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WO2007005249A2 - Nanoparticules et hydrogels a base de polymeres dendritiques les renfermant - Google Patents

Nanoparticules et hydrogels a base de polymeres dendritiques les renfermant Download PDF

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Publication number
WO2007005249A2
WO2007005249A2 PCT/US2006/023723 US2006023723W WO2007005249A2 WO 2007005249 A2 WO2007005249 A2 WO 2007005249A2 US 2006023723 W US2006023723 W US 2006023723W WO 2007005249 A2 WO2007005249 A2 WO 2007005249A2
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Prior art keywords
composition
occurrence
represents independently
nanoparticles
compound
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PCT/US2006/023723
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English (en)
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WO2007005249A3 (fr
Inventor
Michael A. Carnahan
Jeffrey A. Clark
Mark W. Grinstaff
Kenneth E. Stockman
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Hyperbranch Medical Technology, Inc.
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Publication of WO2007005249A2 publication Critical patent/WO2007005249A2/fr
Publication of WO2007005249A3 publication Critical patent/WO2007005249A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • Nanoparticles are small particles typically ranging in size from about one nanometer to several hundred nanometers in diameter. Many nanoparticles exhibit interesting properties, e.g., high refractive index, due to their size and composition. The small size of nanoparticles allows them to be useful for producing a variety of products such as dyes and pigments; tools for biological discovery, medical imaging, and therapeutics; magnetic recording media; quantum dots; and even uniform and nanosize semiconductors.
  • Nanoparticles have been prepared using an evaporation and condensation method. More recent reports describe the preparation of nanoparticles using sonochemical processing, cavitation processing, microemulsion processing, high-energy ball milling, and aerosol- based methods, such as combustion flame, plasma, laser ablation, chemical vapor condensation, spray pyrolysis, electrospray, and plasma spray.
  • nanoparticles made of metal or a metal oxide suffer from the limitation that they tend to agglomerate in aqueous solutions.
  • nanoparticles made of TiO 2 or ZnO 2 are generally only dispersed in aqueous solutions that have a pH greater than about 8 or a pH less than about 5.
  • the fact that many nanoparticles may agglomerate has, not been a significant problem for many previous uses of nanoparticles because the previous uses did not require a disperse, optically-clear composition.
  • compositions comprising nanoparticles for use in opthamalic applications should be clear. Therefore, the need exists for nanoparticle compositions that are optically clear.
  • the lens is the part of the eye that helps focus light on the retina, which in turn sends the visual signal to the brain. To produce a sharp image, the lens must remain clear and free of defects. Defects in the lens may cause vision problems requring that the lens be replaced with a synthetic material. For example, a natural lens may need to be replaced when a cataract or other disease causes the lens to function poorly. A cataract is a clouding of the lens in the eye that can cause vision problems. A natural lens may also need to be replaced when a patient suffers an eye injury that causes damage to the lens.
  • the optical properties of the normal eye lens are the consequence of a high concentration of proteins called "crystallins" forming a natural hydrogel.
  • a range of differently sized protein assemblies are found creating a medium of high refractive index.
  • the anatomical basis of accommodation includes the lens substance, lens capsule, zonular fibers, ciliary muscle and the elastic part of the choroid. Accommodation occurs through accurately controlled adjustments in the shape and thickness of the lens.
  • the capsular bag is essential in transmitting the various extralenticular forces to the lens substance.
  • Modern cataract surgery can be done through a small incision (usually 2.5-3.5 mm). Once the incision is made, the anterior chamber is filled with a viscoelastic and the capsular bag is pricked with a needle. From this incision, a small continuous circular capsulorhexis (CCC) approximately 1.5 mm in diameter is performed using capsulorhexis forceps. Next endocapsular phacoemulsification is performed and the lens epithelial cells are removed by aspiration.
  • CCC circular capsulorhexis
  • intraocular lens Since removing the cataract leaves the eye without a lens to focus light, an artificial (intraocular) lens is commonly placed inside the eye. Most intraocular lenses are made of plastic, silicone, or acrylic compounds; have no moving parts; and last for the remainder of a person's life. These intraocular lens implants are held in place by the posterior capsule are not able to provide ocular accommodation.
  • IOL materials include plastics, gels or hydrogels. IOL implants that are softer, more flexible are generally favored due to their ability to be compressed, folded, rolled or otherwise deformed. Such softer IOL implants may be deformed prior to insertion through an incision in the eye. Following insertion of the IOL in an eye, the IOL returns to its original pre-deformed shape due to the memory characteristics of the soft material. Softer, more flexible IOL implants can be implanted through a smaller incision than that required for more rigid IOLs, i.e., 5.5 to 7.0 mm.
  • hydrophilic acrylics or "hydrogels” affords IOLs with a relatively low refractive indice.
  • hydrophilic acrylics or "hydrogels”
  • the more rigid IOL implants suffer from the disadvantage that larger incisions are required, which have been found to be associated with an increased incidence of postoperative complications, such as induced astigmatism.
  • a high refractive index is also a desirable feature in the production of IOLs in order to impart high optical power with a minimum of optic thickness.
  • visual acuity deficiencies may be corrected using a thinner IOL.
  • a thin IOL minimizes potentially harmful contacts between the IOL and internal structures of the eye, such as the iris.
  • foldable or compressible materials such as silicone polymers, hydrocarbon and fluorocarbon polymers, hydrogels, soft acrylic polymers, polyesters, polyamides, polyurethane, silicone polymers with hydrophilic monomer units, fluorine-containing polysiloxane elastomers and combinations thereof.
  • Materials for an accommodating IOL or endocapsular lens should have an elastic modulus and relaxation time that is constant.
  • the material should also be comparable to a youthful lens (approximately 1.0 kPa).
  • the material should maintain nearly full optical transmission at a relatively high refractive index (1.41-1.42) and exhibit minimal swelling once the material, e.g., polymer, is cured.
  • Kessler reported one of the first examples of removing a natural lens and refilling with a synthetic compound to provide accommodation. Kessler used Carquille's immersion oil, silicone fluids, damar gum, Silastics, RTV S-5395, and RTV S-5396 as refilling materials to form the physical gels under physiological temperatures. [Kessler, 1964 #17;Kessler, 1966 #32] Kessler's reports demonstrated that a lens capsule could be refilled with a transparent substance both in vitro and in vivo. However, even the best materials used in the reports had a low refractive index, slow cure times, and the mechanical properties were too high.
  • Parel et al. utilized filler-free divinylmethylcyclosiloxane, [Parel, 1986 #16;Haefliger, 1987 #15;Haefliger, 1994 #12], a chemical cross-linker, and other silicone compounds [Haefliger, 1987 #15;Yonemura, 1993 #14], with RIs of 1.402, to form the silicone elastomers. Parel's group reported favorable mechanical properties and anterior chamber shallowing, indicating restoration of some accommodation, but the presence of lens epithelial cells was a major hindrance in obtaining accurate information for the degree of accommodation.
  • Nishi et al. used a polymethyldisiloxane liquid containing a hydrogen polysiloxane crosslinking agent with a silicone plug for sealing the capsular opening to prevent leakage of the injected material.
  • Major obstacles included the appearance of posterior capsular opacification (PCO), and some small leaking which was reported to be surgically removed.
  • PCO posterior capsular opacification
  • Silicones generally have a low specific gravity, and PCO has been reported to be a complication.
  • Hettlich et al. reported endocapsular polymerization in which a monomer mixture was injected and photopolymerized in situ to form the gel. [Hettlich, 1994 #38]
  • compositions comprising polymers and nanoparticles that form hydrogels useful as lens replacement materials, lens substitute materials, corneal inlays, and intraocular lenses.
  • the hydrogels of the invention are superior materials for ophthalmologic applications because they can form transparent, stable, high refractive-index composites.
  • the hydrogels of the invetion can be formed using a polyacrylate, silicone, or dendritic macromolecule.
  • the polymer is a dendritic macromolecule.
  • the lens may be formed in situ by injecting a solution containing the materials to form the hydrogel into an empty lens capsule. Once injected, the materials polymerize to form a hydrogel mimic of the natural lens.
  • the lens may be formed ex vivo and then implanted as a thin disk-shaped material.
  • the hydrogels of the invention comprise nanoparticles ranging in diameter from about 0.1 nm to about 100 nm.
  • the nanoparticles are generally dispersed throughout the hydrogel and may be covalently or noncovalently crosslinked.
  • the nanoparticles may be made of a metal, metal oxide, or ceramic.
  • the nanoparticles comprise a ceramic core coated with a layer of silica.
  • the hydrogels of the invention may be reversible or non-reversible.
  • the hydrogel is non-reversible.
  • the lens is sterilzed by treatment with ethylene oxide, hydrogen peroxide, heat, gamma irradiation, electron beam irradiation, microwave irradiation, visible light irradiation or filtration.
  • the sterilized lens is then delivered in vivo using a sterile delivery device, such as a syringe or other applicator.
  • Another aspect of the present invention relates to a method of forming a lens composition
  • a method of forming a lens composition comprising treating a mixture of a polymerizable dendrimeric compound and nanoparticles with a polymerization agent.
  • the polymerization agent is ultraviolet or visible light.
  • the method of the invention further comprises the step of delivering a mixture comprising the hydrogel-forming components to the lens bag of a patient.
  • the nanoparticles are a metal oxide or ceramic coated with a layer of silica.
  • a nanoparticle comprising a core coated with a layer of silica.
  • the core is made of a metal, metal oxide, or ceramic.
  • the core is made of a ceramic.
  • Another aspect of the invention relates to a kit for forming a lens comprising a polymerizable dendrimeric compound, nanoparticles, and a system for delivering the dendrimeric compound and nanoparticles to the lens bag of a patient.
  • the kit further comprises a desiccant and a syringe.
  • the kit further comprises a polymerization agent.
  • Figure 1 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 2 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 3 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 4 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 5 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 6 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 7 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 8 depicts a dendrimer terminated with nucleoside groups amenable to the invention.
  • Figure 9 depicts dendrimers and compounds useful for making dendrimers amenable to the present invention.
  • Figure 10 depicts a dendrimer amenable to the present invention.
  • Figure 11 depicts photocrosslinkable PEG 34 Oo-(PGLS A-M A 4 ) 2 macromer 1 for hydrogel formation.
  • Figure 12 depicts a double-acting, single-barrel syringe.
  • Figure 13 depicts a double-barrel syringe.
  • aspects of the present invention relate to nanoparticles and compositions comprising nanoparticles, where the nanoparticles afford an optically-clear, high refractive index composition when dispersed in an aqueous solution at neutral pH.
  • the nanoparticles may be coated to achieve desirable physical properties. For example, TiO 2 particles coated with lactic acid or a silane derivate were prepared. The coated TiO 2 particles remained dispersed in an aqueous solution at neutral pH.
  • the metal-oxide nanoparticles of the invention can be entrapped in a hydrogel at neutral pH. The hydrogel is useful in ophthalmic applications. Accordingly, aspects of the present invention also include the preparation and use of nanoparticles in ophthalmic applications.
  • one aspect of the present invention relates to hydrogel compositions comprising nanoparticles for use as endocapsular lenses, intraocular lenses, or contact lenses; and methods of preparing the hydrogel compositions.
  • the hydrogel compositions can be used in clinical applications, such as restoring vision using a synthetic lens.
  • the hydrogel compositions of the invention are used as a synthetic lens material for restoring vision after a cataract procedure.
  • the hydrogel may comprise crosslinkable polymers, such as dendritic macromolecules.
  • the nanoparticles can be either noncovalently or covalently crosslinked.
  • the nanoparticles can be dispersed throughout the hydrogel-nanoparticle composite.
  • the hydrogel composition can be formed in vitro, in vivo, or in situ.
  • the compositions used to create the lens comprise a dendrimer and nanoparticle.
  • the dendrimer has an acrylate group attached at the periphery of the dendrimer. Treating acrylated-capped dendrimers with ultraviolet radiation or a radical inititiator in the presence of nanoparticles causes the dendrimers to polymerize forming a hydrogel-nanoparticle endocapsular lens, intraocular lens, or contact lens.
  • the dendritic polymers comprise a lysine, cysteine, or isocysteine residue or other nucleophilic group attached to the periphery of the dendrimer.
  • Addition of a compound containing two or more electrophilic groups, such as an aldehyde, activated ester, or acrylate, to the lysine-capped, cysteine-capped, or isocysteine- capped dendrimers in the presence of nanoparticles produces a polymeric compound that can form a endocapsular lens, intraocular lens, or contact lens.
  • a compound containing two or more electrophilic groups such as an aldehyde, activated ester, or acrylate
  • compositions used to form the lens comprise nanoparticles and a compound that has a poly(lysine) core to which cysteine or isocysteine groups or other nucleophilic groups are attached; and the composition is then added to a compound containing an electrophilic group, such as an aldehyde, activated ester, or acrylate, to produce a polymeric endocapsular lens, intraocular lens, or contact lens.
  • an electrophilic group such as an aldehyde, activated ester, or acrylate
  • Crosslinking such as with a methacrylated functionalized denditic polymer, can be achieved using a photochemical or chemical reaction or a combination of both.
  • An embodiment of this invention is the preparation of crosslinkable biodendritic macromolecules that can undergo a covalent or non-covalent crosslinking reaction to form a three-deminsional crosslinked gel or network, wherein the crosslinking reaction does not involve a single or multi-photon process (i.e., light).
  • the dendritic polymer can be used for the encapsulation or the covalent attachment of pharmaceutical agents, such as bioactive peptides (e.g., growth factors), antibacterial compositions, antimicrobial compositions, and antiinflammatory compounds to aid in the clinical outcome.
