EP1173517A4 - Hydrogels se constituant in situ - Google Patents

Hydrogels se constituant in situ

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Publication number
EP1173517A4
EP1173517A4 EP00931980A EP00931980A EP1173517A4 EP 1173517 A4 EP1173517 A4 EP 1173517A4 EP 00931980 A EP00931980 A EP 00931980A EP 00931980 A EP00931980 A EP 00931980A EP 1173517 A4 EP1173517 A4 EP 1173517A4
Authority
EP
European Patent Office
Prior art keywords
hydrogel
polymer
protecting group
interacting groups
physical chemical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00931980A
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German (de)
English (en)
Other versions
EP1173517A1 (fr
Inventor
Jeffrey A Hubbell
Julia A Kornfield
Giyoong Tae
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
California Institute of Technology CalTech
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California Institute of Technology CalTech
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Publication date
Application filed by California Institute of Technology CalTech filed Critical California Institute of Technology CalTech
Publication of EP1173517A1 publication Critical patent/EP1173517A1/fr
Publication of EP1173517A4 publication Critical patent/EP1173517A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof

Definitions

  • the present invention relates to materials and methods for inducing in situ transitions of a hydrogel precursor compositions from an injectable state to a hydrogel.
  • a mechanism for gently transitioning a hydrogel precursor composition from a liquid state to a solid state such that the transition can be carried out in situ, directly in intimate contact with sensitive biological materials, is of special interest for medical purposes.
  • the in situ formation of a hydrogel at an implantation site has two potential advantages: the ability to match the morphology of a material implant to various complex tissue shapes in the body, and the ability to deliver a large device through a small hole in the body via minimally invasive surgery
  • this type of transitioning system can be used as a carrier for the controlled release of drugs, for the delivery of living cells in cell transplantation, as a barrier for the prevention of postoperative adhesions, or as a structural support at tissue sites.
  • hydrogel precursor composition we have developed methods and materials for the transition of a hydrogel precursor composition to a hydrogel. These methods and materials are sufficiently gentle that the transition can be carried out in situ, for example in direct contact with a tissue.
  • the methods of the invention can be performed without the use of any complex instrumentation or high temperatures that might otherwise be harmful to the tissue at the site where the gel forms.
  • the hydrogels that result from these methods possess high mechanical strength, and degradation rates that are of therapeutic use.
  • these hydrogel precursors can be constructed to form in a manner that is selective for the intended target site, i.e., the transition to the precursor composition a hydrogel state can be controlled so that undesired chemical reactions with surrounding tissues do not occur.
  • the invention features a hydrogel precursor composition
  • a hydrogel precursor composition comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions.
  • the hydrogel precursor composition also comprises a physical chemical protecting group that prevents gelation of the hydrogel precursor composition until desirable.
  • the invention features a hydrogel or hydrogel precursor composition
  • a hydrogel or hydrogel precursor composition comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions.
  • the hydrogel or hydrogel precursor composition also comprises a physical chemical protecting group that prevents gelation of the hydrogel precursor composition or hydrogel.
  • the hydrogel or hydrogel precursor composition further comprises a molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups.
  • the polymer domain comprises poly (ethylene glycol) (PEG), poly( vinyl alcohol), poly(vinyl pyrrolidone), poly(ethyl oxazoline), poly(acrylic acid), poly(acrylamide), poly(styrene sulfonate), poly(amino acids), polysaccharides, or copolymers thereof.
  • the polymer domain comprises poly (ethyl ene glycol).
  • the hydrophobic interacting groups are hydrocarbons, preferably perfluorinated hydrocarbons.
  • the physical chemical protecting group is cyclodextrin, preferably ⁇ -cyclodextrin.
  • the physical chemical protecting group is a molecule that covalently binds to the hydrophobic interacting group.
  • the molecule is hydrophilic.
  • the polymer of the first or second aspects may be linear or branched, and may comprise a multi-arm poly(ethylene glycol).
  • the hydrophobic interacting groups may be positioned at the termini of the polymer domain, or within the polymer domain.
  • the linkage between the polymer domain and the hydrophobic interacting groups may be stable or degradable.
  • the degradable linkage is an anhydride linkage, an ester linkage, a carbonate linkage, an amide linkage, or an oligomeric linkage.
