WO2006122414A1 - Depot for sustained and controlled delivery of methotrexate - Google Patents

Depot for sustained and controlled delivery of methotrexate Download PDF

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Publication number
WO2006122414A1
WO2006122414A1 PCT/CA2006/000805 CA2006000805W WO2006122414A1 WO 2006122414 A1 WO2006122414 A1 WO 2006122414A1 CA 2006000805 W CA2006000805 W CA 2006000805W WO 2006122414 A1 WO2006122414 A1 WO 2006122414A1
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Prior art keywords
poly
product
mold
derivatives
process according
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PCT/CA2006/000805
Other languages
French (fr)
Inventor
Thomas Freier
Rivelino Montenegro
Molly S. Shoichet
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Matregen Corp.
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Priority to US68172905P priority Critical
Priority to US60/681,729 priority
Application filed by Matregen Corp. filed Critical Matregen Corp.
Publication of WO2006122414A1 publication Critical patent/WO2006122414A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules, nanotubes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Abstract

An implantable device for sustained and controlled delivery of methotrexate in treating cancer, severe psoriasis and rheumatoid arthritis, and a method for producing a hydrogel casing using centrifugal forces are disclosed. Said device with a variety of hollow structures and morphologies was produced with a rotational spinning technique using an aminated glass tube as the mold.

Description

DEPOT FOR SUSTAINED AND CONTROLLED DELIVERY OF

METHOTREXATE

FIELD OF INVENTION

This invention relates to depots or encapsulation techniques suitable for implanting into a living host for sustained and controlled delivery of methotrexate.

BACKGROUND OF THE INVENTION

Methotrexate is a widely used antimetabolite for the treatment of cancer, including breast cancer, cancers of the head and neck, lung cancer, and non-Hodgkin's lymphomas. It is also indicated in the control of severe psoriasis, and in the management of rheumatoid arthritis.

Taken orally or directly injected, methotrexate is known for its potential to cause severe toxic side-effects. For example, methotrexate has been reported to cause fetal death and/or congenital anomalies and is therefore not recommended for women of childbearing potential. Unexpectedly severe and sometimes fatal bone marrow suppression and gastrointestinal toxicity have been reported with concomitant administration of methotrexate along with some nonsteroidal anti-inflammatory drugs. Furthermore, methotrexate can cause hepatotoxicity, fibrosis and cirrhosis after prolonged use. Methotrexate- induced lung disease is a potentially dangerous lesion, which may occur acutely during therapy and which has been reported at doses as low as 7.5 mg/week. Other side-effects include diarrhea and ulcerative stomatitis which may lead to hemorrhagic enteritis and death from intestinal perforation if the therapy is not interrupted. Severe, occasionally fatal, skin reactions have also been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Potentially fatal opportunistic infections may also occur with methotrexate therapy. Finally, methotrexate given concomitantly with radiotherapy may increase the risk of tissue necrosis. Unfortunately, because of its potential to cause serious toxic reactions including death, methotrexate use is largely limited to life threatening cancer diseases or severe psiorasis and rheumatoid arthritis. In addition, patients have to be monitored very closely for bone marrow, liver, lung and kidney toxicities.

Also due to the side-effects, toxicity and refractory issues, 20-30% of patients discontinue methotrexate within the first year, and approximately 50% of patients within 3 years. This despite the fact that methotrexate is a proven, effective treatment. Providing a safe, convenient delivery alternative for methotrexate in a manner that increases patient compliance, clinical efficacy, lowers refractory incidence and obviates side-effects and tolerability concerns would be a significant advantage to patients and physicians.

Toxicity of a drug can generally be related to dose or frequency of its administration. Typical administration routes for methotrexate, oral and direct injection, cause burst effects with plasma levels reaching the Maximum Tolerable Dosage, which in turn cause toxicity, side-effects, and ultimately lower efficacy as patients become refractory.

Metronomic drug delivery is a much lower but still efficacious concentration delivered continuously. Impacts of toxicity, efficacy, and resistance can be significantly lessened if one is able to deliver lower concentrations achieving nearly constant plasma concentrations in the therapeutic window well below toxic concentrations.

Drug delivery systems have emerged as technology for controlled and sustained release of drugs in a metronomic manner to limit dose-related efficacy/toxicity issues of drugs taken orally or by direct injections. First generation injectable polymeric drug depots based on microparticles or injectable gels have significant draw-backs such as low drug loading capacity and significant burst release with the potential of overdose. Implantable depots, on the other hand, allow for rapid rise to optimal release concentration without burst effect, a steady concentration of therapeutic agent, and due to the cumulative low metronomic concentrations released, could offer equal efficacy whilst lowering the experience and severity of side-effects related to oral or direct injection usage.

Methotrexate is frequently considered to have a very low aqueous solubility. Thus for example, US patent 6,001 ,386 to Ashton et al. teaches a non-release rate limiting, implantable drug delivery device with an inner core comprising the active agent. The technology is taught to only work with active agents with very low solubility (for example, less than 10 μg/ml), due to the non-release rate limiting nature of the delivery device. Included among a long list of hypothetical possible active agents is methotrexate. The polymeric casing of Ashton is designed to be permeable to the agent without being release rate limiting. Thus, though the prior art teaches the use of methotrexate in an implantable drug delivery device, the methods by which it is taught will not work to provide a controlled and sustained release of the drug over a long period of time.

The solubility of methotrexate is an area of considerable disagreement in the scientific literature. For example, it is reported elsewhere that methotrexate is in fact a highly water-soluble drug (Wallace et al., Can J Pharm Sci 1978; 13:66; Fort et al., lnt J Pharm 1990;59:271 ), suggesting that the prior art teaching of a delivery vehicle such as that described in '386 which has no rate-limiting properties would inevitably result in a fast release of high doses of methotrexate with the potential of toxic concentrations.

Hydrogel-based tubes to be used as drug delivery matrices have been described in the international patent publication WO 2004/071736 to Dalton et al. However, these drug delivery vehicles allow for fast penetration of water into the drug-containing core leading to fast dissolution and release of highly water-soluble, low-molecular weight drugs. Incorporation of methotrexate in hydrogel tubes such as those described by Dalton et al. would also result in a fast dissolution and release of high doses of methotrexate associated with potential of toxic concetrations. Thus the teachings of Dalton et al. would not work to provide a controlled and sustained release of the drug over a long period of time. In addition, the teachings of Dalton et al. would not be applied to methotrexate, since teachings in the art such as Ashton suggest methotrexate would be better suited for a non-rate release limiting capsule.

By considering the limitations of the aforementioned methods it would be advantageous to manufacture depots or coatings which would allow for controlled and sustained delivery of highly water-soluble drugs such as methotrexate in non-toxic concentrations.

SUMMARY OF INVENTION

According to one aspect of the invention is a methotrexate compound comprising a hydrogel casing, methotrexate contained within said hydrogel casing, wherein the hydrogel casing limits the rate of dissolution of methotrexate through said casing.

According to a further aspect of the invention, the methotrexate compound further comprises a polymer coating between said hydrogel casing and said methotrexate.

According to a further aspect of the invention is the methotrexate compound wherein the hydrogel casing is prepared from a monomer selected from the group consisting of acrylates, methacrylates and derivatives there of such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2- polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate; acrylamides and derivatives thereof including methacrylamide, hydroxypropyl methacrylamide, N,N-diethyl acrylamide, N, N -dimethyl acrylamide, 2-chloroethyl acrylamide, 2- nitrobutyl acrylamide; N-yinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoide, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl- ethylene, chlorotrifluoroethylene, dichloroethylene, tetrachloro-ethylene; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate; itaconate and derivatives therof; itaconamide and derivatives thereof; diethyl maleate, 2-

(acryloyloxy)ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.

A further aspect of the invention is the methotrexate compound wherein the hydrogel is comprised of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate).

A further aspect of the invention is the methotrexate compound wherein the polymer coating comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharide, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex-GMA, dex-

HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.

A further aspect of the invention is the methotrexate compound wherein the polymer coating comprises poly(caprolactone).

A further aspect of the invention is the methotrexate compound wherein the polymer coating comprises 1 % poly(caprolactone).

A further aspect of the invention is the methotrexate compound wherein the methotrexate compound provides sustained release of methotrexate for over 30 days.

A further aspect of the invention is the methotrexate compound wherein the methotrexate compound provides about linear release of methotrexate for over 30 days.

A further aspect of the invention is the methotrexate compound wherein the methotrexate compound provides about the same amount of methotrexate released at day 3 and at day 30. A further aspect of the invention is the methotrexate compound wherein the methotrexate compound provides continuous release of methotrexate for over 30 days.

A further aspect of the invention is the methotrexate compound wherein the methotrexate compound provides continuous release of methotrexate for over 42 days.

A further aspect of the invention is the methotrexate compound wherein the methotrexate compound provides continuous release of methotrexate for over 100 days.

A further aspect of the invention is a depot suitable for implanting into a living host for delivery of at least one substance, comprising a casing capable of containing said substance, said casing being formed by a method comprising: a) filling an interior of a mold with a mixture, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) depositing at least one of the phases onto an inner surface of the mold by rotating said mold; c) forming said casing by stabilizing said at least one of the phases deposited onto the inner surface of the mold; and d) removing said casing from said mold; wherein said depot is capable, when filled with methotrexate, of limiting the rate of dissolution of methotrexate.

A further aspect of the invention is the depot wherein at least one of said components is selected from monomers selected from the group consisting of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2- hydroxyethyl methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate; acrylamides and derivatives thereof including methacrylamide, hydroxypropyl methacrylamide, N,N-diethyl acrylamide, N1N- dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide; N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride, allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro- ethylene, dichloroethylene, tetrachloro-ethylene; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleate, 2-(acryloyloxy)ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.

