polymeric materials. In a more preferred embodiment the polymeric material incorporates a radiopaque moiety, preferably a halogen, and most preferably iodine and/or bromine. As used herein, the term "bioresorbable" designates a polymer that undergoes biodegradation (chemical degradation by the action of water and/or enzymes) and at least some of the degradation products are excreted and/or reabsorbed by the body. The term "radio-opaque" as used herein is meant to include analytical techniques such as, but not limited to, x-ray photography, fluoroscopy, other forms of radiation, MRI, electromagnetic energy, structural imaging (e.g., computerized or computerized Tomography) and functional imaging (such as ultrasonography) methods of visualization of objects or materials containing said objects.

Furthermore, Applicants have discovered that the halogenated polymers of the present invention exhibit a unique combination of properties including radiopacity, biocompatibility and bioresorbability that are particularly advantageous for embolotherapy use. These polymers may include, for example, embodiments of the class described in U.S. Pat. No. 6,475,477 (which is incorporated herein by reference in its entirety), and more particularly iodinated and/or brominated biocompatible diphenols and polyphenols. (alkylene glycols), which exhibit a unique combination of properties that are particularly advantageous for embolic therapeutic uses. Importantly, while U.S. Patent No. 6,475,477 describes a large number of different polymers with different properties and combinations of characteristics, applicants have now discovered that certain polymers exhibit combinations of properties that are significantly and surprisingly superior to those described in U.S. Patent No. 6,475,477 Polymers disclosed in .

As used herein, "embolotherapy product" refers to any polymeric formulation suitable for embolization of a body lumen (eg, to control bleeding, prevent blood loss, and/or restrict or block blood flow). Examples include compositions such as injectable polymeric formulations, microparticles, hydrogels, and the like.

Embolization therapy products according to preferred embodiments are prepared by conventional design, replacing conventionally used non-therapeutic structural materials with disclosed radiopaque, biocompatible, bioresorbable polymers. Such products are intrinsically effective. An effective amount of an embolization therapy product according to a preferred embodiment is administered to the embolization site by conventional means.

Applicants have discovered that biocompatible, bioresorbable, intrinsically radiopaque polymers can be prepared from a wide variety of biocompatible, bioresorbable aryl-containing polymers. For example, among all the biocompatible, bioresorbable polymers reported in Table 1 below, halogenated (especially brominated and iodized (C) effect can introduce radiopacity into the aromatic ring. In fact, US Patent No. 6,475,477 demonstrates a large class of inherently radiopaque, biocompatible, bioresorbable polymers prepared in this way. Radiopacity can be imparted to the monomeric components of the other polymers in this table in a similar manner.

Table 1 US Patent patent title Guidance content 6,475,477 Radiopaque polymeric biomaterials Synthesis of iodine- and bromine-substituted diphenol monomers Synthesis of iodine- and bromine-substituted polycarbonate homopolymers and copolymers Synthesis of iodine- and bromine-substituted polyarylate homopolymers and copolymers 5,658,995 Copolymers of tyrosine-based polycarbonates and poly(alkylene oxides) Random block copolymers synthesized from tyrosine-derived diphenolic monomers and poly(alkylene oxide) 6,048,521 Copolymers of tyrosine-based polyarylates and poly(alkylene oxides) Random block copolymers of polycarbonates and polyarylates with poly(alkylene oxides) 6,120,491 Biodegradable anionic polymer derived from the amino acid L-tyrosine Synthesis of polycarbonate and block copolymers of polyarlates with pendant carboxylic acid groups and poly(alkylene oxide) groups on the main chain 6,284,862 Monomers derived from hydroxy acids and polymers prepared therefrom ●Synthesis of aliphatic-aromatic dihydroxy monomers and bioresorbable polymers 4,863,735 Biodegradable polymeric drug delivery system with adjuvant activity ●Synthesis of poly(iminocarbonate) 6,238,687 Biodegradable polymers, compositions, products, and methods of making and using them ●A method for preparing phosphorus and deaminotyrosyl L-tyrosine linkages on the polymer backbone 5,912,225 Biodegradable poly(phosphate-co-deaminotyrosyl L-tyrosine ester) compounds, compositions, products, and methods of making and using them ●Process for preparing polymers containing phosphorus and deaminotyrosyl L-tyrosine linkages 4,638,045 Non-peptidic acid is biodigestible ●Most monomer units have 2 or 3 amino groups polymer acid polymer 6,602,497 Strictly alternating poly(alkylene oxide ether) copolymers ●Polyethers of strictly alternating poly(alkylene oxide) and tyrosine-derived monomeric repeat units 5,198,507 Synthesis of amino acid-derived biodigestible polymers Polymer blends of amino acid-derived polycarbonate and polyiminocarbonate prepared from diphenolic starting materials derived from the same amino acid

All US patents described in Table 1 and their methods of preparation are hereby incorporated by reference in their entirety. The polyethers of US Patent No. 6,602,497 may require crosslinking prior to use in embolization therapy. However, suitable crosslinking methods are essentially routine and without undue experimentation to those skilled in the art.

As used herein, the term "ortho-oriented" refers to orientation relative to the phenoxyol group.

As used herein, the term "intrinsically radiopaque" refers to a polymer that is substantially radiopaque due to the covalent bonding of halogen species to the polymer. Thus, the term does not include polymers simply mixed with halogenated species or other radiopaque agents such as metals and complexes thereof.

Variations in polymer halogenation combinations in Table 1 can generally be represented by the following formula. It should be noted that the combination ranges indicated below exceed those described in Table 1.

It is to be understood that the various polymer formula representations may include homopolymers and heteropolymers, and also include their stereoisomers. As used herein, homopolymer refers to a polymer that includes all monomers of the same type. A heteropolymer as used herein refers to a polymer comprising two or more different types of monomers, also known as a copolymer. Heteropolymers or copolymers may be of the known block, random and alternating types. Further in terms of different polymer formula forms, embolotherapy products according to embodiments of the present invention may include homopolymers, heteropolymers and/or mixtures of such polymers.

preferred polymer

According to a preferred embodiment of the present invention there is disclosed an embolization product comprising an intrinsically radiopaque, biocompatible, bioresorbable polymer, including homopolymers, copolymers and mixtures thereof, wherein the polymer Contains one or more of the following units (Formula I):

Wherein X=1 or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4;

Wherein the range of f and g can be specified from 0 to 1 according to the combined/performance needs, provided that f is less than 1 and f+g is between 0 and 1 (including 0 and 1);

R and _R can be independently selected from:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a; wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n; wherein a and n are independently between 0 and 8 (inclusive); and J ₁ and J ₂ are independently Br or I; and for each R ₂ , Q contains a free carboxylic acid group , and for each R, Q is selected from hydrogen and carboxylic acid esters and amides, wherein the esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and biologically and pharmaceutically active Esters and amides of compounds.

In a more preferred embodiment of formula I, R and _R can be independently selected from:

wherein R for _each R _is H and _R for each R is independently a long-chain aliphatic hydrocarbon, and in some embodiments, is from 1 containing 0 to 5 heteroatoms selected from O and N Alkyl groups of up to about 18 carbon atoms;

Wherein j and m are independently integers from 1 to 8 (including 1 and 8);

wherein Z is independently O or S;

A is:

Wherein R ₁ is as previously defined;

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; and

wherein B is an aliphatic linear or branched diol or poly(alkylene glycol) unit.

According to one embodiment of the present invention there is provided a product wherein the intrinsic radiopaque, biocompatible, bioresorbable polymer contains one or more units described by formula II:

wherein X _of each polymer unit is independently Br or I, Y is between 1 and 4 inclusive, and R is a compound containing up to about 18 carbon atoms and 0 to 8 members selected from O and N Alkyl, aryl, or alkaryl of heteroatoms.

When R is _alkyl , it preferably has the following structure:

wherein R of each unit is independently an alkyl, aryl, or alkaryl group containing up to about 18 carbon atoms and 0 _to 8 heteroatoms selected from O and N; and _{each of} R and _R is independently selected from hydrogen and alkyl groups having up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N.

Each R ₉ preferably contains a pendant COOR ₁ group, wherein the subunit R ₁ is as previously defined. In one embodiment, _R9 is:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ )a; wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ - ) n; wherein a and n are independently between 0 and 8 (inclusive); and J _{and J} are independently Br or I; and Q is selected from hydrogen, free carboxylic acid groups, and carboxylate and amides, wherein the esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds.

More preferably, each _R independently has the following structure:

wherein R _5a is as defined before, and the COOR ₁ group is as defined herein; and wherein m is an integer from 1 to 8 inclusive.

In another preferred embodiment, _R9 is:

wherein j and m are independently integers from 1 to 8 inclusive, and the COOR ₁ group is as described for R ₉ .

Preferred polymer embodiments containing R ₄ aryl or alkaryl groups are selected such that the units described by Formula II are diphenols.

In another preferred embodiment of the invention, the diphenolic polymer may contain one or more diphenolic units described by formula III:

Wherein X and R ₂ are identical to the description of formula I and formula II herein, Y1 and Y2 are independently between 0 and 4 (including 0 and 4), and Y1+Y2 are between 1 and 8 (including 1 and 8) .

In a more preferred aspect of this polymer embodiment, the diphenolic polymer contains one or more units described by formula IV:

Wherein each X is independently I or Br, Y1 and Y2 of each diphenol unit are independently between 0 and 4 (including 0 and 4), and Y1+Y2 of each diphenol unit is between 1 and 8 room (including 1 and 8);

Each R and R are _{independently} alkyl, aryl, or alkaryl containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N, wherein R _also includes pendant carboxylic acid groups ;

A is:

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; P is poly( C ₁ -C ₄ alkylene glycol) units; f between 0 and less than 1 (including 0 and 1); g between 0 and 1 (including 0 and 1), f+g between 0 and 1 between (including 0 and 1); and the poly(alkylene glycol) is about 75% or less by weight. P is preferably poly(ethylene glycol) in an amount by weight of about 50% or less, and more preferably about 30% or less.

R and R _preferably each contain _a pendant COOR group wherein for R the subunit _R is independently an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N , and for R ₂ , the subunit R ₁ is a hydrogen atom.

In a preferred embodiment, each R and R _{independently} have the following structure:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a; wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n; wherein a and n are independently between 0 and 8 (inclusive); and J ₁ and J ₂ are independently Br or I; and for each R ₂ , Q contains a free carboxylic acid group , and for each R, Q is independently selected from hydrogen, carboxylic acid esters and amides, wherein the esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and biological and pharmaceutical Esters and amides of the above active compounds.

More preferably, each R and R _{independently} have the following structure:

wherein R _5a is as previously defined for formula II and the COOR ₁ group is as defined herein for R and R ₂ . In more preferred embodiments, R and R _species may be selected from:

wherein j and m are independently integers from 1 to 8 inclusive, and COOR ₁ is as defined for R and R ₂ .

In another variation of the polymer, each _R subunit of R is ethyl or butyl.

In another embodiment, A is -C(=O)-.

In another embodiment, A is:

wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N, and more preferably C ₄ -C ₁₂ alkyl, C ₈ -C ₁₄ aryl or C ₈ -C ₁₄ alkaryl. In another preferred embodiment, R ₃ may be selected from -CH ₂ -C(=O)-, -CH ₂ -CH ₂ -C(=O)-, -CH=CH- and (-CH ₂ -) z, wherein z is an integer from 0 to 8 (inclusive).