  • the oligomeric linkage comprises oligomers of lactic acid, glycolic acid, or epsilon-caproic acid, or oligomers of trimethylene carbonate, or co-oligomers thereof.
  • the hydrophobic interacting groups interact with the physical chemical protecting group through a noncovalent bond.
  • the interaction occurs by the formation of an inclusion complex.
  • the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups is a molecule that binds to the physical chemical protecting group better than the hydrophobic interacting groups bind to the physical chemical protecting group.
  • the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups is a one-end modified polymer domain. Most preferably the one-end modified polymer domain comprises poly(ethylene glycol), and is modified with a perfluorinated hydrocarbon.
  • the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups is a molecule that degrades the linkage between the physical chemical protecting group and the hydrophobic interacting groups, or is a molecule that degrades the physical chemical protecting groups themselves. Most preferably a molecule that degrades the physical chemical protecting group is ⁇ -amylase or amyloglucosidase.
  • the polymer domain comprises poly(ethylene glycol), the hydrophobic interacting groups are perfluorinated hydrocarbons, and the chemical protecting group is ⁇ - cyclodextrin.
  • the invention features a method for forming a hydrogel in contact with a tissue, involving providing a solution comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions, and a physical chemical protecting group that prevents gelation of the polymer.
  • the method involves providing a molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups.
  • the invention features a method for forming a hydrogel in contact with a tissue.
  • the method involves providing a solution comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions, and a water soluble organic solvent that prevents gelation of the polymer.
  • the method further involves removing all or part of the organic solvent from the solution, and prior to, during, or after this removal, the solution and organic solvent are contacted with a tissue. Finally, the mixture is allowed to gel in contact with the tissue.
  • the invention features a method for forming a hydrogel in contact with a tissue.
  • This method involves providing a solution comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions, and a water soluble organic solvent that prevents gelation of the polymer.
  • the method also involves contacting the solution with a tissue, and allowing gelation of the mixture in contact with the tissue.
  • the invention features a method for incorporating a sensitive biological material into a hydrogel composition, involving providing a solution comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions, and a physical chemical protecting group that prevents gelation of the polymer.
  • the method further involves providing a molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups, and providing a sensitive biological material.
  • the sensitive biological material is combined with either the solution or with the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups.
  • the solution with the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups and the sensitive biological material are then combined to form a mixture, and allowed to gel.
  • the invention features a method for incorporating a sensitive biological material into a hydrogel composition.
  • the method involves, providing a solution comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions, and an organic solvent that prevents gelation of the polymer.
  • the method also involves providing a sensitive biological material.
  • the sensitive biological material is combined with the solution to form a mixture, and prior to, during, or after, the combining, all or part of the organic solvent is removed from the solution. Finally, the solution is allowed to gel.
  • the invention features a method for incorporating a sensitive biological material into a hydrogel composition, involving providing a solution comprising a polymer, wherein the polymer comprises a water soluble polymer domain with at least two hydrophobic interacting groups attached to it, and wherein the polymer is capable of assembling into a hydrogel under physiological conditions, and an organic solvent that prevents gelation of the polymer, and providing a sensitive biological material.
  • the sensitive biological material is combined with the solution to form a mixture, and prior to, during, or after the combining, the solution and/or said sensitive biological material is contacted with a tissue. Gelation is then allowed to occur.
  • the mixture is contacted with a tissue.
  • the polymer domain comprises poly(ethylene glycol) (PEG), poly (vinyl alcohol), poly(vinyl pyrrolidone), poly (ethyl oxazoline), poly (acrylic acid), poly (aery lamide), poly (styrene sulfonate), poly (amino acids), polysaccharides, or copolymers thereof.
  • the polymer domain comprises poly(ethylene glycol).
  • the hydrophobic interacting groups are hydrocarbons, preferably perfluorinated hydrocarbons.
  • the polymer domain comprises poly (ethyl ene glycol), the hydrophobic interacting groups are perfluorinated hydrocarbons.
  • the polymer is linear or branched.
  • the branched polymer may comprise a multi-arm poly (ethylene glycol).
  • the hydrophobic interacting groups may be positioned at the termini of the polymer domain, or within the polymer domain.