A further aspect of the invention is the depot wherein at least one of said components is selected from polymers selected from the group consisting of polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharide, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex-GMA, dex- HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.

A further aspect of the invention is the depot wherein at least one of said components is selected from solvents selected from the group consisting of water, alcohols, ethylene glycol, ethanol, acetone, poly(ethylene glycol) and derivatives thereof; solutions of poly(ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof; acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2-chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, di(ethylene glycol), di(ethylene glycol) monomethyl ether, 1 ,4 dioxane, N1N, dimethyl acetamide, N1N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane, hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyridene, tetrahydrofuran, toluene, trichloroethylene, o-xylene and p-xylene, a monomer, a macromer, a liquid crosslinking agent, or mixtures thereof.

A further aspect of the invention is the depot wherein said casing has a cylindrical hollow shape, a top end, and a bottom end.

A further aspect of the invention is the depot wherein the method of forming of the depot further comprises plugging the top end and the bottom end after removing the casing from the mold.

A further aspect of the invention is the depot wherein the substance is added to the casing prior to plugging at least one of the top end and the bottom end. A further aspect of the invention is the depot wherein the casing is a hydrogel.

A further aspect of the invention is the depot wherein the casing is porous.

A further aspect of the invention is the depot having a pore size between 0.001 μm and 100 μm.

A further aspect of the invention is the depot wherein the substance is methotrexate.

A further aspect of the invention is the depot wherein the casing is impregnated with a polymer before the substance is added.

A further aspect of the invention is the depot wherein the casing is coated with a polymer before the substance is added.

A further aspect of the invention is the use of the depot to prepare a drug delivery product, wherein the substance is a phamaceutical compound.

A further aspect of the invention is the use of the depot wherein the pharmaceutical compound is methotrexate.

A further aspect of the invention is the use of the drug delivery product to treat a disease or disorder selected from the group consisting of cancer, psiorasis, and rheumatoid arthritis.

A further aspect of the invention is a process of producing a product, comprising: a) filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the mold comprises an aminated glass tube.

A further aspect of the invention is the process including removing said product from said mold.

A further aspect of the invention is the process wherein of said at least two components, at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least the monomer or macromer, and wherein the step of stabilizing said deposited phase includes gelation of the monomer or macromer by polymerization thereof.

A further aspect of the invention is the process wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators.

A further aspect of the invention is the process wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof. A further aspect of the invention is the process wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein said hollow mold is a cylindrical tube so that said product is a polymeric tube.

A further aspect of the invention is the process wherein said cylindrical tube includes pre-selected surface features on said inner surface of the cylindrical tube.

A further aspect of the invention is the process including inserting a porous structure into said mold prior to filling said mold with said mixture, and wherein said product is coated on an outer surface of said porous structure.

A further aspect of the invention is the process wherein said mixture includes a cross-linking agent.

A further aspect of the invention is the process wherein the crosslinking agent is selected from the group consisting of multifunctional ester, carbonate, multi- isocyanate, methacrylate or poly-N-isopropyl acrylamide or acrylate, acrylamide or methacrylamide and preferably one of ethylene glycol di methacrylate (EDMA), hexamethylene dimethacrylate (HDMA), poly (ethylene glycol) dimethacrylate, 1 ,5-hexadiene-3, 4-diol (DVG), 2, 3- dihydroxybutanediol 1 , 4-dimethacrylate (BHDMA), 1 , 4-butanediol dimethacrylate (BDMA), 1 ,5- hexadiene (HD) multi-functional star polymers of poly (ethylene oxide), bifunctional peptides, oligopeptidic crosslinkers, proteins and protein fragments, including enzyme degradable crosslinking agents, hydrolysable crosslinking agent, oligopeptidic crosslinking agents, nitrenes and exposure to light.

A further aspect of the invention is the process wherein said monomer is selected from the group consisting of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate ; acrylamides and derivatives thereof includingmethacrylamide, hydroxypropyl methacrylamide, N, N-diethyl acrylamide, N, N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide ; N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride, allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro- ethylene, dichloroethylene, tetrachloro-ethylene ; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate ; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleat, 2- (acryloyloxy) ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.

A further aspect of the invention is the process wherein said solvent is selected from the group consisting of a neucleophilic, electrophilic or amphiphilic molecule selected from the group of water, alcohols, ethylene glycol, ethanol, acetone, poly (ethylene glycol) and derivatives thereof; solutions of poly (ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof; acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2- chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, di (ethylene glycol), di (ethylene glycol) monomethyl ether, 1 ,4 dioxane, N, N, dimethyl acetamide, N, N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane,hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyridene, tetrahydrofuran, toluene, trichloroethylene, o-xylene and p-xylene, a monomer, a macromer, a liquid crosslinking agent, or mixtures thereof.

A further aspect of the invention is the process wherein said solvent solubilizes said monomer or macromer but not a polymer or crosslinked polymer formed from said monomer or macromer.

A further aspect of the invention is the process wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 75% by weight.

A further aspect of the invention is the process wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 60% by weight.

A further aspect of the invention is the process wherein said polymer is selected from the group consisting of polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly (methyl methacrylate), poly (ethoxyethyl methacrylate), poly (hydroxyethylmethacrylate) , poly (vinyl acetate) s polyacetates, polyesters, polyamides, polycarbonates, polyanhydπdes, polyamino acids including poly (N-vinyl pyrrohdinone), poly (vinyl actetate), poly (vinyl alcohol), poly (hydroxypropyl methacrylamide), poly (caprolactone), poly (dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly (trimethylene carbonate) s, poly (butadiene), polystyrene, polyacrylonitπle, poly (chloroprene), neoprene, poly (isobutene), poly (isoprene), polypropylene, polytetrafluoroethylene, poly(vιnylιdene fluoride), poly (chlorotπfluoroethylene), poly (vinyl chloride), poly (oxymethylene), poly (ethylene terephthalate), poly (oxyethylene) poly (oxyterephthaloyl), polyamides such as but not limited to, poly [ιmιno(1- oxohexamethylene)], poly (iminoadipoyl-iminohexamethalene), poly (iminohexamethylene-iminosebacoyl), poly [ιmιno(i-oxododecamethylene)], cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharides, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex- lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof, chitin, and mixtures thereof, starch, starch derivatives, cellulose and derivatives

A further aspect of the invention is the process including physically or chemically modifying the inner surface of the mold upon which pre-selected morphologies are induced into the wall of the said product by inducing beading or spreading of the separated liquid phase

A further aspect of the invention is the process with molecules including silanating agents A further aspect of the invention is the process including the step of removing the solvent and including repeating steps a) b) and c), at least once to produce a multi-layered product.

A further aspect of the invention is the process including the step of removing the solvent and including repeating steps a), b) and c), and wherein said mixture includes particles in step a) to produce a multi-layered product with constituents embedded in the wall of the product, and wherein the constituents include one or a combination of cells, proteins, peptides, enzymes, genes, vectors, growth factors, hormones, nucleotides, therapeutics, drugs and carbohydrates.

A further aspect of the invention is the process wherein said constituents are embedded directly in the wall of the product.

A further aspect of the invention is the process wherein said constituents are embedded in microspheres or nanoparticles which are embedded in the wall of the product.

A further aspect of the invention is the process wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to increase adherence of the product deposited thereon during rotation.

A further aspect of the invention is the process wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to prevent adherence of the product deposited thereon during rotation.

A further aspect of the invention is a process of producing a product, comprising: a) inserting an securing a structure of pre-selected size and shape into an interior of a mold and filling the remaining interior of the mold with a mixture so that substantially all gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing the structure and the mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an outer surface of the structure; and c) forming the product by stabilizing the at least one of the phases deposited onto the inner surface of the mold; wherein the mold comprises an aminated glass tube.

A further aspect of the invention is the process wherein the mixture includes a solution of chitosan in aqueous acetic acid diluted with an equal volume of ethanol and mixed with a twofold molar excess of acetic anhydride, and wherein the product is chitin formed by phase separation using gelation and syneresis and deposited on the outside of the structure of pre-selected size and shape.

A further aspect of the invention is the process wherein the solution of chitosan is 3% solution of chitosan in 2% aqueous acetic acid, and wherein the structure of pre-selected size and shape is removed from the mold and, including one of leaving the chitin product from the structure of pre-selected size and shape, removing the chitin product from the structure of pre-selected size and shape, and drying the chitin product by storage in air prior to the removal from the structure of pre-selected size and shape.

A further aspect of the invention is a product produced by a method comprising the steps of: filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the mold comprises an aminated glass tube.

A further aspect of the invention is the product including removing said product from said mold.

A further aspect of the invention is the product wherein said hollow mold is a cylindrical tube so that said product is a tube.

A further aspect of the invention is the product wherein of said at least two components at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least one of the monomer and macromer, and wherein the step of stabilizing said deposited phase includes gelation of the at least one of the monomer and macromer by polymerization thereof.

A further aspect of the invention is the product wherein said phase separation agent is selected from the group consisting of solution immiscibility, polymer immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure. A further aspect of the invention is the product wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to a lumenal side, resulting in spotting on an outer wall surface.

A further aspect of the invention is the product wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof.

A further aspect of the invention is the product wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to alumenal side, resulting in spotting on an outer wall surface.

A further aspect of the invention is the product wherein said product is a multilayered product produced by repeating steps a), b) and c), at least once to produce a multi-layered product.

A further aspect of the invention is the product wherein the wall structure is used as a reservoir for the delivery of drugs, therapeutics, cells, cell products, genes, viral vectors, proteins, peptides, hormones, carbohydrates, growth factors, enzymes.

A further aspect of the invention is the product wherein the wall structure is used as a reservoir for the delivery of drugs, therapeutics, cells, cell products, genes, viral vectors, proteins, peptides, hormones, carbohydrates, growth factors, enzymes.