Polymers according to the invention include embodiments in which both iodine and bromine occur as ring substituents.

According to another aspect of the preferred embodiment, there is provided an embolotherapy product formed from a ring-substituted polymer comprising one or more units described by formula V:

wherein each X _is independently iodine or bromine; each y is independently 1 or 2; each R and R is _{independently} a heteroatom containing up to 18 carbon atoms and 0 to 8 selected from O and N Alkyl, aryl or alkaryl; and A, P, f and g are the same as described above for formula IV.

R ₄ and R ₆ preferably each contain a pendant COOR ₁ group, wherein for R ₆ the subunit R ₁ is independently an alkane of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O or N and for R ₄ , the subunit R ₁ is a hydrogen atom. More preferably, each R ₄ and R ₆ is:

wherein R _5a is as previously defined for formula II and the COOR ₁ group is as defined herein for R ₄ and R ₆ .

It should be understood that the forms of the different polymer formulas are schematic only and that the represented polymer structures of Formulas IV and V are random copolymers with respect to the P position, so that different subunits may occur in random sequences throughout the polymeric backbone. In most cases, A is attached to P or a phenolic ring.

Typically, P is a poly(alkylene glycol) unit having a molecular weight of about 10,000 or less, and more preferably about 4000 or less. P is preferably a poly(ethylene glycol) unit having a molecular weight between about 1000 and 2000.

When A is a carbonyl group (C=O), preferred embodiments are polymers of formula IV comprising polycarbonate and polymers of formula V comprising poly(amide carbonate). When A is:

Preferred embodiments are polymers of Formula IV containing polyarylates and polymers of Formula V containing poly(esteramides).

In the embodiment wherein formula IV is defined as polyarylate and formula V is defined as poly(ester amide), R _is saturated or unsaturated, substituted or unsubstituted containing up to about 18 carbon atoms and 0 to 8 an alkyl, aryl or alkaryl group of heteroatoms selected from O and N. In a preferred embodiment, _R3 is an alkyl group containing from about 2 to about 12 carbon atoms. In some preferred embodiments, R ₃ is linear or branched alkyl. In a more preferred embodiment, the R ₃ group is -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -. The _R3 group may be substituted with any suitable functional group which preferably does not or is not prone to cross-react with other monomeric compounds during polymerization which would otherwise seriously interfere with the formation of the polymers of the present invention by polymerization as described below. Where cross-reactivity may occur, methods can be employed by those skilled in the art (eg, using protecting groups or other methods known in the art) to obtain preferred compounds.

In certain preferred embodiments, _R3 is selected such that moieties A of Formulas IV and V are derived from naturally occurring metabolites dicarboxylic acids or highly biocompatible compounds. For example, in some embodiments, _R is selected such that the polyarylate A moiety of Formula III is derived from an intermediate dicarboxylic acid known to be an intermediate of the Krebs cycle of the cellular respiration pathway. Such dicarboxylic acids include sebacic, adipic, oxalic, malonic, glutaric, pimelic, suberic and azelaic acids. Therefore, R ₃ is more preferably a moiety selected from -CH═CH- and (-CH ₂ -)z, wherein z is an integer from 0 to 8, and preferably 4 to 8 inclusive.

In certain embodiments, X of Formulas IV and V is preferably iodine. In certain embodiments, when P occurs in Formulas IV and V, then P is preferably a poly(ethylene glycol) unit. In formulas IV and V, when f occurs, preferably F is from greater than 0.1 to about 0.3 inclusive, and more preferably from greater than 0.2 to about 0.25. As described in Formulas IV and V, unless otherwise indicated, are dicarboxylic acid or -C(=O)- units, carboxylate monomer units, free carboxylic acid units in the polymerized units of Formulas IV and V and the total molar amount of poly(alkylene glycol) units are reported as mole fractions.

Applicants have recognized that the mole fraction of free carboxylic acid units (e.g., desaminotyrosyl-tyrosine (DT) units) in the polymers of the preferred embodiments can be adjusted as can be adjusted in the embolotherapy compositions of the present invention. degradation/resorbability. For example, applicants have recognized that a polymer containing about 35% free carboxylic acid units (mole fraction about 0.35) resorbs about 90% in about 15 days, which may be a clinical requirement for an embolic therapeutic. Stated another way, the higher the mole fraction of carboxylic acid units, the shorter the lifetime of the embolic therapeutic agent in the body. In certain embodiments where the lifetime of the embolic therapeutic agent is desired to be several weeks to several months, a polymer having a "g" value of from about 0.2 to about 0.3 is desired. According to a preferred embodiment, the mole fraction of repeating units derived from carboxylic acid units in Formulas IV and V, g, ranges from greater than about 0.1 to about 0.3 inclusive, preferably from greater than about 0.2 to about 0.3. However, the present invention also includes the use of polymers wherein g=0 to prepare slow resorbing compositions and devices.

In certain preferred embodiments of the embolic therapeutic agent, the copolymer used has a weight average molecular weight (Mw) of from about 20,000 to about 200,000, preferably from about 50,000 to about 150,000, and more preferably from about 75,000 to about 100,000. The polydispersity (Pd) values of the copolymers range from about 1.5 to about 2.5 and are typically about 2. The corresponding number average molecular weight (Mn) of the copolymer for the embolic therapeutic agent can be calculated as described above and has a value of about 10,000 to about 100,000, more preferably about 25,000 to about 75,000, and even more preferably about 37,500 to about 50,000. Molecular weights were measured by gel permeation chromatography (GPC) relative to polystyrene standards without further correction.

Preparation

The embolotherapeutic polymers of Formula IV can be prepared by any number of methods. As noted above, the polymers described by Formula IV optionally include ring-substituted diphenolic polycarbonates or polyarylates containing diphenolic ester units of pendant _COOR groups in defined relative amounts, pendant COOH groups Groups of diphenol units and poly(alkylene glycol) units. Accordingly, a method for preparing polymers with free carboxylic acid groups involves combining desired ratios of poly(alkylene glycol) and one or more ring-substituted diphenolic monomeric compounds (including a certain amount of compounds having pendant COOR groups ₎ A monomeric compound of a group in which the subunit _R is a protecting group, preferably a tert-butyl ester group, the stoichiometric amount corresponding to the mole fraction of the desired pendant COOH group) polymerized, followed by removal by deprotection tert-butyl ester protecting group, forming a pendant COOH group.

Likewise with a desired ratio of poly(alkylene glycol) and ring _{-substituted aliphatic-aromatic dihydroxyester units with pendant COOR 1 groups} (including a certain amount of mono A body compound, wherein the subunit R ₁ is a protecting group, preferably a tert-butyl ester group, the stoichiometric amount is equivalent to the molar fraction of the required side group-COOH group) polymerization, and then deprotected to prepare the poly( amide carbonate) and poly(ester amide).

Examples of methods suitable for making the polycarbonate or polyarylate polymers of the preferred embodiments are disclosed in U.S. Patent Nos. 5,099,060, 5,587,507, 5,658,995, 5,670,602, 6,120,491, and 6,475,477, the disclosures of which are incorporated herein by reference . Other suitable methods, associated catalysts and solvents are known in the art and are described in Schnell, Chemistry and Physics of Polycarbonates (Interscience, New York 1964), which is taught by incorporated herein by reference.

Also available in the commonly owned (commonly owned) filed on August 13, 2004, but concurrently pending, by Joachim B. ) U.S. Patent Application (Attorney No. (Attomey Docket No) P27,286 USA) for the preparation of polycarbonates by a new polymerization process, entitled "Radiopaque Polymeric Medical Devices (Radiopaque Polymeric Medical Devices)", which discloses The contents of are incorporated herein by reference in their entirety. Briefly, the method involves dissolving diphenolic monomers and polyethylene glycol in dichloromethane containing 0.1M pyridine or triethylamine. A solution of phosgene in toluene was then added at a constant rate, followed by quenching and work-up of the polymer. Residual pyridine, if used, is then removed by stirring a tetrahydrofuran (THF) polymer solution of a strong acid form resin (eg, AMBERLYST ^™ 15). This method is broadly applicable to any polycarbonate of formula II.

Methods of preparing the diphenolic monomers used to prepare the polymers of the present invention are disclosed, for example, in US Patent Nos. 5,587,507 and 5,670,602. In particular, such documents disclose the preparation of non-ester desaminotyrosyl-tyrosine free carboxylic acids (DT) and desaminotyrosyl-tyrosine esters, including ethyl esters (DTE), butyl esters ( DTB), hexyl ester (DTH), octyl ester (DTO), benzyl ester (DTBn) and other ester methods. Iodine- and bromine-substituted diphenolic monomers can be prepared, for example, by coupling together two phenolic compounds in which one or both phenolic rings are substituted with iodine or bromine, by any of the methods disclosed herein, or by any suitable iodine The iodinated or brominated method forms iodinated or brominated diphenols by coupling.

The preparation of poly(ester amides) and poly(amide carbonates) of formula V and the aliphatic-aromatic dihydroxy monomers (including ring-iodinated or brominated monomers) from which they are polymerized is described in U.S. Patent No. 6,284,862 ), the disclosure of which is incorporated herein by reference. The disclosed poly(amide carbonate) polymerization process is adapted to the process discussed above, wherein the toluene solution of phosgene replaces the bubbled gaseous phosgene throughout the monomer solution.

Although any of the methods described above are suitable for use herein, in a preferred embodiment, polycarbonate, polyaryl For compounds, poly(ester amides) and poly(amide carbonates), cross-reaction of monomeric carboxylic acid groups with comonomers may occur. Accordingly, in certain preferred embodiments, the polymers of the preferred embodiments are formed by combining an iodo or bromo ring substituted alkyl ester monomer with a poly(alkylene glycol) and a temporarily protected free acid monomer (where the free acid prepared by polymerization of monomers whose functional groups are masked by temporary protecting groups), which may also have iodo or bromo ring substituents, to form polycarbonates, polyarylates, poly(esteramides) or poly(amide carbonates) Polymerized units from which transient protecting groups are selectively removed to yield the corresponding free carboxylic acid groups. This method is broadly applicable to any polymer of formula II where pendant free carboxylic acid groups are expected to be produced.

Any suitable protection/deprotection method is suitable for use in preparing the preferred embodiment polymerization devices, including, for example, the method for converting DTBn moieties to DT moieties described in US Patent 6,120,491, which is incorporated herein by reference. A similar process is described in above-mentioned US Patent No. 6,284,862, in which poly(ester amides) and poly(amide carbonates) with free carboxylic acid groups are prepared by hydrogenolysis of the corresponding benzyl ester copolymers. In other words, the method of US Patent No. 6,120,491 can be extended to any polymer of Formula II where pendant free carboxylic acid groups are desired. In preferred embodiments, the polymers of the preferred embodiments are prepared using the novel method of deprotection of commonly owned U.S. Patent Application No. 60/601,743, prepared by Joachim B. Kohn, Durgadas Bolikal, Aaron F. Pesnell, Joan Zeltinger, Donald K. .Brandom and Eric Schmid, 13 August 2004, entitled "Radiopaque Polymeric Medical Devices." Selective removal of tert-butyl ester protecting groups on hydrolytically unstable polymers provides new polymers with free carboxylic acid groups in place of tert-butyl ester groups.