  • the linkage between the polymer domain and the hydrophobic interacting groups may be stable or degradable.
  • the degradable linkage is an anhydride linkage, an ester linkage, a carbonate linkage, an amide linkage, or an oligomeric linkage.
  • the oligomeric linkage comprises oligomers of lactic acid, glycolic acid, or epsilon-caproic acid, or oligomers of trimethyl ene carbonate, or co-oligomers thereof.
  • the physical chemical protecting group is a molecule that covalently binds to the hydrophobic interacting group.
  • the molecule is hydrophilic.
  • the hydrophobic interacting groups interact with the physical chemical protecting group through a noncovalent bond.
  • the interaction occurs by the formation of an inclusion complex.
  • the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups is a molecule that binds to the physical chemical protecting group better than the hydrophobic interacting groups bind to the physical chemical protecting group.
  • the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups is a one-end modified polymer domain.
  • the one-end modified polymer domain comprises poly (ethylene glycol), and is modified with a perfluorinated hydrocarbon.
  • the molecule that disrupts an interaction between the physical chemical protecting group and the hydrophobic interacting groups is a molecule that degrades the linkage between the physical chemical protecting group and the hydrophobic interacting groups, or is a molecule that degrades the physical chemical interacting groups themselves. Most preferably the molecule that degrades the physical chemical interacting groups is ⁇ -amylase or amyloglucosidase.
  • the polymer domain comprises poly (ethylene glycol), the hydrophobic interacting groups are perfluorinated hydrocarbons, and the chemical protecting group is ⁇ -cyclodextrin.
  • the organic solvent is removed is by evaporating or diffusing all or part of it.
  • the organic solvent is N-methylpyrrolidone.
  • hydrophobic interacting group is a group attached to the water soluble domain of a polymer, that would otherwise not be soluble under physiological conditions were it not attached to the water soluble domain of a polymer.
  • a “physical chemical protecting group” is meant a group or a molecule that interacts with a hydrophobic interacting group in a manner such that the hydrophobic interacting groups are prevented from interacting with each other to an extent such that gelation occurs.
  • gelation is meant the formation of a material into a gelled state.
  • a material is considered to be in a gelled state when its viscosity is at least 10- fold less than its viscosity when in the presence of a physical chemical interacting group or an organic solvent that prevents the hydrophobic interacting molecules of the material from interacting to an extent such that the material is not in a liquid state.
  • two-end modified polymer domain is meant a polymer domain that is modified on each end to contain hydrophobic interacting groups.
  • the polymer domain comprises PEG.
  • one-end modified polymer domain is meant a polymer domain that is modified on only one end to contain a hydrophobic interacting group.
  • the polymer domain comprises PEG.
  • rupts prevents the interaction of two molecules, for example, two hydrophobic interacting groups of a polymer.
  • the interaction between two hydrophobic interacting groups is sufficient such that the polymer does not form a hydrogel.
  • prevents is meant inhibiting the interaction of hydrophobic interacting groups of a polymer in a hydrogel precursor composition, thereby inhibiting gelation of the composition.
  • the interaction of the hydrophobic interacting groups is prevented such that the viscosity of the composition is at least 10-fold less than its viscosity when in the presence of a physical chemical protecting group or an organic solvent that inhibits the interaction of the hydrophobic interacting molecules of the material, to an extent such that the composition is not in a liquid state.
  • stable linkage is meant a linkage in a material that is cleaved, whether by hydrolysis or oxidation, at a rate slower than the rest of the material is degraded, or otherwise cleared from a site or the body.
  • stable linkage is meant a linkage in a material that is cleaved, whether by hydrolysis or oxidation, at a rate that is faster than the rest of the material is degraded or otherwise cleared from a site or the body.
  • the degradation of an unstable linkage determines, at least in part, the overall rate of degradation of the material or its clearance from a site or the body.
  • an inclusion complex is meant a complex between two components.
  • an inclusion complex is formed between a hydrophobic interacting group(s) and a physical protecting group, such that the one component (the hydrophobic interacting group) is partially or wholly surrounded by the second component (the physical chemical protecting group).
  • a sensitive biological material is meant a material that has biological activity.
  • a sensitive biological material may include, for example, peptides, polypeptides, proteins, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, carbohydrates, lipids, cells, tissues, tissue or cell aggregates, and components thereof.