  • the pharmaceutical agent causes a reduction or prevention of posterior capsule opacification (PCO).
  • a further embodiment of this invention is the use of a dendritic polymer and nanoparticle to afford a synthetic hydrogel lens or lens material in situ.
  • the crosslinkable formulation is injected via a small opening into an empty lens-capsule bag. Subsequent crosslinking by a photochemical or chemical reaction affords a hydrogel lens.
  • the crosslinked hydrogel can be prepared, and then this preformed lens can be injected in the empty lens bag. In the latter case, the preformed lens can be pre-extracted to remove impurities and pre-swollen.
  • these dendritic polymers can be combined with conventional IOL materials, such as acrylates, and used in a cataract or other lens removal and replacement procedure.
  • An additional embodiment is the use of the branched structures, aromatic amino acids, other aromatics, or heterocycles into the dendritic structure to increase the refractive index.
  • nanoparticles (2-25 nm) can be added to the resulting polymeric endocapsular lens, intraocular lens, or contact lens at a weight percent of 1% to 35% in order to alter the refractive index.
  • the nanoparticles can be either non-covalently or covalently crosslinked throughout the composite.
  • the above nanoparticles/hydrogel compositions can be used in conjunction with a polymer plug to close the capsulorrhexis. The lens material can be injected through the plug or the plug can be put into place after the lens has been inserted.
  • the lens compositions of the invention can also be formed by combining nanoparticles with polymers, such as a silicone, acrylic, polymethylmethacrylate (PMMA), block copolymers of styrene-ethylene-butylene-styrene (C-FLEX) or other styrene-base copolymers, polyvinyl alcohol (PVA), polyurethanes, or polymers comprising polyacrylates, e.g., PHE.
  • polymers such as a silicone, acrylic, polymethylmethacrylate (PMMA), block copolymers of styrene-ethylene-butylene-styrene (C-FLEX) or other styrene-base copolymers, polyvinyl alcohol (PVA), polyurethanes, or polymers comprising polyacrylates, e.g., PHE.
  • Dendritic polymers are globular monodispersed polymers composed of repeated branching units emitting from a central core.
  • dendrimers are highly ordered, possess high surface area to volume ratios, and exhibit numerous end-groups for functionalization. Consequently, dendrimers display several favorable physical properties for both industrial and biomedical applications including: small polydispersity indexes (PDI), low viscosities, high solubility and miscibility, and excellent adhesive properties.
  • PDI polydispersity indexes
  • the majority of dendrimers investigated for biomedical/biotechnology applications e.g., MRI, gene delivery, and cancer treatment
  • are derivatives of aromatic polyether or aliphatic amides are not ideal for in vivo uses. See Service, R. F. Science 1995, 267, 458- 459. Lindhorst, T. K.; Kieburg, C. Angew. Chem.
  • Biodendrimers are a novel class of dendritic macromolecules composed entirely of building blocks known to be biocompatible or are natural metabolites in vivo. Biodendrimers may or may not be degradable.
  • One aspect of the present invention relates to the synthesis, characterization, and use of novel dendrimers and dendritic macromolecules called
  • the dendrimers of the present invention comprise biocompatible or natural metabolite monomers such as glycerol, lactic acid, glycolic acid, succinic acid, ribose, adipic acid, malic acid, glucose, citric acid, glycine, lysine, cysteine, alanine, etc.
  • a further embodiment of the invention is a dendritic structure that possess glycerol and one or more of lactic acid, glycolic acid, succinic acid, ribose, adipic acid, malic acid, glucose, citric acid, glycine, lysine, cysteine, alanine, and the like as a building block.
  • An additional embodiment of the invention relates to a dendrimer comprising all lysine resides such that it is a generation one or higher or a lysine dendritic macromolecule terminated with cystene residues such that it is a generation one or higher.
  • the polymers used in the hydrogels of the present invention may be dendritic polymers or copolymers of polyesters, polyethers, polyether-esters, and polyamino acids, polyurethanes, etc or combinations thereof. Careful selection of the monomer, linkage, size, and generation number permits controll over the degradation rate of the polymer.
  • one aspect of the present invention relates to dendritic polymers and copolymers of polyesters and polyamino acids, polyethers, polyurethanes, polycarbonates, polycarbamates, polyamino alcohols or combinations of these polymer classess that are chemically modified for different biomedical applications, such as ophthalmic lens.
  • dendritic polymers and copolymers of polyesters and polyamino acids with improved properties such as limited, or no, biodegradability, biocompatibility, and mechanical strength. It is still another aspect of the invention to provide dendritic polymers that can be derivatized to include functionalities such as peptide sequences or growth factors to improve the interaction of the polymer with cells and tissues.
  • the dendritic polymers of the invention provide numerous advantages including multiple end-groups for functionalization, crosslinked gels with high crosslinking densities at low polymer concentration, globular structure, low viscosities, and a well-defined composition.
  • the properties of conventional linear polymers often cannot be easily controlled or modified because they (e.g., PLA) do not possess functional groups, other than end groups, permiting chemical modification.
  • Conventional polymers also suffer from the disadvantage that they do not adopt a well- defined structure in solution.
  • Dendritic polymers described herein can be used with linear polymers at ratios of 0.1 to 99.9% to afford ophthalmic lens materials that possess good optical, mechanical, and degradation properties.
  • another aspect of the present invention is the use of linear polyacrylates and siloxanes, silicones, acrylics, polymethylmethacrylate (PMMA), block copolymers of styrene-ethylene-butylene-styrene (C-FLEX) or other styrene-base copolymers, polyvinyl alcohol (PVA), polyurethanes, or any other suitable polymers or monomers polyacrylates (e.g., PHE) in combination with dendritic polymers.
  • the linear polymers can also be block copolymers.
  • a prefered example of a linear polymer is a copolymer of 2-hydroxyethyl methacrylate (HEMA) and 6-hydroxyhexyl methacrylate (HOHEXMA), i.e., poly(H£M4-co-HOHEXMA).
  • HEMA 2-hydroxyethyl methacrylate
  • HOHEXMA 6-hydroxyhexyl methacrylate
  • One aspect of the present invention relates to an in situ, ex vivo, in vitro, or in vivo method for preparing and administrating a biocompatible gel, comprising: (a) forming a reactive composition by admixing a biocompatible crosslinking polymer having two different nucleophilic groups, such as sulfhydryl and amine groups where there is at least one amine or sulfhydryl group on the polymer with a biocompatible crosslinking polymer B having amine- and sulfhydryl-reactive groups, and further wherein the amine- and sulfhydryl- reactive groups are capable of covalent reaction with the amine and sulfhydryl groups upon admixture of polymers A and B under effective crosslinking conditions to form a gel in less than one day; and (b) allowing the components of the reactive composition to crosslink and thereby form a gel.
  • a biocompatible crosslinking polymer having two different nucleophilic groups, such as sulfhydry
  • Another aspect of the present invention relates to dendritic or branched polymers or copolymers composed of monomers synthesized by combining branching compounds with other linear or branched building blocks.
  • Both components are known to be biocompatible or are natural metabolites in vivo including but not limited to glycerol, citric acid, lactic acid, glycolic acid, adipic acid, caproic acid, ribose, glucose, succinic acid, malic acid, amino acids, peptides, synthetic peptide analogs, poly(ethylene glycol), poly(hy.droxyacids) [e.g., PGA. PLA], including where one of the monomers is a branched structure such as glycerol combined with one of the other components.
  • the present invention relates to the aforementioned polymers derivatized with peripheral compounds possessing an olefin, including, but not limited to, acrylate and methacrylate.
  • the present invention relates to the the aforementioned polymers derivatized with peripheral compounds, including, but not limited to, cysteine, lysine, other amino acids, or any other compounds that would provide terminal nucleophiles (including, but not limited to, amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones).
  • peripheral compounds including, but not limited to, cysteine, lysine, other amino acids, or any other compounds that would provide terminal nucleophiles (including, but not limited to, amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones).
  • the present invention relates to the the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure with either olefinic, electrophilic or nucleophilic groups, respectively to form a gel.
  • the present invention relates to the the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure via a photopolymerization process (single or multi-photon process) to form a gel.
  • a branching structure with at least three functional groups composed of, but not limited to, glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic strucutures synthesized to produce terminal olefins (including, but not limited to, acrylate or methacrylate groups), nucleophiles (including but not limited to amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones) for subsequent polymerization/crosslinking with another linear or branched structure with either olefmic, electrophilic or nucleophilic groups, respectively.
  • Another aspect of the present invention relates to a branching structure with at least three functional groups composed of but not limited to glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic structures derivatized with peripheral compounds including, but not limited to, cysteine, lysine, other amino acids, or any other compounds that would provide terminal olefins (including, but not limited to, acrylate or methacrylate groups), nucleophiles (including, but not limited to, amines, thiols, and hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, and ketones) for subsequent polymerization/crosslinking with another linear or branched structure with either olefinic, electrophilic or nucleophilic groups, respectively.
  • functional groups composed of but not limited to glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs
  • Another aspect of the present invention relates to a branching structure composed of three lysine amino acids with four cysteine amino acids on the periphery with the structure CysLys(Cys)Lys(CysLys(Cys))OMe*4HCl as described in the examples.
  • Another aspect of the present invention relates to a branching structure composed of three lysine amino acids with amines on the periphery with the structure (Lys)Lys(Lys)OMe»4HCl as described in the examples.
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure with olefinic, electrophilic or nucleophilic groups to form a gel.
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure through thiazolidine linkages to form a gel.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with at least two electrophilic groups.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a ⁇ oly(ethylene glycol) molecular weight of about 200 to about 200,000 with at least two nucleophilic groups.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with functional groups including, but not limited to, olefins, aldehydes, maleimides, or NHS esters.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with aldehyde functional groups to form hydrogels through the formation of thiazolidine linkages.
  • the present invention relates to the the aforementioned formulations in which each of the components are dissolved or suspended in an aqueous solution wherein the said aqueous solution is selected from water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates or combinations of any two or more thereof.
  • the present invention relates to the application of the aforementioned formulation through a delivery device which physically separates the components until the components are physically mixed by the end user, including, but not limited to, a dual barrel syringe with a mixing device.
  • Another aspect of the present invention relates to packaging of the aforementioned branching compounds in an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above and the packaging of the second compound in an aqueous solution at another preselected pH and molarity selected from the aqueous solutions described above.
  • the pH and molarities of the two solutions produce a final desired solution with a different pH.
  • Another aspect of the present invention relates to packaging of the aforementioned branching compounds in an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above and the packaging of the second compound in an aqueous solution at another preselected pH and molarity selected from the aqueous solutions described above.
  • the contents are packaged free of oxygen and shielded from light.
  • the pH and molarities of the two solutions produce a final desired solution with a different pH.
  • Another aspect of the present invention relates to packaging of the aforementioned branching compounds as a powder and adding an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above before use.
  • the second component may either be packaged by dissolving the second compound in an aqueous solution at another preselected pH and molarity selected from the aqueous solutions described above or packaged similar to the first compound in which the compound stored as a powder and an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above is added before use.
  • the contents are packaged free of oxygen and shielded from light.
  • the pH and molarities of the two solutions produce a final desired solution with a different pH.
  • Another aspect of the present invention relates to the storage of the aforementioned cystein-terminated polymers in an acidic, oxygen-free solution to minimize the formation of disulfide bonds.
  • Another aspect of the present invention relates to the storage of the aforementioned aldehyde-terminated polymers in an acidic, oxygen-free solution to maximize the percent reactivity of the polymer and minimize aldol condensation and reverse Michael additions.
  • Another aspect of the present invention relates to the addition of various additives that might be incorporated into the polymer formulations including, but not limited to, antioxidants, colorants, viscosity modifiers, plasticizers, small molecule carbohydrates, large molecule carbohydrates, amino acids, peptides, or other water soluble polymers (linear or branched).
  • additives may be added to increase the shelf life, increase the polymerization rate, modifiy the pH or molarity of the solution, change the refractive index, modify the mechanical properties, change crosslinking density, decrease swelling, or aid in visualization.
  • Another aspect of the present invention relates to the addition of various additives or antimicrobial agents such has polyhexamethylene biguanide (PHMB) that might be incorporated into the polymer formulations.
  • Another aspect of the present invention relates to the resulting hydrogels formed by mixing the aforementioned compounds as described and prepared above. In certain instances, the present invention relates to hydrogels formed by photopolymerization of the aforementioned compounds.
  • PHMB polyhexamethylene biguanide
  • Another aspect of the present invention relates to a method of using crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for delivery of therapeutics.
  • Another aspect of the present invention relates to a crosslinkable/polymerizable/reactionary dendritic polymer or monomer wherein the crosslinking is of covalent, ionic, electrostatic, and/or hydrophobic nature.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction involves a nucleophile and electrophile.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction is a photochemical reaction using a UV or visible photoinitiator chromophore.
  • Another aspect of the present invention relates to a method of using a crosslinkable branched or dendritic polymer combined with a crosslinkable small molecule(s) (molecular weight less than about 1000 daltons) for a medical or tissue engineering application.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer or monomer wherein the said crosslinking dendritic polymer is combined with one or more linear, comb, multi-block, star polymers or crosslinkable comb, multi- block, star polymers.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their resulting hydrogels wherein the polymer or crosslinkable monomer is D or L configuration or a mixture.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their hydrogels wherein the dendritic structure is asymmetric at the surface such as a surface block structure where a carboxylate acid(s) and alkyl chains, or acrylate(s) and PEG(s) are present, for example, or within the core and inner layers of the dendrimer such as amide and ester linkages in the structure.