A further aspect of the invention is the product wherein the solution contains particles containing pre-selected constituents, and wherein the product includes said particles are distributed either uniformly or in a gradient within the wall structure of the product.

A further aspect of the invention is the product wherein the particles are microspheres or nanospheres and said pre-selected constituents include enzymes, proteins, peptides, genes, vectors, growth factors, hormones, nucleotides, carbohydrates, drugs, therapeutics, or cells.

A further aspect of the invention is the product wherein the cells include neurons, stem cells, stem cell derived cells, olfactory ensheathing cells, Schwann cells, astrocyte cells, microglia cells, or oligodendrocyte cells, endothelial cells, epithelial cells, fibroblasts, keratinocytes, smooth muscle cells, hepatocytes, bone marrow-derived cells, hematopoetic cells, glial cells, inflammatory cells, and immune system cells.

A further aspect of the invention is the product wherein the particles are microspheres or nanospheres and said pre-selected constituents include enzymes, proteins, peptides, genes, vectors, growth factors, hormones, oligonucleotides, or cells.

A further aspect of the invention is the product wherein the cells include neurons, stem cells, stem cell derived cells, olfactory ensheathing cells,

Schwann cells, astrocyte cells, microglia cells, or oligodendrocyte cells, endothelial cells, epithelial cells, fibroblasts, keratinocytes, smooth muscle cells, hepatocytes, bone marrow-derived cells, hematopoetic cells, glial cells, inflammatory cells, and immune system cells.

A further aspect of the invention is the product wherein the particles are degradable particles thereby releasing said constituents over time.

A further aspect of the invention is the process including a step of inserting an object into the mold to be coated with wherein said object is coated with said at least one of the phases which is stabilized on said object.

A further aspect of the invention is the process wherein the object is selected from the group consisting of meshes, scaffolds, stents, coils, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for abdominal aortic aneurysms and esophageal scaffolds and fibers that occupy a periphery of the mold.

A further aspect of the invention is the product wherein the process includes a step of inserting an object into the mold to be coated with wherein said product includes said object being coated with said at least one of the phases and which is stabilized on said object. A further aspect of the invention is the process wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product produced as described above, for use as a coronary artery bypass graft, vascular graft, artificial fallopian tubes, a drainage implant for glaucoma, a drainage implant for the lacrymal duct, artificial tissues such as intestines, ligaments, tendons, nerve guidance channels, ureter and urethra replacements, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for aortic aneurysms, esophageal scaffolds, composite catheters, shunts, delivery matrices, coatings applied to pacemaker leads, implantable sensor wire leads, wires forinterventional cardiology, and biosensors.

A further aspect of the invention is a process of producing a product, comprising: a) partially filling an interior of a mold with a mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the mold comprises an aminated glass tube.

A further aspect of the invention is the process wherein the mixture is a solution comprising at least one polymer which is biodegradable and selected from the group of polysaccharides ; polyesters, polycarbonates, polyesterethers, polyesterurethanes, polyanhydrides, polypeptides, proteins and derivatives thereof.

A further aspect of the invention is the process wherein said cylindrical tube is filled with more than one distinct monomer/macromer formulation in a sequential manner so as to create a polymer tube product comprised of graded wall composition.

A further aspect of the invention is the process wherein said distinct monomer/macromer formulations are introduced into the cylindrical hollow mold in a graded manner using a commercially available gradient-making apparatus, syringe pumps, or custom controlled liquid delivery apparatus.

A further aspect of the invention is the process of producing a product, comprising: a) filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.

A further aspect of the invention is the process including removing said product from said mold

A further aspect of the invention is the process wherein of said at least two components, at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least the monomer or macromer, and wherein the step of stabilizing said deposited phase includes gelation of the monomer or macromer by polymerization thereof

A further aspect of the invention is the process wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields

A further aspect of the invention is the process wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators

A further aspect of the invention is the process wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof

A further aspect of the invention is the process wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein said hollow mold is a cylindrical tube so that said product is a polymeric tube.

A further aspect of the invention is the process wherein said cylindrical tube includes pre-selected surface features on said inner surface of the cylindrical tube.

A further aspect of the invention is the process including inserting a porous structure into said mold prior to filling said mold with said mixture, and wherein said product is coated on an outer surface of said porous structure.

A further aspect of the invention is the process wherein said mixture includes a cross-linking agent.

A further aspect of the invention is the process wherein the crosslinking agent is selected from the group consisting of multifunctional ester, carbonate, multi- isocyanate, methacrylate or poly-N-isopropyl acrylamide or acrylate, acrylamide or methacrylamide and preferably one of ethylene glycol dimethacrylate (EDMA), hexamethylene dimethacrylate (HDMA), poly (ethylene glycol) dimethacrylate, 1 ,5-hexadiene-3, 4-diol (DVG), 2, 3- dihydroxybutanediol 1 , 4-dimethacrylate (BHDMA), 1 , 4-butanediol dimethacrylate (BDMA), 1 ,5- hexadiene (HD) multi-functional star polymers of poly (ethylene oxide), bifunctional peptides, oligopeptidic crosslinkers, proteins and protein fragments, including enzyme degradable crosslinking agents, hydrolysable crosslinking agent, oligopeptidic crosslinking agents, nitrenes and exposure to light.

A further aspect of the invention is the process wherein said monomer is selected from the group consisting of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate ; acrylamides and derivatives thereof includingmethacrylamide, hydroxypropyl methacrylamide, N, N-diethyl acrylamide, N, N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide ; N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride, allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro- ethylene, dichloroethylene, tetrachloro-ethylene ; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate ; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleat, 2- (acryloyloxy) ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.

A further aspect of the invention is the process wherein said solvent is selected from the group consisting of a neucleophilic, electrophilic or amphiphilic molecule selected from the group of water, alcohols, ethylene glycol, ethanol, acetone, poly (ethylene glycol) and derivatives thereof; solutions of poly (ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof; acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2- chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, di (ethylene glycol), di (ethylene glycol) monomethyl ether, 1 ,4 dioxane, N, N, dimethyl acetamide, N, N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane,hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyridene, tetrahydrofuran, toluene, trichloroethylene.o-xylene and p-xylene, a monomer, a macromer, a liquid crosslinking agent, or mixtures thereof.

A further aspect of the invention is the process wherein said solvent solubilizes said monomer or macromer but not a polymer or crosslinked polymer formed from said monomer or macromer.

A further aspect of the invention is the process wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 75% by weight.

A further aspect of the invention is the process wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 60% by weight.

A further aspect of the invention is the process wherein said polymer is selected from the group consisting of polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly (methyl methacrylate), poly (ethoxyethyl methacrylate), poly (hydroxyethylmethacrylate) ; poly (vinyl acetate) s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly (N-vinyl pyrrolidinone), poly (vinyl actetate), poly (vinyl alcohol), poly (hydroxypropyl methacrylamide), poly (caprolactone), poly (dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly (trimethylene carbonate) s, poly (butadiene), polystyrene, polyacrylonitrile, poly (chloroprene), neoprene, poly (isobutene), poly (isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly (chlorotrifluoroethylene), poly (vinyl chloride), poly (oxymethylene), poly (ethylene terephthalate), poly (oxyethylene) poly (oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharides, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran- acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.

A further aspect of the invention is the process including physically or chemically modifying the inner surface of the mold upon which pre-selected morphologies are induced into the wall of the said product by inducing beading or spreading of the separated liquid phase.

A further aspect of the invention is the process with molecules including silanating agents.

A further aspect of the invention is the process including the step of removing the solvent and including repeating steps a) b) and c), at least once to produce a multi-layered product.

A further aspect of the invention is the process including the step of removing the solvent and including repeating steps a), b) and c), and wherein said mixture includes particles in step a) to produce a multi-layered product with constituents embedded in the wall of the product, and wherein the constituents include one or a combination of cells, proteins, peptides, enzymes, genes, vectors, growth factors, hormones, nucleotides, therapeutics, drugs and carbohydrates.

A further aspect of the invention is the process wherein said constituents are embedded directly in the wall of the product.

A further aspect of the invention is the process wherein said constituents are embedded in microspheres or nanoparticles which are embedded in the wall of the product.

A further aspect of the invention is the process wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to increase adherence of the product deposited thereon during rotation.

A further aspect of the invention is the process wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to prevent adherence of the product deposited thereon during rotation.

A further aspect of the invention is a process of producing a product, comprising: a) inserting and securing a structure of pre-selected size and shape into an interior of a mold and filling the remaining interior of the mold with a mixture so that substantially all gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing the structure and the mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an outer surface of the structure; and c) forming the product by stabilizing the at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.

A further aspect of the invention is the process wherein the mixture includes a solution of chitosan in aqueous acetic acid diluted with an equal volume of ethanol and mixed with a twofold molar excess of acetic anhydride, and wherein the product is chitin formed by phase separation using gelation and syneresis and deposited on the outside of the structure of pre-selected size and shape.

A further aspect of the invention is the process wherein the solution of chitosan is 3% solution of chitosan in 2% aqueous acetic acid, and wherein the structure of pre-selected size and shape is removed from the mold and, including one of leaving the chitin product from the structure of pre-selected size and shape, removing the chitin product from the structure of pre-selected size and shape, and drying the chitin product by storage in air prior to the removal from the structure of pre-selected size and shape.

A further aspect of the invention is the product produced by a method comprising the steps of: filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.

A further aspect of the invention is the product including removing said product from said mold.

A further aspect of the invention is the product wherein said hollow mold is a cylindrical tube so that said product is a tube.

A further aspect of the invention is the product wherein of said at least two components at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least one of the monomer and macromer, and wherein the step of stabilizing said deposited phase includes gelation of the at least one of the monomer and macromer by polymerization thereof.

