Method of formation of shape-retentive aggregates of gel particles and their uses
Inventors
Moro, Daniel G. • St. John, John V. • Shannon, Kevin F. • Ponder, Bill C.
Assignees
Publication Number
US-7811605-B2
Publication Date
2010-10-12
Expiration Date
2022-11-06
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Abstract
The present invention relates to a method of forming shape-retentive aggregates of gel particles in which the aggregates are held together by non-covalent bond physical forces such as, without limitation, hydrophobic-hydrophilic interactions and hydrogen bonds. The method comprises introducing a suspension of gel particles in a polar liquid at a selected concentration, wherein the gel particles have an absolute zeta potential, into a medium in which the absolute zeta potential of the gel particles is decreased, resulting in the gel particles coalescing into the claimed shape-retentive aggregate. This invention also relates to uses of the method of formation of the shape-retentive aggregates of gel particles.
Core Innovation
The invention relates to a method for forming shape-retentive aggregates of gel particles held together by non-covalent physical forces including hydrophobic-hydrophilic interactions and hydrogen bonds. This method involves introducing a suspension of gel particles dispersed in a polar liquid, with particles having a first absolute zeta potential, into a receiving medium where the absolute zeta potential is reduced, causing the particles to coalesce into a shape-retentive aggregate. The gel particles can be produced by polymerizing monomers containing hydroxyl and/or ether groups in the presence of surfactants or by using preformed dry gel particles mixed with liquid and surfactants.
The problem addressed by the invention is the difficulty in controlling the dissemination and localization of particulate gels and the inability of currently available particulate gels to be shape-retentive, unlike bulk hydrogels. Bulk hydrogels, while useful for biomedical applications, are amorphous masses with limited swelling rates and substance release is non-uniform. Particulate gels allow for more uniform substance release but lack shape-retentiveness and are challenging to apply in situ with desired shapes. The invention provides a method to form shape-retentive gel aggregates in situ, including in vivo environments, where the aggregate shape is dictated by the application site, offering improved drug delivery, tissue repair, and cosmetic surgery benefits.
The method allows for control over gel particle concentration, size, chemical composition, and polydispersivity, as well as surfactant types and introduction rates through an orifice such as a hypodermic needle. By manipulating these parameters and the receiving medium's properties, the method achieves aggregation driven by reduced zeta potential, resulting in stable or degradable shape-retentive aggregates capable of occluding or entrapping working substances including biomedical agents. The aggregates can be elastic and degrade under environmental or physiological conditions, enabling controlled delivery and scaffold applications.
Claims Coverage
The patent contains one independent claim that outlines a method for forming shape-retentive aggregates of gel particles with several inventive features focusing on particle preparation, suspension, and aggregation conditions.
Method for forming shape-retentive aggregates of gel particles
The method comprises providing a suspension system of gel particles with an average diameter less than about 955 nanometers made by polymerizing selected monomers with 0.1 to 10 mol percent surfactant in a polar liquid containing hydroxyl groups, where the gel particles have a first absolute zeta potential. The suspension is then introduced into a receiving medium where the gel particles acquire a reduced second absolute zeta potential, causing them to coalesce into shape-retentive aggregates held together by non-covalent hydrophobic-hydrophilic interactions and hydrogen bonds.
Control over concentration and composition of gel particles in suspension
The gel particles in the suspension system are maintained at concentrations from about 1 to about 500 mg wet weight/mL, with preferred ranges from about 25 to 250 mg/mL, including the use of one or more particle sizes with narrow or broad polydispersivity, and particle concentrations that induce cluster formation up to about 500 mg/mL.
Preparation and introduction of suspension system
The suspension system can be prepared by mixing preformed dry gel particles with liquids and surfactants. The suspension is introduced into the receiving medium via an orifice such as a hollow needle of 10 to 30 gauge, preferably 15 to 27 gauge, at a selected introduction rate between about 0.05 to 15 mL/minute, preferably 0.25 to 10 mL/minute.
Receiving medium and particle composition specifics
The receiving medium can be an in vivo medium comprising bodily tissues such as epithelium, connective tissue (blood, bone, cartilage), muscle, and nerve. The monomers used are selected from groups including 2-alkenoic acids, hydroxyalkyl 2-alkenoates, and others capable of hydrogen bonding, with preferred monomers such as 2-hydroxyethyl methacrylate and related compounds.
Use of cross-linking agents and working substances
The method may include adding from about 0.1 to 15 mol percent of cross-linking agents to the polymerization system to cross-link polymer strands, wherein cross-linkers can be degradable or non-degradable. Working substances, including biomedical agents and pharmaceutical excipients, may be added prior to polymerization for occlusion in gel particles or added to the suspension system for entrapment within the aggregate, with concentrations ranging from about 0.1 to 90 weight percent.
Aggregation resulting in elastic shape-retentive aggregates
The formed shape-retentive aggregate maintains a definite shape indefinitely and the gel particles are held by non-covalent forces. The aggregate can be elastic, capable of deformation and recovery.
The claims collectively cover a method for producing shape-retentive aggregates by controlling gel particle size, chemical composition, concentration, suspension conditions, introduction parameters, receiving medium characteristics, and inclusion of working substances or cross-linkers, enabling formation of aggregates held together via specific non-covalent interactions.
Stated Advantages
Provides shape-retentive aggregates combining substance release control of particulate gels with shape-retentiveness of bulk hydrogels.
Allows in situ formation of aggregates with shapes dictated by the locus of application, particularly useful in vivo.
Enables controlled delivery of biomedical and pharmaceutical agents with potential for sequential or simultaneous release.
Supports formation of elastic aggregates with improved mechanical properties suitable for biomedical applications such as tissue scaffolding.
Facilitates formation of biodegradable or erodible aggregates by selecting degradable cross-linkers or particle compositions.
Offers precise control over aggregation rates and release profiles by manipulating particle size, concentration, surfactants, and environmental conditions.
Documented Applications
Biomedical applications including joint reconstruction, wound repair, drug delivery, and cosmetic surgery.
Soft contact lenses and ocular drug delivery devices.
Burn and wound dressings with incorporated drugs for healing.
Medical device surface coatings to improve wettability.
Sustained release devices for biologically active substances.
Tissue-growth scaffolding for orthopedic applications such as cartilage and bone repair, meniscus repair/replacement, artificial spinal discs, tendons, ligaments, and bone defect fillers.
Cosmetic tissue enhancement including breast reconstruction, lip enhancement, wrinkle removal, facial tissue reconstruction.
In vivo formation of medicated or unmedicated catheters or stents.
Agricultural delivery of fungicides, insecticides, herbicides, and nutrients to crops or soil.
Veterinary delivery of medicaments to animals.
Environmental remediation by controlled degradation of contaminants in soil.
Incorporation of materials such as metals, semiconductors, magnetic particles for applications including MEMS/NEMS devices, proton exchange membranes for fuel cells, and three-dimensional array analytical tools for biotechnology.
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