The polymer is contacted with the acid by dissolving the polymer in a suitable solvent containing an effective amount of the acid. Any suitable inert solvent in which the deprotected polymer is soluble may be used in the reaction mixture in the previous step of the process. Examples of suitable solvents include, but are not limited to, chloroform, dichloromethane, THF, dimethylformamide, and the like. In certain preferred embodiments, the solvent contains dichloromethane.

Any suitable weak acid that facilitates the selective removal of the tert-butyl protecting group on the carboxylic acid group of the donating polymer by acidolysis may be used in accordance with the present method. Examples of some suitable weak acids include acids with a pKa of from about 0 to about 4, including formic acid, trifluoroacetic acid, chloroacetic acid, and the like. In certain preferred embodiments, the weak acid is trifluoroacetic acid.

The amount of weak acid used should be the maximum amount which does not affect the solubility of the polymer after addition of solvent. Among them, the weak acid can be used as a solvent for dissolving the polymer. In this embodiment, the preferred acid is formic acid.

The contacting step, or portions thereof, can be carried out under any suitable conditions effective to selectively remove the tert-butyl protecting group by acidolysis. Those skilled in the art can readily adopt any acid hydrolysis method for the contacting step of the preferred embodiment to selectively remove the tert-butyl group without undue experimentation. For example, in certain preferred embodiments, the contacting step is performed at about 25°C and about 1 atm.

Based on the disclosure herein, one skilled in the art will readily prepare a variety of hydrolytically labile polymers bearing free carboxylic acid groups from corresponding polymers containing t-butyl protected free carboxylic acid repeat units, and in particular The polymers of the preferred embodiments are used, for example, in various medical devices.

Following polymerization and deprotection, suitable workup of the polymers of the preferred embodiments can be accomplished by any known method to prepare embolotherapeutic compositions and devices for use in the methods of the preferred embodiments. For example, in certain preferred embodiments, the polymer is shaped into microparticles suitable for use in compositions for embolization or occlusion of body lumens, preferably blood vessels. Examples of preferred microparticles include, but are not limited to, spherical microparticles, geometrically inhomogeneous microparticles, porous microparticles, solid microparticles, hollow microparticles, and those having an exclusion diameter of from about 10 to about 3000 microns, and more preferably from about 40 to about 2,400 microns. particle. Among other embolotherapy products, polymers can form hydrogels for embolization or occlusion of body lumens.

Any conventional method for preparing polymer microparticles, hydrogels, etc. may be used for the preferred embodiments. Based on the disclosure herein, embolization products of preferred embodiments can be readily prepared by those skilled in the art without undue experimentation.

For example, polymer microparticles are typically prepared by adding a dilution (approximately 5 wt %) of the polymer in a solvent for the polymer (e.g., dimethyl sulfoxide (DMSO)) to a solvent containing a suitable surfactant using a finely metered needle. prepared in water. The metering needle selected will determine the polymer particle size. Precipitated polymer spheres were isolated by filtration through a dropping funnel and air-dried, followed by cryogenic grinding and drying under vacuum optionally at elevated temperature (approx. 50° C.) to prevent agglomerate formation.

The polymers used in the preferred embodiments can be adapted by those skilled in the art without undue experimentation to known methods of preparing embolotherapy polymer microparticles. The particle size range will vary depending on the embolization indication. Typical polymer particle sizes range from about 10 to 3000 microns, and are more typically divided into the following clusters: about 45 to about 90 microns (μm), about 90 to about 190 μm, about 190 to about 300 μm, about 300 to about 500 About 500 to about 710 μm, about 710 to about 1,000 μm, about 1,000 to about 1,400 μm, about 1,400 to about 2,000 μm, about 2,000 to about 2,400 μm, and about 2,400 to about 3,000 μm.

The PEG-containing polymers used in the preferred embodiments have been found to have surface properties well suited to the formation of micron-sized particles by fine metering needles.

Polymer preparation

In another preferred embodiment of the products and methods described above, the polymer is formulated with an effective amount of at least one magnetic resonance enhancer. In yet another preferred embodiment of the products and methods described above, the polymer is formulated with an effective amount of at least one therapeutic agent and at least one magnetic resonance enhancing agent. In yet another preferred embodiment of the products and methods described above, the polymer is formulated with a radiopaque agent such as, but not limited to, iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten, and mixtures thereof.

In a preferred aspect, inherently radiopaque, biocompatible, bioresorbable polymers can be prepared in the form of spherical microparticles. Alternatively, the polymers can be prepared in geometrically non-uniform particulate form. Spherical or geometrically inhomogeneous microparticles can be characterized as hydrogels, where the microparticles are porous, solid or hollow. The microparticles may have an excluded diameter ranging from about 10 to about 5000 microns, preferably from about 40 to 3000 microns and more preferably from about 45 to 2,400 microns. Microparticles may incorporate one or more of the therapeutic agents, magnetic resonance enhancing agents, and radiopaque agents disclosed above.

Examples of preferred magnetic resonance enhancers include, but are not limited to, gadolinium salts such as gadolinium carbonate, gadolinium oxide, gadolinium chloride, mixtures thereof, and the like. In compositions and devices containing a magnetic resonance enhancing agent, a sufficient amount of magnetic resonance enhancing agent for radiographic imaging is used, as can also be determined by one of ordinary skill in the art without undue experimentation.

In certain embodiments, the embolotherapy compositions and devices of the preferred embodiments also contain a radiopaque agent. In certain embodiments, embolotherapy compositions and devices also comprise compositions and devices formed with non-iodinated and non-brominated analogs of polymers of formula II to which radiopaque agents have been added. Preferred embodiments may include polymers of Formula II as such compound analogs. Radiopaque agents may be added to the polymers of Formula II to enhance their radiopacity. Examples of preferred radiopaque agents include, but are not limited to, metal iodide, organoiodine compounds, bromine, barium sulfate, bismuth oxide, gold, platinum, tantalum, tungsten, mixtures thereof, and the like.

embolization therapy

According to another aspect of the preferred embodiment, there are disclosed methods of embolizing a body lumen by introducing into the body lumen an effective amount of an embolotherapy product prepared from an inherently radiopaque, biocompatible, bioresorbable polymer disclosed herein. method.

In another preferred embodiment of the products described above, resorbable intrinsic radiopaque compositions of biocompatible embolic microparticles can be formulated for specific treatment and retreatment of cancerous tumors. Reabsorbing formulations can be used in the treatment of multiple chemotherapy. Furthermore, it is preferred that the flexible chemistry of the embolization product allows for tuning of the reabsorption profile so that intravascular residence time can be readily varied by altering the polymer structure as detailed below. For example, to limit the application of chemotherapeutic agents to cancerous tissue, embolic microparticles of the invention chemically formulated to resorb can be implanted in conjunction with chemotherapeutic agents. In the case of liver cancer, for example, such a focused attack on cancer cells is particularly required. The chemotherapeutic agent can be on the microparticle, within the microparticle and/or bound to the microparticle polymer and/or introduced through the polymer in the release solution. In this form, the formulation can have its therapeutic effect. The procedure may then be repeated as the embolic agent is reabsorbed and the vessel recanalized. Intrinsically radiopaque microparticles allow for more controlled release of the microparticles and therapeutic agent and allow for multiple therapeutic routes, which is not currently possible and represents an important unmet therapeutic need.

Accordingly, according to another aspect of the preferred embodiments, there is disclosed a method of enhancing the localized release of a therapeutic agent to tissue comprising (1) an intrinsic radiopaque, biocompatible compound disclosed herein that will sufficiently reduce tissue blood flow. 1. The embolic therapy product prepared from a bioresorbable polymer is administered to the blood vessel associated with the tissue; (2) the therapeutic agent is administered to the blood vessel alone or in combination with the embolic therapy product, so as to enhance the local release of the therapeutic agent; and ( 3) After the embolization therapy product administered for the first time has been sufficiently degraded to allow readministration to the blood vessel, the step of administering the embolization therapy product and the therapeutic agent is repeated.

According to another preferred embodiment of the present invention, a method of embolizing a body lumen is disclosed. The method comprises introducing into a body cavity an effective amount of a composition comprising a biocompatible, bioresorbable polymer, wherein the polymer comprises a compound selected from the group consisting of iodine, bromine, barium, bismuth, gold, platinum, tantalum, Radiopaque portion of tungsten and its mixtures. More preferably, the method includes the step of introducing embolotherapeutic microparticles into the blood vessel, the microparticles comprising a biocompatible, bioresorbable polymer containing sufficient halogen atoms to render the microparticles radiopaque.

In certain embodiments, when embolizing tumors, vascular malformations, such as uterine fibroids, tumors (i.e., chemoembolization), hemorrhages (e.g., in trauma with bleeding), and arteriovenous malformations, fistulas, and aneurysms, these bioreproducible Absorbed, inherently radiopaque embolic agents can be released by conventional delivery systems such as guide catheters. In another embodiment, these bioresorbable, inherently radiopaque embolic agents can be released by non-conventional delivery systems, such as direct injection into body cavities via syringe or other non-catheter systems, providing protection against spider veins and/or varices. Cosmetic treatment of veins. In fact, the polymeric embolization product may not need to be radiopaque where it is injected directly into a superficial vein. Thus, for applications such as the cosmetic treatment of spider veins and/or varicose veins, non-halogenated polymers according to certain embodiments of the present invention may be effective. Addition of therapeutic agents and/or polymer based release of therapeutic agents may also facilitate such cosmetic clinical indications.

Preferred embodiments also provide methods of embolizing a body lumen comprising introducing an embolic composition prepared from a polymer of formula II into a body lumen. According to certain preferred embodiments, an effective amount of a composition comprising one or more of the following: spherical particles, geometrically inhomogeneous particles, porous particles, solid particles, hollow particles, having an excluded diameter in the range of about 10 Microparticles, hydrogels, and any combination thereof to about 3000 microns and more preferably from about 40 to about 2,400 microns. Any suitable conventional method of introducing an embolic therapeutic composition into a body lumen for embolization of the body lumen may be used in the preferred embodiment. For example, conventional methods of introducing PVA plugs into body cavities can be used, but with the compositions of the preferred embodiments in place of the PVA plugs.

therapeutic agent

According to preferred embodiments of the embolization therapy products and methods described above, the polymer may be formulated with an effective amount of at least one therapeutic agent (eg, a drug and/or a biologic) sufficient to exert a selective therapeutic effect. The term "drug" as used herein includes substances intended to alleviate, treat or prevent disease, which stimulate specific physiological (metabolic) responses. The term "biologic" as used herein includes any substance that has structural and/or functional activity in a biological system, including but not limited to organs, tissues or cell-based derivatives, cells, viruses, vectors, derived from natural and Recombinant and synthetic nucleic acids (animal, plant, microbial and viral), antibodies, polynucleotides, oligonucleotides, cDNA's, tumor genes, proteins, peptides, amino acids, lipoproteins, of any sequence and size , glycoproteins, lipids, carbohydrates, polysaccharides, lipids, liposomes or other cellular components or organelles such as receptors and ligands. The term "biological agent" as used herein also includes viruses, sera, toxins, antitoxins, vaccines, blood, blood components or derivatives, allergen products or similar products, or arsines for the prevention, treatment or cure of human disease or injury. Phanamine or its derivatives (or any trivalent organic arsenic-containing compound) (per Section 351(a) of the Public Health Service Act (42 U.S.C. 262(a))). The term "biologics" as used herein may also include 1) "biomolecules", including biologically active peptides, proteins, carbohydrates, vitamins, lipids produced and purified from naturally occurring or recombinant organisms, antibodies, tissues or cell lines or nucleic acids or synthetic analogs of such molecules; 2) "genetic material" as used herein includes nucleic acids (deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)), genetic elements, genes, factors, alleles , operon, structural gene, regulatory gene, operator, gene complement, genome, genetic code, codon, anticodon, messenger RNA (mRNA), transfer RNA (tRNA), extrachromosomal genetic components of ribosomes, cytoplasm Genes, plasmids, transposons, genetic mutations, gene sequences, exons, introns; and 3) "processed biological agents" as used herein, such as treated cells, tissues or organs. Therapeutic agents may also include vitamins or minerals or other natural elements.

