Link:  Pharm/Biotech Resources

Title:  Hydrogels that undergo volumetric expansion in response to changes in their environment and their methods of manufacture and use

United States Patent:  6,878,384

Issued:  April 12, 2005

Inventors:  Cruise; Gregory M. (Rancho Santa Margarita, CA); Constant; Michael J. (Mission Viejo, CA)

Assignee:  MicroVention, Inc. (Aliso Viego, CA)

Appl. No.:  804935

Filed:  March 13, 2001

Abstract

Hydrogels that expand volumetrically in response to a change in their environment (e.g., a change in pH or temperature) and their methods of manufacture and use. Generally, the hydrogels are prepared by forming a liquid reaction mixture that contains a) monomer(s) and/or polymer(s) at least portion(s) of which are sensitive to environmental changes (e.g., changes in pH or temperature), b) a crosslinker and c) a polymerization initiator. If desired, a porosigen may be incorporated into the liquid reaction mixture to create pores. After the hydrogel is formed, the porosigen is removed to create pores in the hydrogel. The hydrogel may also be treated to cause it to assume a non-expanded volume in which it remains until a change in its environment causes it to expand. These hydrogels may be prepared in many forms including pellets, filaments, and particles. Biomedical uses of these hydrogels include applications wherein the hydrogel is implanted in the body of a patient and an environmental condition at the implantation site causes the hydrogel to expand in situ.

Description of the Invention

FIELD OF THE INVENTION

The present invention relates generally to certain hydrogel compositions, methods of manufacturing such hydrogel compositions and methods of using such hydrogel compositions. More particularly, the present invention relates to hydrogels that exhibit controlled rates of expansion in response to changes in their environment, the methods by which such hydrogels may be prepared and methods of using such hydrogels in biomedical applications (e.g., the treatment of aneurysms, fistulae, arterio-venous malformations, and for embolization or occlusion of blood vessels or other luminal anatomical structures).

BACKGROUND OF THE INVENTION

Generally, the term "hydrogel" refers generally to a polymeric material that is capable swelling in water. The swelling of a hydrogel in water results from diffusion of water through the glassy polymer causing disentanglement of polymer chains and subsequent swelling of the polymer network. Typically, hydrogels of the prior art have been prepared by the crosslinking of monomers and/or polymers by radiation, heat, reduction-oxidation, or nucleophilic attack. Examples of the crosslinking of ethylenically unsaturated monomers include the preparation of contact lenses from 2-hydroxyethyl methacrylate and the preparation of absorbent articles from acrylic acid. Examples of crosslinking of polymers include wound dressings by crosslinking aqueous solutions of hydrophilic polymers using ionizing radiation and surgical sealants by crosslinking aqueous solutions of hydrophilic polymers modified with ethylenically unsaturated moieties.

In or about 1968, Krauch and Sanner described a method of polymerizing monomers around a crystalline matrix and subsequently removing the crystaline matrix to produce an interconnected porous polymer network. Since that time, porous hydrogels have been prepared using salt, sucrose, and ice crystals as the porosigen. These porous hydrogels of the prior art have been used as membranes for affinity chromatography and as tissue engineering substrates wherein tissues are intended to ingrow into the porous hydrogel network. Examples of these porous hydrogels are found in U.S. Pat. No. 6,005,161 (Brekke, et al.) entitled Method And Device For Reconstruction of Articular Cartilage, U.S. Pat. No. 5,863,551 (Woerly) entitled Implantable Polymer Hydrogel For Therapeutic Uses and U.S. Pat. No. 5,750,585 (Park et al.) entitled Super Absorbant Hydrogel Foams.