  • Fig. 1 is a graph illustrating the storage modulus of gel phases in equilibrium at 298 °K.
  • Fig. 2 is graph illustrating the loss modulus of gel phases in equilibrium at 298 °K.
  • Fig. 3 is a graph illustrating the viscosity change of 10KC8 in aqueous solution, induced by addition of N-methylpyrrolidone (NMP) to disrupt the association of 10KC8.
  • NMP N-methylpyrrolidone
  • Fig. 4 is a graph illustrating the re-establishment of the associated state of 10KC8 by solvent exchange, from NMP to water.
  • the present invention features hydrogels formed by the physical association of polymers in a hydrogel precursor composition.
  • the hydrogel may comprise any hydrophilic (soluble) and biocompatible polymer domain, modified with any hydrophobic interacting groups at two or more sites along the chain (e.g., at the ends or in the domain of the polymer). These hydrophobic interacting groups bind strongly to each other in an interchain manner to form a gel matrix in situ.
  • An injectable state of the polymer matrix is produced either by the addition of molecules termed "physical chemical protecting groups” that act to disrupt association among the hydrophobic interacting groups of the polymer matrix, or by changing the solvent state to disrupt association among the hydrophobic interacting groups of the polymer matrix.
  • the injectable state of the hydrogel precursor composition can be switched to a solid hydrogel state by removal of the physical chemical protecting groups after or during delivery to the desired site so that association among the hydrophobic interacting groups is re-established.
  • the physical chemical protecting groups may be removed by their degradation, using, for example, an enzyme, or by addition of a competitor that binds the physical chemical protecting groups, transferring them away from the association sites of the polymer matrix.
  • a PEG molecule with one end modified with a hydrophobic interacting group is one example of a competitor that may be used.
  • the physical chemical protecting groups may also be removed by disrupting the bonds formed between the hydrophobic interacting groups and the physical chemical protecting groups.
  • the injectable state of the hydrogel precursor composition can also be switched to a solid hydrogel state by changing the solvent conditions to replace a solvent that does not permit association of the hydrophobic interacting groups with a solution that does permit such association.
  • a solvent that does not permit association of the hydrophobic interacting groups with a solution that does permit such association.
  • an organic solvent such as N-methylpyrrolidone (NMP) does not permit association of the hydrophobic interacting groups, but replacing the solvent with an aqueous solution, for example that of a tissue or other body fluid, or evaporating the organic solvent off does permit association.
  • NMP N-methylpyrrolidone
  • This novel approach to making polymeric compositions that transition from a liquid state to a solid state is advantageous for the following reasons. It is safe and economical, because it does not involve chemical reactions or the transfer of heat, and it does not require the use of complex instruments and surgical devices that supply both fluids and light to a site.
  • the hydrogel precursor composition may be applied to a site, for example, a tissue, and formed to the morphology of the site. Another advantage of this method is that a large amount of material may be delivered to a site using minimally invasive surgery, because the material is in a liquid, injectable state.
  • any polymer domain that is substantially water-soluble may be used in the present invention.
  • polymer domains include, but are not limited to, poly(ethylene glycol), poly( vinyl alcohol), poly(vinyl pyrrolidone), poly(ethyl oxazoline), poly( acrylic acid), poly(acrylamide), poly(styrene sulfonate), poly( amino acids), polysaccharides, and copolymers thereof.
  • initiation and termination of polymerization can be performed so as to obtain good control over the identity of polymer end groups, allowing the hydrophobic interacting groups to be attached thereto.
  • the hydrophobic interacting groups can be attached as side groups on the polymer domain, either directly by coupling to the side group on the polymer domain (e.g., coupling to the carboxylic acid side groups on poly( acrylic acid)) or indirectly, by coupling to side groups incorporated into the polymer domain by copolymerization (e.g., coupling to carboxylic acid side groups on poly(acrylamide-co-acrylic acid)).
  • side groups on the polymer domain e.g., coupling to the carboxylic acid side groups on poly( acrylic acid)
  • side groups incorporated into the polymer domain by copolymerization e.g., coupling to carboxylic acid side groups on poly(acrylamide-co-acrylic acid)
  • PEG homopolymers that are approximately 4,000 to 10,000 g/mol are particularly useful.