  • Another aspect of the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer wherein the polymer is a star biodendritic polymer or copolymer as shown in at least one of the formulas below: where Y and X are the same or different at each occurrence and are O, S, Se, N(H), or P(H) and where Rj, R 2 , R 3 , R 4 , R 5 R 6 , R 7 , R 8 , A or Z are the same or different and include -H, -CH 3 , -OH, carboxylic acid, sulfate, phosphate, aldehyde, methoxy, amine, amide, thiol, disulfide, straight or branched chain alkane, straight or branched chain alkene, straight or branched chain ester, straight or branched chain ether, straight or branched chain silane, straight or branched chain urethane, straight or branched chain, carbonate, straight or
  • Another aspect of the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer where the straight or branched chain is of about 1-50 carbon atoms wherein the chain is fully saturated, fully unsaturated or any combination therein
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer where the straight or branched chain is of about 1-50 carbon atoms wherein the chain is fully saturated, fully unsaturated or any combination therein.
  • the present invention relates to the aforementioned crosslinlcable or noncrosslinkable polymer wherein straight or branched chains are the same number of carbons or different wherein R 1 , R 2 , R 3 , R 4 , Rs.R ⁇ , R 7 , R 8 , A or Z are any combination of the linkers including ester, silane, urea, amide, amine, carbamate, urethane, thiol-urethane, carbonate, thio-ether, thio-ester, sulfate, phosphate and ether.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer which includes at least one chain selected from the group consisting of hydrocarbons, flourocarbons, halocarbons, alkenes, and alkynes.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer which includes at least one chain selected from the group consisting of linear and dendritic polymers.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer wherein said linear and dendritic polymers include at least one selected from the group consisting of polyethers, polyesters, polyamines, polyacrylic acids, polycarbonates, polyamino acids, polynucleic acids and polysaccharides of molecular weight ranging from about 200-1,000,000, and wherein said chain contains 0, 1 or more than 1 photopolymerizable group.
  • Another aspect of the present invention relates to a crosslinkable or noncrosslinkable polymer, wherein the polyether is PEG, and wherein the polyester is PLA, PGA or PLGA.
  • Another aspect of the present invention relates to a linear polymer wherein the chain is a polymer or copolymer of a polyester, polyamide, polyether, or polycarbonate of or the aforementioned polymer in combination with a polyester, polyamide, polyether, or polycarbonate of:
  • the present invention relates to the aforementioned polymer comprised of repeating units of general Structure I, where A is O, S, Se, or N-R 7 .
  • the present invention relates to the aforementioned polymer, where W, X, and Z are the same or different at each occurrence and are O, S, Se, N(H), or P(H).
  • the present invention relates to the aforementioned polymer, where Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned polymer, where Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents.
  • Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group substituted internally or terminally by one or more hydroxyl, hydroxyether, carb
  • the present invention relates to the aforementioned polymer, where Ri is a polymer (such as poly(ethylene glycol), poly(ethylene oxide), or a poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor.
  • Ri is a polymer (such as poly(ethylene glycol), poly(ethylene oxide), or a poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor.
  • Ri is a polymer (such
  • the present invention relates to the aforementioned polymer, where Rj is a photocrosslinkable, chemically, or ionically crosslinkable group.
  • the present invention relates to the aforementioned polymer, in which D is a straight or branched alkyl chain of about 1-5 carbons, m is 0 or 1, and R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are the same or different at each occurrence and are hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, alkoxy, aryloxy, olefin, alkylamine, dialkylamine, arylamine, diarylamine, alkylamide, dialkylamide, arylamide, diarylamide, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned polymer comprised of repeating units of General Structure II, where L, N, and J are the same or different at each occurrence and are O, S, Se, N(H), or P(H).
  • the present invention relates to the aforementioned polymer where Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned polymer where Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents.
  • the present invention relates to the aforementioned polymer where Ri is a polymer selected from the group consisting of poly(ethylene glycols), poly(ethylene oxides), and poly(hydroxyacids, or is a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, a DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or an epitope for a biological receptor.
  • the present invention relates to the aforementioned polymer where Ri is a photocrosslinkable, chemically, or ionically crosslinkable group.
  • the present invention relates to the aforementioned polymer, where D is a straight or branched alkyl chain of about 1-5 carbons, q and r are the same or different at each occurrence and are 0 or 1, and R 7 , R 8 , R 9 , R 10 , Rn, Ri 2 , R 13 , and Ri 4 are the same or different at each occurrence and are hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, alkoxy, aryloxy, olefin, alkylamine, dialkylamine, arylamine, diarylamine, alkylamide, dialkylamide, arylamide, diarylamide, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned block or random copolymer comprised of repeating units of general Structure III, where M, T, and Q are the same or different at each occurrence and are O, S, Se, N(H), or P(H), e is 0 or 1-9, and Ri 5 is a straight or branched alkyl chain of about 1-5 carbons, unsubstituted or substituted with one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents
  • the present invention relates to the aforementioned block or random copolymer comprised of repeating units of general Structure III, where M, T, and Q are the same or different at each occurrence and are O, S, Se, N(H), or P(H), and R 15 is a straight or branched alky
  • the present invention relates to the aforementioned block or random copolymer comprised of repeating units of general Structure III, where M, T, and Q are the same or different at each occurrence and are O, S, Se, N(H), or P(H), and Rl 5 is a straight or branched alkyl chain of about 1-5 carbons, unsubstituted or substituted with one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents.
  • Another aspect of the present invention relates to a higher order block or random copolymer comprised of three or more different repeating units, and having one or more repeating units described above, such as a polyglyerol glycine carbonate-polyglycerol succinic acid copolymer.
  • Another aspect of the present invention relates to a block or random copolymer as described above, which includes at least one terminal crosslinkable group selected from the group consisting of amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
  • the present invention relates to the aforementioned block or random copolymer where X, Y, M is O, S, N-H, N-R, and wherein R is -H, CH 2 , CR 2 , Se or an isoelectronic species of oxygen.
  • the present invention relates to the aforementioned block or random copolymer wherein an amino acid(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein a polypeptide(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein an antibody(ies) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z. In certain instances, the present invention relates to the aforementioned block or random copolymer wherein a nucleotide(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein a nucleoside(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein an oligonucleotide(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein a ligand(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z that binds to a biological receptor.
  • the present invention relates to the aforementioned block or random copolymer wherein a pharmaceutical agent(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer or copolymer wherein the polymer is a dendritic macromolecule including at least one polymer selected from the group consisting of dendrimers, hybrid linear-dendrimers, dendrons, or hyperbranched polymers according to one of the general formulas or such similar structures below, where R 3 , R 4 , which may be the same or different, are a repeat pattern of B, and n is about 0 to 50.
  • the present invention relates to the aforementioned polymer, wherein X, Y, M is O, S, N-H, N-R, wherein R is -H, CH 2 , CR 2 or a chain as defined above, Se or any isoelectronic species of oxygen
  • the present invention relates to the aforementioned polymer, wherein X, Y, M is O, S, N-H, N-R, wherein R is -H, CH 2 , CR 2 or a chain as defined above, Se or any isoelectronic species of oxygen.
  • the present invention relates to the aforementioned polymer where R 3 and R 4 are carboxylic acid with a protecting group such as but not limited to a phthalimidomethyl ester, a t-butyldimethylsilyl ester, or a t-butyldiphenylsilyl ester.
  • a protecting group such as but not limited to a phthalimidomethyl ester, a t-butyldimethylsilyl ester, or a t-butyldiphenylsilyl ester.
  • the present invention relates to the aforementioned polymer where R 3 , R 4 , A, and Z are the same or different, R 3 and R 4 are repeated a certain number of times, and terminate in -H, -OH, -CH 3 , carboxylic acid, sulfate, phosphate, aldehyde, activated ester, methoxy, amine, amide, thiol, disulfide, straight or branched chain alkane, straight or branched chain alkene, straight or branched chain ester, straight or branched chain ether, straight or branched chain silane, straight or branched chain urethane, straight or branched chain, carbonate, straight or branched chain sulfate, straight or branched chain phosphate, straight or branched chain thiol urethane, straight or branched chain amine, straight or branched chain thiol urea, straight or branched chain thiol ether, straight or
  • the present invention relates to the aforementioned polymer having a straight or branched chain of 1-50 carbon atoms and wherein the chain is fully saturated, fully unsaturated or any combination therein.
  • the present invention relates to the aforementioned polymer wherein straight or branched chains are the same number of carbons or different and wherein R 3 , R 4 , A, Z are any combination of linkers selected from the group consisting of esters, silanes, ureas, amides, amines, urethanes, thiol-urethanes, carbonates, carbamates, thio-ethers, thio-esters, sulfates, phosphates and ethers.
  • the present invention relates to the aforementioned polymer wherein chains include at least one selected from hydrocarbons, flourocarbons, halocarbons, alkenes, and alkynes.
  • the present invention relates to the aforementioned polymer wherein said chains include polyethers, polyesters, poly amines, polyacrylic acids, polyamino acids, polynucleic acids and polysaccharides of molecular weight ranging from
  • the present invention relates to the aforementioned polymer wherein the chains include at least one of PEG, PLA, PGA, PGLA, and PMMA.
  • the present invention relates to the aforementioned block or random copolymer, which includes at least one terminal crosslinkable or photopolymerizable group selected from the group consisting of amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, activated esters, malemides, aldehydes, and alkynes.
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with amino acid(s), such as cysteine, attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with polypeptide(s) attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with an antibody(ies) or single chain antibody(ies) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a nucleotide(s) attached to Z, A, R 3 , and/or R 4 ..
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a nucleoside(s) attached to Z 3 A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with oligonucleotide(s) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with ligand(s) attached to Z, A, R 3 , and/or R 4 that binds to a biological receptor.
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a pharmaceutical agent(s) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a pharmaceutical agent attached to Z, A, R 3 , and/or R 4 and is at least one selected from the group consisting of antibacterial, anticancer, anti-inflammatory, and antiviral.
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times to produce a polymer in which a pharmaceutical agent(s) is encapsulated or chemically bound to the polymer.
  • the present invention relates to the aforementioned polymer wherein camptothecin or a deriviative of campothethcin is encapsulated
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a carbohydrate(s) attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with the carbohydrate mannose or sialic acid attached to the polymer.
  • the present invention relates to the aforementioned polymer which includes a polymer or copolymer of a polyester, polyamide, polyether, or polycarbonate at the center or periphery of the polymers above taken from the structures below.
  • the present invention relates to the aforementioned polymer block or random copolymer which includes at least one terminal or internal crosslinkable group selected from the group consisting of amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
  • the present invention relates to the aforementioned polymer wherein X, Y, M is O, S, N-H, N-R, wherein R is -H, CH 2 , CR 2 or a chain as defined above, Se or any isoelectronic species of oxygen.
  • the present invention relates to the aforementioned polymer wherein an amino acid(s) is attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein a polypeptide(s) is attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein an antibody(ies) or single chain antibody(ies) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a nucleotide(s) is attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein a nucleoside(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein an oligonucleotide(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a ligand(s) is attached to Z 5 A, R 3 , and/or R 4 that binds to a biological receptor.
  • the present invention relates to the aforementioned polymer wherein a pharmaceutical agent(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a carbohydrate(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a pharmaceutical agent(s) is attached to Z, A, R 3 , and/or R 4 and is at least one selected from the group consisting of antibacterial, anticancer, anti-inflammatory, and antiviral.
  • the present invention relates to the aforementioned polymer wherein the carbohydrate is mannose or sialic acid is covalently attached to the polymer.
  • Another aspect of the present invention relates to a surgical procedure which comprises using a photopolymerizable, or chemically crosslinkable, or non-covalently crosslinkable dendritic polymer or copolymer.
  • the present invention relates to the dendritic polymer or copolymer which optionally contains at least one stereochemical center.
  • the present invention relates to the dendritic polymer or copolymer which is of D or L configuration.
  • the present invention relates to the dendritic polymer or copolymer wherein the final dendritic polymer or monomer is chiral or is achiral. In certain instances, the present invention relates to the dendritic polymer or copolymer which contains at least one site where the branching is incomplete.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete which forms a hydrogel.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete and used for drug delivery.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete and used as a lens. In certain instances, the present invention relates to a dendritic polymer or copolymer made by a convergent or divergent synthesis.
  • the dendritic polymer of the invention relates to
  • One aspect of the present invention relates to using dendritic polymeric gels and hydrogels that contain nanoparticles for ophthalmic lens applications.
  • Simple polymer gels (including hydrogels) are 3D polymeric materials that exhibit the ability to swell in water and to retain a fraction of water within the structure without dissolving.
  • the physical properties exhibited by gels, such as water content, sensitivity to environmental conditions ⁇ e.g., pH, temperature, solvent, and stress), soft, adhesivity, and rubbery consistency are favorable for biomedical and biotechnological applications.
  • gels may be used as coatings (e.g., biosensors, catheters, and sutures), as "homogeneous” materials (e.g., contact lenses, burn dressings, and dentures), and as devices (e.g., artificial organs and drug delivery systems)
  • coatings e.g., biosensors, catheters, and sutures
  • homoogeneous materials e.g., contact lenses, burn dressings, and dentures
  • devices e.g., artificial organs and drug delivery systems
  • crosslinkable nanoparticles are used with crosslinkable polymers to form transparent hydrogels.