The prior art has also included certain hydrogels that undergo a volume change in response to external stimuli such as changes in the solvent composition, pH, electric field, ionic strength, and temperature. The hydrogel's response to the various stimuli is due to the judicious selection of the monomer units. For example, if temperature sensitivity is desired, N-isopropyl acrylamide is frequently used. If pH sensitivity is desired, a monomer with an amine group or a carboxylic acid is frequently used. Stimuli responsive hydrogels have primarily been used as controlled drug delivery vehicles. Examples of these stimuli-responsive hydrogels are found in U.S. Pat. No. 6,103,865 (Bae, et al.) entitled pH-Sensitive Polymer Containing Sulfonamide And Its Synthesis Method, U.S. Pat. No. 5,226,902 (Bae et al.) entitled Pulsatile Drug Delivery Device Using Stimuli Sensitive Hydrogel and U.S. Pat. No. 5,415,864 (Kopeck, et al.) entitled Colonic-Targeted Oral Drug-Dosage Forms Based On Crosslinked Hydrogels Containing Azobonds And Exhibiting pH-Dependent Swelling.

Despite these advances in the capabilities of the hydrogel material, a hydrogel material that permits cellular ingrowth and has controlled rate of expansion optimized for delivery through a microcatheter or catheter without the need for a non-aqueous solvent or a coating has not been developed. Accordingly, there remains a need in the art for the development of such a hydrogel useable in various applications, including, but not limited to, medical implant applications wherein the hydrogel is used as or in conjunction with aneurysms, fistulae, arterio-venous malformations, and vessel occlusions.

SUMMARY OF THE INVENTION

The present invention provides hydrogels that undergo controlled volumetric expansion in response to changes in their environment, such as changes in pH or temperature (i.e., they are "stimulus-expandable"). In one embodiment, the hydrogels are sufficiently porous to permit cellular ingrowth. The hydrogels of the present invention are prepared by forming a liquid reaction mixture that contains a) monomer(s) and/or polymer(s) at least portion(s) of which are sensitive to environmental changes (e.g., changes in pH or temperature), b) a crosslinker and c) a polymerization initiator. If desired, a porosigen, (e.g., sodium chloride, ice crystals, and sucrose) may be incorporated into the liquid reaction mixture. Porosity is formed by the subsequent removal of the porosigen from the resultant solid hydrogel (e.g, by repeated washing). Typically, a solvent will also be used to dissolve solid monomer(s) and/or polymers. However, in cases where only liquid monomers are used, there may be no need for inclusion of a solvent. Generally, the controlled rate of expansion of the present invention is imparted through the incorporation of ethylenically unsaturated monomers with ionizable functional groups, (e.g. amines, carboxylic acids). For example, if acrylic acid is incorporated into the crosslinked network, the hydrogel is incubated in a low pH solution to protonate the carboxylic acids. After the excess low pH solution has been rinsed away and the hydrogel dried, the hydrogel can be introduced through a microcatheter filled with saline at physiological pH or blood. The hydrogel cannot expand until the carboxylic acid groups deprotonate. Conversely, if an amine containing monomer is incorporated into the crosslinked network, the hydrogel is incubated in a high pH solution to deprotonate amines. After the excess high pH solution has been rinsed away and the hydrogel dried, the hydrogel can be introduced through a microcatheter filled with saline at physiological pH or blood. The hydrogel cannot expand until the amine groups protonate.

Optionally, a stimulus-expandable hydrogel material of the present invention may be rendered radiopaque for visualization under radiographic imaging. The incorporation of radiopaque particles (e.g., tantalum, gold, platinum, etc.) into the liquid reaction mixture would impart radiopacity to the entire hydrogel. Alternatively, a radiopaque monomer may be incorporated into the liquid reaction mixture to impart radiopacity to the entire hydrogel.