The amount of therapeutic agent is preferably sufficient to act as, but not limited to, a chemotherapeutic agent, a non-steroidal anti-inflammatory agent and/or a steroidal anti-inflammatory agent to promote a desired biological and/or physiological response or to affect some other state of the embolized tissue, e.g. Attracting healing cells or those cells that produce extracellular matrix aids in the healing of the embolized body cavity.

Therapeutic agents may be added to at least one area on the surface of the embolization product, or sometimes within the product, thereby providing localized release of such formulations. In some preferred embodiments, the therapeutic agent is released from a thin polymer coating on the surface of the polymer microparticles. In another preferred variation, the therapeutic agent is released through the polymer coating. In other preferred embodiments of the embolotherapy product, the therapeutic agent is released from at least one region or one surface of the embolotherapy product. In other preferred embodiments of the embolotherapy product, the therapeutic agent is contained within the embolotherapy product as it is admixed with a polymer or mixed by other methods known to those skilled in the art.

Therapeutic agents according to preferred aspects of the invention can be classified according to their site of action within the host, eg they can exert their action extracellularly or at specific membrane receptor sites, at the plasma membrane, within the cytoplasm and within the nucleus. Therapeutic agents can be polar or have a net negative or positive or neutral charge; they can be hydrophobic, hydrophilic or zwitterionic or have a high affinity for water. Release is accomplished by controlled release mechanisms, dispersion, interaction with other formulations delivered by intravenous injection, nebulization or oral delivery. Release can also be accomplished through the application of a magnetic field, an electric field, or with ultrasound.

Examples of suitable therapeutic agents include, but are not limited to, chemotherapeutic agents, non-steroidal anti-inflammatory agents, steroidal anti-inflammatory agents. Examples of preferred chemotherapeutic agents include, but are not limited to, taxanes, paclitaxel, paclitaxel, paclitaxel, dioxrubicin, cisplatin, doxorubicin, bleomycin, and the like. Examples of preferred non-steroidal anti-inflammatory compounds include, but are not limited to, aspirin, dexamethasone, ibuprofen, naproxen, Cox-2 inhibitors such as rofecoxib, celecoxib, and valdecoxib, and the like. Examples of preferred steroidal anti-inflammatory compounds include, but are not limited to, dexamethasone, beclomethasone, hydrocortisone, prednisone, and the like.

Any suitable amount of one or more therapeutic agents can be used. Preferably, the locally effective therapeutic agent is used in an effective amount, which amount can be readily determined by one of ordinary skill in the art without undue experimentation.

Embolization therapy product with surface coating

In addition to releasable therapeutic agents, for example, biopolymers on the release product such as thrombogenic collagen or fibronectin or phosphorylcholine for detumescence, embolization products can also be used in advance due to the needs of certain clinical effects. Release or coating of defined bioresorbable polymers that promote biological responses in embolized body lumens. Coatings can also be used to mask the surface properties of the polymer used to comprise the embolic therapy microparticles. The coating may be selected from any non-halogenated or halogenated, biocompatible, bioresorbable polymer, which may or may not contain any poly(alkylene glycol). These polymers may include variations in composition, including homopolymers and heteropolymers, stereoisomers, and/or mixtures of such polymers. These polymers may include, for example but not limited to, polycarbonate, polyarylate, poly(ester amide), poly(amide carbonate), cyclopropane carbonate, polycaprolactone, polydioxane, poly Hydroxybutyrates, polyhydroxyvalerates, polyglycolides, polylactides and stereoisomers and copolymers thereof, eg glycolide/lactide copolymers. In a preferred embodiment, the embolization product is coated with a polymer having a high absorption affinity for fibrinogen or plasma proteins to promote clot formation, for example during bleeding. Examples include poly(DTE carbonate) and poly(I2DTE carbonate) that promote high levels of fibrinogen adsorption; coatings may also contain positively charged polymers that attract the negative charges of the outer membrane of red blood cells, thereby inducing the body's normal coagulation process . In another preferred embodiment, the product of embolization therapy is coated with a polymer that has an affinity for cells (e.g., mesenchymal cells, fibroblasts, stromal cells, and parenchymal cells) to promote healing and tissue reabsorption and remodeling of embolized tissue. plastic, for example in the treatment of uterine fibroids. In yet another preferred embodiment, the embolization product is coated with a polymer that repells the attachment and/or proliferation of specialized cells, such as microvascular endothelial cells known to vascularize into tumors, in which case the polymeric The drug coating can slow down or inhibit the further vascularization of the embolized tumor. In another preferred embodiment, the embolization product is coated with a polymer that attracts cells and/or promotes the proliferation and/or deposition of extracellular matrix molecules that contribute to the formation of repair tissue (eg, granulation tissue). This may include attracting inflammatory cells such as macrophages, leading to successful healing and/or formation of fibrous connective tissue. In a preferred embodiment, the embolization product is coated with a polymer that promotes tissue deposition, as in the case of arteriovenous malformations and aneurysms.

The following non-limiting examples, enumerated next, illustrate certain aspects of the invention. These examples are not intended to limit the scope, but to illustrate preferred embodiments. All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise indicated.

Example

Nomenclature and Abbreviations Used

The following abbreviations are used to identify the different iodinated compounds. TE stands for ethyl tyrosine, DAT stands for desaminotyrosine and DTE stands for desaminotyrosyltyrosine ethyl ester. Poly(DTE carbonate) denotes a polymer obtained by the phosgenation of DTE. "I" before the abbreviation means mono-iodination (eg ITE stands for mono-iodination TE) and _I2 before the abbreviation means di-iodination (eg _I2DAT stands for di-iodination DAT). In DTE, if "I" is before D, it means iodine is on DAT and if "I" is after D, it means iodine is on tyrosine ring (eg DI ₂ TE means there are 2 on tyrosine ring DTE of iodine atom). The figure below further illustrates this nomenclature.

General structure of iodinated DTE monomers

R ₁ = _I , R ₂ , R ₃ , R ₄ = H; IDTE

R ₁ , R ₂ = _I , R ₃ , R ₄ = H; I ₂ DTE

R ₁ , R ₂ =H, R ₃ , R ₄ =I; DI ₂ TE

R ₁ , R ₃ =I, R ₂ , R ₄ =H; IDITE

reabsorption test

Polymer degradation rates were measured in vivo and in vitro using the materials and methods described by Abramson et al., "Small changes in polymer structure can dramatically increase degradation rates: the effect of free carboxylate groups on the properties oftyrosine-derived polycarbonates Significantly Increased Degradation Rate: Effect of Free Carbonate Groups on Properties of Tyrosine-Derivatized Polycarbonates), Report of the Sixth World Biomaterials Conference, Biomaterials Society 26th Annual Meeting, Abstract 1164 (2000), published in The contents are incorporated herein by reference.

Example 1: Preparation of poly(60% I ₂ DTE-co-20% I ₂ DT-co-20% PEG2K carbonate)

Add 18.3g (0.03mol) I ₂ DTE, 6.38g (0.01mol) I ₂ DTtBu, 20g (0.01mol) PEG2000 and 300ml dichloromethane into a three-necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux Condenser and rubber septa. A clear pale yellow solution was obtained by stirring. 15.1 ml (0.15 mol) of pyridine was added. 30 ml of phosgene in 20% toluene (0.0576 mol) was placed in a gas-tight plastic syringe and added to the reaction flask with a syringe pump over 3 hours. Molecular weight was determined by GPC analysis of an aliquot of the reaction mixture. Additional phosgene solution (up to 10%) was required to achieve the desired molecular weight. The reaction mixture was quenched with 110 ml THF and 10 ml water. The polymer was precipitated by adding the reaction mixture to 1.5 L of cold 2-propanol in a high speed Waring mixer.

The resulting gummy polymer was triturated with two 0.5 L portions of 2-propanol. Fine particulate polymer particles were isolated by filtration and dried in a vacuum oven. To remove the t-butyl protecting group, the polymer was dissolved in trifluoroacetic acid to obtain a 20% solution. After stirring the solution at room temperature for 4 hours, 2-propanol was added to precipitate the polymer, which was then further triturated with 2-propanol to remove excess TFA. The product was isolated by filtration, rinsed with IPA and dried in a vacuum oven.

Those skilled in the art will understand that radiopaque bromine-substituted polymers can likewise be prepared by substituting bromine for iodine in the starting material.

Example 2: Preparation of poly(I ₂ DTE-co-2.5mole% PEG2K carbonate)

A 2000 molecular weight polymer (poly(97.5% _I2DTE -co-2.5% PEG2K carbonate)) containing 97.5% mole percent _I2DTE and 2.5% poly(ethylene glycol) was prepared as follows. 29.7g (0.0488mol) _I2DTE , 2.5g (0.00125mol) PEG2000 and 215ml dichloromethane were charged into a three-neck round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and rubber septum. A clear pale yellow solution was obtained by stirring. 15.1 ml (0.15 mol) of pyridine was added thereto. 30 ml of phosgene in 20% toluene (0.0576 mol) was placed in a gas-tight plastic syringe and added to the reaction flask with a syringe pump over 3 hours. Molecular weight was determined by GPC analysis of an aliquot of the reaction mixture. Additional phosgene solution (up to 10%) was added to achieve the desired molecular weight. The reaction mixture was quenched with 110 ml tetrahydrofuran and 10 ml water. The polymer was precipitated by adding the reaction mixture to 1.5 L of cold 2-propanol in a high speed Waring blender. The resulting polymer was triturated with two 0.5 L portions of 2-propanol. Fine particulate polymer particles were isolated by filtration and dried in a vacuum oven.

Example 3: Formation of Embolization Therapeutic Microparticles

A 5% w/w DMSO solution of the polymer of Example 2 was prepared by dissolving 0.650 g of polymer in 12.35 g of DMSO. A precipitation solution was prepared by adding 3 ml of a 10 vol% aqueous solution of ALCONOX surfactant (from the concentrate) to 300 ml of water. The precipitation solution was placed in a 600ml container and stirred slowly (<100RPM). The polymer spheres were precipitated by adding the DMSO polymer solution to the precipitating solution dropwise with a syringe through a 26-gauge needle. 26 - Metering needle grinds to a point to buff off the silicone coating. This lowers the surface tension, allowing the formation of smaller droplets of polymer when dispensed.