  • Nanoparticles are particles that generally have a diameter of less than about 500 nm. Many nanoparticles exhibit interesting properties, e.g., high refractive index, due to their size and composition. It has been reported that nanoparticles added to an optically clear plastic cause an increase in the refractive index of the plastic, and thus are useful for optical applications (Naussbaumer, Rene J. et al "Polymer-TiC>2 Nanocomposites: A Route Towards Visually Transparent Broadband UV Filters and High Refractive Index Materials” Marcomol. Mater. Eng. 2003, 288, No.l). Likewise, nanoparticles (i.e., iron nanoparticles) dispersed in a hydrogel at pH 7 exhibit magnetic properties. V.
  • nanoparticle compositions are amenable to the present invention.
  • Representative examples of nanoparticle compositions include various metals, metal oxides, sulfides, zeolites, silica, ceramic, or combinations thereof.
  • the nanoparticles are made of titanium dioxide, zinc oxide, aluminium oxide, gold, diamond, silver oxides, silicon dioxide, zirconium dioxide, cerium dioxide, calcium oxide, protein, or ceramic.
  • the nanoparticles are carbon-based nanoparticles.
  • the nanoparictles of the invention may also be a composite of one or more metal oxides or sulfides.
  • Nanoparticles or micron-sized particles are commercially available from various manufacturers including: Bangs Laboratories (Fishers, Ind.); Promega (Madison, Wis.); Dynal Inc.(Lake Success, N. Y.); Advanced Magnetics Inc. (Surrey, U.K.); CPG Inc. (Lincoln Park, N.J.); Cortex Biochem (San Leandro, Calif.); European Institute of Science (Lund, Sweden); Ferrofluidics Corp. (Nashua, N.H.); FeRx Inc.; (San Diego, Calif.); Immunicon Corp.; (Huntingdon Valley, Pa.); Magnetically Delivered Therapeutics Inc.
  • Nanoparticles can also be manufactured by a gas condensation process, such as that described in U.S. Pat. Nos. 5,128,081 and 5,320,800, the contents of which are incorporated herein by reference.
  • a gas condensation process for the preparation of nanoparticles typically involves evaporation of a metal precursor material from which the nanoparticles will be synthesized at gas pressures of less than one or equal to one atmosphere.
  • the evaporated metal condenses into small particles in the gas atmosphere and the resulting nanoparticles are collected on a surface within the reactor.
  • Any metal or metal compound capable of being volatilized may be used to form the nanoparticles for use in the present invention.
  • Exemplary metals are titanium, copper, silver, gold, platinum, and palladium.
  • the metal nanoparticles may be further subjected to a reactive gas atmosphere to form oxides, nitrides, carbides, sulfides, fluorides, and chlorides.
  • Exemplary metal oxide nanoparticles are those composed of aluminum oxide, antimony tin oxide, cerium oxide, copper oxide, indium oxide, indium tin oxide, iron oxide, silicon dioxide, tin oxide, titanium dioxide, yttrium oxide, zinc oxide, barium oxide, calcium oxide, chromium oxide, magnesium oxide, manganese oxide, molybdenum oxide, neodymium oxide, and strontium oxide.
  • Metal titanate and metal silicate nanoparticles including, for example, strontium titanate, barium titanate, barium strontium titanate, and zirconium silicate may also be used. Titanium dioxide nanoparticles are preferred for use as polymer fillers. Titanium dioxide nanoparticles of varying particle size, synthesized by a gas condensation process, are commercially available from Nanophase Technologies Corporation. Nanophase Technologies also manufactures the metal, metal oxide, metal titanate and metal silicate nanoparticles listed above.
  • Nanoparticles of various sizes are amenable to the present invention.
  • the nanoparticles have a diameter of about 0.1 nm to about 200 nm.
  • the nanoparticles have a diameter of about 0.1 nm to about 100 nm.
  • the nanoparticles have a diameter of about 0.1 nm to about 50 nm.
  • the nanoparticles have a diameter of about 0.1 nm to about 25 nm.
  • nanoparticles have a diameter less than about 50 nm.
  • nanoparticles have a diameter less than about 20 nm.
  • Nanoparticles may be modified with small molecules or polymers via covalent or non-covalent interactions (e.g., electrostatics) to improve their properties for an ophthalmic use.
  • these organic-coated nanoparticles can improve stability, optical clarity, and improve dispersion in a polymer matrix.
  • nanoparticles can improve anti-microbial properties, cross-linking, modulus, viscosity, swelling properties, adhesion to capsular bag, and specific wavelength absorption.
  • the nanoparticle contains titanium dioxide or zinc oxide, this will absorb harmful UV light and act as an antibacterial agent or anti-proliferative agent.
  • Methods for the preparation of hybrid organic-inorganic nanoparticles and inorganic/ceramic nanoparticles are described herein.
  • TiO 2 has low surface potential ( ⁇ 20 mv) between pH 5.5 to 7.5
  • ZnO has a low surface potential between pH 7.5 and 10.
  • the low surface potential corresponds to relatively neutral particles.
  • the low surface potential does not allow for charge-charge repulsion of the individual particles, and thus leads to aggregation in aqueous solutions.
  • the low surface- potential near biological pH is generally true for unmodified inorganic nanoparticles. To overcome the particle aggregation it is important to design nanoparticles that are thermodynamically stable near the pH of the biological system. This can be accomplished in a number of ways.
  • the present application describes surface modification of nanoparticles by either post- reaction of the nanoparticles with organic groups or in situ surface-modification during particle formation.
  • the former entails reaction of alkyltrialkoxysilanes, dialkyldialkoxysilanes, trialkylalkoxysilanes, alkylchlorosilanes, dialkyldichlorosilanes, or trialkylchlorosilanes with the surface of inorganic particles.
  • the inorganic particles are less than about 10 nm in diameter.
  • the alkyl group consists of an alkyl space between the silicon and an organic functional group. In certain instances, the alkyl group is substituted with a functional group.
  • Representative functional groups include amino, vinyl, allyl, acrylate, methacrylate, alkanolamine, sulfate, carboxylic acid, hydroxyl, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, epoxide, aldehyde, ketone, 1,3-diketone, amide, ester, and polar cylic organic moieties, such as imidazoles and pyrolidinones, and ureido. These organic functional groups can be used as is or further modified to create a charged surface at the pH of a biological system.
  • In situ surface modification during particle formation occurs by addition of the above reactive molecules during the particle formation.
  • the derivatized silanes are placed in the aqueous phase to form micelles or nucleation sites for the particle formation.
  • TiCl 4 , tetralkoxytitanium, or tetralkoxysilane is then added to the solution and hydrolyzed to create a nanoparticle with a preformed surface. This could be accomplished in an inverse phase process.
  • alkyltrialkoxysilane or alkylSi(OH) 3 could be added to a high boiling alkane (octane or dodecane). This would form inverse micelles with the polar groups on the interior of the micelles.
  • TiCl 4 or SiCl 4 would migrate to the micelles during a controlled hydrolysis (under reflux, the HCl would leave the system since it would not be soluble in the organic phase).
  • Another approach is to modify the surface through the use of chelating organic molecules. It is well known that increased stability can be obtained in otherwise reactive molecules. For example, simple titanium alkoxylates, such as tetramethoxytitanium, readily undergoe hydrolysis in the presence of trace water, while the addition of chelating groups, such as acetylacetonate, triethanolamine, or lactate, greatly reduce the rate of hydrolysis.
  • Another aspect of the invention relates to the fixation of organic chelates to the surface of inorganic particles.
  • the organic chelates contain groups that will be charged at the pH of a biological system.
  • the acid exists as the salt, ammonium or sodium, at elevated pH (>5). This gives the desired surface charge at pH 7.
  • polymer e.g., latex
  • polymer encapsulated inorganic particles that are ⁇ 20 nm can be formed using emulsion polymerization techniques, including batch, semi- batch, mini, and micro emulsion techniques. In this size range, complete encapsulation may be obtained. However, it is only necessary that the particles are sufficiently encapsulated to prevent aggregation upon a change in pH. During the encapsulation, the particle size will grow and possibly begin to refract light. To retain optical clarity, the organic layer may be made to swell such that the organic phase becomes a gel with the particle locked in the gel. In addition, polymerizable groups can be prefixed to the surface of the particles.
  • emulsion polymerization techniques including batch, semi- batch, mini, and micro emulsion techniques. In this size range, complete encapsulation may be obtained. However, it is only necessary that the particles are sufficiently encapsulated to prevent aggregation upon a change in pH. During the encapsulation, the
  • the nanoparticles can be further modified so that they are covalently linked to a polymer in the hydrogel.
  • the nanoparticle can be modified to include a nucleophile on the surface of the nanoparticle. The nucleophile-active nanoparticle is then combined with the polymers for formation of the hydrogel composite.
  • the nucleophile- active nanoparticle would couple to the one or more of the electrophilic groups on the polymer and become crosslinked with the hydrogel.
  • Mori's nanoparticles contain free alcohols on the surface. These may be converted to a N-terminal cysteine moiety in a dendritic fashion to provide a thiol group for crosslinking.
  • Representative examples of nucleophilic functional groups amenable to the present invention include thiol, amino, hydroxyl, and the like.
  • the opposite reactivity system, an electrophile-active nanoparticle is also possible.
  • Representative examples of electrophilic functional groups include aldehydes, activated esters, acrylates, and the like.
  • Nanoparticles containing olefins, alkenes, or alkynes which can be crosslinked within the hydrogel. These types of functional groups can be crosslinked using photochemistry or a radical initiator. Nanoparticles can also be suspended in aqueous, saline, ionic, supercritical gas (such as liquid carbon dioxide) or organic solvents to aid in the dispersion within the polymer lens during lens formation, such as in the formation of a contact lens or intraocular lens (IOL).
  • the lens formation process can be performed in vivo, in vitro, or ex vivo.
  • the nanoparticle suspension does not degrade the optical transmission properties to the extent that the lens becomes unsuitable for use in the human eye.
  • the nanoparticle suspension may improve certain characteristics, such as refractive index, clarity, specific wavelength absorption, or modulus of the material.
  • the nanoparticle-lens composites can be also used to prepare a gradient refractive-index lens for ocular use, where different regions or zones of the lens contains different concentrations of nanoparticles, and thus a different refractive index.
  • the use of nanoparticles may be used to manipulate characteristics of the replacement lens such that errors present in the original lens are corrected or improved upon. For instance, manipulation of the polymer's refractive index can enable correction of spherical refractive errors. [Ho 5 2001 #10]
  • the refractive index can also be changed or tuned, independently of changing other properties, such as modulus, and polymeric make-up.
  • the ability to independently modify the refractive index is highly desirable because it simplifies the formulation process. Removing the link between polymer content and refractive index also allows the design of a weak, low polymer-content gel.
  • the refractive index of a solution can be varied from 1.33 to more than 1.42 by increasing the weight percent to greater than 12 w/t%. Importantly, the viscosity of these solution changes only minimally (1 to 6 cps).
  • dendrimers or dendritic polymers are crosslinked using either light or a chemical crosslinking reaction in the presence of nanoparticles.
  • a further embodiment of this invention is the crosslinking between a first dendritic polymer and and second dendritic polymer or between a dendritic polymer and a linear polymer. The crosslinking event produces a gel or network in the presence of nanoparticles.
  • An additional embodiment of this invention is the crosslinking between dendritic polymers, linear polymers, and nanoparticles or any combination thereof to form a crosslinked gel or network to form a transparent hydrogel lens.
  • the gels can be highly hydrated and hydrophilic.
  • the nanoparticles are present in about 1 to about 40 weight percent.
  • the weight percent is calculated by dividing the cumulative weight of the nanoparticles by the total weight of the hydrogel composition.
  • the nanoparticles are present in about 1 to about 30 weight percent or in about 1 to about 20 weight percent.
  • the nanoparticles are present in about 1 to about 10 weight percent or in about 1 to about 5 weight percent.
  • the nanoparticles are present in about 5 to about 25 weight percent.
  • the nanoparticles are present in about 15 to about 40 weight percent.
  • the polymers and/or nanoparticles contain functional groups that will react with each other to form the gel.
  • the dendritic polymers have more than two nucleophilic functional groups, such as primary amino (-NH 2 ) or thiol (-SH) groups, which can react with electrophilic groups.
  • the electrophilic group is an acrylate, aldehyde, or activated ester.
  • each functional group on a multifunctionally dendritic polymer is capable of covalently binding with another polymer. Formation of a covlant linkage between the dendrimers creates the hydrogel network.
  • Covalently crosslinked networks can be formed by reacting an activated ester (such as an N-hydroxysuccinimide) with an amine or thiol (such as a terminal primary or secondary amine, lys, cys, etc.).
  • an activated ester such as an N-hydroxysuccinimide
  • an amine or thiol such as a terminal primary or secondary amine, lys, cys, etc.
  • Thiol- or cysteine-terminated dendritic structures that form a disulfide crosslinked network with another thiol- or cysteine-terminated dendritic or linear polymer will also form a gel.
  • gels may be formed by reaction of an aldehyde- functionalized small molecule or polymer and an amine- or cysteine- functionalized polymer.
  • An alternative method is to have a maleimide- or vinylsulfone-functionalized dendritic polymer react with a thiol-functionalized dendritic, linear, comb, or other polymer to form the gel.
  • a functionalized succinimidyl glutarate dendritic polymer with an acid- terminated dendritic, linear, comb, or other polymer can also be used to from a gel.
  • An acrylate-functionalized polymer reacts with an amine- or thiol-functionalized polymer to form the crosslinked gel.
  • a further embodiment of this invention is the use of a chemical peptide ligation reaction to create a crosslinked gel involving a dendritic polymer. In this reaction an aldehyde or aldehyde-acid reacts with a cysteine functionalized polymer to form a gel or crosslinked network.