In accordance with this invention, there are provided methods for treating various diseases, conditions, malformations, or disorders of human or veterinary patients by implanting (e.g. injecting, instilling, implanting surgically or otherwise, introducing through a cannula, catheter, microcatheter, needle or other introduction device or otherwise placing) a stimulus-expandable hydrogel material of the present invention that occupies a first volume into an implantation site within the body whereby the conditions (e.g., pH, temperature) at the implantation site cause the hydrogel to expand to a second volume larger than the first volume. Specifically, the hydrogels of the present invention may be implanted subcutaneously, in a wound, in a tumor or blood vessels that supply blood to the tumor, in an organ, in an aberrant blood vessel or vascular structure, in a space located between or among tissues or anatomical structures or within a surgically created pocket or space. In this manner, the hydrogels that have controllable rates of expansion of the present invention are useable for the treatment of aneurysms, fistulae, arterio-venous malformations, vessel occlusions, and other medical applications.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description and examples are provided for the limited purpose of illustrating exemplary embodiments of the invention and not for the purpose of exhaustively describing all possible embodiments of the invention.

A. Preferred Method for Preparing pH-responsive Expandable Hydrogels from Monomer Solutions

The following is a description of one method for preparing pH-responsive expandable hydrogels according to the present invention.

Selection and Addition of the Monomers

In this embodiment, the monomer solution is comprised of ethylenically unsaturated monomers, ethylenically unsaturated crosslinker, the porosigen, and the solvent. At least a portion, preferably 10%-50% of the monomers, more preferably 10%-30% of the monomers, of the monomers selected must be pH sensitive. The preferred pH sensitive monomer is acrylic acid. Methacrylic acid and derivatives of both acids will also impart pH sensitivity. Since the mechanical properties of hydrogels prepared exclusively with these acids are poor, a monomer to provide additional mechanical properties should be selected. A preferred monomer for conferrance of mechanical properties is acrylamide, which may be used in combination with one or more of the above-mentioned pH sensitive monomers to impart additional compressive strength or other mechanical properties. Preferred concentrations of the monomers in the solvent range from 20% w/w to 30% w/w.

Selection and Addition of the Crosslinker(s)

The crosslinker can be any multifunctional ethylenically unsaturated compound. N,N'-methylenebisacrylamide is the preferred crosslinker. If biodegradation of the hydrogel material is desired, a biodegradable crosslinker should be selected. Preferred concentrations of the crosslinker in the solvent are less than 1% w/w, more preferably less than 0.1% w/w.

Selection and Addition of the Porosigen(s)

The porosity of the hydrogel material is imparted due to a supersaturated suspension of a porosigen in the monomer solution. A porosigen that is not soluble in the monomer solution, but is soluble in the washing solution can also be used. Sodium chloride is the preferred porosigen, but potassium chloride, ice, sucrose, and sodium bicarbonate can also be used. It is preferred to control the particle size of the porosigen to less than 25 microns, more preferably less than 10 microns. The small particle sizes aid the suspension of the porosigen in the solvent. Preferred concentrations of the porosigen range from 5% w/w to 50% w/w, more preferably 10% w/w to 20% w/w, in the monomer solution. Alternatively, the porosigen can omitted and a non-porous hydrogel can be fabricated.

Selection and Addition of Solvent (if required)

The solvent, if necessary, is selected based on the solubilities of the monomers, crosslinker, and porosigen. If a liquid monomer (e.g. 2-hydroxyethyl methacrylate) is used, a solvent is not necessary. A preferred solvent is water, however ethyl alcohol can also be used. Preferred concentrations of the solvent range from 20% w/w to 80% w/w, more preferably 50% w/w to 80% w/w.

The crosslink density substantially affects the mechanical properties of these hydrogel materials. The crosslink density (and hence the mechanical properties) can best be manipulated through changes in the monomer concentration, crosslinker concentration, and solvent concentration.

Selection and Addition of Initiator(s) to Cause Crosslinking of the Monomer Solution

The crosslinking of the monomer can be achieved through reduction-oxidation, radiation, and heat. Radiation crosslinking of the monomer solution can be achieved with ultraviolet light and visible light with suitable initiators or ionizing radiation (e.g. electron beam or gamma ray) without initiators. A preferred type of crosslinking initiator is one that acts via reduction-oxidation. Specific examples of such red/ox initiators that may be used in this embodiment of the invention are ammonium persulfate and N,N,N',N'-tetramethylethylenediamine.