The precipitated polymer spheres were separated through a filtered dropping funnel and air dried. The balls are then cryogenically ground with added _CO2 in a coffee grinder at about 20,000RPM. The milled microparticles were then dried overnight in a vacuum oven at 50°C under dynamic vacuum. The drying balls are then sieved by hand into the following particle ranges:

90-180 micron diameter

180-300 micron diameter

300-500 micron diameter

500-710 micron diameter

Example 4: In Vivo Assessment or Microparticle Radiopacity

The apparent radiopacity of the embolization microparticles of Example 3 was assessed by injecting them into the renal arterial bed of pigs. Microparticles are injected through a catheter inserted distal to the renal artery bed.

The renal arterial bed was reached with a 5F catheter over 0.035" wire. A low-profile catheter was entered distally to the vascular bed to provide a less-sub-selective injection. Baseline angiograms were taken on film. In a beaker About every 300 mg embolization microparticles were mixed with 5cc saline and drawn into a 3cc syringe. The filled 3cc syringe and 1cc empty syringe were connected to the three-way stopcock. The suspension was moved back and forth between the two syringes to prevent the particles from settling.

The plunger assembly was attached to the placed 5-Fr (0.038" ID) multipurpose catheter. The contents of the syringe were injected rapidly and vigorously. The priming and injection procedure was repeated until blood flow to the target area ceased. Blood flow cessation was confirmed by injection of contrast medium.

The contents of the syringe contain the following particulate masses ^* :

90-180um: 110mg

180-300um: 221mg

300-500um: 233mg ^*

500-710um: 122mg ^*

^* Undetermined amount of each of these size ranges not injected due to catheter blockage.

Microparticles were fully visualized under fluoroscopy when no contrast agent was injected. They appear on the fluoroscopy display as short flashes of white on a black background, similar to how contrast agents would appear, even though there is no contrast agent in the injected solution. Subsequent injections of contrast media showed effective embolization of the vascular bed.

The kidney was removed and x-rayed ex vivo (Figures 1A and 1B). In Figure 1A, the large branches (approximately fourth order) of the renal arteries (approximately 2 to 3 mm in diameter) are seen filled with embolization material (arrows). The same artery filled with commercially available polymer spheres was not visualized on x-ray. In Figure 1B, the small renal arteries (arrows) are also seen to be filled with 100-300 micron particles.

These figures illustrate that the intrinsic radiopaque microparticles of the preferred embodiment produce visible casts on x-ray that are substantially evenly distributed in the different branches of the renal arteries. Embolization procedures are hazardous and require near-perfect control of particle release. Microparticles visualized on x-rays are better controlled than non-visualized microparticles because their deployment can be monitored in real time, allowing more precise determination of release endpoints. Instant feedback on particle distribution also helps to calibrate particle size distribution for more precise release. The microparticles of the preferred embodiments also facilitate x-ray monitoring of embolized tissue and subsequent polymer reabsorption, replacing biopsy methods and indirect assessment procedures currently employed.

The above polymers demonstrating preferred embodiments hold great promise as inherently radiopaque, non-permanent, biocompatible therapeutic embolic agents. Although using less than standard volumes, effective embolization was confirmed with dynamic fluoroscopy, followed by clear identification of x-rays with intrinsic radiopaque particulate masses within the vascular bed. It should be noted that the radiopacity of the microparticles is a result of the intrinsic characteristics of the polymer since the contrast agent was only injected before and after embolization.

Example 5: In vitro drug elution kinetics

This is to determine the drug release of certain polymers, based on the physiochemical characteristics and solvent extraction requirements under "sink" conditions at 37°C, and stirring to ensure a homogeneous solution. Therapeutic substances (such as drugs) in polymers (see table below) can be coated on the surface of the polymer film surface, and it can be implanted or mixed with the polymer before pressing the film, in these tests it emulates Treatment of embolic products.

Adjust film size to accommodate drug loading and detection limit of quantitation. Typical procedures may include compound extraction or precipitation followed by quantification by high performance liquid chromatography (HPLC). Use an appropriate dissolution medium such as 3% bovine serum albumin (BSA) or 35% Tween 20 in phosphate buffered saline (PBS). Solubility can be measured from 24 hours to 28 days. After dissolution, the films and/or media were analyzed for drug content. The dissolution rate of each drug was calculated from the mass balance determined by the HPLC assay. Percent dissolved was calculated using the amount measured at each time point for all dissolution profiles.

Table 2

Summary of Tests for Tyrosine-Derivatized Polycarbonate Coatings Poly(100%DTE)carbonate Poly(90%DTE-co-10%DT) ^carbonate1 Poly(76%DTE-co-24%DT) carbonate ² Poly(67%DTE-co-33%DT)carbonate Poly(95%DTE-co-5%PEG1K)carbonate Poly(97.5% I ₂ DTE-co-2.5% PEG 2K) carbonate Poly(77.5% I ₂ DTE-co-20% I ₂ DT-2.5% PEG 2K) carbonate Poly(67.5% I ₂ DTE-co-30% I ₂ DT-2.5% PEG 2K) carbonate Poly(70% I ₂ DTE-co-20% I ₂ DT-10% PEG 2K) carbonate Poly(80%I ₂ DTE-co-20%PEG 2K)carbonate

¹ Testing drug elution in coated and drug-implanted films

² Test drug elution only in drug-implanted films

Drug elution of different polymers (Table 2) coated on the polymer surface or embedded in the polymer and pressed into the film has demonstrated the elution of the drug. Figure 2 shows the elution of embolic therapeutic agents from poly-DTE-carbonate. Other biocompatible bioresorbable polymers can be used for this purpose. In the case of polycarbonate, drug elution can be tailored by modifying the polymer with iodine on the DAT ring or adding PEG to the polymer backbone.

Example 6: Preparation of poly(I ₂ DTE-co-2.5mole% PEG _2k adipate)

Diphenol I ₂ DTE (2.97g, 4.87mmol), PEG2000 (0.250g, 0.125mmol) and adipic acid (0.731g, 5.04mmol) and 0.4g of DPTS (dimethyl monopyridyl-p-toluenesulfonate , catalyst) were weighed and added to a 100ml brown bottle with a Teflon cap. Add 40ml of dichloromethane to the bottle and make sure the cap is tight. The bottle was shaken for 10-15 minutes, then 2.5ml (2.02g, 16mmol) of diisopropylcarbodiimide was added and shaking continued for 2 hours. Aliquots of the samples were removed and processed appropriately for analysis by GPC. The required Mw is about 100,000. Once the desired Mw was reached, 200 ml of 2-propanol was added to the reaction mixture with stirring. The precipitate was collected and dried under nitrogen flow. The precipitate was then dissolved in 20 ml of dichloromethane and precipitated with 200 ml of methanol. The polymer was then dried under nitrogen, followed by drying in a vacuum oven.

Example 7: Polymerization of Poly(60% I ₂ DTE-co-20% I ₂ DT-co-20% PEG _2k Adipate)

The diol (diolic) component (1.83g, 3.00mmol I ₂ DTE, 0.638g, 1.00mmol _I DTtB and 2.000g 1.00mmol PEG2000) and diacid (0.731g, 5mmol adipic acid) and 0.4g DPTS were weighed and Add to a 100ml brown bottle with a Teflon cap. Add 40ml of dichloromethane to the bottle and make sure the cap is tight. The bottle was shaken for 10-15 minutes, then 2.5ml (2.02g, 16mmol) of diisopropylcarbodiimide was added and shaking continued for 2 hours. Aliquots of the samples were removed and processed appropriately for analysis by GPC. The required Mw is about 100,000. Once the desired Mw was reached, 200 ml of 2-propanol was added to the reaction mixture with stirring. The precipitate was collected and dried under nitrogen flow. The precipitate was then dissolved in 20 ml of dichloromethane and precipitated with 200 ml of methanol. The polymer was then dried under nitrogen, followed by drying in a vacuum oven.

Deprotection: The resulting polymer was dissolved in trifluoroacetic acid (10% w/v) and stirred overnight. The next day, the polymer was precipitated in isopropanol with a mixed stirrer. The polymer was then triturated twice with fresh isopropanol, filtering through a glass frit filter between rinses. The polymer was then dried under nitrogen, followed by drying in a vacuum oven.

Example 8: Preparation of poly(I ₂ DTE-co-2.5mole% PEG _2k sebacate)

Diphenol I ₂ DTE (2.98g, 4.89mmol), PEG2000 (0.250g, 0.125mmol) and sebacic acid (1.01g, 5.00mmol) and 0.4g of DPTS were weighed and added to a 100ml brown bottle with a Teflon cap . Add 40ml of dichloromethane to the bottle and make sure the cap is tight. The bottle was shaken for 10-15 minutes, then 2.5ml (2.02g, 16mmol) of diisopropylcarbodiimide was added and shaking continued for 2 hours. Aliquots of the samples were removed and processed appropriately for analysis by GPC. The required Mw is about 100,000. Once the desired Mw was reached, 200 ml of 2-propanol was added to the reaction mixture with stirring. The precipitate was collected and dried under nitrogen flow. The precipitate was then dissolved in 20 ml of dichloromethane and precipitated with 200 ml of methanol. The polymer was then dried under nitrogen, followed by drying in a vacuum oven.

Example 9: Preparation of triiodide DTE (I ₂ DITE):

By substituting _I2DAT for DAT and ITE for TE, the triiodinated monomer ( _I2DITE ) was prepared using those procedures published in the literature. A typical operation is, in a 1 liter round bottom flask, 85.8 g (0.255 mol) 3-iodotyrosine ethyl ester (ITE), 104 g (0.250 mol) I ₂ DAT and 3 g (0.025 mol) 1-hydroxybenzene The triazole was stirred with 500 ml of tetrahydrofuran. Cool the flask to 10-18°C in an ice-water bath, add 50 g (0.255 mol) of EDCI and stir at 15-22°C for 1 hour. The reaction mixture was then stirred at ambient temperature for 5 hours. The reaction mixture was concentrated to 250 m, then stirred with 1 L of water and 1 L of ethyl acetate. The lower aqueous layer was separated and drained with a separatory funnel. The organic layer was washed successively with 500 ml each of 0.4M HCl, 5% sodium bicarbonate solution and 20% sodium chloride solution. After drying over sodium sulfate, the organic layer was concentrated to a slurry and triturated with hexanes. An off-white solid was obtained. The product was characterized by HPLC and ¹ HNMR.

Example 10: Preparation of tetraiodide DTE (I ₂ DI ₂ TE)

DTE (16.4 g, 0.046 mol) was dissolved in 300 ml of 95% ethanol. 46 g (0.19 mol) of PyICl were added to the solution with stirring. The solution was stirred for 2 hours during which time the solid slowly dissolved giving a pale yellow solution. This was added to 1 liter of water containing 10 g of sodium thiosulfate with stirring over 30 minutes. An off-white solid separated and was isolated by filtration and rinsed with several portions of deionized water.

The wet mass (approximately 150 g) was heated with 1.5 L of ethanol until it dissolved, then cooled to room temperature. The white crystalline solid formed was isolated by filtration and rinsed with 95% ethanol and dried. 32 g (81%) of dry product are obtained. The product was characterized by HPLC and ¹ H NMR.