  • Another aspect of the present invention relates to dendritic or branched polymers or copolymers composed of monomers synthesized by combining branching compounds with other linear or branched building blocks. Both components are biocompatible or are natural metabolites in vivo such as glycerol, citric acid, lactic acid, glycolic acid, adipic acid, caproic acid, ribose, glucose, succinic acid, malic acid, amino acids, peptides, synthetic peptide analogs, or poly(ethylene glycol).
  • one of the monomers is a branched structure, such as glycerol, combined with one of the other components.
  • the present invention relates to polymers and/or nanoparticles derivatized with peripheral compounds possessing an olefin such as acrylate or methacrylate.
  • the present invention relates to the aforementioned polymers and/or nanoparticles derivatized with peripheral compounds such as cysteine, lysine, other amino acids, or any other compounds that would provide terminal nucleophiles (such as amines, thiols, or hydroxyl groups) or electrophiles (such as NHS esters, maleimides, aldehydes, or ketones).
  • peripheral compounds such as cysteine, lysine, other amino acids, or any other compounds that would provide terminal nucleophiles (such as amines, thiols, or hydroxyl groups) or electrophiles (such as NHS esters, maleimides, aldehydes, or ketones).
  • the present invention relates to the forementioned polymers and/or nanoparticles for subsequent polymerization/crosslinking/reaction with another linear or branched structure with either olefmic, electrophilic or nucleophilic groups, respectively to form a gel.
  • the present invention relates to the aforementioned polymers and/or nanoparticles for subsequent polymerization/crosslinking/reaction with another linear or branched structure via a photopolymerization process (single or multi-photon process) to form a gel.
  • Another aspect of the present invention relates to a branching structure with at least three functional groups comprising glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic strucutures synthesized to produce terminal olefins, such as acrylate or methacrylate groups; nucleophiles such as amines, thiols, hydroxyl groups; or electrophiles, such as NHS esters, maleimides, aldehydes, or ketones for subsequent polymerization/crosslinking with another linear or branched structure with either olefinic, electrophilic or nucleophilic groups, respectively in the presence of functionalized or nonfunctionalized nanoparticles.
  • functional groups comprising glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic strucutures synthesized to produce terminal olefins, such as acrylate or methacrylate groups;
  • Another aspect of the present invention relates to a branching structure with at least three functional groups, such as glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic structures derivatized with peripheral compounds including, but not limited to, cysteine, lysine, other amino acids, or any other compounds that would provide terminal olefins (such as acrylate or methacrylate groups), nucleophiles (such as amines, thiols, and hydroxyl groups) or electrophiles (such as NHS esters, maleimides, aldehydes, and ketones) for subsequent polymerization/crosslinking with another linear or branched structure with either olefinic, electrophilic, or nucleophilic groups, respectively in the presence of nanoparticles.
  • functional groups such as glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic structures derivat
  • Another aspect of the present invention relates to a branching structure composed of three lysine amino acids with four cysteine amino acids on the periphery with the structure CysLys(Cys)Lys(CysLys(Cys))OMe*4HCl as described in the examples.
  • the present invention relates to a branching structure composed of three lysine amino acids with peripheral amines on the periphery with the structure
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure with olefinic, electrophilic, or nucleophilic groups to form a gel.
  • poly(ethylene glycol) has a number average molecular weight of about 200 g/mol to about 200,000 g/mol.
  • the poly(ethylene glycol) has at least two electrophilic groups.
  • the poly(ethylene glycol) has at least two nucleophilic groups.
  • the poly(ethylene glycol) has a number average molecular weight of about 200 g/mol to about 200,000 g/mol and is functionalized with an olefin, aldehyde, maleimide, or NHS ester.
  • the hydrogels of the present invention can be prepared by combining solutions containing the components described above, e.g., the nanoparticle and dendrimer.
  • the components may be dissolved or suspended in an aqueous solution.
  • the aqueous solution can be water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates or combinations of any two or more thereof.
  • the components used to prepare the hydrogel are contained in a delivery device that physically separates the components until the components are mixed by the end user.
  • the delivery device may be a dual-barrel syringe with a mixing device.
  • Another aspect of the present invention relates to packaging of the polymerizable dendrimeric compounds in an aqueous solution at a preselected pH and molarity.
  • a poly(ethylene glycol) having a number average molecular weight of about 200 g/mol to about 200,000 g/mol with at least two electrophilic or nucleophilic groups is contained in another aqueous solution at a preselected pH and molarity.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as a drug delivery vehicle and an adhesive/sealant to aid in the repair or sealing of an ophthalmic wound.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, nanoparticles and their hydrogels for ophthalmic procedure wherein the drug has properties such as antimicrobial, antibacterial, anti-inflamatory, etc.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as a drug delivery vehicle and an adhesive/sealant to aid in the repair or sealing of an ophthalmic wound wherein the drug has antimicrobial or antibacterial properties.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary coating on the nanoparticle such that the nanoparticle is covalently bound to the hydrogel network.
  • This coating can contain one or more of the same or different electrophile or nucloephile such that the nanoparticles will react with dendritic and/or linear polymers that constitute the hydrogel.
  • Another aspect of the present invention relates to a crosslinkable/polymerizable/reactionary dendritic polymer or monomer wherein the crosslinking is of covalent, ionic, electrostatic, and/or hydrophobic nature.
  • Another aspect of the present invention relates to a crosslinkable/polymerizable/reactionary nanoparticle, dendritic polymer or monomer wherein the crosslinking is of covalent, ionic, electrostatic, and/or hydrophobic nature.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer, linear polymer, monomer, or nanoparticle wherein the crosslinking reaction involves a nucleophile and electrophile.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer, linear polymer, monomer, or nanoparticle wherein the crosslinking reaction is a peptide ligation reaction.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer, linear polymer, monomer, or nanoparticle wherein the crosslinking reaction is a
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer, linear polymer, monomer, or nanoparticle wherein the crosslinking reaction is a Michael Addition reaction.
  • Another aspect of the present invention relates to a crosslinkable crosslinkable dendritic polymer, linear polymer, monomer, or nanoparticle wherein the crosslinking reaction is a photochemical reaction using a UV or vis photoinitiator chromophore.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer in combination with a linear, comb, multi-block, star polymer(s), dendritic polymer and a nanoparticle as a lens material.
  • Another aspect of the present invention relates to a method of using a crosslinkable branched or dendritic polymer combined with a crosslinkable small molecule(s) having a molecular weight less than about 1000 daltons for a medical or tissue engineering application.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer or monomer, wherein the crosslinking dendritic polymer is combined with one or more linear, comb, multi-block, star polymers or crosslinkable comb, multi- block, star polymers.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the final polymeric form is a gel or sheet.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their resulting hydrogels wherein the polymer or crosslinkable monomer is D or L configuration or a mixture.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their resulting hydrogels wherein the branching structure, linkages and or the incorporation of aromatic or hterocyclic groups changes the refractive index.
  • the hydrogels of the invention may also comprise an ingredient that absorbs ultraviolate light.
  • materials that absorb ultra-violate light include titanium dioxide, zinc oxide, octocrylene, octdyl slicylate, homosalate, octyl methoxycinnamate, avobenzone-Parson 1789, cinoxate, ethylhexyl p- methoxycinnamate, oxybenzone, and benzophenone-3.
  • the ingredient that absorbs ultraviolate light is titanium dioxide or zinc oxide.
  • a variety of procedures are known in the art for sterilizing a chemical composition. Sterilization may be accomplished by chemical, physical, or irradiation techniques. Examples of chemical methods include exposure to ethylene oxide or hydrogen peroxide vapor. Examples of physical methods include sterilization by heat (dry or moist), retort canning, and filtration. The British Pharmacopoeia recommends heating at a minimum of 160 0 C for not less than 2 hours, a minimum of 170 0 C for not less than 1 hour and a minimum of 180 0 C for not less than 30 minutes for effective sterilization. For examples of heat sterilization, see U.S. Patent 6,136,326, which is hereby incorporated by reference. Passing the chemical composition through a membrane can be used to sterilize a composition.
  • the composition is filtered through a small pore filter such as a 0.22 micron filter which comprises material inert to the composition being filtered.
  • a small pore filter such as a 0.22 micron filter which comprises material inert to the composition being filtered.
  • the filtration is conducted in a Class 100,000 or better clean room.
  • irradiation methods include gamma irradiation, electron beam irradiation, microwave irradiation, and irradiation using visible light.
  • One preferred method is electron beam irradiation, as described in U.S. Patents 6,743,858; 6,248,800; and 6,143,805, each of which is hereby incorporated by reference.
  • the two main groups of electron beam accelerators are: (1) a Dynamitron, which uses an insulated core transformer, and (2) radio frequency (RF) linear accelerators (linacs).
  • the Dynamitron is a particle accelerator (4.5 MeV) designed to impart energy to electrons.
  • the high energy electrons are generated and accelerated by the electrostatic fields of the accelerator electrodes arranged within the length of the glass-insulated beam tube (acceleration tube).
  • These electrons traveling through an extension of the evacuation beam tube and beam transport (drift pipe) are subjected to a magnet deflection system in order to produce a "scanned" beam, prior to leaving the vacuum enclosure through a beam window.
  • the dose can be adjusted with the control of the percent scan, the beam current, and the conveyor speed.
  • the electron-beam radiation employed may be maintained at an initial fluence of at least about 2 ⁇ Curie/cm 2 , at least about 5 ⁇ Curie/cm 2 , at least about 8 ⁇ Curie/cm 2 , or at least about 10 ⁇ Curie/cm 2 .
  • the electron-beam radiation employed has an initial fluence of from about 2 to about 25 ⁇ Curie/cm 2 .
  • the electron- beam dosage is from about 5 to 50 kGray, or from about 15 to about 20 kGray with the specific dosage being selected relative to the density of material being subjected to electron- beam radiation as well as the amount of bioburden estimated to be therein. Such factors are well within the skill of the art.
  • the composition to be sterilized may be in any type of at least partially electron beam permeable container such as glass or plastic.
  • the container may be sealed or have an opening.
  • glass containers include ampules, vials, syringes, pipettes, applicators, and the like.
  • the penetration of electron beam irradiation is a function of the packaging. If there is not enough penetration from the side of a stationary electron beam, the container may be flipped or rotated to achieve adequate penetration. Alternatively, the electron beam source can be moved about a stationary package. In order to determine the dose distribution and dose penetration in product load, a dose map can be performed. This will identify the minimum and maximum dose zone within a product.
  • the visible light for sterilization can be generated using any conventional generator of sufficient power and breadth of wavelength to effect sterilization. Generators are commercially available under the tradename PureBright® in-line sterilization systems from PurePulse Technologies, Inc. 4241 Ponderosa Ave, San Diego, Calif. 92123, USA.
  • PureBright® in-line sterilization system employs visible light to sterilize clear liquids at an intensity approximately 90000 times greater than surface sunlight. If the amount of UV light penetration is of concern, conventional UV absorbing materials can be used to filter out the UV light.
  • the composition is sterilized to provide a Sterility
  • the Sterility Assurance Level may be at least about 10 "4 , at least about 10 "5 , or at least about 10 "6 .
  • the materials used to form the lens of the present invention may be delivered to a lens bag of a patient before the hydrogel forms.
  • a large number of delivery systems are known in the art and are amenable to the present invention.
  • a mixture comprising a polymerizable dendrimeric compound and nanoparticles is delivered to a lens bag of a patient.
  • a first mixture comprising a polymerizable dendrimeric compound and nanoparticles is combined with a polymerization agent to form a second mixture, and the second mixture is delivered to the lens bag of a patient.
  • the materials delivered to the lens bag have been sterilized.
  • the delivery system may be a single-barrel syringe system.
  • the single-barrel syringe is a double acting, single-barrel syringe system as displayed in Figure 12.
  • a double- or multi-barrel syringe system as displayed in Figure 13, may be preferable.
  • a delivery device that flows two or more streams of liquid in a mixing chamber may be preferable.
  • a delivery device that mixes two solids and two liquids and then separately flows these streams of liquid to a mixing chamber may be advantageous.
  • a delivery system is used to deliver the lens-forming materials to the lens bag, wherein at least two dry, reactive components are stored together in a dry state and introduced into a liquid component(s) at the time of use to form a mixture that forms a hydrogel.
  • a sterilized hydrogel-nanoparticle composite is delivered to the lens bag using a syringe where the components of the hydrogel-nanoparticle composite are in liquid form, solid form, or a combination of solid and liquid forms prior to delivery.
  • non-reversible hydrogel refers to a hydrogel that does not undergo a transition between a gel and a solution state in response to temperature, pH, ionic strength, solvent composition, oxidative conditions sufficient to form a disulfide bond, or reducing conditions sufficient to reduce a disulfide bond.
  • the non-reversible hydrogel comprises polymeric materials bonded together by C-C, C-N, C-O, and/or C-S covalent bonds.
  • reversible hydrogel refers to a hydrogel that undergoes a transition between a solution and a gel state in response to temperature, pH, ionic strength, solvent composition, oxidative conditions sufficient to form a disulfide bond, or reducing conditions sufficient to reduce a disulfide bond.
  • the reversible hydrogel comprises polymeric materials bonded together by S-S covalent bonds.
  • non-reversible polymer-nanoparticle composite refers to a composition comprising a polymer and a nanoparticle that does not dissociate when subjected to reducing conditions sufficient to convert a disulfide moiety to thiols.
  • nanoparticle refers to a particle that has a diameter of less than about 500 nm. In certain instances, the nanoparticle has a diameter of about 0.1 nm to about 500 ran. In certain instances, the nanoparticle is made of a metal, metal oxide, metal sulfoxide, or ceramic. In certain instances, the nanoparticle is not made of protein.