  • Perfluorinated hydrocarbons are the hydrophobic interacting groups that provide for the desired gelation transitions.
  • Other hydrocarbon groups can also provide these desired gelation interactions, and may be used, although they interact with less affinity than the corresponding perfluorinated hydrocarbon groups. Connecting schemes between the polymer and the hydrophobic interacting groups
  • the linkage between the hydrophobic interacting groups and the polymer domain may be selected to be relatively stable or readily degradable.
  • the hydrophobic interacting groups can be attached via anhydride, ester, carbonate, or amide linkages, to make them susceptible to hydrolysis.
  • Oligomeric linkages e.g. oligomers of lactic, glycolic, or epsilon-caproic acid or oligomers of trimethylene carbonate
  • This allows for the regulation of degradation by a process that is hydrolytically controlled.
  • the design and incorporation of such degradable linkages will lead to more predictable toxicology and pathways for elimination of the polymer from the body.
  • the polymers of the present invention may be linear or branched. A branched conformation may lead to more effective gel formation due to the existence of multiple points for interaction. Thus, multi-arm PEGs (e.g., those PEGs having more than 2 arms) are effective polymer domains. Even more complex branching can be included in the polymer conformations of the invention.
  • the polymers of the present invention may possess terminal hydrophobic interacting groups or the hydrophobic interacting groups may be incorporated along the polymer domain, either by copolymerization or by copolymerization of a site for secondary grafting of the hydrophobic interacting group. Incorporation of hydrophobic interacting groups along the polymer domain provides for a greater density of hydrophobic interacting groups. Physical chemical protecting groups
  • the physical chemical protecting groups may interact with the hydrophobic interacting groups in various ways.
  • the physical chemical protecting groups and the hydrophobic interacting groups may exist as an inclusion complex.
  • Examples of physical chemical protecting groups include, but are not limited to, cyclodextrins, for example, ⁇ -, ⁇ -, or ⁇ - cyclodextrin.
  • the physical chemical protecting group may be removed by an enzyme, for example, a cyclodextrinase, thus exposing the hydrophobic interacting groups .
  • a hydrophilic bulky group (the physical chemical protecting group) can be attached beside or on the terminus of the hydrophobic interacting group, with a hydrolytically sensitive linkage.
  • Rapid hydrolysis then triggers a transition from the sol (soluble state) to the gel state.
  • a hydrophilic group may be a PEG chain, for example, and the linkage may be a hydrolytically sensitive ester anhydride, amide, carbonate, or oligomeric linkage. This linkage may also be an enzymatically cleavable site, which results in degradation (and thus gelation) after addition of the appropriate enzyme.
  • Organic solvents may be used to prevent hydrophobic interacting groups from associating, thus prevent gel formation.
  • the injectable state of the hydrogel precursor composition can be switched to a solid hydrogel state by changing the solvent conditions to replace a solvent that does not permit association of the hydrophobic interacting groups with a solution that does permit such association.
  • an organic solvent such as N- methylpyrrolidone (NMP) does not permit association of the hydrophobic interacting groups.
  • NMP N- methylpyrrolidone
  • replacing the organic solvent with an aqueous solution, including that of a tissue or other body fluid, or evaporating the organic solvent off does permit association of the hydrophobic interacting groups.
  • the preferred solvent is NMP (because of the low toxicity).
  • NMP because of the low toxicity.
  • a number of organic solvents may be used, including, for example, ethyl acetate. Such the solvents may be removed prior to introduction of the hydrogel to an in vivo site.
  • the organic solvent may be removed by evaporation, thus allowing the precursor hydrogel solution to form a hydrogel.
  • the organic solvent may be evaporated from a solution of polymer and NMP or methylene chloride, resulting in formation of a polymer matrix. Then the polymer matrix may be rehydrated in water, either in vitro or in vivo.
  • the hydrogels of the present invention may be formed in contact with a tissue.
  • tissue is within a tumor, subcutaneous, intramuscular, adjacent to a tooth, upon the inner or outer surface of an artery or vascular graft, or upon any tissue surface when used to prevent postoperative adhesions.
  • a sensitive biological material may be incorporated into a hydrogel through the practice of this invention.
