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Title:  Partially acetalized polyvinyl alcohol embolization particles, compositions containing those particles and methods of making and using them

United States Patent:  6,911,219

Issued:  June 28, 2005

Inventors:  Matson; Louis R. (El Dorado Hills, CA); Brandom; Donald K. (Davis, CA)

Assignee:  Surgica Corporation (El Dorado Hills, CA)

Appl. No.:  133177

Filed:  April 25, 2002

This relates to partially acetalized polyvinyl alcohol embolization particles suitable for implanting in the human body, to compositions containing those particles, and to methods of making and using them.

SUMMARY OF THE INVENTION

This invention includes a composition for forming an occlusion in a body opening or cavity that is made up of a combination of hydrated, partially acetalized, polyvinyl alcohol foam particles having particle size, pore size, and particle porosity and selected injectable, biologically acceptable, liquid media. The liquid media has a liquid medium specific gravity, generally in a range having a lower limit of about 1.0 and has an upper limit of about 1.50, although the liquid medium specific gravity may fall in a range with a lower limit of about 1.1 and an upper limit of about 1.40, or a lower limit of about 1.15 and an upper limit of about 1.40.

The liquid medium may be made up of one or more members selected from the group consisting of saline solution, radio-opacifiers, antibiotics, chemotherapy drugs, pharmaceuticals, growth factors, anti-growth factors, and natural and synthetic hormones or, perhaps one or more imaging or contrast agents. The radio-opacifiers may comprise one or more iodine-based imaging or contrast agents such as the well known and commercially available Oxilan 300, Oxilan 350, Ultravist 150, Ultravist 240, Ultravist 300, Ultravist 370, and Omnipaque 350.

The composition may include gaseous negative contrast agents for flouroscopy such as CO₂ and gaseous contrast agents for Magnetic Resonance (MR) imaging techniques such as hyperpolarized gases (e.g., inert gases such as helium, xenon, and argon).

For certain uses, the liquid medium may also contain one or more anticoagulants, such as heparin, or one or more clotting agents, such as thrombin.

The particles may have a mean size falling in a range having a lower limit of about 20 μm and an upper limit of about 10 mm, possibly with a lower limit of about 30 μm and an upper limit of about 10 mm or a range with a lower limit of about 45 μm and an upper limit of about 2800 μm. Several tailored size ranges are applicable: 1.) lower limit of about 90 μm and an upper limit of about 2000 μm, 2.) a lower limit of about 180 μm and an upper limit of about 1400 μm, 3.) a lower limit of about 300 μm and an upper limit of about 1000 μm, 4.) a lower limit of about 500 μm and an upper limit of about 750 μm, 5.) a lower limit of about 180 μm and an upper limit of about 300 μm, 6.) a lower limit of about 300 μm and an upper limit of about 500 μm, and 7.) a lower limit of about 500 μm and an upper limit of about 710 μm.

Similarly, the particle porosity may fall in a range having a lower limit of about 50% and has an upper limit of about 98%, perhaps with a lower limit of about 80% and an upper limit of about 96%.

Combinations of these particle sizes and porosities and the liquid medium specific gravity are suitable for the composition, e.g., where the particle size has a lower limit of about 30 μm and an upper limit of about 10 mm and where the liquid medium specific gravity has a lower limit of about 1.0 and an upper limit of about 1.50; or perhaps, where the particle size falls in a range that has a lower limit of about 180 μm and an upper limit of about 710 μm and where the liquid medium specific gravity has a lower limit of about 1.2 and an upper limit of about 1.4.

Combinations suitable for certain liquid medium include those where the particle porosity has a lower limit of about 50% and has an upper limit of about 98% and where the liquid medium specific gravity has a lower limit of about 1.0 and has an upper limit of about 1.50; a particle porosity with a lower limit of about 80% an upper limit of about 96% and where the liquid medium specific gravity has a lower limit of about 1.2 and an upper limit of about 1.4.

The particles may further comprise radio-opacifiers, antibiotics, chemotherapy drugs, pharmaceuticals, growth factors, anti-growth factors, and natural and synthetic hormones as well as imaging or contrast agents such as barium sulfate, gold, tantalum, platinum, tungsten, bismuth oxide, and mixtures.

The particles may contain one or more anticoagulants such as heparin and one or more clotting agents, such as thrombin.

The particles may be diminuted to an appropriate size or size range distribution by, e.g., grinding, cutting, chopping, die cutting, etc., prior to their introduction into the liquid medium.

The resulting composition generally contains particles, when properly selected, that are generally homogeneous or evenly distributed throughout the liquid medium for a period of time at least adequate to perform a normal embolization procedure. This homogeneity of particles in the liquid medium allows the particle/liquid combination to be substantially non-clogging when passed through a catheter delivery system and permits a predictable and even delivery of the particles.