  • hybrid organic-inorganic nanoparticle refers to a nanoparticle that has a core to which at least one organic compound is attached, wherein said core comprises a metal oxide, metal sulfoxide, or ceramic.
  • sica coated nanoparticle refers to a nanoparticle that has a core coated with silica or silica oxide, wherein said core comprises a metal, metal oxide, alkali metal oxide, metal sulfoxide or ceramic. In certain instances, an organic compound is attached to said nanoparticle.
  • organic compound refers to a compound having a molecular weight less than about 1500 g/mol and having at least about 90 weight percent C, H, N, or O atoms. In certain instances, the organic compound has a molecular weight less than about 750 g/mol. In certain instances, the organic compound has a molecular weight less than about 200 g/mol.
  • generation refers to the number of branched repeat units which emanate from the central core.
  • a third generation (or G3) PGLSA dendrimer has three branching layers not including the core.
  • polymerize refers to the process of converting a monomer to a chain of momomers, wherein the chain of momomers comprises at least about 5 monomers.
  • the chain of monomers comprises at least about 10 or 15 momomers.
  • the chain of monomers comprises at least about 25 or 40 momomers.
  • the chain of monomers comprises at least about 50 or 75 momomers. In certain instances, the chain of monomers comprises at least about 100 or 150 momomers.
  • the term "polymerize" indicates that at least one of the functional groups capable of forming a bond in the polymerization reaction forms a bond with another compound, generally speaking, the other compound is another monomer. In certain instances, at least about 10% of the functional groups capable of forming a bond in a polymerization reaction form a bond to another monomer. In certain instances, at least about 25% of the functional groups capable of forming a bond in a polymerization reaction form a bond to another monomer.
  • At least about 50% of the functional groups capable of forming a bond in a polymerization reaction form a bond to another monomer. In certain instances, at least about 75% of the functional groups capable of forming a bond in a polymerization reaction form a bond to another monomer. In certain instances, about 20% to about 50% of the functional groups capable of forming a bond in a polymerization reaction form a bond to another monomer.
  • the term "polymerize" only requires that at least some of the monomer units in a given solution react to form a chain of monomers. In certain instances, about 10% to about 30% of the monomers react to form a chain of monomers. In certain instances, about 30% to about 50% of the monomers react to form a chain of monomers.
  • the monomers react to form a chain of monomers. In certain instances, about 75% to about 85% of the monomers react to form a chain of monomers. In certain instances, about 85% to about 95% of the monomers react to form a chain of monomers. In certain instances, greater than about 95% of the monomers react to form a chain of monomers.
  • Mw weight average molecular weight in g/mol.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • alkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, anthracene, naphthalene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, />-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, j9-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presentd in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • nitro means -NO2; the term “halogen” designates -F, -Cl, -Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH 2 ) m -R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
  • R50 is as defined above
  • R54 represents a hydrogen, an alkyl, an alkenyl or - (CH 2 ) m -R61, where m and R61 are as defined above.
  • amide is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula: wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 ) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • X50 is an oxygen, and R56 is hydrogen
  • the formula represents a "formate".
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a "thiolcarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a "thiolester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a "thiolcarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a "thiolformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a "ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an "aldehyde” group.
  • oxime and "oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • the moiety is an "oxime” when R is H; and it is an "oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O ⁇ (CH 2 ) m -R61, where m and R61 are described above.
  • R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfonyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • sulfoxido is art-recognized and refers to a moiety that may be represented by the general formula:
  • phosphoryl is art-recognized and may in general be represented by the formula: wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl.
  • R59 represents hydrogen, a lower alkyl or an aryl.
  • the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:
  • Q50 and R59 each independently, are defined above, and Q51 represents O, S or N.
  • Q50 is S
  • the phosphoryl moiety is a "phosphorothioate”.
  • R60 represents a lower alkyl or an aryl.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • selenoalkyl is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto.
  • exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and - Se ⁇ (CH 2 ) m -R61, m and R61 being defined above.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and /r ⁇ «s-isomers, R- and iS'-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group.
  • AU such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., functioning as analgesics), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to sigma receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • alkali metal refer to those elements listed in Group 1 of the periodic table. The following elements are alkali metals: Li, Na, K, Rb, Cs, and Fr.
  • One aspect of the present invention relates to a lens composition comprising nanoparticles and a non-reversible hydrogel.
  • the present invention relates to the aforementioned composition, wherein said non-reversible hydrogel comprises a dendrimeric macromolecule.
  • the present invention relates to the aforementioned composition, wherein said non-reversible hydrogel comprises a dendrimeric macromolecule and polymer selected from the group consisting of a polyacrylate, siloxane, silicone, polymethylmethacrylate, styrene-ethylene-butylene-styrene block copolymer, polyvinyl alcohol, polyurethane, and a copolymer of 2-hydroxyethyl methacrylate and 6-hydroxyhexyl methacrylate. '
  • the present invention relates to the aforementioned composition, wherein said non-reversible hydrogel comprises a dendrimeric macromolecule formed by treating a dendrimeric compound of formula Ia or formula Ib with a polymerization agent selected from the group consisting of ultraviolet light, visible light, compound II, compound in, compound IV, and compound V; wherein formula Ia is represented by:
  • A is alkyl, aryl, aralkyl, -Si(R ) 3 , or
  • A represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y 1 represents independently for each occurrence R 4 , A 4 ,
  • Z 1 represents independently for each occurrence -X 1 -R 4 , E, or
  • Y 2 represents independently for each occurrence R 5 , A 4 ,
  • Z represents independently for each occurrence -X 1 -R r>5 , E, or
  • Y 3 represents independently for each occurrence R 6 , A 4 ,
  • Z represents independently for each occurrence -X 1 - rR> 6 , E, or
  • Y 4 represents independently for each occurrence R 7 , A 4 ,
  • Z 4 represents independently for each occurrence -X 1 -R 7 , E, or
  • Y 5 represents independently for each occurrence R 8 , A 4 ,
  • Z 5 represents independently for each occurrence -X 1 -R 8 , E, or
  • Y 6 represents independently for each occurrence R 9 , A 4 ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R I0 ) 2 , -SH, hydroxyalkyl, or -[C(R 1 ) 2 ] d R 16 ;
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H
  • R 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 11 represents independently for each occurrence H, -OH, -N(R 1 °) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R 1 ) 2 ] d R 16 ;
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10 ;
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl,. imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or -C(NH 2 )N(R 10 ) 2 ;
  • d represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • n represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • p 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7; or 8;
  • p 2 represents independently for each occurrence 0, 1, 2, 3, or 4;
  • p 3 represents independently for each occurrence 1, 2, or 3;
  • p 4 represents independently for each occurrence 0, 1, 2, or 3;
  • t represents independently for each occurrence 2, 3, 4, or 5 in accord with the rules of valence;
  • v 1 and v 2 each represent independently for each occurrence
  • A represents independently for each occurrence
  • X 5 represents independently for each occurrence O or -N(R 22 )-;
  • R 17 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R 18 represents independently for each occurrence H or alkyl
  • R 19 represents independently for each occurrence H, halogen, or alkyl
  • R 20 represents independently for each occurrence H or alkyl
  • R 21 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R 22 represents independently for each occurrence H, alkyl, aryl, or aralkyl; n 1 and h each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; p 5 represents independently for each occurrence 1, 2, 3, 4, or 5; v represents independently for each occurrence 2, 3, or 4; and w is an integer in the range of about 5 to about 700, inclusive; said compound II is represented by:
  • R 1-II represents independently for each occurrence H or
  • R 2-II represents independently for each occurrence H or alkyl
  • R 3-II represents independently for each occurrence H, halogen, or alkyl
  • R 4-II represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5"11 represents independently for each occurrence H or and z represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; said compound III is represented by:
  • R 1-111 is -(C(R 2 - IU ) 2 ) X C(O)H, -C(O)(C(R 2 - IU ) 2 ) y C(O)H, -(C(R 2 - ⁇ I ) 2 ) X C(O)R 3 - ⁇ I , or -
  • R 2-111 represents independently for each occurrence H, alkyl, or halogen; R ,3 > -m m is flu ⁇ roalkyl, chloroalkyl, -CH 2 NO 2 , or
  • B is alkyl diradical, heteroalkyl diradical
  • x represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • y represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;
  • v represents independently for each occurrence 2, 3, or 4;
  • w is an integer in the range of about 5 to about 700, inclusive;
  • a 2 is alkyl, aryl, aralkyl,r -Si(R 3 ) 3 ,
  • A represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Z 1 represents independently for each occurrence -X 1 -R 4 , E, or
  • Y 2 represents independently for each occurrence R 5 ,
  • Z represents independently for each occurrence -X 1 -R 5 , E, or
  • Y 3 represents independently for each occurrence R ,
  • Z 3 represents independently for each occurrence -X 1 -R 6 , E, or
  • Z 4 represents independently for each occurrence -X 1 -R 7 , E, or
  • Y represents independently for each occurrence R ,
  • Z 5 represents independently for each occurrence -X 1 -R 8 , E, or
  • Y represents independently for each occurrence R ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R represents independently for each occurrence H, alkyl, -OH, -N(R ) 2 , -SH, hydroxyalkyl, or -[C(R 1 ) 2 ] d R 16 ;
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H;
  • R 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 11 represents independently for each occurrence H, -OH, -N(R 1 °) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R 1 ) 2 ] d R 16 ;
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R l0 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or -C(NH 2 )N(R 1 °) 2 ;
  • n represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • p 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7; or 8;
  • p 2 represents independently for each occurrence 0, 1, 2, 3, or 4;
  • p 3 represents independently for each occurrence 1, 2, or 3;
  • p 4 represents independently for each occurrence 0, 1, 2, or 3;
  • d represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • t represents independently for each occurrence 2, 3, 4, or 5 in accord with the rules of valence;
  • v 1 and v 2 each represent independently for each
  • X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-;
  • X 3 represents independently for each occurrence O, N(R 10 ), or C(R 15 )(CO 2 R 10 );
  • X 6 represents independently for each occurrence O or -N(R 30 )-;
  • R 23 represents independently for each occurrence
  • R 24 represents independently for each occurrence H or alkyl
  • R 25 represents independently for each occurrence H, halogen, or alkyl
  • R 26 represents independently for each occurrence H or alkyl
  • R 27 represents independently for each occurrence H, alkyl, or halogen
  • R 28 represents independently for each occurrence H, alkyl, -OH, -N(R 30 ) 2 , -SH, or hydroxyalkyl;
  • R 29 represents independently for each occurrence H, -OH, -N(R 30 ) 2 , -SH, alkyl, or hydroxyalkyl;
  • R 30 and R 31 represent independently for each occurrence H, alkyl, aryl, or aralkyl;
  • Z 6 represents independently for each occurrence E 1 or
  • R represents independently for each occurrence
  • Z 7 represents independently for each occurrence E 1 or
  • R >33 represents independently for each
  • R 34 represents independently for each occurrence H, alkyl, or -CO 2 R 30,
  • E represents independently for each occurrence H, -[C(R 24 ) 2 ]jC(O)H, or
  • the present invention relates to the aforementioned composition, wherein said dendrimeric compound is compound of formula Ia, and said polymerization agent is ultraviolet light, visible light, compound II, or compound III.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein Z 1 represents independently for each occurrence -X 1 -R 4 or
  • the present invention relates to the aforementioned composition, wherein Z 2 represents independently for each occurrence -X 1 -R 5 or
  • the present invention relates to the aforementioned composition, wherein Z 3 represents independently for each occurrence -X 1 -R 6 or
  • the present invention relates to the aforementioned composition, wherein Z 4 represents independently for each occurrence -X 1 -R 7 or
  • the present invention relates to the aforementioned composition, wherein Z 5 represents independently for each occurrence -X'-R 8 or
  • the present invention relates to the aforementioned composition, wherein X 1 is O.
  • the present invention relates to the aforementioned composition, wherein X 1 and X 2 are O.
  • the present invention relates to the aforementioned composition, wherein n is 1. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 2, 3, or 4.
  • the present invention relates to the aforementioned composition, wherein p 2 is 1.
  • the present invention relates to the aforementioned composition, wherein R 1 is H.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H, B m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is m
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition,
  • R 1 is H
  • B is , m
  • the present invention relates to the aforementioned composition, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein p 1 is 4. In certain instances, the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H, B is , m is 1
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H, B , m is 1
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H, B is , m is 1
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 4.
  • the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein R 2 is (C r C 3 )alkyl.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H, B and v 1 is 2.
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is o P I ' v 1 is 2
  • a 2 m is 1 or 2
  • Y 1 is /D 1
  • Z 1 is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned composition
  • R 1 is H 3 B is , v 1 is 2, A 2
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • the present invention relates to the aforementioned composition
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is P I
  • v' is 2
  • a 2 is
  • the present invention relates to the aforementioned composition, wherin w 1 is an integer in the range of about 50 to about 250.
  • the present invention relates to the aforementioned composition, wherein w 1 is an integer in the range of about 60 to about 90. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, and R 3 is (C 1 -C 5 )alkyl.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, R 3 is (Ci-C 5 )alkyl, and w 1 is an integer in the range of about 60 to about 90. In certain instances, the present invention relates to the aforementioned composition,
  • R 1 is H
  • B is A 2
  • R 3 is alkyl
  • v 2 i IS
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is ,
  • R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 3 is alkylj V 2 is
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is
  • R 3 is alkyl
  • ⁇ is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is
  • R 3 is alkyl
  • v 2 i IS
  • said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, and R 3 is (C 1 -C 5 )alkyl. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, and R 3 is l (Ci-C 5 )alkyl, and w 2 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is , m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is compound II. In certain embodiments, the present invention relates to the aforementioned composition, wherein said polymerization agent is compound III.