A further aspect of the invention is the product wherein said phase separation agent is selected from the group consisting of solution immiscibility, polymer immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to a lumenal side, resulting in spotting on an outer wall surface. A further aspect of the invention is the product wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof.

A further aspect of the invention is the product wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.

A further aspect of the invention is the product wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to alumenal side, resulting in spotting on an outer wall surface.

A further aspect of the invention is the product wherein said product is a multilayered product produced by repeating steps a), b) and c), at least once to produce a multi-layered product. A further aspect of the invention is the product wherein the wall structure is used as the reservoir for the delivery of the methotrexate.

A further aspect of the invention is the product wherein the wall structure is used as the reservoir for the delivery of the methotrexate.

A further aspect of the invention is the product wherein the solution contains particles containing pre-selected constituents, and wherein the product includes said particles are distributed either uniformly or in a gradient within the wall structure of the product.

A further aspect of the invention is the process including a step of inserting an object into the mold to be coated with wherein said object is coated with said at least one of the phases which is stabilized on said object.

A further aspect of the invention is the process wherein the object is selected from the group consisting of meshes, scaffolds, stents, coils, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for abdominal aortic aneurysms and esophageal scaffolds and fibers that occupy a periphery of the mold.

A further aspect of the invention is the product wherein the process includes a step of inserting an object into the mold to be coated with wherein said product includes said object being coated with said at least one of the phases and which is stabilized on said object.

A further aspect of the invention is the process wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the process wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.

A further aspect of the invention is the product for use as a coronary artery bypass graft, vascular graft, artificial fallopian tubes, a drainage implant for glaucoma, a drainage implant for the lacrymal duct, artificial tissues such as intestines, ligaments, tendons, nerve guidance channels, ureter and urethra replacements, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for aortic aneurysms, esophageal scaffolds, composite catheters, shunts, delivery matrices, coatings applied to pacemaker leads, implantable sensor wire leads, wires for interventional cardiology, and biosensors.

A further aspect of the invention is a process of producing a product, comprising: a) partially filling an interior of a mold with a mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold;wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.

A further aspect of the invention is the process wherein the mixture is a solution comprising at least one polymer which is biodegradable and selected from the group of polysaccharides ; polyesters, polycarbonates, polyesterethers, polyesterurethanes, polyanhydrides, polypeptides, proteins and derivatives thereof.

A further aspect of the invention is the process wherein said cylindrical tube is filled with more than one distinct monomer/macromer formulation in a sequential manner so as to create a polymer tube product comprised of graded wall composition.

A further aspect of the invention is the process wherein said distinct monomer/macromer formulations are introduced into the cylindrical hollow mold in a graded manner using a commercially available gradient-making apparatus, syringe pumps, or custom controlled liquid delivery apparatus.

A further aspect of the invention is the depot wherein the impregnated polymer comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl meth aery late), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharids, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran- acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.

A further aspect of the invention is the depot wherein the coated polymer comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethyl methacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), polyfcaprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharids, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran- acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.

A further aspect of the invention is the compound further comprising a stabilizer.

A further aspect of the invention is the compound wherein the stabilizer is polycaprolactone fibers. BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows the release profile of methotrexate in an extended release depot formulation according to one embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that the teachings of Dalton et al.

(WO 2004/071736, which is incorporated herein in its entirety) could be altered for use in delivering methotrexate in a sustained release, controlled, implantable, manner which provides a lowering of the side effects of the drug.

The drug depots produced according to the present invention may be used for a variety of applications including but not limited to the treatment of cancer, psiorasis, and rheumatoid arthritis.

Briefly, Dalton et al. generated coatings and tubular structures utilizing the inertial forces associated with rotating a mold. A mold was filled with a mixture containing at least two liquid phase components (that are to be phase separated to produce the final product) thereby displacing substantially all of the visible gas bubbles (for example air) inside the mold. The mold was then rotated at some pre-determined speed, for example by being inserted into a rotating device, such as a drill chuck or lathe. The process of completely filling the interior of the mold with the liquid mixture was used to ensure that all visible gas bubbles were removed from the mold. However, it was taught in Dalton et al that small or minute amounts of dissolved gases may still be present in the liquid mixture, and that these minute amounts of gas may be desirable in producing certain types of structures.

Dalton et al. taught that the separation process could begin immediately upon producing the mixture with separation continuing during rotation of the mold, or initiated after the mixture was formed by exposing the mixture to a phase separation agent when desired. Phase separation could be completed prior to rotation or could be going on while the mold is rotating.

Dalton et al. taught that the rotation of the mold would send one phase to the inner surface of the mold, which would adopt the shape of the inner surface of the mold and then be stabilized to produce the product, and that, generally, the method of stabilization will depend on the nature of the material in the separated phase. The separated phase should be stabilized at the surface of the mold and generally the method of stabilization would depend on the nature of the material in the separated phase.

Dalton et al. also taught that the phase which is driven out to the inner surface of the mold would not necessarily adhere to the surface and in fact adherence was generally undesirable, and that it might be desirable to treat the inner surface of the mold to preferentially avoid adherence if the phase being separated is typically prone to forming an adhering layer. The materials from which the mold is produced could also be selected to minimize adherence depending on the material of the separated phase.

Dalton et al. taught that, when the products are polymeric, the components of the solution may contain monomers, macromers or polymers or any combination of two or three of these components. The phase separation process may result from changes in solubility as induced by changes in polymer chain length, changes in temperature, newly formed chemical reactants, changes in pH, exposure to light (UV, visible, IR, laser), introduction of immiscible liquids, polymer-polymer immiscibility in aqueous solutions, electric or magnetic fields. The greater density of one of the phase- separated phases resulted in that particular phase adopting the shape of the inner surface of the mold, and that it would be understood that the phase separation process may start upon mixture of the liquid components or upon filling the mold with the mixture and the phase separation process may continue during rotation of the mold or it may be complete prior to rotation of the mold.

In addition, Dalton et al. taught that gelation of the separated phase may be used to fix or stabilize the morphology of the formed product and the solvent phase remains in the center of the mold. Depending on the material, gelation could be achieved using a number of methods, including but not restricted to, continued polymerization in the separated phase (where the deposited phase comprose monomers), cooling or heating of the mold, creation of a chemical reaction product within the mold, changing the pH of the phase-separated mixture and shining a certain frequency or frequencies of light at the phase-separated mixture. By controlling rotational speed, formulation chemistry, surface chemistry and dimensions of the mold, the morphology, mechanical and porosity properties of the resulting product can be manipulated.

Dalton et al. also taught that other methods of stabilizing the denser phase may include more broadly polymerization (of which gelation is but one example), changes in temperature (either increase or decrease depending on the composition of the denser phase), light, change in pH, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, as well as electric and/or magnetic fields.

Dalton et al. taught the manufacture of hollow structures made using the invention and synthesized in custom-built disposable molds. The mold taught could be a glass tubing with an inside diameter between 0.01 and 100 mm, cut to desired length in the order of tens of centimeters. A rubber septum was slipped over each end of the glass tube to serve as an injection port, and the tube was filled, using a needle pushed through the upper injection port to permit the exit of gas during liquid injection. The desired mixture was injected via the needle through the septum at the lower end of the mold, displacing all of the visible gas within the mold. The needles were withdrawed, resulting in a sealed, liquid filled mold. For concentricity and a uniform hollow structure along the length, the sealed mold was placed into the chuck of a drill that had been mounted horizontally using a spirit level. The mold was then spun at various rotation speeds, using a variety of different spinning techniques. There was a process of phase separation during the rotation of the mold, allowing the separation where the dense phase is essentially centrifuged to the periphery of the mold where it adopts the shape of the mold. Phase separation may result in either liquid-liquid or viscoelastic solid-liquid interfaces within the mold, while the mold is static or rotating.

Phase separation could be induced using a range of different techniques and environmental changes. The addition of a propagating radical to a monomer solution could induce phase separation, as could changes in temperature, pH, exposure of the mold to light, introduction of immiscible liquids, electric and magnetic fields.

Dalton et al. taught that one or more of the phases would be forced to the periphery if the densities of the phases were different. The phase separated particles then gelled together, through covalent or physical bonding, to form a three-dimensional network between the separated phases.

The gelation of particles could commence at a finite time after the onset of phase separation within the process of the invention.

Dalton et al also taught that a porous material can have an outer coating applied to it using this technology. Prior to the injection of a mixture into the mold, a plug of porous material could be inserted into the mold. After insertion of the porous structure into the mold, a mixture could be injected into the mold and rotated at a desired speed. The phase separated phase was centrifuged through the pores of the inserted plug, forming a structure on the outer surface of the porous plug, therefore sealing the material without blocking the internal pores. A porous material could also be a hollow structure, and the polymeric material could coat the hollow structure. In another embodiment taught by Dalton et al., hollow structures could be manufactured by inserting a structure into a mold, and filling the remaining interior of the mold completely with a solution comprising at least two components which can be phase separated by a phase separation agent into a last two phases. Under rotation of said mold at least one of the phases deposits onto the surface of the core, and forms said product by tabilizing said phase deposited onto the surface of the core. By using this method, the manufacturing of hollow structures with inner dimensions defined by the outer dimensions of the inserted core structure was taught.

Dalton et al. taught that in a preferred embodiment of the invention, the mixture includes at least two or more phases, one being a monomer, macromer or polymer, and the other a solvent.

Dalton et al also taught that, for mixtures containing monomer to be initiatied, the initiation agent may be free radical initiators, thermal or UV initiators and redox initiators or ionic initiators. Examples of initiators taught included ammonium persulfate or potassium persulfate with sodium metabisulfinte, or tetramethylethylene diamine or ascorbic acid, azonitriles and derivatives thereof, alkyl peroxides and dedrivatives thereof, acyl peroxides and derivatives thereof, hydroperoxides and derivatives thereof; ketone peroxides and derivatives thereof, peresters and derivatives thereof and peroxy carbonates and derivatives thereof.