Example 11: Triiodinated Polymers Containing Poly(ethylene glycol)

A 2000 molecular weight polymer (poly(80% _I2DITE -co-20% PEG2K carbonate)) containing 80% mole percent _I2DITE and 20% poly(ethylene glycol) was prepared as follows. Add 6.0g (8.1mmol) I ₂ DITE and 4.1g (2.05mmol) PEG2000 and 66ml dichloromethane and 3.1ml (39mmol) pyridine into a three-neck round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and rubber septa. A clear almost colorless solution was obtained by stirring. 6.5 ml of a 20% solution of phosgene in toluene (12.5 mmol) was placed in a gas-tight plastic syringe and added to the reaction flask via a syringe pump over 3 hours. Molecular weights were determined by analyzing an aliquot of the reaction mixture by GPC. Polystyrene having a molecular weight equivalent to 200,000 was obtained. The reaction mixture was quenched with 55 ml tetrahydrofuran and 5 ml water. The polymer was precipitated by adding the reaction mixture to 1 L of cold 2-propanol in a high speed Waring mixer. The resulting gummy polymer was triturated with two 0.5 L portions of 2-propanol. Fine particulate polymer particles were isolated by filtration and dried in a vacuum oven.

Example 12: Tetraiodide Polymers Containing Poly(ethylene glycol)

A 2000 molecular weight polymer (poly ₍ 80% _I2DI2TE -co-20% PEG2K carbonate) ₎ containing 80% mole percent _I2DI2TE and 20% poly(ethylene glycol) was prepared as follows. Add 1.55g (1.80mmol) I ₂ DI ₂ TE and 0.9g (0.45mmol) PEG2000 and 20ml methylene chloride and 0.68ml (8.6mmol) pyridine into a three-necked round bottom flask equipped with a mechanical stirrer, thermometer, Reflux condenser and rubber septa. A clear almost colorless solution was obtained by stirring. 1.4 ml of phosgene in 20% toluene (2.7 mmol) was placed in a gas-tight plastic syringe and added to the reaction flask via a syringe pump over 3 hours. Molecular weights were determined by analyzing an aliquot of the reaction mixture by GPC. Polystyrene having a molecular weight equivalent to 25,000 was obtained. The reaction mixture was quenched with 18 ml tetrahydrofuran and 2 ml water. The polymer was precipitated by adding the reaction mixture to 200 ml of cold 2-propanol in a beaker with a magnetic stirrer. The resulting gum polymer was triturated with 200 ml of 2-propanol. The polymer obtained was still a gum, probably due to the low molecular weight and high poly(ethylene glycol) content.

Figures 3a-b show x-ray comparisons of radiopaque bioresorbable diiodinated and triiodinated tyrosine-derived polycarbonate films. The optical density of poly( _I2DITE -co-20%PEG2k) carbonate 114 micron films was comparable to that of human bone. The optical density of poly(80% _I2DTE -co-20%PEG2k)carbonate was lower.

Example 13: Adsorption of fibrinogen to polymeric surfaces

The time course of adsorption of human fibrinogen to the test polymer surface was measured with a quartz crystal microbalance with emission monitoring (QCM-D, Q-Sense AB, model D300, Goeteborg, Sweden).

QCM-D is a gravimetric technique that can be used to instantly measure the mass of a liquid material adhered to a surface. The increased weight bound to the quartz surface causes the crystal's oscillation frequency to decrease. Furthermore, this device can measure the change in dissipation induced by the mass adsorbed on the surface.

Quartz crystals (Q-Sense, Cat# QSX-301 ) were spin coated with a polymer solution (1% polymer in dichloromethane). A commercially available quartz crystal coated with a thin layer of stainless steel (Q-Sense, Cat# QSX-304) was included for comparison. To begin a representative experiment, crystals were inserted into the QCM-D instrument and incubated at 37°C in phosphate buffered saline (PBS). After a stable baseline was reached, fibrinogen solution was injected and changes in frequency and dissipation induced by the adsorbed mass were recorded instantaneously. The fibrinogen solution was incubated until binding saturation was reached (indicated by no further significant changes in frequency and fugitive values). All washing steps were performed with fibrinogen-free PBS to remove unbound fibrinogen on the sensor surface after the adsorption process. Human fibrinogen was purchased from Calbiochem (Cat #341576) and diluted in PBS to a final concentration of 3 mg/ml. All experiments were performed in triplicate with a standard deviation of less than 12% (mean standard error).

The quartz crystal can be reused up to 10 times by the following cleaning method: Treat the quartz crystal with a cleaning solution consisting of H ₂ O ₂ (30%), NH ₄ OH and ultrapure water in a ratio of 1:1:5 (80°C, 15min ). Thereafter, the crystals were well rinsed with ultrapure water and blown dry with nitrogen. Finally, the crystals were exposed to UV and ozone for 15 minutes (UVO cleaner, Jelight Company, Irvine, CA, USA).

Table 3 summarizes the comparative evaluation of different stent polymer formulations with respect to in vitro fibrinogen adsorption. Fibrinogen is the major blood protein. The degree of adsorption of fibrinogen on artificial surfaces in contact with blood is generally regarded as a reliable indicator of whether said surface is tending to be hemocompatible. As a general rule known to those skilled in the field of biomedical engineering, the lower the level of fibrinogen adsorption to a material, the more blood compatible the material.

table 3

In Vitro Measurement of Fibrinogen on the Test Surface by Frequency Shifting of a Quartz Microbalance (Q-sense)

relative level of adsorption project test material Fibrinogen adsorption (relative unit) 1234567 Stainless steel, SS2343 PET (Dacron) poly(DTE-carbonate) poly(I ₂ DTE-carbonate) poly(76% DTE-co-24% DT-carbonate) poly(I ₂ DTE-co-2.5% PEG2000-carbonic acid ester) poly(I ₂ DTE-co-3.4% PEG2000-carbonate) 8317915813312510072

Referring to Table 3, item 1 (stainless steel) indicates a clinically used material known to have a low level of thrombus formation and good hemocompatibility. Stainless steel served as a control and had acceptable levels of fibrinogen adsorption. Item 2 in Table 3 is Dacron, a known thrombogenic material whose clinical use is limited to vascular applications. Dacron had the highest level of fibrinogen adsorption of all materials tested. Item 3 is poly(DTE carbonate), the base material in the polymer represented by Formula I. Its high level of fibrinogen adsorption suggests that this polymer is not a promising candidate for use in blood-contacting medical devices. Addition of iodine alone (item 4) or DT units alone (item 5) helped reduce the level of fibrinogen adsorption.

The above demonstrates that simultaneous addition of iodine, DT, and PEG results in a marked decrease in fibrinogen adsorption at levels of PEG that still meet the needs of the polymer to provide mechanical strength. Within this general rule, applicants now provide yet another unexpected finding: Comparing items 6 and 7 shows that a very small increase in the amount of PEG within the polymer composition can have an insignificant and unpredictable effect on protein adsorption. While the adsorption of fibrinogen to Polymer Composition 6 was low enough to make this composition a promising candidate for less thrombotic applications, Polymer Composition 7 after addition of as little as 0.9 mol% PEG provided The polymer composition of ® appears to be better than clinical stainless steel in terms of its hemocompatibility.

Polymer composition 7 in Table 3 illustrates another important design principle identified for the first time by applicants: when iodine and PEG are concomitantly added to the polymer composition covered by formula I, very low molar ratios of PEG are sufficient to significantly reduce fiber Protein surface adsorption level. Combining the previously described effects of iodine and PEG on the mechanical properties of polymer compositions, Applicants have discovered a way to simultaneously optimize the mechanical and biological properties of polymers. Thus, the level of thrombosis (ie, increased and decreased affinity of blood cells and proteins and other molecules involved in thrombosis) can be engineered into the product of embolization by varying the relative levels of iodine and percent PEG, DT and DTE.

Additionally, embolization products may be delivered or coated with other biocompatible, bioresorbable polymers that are designed to facilitate the biological response in the embolized body lumen required for certain clinical effects. The coating may be selected from any biocompatible bioresorbable polymer, which may include any one or combination of the following materials: tyrosine-derived polycarbonate, tyrosine-derived polyaromatic Polyesteramide, polyamide carbonate, cyclopropane carbonate, polycaprolactone, polydioxane, polyhydroxybutyrate and polyhydroxyvalerate, polyglycolide, polylactide Esters and their stereoisomers and copolymers for any biocompatible bioresorbable polymer, such as glycolide/lactide copolymers. Coatings can induce and/or inhibit biological responses.

In one example, most embolic therapy products (in this example microparticles) may contain a high percentage of PEG in the iodinated polycarbonate composition to achieve the required compressibility and elasticity of the microparticles for local release through catheters . Microparticles may also contain fibrinogen absorbing coatings such as chitosan or poly(DTE carbonate) for thrombus formation where desired. Such microparticles can be prepared by any method and technique known to those skilled in the art, such as standard powder coating methods used in the pharmaceutical industry, tip coating methods used in the medical device industry (which can be used in pharmaceutical dryers and spray coating device and dip coating, etc.).

Examples of such methods and techniques are disclosed in: Ravina et al., "Arterial Embolization to Treat Uterine Myomata," Lancet, 346, 671-672 (Sep.9, 1995); Hilal et al., "Therapeutic percutaneous embolization for extra-axial vascular lesions of the head, neck, and spine (percutaneous embolization for extra-axial vascular lesions of the head, neck, and spine)," J. Neurosurg 43(3), 275-287(1975); Solomon et al. "Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S. Ethylene alcohol chemoembolization for hepatocellular carcinoma: a prospective assessment of response and survival in a US population)," J Vasc IntervRadiol., 1O(6), 793-8 June 1999); Tseng et al., "Angiographic embolization for epistaxis: a review of 114cases (Angiographic embolization of epistaxis: a review of 114 cases)." Laryngoscope, 108 (4 Pt l), 615-9 (April 1998); Kerber et al., "Flow-controlled therapeutic embolization: a physiologic and safetechnique (flow-controlled therapeutic Embolization: Physiological and Safe Approaches), "Am.J.Roentgenol., 134(3), 557-61 (March 1980); Latchaw et al., "PolyvinylFoam Embolization of Vascular and Neoplastic Lesions of the Head, Neck and Spine (Head, Polyvinyl Alcohol (Ivalon) A New Embolic Material (Polyvinyl Alcohol (Ivalon) A New Embolic Material (Polyvinyl Alcohol (Ivalon) A New embolic material), "Am.J.Roentgenol.: Radium Therapy and Nuclear Medicine, 125, 609-616 (1975).

While a number of preferred embodiments of the invention and variations thereof have been described in detail, it is apparent that other modifications and uses will be apparent to those skilled in the art. Therefore, it should be understood that various applications, modifications and substitutions and equivalents can be made without departing from the subject matter of the present invention or the scope of claims.