Additionally, the particles and medium may be associated, perhaps in a physical kit, for producing the dispersed or homogeneous composition.

The method for producing the partially acetalized polyvinyl alcohol foam or sponge particles is made up of the steps of mixing polyvinyl alcohol reactant, at least one acidic catalyst, and at least one acetalizing agent under reactions conditions suitable for forming partially acetalized foam particles. The reaction medium may be stirred, perhaps after the combination of at least one substantially non-reactive liquid phase, such as water or an aqueous starch or aqueous polyethylene oxide or aqueous polyethylene glycol mixture, with the polyvinyl alcohol reactant.

The polyvinyl alcohol reactant may have a viscosity average molecular weight in a range having a lower boundary of 50,000 and an upper boundary of 200,000 or in a range having a lower boundary of 125,000 and an upper boundary of 175,000. The polyvinyl alcohol reactant may have a percentage of saponification in a range having a lower boundary of 75% and an upper boundary of 99.3% or in a range having a lower boundary of 85% and an upper boundary of 95%.

The acetalization reaction is acid catalyzed by at least one organic acid, such as carboxylic acids, formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, caproic acid, caprylic acid, capric acid, benzoic acid and oxalic acid or by at least one inorganic acid, such as the salts of hydroacids, hydrochloric acid, hydrobromic acid and hydrofluoric acid; salts of oxoacids, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, chloric acid, silicic acid, perchloric acid, chlorous acid, hypochlorous acid, chlorosulfuric acid, amidosulfuric acid, disulfuric acid and tripolyphosphoric acid; salts of thioacids, and thiosulfuric acid.

The reactant acetalizing agent may be at least one member selected from the group consisting of formaldehyde, formaldehyde dimethyl acetal, acetaldehyde, propylaldehyde, butyraldehyde, pentaldehyde, glutaraldehyde, long chain aldehydes containing at least six C atoms, trioxane, paraformaldehyde, benzaldehyde, phenylacetaldehyde, and their mixtures.

Typically, the reaction sequence will also include the steps of stirring the mixture, aging the mixture, washing the mixture to remove additional reactants or acidic catalyst, separating the particles, and grinding the particles. Ground particles may be separated into specific size ranges by, e.g., sieving them.

Particles produced by these methods form a component of this invention.

A following and separate procedure involves selecting appropriate partially hydrolyzed polyvinyl alcohol foam particles produced by the processes discussed above appropriate for a particular injectable, biologically acceptable, liquid medium such that, once hydrolyzed, the particles are substantially suspendable or suspended in the selected liquid medium. The next step involves combining the selected particles and the medium to hydrate the particles and to produce the composition.

DESCRIPTION OF THE INVENTION

Described below are chemical processes for forming partially acetalized polyvinyl alcohol foam particles having particle size, pore size, density and particle porosity that are suitable for inclusion in selected injectable, biologically acceptable, liquid media having a liquid medium specific gravity and desirably are dispersed sufficiently so not to aggregate nor to clump in delivery equipment during an embolization procedure. The particles may be substantially homogeneously suspended in the medium to so prevent the clogging.

The methods for producing the partially acetalized polyvinyl alcohol foam or sponge particles are made up of: the steps of mixing polyvinyl alcohol reactant, at least one acidic catalyst, and at least one acetalizing agent under reaction conditions suitable for forming partially acetalized foam particles. The reaction medium may be stirred, perhaps after the combination of at least one substantially non-reactive liquid phase, such as water or an aqueous starch mixture or aqueous polyethylene oxide or aqueous polyethylene glycol mixture, with the polyvinyl alcohol reactant. Alternatively, the reaction medium may be air-whipped prior to the acetalization reaction step thereby forming an air-whipped foam.

The polyvinyl alcohol reactant may have a viscosity average molecular weight in a range having a lower boundary of 50,000 and an upper boundary of 200,000 or in a range having a lower boundary of 125,000 and an upper boundary of 175,000. The polyvinyl alcohol reactant may have a percentage of saponification in a range having a lower boundary of 75% and an upper boundary of 99.3% or in a range having a lower boundary of 85% and an upper boundary of 95%.

The acetalization reaction is acid catalyzed. The catalyst may be: a.) at least one organic acid, such as carboxylic acids, formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, caproic acid, caprylic acid, capric acid, benzoic acid and oxalic acid or b.) at least one inorganic acid, such as the salts of hydroacids, hydrochloric acid, hydrobromic acid and hydrofluoric acid; salts of oxoacids, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, chloric acid, silicic acid, perchloric acid, chlorous acid, hypochlorous acid, chlorosulfuric acid, amidosulfuric acid, disulfuric acid and tripolyphosphoric acid; salts of thioacids, and thiosulfuric acid. Obviously, the catalyst may be of mixtures or combinations of any of these.