Dalton et al. also taught that the mixture could include a cross-linking agent depending on the structure of the final product that was desired and the polymer material that is formed. The crosslinking agent could be a multifunctional molecule with at least two reactive functionalities and included multi-functional methacrylates or multi-functional acrylates, multi-functional acrylamides or multi-funtional methacrylamides, or multi-functional star polymers of polyethylene glycol and preferably, but not limited to, one of ethylene glycol dimethacrylate (EDMA), hexamethylene dimethacrylate (HDMA), poly(ethylene glycol) dimethacrylate, 1 ,5-hexadiene-3,4-diol (DVG), 2,3-dihydroxybutanediol 1 ,4-dimethacrylate (BHDMA), 1 ,4-butanediol dimethacrylate (BDMA), 1 ,5-hexadiene (HD), methylene bisacrylamide (MBAm) multi-functional star polymers of poly(ethylene oxide), oligopeptidic crosslinkers, multifunctional proteins and derivatives thereof; or combinations thereof.

An exemplary, non-limiting list of monomers that could be used in the mixture included any one of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate; acrylamides and derivatives thereof such as, but not limited to, methacrylamide, hydroxypropyl methacrylamide, N,N-diethyl acrylamide, N,N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide, N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof, propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride, allylbenzene, butadiene and derivatives thereof, N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof, citraconimide and derivatives thereof, crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro- ethylene, dichloroethylene, tetrachloro-ethylene; fumarates and derivatives thereof, hexene and derivatives thereof, isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleate, 2-(acryloyloxy)ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof, maleic anhydride, maleimide, silicone polymers, and derivatives thereof; polysaccharides and derivatives thereof; carbohydrates and derivatives thereof; peptides and protein fragments and derivatives thereof; chitosan and derivatives thereof; alginate and derivatives thereof; and any combination thereof.

An exemplary, non-limiting list of polymers that could be in the mixture included any of polyacrylates, polysaccharides and derivatives thereof, such as, but not limited to glycidyl methacrylated derivatized dextran, 2- hydroxyethyl methacrylate-derivatized dextrans, dextran methacrylate, dextran acrylates, carbohydrates and derivatives thereof, polysulfone, peptide sequences, proteins, oligopeptides, collagen, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate; polyvinyl acetates polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids, such as but not limited to poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol, poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and polytrimethylene carbonates, poly(butadiene), polystyrene, polyacrylpnitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides such as but not limited to, poly[imino(1 -oxohexamethylene)], poly(iminoadipoyl-iminohexamethalene), poly(iminohexamethylene-iminosebacoyl), poly[imino(1 - oxododecamethylene)], cellulose, polysulfones, hyalonic acid, sodium hyaluronate, alginate, agarose, chitosan, chitin, and mixtures thereof.

A non-limiting list of solvents taught in Dalton et al. for the monomer and/or polymers includes any one of water, a neucleophilic or electrophilic molecule including, but not necessarily restricted to an alcohol and preferably ethylene glycol, ethanol, acetone, poly(ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof, acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2-chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, dι(ethylene glycol), dι(ethylene glycol) monomethyl ether, 1 ,4 dioxane, N1N, dimethyl acetamide, N1N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane, hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyndene, tetrahydrofuran, toluene, tπchloroethylene, o-xylene and p-xylene, or aforementioned monomers or crosslinking agents, or mixtures thereof The solvent could be chosen to solubilize the monomer but not a polymer or crosslinked polymer formed from the monomer One of the components could include a polymer dissolved in a solvent The two phase-mixture may also be an emulsion

Dalton et al also taught that an aqueous two-phase system could be formed from two water soluble polymers, the two water soluble polymers being incompatible in solution and at least one of these polymers being crosslinkable, the crosslinkable polymer phase being emulsified in the other polymer phase Crosslinking could be achieved chemically, with free radical or redox initiation, acid/base catalysis, heat, electrophilic or nucleophilic attack, or radiation An advantage of this latter crosslinking is that in one step sterile hollow structures can be obtained Further, crosslinking by UV radiation and physical crosslinking using hydrophobic tails coupled to a polymer are possible techniques This aqueous polymer immiscibility occurs with many combinations of water-soluble polymers (e g combinations of dextran, poly(ethylene glycol) (PEG), polyvinyl alcohol), poly(vιnylpyrrolιdone), gelatin, soluble starch or ficoll) The polymers stay in solution, but separate in two aqueous phases above a certain concentration After emulsification, the polymer in the dispersed phase can be crosslinked under centrifugal forces to form a tube with hydrogel character Examples of emulsion systems suitable for hollow structures included glycidyl methacrylated denvatized dextran(dex-GMA) / poly(ethylene glycol) (PEG), 2-hydroxyethyl methacrylate-deπvatized dextrans (dex-HEMA) / PEG, dex-lactate-HEMA / PEG; dex-GMA/Pluronic F68; PEG-dimethacrylate (PEG-MA2) / dextran with or without salt, such as MgSO4; PEG-MA2/ cloud point agent such as MgSO4; Gelatin/ Poly(vinylpyrrolidone); Gelatin/ dextran, among others.

Dalton et al., also taught that macromers could be used, comprising hydrophilic oligomers having biodegradable monomeric or oligomeric extensions or side chains, which biodegradable segments are terminated on the free end thereof with end cap monomers or oligomers capable of polymerization and cross linking. Macromers included, for example, modified dextran-oligopeptide-methacrylate or PEG-oligopeptides-acrylates where the peptide sequence could be recognized by enzymes, resulting in biodegradable segments.

Dalton also taught, in another embodiment, a tapered hollow structure with changing dimensions along its length can be manufactured using a holding device, which holds the sealed mold at a predetermined angle between O and 90° from the axis of rotation. The holder holds a cylindrical mold so it is rotated about an axis other than its long axis for producing tubes. Dalton et al. taught a holding device preferably made of aluminum having a stem which is held in the rotating device. A hole drilled though the holding device at an angle (theta) from the axis of rotation permits the insertion of the mold. The mold is held in place by two rubber o-rings and capped with two rubber septa. The angle and speed of rotation will result in non-uniform wall thickness dimensions along the length of the mold.

Dalton also taught a holding device with the centre of gravity not on the axis of rotation so the molds, when inserted into the holding device, could have an axis of rotation that is parallel to the axis of rotation of the rotating device. The resultant hollow structures retrieved from such molds had nonuniform wall thicknesses. Alternatively the mold could have a centre of gravity not on the axis of rotation. Dalton et al., taught controlling the viscoelastic properties of the separated phase and/or the rotation speed to create cell-invasive hollow structures. If the separated phase had substantial elastic properties, they would not coalesce, and after gelation, the porous network between the phases is large enough for the penetration of cells into the construct.

Dalton et al. also taught cylindrical hollow structures could be manufactured with walls comprising several polymers distributed as a gradient along the longitudinal axis resulting in a hollow structure with walls of graded physical and chemical properties along the longitudinal axis. Such properties included but were not limited to: diffusivity, porosity, degradation, piezoelectric conductivity, viscoelasticity and cell-invasiveness.

Dalton et al. also taught multi-layered structures can be formed by repeating the process as many times as desired. After forming the first layer, the solvent could be tipped out and another mixture injected into the mold. The first layer coating the mold, effectively became the mold for the next coating and the second formation may penetrate into the first coating, binding them together after gelation. The multi-layered hollow structures could be manufactured using any or all of the types of tubes described in the examples, made from any material, similar or different materials, in any order required, as many times as required. A layered wall structure (ie. gel-like and porous) could be made by multiple formulations and multiple rotations or in one formulation/one rotation. The layers may result in composite polymer walls comprising polymers, polymer blends of biopolymers (such as collagen, matrix molecules, glycosaminoglycans), or any type of biodegradable material, and could contain polymer beads or spheres, colloids, drugs, living cells and other mixtures concentrically arranged in the wall radius.

Dalton et al. also taught that various shaped structures could be manufactured using a mold shape that is non-symmetrical along any axis, and that composite hollow structures could be formed with another structure, such as but not limited to a mesh, scaffold, stent, coil and/or fiber(s) that occupies the periphery of the mold. Both physically and chemically crosslinked hollow structures were possible using the methods of Dalton et al. as was the manufacture of both degradable and non-degradable polymer tubes.

Dalton et al. taught that hollow structures could be manufactured that allowed molecules to diffuse across the wall structure. Also hollow structures can be produced that selectively allow the diffusion of molecules based on size and/or shape to diffuse across the wall structure and to allow preferential directional drug delivery, and hollow structures with the appropriate mechanical properties for their end use, for example to match the mechanical properties of the tissue in which they are to be implanted.

Dalton taught that the method could be used to produce hollow structures that have an outer gel phase and an inner porous phase or to provide a hollow structure with overlapping regions of porous phase/gel phase.

The method taught in Dalton et al. could be used to make hollow structures of various dimensions with internal diameters from 10μm to 100cm, to make composite hollow structures with various materials and shapes as well as thin coatings on the inner surface of other hollow structures.

Dalton et al also taught partially filling the interior of a mold with a solution comprising at least one polymer which is biodegradable and selected from (but not limited to) the group of polysaccharides, polypeptides, polyesters, polycarbonates, polyesterethers, polyesterurethanes, polyanhydrides and derivatives thereof; rotating said mold containing said solution at an effective rotational velocity so that under rotation the liquid phase deposits onto the inner surface of the mold; and forming said product by stabilizing said liquid phase deposited onto the inner surface of the mold by a phase separation agent. The stabilization of the deposited liquid phase can be achieved by its gelation (liquid-liquid phase separation) with or without subsequent removal of the solvent. The stabilization of the deposited liquid phase can also be achieved by its freezing (solid-liquid phase separation) and subsequent removal of the solvent. The solvent can be removed by freeze- drying or by replacing with a non-solvent, thereby forming a porous polymer structure.