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is compound III, R 1"111 is -C(O)H, and R 2"111 is H.
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is compound III, R 1"111 is -C(O)H, R 2"111 is H, and B 1"111 is
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is compound III, R 2"m is -C(O)H, R 2"111 is H, B 1"111 is
  • w is an integer in the range of about 60-90.
  • the present invention relates to the aforementioned composition, wherein said compound of formula Ia is
  • said polymerization agent is UV light.
  • the present invention relates to the aforementioned composition, wherein said dendrimeric compound is a compound of formula Ib. In certain embodiments, the present invention relates to the aforementioned composition, wherein v is 2.
  • the present invention relates to the aforementioned composition, wherein X 5 is -N(H)-.
  • the present invention relates to the aforementioned composition, wherein R 18 is H.
  • the present invention relates to the aforementioned composition, wherein R 19 is H.
  • the present invention relates to the aforementioned composition, wherein R 20 is H. In certain embodiments, the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 20-500.
  • the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 40-250.
  • the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 60-90.
  • the present invention relates to the composition, said compound of formula Ib is
  • the present invention relates to the aforementioned composition, said polymerization agent is compound V.
  • the present invention relates to the aforementioned composition, wherein v is 2.
  • the present invention relates to the aforementioned composition, wherein X 6 is -N(H)-. In certain embodiments, the present invention relates to the aforementioned composition, wherein R 24 is H.
  • the present invention relates to the aforementioned composition, wherein R 25 is H.
  • the present invention relates to the aforementioned composition, wherein R 26 is H.
  • the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 20-500.
  • the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 40-250. In certain embodiments, the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 60-90.
  • the present invention relates to the aforementioned composition, wherein R 23 represents independently for each occurrence
  • the present invention relates to the aforementioned composition, wherein R 23 represents independently for each occurrence
  • the present invention relates to the aforementioned composition, said compound V is o
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is ultraviolet light.
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is light with a ⁇ of 400-600 nm.
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is light with a ⁇ of 450-550 nm. In certain embodiments, the present invention relates to the aforementioned composition, wherein said polymerization agent is light with a ⁇ of 488-514 nm.
  • the present invention relates to the aforementioned composition, wherein said non-reversible hydrogel comprises a dendrimeric macromolecule formed by treating a compound of formula VI with a polymerization agent represented by formula VII, wherein formula VI is represented by:
  • R 1 represents independently for each occurrence H, -(C(R 3 ) 2 ) m SH, -
  • R 2 represents independently for each occurrence H or alkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -
  • R 1 -TM represents independently for each occurrence -(C(R 2-v ⁇ ) 2 ) x C(O)H, -C(O)(C(R 2 -
  • R 2-v ⁇ represents independently for each occurrence H, alkyl, or halogen;
  • R ,3 J - " V V I U I is is fluoroalkyl, chloroalkyl, -CH 2 NO
  • B is alkyl diradical, heteroalkyl diradical, or v .,2-VII represents independently for each occurrence 2, 3, or 4; and w 2"v ⁇ is an integer in the range of about 5 to 700, inclusive.
  • w 2"v ⁇ is an integer in the range of about 50 to about 250.
  • w 2"v ⁇ is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition, whe erreeiin said polymerization agent is a compound of formula VII, R 2"VI1 is -C(O)H, and R 2" v ⁇ is H.
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is a compound of formula VII, R 2 ⁇ v ⁇ is -C(O)H, R 2-v ⁇ is
  • the present invention relates to the aforementioned composition, wherein said polymerization agent is a compound of formula VII, R 2'v ⁇ is -C(O)H, R 2 ⁇ v ⁇ is
  • H, B is ⁇ -VH is an integer in the range of about 60-90.
  • the present invention relates to the aforementioned composition, wherein n is 3, 4, or 5.
  • the present invention relates to the aforementioned composition, wherein n is 4. In certain instances, the present invention relates to the aforementioned composition, wherein R 2 is H.
  • the present invention relates to the aforementioned composition, wherein R 3 is H. In certain instances, the present invention relates to the aforementioned composition, wherein R 4 is alkyl.
  • the present invention relates to the aforementioned composition, wherein R 4 is methyl or ethyl.
  • the present invention relates to the aforementioned composition, wherein n is 4, R 2 and R 3 is H, and R 4 is alkyl.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 and p is l.
  • the present invention relates to the aforementioned composition
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is and p is 1.
  • the present invention relates to the aforementioned composition
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is and p is 1.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and a Bronstead acid.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and HA, wherein A is halogen or -O 2 CR 6 , and R 6 is alkyl, fluoroalkyl, aryl, or aralkyl.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and an acid selected from group consisting of HCl and HBr.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and HO 2 CR 6 , wherein R 6 is fluoroalkyl.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and CF 3 CO 2 H.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are a metal, metal oxide, metal sulfide, zeolite, protein, ceramic, silica, or a combination thereof.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are titanium dioxide, zinc oxide, aluminium oxide, gold, diamond, silver oxide, silicon dioxide, zirconium dioxide, cerium dioxide, calcium oxide, protein, ceramic, or carbon-based nanoparticles.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are zinc oxide, aluminium oxide, diamond, zirconium dioxide, cerium dioxide, calcium oxide, or carbon-based nanoparticles.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are a metal oxide coated with an organic compound, a metal sulfoxide coated with an organic compound, or a ceramic material coated with an organic compound.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are a metal oxide coated with a layer of silica or a ceramic material coated with a layer of silica.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles comprise a core coated with a layer of silica or functionalized with an organic compound, and said core comprises titanium dioxide, zinc oxide, aluminum oxide, diamond, zirconium dioxide, cerium dioxide, or calcium oxide.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles have a core comprising titanium dioxide, and said core is functionalized with lactic acid or a trimethoxysilyl group. In certain embodiments, the present invention relates to the aforementioned composition, wherein said nanoparticles are covalently bonded to a polymer in said hydrogel.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are stable, and said nanoparticles remain dispersed when placed in an aqueous solution having a pH in the range of about 6.5 to about 7.5.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are present in about 1 to about 40 weight percent.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are present in about 5 to about 25 weight percent. In certain embodiments, the present invention relates to the aforementioned composition, wherein the diameter of said microparticles is less than about 50 nm.
  • the present invention relates to the aforementioned composition, wherein the diameter of said microparticles is less than about 20 nm.
  • the present invention relates to the aforementioned composition, wherein said lens is an intraocular lens, accommodating intraocular lens, or endocapsular lens. In certain embodiments, the present invention relates to the aforementioned composition, wherein said lens is transparent.
  • the present invention relates to the aforementioned composition, wherein said lens swells less than about 100% in aqueous solution. In certain embodiments, the present invention relates to the aforementioned composition, further comprising a material that absorbs ultraviolet light.
  • the present invention relates to the aforementioned composition, wherein said composition has a sterility assurance level of at least about 10 "3 .
  • the present invention relates to the aforementioned composition, wherein said composition has a sterility assurance level of at least about 10 "5 .
  • the present invention relates to the aforementioned composition, wherein less than about 30% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • the present invention relates to the aforementioned composition, wherein less than about 15% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • the present invention relates to the aforementioned composition, wherein less than about 5% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond. In certain embodiments, the present invention relates to the aforementioned composition, wherein less than about 1% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • Another aspect of the present invention relates to a lens composition comprising nanoparticles and a reversible hydrogel, wherein said hydrogel comprises a dendrimeric macromolecule.
  • the present invention relates to the aforementioned composition, wherein said reversible hydrogel further comprises a polymer selected from the group consisting of a polyacrylate, siloxane, silicone, polymethylmethacrylate, styrene- ethylene-butylene-styrene block copolymer, polyvinyl alcohol, polyurethane, and a copolymer of 2-hydroxyethyl methacrylate and 6-hydroxyhexyl methacrylate.
  • a polymer selected from the group consisting of a polyacrylate, siloxane, silicone, polymethylmethacrylate, styrene- ethylene-butylene-styrene block copolymer, polyvinyl alcohol, polyurethane, and a copolymer of 2-hydroxyethyl methacrylate and 6-hydroxyhexyl methacrylate.
  • the present invention relates to the aforementioned composition, wherein said reversible hydrogel comprises a dendrimeric macromolecule formed by treating a compound of formula VIII or formula IX with an oxidizing agent sufficient to polymerize said dendrimeric compound, wherein formula VIII is represented by: )
  • a 2 is alkyl, aryl, aralkyl, -Si(R J ) 3 , or
  • A represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y 1 represents independently for each occurrence R 4 ,
  • Z 1 represents independently for each occurrence -X 1 -R 4 , E, or
  • Y 2 represents independently for each occurrence R 5 ,
  • Z 2 represents independently for each occurrence -X 1 -R 5 , E, or
  • Y represents independently for each occurrence R ,
  • Z 3 represents independently for each occurrence -X 1 -R 6 , E, or
  • Y 4 represents independently for each occurrence R 7 ,
  • z 4 - represents independently for each occurrence -X 1 -R 7 , E, or
  • Y 5 represents independently for each occurrence R 8 ,
  • Z 5 represents independently for each occurrence -X 1 -R 8 , E, or
  • Y 6 represents independently for each occurrence R 9 ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R represents independently for each occurrence H, alkyl, -OH, -N(R 10 ) 2 , -SH, hydroxyalkyl, or -[C(R 1 ) 2 ] d R 16 ;
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H;
  • R , 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 11 represents independently for each occurrence H, -OH, -N(R 1 °) 2 , -SH, alkyl, hydroxyalkyl, or -[CtR ⁇ R 16 ;
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10 ;
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or -C(NH 2 )N(R 10 ) 2 ;
  • d represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • n represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • p 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7; or 8;
  • p 2 represents independently for each occurrence 0, 1, 2, 3, or 4;
  • p 3 represents independently for each occurrence 1, 2, or 3;
  • p 4 represents independently for each occurrence O 5 1, 2, or 3;
  • t represents independently for each occurrence 2, 3, 4, or 5 in accord with the rules of valence;
  • v 1 and v 2 each represent independently for each occurrence
  • w 1 and w 2 each represent independently for each occurrence an integer from about 5 to about 700, inclusive; x is l, 2, or 3; y is 0, 1, 2, 3, 4, or 5; z 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; z 2 and z 3 each represent independently for each occurrence 1, 2, 3, 4, or 5;
  • X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-; X 3 represents independently for each occurrence O, N(R 10 ), or C(R 1S )(CO 2 R 10 );
  • X s represents independently for each occurrence O or -N(R 22 )-;
  • R 17 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R 18 represents independently for each occurrence H or alkyl
  • R 19 represents independently for each occurrence H, halogen, or alkyl
  • R 20 represents independently for each occurrence H or alkyl
  • R 21 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R ,22 represents independently for each occurrence H, alkyl, aryl, or aralkyl; n 1 and h each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; p 5 represents independently for each occurrence 1, 2, 3, 4, or 5; v represents independently for each occurrence 2, 3, or 4; and w is an integer in the range of about 5 to about 700, inclusive.
  • the present invention relates to the aforementioned composition, wherein a compound of formula VIII contains at least two thiol groups.
  • the present invention relates to the aforementioned composition, wherein a compound of formula VIII contains at least five thiol groups. In certain instances, the present invention relates to the aforementioned composition, wherein a compound of formula IX contains at least two thiol groups.
  • the present invention relates to the aforementioned composition, wherein a compound of formula IX contains at least five thiol groups.
  • the present invention relates to the aforementioned composition
  • a 1 , and m is 1 or 2.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein Z 1 represents independently for each occurrence -X*-R 4 or
  • the present invention relates to the aforementioned composition, wherein Z 2 represents independently for each occurrence -X 1 -R 5 or
  • the present invention relates to the aforementioned composition, wherein Z 3 represents independently for each occurrence -X 1 -R 6 or
  • the present invention relates to the aforementioned composition, wherein Z represents independently for each occurrence -X 1 - nR7 or
  • the present invention relates to the aforementioned composition, wherein Z 5 represents independently for each occurrence -X 1 -R 8 or
  • the present invention relates to the aforementioned composition, wherein X 1 is O. In certain instances, the present invention relates to the aforementioned composition, wherein X 1 and X 2 are O.
  • the present invention relates to the aforementioned composition, wherein n is i.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, 3, or 4. In certain instances, the present invention relates to the aforementioned composition, wherein p 2 is 1.
  • the present invention relates to the aforementioned composition, wherein R 1 is H. In certain instances, the present invention relates to the aforementioned composition,
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • Y 1 is In certain instances, the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is , m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 4.
  • the present invention relates to the aforementioned composition, wherein m is 1. In certain instances, the present invention relates to the aforementioned composition,
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H, B is , m is 1
  • the present invention relates to the aforementioned composition
  • R 1 is H, B is , m is 1
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is
  • the present invention relates to the aforementioned composition, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein p 1 is 4. In certain instances, the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein R 2 is (d-C 3 )alkyl.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • n 1 or 2
  • Y 1 is P 1
  • Z 1 is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • the present invention relates to the aforementioned composition, wherin w 1 is an integer in the range of about 50 to about 250.
  • the present invention relates to the aforementioned composition, wherein w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-C 5 )alkyl. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, R 3 is (C 1 -Cs)alkyl, and w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is
  • R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is ,
  • R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is
  • R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is O, and R 3 is (C 1 -C 5 )alkyl. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-Cs)alkyl, and w 2 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is , m IS 1, or 2
  • Y 1 IS is
  • the present invention relates to the aforementioned composition
  • R 1 is H, B , m
  • the present invention relates to the aforementioned composition, wherein said dendrimeric molecule is
  • n is an integer in the range of about 70 to about 80, and said polymerization agent is O 2 .