The reactant acetalizing agent may be any compound performing the acetalization function, but may be at least one member selected from the group consisting of formaldehyde, formaldehyde dimethyl acetal, acetaldehyde, propylaldehyde, butyraldehyde, pentaldehyde, glutaraldehyde, long chain aldehydes (e.g., containing at least six C atoms), trioxane, paraformaldehyde, benzaldehyde, phenylacetaldehyde, and their mixtures.

Typically, the reaction sequence will also include the steps of stirring the mixture, aging the mixture at a modestly elevated temperature, e.g., about 30° C. to about 65° C. (to achieve an acceptable level of conversion to acetal), washing the mixture to remove extraneous reactants and the acidic catalyst, separating the particles, and grinding, cutting, chopping, or die cutting the particles to suitable sizes. These particles may be separated into specific size ranges by, e.g., sieving them or by other appropriate sizing or separating procedures.

As is shown in detail in the Examples below, we have observed that varying the following reaction or reactant parameters directionally from the reaction conditions found in those Examples produces the following changes to the particles. Lowering the molecular weight of the feed polyvinyl alcohol generally lowers the overall biocompatibility, elasticity, tear strength, and resilience of the resulting particle. Raising the molecular weight of the feed polyvinyl alcohol has the opposite effect on those particle parameters.

For the practical reaction parameters discussed here, lowering the degree of hydrolysis of the feed polyvinyl alcohol generally increases both the level of achievable hydration and the rate at which the particle may be hydrated or hydrates. Such a change increases the elasticity and resilience of the product particle. Raising the degree of hydrolysis (or degree of saponification) of the feed polyvinyl alcohol causes the opposite effects to occur.

Similarly, within the scope of practical reaction conditions suitable for the particles discussed here, the extent of the reaction or conversion to acetal may be used to control the following particle parameters: Lowering the extent of the reaction or conversion to acetal again increases both the level of achievable hydration and the rate at which the particle may be hydrated or hydrates, elasticity, resilience, and compressibility of the product particle but lowers the resulting modulus. Again raising the extent of reaction will have the opposite effects on the product particle.

We have observed that an increase of the initial reaction rate, e.g., perhaps by increase of the initial reaction temperature or by increase in the catalyst or acetalizing agent concentration or any or all of these changes, lowers the particles' cell or pore size. Lowering that initial rate increases the size of those pores or cells.

The directional changes outlined above are used to tailor a particle suitable for suspension in a selected liquid delivery medium.

The overall effects of the product particle parameters in an embolization procedure are these: as the bulk and polymer modulus or the polymer density go down, the particles become generally more compressible, conform to the tissue site more easily, and are able to penetrate further and pack more efficiently at the treatment site. Numerically higher values of these parameters also cause higher point forces on delicate vessel surfaces. Likewise, if the polymer and bulk modulus and density are higher and compressibility becomes lower, the penetration to a vessel treatment site is compromised or limited due to aggregation of inflexible particles.

Pore size has the following effect on particle uniformity. Larger pores, in comparison to the size of the particle, may yield a particle having extraneous material hanging on the edges. These projections likely accentuate clogging in the delivery device via mechanical interlocking. Conversely, particles with pores smaller by comparison with the particle diameter generally have more of a spherical shape and are less likely to clog during delivery. Packing in a vascular cavity is typically more efficient, as well. Other practical effects of particle pore (or cell) size as deposited in the vasculature are that small pores (generally <200 um) do not permit ease of tissue in-growth. Larger cell sizes permit a high degree of tissue in-growth.

Porosity of the product foam particle (a value inversely related to the bulk foam, or relative, density) exhibits the following in this polymer system: lowering the porosity increases the bulk foam density, bulk modulus, and resilience but lowers the particle's compressibility. Raising the porosity has opposite effects.

In the reactive phase-separation process (all of the examples used in this application), the bulk density and porosity are controlled primarily through the relative proportion of intial PVAOH in the system. A greater amount of non-reactive phase (lower relative PVAOH) will ultimately wash out leaving a lower bulk density and higher porosity. Care must be taken to include an appropriate starting amount of PVAOH, since too low an initial initial PVAOH amount will result in a collapsed solid mass.

In the air-whipped process the bulk density is controlled by the amount of air whipped into the polymer. The greater the proportion of air, the greater the porosity and lower bulk density.

The resultant degree of hydration inherent in the produced particle has several effects: if a particle exhibits lower hydration, it is generally less biocompatible and is generally less able to imbibe hydrophilic agents or solutions. The ability to imbibe non-hydrophilic agents is to be observed on a case-to-case basis.

A high particle hydration rate, that is, during the period just prior to introduction into the body, is desirable because the particle is more rapidly suspended in the carrier medium. Particles having comparatively lower hydration rates may initially float or sink depending upon bulk foam density and morphology and slow the period of time required for the embolization procedure.