The method taught in Dalton et al. has now been significantly improved, as follows.

Surprisingly, the present inventors discovered that the method taught in Dalton et al. could be used to deliver a substance customarily thought of as highly insoluble (methotrexate) in a sustained, controlled release. The present inventors found that, in order to control the rate of release, many modifications needed to be done to the general technique used in Dalton et al. Specifically, the present inventors found that the pore size of the hydrogel tube needed to be optimized to allow for the appropriate amount of methotrexate to dissolve through the tube. The present inventors found that pore size could be varied, in part, by preparing the mold surface. The preparation of aminated glass molds was found to be the preferred technique for optimizing pore size of the tube for methotrexate.

The present inventors have also discovered a preferred mixture of ingredients for use in the preparation of the hydrogel tubes for use in controlled and sustained delivery of methotrexate. Although the preferred embodiment of the composition of the hydrogel tube optimized for methotrexate is shown below (for example, in Example 2), it would be understood to a person skilled in the art that a variety of combinations of substances having equivalent or similar properties to the ones discussed below could be used to make hydrogel tubes that could be used for the controlled and sustained delivery of methotrexate. The present inventors also teach a method by which methotrexate can be loaded into the tubes.

The present inventors teach a manner in which the methotrexate- loaded tubes can be plugged, and a coating for the inside or impregnation of the tubes for improving the sustained controlled delivery of methotrexate. Methods of plugging tubes include sealing the ends with either permeable, semi-permeable or non-permeable materials, including but not limited to: silicones, siloxanes, epoxy resins, acrylates (including light-activated acrylates), urethanes, fast gelling hydrogels, thermal-gelling hydrogels, crosslink-able gels, physical gels, pH gels, gels of natural (i.e. collagen, alginate, agarose, chitosan, dextran, polysaccharides, polypeptides, proteins) or synthetic (polyethylene glycol, polyethylene oxide, polyurethanes, acrylate- functionalized oligomers, monomers or polymers) origin.

Methods of coating tubes includes coating mold with release agent, impregnating tube wall with polymer that is miscible in a non-solvent for the tube that allows the diffusion of the second polymer into the tube wall over a specified time, dip-coating the tube in a second polymer, spray-coating the tube in a second polymer, plasma modification of the tube wall, polymerization from the tube wall by: plasma, radical/anionic/cationic/ring-opening polymerization. Polymers used for coating or impregnation comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides such as but not limited to, poly[imino(1- oxohexamethylene)], poly(iminoadipoyl-iminohexamethalene), poly(iminohexamethylene-iminosebacoyl), poly[imino(1 - oxododecamethylene)], cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharide, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran- acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.

Example 1

This example shows the preparation of aminated glass molds for use in the preparation of the hydrogel tubes according to an aspect of the present invention.

Aminated glass molds were prepared by first immersing glass molds for 15 min in a solution containing nine parts of concentrated sulfuric acid and one part of 30% (w/w) hydrogen peroxide in water, rinsing with water, and air- drying. Thus activated glass molds were immersed for 10 min in a solution of 2% (w/w) N-(2-aminoethyl)-3-aminopropyl trimethoxysilane in 95% aqueous methanol, rinsed three times in 95% aqueous methanol, and air-dried to provide aminated glass molds.

Example 2

This example shows a method and composition suitable for preparing hydrogel tubes for controlled and sustained release of methotrexate according to an aspect of the present invention. Hydrogel tubes for controlled and sustained delivery of methotrexate were made by initiating (by addition of 0.15% (w/w) ammonium persulfate and 0.12% (w/w) sodium metabisulfite) a homogeneous mixture comprising of 33% (w/w) monomers (2-hydroxyethyl methacrylate/methyl methacrylate

86/14 (w/w), containing 0.1 % ethylene glycol dimethacrylate), 10% (w/w) ethylene glycol, and water, injecting it into a cylindrical aminated glass mold prepared using the method of Example 1 , and spinning the cylinder around its long axis. Liquid-liquid phase separation occured when the propagating polymer radical became insoluble in the water. Under centrifugal forces, the denser, phase-separated monomer/polymer phase sedimented at the periphery. Gelation of the phase-separated particles resulted in a hydrated tubular structure and water in the center of the mold. After their preparation, the tubes were removed from the glass molds, extracted in 10% aqueous ethanol for 24 hours, and air-dried.

Example 3

A tube manufactured with a methodology as described in Example 2 can be loaded with a drug as exemplified below.

100 mg of methotrexate was mixed with 10 mg of poly(caprolactone) fibers as stabilizer (1 mm length, 150 μm diameter). The mixture was transferred to the cavity (20 mm length, 1.6 mm diameter) of a custom-made manual pellet press. A metal plunger was used to compress the power into a pellet. The mold was opened and the pellet was removed. After inserting the drug pellet into the tube, silicone glue mixed with 10% (w/w) barium sulfate was injected into both ends of the tube for plugging. The resulting delivery matrix was stored for 24 hours under dry conditions at room temperature for curing of the silicone plugs. Example 4

A tube manufactured with a methodology as described in Example 2 can be loaded with a drug as exemplified below.

100 mg of methotrexate was mixed with 10 mg of poly(caprolactone) fibers as stabilizer (1 mm length, 150 μm diameter). The mixture was transferred to the cavity (20 mm length, 1.6mm diameter) of a custom-made manual pellet press. A metal plunger was used to compress the power into a pellet. The mold was opened and the pellet was removed. Subsequently, the pellet was polymer-coated by dipping into a solution of 1% poly(caprolactone) in acetone (w/v), removing and drying at room temperature. After inserting the polymer-coated drug pellet into the tube, silicone glue mixed with 10% (w/w) barium sulfate was injected into both ends of the tube for plugging. The resulting delivery matrix was stored for 24 hours under dry conditions at room temperature for curing of the silicone plugs.

Example 5

This example shows a polymer coating that improves the suitability of the tube described in the present invention for sustained controlled delivery of methotrexate.

A tube manufactured with a methodology as described in Example 2 was further modified by coating with a polymer layer prior to insertion of the drug. For this, dried tubes were treated by injecting a solution of 1 % poly(caprolactone) in acetone (w/v) into the tube lumen. After drying at room temperature, polymer-coated tubes were stored in a dry place. Example 6

This example shows a polymer impregnation that improves the suitability of the tube described in the present invention for sustained controlled delivery of methotrexate.

A tube manufactured with a methodology as described in Example 2 was further modified by impregnating with a polymer prior to insertion of the drug. For this, hydrogel tubes were stored in acetone solution for approximately 5 minutes and removed. This process was repeated another 2 times. Finally, the acetone-soaked tubes were stored in a solution of 1% poly(caprolactone) in acetone (w/v) for approximately 1 hour. After removal, polymer-impregnated tubes were dried at room temperature and stored in a dry place.

Example 7

Tubes impregnated with 1% poly(caprolactone) and filled with either methotrexate powder or methotrexate pellets provides controlled, sustained release of methotrexate.

Tubes were prepared using the method of Examples 1 and 2, and filled with either methotrexate powder, or with methotrexate pellets prepared using the method of Example 3. Tubes were also prepared using the method of Examples 1 and 2, impregnated with 1 % polyfcaprolactone) using the method of Example 6, then filled with methotrexate pellets using the method of Example 3. Alternatively, the method of Example 4 may have been used to prepare the impregnated tubes filled with methotrexate. All tubes were sealed using the method of Example 3. Tubes were subjected to in vitro release testing by incubation in phosphate bufferred solution (pH 7.4, 37°C) to determine the release profile of methotrexate from the tubes. Figure 1 exemplifies the release profile of methotrexate powder and pellets embedded in the core of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) casings, including the effect of impregnating the casing with 1 % poly(caprolactone) dissolved in acetone.

The foregoing description of the preferred embodiments of the invention have been presented to illustrate the principles of the invention and not to limit the invention to the particular embodiment illustrated. It is intended that the scope of the invention be defined by all of the embodiments encompassed within the following claims and their equivalents.