  • sensitive biological materials include, but are not limited to drugs, proteins, peptides, RNA, DNA, inorganic and organic molecules, carbohydrates, lipids, cells, tissues, tissue or cell aggregates, and combinations thereof.
  • sensitive biological materials that may be incorporated into the hydrogels include, enzymes, antibiotics, antineoplastic agents, local anesthetics, hormones, antiangiogenic agents, antibodies, neurotransmitters, psychoactive drugs, drugs affecting reproductive organs, oligonucleotides, including antisense oligonucleotides, vasoactive agents, anticoagulants, immunomodulators, cytotoxic agents, antiviral agents, and combinations thereof.
  • Exemplary sensitive biologicals materials which may be incorporated into the hydrogels of the present invention include growth hormone, for example, human growth hormone, calcitonin, granulocyte macrophage colony stimulating factor (GMCSF), ciliary neurotrophic factor, and parathyroid hormone.
  • growth hormone for example, human growth hormone, calcitonin, granulocyte macrophage colony stimulating factor (GMCSF), ciliary neurotrophic factor, and parathyroid hormone.
  • Other specific therapeutic agents include parathyroid hormone-related polypeptide, somatostatin, testosterone, progesterone, estradiol, nicotine, fentanyl, norethisterone, clonidine, scopolomine, salicylate, salmeterol, formeterol, albeterol, and valium.
  • Drugs for the treatment of pneumonia may be used, including pentamidine isothionate.
  • Drugs for the treatment of pulmonary conditions, such as asthma may be used, including albuterol sulfate, ⁇ -agonists, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate, and protein or polypeptide drugs such as TNF antagonists or interleukin antagonists.
  • therapeutic agents include cancer chemotherapeutic agents, such as cytokines, chemokines, lymphokines, and substantially purified nucleic acids, and vaccines, such as attenuated influenza virus.
  • Substantially purified nucleic acids that can be incorporated include genomic nucleic acid sequences, cDNAs encoding proteins, expression vectors, antisense molecules that bind to complementary nucleic acid sequences to inhibit transcription or translation, and ribozymes.
  • genes for the treatment of diseases such as cystic fibrosis, for example, cystic fibrosis transmembrane regulator can be administered.
  • Polysaccharides, such as heparin can also be administered.
  • Further therapeutic agents include tissue plasminogen activator
  • t-PA superoxide dismutase
  • catalase luteinizing hormone releasing hormone (LHRH) antagonists IL-11 platelet factor, IL-4 receptor, enbrel, IL-1 receptor antagonists, TNF receptor fusion proteins, megakaryocyte growth and development factor (MGDF), stemgen, anti-HER-2 and anti-NEGF humanized monoclonal antibody, anti-Tac antibody, GLP-1 amylin, and GLP-1 amylin analogues.
  • Additional therapeutic agents include atrial natriuretic factor, atrial natriuretic peptide, beta-human chorionic gonadotropin, basic fibroblast growth factor, bovine growth hormone, bone morphogenetic protein, B cell stimulating factor-1, B cell stimulating factor-2, bovine somatotropin, carcinobreaking factor, cartilage induction factor, corticotropin releasing factor, colony stimulating factor, differentiating factor-1, endothelial cell growth factor, erythroid differentiation factor, elongation factor 1 -alpha, epidermal growth factor, erythropoietin, thrombopoietin, thymopoietin, fibroblast growth factor, follicle stimulating hormone, granulocyte colony stimulating factor, glial fibrillary acidic protein, growth hormone releasing factor, human alpha- 1 antitrypsin, human atrial natriuretic factor, human chorionic gonadotropin, human leukemia inhibitory factor, hemopoi
  • Drugs may be dissolved or suspended as precipitates within the polymer form in its dissociated state.
  • This dissociated state can be converted into the associated hydrogel state by any of the methods described above, e.g., by solvent exchange, by drying, by degradation of a protecting group, or by competitive displacement of a protecting group.
  • the associating polymers are dissolved in dichloromethane at about 40% by weight and a protein drug is added as a suspension.
  • the solution is dried by evaporation to form a film or particles.
  • the dry polymer-protein depot is then re-hydrated by addition of a limited amount of buffered saline (e.g., an amount necessary to bring the material to its equilibrium swelling state).
  • the material is injected, for example, as a particulate, or placed in a tissue site to release its drug.