  • the present invention relates to the aforementioned composition, wherein said dendrimeric compound is a compound of formula IX. In certain embodiments, the present invention relates to the aforementioned composition, wherein v is 2.
  • the present invention relates to the aforementioned composition, wherein X s is -N(H)-.
  • the present invention relates to the aforementioned composition, wherein R 18 is H.
  • the present invention relates to the aforementioned composition, wherein R 19 is H.
  • the present invention relates to the aforementioned composition, wherein R 20 is H. In certain embodiments, the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 20-500.
  • the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 40-250.
  • the present invention relates to the aforementioned composition, wherein w is an integer in the range of about 60-90.
  • the present invention relates to the aforementioned composition, said compound of formula IX is:
  • the present invention relates to the aforementioned composition, wherein said oxidizing agent is O 2 .
  • the present invention relates to the aforementioned composition, wherein about 1% to about 70% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • the present invention relates to the aforementioned composition, wherein about 5% to about 50% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond. In certain embodiments, the present invention relates to the aforementioned composition, wherein about 5% to about 30% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • the present invention relates to the aforementioned composition, wherein said reversible hydrogel comprises a dendrimeric macromolecule formed by treating a compound of formula X with an oxidizing agent sufficient to polymerize said compound of formula X, wherein formula X is represented by:
  • R 1 represents independently for each occurrence H, -(C(R 3 ) 2 ) m SH, -
  • R 2 represents independently for each occurrence H or alkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH
  • the present invention relates to the aforementioned composition, wherein said compound of formula X has at least two thiol groups.
  • the present invention relates to the aforementioned composition, wherein said compound of formula X has at least five thiol groups.
  • the present invention relates to the aforementioned composition, wherein n is 3, 4, or 5.
  • the present invention relates to the aforementioned composition, wherein n is 4.
  • the present invention relates to the aforementioned composition, wherein R 2 is H. In certain instances, the present invention relates to the aforementioned composition, wherein R 3 is H.
  • the present invention relates to the aforementioned composition, wherein R 4 is alkyl.
  • the present invention relates to the aforementioned composition, wherein R 4 is methyl or ethyl.
  • the present invention relates to the aforementioned composition, wherein n is 4, R 2 and R 3 is H, and R 4 is alkyl.
  • the present invention relates to the aforementioned composition
  • R 1 is and p is 1.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is and p is l.
  • the present invention relates to the aforementioned composition
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is and p is 1.
  • the present invention relates to the aforementioned composition
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is and p is 1.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula X and a Bronstead acid.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula X and HA, wherein A is halogen or -O 2 CR 6 , and R 6 is alkyl, fluoroalkyl, aryl, or aralkyl.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula X and an acid selected from group consisting of HCl and HBr. In certain instances, the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula X and HO 2 CR 6 , wherein R 6 is fluoroalkyl.
  • the present invention relates to the aforementioned composition, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula X and CF 3 CO 2 H.
  • the present invention relates to the aforementioned composition, wherein said oxidizing agent is O 2 .
  • the present invention relates to the aforementioned composition, wherein about 1% to about 70% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • the present invention relates to the aforementioned composition, wherein about 5% to about 50% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond. In certain embodiments, the present invention relates to the aforementioned composition, wherein about 5% to about 30% of the thiol groups present in said dendrimeric macromolecule form a disulfide bond.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are a metal, metal oxide, metal sulfide, zeolite, protein, ceramic, silica, or a combination thereof.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are titanium dioxide, zinc oxide, aluminium oxide, gold, diamond, silver oxide, silicon dioxide, zirconium dioxide, cerium dioxide, calcium oxide, protein, ceramic, silica, or carbon-based nanoparticles.
  • said nanoparticles are titanium dioxide, zinc oxide, aluminium oxide, gold, diamond, silver oxide, zirconium dioxide, cerium dioxide, calcium oxide, ceramic, or carbon-based nanoparticles.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are zinc oxide, aluminium oxide, diamond, zirconium dioxide, cerium dioxide, calcium oxide, or carbon-based nanoparticles.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are a metal oxide coated with an organic compound, a metal sulfoxide coated with an organic compound, or a ceramic material coated with an organic compound.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are a metal oxide coated with a layer of silica or a ceramic material coated with a layer of silica.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles comprise a core coated with a layer of silica or functionalized with an organic compound, and said core comprises titanium dioxide, zinc oxide, aluminum oxide, diamond, zirconium dioxide, cerium dioxide, or calcium oxide.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles have a core comprising titanium dioxide, and said core is functionalized with lactic acid or a trimethoxysilyl group. In certain embodiments, the present invention relates to the aforementioned composition, wherein said nanoparticles are covalently bonded to said dendrimeric macromolecule.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are stable, and said nanoparticles remain dispersed when placed in an aqueous solution having a pH in the range of about 6.5 to about 7.5. In certain embodiments, the present invention relates to the aforementioned composition, wherein said nanoparticles are present in about 1 to about 40 weight percent.
  • the present invention relates to the aforementioned composition, wherein said nanoparticles are present in about 5 to about 25 weight percent. In certain embodiments, the present invention relates to the aforementioned composition, wherein the diameter of said microparticles is less than about 50 nm.
  • the present invention relates to the aforementioned composition, wherein the diameter of said microparticles is less than about 20 nm.
  • the present invention relates to the aforementioned composition, wherein said lens is an intraocular lens, accommodating intraocular lens, or endocapsular lens. In certain embodiments, the present invention relates to the aforementioned composition, wherein said lens is transparent.
  • the present invention relates to the aforementioned composition, wherein said lens swells less than about 100% in aqueous solution. In certain embodiments, the present invention relates to the aforementioned composition, further comprising a material that absorbs ultraviolet light.
  • the present invention relates to the aforementioned composition, wherein said composition has a sterility assurance level of at least about 10 "3 .
  • the present invention relates to the aforementioned composition, wherein said composition has a sterility assurance level of at least about 10 "5 .
  • Another aspect of the present invention relates to a lens composition
  • a lens composition comprising nanoparticles and a reversible hydrogel, wherein said nanoparticles have a core made of a metal, metal sulfide, zeolite, ceramic, diamond, titanium dioxide, zinc oxide, aluminium oxide, silver oxide, zirconium dioxide, cerium dioxide, calcium oxide, carbon, or a combination thereof.
  • the present invention relates to the aforementioned composition, wherein said reversible hydrogel comprises a dendrimeric macromolecule.
  • the present invention relates to the aforementioned composition, wherein said reversible hydrogel comprises a dendrimeric macromolecule and polymer selected from the group consisting of a polyacrylate, siloxane, silicone, polymethylmethacrylate, styrene-ethylene-butylene-styrene block copolymer, polyvinyl alcohol, polyurethane, and a copolymer of 2-hydroxyethyl methacrylate and 6-hydroxyhexyl methacrylate.
  • the present invention relates to the aforementioned composition, wherein said reversible hydrogel comprises a dendrimeric macromolecule formed by treating a compound of formula VIQ or formula IX with an oxidizing agent sufficient to polymerize said dendrimeric compound, wherein formula VIII is represented by:
  • A represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y 1 represents independently for each occurrence R 4 ,
  • Z 1 represents independently for each occurrence -X 1 -R 4 E, or
  • Y represents independently for each occurrence R 5 ,
  • Z 2 represents independently for each occurrence -X 1 -R 5 , E, or
  • Y 3 represents independently for each occurrence R 6 .
  • Z 3 represents independently for each occurrence -X 1 -R 6 , E, or
  • Y 4 represents independently for each occurrence R 7 ,
  • Z 4 represents independently for each occurrence -X 1 -R 7 , E, or
  • Y represents independently for each occurrence R 8 ,
  • Z 5 represents independently for each occurrence -X 1 -R 8 , E, or
  • Y represents independently for each occurrence R 9 ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R I0 ) 2 , -SH, hydroxyalkyl, or -[C(R 1 ⁇ J d R 16 ;
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H
  • R 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 11 represents independently for each occurrence H, -OH, -N(R 10 ) 2 , -SH, alkyl, hydroxyalkyl, or -[qR 1 ) ⁇ 16 ;
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10 ;
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or -C(NH 2 )N(R 10 ) 2 ;
  • d represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • n represents independently for each occurrence 1, 2, 3, 4, 5, or 6;
  • p 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7; or 8;
  • p 2 represents independently for each occurrence 0, 1, 2, 3, or 4;
  • p 3 represents independently for each occurrence 1, 2, or 3;
  • p 4 represents independently for each occurrence 0, 1, 2, or 3;
  • t represents independently for each occurrence 2, 3, 4, or 5 in accord with the rules of valence;
  • v 1 and v 2 each represent independently for each occurrence 2,
  • X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-; X 3 represents independently for each occurrence O, N(R 10 ), or C(R 15 )(CO 2 R 10 );
  • X 5 represents independently for each occurrence O or -N(R 22 )-;
  • R 17 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH,
  • R 18 represents independently for each occurrence H or alkyl
  • R 19 represents independently for each occurrence H, halogen, or alkyl
  • R 20 represents independently for each occurrence H or alkyl
  • R 21 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R 22 represents independently for each occurrence H, alkyl, aryl, or aralkyl; n 1 and h each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; p 5 represents independently for each occurrence 1, 2, 3, 4, or 5; v represents independently for each occurrence 2, 3, or 4; and w is an integer in the range of about 5 to about 700, inclusive.
  • the present invention relates to the aforementioned composition, wherein a compound of formula VIII contains at least two thiol groups.
  • the present invention relates to the aforementioned composition, wherein a compound of formula VIII contains at least five thiol groups. In certain instances, the present invention relates to the aforementioned composition, wherein a compound of formula IX contains at least two thiol groups.
  • the present invention relates to the aforementioned composition, wherein a compound of formula IX contains at least five thiol groups.
  • the present invention relates to the aforementioned composition
  • a 1 , and m is 1 or 2.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein Z 1 represents independently for each occurrence -X'-R 4 or
  • the present invention relates to the aforementioned composition, wherein Z 2 represents independently for each occurrence -X 1 -R 5 or
  • the present invention relates to the aforementioned composition, wherein Z 3 represents independently for each occurrence -X 1 -R 6 or
  • the present invention relates to the aforementioned composition, wherein Z 4 represents independently for each occurrence -X 1 -R 7 or
  • the present invention relates to the aforementioned composition, wherein Z 5 represents independently for each occurrence -X 1 -R 8 or
  • the present invention relates to the aforementioned composition, wherein X 1 is O. In certain instances, the present invention relates to the aforementioned composition, wherein X 1 and X 2 are O.
  • the present invention relates to the aforementioned composition, , wherein n is 1.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, 3, or 4. In certain instances, the present invention relates to the aforementioned composition, wherein p 2 is 1.
  • the present invention relates to the aforementioned composition, wherein R 1 is H. In certain instances, the present invention relates to the aforementioned composition,
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is , m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2. 2006/023723
  • the present invention relates to the aforementioned composition, wherein p 1 is 4.
  • the present invention relates to the aforementioned composition, wherein m is 1. In certain instances, the present invention relates to the aforementioned composition,
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is
  • the present invention relates to the aforementioned composition
  • R 1 is H, B is , m is 1
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2 is m is 1
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein p 1 is 4. In certain instances, the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein R 2 is (Ci-C 3 )alkyl.
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • IS m is 1 or 2
  • Y 1 is Z 1 is
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is A 2
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v ! is 2
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition, wherin w 1 is an integer in the range of about 50 to about 250. i In certain instances, the present invention relates to the aforementioned composition, wherein w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2.
  • the present invention relates to the aforementioned composition, wherein m is 1.
  • the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-Cs)alkyl. In certain instances, the present invention relates to the aforementioned composition, wherein p 1 is 2, p 2 is 0, R 3 is (Ci-C 5 )alkyl, and w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B w 2 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned composition
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is v 1 is 2
  • the present invention relates to the aforementioned composition
  • R 1 is H
  • B is ,
  • R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned composition

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Prostheses (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Polymerisation Methods In General (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Selon un aspect, compositions à polymères et nanoparticules formant des hydrogels utiles comme matériaux de remplacement de lentille, de substitution de lentille, implants cornéens et lentilles intra-oculaires. On peut former les hydrogels avec une macromolécule de polyacrylate, de silicone ou dendritique. Parfois, ces hydrogels comportent des nanoparticules de diamètre compris entre environ 0,1 nm et environ 100 nm. En règle générale, les nanoparticules sont dispersées dans l'hydrogel et peuvent être à réticulation covalente ou non covalente. Elles peuvent être en métal, oxyde métallique ou en céramique. Parfois, elles comprennent un noyau de céramique revêtu d'une couche de silice. Selon un autre aspect, on décrit un procédé de formation de composition de lentille : traitement de mélange de composé dendrimère polymérisable et d'agent de polymérisation, ou encore on décrit une nanoparticule à noyau revêtu de couche de silice. Parfois, le noyau est en métal, oxyde métallique ou céramique. Enfin, un autre aspect concerne un kit de formation de lentille comprenant un composé dendrimère polymérisable, des nanoparticules et un système de délivrance de composé dendrimère et de nanoparticules à la poche de lentille du patient.
PCT/US2006/023723 2005-06-29 2006-06-19 Nanoparticules et hydrogels a base de polymeres dendritiques les renfermant WO2007005249A2 (fr)

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