Cited Literature

1) 6,475,477 Radiopaque polymer biomaterials

2) 6,358,228 Vaso-occlusive devices comprising many asymmetric fibers

3) 6,337,198 Porous polymer scaffolds for tissue engineering

4) 6,319,492 Copolymers of tyrosine-based polyarylates and poly(alkylene oxides)

5) 6,284,862 Monomers derived from hydroxy acids and polymers prepared therefrom

6) RE37,160 Synthesis of tyrosine-derived diphenol monomers

7) 6,120,491 Biodegradable anionic polymers derived from the amino acid L-tyrosine

8) 6,117,157 Helical embolism ring

9) 6,103,255 Porous polymer scaffolds for tissue engineering

10) 6,048,521 Copolymers of tyrosine-based polyarylates and poly(alkylene oxides)

11) 5,877,224 Polymeric pharmaceutical preparations

12) 5,851,508 Composition for embolizing blood vessels

13) 5,670,602 Synthesis of tyrosine-derived diphenol monomers

14) 5,658,995 Copolymers of tyrosine-based polycarbonate and poly(alkylene oxide)

15) 5,587,507 Synthesis of tyrosine-derived diphenol monomers

16) 5,317,077 Polyarylates containing derivatives of natural amino acid 1-tyrosine

17) 5,216,115 Polyarylates containing natural amino acid L-tyrosine derivatives

18) 5,198,507 Synthetic amino acid derived bioabsorbable polymer

19) 5,099,060 Synthetic amino acid-derived bioabsorbable polymers

20) 4,819,637 Artificial blood vessel embolization system and its application device

21) 4,441,495 Detachable balloon catheter device and method of use

Other publications

1) Interventional Radiology, Dandlinger et al., ed., Thieme, N.Y., 1990: 295-313.

2) "Polyvinyl Alcohol Foam Particle Sizes and Concentrations Injectable through Microcatheters (Polyvinyl Alcohol Foam Particle Sizes and Concentrations Injectable through Microcatheters)", JVIR 1998; 9: 113-115

3) "Polyvinyl Alcohol Particle Size and Suspension Characteristics (polyvinyl alcohol particle size and suspension characteristics)", American Journal of Neuroradiology June 1995; 16: 1335-1343.

4) Ravina et al., Arterial Embolization to Treat Uterine Myomata (Arterial Embolization to Treat Uterine Myoma), Lancet, Sep.9, 1995; vol.346, pp.671-672.

5) "Therapeutic percutaneous embolization for extra-axial vascularlesions of the head, neck, and spine (percutaneous embolization for extra-axial vascular lesions of the head, neck, and spine)", Hilal et al., J.Neurosurg.43(3), 275 -287(1975).

6) "Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S.population (with cisplatin, doxorubicin, mitomycin-C, ethyl iodide Chemoembolization of hepatocellular carcinoma with oil and polyvinyl alcohol: a prospective assessment of response and survival in a US population)." J Vasc Interv Radiol. 1999 Jun; 10(6): 793-8. Solomon B, Soulen MC, Baum RA, Haskal ZJ, Shlansky-Goldberg RD, Cope C.

7) "Hydrogel embolic agents. Theory and practice of adding radio-opacity (hydrogel embolic agent. Increase radiopacity principle and practice)." Link DP, Mourtada FA, Jackson J, Blashka K, Samphilipo MA. Invest Radiol .1994Aug;29(8):746-51.

8) "Angiographic embolization for epistaxis: a review of 114 cases" Tseng EY, Narducci CA, WillingSJ, Silers MJ., Laryngoscope. 1998 Apr; 108(4 Pt 1) :615-9.

9) "Supraselective embolization in extractable epistaxis: review of 45 cases" Moreau S, De RugyMG, Babin E, Courteoux P, Valdazo A., Laryngoscope.1998 Jun; 108(6):887-8.

10) "Polyvinyl alcohol particle size and suspension characteristics (polyvinyl alcohol particle size and suspension characteristics)", Derdeyn CP, Moran CJ, Cross DT, Dietrich HH, Dacey RG Jr., AJNR Am J Neuroradiol.1995 Jun-Jul; 16(6):1335-43.

11) "Polyvinyl alcohol foam particle sizes and concentrations injectable through microcatheters (polyvinyl alcohol foam particle sizes and concentrations injectable through microcatheters).", Barr JD, Lemley TJ, Petrochko CN., J Vasc Interv Radiol. 1998 Jan-Feb ;9(1 Pt 1):113-8.

12) "Flow-controlled therapeutic embolization: a physiologic and safe technique", Kerber CW., AJR Am J Roentgenol. 1980 Mar; 134(3): 557-61.

13) "Polyvinyl alcohol foam: prepackaged emboli for therapeutic embolization" KerberCW, Bank WO, Horton JA., AJR Am J Roentgenol. 1978 Jun; 130(6 ): 1193-4.

14) Interventional Radiology, Dandlinger et al., Thieme, N.Y., 1990: 295-313.

15) "Polyvinyl Alcohol Foam Particle Sizes and Concentrations Injectable through Microcatheters (Polyvinyl Alcohol Foam Particle Sizes and Concentrations Injectable through Microcatheters)", JVIR 1998; 9: 113-115.

16) "Polyvinyl Alcohol Particle Size and Suspension Characteristics (polyvinyl alcohol particle size and suspension characteristics)", American Journal of Neuroradiology June 1995; 16:1335-1343.

17) "Biodegradable microspheres of poly(DL-lactic acid) containing piroxicam as a model drug for controlled release via the parenteral route" Degradable Microspheres)", Lalla JK, Sapna K., J Microencapsul.1993 Oct-Dec; 10(4):449-60.

18) "Gelfoam embolization: a simplified technique", Bank WO, Kerber CW., AJR Am J Roentgenol. 1979 Feb; 132(2): 299-301.

19) R.E.Latchaw, L.H.Gold: "Polyvinyl Foam Embolization of Vascular and Neoplastic Lesions of the Head, Neck and Spine (Polyvinyl Foam Embolization of Vascular and Neoplastic Lesions of the Head, Neck and Spine)," Radiology, 131(1979), 669- 679.

20) S.M.Tadavarthy, J.H.Moller, K.Amplatz: "Polyvinyl Alcohol (Ivalon) A New Embolic Material (polyvinyl alcohol (Ivalon) a new embolic material), "American Journal of Roentgenology: Radium Therapy and Nuclear Medicine, 125 (1975), 609-616.

21) Kerber, CW, "Catheter therapy: fluoroscopic monitoring of deliberate embolic occlusion (catheter therapy: fine fluoroscopic monitoring of embolic occlusion)." Radiology.1977 Nov; 125(2): 538-40.

22) Horak et al., "Hydrogels in endo-vascular embolization.IV.Effect of radiopaque spherical particles on the living tissue (hydrogel formed by intravascular embolism. IV. The effect of radiopaque spherical particles on living tissue)."Biomaterials 9, 367-371, 1988.

23) Horak, D et al. "Hydrogels in endovascular embolization. III. Radiopaque spherical particles, their preparation and properties (hydrogels formed by endovascular embolization. III. Radiopaque spherical particles, their preparation and properties)." Biomaterials 8, 142-145, 1987.

Claims (79)

1. An embolization product comprising a microparticle formulation comprising a biocompatible, bioresorbable polymer and optionally including stereoisomers thereof, wherein said polymer contains a sufficient number of halogen atoms to enable embolization The product is inherently radiopaque. 2. The embolotherapy product of claim 1, wherein said polymer further comprises a homopolymer, a heteropolymer or a mixture thereof. 3. The embolotherapy product of claim 1, wherein said polymer contains one or more units described by formula I:

Wherein X=1 or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4; Where f is between 0 and less than 1; g is between 0 and 1, including 0 and 1; and f+g is between 0 and 1, including 0 and 1; where A is: wherein _R is independently H or an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N; wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; wherein B is an aliphatic linear or branched diol or poly(alkylene glycol) unit; and Wherein R and _R can be independently selected from:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a; wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n; wherein a and n are independently between 0 and 8, inclusive; J ₁ and J ₂ are independently Br or I; and wherein Q of R ₂ contains a free carboxylic acid group and each R Q is independently selected from hydrogen and carboxylic acid esters and amides, wherein the esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds amides. 4. The embolization therapy product of claim 3, wherein R and _R are selected from:

or or

wherein for each R, _R1 is independently an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N and for each _R2 , _R1 is H; wherein j and m are independently integers from 1 to 8, inclusive; and wherein Z is independently O or S. 5. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by formula II: wherein X of each polymer unit is independently Br or I, Y is between 1 and 4 inclusive, and R is up to ₁₈ carbon atoms and 0 to 8 heteroatoms selected from O and N Alkyl, aryl or alkaryl. 6. The embolotherapy product of claim 5, wherein all X groups are ortho-oriented and Y is 1 or 2. 7. The embolotherapy product of claim 5, wherein _R4 is alkyl. 8. The embolization therapy product of claim 7, wherein _R has the following structure:

wherein R of each unit is independently alkyl, aryl, or alkaryl containing up to 18 carbon atoms and 0 _to 8 heteroatoms selected from O and N; and R _{and R} are each independently selected from from hydrogen and alkyl containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N. 9. The embolization therapy product of claim 8, wherein at least one unit of _R contains a side group _-COOR group, wherein for each unit in which a side group is present, the subunit _R is independently hydrogen or contains 0 to 5 An alkyl group of from 1 to about 18 carbon atoms selected from O and N heteroatoms. 10. The embolization therapy product of claim 8, wherein each _R independently has the following structure:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a, wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n, wherein a and n are independently between 0 and 8, inclusive; and J _{and J} are independently Br or I; and Q is selected from hydrogen, free carboxylic acid groups, and carboxylic acids Esters and amides, wherein said esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds. 11. The embolization therapy product of claim 8, wherein each _R independently has the following structure: wherein R is _an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8, inclusive; and R _is independently hydrogen or An alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N. 12. The embolization therapy product of claim 8, wherein each _R independently has the following structure:

or wherein j and m are independently an integer from 1 to 8, inclusive, and _R is independently hydrogen or an alkane of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N base. 13. The embolotherapy product of any one of claims 3-12, wherein the polymer is copolymerized with poly(C ₁ -C ₄ alkylene glycol). 14. The embolotherapy product of claim 13, wherein said poly( _C1 - _C4 alkylene glycol) is present in a weight fraction of less than about 75 wt%. 15. The embolotherapy product of claim 14, wherein the poly(alkylene glycol) is poly(ethylene glycol). 16. The embolotherapy product of claim 13, wherein from about 0.01 to about 0.99% of said polymer units contain pendant -COOH groups. 17. The embolization therapy product of claim 5, wherein _R4 is aryl or alkaryl. 18. The embolotherapy product of claim 17, wherein R ₄ aryl or alkaryl is selected such that the polymer unit is a diphenol. 19. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by formula III: wherein X of each polymer unit is independently Br or I, Y1 and Y2 are each independently between 0 and 4, including 0 and 4, and Y1+Y2 of each unit is independently between 1 and 8, including 1 and 8, and R for each polymer unit is _{independently} an alkyl, aryl or alkaryl group containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N. 20. The embolotherapy product of claim 19, wherein all X groups are ortho-oriented. 21. The embolization therapy product of claim 19, wherein Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4. 22. The embolization therapy product of claim 19, wherein at least one unit of R contains a side group -COOR ₁ group, wherein for each unit in _which the -COOR ₁ group exists, subunit R ₁ is independently hydrogen or An alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N. 23. The embolization therapy product of claim 19, wherein each _R independently has the following structure:

wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a, wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n, wherein a and n are independently between 0 and 8, inclusive; and J _{and J} are independently Br or I; and Q is selected from hydrogen, free carboxylic acid groups, and carboxylic acids Esters and amides, wherein said esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds. 24. The embolization therapy product of claim 19, wherein each _R independently has the following structure: wherein R is _an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8, inclusive; and R _is independently hydrogen or An alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N. 25. The embolization therapy product of claim 19, wherein _each R independently has the following structure: or wherein j and m are independently an integer from 1 to 8, inclusive, and _R is independently hydrogen or an alkane of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N base. 26. The embolotherapy product of claim 19, wherein from about 0.01 to about 0.99% of said polymer units contain pendant -COOH groups. 27. The embolotherapy product of claim 19, wherein said polymer is copolymerized with up to 75% by weight of poly(C ₁ -C ₄ alkylene glycol). 28. The embolotherapy product of claim 27, wherein said poly( _C1 - _C4 alkylene glycol) is poly(ethylene glycol). 29. The embolotherapy product of claim 1, wherein said polymer comprises one or more units described by formula IV:

wherein each X is independently I or Br, Y1 and Y2 of each diphenol unit are independently between 0 and 4, including 0 and 4, and Y1+Y2 of each diphenol unit is between 1 and 8 , including 1 and 8; Each R and _R2 is independently an alkyl, aryl, or alkaryl group containing up to 18 carbon atoms and 0 to 8 heteroatoms selected from O and N, wherein _R2 also contains pendant carboxylic acid groups ; where A is:

or wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; P is a poly(C ₁ -C ₄ alkylene glycol) unit having about 75% by weight or less; f is between 0 and less than 1; g is between 0 and 1, inclusive; And f+g is between 0 and 1, including 0 and 1. 30. The embolotherapy product of claim 29, wherein P is poly(ethylene glycol), which is present in about 50% or less by weight. 31. The embolotherapy product of claim 29, wherein P is poly(ethylene glycol), which is present in about 30% or less by weight. 32. The embolization therapy product of claim 29, wherein R and R ₂ all contain a side group COOR ₁ group; wherein for R, the subunits _R are independently an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N; and Wherein for R ₂ , the subunit R ₁ is a hydrogen atom. 33. The embolization therapy product of claim 29, wherein each R and _R independently have the following structure: wherein R ₇ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -)a, wherein R ₈ is selected from -CH=CH-, -CHJ ₁ -CHJ ₂ - and (-CH ₂ -) n, wherein a and n are independently between 0 and 8, inclusive; and J ₁ and J ₂ are independently Br or I; and wherein for each R ₂ , Q contains a free carboxylic acid group and for each R, Q is independently selected from hydrogen and carboxylic acid esters and amides, wherein the esters and amides are selected from esters and amides of alkyl and alkaryl groups containing up to 18 carbon atoms and biological and pharmaceutical Esters and amides of the above active compounds. 34. The embolization therapy product of claim 29, wherein each _R independently has the following structure: wherein R _5a is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; wherein m is an integer from 1 to 8 inclusive; and wherein for each R ₂ , R ₁ is hydrogen, and for each R, R ₁ is independently an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N. 35. The embolization therapy product of claim 29, wherein each _R independently has the following structure:

or

wherein j and m are independently integers from 1 to 8, inclusive, and wherein for each R ₂ , R ₁ is hydrogen, and for each R, R ₁ is independently 0 to 5 selected from O An alkyl group of from 1 to about 18 carbon atoms, and a heteroatom of N. 36. The embolotherapy product _of claim 34 or 35, wherein each R subunit of R of the polymer is ethyl or butyl. 37. The embolotherapy product of claim 29, wherein A of said polymer is a -C(=O)- group. 38. The embolotherapy product of claim 29, wherein A of the polymer is:

Wherein R ₃ is C ₄ -C ₁₂ alkyl, C ₈ -C ₁₄ aryl or C ₈ -C ₁₄ alkaryl. 39. The embolization therapy product of claim 38, wherein _R3 is selected such that A is part of a naturally occurring metabolite dicarboxylic acid. 40. The embolotherapy product of claim 38, wherein _R3 of the polymer is selected from the group consisting of _-CH2 -C(=O)-, _{-CH2- CH2} -C(=O)-, -CH=CH - and the moiety of (-CH ₂ -)z, where z is an integer from 1 to 8 inclusive. 41. The embolotherapy product of claim 29, wherein all X groups are ortho-oriented. 42. The embolization therapy product of claim 29, wherein Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4. 43. The embolotherapy product of claim 42, wherein all X groups are iodine. 44. The embolotherapy product of claim 29, wherein f is greater than 0.1 to about 0.3. 45. The embolotherapy product of claim 44, wherein f is greater than 0.2 to about 0.25. 46. The embolotherapy product of claim 29, wherein said poly( _C1 - _C4 alkylene glycol) is present in an amount by weight of less than about 25 wt%. 47. The embolotherapy product of claim 29, wherein g is greater than about 0.1 to about 0.35. 48. The embolotherapy product of claim 47, wherein g is greater than about 0.2 to about 0.3. 49. The embolotherapy product of claim 1, wherein said polymer contains one or more units of formula V: wherein each x is independently iodine or bromine; each y is independently between 0 and 4, inclusive, wherein the total number of ring-substituted iodine and bromine is between 1 and 8, inclusive; Each R _{and R} are independently alkyl, aryl or alkaryl containing up to 18 carbon atoms _and 0 to 8 heteroatoms selected from O and N, and R also includes a pendant carboxylic acid group ; where A is:

or wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkaryl group containing up to about 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; P is less than about 75 weight percent poly(C ₁ -C ₄ alkylene glycol) units by weight; f is between 0 and less than 1; g is between 0 and 1, inclusive; and f+g is between 0 and 1, inclusive. 50. The embolotherapy product of claim 49, wherein P is a poly(ethylene glycol) unit. 51. The embolotherapy product of claim 49, wherein each _R4 and _R6 of the polymer contains a side group _-COOR1 group, wherein for each _R6 , each subunit _R1 independently contains O an alkyl group of from 1 to about 18 carbon atoms to 5 heteroatoms selected from O and N, and for each R ₄ , each subgroup R ₁ is a hydrogen atom. 52. The embolotherapy product of claim 49, wherein each _of R and _R of said polymer is:

wherein R _5a is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and wherein for each R ₄ , Each subgroup R ₁ is hydrogen, and for each R ₆ , each subgroup R ₁ is independently an alkyl group of from 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from O and N . 53. The embolotherapy product of claim 52, wherein each _R1 subunit of _R4 of the polymer is ethyl or butyl. 54. The embolotherapy product of claim 49, wherein A is a -C(=O)- group. 55. The embolization therapy product of claim 49, wherein A is: Wherein R ₃ is C ₄ -C ₁₂ alkyl, C ₈ -C ₁₄ aryl or C ₈ -C ₁₄ alkaryl. 56. The embolization therapy product of claim 49, wherein _R3 is selected such that A is part of a naturally occurring metabolite dicarboxylic acid. 57. The embolotherapy product of claim 56, wherein _R3 of the polymer is selected from the group consisting of _-CH2 -C(=O)-, _{-CH2- CH2} -C(=O)-, -CH=CH - and the moiety of (-CH ₂ -)z, wherein z is an integer from 1 to 8 inclusive. 58. The embolotherapy product of claim 49, wherein all X groups are ortho-oriented and y is 2 or 3. 59. The embolotherapy product of claim 58, wherein each X group is iodine. 60. The embolotherapy product of claim 49, wherein f is greater than about 0.1 to about 0.3. 61. The embolotherapy product of claim 49, wherein g is greater than about 0.1 to about 0.35. 62. The embolization therapy product of claim 1, wherein said microparticle formulation is formulated for administration by injection. 63. The embolization therapy product of claim 1, wherein said formulation contains polymer particles selected from the group consisting of spherical particles, geometrically inhomogeneous particles, porous particles, hollow particles, solid particles, and particles having an exclusion diameter Particles of about 10 microns to about 5,000 microns, and combinations thereof. 64. The embolotherapy product of claim 1, wherein said formulation comprises a polymeric hydrogel composition. 65. The embolotherapy product of claim 1, wherein said polymer further comprises an effective amount of at least one therapeutic agent. 66. The embolization therapy product of claim 65, wherein said at least one therapeutic agent is selected from a chemotherapeutic agent, a non-steroidal anti-inflammatory agent or a steroidal anti-inflammatory agent. 67. The embolization therapy product of claim 1, wherein said microparticle formulation further comprises an effective amount of a magnetic resonance enhancing agent. 68. The embolization therapy product of claim 1, wherein said particulate formulation further comprises an effective amount of a radiopaque agent selected from the group consisting of iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten, and mixtures thereof. 69. The embolization therapy product of claim 1, wherein said microparticle formulation further comprises a coating of a biocompatible, bioresorbable polymer suitable for promoting a selected biological response. 70. The embolization therapy product of claim 69, wherein said biological response is selected from the group consisting of thrombus formation, cell adhesion, cell proliferation, attraction of inflammatory cells and deposition of matrix proteins, inhibition of thrombus formation, inhibition of cell adhesion, inhibition of cell proliferation, inhibition of Inflammatory cells and inhibitory matrix protein deposition or their combination. 71. An embolization therapy product comprising a microparticle formulation comprising formula I: Wherein X=1 or Br; Y1 and Y2 can independently=0, 1, 2, 3 or 4; where f and g can range from 0 to 1; Wherein R and _R can be independently selected from:

or

or

wherein for each _R2 , each subunit _R1 is H, and for each R, each subunit _R1 is independently a long chain aliphatic hydrocarbon; Wherein j and m are independently integers from 1 to 8, including 1 and 8; wherein Z is independently O or S; wherein A is selected from: wherein _R is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N; and wherein B is an aliphatic linear or branched diol or poly(alkylene glycol) unit. 72. A method of embolizing a body cavity comprising introducing into the body cavity an effective amount of the embolization therapy product of claim 1. 73. The method of claim 72, wherein said introducing is accomplished by catheter or syringe injection. 74. A method of treating varicose veins and/or spider veins, which comprises administering an effective amount of the embolization product of claim 1 into said varicose veins and/or spider veins. 75. The method of claim 74, wherein said administering is accomplished by catheter or syringe injection. 76. A method of enhancing local release of a therapeutic agent to tissue comprising the steps of: administering the embolization product of claim 1 to a blood vessel associated with said tissue in an amount sufficient to reduce blood flow to said tissue; administering a therapeutic agent to said blood vessel alone or in combination with an embolization product to enhance local release of the therapeutic agent; and The step of administering the embolization product and therapeutic agent is repeated after the first dose of the embolization product has degraded sufficiently to allow readministration of the vessel. 77. A method of retreating a body cavity comprising the steps of: administering to a vascular region associated with said tissue an amount of the embolization therapy product of claim 1 sufficient to reduce blood flow to said tissue over a period of time; and Any embolization products are administered at a later time in approximately the same area of the blood vessel as the tissue is concerned so that the tissue can be retreated or allowed for other forms of reintervention. 78. The embolotherapy product of claim 1, wherein said polymer comprises an inherently bioresorbable radiopaque polymer that does not occur naturally. 79. The embolotherapy product of claim 1, wherein said polymer comprises a bioresorbable intrinsic radiopaque polymer comprising at least one amino acid.

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