  • the associating polymers are dissolved in NMP at about 50% by weight and the protein is added as a suspension.
  • the polymer-protein-NMP mixture is injected into a tissue site, whereupon diffusion of the NMP from the system and counter-diffusion of water into the system results in a swollen gel depot.
  • the NMP is exchanged against water away from a tissue site, to produce a swollen material that is then injected as a particulate, or placed in a tissue site.
  • the protein is released by diffusion from the depot, with some contribution to the release process also being given by dissolution of the material from the surface of the depot.
  • Isophorone diisocyanate (IPDI), dibutyltin diacetate and anhydrous tetrahydrofuran (THF) were purchased from Aldrich.
  • One-end modified PEG molecules can be generated using a monomethoxy PEG, and keeping the molar ratios in the reaction the same as those described above.
  • nKCm is the sample, in which nK denotes the PEG molecular weight and Cm denotes the length of the C m F 2rn+1 CH 2 CH 2 OH group.
  • each sample modified with C 10 F 21 was checked by reverse phase HPLC.
  • a C18 column was used with the Water HPLC system with a gradient input of mixed solvent (ranging from 20:80 of acetonitrile: ethanol to 100% acetonitrile) that can separate unmodified, one-end modified, and two-end modified samples.
  • mixed solvent ranging from 20:80 of acetonitrile: ethanol to 100% acetonitrile
  • phase behavior of two-end modified PEGs was governed by the relative length of the PEG chain and the perfluorinated hydrocarbon end groups (Table 2). Some of the two-end modified PEGs showed phase separation and others did not. This phase separation phenomenon can provide useful applications for these transition systems; when this system is used as a delivery device in the open system, it will maintain the high modulus matrix of the equilibrium composition, compared to the systems using materials which do not show the phase separation, since the matrix formed from these would be dissolved with continuous lowering of the modulus for the same concentration of polymers.
  • 6KC10 did not exist as a homogeneous phase in water, rather only as a slightly swollen precipitate.
  • 20KC10 and 20KC8 existed as homogeneous solutions over the whole range of polymer concentrations, though the viscosity increased drastically as the concentration of polymer increased.
  • PBS phosphate buffered saline
  • the low concentration of the dilute phase means that a small driving force for the degradation of these gels would be present when they are exposed to an open system (e.g., as an implant) in the case of diffusion in the dilute phase to be rate-determining step, compared to the systems which do not show phase separation for the same concentration of polymers.
  • Cyclodextrins are cyclic starches consisting of 6, 7, or 8 ⁇ -1,4- linked glucose monomers called ⁇ , ⁇ , and ⁇ - cyclodextrin, respectively. These molecules are ring or torus-shaped and possess a hydrophobic cavity and a hydrophilic exterior. The partial hydrophobic nature of CD allows it to associate with nonpolar organic moieties or molecules to form inclusion complexes (Shieh et al., Pure Appl. Chem. A33:673-683, 1996).
  • ⁇ -amylase from aspergillus oryzae (crude powder), and amyloglucosidase from aspergillus niger (solution in 1 M glucose), both purchased from Sigma.
  • 0.008 g of ⁇ -amylase was added to 0.55 g of the homogeneous complex solution of 10KC8 and ⁇ -CD (7.73 weight % for 10KC8, and 3.35 weight % for ⁇ -CD). After shaking to mix, the sample was kept at 37 °C. The sample started to become viscous upon mixing, and after 20 minutes, it exhibited a gel-like structure.
  • amyloglucosidase from aspergillus niger was added to 0.513 g of the precursor solution (7.59 weight % for 10KC8, and 3.27 weight % for ⁇ -CD). After 30 minutes, the sample started to become viscous, and after 70 minutes, it became insoluble.
  • Example 6 Reformation of a gel by transfer of CD to a one-end modified P_EG PEGs modified to contain a hydrophobic interacting group on only one end will form a micelle-like structure in aqueous solutions, and in this structure they are injectable even when present below the critical transition concentration. Furthermore, the affinity of a one-end modified PEG having a small molecular weight of a PEG for CD is greater than the affinity of a two- end modified PEG having a large molecular weight of PEG for CD (Amiel et al., J. Inclusion Phen. & Mol. Recog., 25:61-67, 1996).