Claims

1. A methotrexate compound comprising: a hydrogel casing; methotrexate contained within said hydrogel casing; wherein the hydrogel casing limits the rate of dissolution of methotrexate through said casing.
2. The methotrexate compound of claim 1 further comprising a polymer coating between said hydrogel casing and said methotrexate.
3. The methotrexate compound of any one of claims 1 or 2 wherein the hydrogel casing is prepared from a monomer selected from the group consisting of acrylates, methacrylates and derivatives there of such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate; acrylamides and derivatives thereof including methacrylamide, hydroxypropyl methacrylamide, N,N-diethyl acrylamide, N,N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide; N-yinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoide, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoroethylene, dichloroethylene, tetrachloro-ethylene; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate; itaconate and derivatives therof; itaconamide and derivatives thereof; diethyl maleate, 2- (acryloyloxy)ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.
4. The methotrexate compound of any one of claims 1-3 wherein the hydrogel is comprised of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate).
5. The methotrexate compound of any one of claims 2-4 wherein the polymer coating comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolicacid, polylacticacid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharide, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.
6. The methotrexate compound of claim 5 wherein the polymer coating comprises poly(caprolactone).
7. The methotrexate compound of claim 6 wherein the polymer coating comprises 1 % polyCcaprolactone).
8. The methotrexate compound of any one of claims 1-7 wherein the methotrexate compound provides sustained release of methotrexate for over 30 days.
9. The methotrexate compound of any one of claims 1 -7 wherein the methotrexate compound provides about linear release of methotrexate for over 30 days.
10. The methotrexate compound of any one of claims 1-9 wherein the methotrexate compound provides about the same amount of methotrexate released at day 3 and at day 30.
11. The methotrexate compound of any one of claims 1 -10 wherein the methotrexate compound provides continuous release of methotrexate for over 30 days.
12. The methotrexate compound of claim 1 1 wherein the methotrexate compound provides continuous release of methotrexate for over 42 days.
13. The methotrexate compound of claim 12 wherein the methotrexate compound provides continuous release of methotrexate for over 100 days.
14. A depot suitable for implanting into a living host for delivery of at least one substance, comprising a casing capable of containing said substance, said casing being formed by a method comprising: a) filling an interior of a mold with a mixture, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) depositing at least one of the phases onto an inner surface of the mold by rotating said mold; c) forming said casing by stabilizing said at least one of the phases deposited onto the inner surface of the mold; and d) removing said casing from said mold; wherein said depot is capable, when filled with methotrexate, of limiting the rate of dissolution of methotrexate.
15. A depot in accordance with claim 14 wherein at least one of said components is selected from monomers selected from the group consisting of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate; acrylamides and derivatives thereof including methacryl amide, hydroxypropyl methacrylamide, N,N-diethyl acrylamide, N,N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide; N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein, N- vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride, allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N-vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro-ethylene, dichloroethylene, tetrachloro- ethylene; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleate, 2-(acryloyloxy)ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.
16. A depot in accordance with claim 14 wherein at least one of said components is selected from polymers selected from the group consisting of polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharids, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex- GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.
17. A depot in accordance with claim 14 wherein at least one of said components is selected from solvents selected from the group consisting of water, alcohols, ethylene glycol, ethanol, acetone, poly(ethylene glycol) and derivatives thereof; solutions of poly(ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof; acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2-chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, di(ethylene glycol), di(ethylene glycol) monomethyl ether, 1 ,4 dioxane, N1N, dimethyl acetamide, N1N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane, hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyridene, tetrahydrofuran, toluene, trichloroethylene, o-xylene and p-xylene, a monomer, a macromer, a liquid crosslinking agent, or mixtures thereof.
18. A depot in accordance with claim 14 wherein said casing has a cylindrical hollow shape, a top end, and a bottom end.
19. A depot in accordance with claim 18 wherein the method of forming of the depot further comprises plugging the top end and the bottom end after removing the casing from the mold.
20. A depot in accordance with claim 19 wherein the substance is added to the casing prior to plugging at least one of the top end and the bottom end.
21. A depot in accordance with any of the claims 14-20 wherein the casing is a hydrogel.
22. A depot in accordance with any of the claims 1-21 wherein the casing is porous.
23. A depot in accordance with claim 22 having a pore size between 0.001 μm and 100 μm.
24. A depot in accordance with any of the claims 14-23 wherein the substance is methotrexate.
25. The depot according to claim 14 wherein the casing is impregnated with a polymer before the substance is added.
26. The depot according to claim 14 wherein the casing is coated with a polymer before the substance is added.
27. Use of the depot of claim 20 to prepare a drug delivery product, wherein the substance is a pharmaceutical compound.
28. Use of the depot according to claim 27 wherein the pharmaceutical compound is methotrexate.
29. Use of the drug delivery product of any of claims 27 or 28 to treat a disease or disorder selected from the group consisting of cancer, psiorasis, and rheumatoid arthritis.
30. A process of producing a product, comprising: a) filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold , and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold, wherein the mold compnses an aminated glass tube
31 The process according to claim 30 or 90 including removing said product from said mold
32 The process according to claim 30, 31 or 90 wherein of said at least two components, at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least the monomer or macromer, and wherein the step of stabilizing said deposited phase includes gelation of the monomer or macromer by polymerization thereof
33 The process according to claim 30, 31 or 90 wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields
34 The process according to claim 33 wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators
35 The process according to claim 30, 31 or 90 wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof.
36. The process according to claim 35 wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
37. The process according to claim 35 wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
38. The process according to claim 30-37 or 90 wherein said hollow mold is a cylindrical tube so that said product is a polymeric tube.
39. The process according to claim 38 wherein said cylindrical tube includes preselected surface features on said inner surface of the cylindrical tube.
40. The process according to claim 30-39 including inserting a porous structure into said mold prior to filling said mold with said mixture, and wherein said product is coated on an outer surface of said porous structure.
41. The process according to claim 30, 31 or 32 wherein said mixture includes a cross-linking agent.
42. The process according to claims 41 wherein the crosslinking agent is selected from the group consisting of multifunctional ester, carbonate, multi- isocyanate, methacrylate or poly-N-isopropyl acrylamide or acrylate, acrylamide or methacrylamide and preferably one of ethylene glycol dimethacrylate (EDMA), hexamethylene dimethacrylate (HDMA), poly (ethylene glycol) dimethacrylate, 1 ,5- hexadiene-3, 4-diol (DVG), 2, 3-dihydroxybutanediol 1 , 4-dimethacrylate (BHDMA), 1 , 4-butanediol dimethacrylate (BDMA), 1 ,5- hexadiene (HD) multi-functional star polymers of poly (ethylene oxide), bifunctional peptides, oligopeptidic crosslinkers, proteins and protein fragments, including enzyme degradable crosslinking agents, hydrolysable crosslinking agent, oligopeptidic crosslinking agents, nitrenes and exposure to light.
43. The process according to claim 30, 31 or 32 wherein said monomer is selected from the group consisting of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2- polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate ; acrylamides and derivatives thereof includingmethacrylamide, hydroxypropyl methacrylamide, N, N-diethyl acrylamide, N, N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide ; N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl- acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride, allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N- vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro- ethylene, dichloroethylene, tetrachloro-ethylene ; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate ; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleat, 2- (acryloyloxy) ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.
44. The process according to claim 30, 31 or 32 wherein said solvent is selected from the group consisting of a neucleophilic, electrophilic or amphiphilic molecule selected from the group of water, alcohols, ethylene glycol, ethanol, acetone, poly (ethylene glycol) and derivatives thereof; solutions of poly (ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof; acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2-chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, di (ethylene glycol), di (ethylene glycol) monomethyl ether, 1 ,4 dioxane, N, N, dimethyl acetamide, N, N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane,hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyridene, tetrahydrofuran, toluene, trichloroethylene, o-xylene and p-xylene, a monomer, a macromer, a liquid crosslinking agent, or mixtures thereof.
45. The process according to claim 30, 31 or 32 wherein said solvent solubilizes said monomer or macromer but not a polymer or crosslinked polymer formed from said monomer or macromer.
46. The process according to claim 30, 31 or 32 wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 75% by weight.
47. The process according to claim 30, 31 or 32 wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 60% by weight.
48. The process according to claim 35 wherein said polymer is selected from the group consisting of polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly (methyl methacrylate), poly (ethoxyethyl methacrylate), poly (hydroxyethylmethacrylate) ; poly (vinyl acetate) s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly (N-vinyl pyrrolidinone), poly (vinyl actetate), poly (vinyl alcohol), poly (hydroxypropyl methacrylamide), poly (caprolactone), poly (dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly (trimethylene carbonate) s, poly (butadiene), polystyrene, polyacrylonitrile, poly (chloroprene), neoprene, poly (isobutene), poly (isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly (chlorotrifluoroethylene), poly (vinyl chloride), poly (oxymethylene), poly (ethylene terephthalate), poly (oxyethylene) poly (oxyterephthaloyl), polyamides such as but not limited to, poly [imino(i-oxohexamethylene)], poly (iminoadipoyl- iminohexamethalene), poly (iminohexamethylene-iminosebacoyl), poly [imino(1- oxododecamethylene)], cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharides, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate- HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.
49. The process according to claim 30 to 48 including physically or chemically modifying the inner surface of the mold upon which pre-selected morphologies are induced into the wall of the said product by inducing beading or spreading of the separated liquid phase.
50. The process according to claim 49 with molecules including silanating agents.
51. The process according to claim 30 to 50 including the step of removing the solvent and including repeating steps a) b) and c), at least once to produce a multi- layered product.
52. The process according to claim 30 to 51 including the step of removing the solvent and including repeating steps a), b) and c), and wherein said mixture includes particles in step a) to produce a multi-layered product with constituents embedded in the wall of the product, and wherein the constituents include one or a combination of cells, proteins, peptides, enzymes, genes, vectors, growth factors, hormones, nucleotides, therapeutics, drugs and carbohydrates.
53. The process according to claim 52 wherein said constituents are embedded directly in the wall of the product.
54. The process according to claim 52 wherein said constituents are embedded in microspheres or nanoparticles which are embedded in the wall of the product.
55. The process according to claim 30 to 54 wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to increase adherence of the product deposited thereon during rotation.