Washing to Remove Porosigen(s) and any Excess Monomer

After the polymerization is complete, the hydrogel is washed with water, alcohol or other suitable washing solution(s) to remove the porosigen(s), any unreacted, residual monomer(s) and any unincorporated oligomers. Preferably this is accomplished by initially washing the hydrogel in distilled water.

Treatment of the Hydrogel to Control of the Expansion Rate of the Hydrogel

As discussed above, the control of the expansion rate of the hydrogel is achieved through the protonation/deprotonation of ionizable functional groups present on the hydrogel network. Once the hydrogel has been prepared and the excess monomer and porosigen have been washed away, the steps to control the rate of expansion can be performed.

In embodiments where pH sensitive monomers with carboxylic acid groups have been incorporated into the hydrogel network, the hydrogel is incubated in a low pH solution. The free protons in the solution protonate the carboxylic acid groups on the hydrogel network. The duration and temperature of the incubation and the pH of the solution influence the amount of control on the expansion rate. Generally, the duration and temperature of the incubation are directly proportional to the amount of expansion control, while the solution pH is inversely proportional. It has been determined by applicant that the water content of the treating solution also affects the expansion control. In this regard, the hydrogel is able to expand more in the treating solution and it is presumed that an increased number of carboxylic acid groups are available for protonation. An optimization of water content and pH is required for maximum control on the expansion rate. After the incubation is concluded, the excess treating solution is washed away and the hydrogel material is dried. We have observed that the hydrogel treated with the low pH solution dries down to a smaller dimension than the untreated hydrogel. This is a desired effect since delivery of these hydrogel materials through a microcatheter is desired.

If pH sensitive monomers with amine groups were incorporated into the hydrogel network, the hydrogel is incubated in a high pH solution. Deprotonation occurs on the amine groups of the hydrogel network at high pH. The duration and temperature of the incubation, and the pH of the solution, influence the amount of control on the expansion rate. Generally, the duration, temperature, and solution pH of the incubation are directly proportional to the amount of expansion control. After the incubation is concluded, the excess treating solution is washed away and the hydrogel material is dried.

Claim 1 of 35 Claims

What is claimed is:

1. A method for treating a disease, deformation or disorder of a human or veterinary patient by introduction of a hydrogel polymer through the lumen of a catheter and into an implantation site within the patient's body, said method comprising the steps of:

(A) predicting the approximate pH that will be present at the implantation site when the hydrogel is implanted;

(B) providing a dried, expandable hydrogel that has been prepared by a process comprising the steps of,

(i) combining at least a) an cthylenicallyunsauirated monomer or prepolymer having ionizable functional groups, b) a crosslinker and c) a polymerization initiator, to form a hydrogel polymer;

(ii) contacting the hydrogel with a treatment solution, the pH of said treatment solution and the time and temperature of said contact being such that a) functional groups of the hydrogel become protonated and b) the resultant protonated hydrogel will, when subsequently exposed to the pH predicted at the implantation site, undergo deprotonation and expansion at a desired rate of expansion; and

(iii) drying the hydrogel to from a protonated, dried hydrogel mass sized to pass through the catheter lumen;

(C) placing the dried hydrogel mass within the catheter lumen; and,

(D) positioning the catheter at the implantation site and expelling the dried hydrogel mass into the implantation site such that the hydrogel polymer becomes exposed to the pH present at the implantation site and, if the pH present at the implantation site is substantially the same as predicted in Step A, the hydrogel deprotonates and expands at approximately the desired expansion rate, said desired expansion rate being selected such that the hydrogel mass will remain sufficiently small to be retracted into the catheter lumen for at least 15 minutes following its initial exposure to the approximate pH predicted to be present at the implantation site.

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