  • Dissolution rates of gel phases are measured by direct measurements of dissolved amounts of polymers, or by the shift of the surface plasmon resonance angle of ultrathin gold film coated with the thin film of the polymer matrix that is exposed to the flow of water (Aust et al., TIP 2:313-32, 1994).
  • the compositions of the polymer matrix are the equilibrium gel concentrations.
  • the dissolution rates of 10 weight % of 20KC10 and 12.8 weight % of one-end modified 5K- M-C10, which shows a lyotropic gel phase transition at that concentration were measured (Table 4).
  • phase separation 20KC10 and 5K-M-C10
  • phase-separation 6KC8 showed around 5 times slower dissolution rates than 10KC8, and the rate of 10KC10 dissolution was much slower than 6KC8.
  • the absolute small value of dissolution rates for the phase separating species confirmed that these species can be used as delivery carriers in the open system. Also, by choosing the right ratio of hydrophilic and hydrophobic groups, the degradation rate of the matrix can be controlled. Another feature of polymer matrix degradation is whether the matrix is degraded homogeneously or heterogeneously.
  • Example 8 Disruption of a gel by addition of organic solvents
  • Associative interactions of polymers through their hydrophobic interacting groups may be disrupted by altering the characteristics of the solvent that the polymers are contained in, and these interactions may be re- established by altering the solvent again.
  • Disrupting the associative interactions of the polymer can be achieved, for example, by dissolving the gel- forming polymer in a water mixture with a water-soluble organic solvent, such as NMP, or in the organic solvent neat, and then converting the non-associative state into the associated state by removal of the solvent and addition of water. This may be accomplished in a number of ways.
  • a flowable solution of the polymer in NMP or an NMP- water mixture (in the non-associated state) may be contacted with an aqueous environment, permitting the diffusion of the NMP from the polymer solution and its corresponding replacement by water, thus converting the material into an associative state.
  • the material in the NMP or NMP-water mixture may be injected into a tissue site, and the NMP allowed to exchange with the aqueous component of the body fluids, to achieve the same end.
  • the preferred solvent is NMP, the toxicity of which is very low, although other solvents, including ethyl acetate, may also be useful.
  • the solvent may be removed before introduction into the body.
  • the solvent may be removed by evaporation, such as by drying a solution of the polymer from NMP or methylene chloride, followed by rehydration in water, either in vitro or in vivo.

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  • Medicinal Chemistry (AREA)
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  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
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Abstract

L'invention concerne des matériaux et des procédés servant à effectuer la transition de l'état liquide à l'état solide d'une composition injectable précurseur d'hydrogel en un hydrogel. On peut mettre ces procédés en application in situ.
EP00931980A 1999-04-26 2000-04-26 Hydrogels se constituant in situ Withdrawn EP1173517A4 (fr)

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US133164P 1999-04-26
PCT/US2000/011691 WO2000064977A1 (fr) 1999-04-26 2000-04-26 Hydrogels se constituant in situ.

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CN100519643C (zh) 2002-07-19 2009-07-29 奥默罗斯公司 可生物降解的三嵌段共聚物,它们的合成方法和从它制得的水凝胶和生物材料
WO2004087007A2 (fr) 2003-03-25 2004-10-14 Biocure, Inc. Dispositif medical de fil en hydrogel
GB0307011D0 (en) * 2003-03-27 2003-04-30 Regentec Ltd Porous matrix
ATE489058T1 (de) 2004-06-29 2010-12-15 Inc Biocure Bandscheiben-nucleus-pulposus-implantat
WO2007120818A2 (fr) * 2006-04-12 2007-10-25 Massachusetts Institute Of Technology Compositions et méthodes permettant d'inhiber les adhérences
EP2280739B1 (fr) 2008-06-03 2012-07-04 Actamax Surgical Materials LLC Revêtement de tissu pour empêcher des adhérences tissu-à-tissu indésirables
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JP2018533596A (ja) 2015-11-12 2018-11-15 グレイバグ ビジョン インコーポレイテッド 医学療法のための凝集マイクロ粒子
JP7217022B2 (ja) 2017-03-23 2023-02-02 グレイバグ ビジョン インコーポレイテッド 眼障害の治療のための薬物及び組成物
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WO2000064977A1 (fr) 2000-11-02

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