In any case, the particles produced by these methods and described here form a component of this invention.

A following and separate procedure involves selecting appropriate partially acetalized polyvinyl alcohol foam particles produced by the processes discussed above appropriate for a particular injectable, biologically acceptable, liquid medium such that, once hydrolyzed, the particles are substantially suspendable or suspended in the selected liquid medium. The next step involves combining the selected particles and the medium to hydrate the particles and to produce the composition.

The embolic composition used for forming an occlusion in a body opening or cavity, is a combination of hydrated, partially acetalized, polyvinyl alcohol foam particles made in the fashion described above and have particle size, pore sizes, and particle porosities selected to be generally suspended in a matched, selected injectable, biologically acceptable, liquid media. The homogeneous suspension generally provides for a predictable and even delivery of the particles to the selected site without clogging the delivery apparatus.

The liquid media has a liquid medium specific gravity, generally in a range having a lower limit of about 1.0 and has an upper limit of about 1.50, although the liquid medium specific gravity may fall in a range with a lower limit of about 1.1 and an upper limit of about 1.40, or a lower limit of about 1.15 and an upper limit of about 1.40.

The liquid medium may be made up of one or more members selected from the group consisting of saline solution, radio-opacifiers, antibiotics, chemotherapy drugs, pharmaceuticals, growth factors, anti-growth factors, and natural and synthetic hormones or, perhaps one or more imaging or contrast agents. The radio-opacifiers may comprise one or more iodine-based imaging or contrast agents such as the well known and commercially available Oxilan 300, Oxilan 350, Ultravist 150, Ultravist 240, Ultravist 300, Ultravist 370, and Omnipaque 350.

For certain uses, the liquid medium may also contain one or more anticoagulants, such as heparin., or one or more clotting agents, such as thrombin.

The particles may have a mean size falling in a range having a lower limit of about 20 μm and an upper limit of about 10 mm, possibly with a lower limit of about 30 μm and an upper limit of about 10 mm or a range with a lower limit of about 45 μm and an upper limit of about 2800 μm. Several tailored size ranges are applicable: 1.) lower limit of about 90 μm and an upper limit of about 2000 μm, 2.) a lower limit of about 180 μm and an upper limit of about 1400 μm, 3.) a lower limit of about 300 μm and an upper limit of about 1000 μm, 4.) a lower limit of about 500 μm and an upper limit of about 750 μm, 5.) a lower limit of about 180 μm and an upper limit of about 300 μm, 6.) a lower limit of about 300 μm and an upper limit of about 500 μm, and 7.) a lower limit of about 500 μm and an upper limit of about 710 μm.

Similarly, the particle porosity may fall in a range having a lower limit of about 50% and has an upper limit of about 98%, perhaps with a lower limit of about 80% and an upper limit of about 96%.

Combinations of these particle sizes and porosities and the liquid medium specific gravity are suitable for the composition, e.g., where the particle size has a lower limit of about 30 μm and an upper limit of about 10 mm and where the liquid medium specific gravity has a lower limit of about 1.0 and an upper limit of about 1.50; or perhaps, where the particle size falls in a range that has a lower limit of about 180 μm and an upper limit of about 710 μm and where the liquid medium specific gravity has a lower limit of about 1.2 and an upper limit of about 1.4.

Combinations suitable for certain liquid medium include those where the particle porosity has a lower limit of about 50% and has an upper limit of about 98% and where the liquid medium specific gravity has a lower limit of about 1.0 and has an upper limit of about 1.50; a particle porosity with a lower limit of about 80% an upper limit of about 96% and where the liquid medium specific gravity has a lower limit of about 1.2 and an upper limit of about 1.4.

The particles may further comprise radio-opacifiers, antibiotics, chemotherapy drugs, pharmaceuticals, growth factors, anti-growth factors, and natural and synthetic hormones as well as imaging or contrast agents such as barium sulfate, gold, tantalum, platinum, tungsten, bismuth oxide, and mixtures.

The particles themselves may contain one or more anticoagulants such as heparin and one or more clotting agents, such as thrombin in certain rarely chosen instances.

The particles may be sized, e.g., ground, cut, chopped, or die-cut, to suitable sizes prior to their introduction into the liquid medium.

The resulting composition generally is substantially non-clogging when passed through a catheter delivery system; the homogeneous suspension also generally provides for a predictable and even delivery of the particles.

Claim 1 of 112 Claims

1. A composition for forming an occlusion in a body opening or cavity comprising hydrated, partially acetalized, polyvinyl alcohol foam particles having particle size, pore size, and particle porosity, the particles being substantially suspended in a selected injectable, biologically acceptable, liquid medium having a liquid medium specific gravity.

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