56. The process according to claim 30 to 54 wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to prevent adherence of the product deposited thereon during rotation.
57 A process of producing a product, comprising a) inserting an securing a structure of pre-selected size and shape into an interior of a mold and filling the remaining interior of the mold with a mixture so that substantially all gas bubbles are displaced therefrom, the mixture compnsing at least two components which can be phase separated by a phase separation agent into at least two phases, b) rotating said mold containing the structure and the mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an outer surface of the structure, and c) forming the product by stabilizing the at least one of the phases deposited onto the inner surface of the mold, wherein the mold compπses an aminated glass tube
58 The process according to claim 57 wherein the mixture includes a solution of chitosan in aqueous acetic acid diluted with an equal volume of ethanol and mixed with a twofold molar excess of acetic anhydride, and wherein the product is chitin formed by phase separation using gelation and syneresis and deposited on the outside of the structure of pre-selected size and shape
59 The process according to claim 58 wherein the solution of chitosan is 3% solution of chitosan in 2% aqueous acetic acid, and wherein the structure of preselected size and shape is removed from the mold and, including one of leaving the chitin product from the structure of pre-selected size and shape, removing the chitin product from the structure of pre-selected size and shape, and drying the chitin product by storage in air pnor to the removal from the structure of pre-selected size and shape
60 A product produced by a method comprising the steps of filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold
; and forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the mold comprises an aminated glass tube.
61. The product according to claim 60 including removing said product from said mold.
62. The product according to claim 60 wherein said hollow mold is a cylindrical tube so that said product is a tube.
63. The product according to claim 60 wherein of said at least two components at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least one of the monomer and macromer, and wherein the step of stabilizing said deposited phase includes gelation of the at least one of the monomer and macromer by polymerization thereof.
64. The product according to claim 63 wherein said phase separation agent is selected from the group consisting of solution immiscibility, polymer immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
65. The product according to claim 64 wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators.
66. The product according to claim 63 wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.
67. The product according to claim 63 wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to a lumenal side, resulting in spotting on an outer wall surface.
68. The product according to claim 60 wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof.
69. The product according to claim 68 wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
70. The product according to claim 68 wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
71. The product according to claim 68 wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.
72. The product according to claim 68 wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to alumenal side, resulting in spotting on an outer wall surface.
73. The product according to claim 60 wherein said product is a multilayered product produced by repeating steps a), b) and c), at least once to produce a multi- layered product.
74. The product according to claim 63 wherein the wall structure is used as a reservoir for the delivery of drugs, therapeutics, cells, cell products, genes, viral vectors, proteins, peptides, hormones, carbohydrates, growth factors, enzymes.
75. The product according to claim 68 wherein the wall structure is used as a reservoir for the delivery of drugs, therapeutics, cells, cell products, genes, viral vectors, proteins, peptides, hormones, carbohydrates, growth factors, enzymes.
76. The product according to claim 68 wherein the solution contains particles containing pre-selected constituents, and wherein the product includes said particles are distributed either uniformly or in a gradient within the wall structure of the product.
77. The product according to claim 68 wherein the particles are microspheres or nanospheres and said pre-selected constituents include enzymes, proteins, peptides, genes, vectors, growth factors, hormones, nucleotides, carbohydrates, drugs, therapeutics, or cells.
78. The product according to claim 68 wherein the cells include neurons, stem cells, stem cell derived cells, olfactory ensheathing cells, Schwann cells, astrocyte cells, microglia cells, or oligodendrocyte cells, endothelial cells.epithelial cells, fibroblasts, keratinocytes, smooth muscle cells, hepatocytes, bone marrow-derived cells, hematopoetic cells, glial cells, inflammatory cells, and immune system cells.
79. The product according to claim 68 wherein the particles are microspheres or nanospheres and said pre-selected constituents include enzymes, proteins, peptides, genes, vectors, growth factors, hormones, oligonucleotides, or cells.
80. The product according to claim 79 wherein the cells include neurons, stem cells, stem cell derived cells, olfactory ensheathing cells, Schwann cells, astrocyte cells, microglia cells, or oligodendrocyte cells, endothelial cells, epithelial cells, fibroblasts, keratinocytes, smooth muscle cells, hepatocytes, bone marrow-derived cells, hematopoetic cells, glial cells, inflammatory cells, and immune system cells.
81. The product according to claim 79 wherein the particles are degradable particles thereby releasing said constituents over time.
82. The process according to claim 30 including a step of inserting an object into the mold to be coated with wherein said object is coated with said at least one of the phases which is stabilized on said object.
83. The process according to claim 30 wherein the object is selected from the group consisting of meshes, scaffolds, stents, coils, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for abdominal aortic aneurysms and esophageal scaffolds and fibers that occupy a periphery of the mold.
84. The product according to claim 60 wherein the process includes a step of inserting an object into the mold to be coated with wherein said product includes said object being coated with said at least one of the phases and which is stabilized on said object.
85. The process according to claim 32 wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
86. The process according to claim 35 wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
87. The product produced in accordance with claim 60 for use as a coronary artery bypass graft, vascular graft, artificial fallopian tubes, a drainage implant for glaucoma, a drainage implant for the lacrymal duct, artificial tissues such as intestines, ligaments, tendons, nerve guidance channels, ureter and urethra replacements, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for aortic aneurysms, esophageal scaffolds, composite catheters, shunts, delivery matrices, coatings applied to pacemaker leads, implantable sensor wire leads, wires forinterventional cardiology, and biosensors.
88. A process of producing a product, comprising: a) partially filling an interior of a mold with a mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the mold comprises an aminated glass tube.
89. The process according to claim 88 wherein the mixture is a solution comprising at least one polymer which is biodegradable and selected from the group of polysaccharides ; polyesters, polycarbonates, polyesterethers, polyesterurethanes, polyanhydrides, polypeptides, proteins and derivatives thereof.
90. The process according to claim 38 wherein said cylindrical tube is filled with more than one distinct monomer/macromer formulation in a sequential manner so as to create a polymer tube product comprised of graded wall composition.
91. The process according to claim 90 wherein said distinct monomer/macromer formulations are introduced into the cylindrical hollow mold in a graded manner using a commercially available gradient-making apparatus, syringe pumps, or custom controlled liquid delivery apparatus.
92. A process of producing a product, comprising: a) filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.
93. The process according to claim 92 or 120 including removing said product from said mold.
94. The process according to claim 92, 93 or 143 wherein of said at least two components, at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least the monomer or macromer, and wherein the step of stabilizing said deposited phase includes gelation of the monomer or macromer by polymerization thereof.
95. The process according to claim 92, 93 or 143 wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
96. The process according to claim 95 wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators.
97. The process according to claim 92, 93 or 143 wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof.
98. The process according to claim 97 wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
99. The process according to claim 97 wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
100. The process according to claim 92-99 or 143 wherein said hollow mold is a cylindrical tube so that said product is a polymeric tube.
101. The process according to claim 100 wherein said cylindrical tube includes preselected surface features on said inner surface of the cylindrical tube.
102. The process according to claim 92-101 including inserting a porous structure into said mold prior to filling said mold with said mixture, and wherein said product is coated on an outer surface of said porous structure.
103. The process according to claim 92, 93 or 94 wherein said mixture includes a cross-linking agent.
104. The process according to claims 103 wherein the crosslinking agent is selected from the group consisting of multifunctional ester, carbonate, multi- isocyanate, methacrylate or poly-N-isopropyl acrylamide or acrylate, acrylamide or methacrylamide and preferably one of ethylene glycol dimethacrylate (EDMA), hexamethylene dimethacrylate (HDMA), poly (ethylene glycol) dimethacrylate, 1 ,5- hexadiene-3, 4-diol (DVG), 2, 3-dihydroxybutanediol 1 , 4-dimethacrylate (BHDMA), 1 , 4-butanediol dimethacrylate (BDMA), 1 ,5- hexadiene (HD) multi-functional star polymers of poly (ethylene oxide), bifunctional peptides, oligopeptide crosslinkers, proteins and protein fragments, including enzyme degradable crosslinking agents, hydrolysable crosslinking agent, oligopeptidic crosslinking agents, nitrenes and exposure to light.
105. The process according to claim 92, 93 or 94 wherein said monomer is selected from the group consisting of acrylates, methacrylates, and derivatives thereof such as, but not limited to, 2-hydroxyethyl methacrylate, methyl methacrylate, 2- polyethylene glycol ethyl methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, 2-chloroethyl methacrylate, butyl methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate ; acrylamides and derivatives thereof includingmethacrylamide, hydroxypropyl methacrylamide, N, N-diethyl acrylamide, N, N-dimethyl acrylamide, 2-chloroethyl acrylamide, 2-nitrobutyl acrylamide ; N-vinyl pyrrolidone, acenaphthalene, N-vinyl acetamide, phenyl- acetylene, acrolein, methyl acrolein, N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride, vinyl methyl ketone, vinylidene chloride, styrene and derivatives thereof; propene, acrylonitrile, methacrylonitrile, acryloyl chloride, allyl acetate, allyl chloride.allylbenzene, butadiene and derivatives thereof; N-vinyl caprolactam, N- vinyl carbazole, cinnamates and derivatives thereof; citraconimide and derivatives thereof; crotonic acid, diallyl phthalate, ethylene and derivatives thereof such as, but not limited to 1 ,1 diphenyl-ethylene, chlorotrifluoro- ethylene, dichloroethylene, tetrachloro-ethylene ; fumarates and derivatives thereof; hexene and derivatives thereof; isoprene and derivatives thereof such as, but not limited to isopropenyl acetate, isopropenyl methyl ketone, isopropenylisocyanate ; itaconate and derivatives thereof; itaconamide and derivatives thereof; diethyl maleat, 2- (acryloyloxy) ethyl diethyl phosphate, vinyl phosphonates and derivatives thereof; maleic anhydride, maleimide, silicone monomers, and derivatives thereof; lactones, lactams, carbonates, and any combination thereof.
106. The process according to claim 92, 93 or 94 wherein said solvent is selected from the group consisting of a neucleophilic, electrophilic or amphiphilic molecule selected from the group of water, alcohols, ethylene glycol, ethanol, acetone, poly (ethylene glycol) and derivatives thereof; solutions of poly (ethylene glycol), dimethyl sulfoxide, dimethyl formamide, alkanes and derivatives thereof; acetonitrile, acetic acid, benzene, acetic anhydride, benzyl acetate, carbon tetrachloride, chlorobenzene, n-butanol, 2-chloroethanol, chloroform, cyclohexane, cyclohexanol, dichloromethane, diethyl ether, di (ethylene glycol), di (ethylene glycol) monomethyl ether, 1 ,4 dioxane, N, N, dimethyl acetamide, N, N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane,hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate, propylene glycol, pyridene, tetrahydrofuran, toluene, trichloroethylene.o-xylene and p-xylene, a monomer, a macromer, a liquid crosslinking agent, or mixtures thereof.
107. The process according to claim 92, 93 or 94 wherein said solvent solubilizes said monomer or macromer but not a polymer or crosslinked polymer formed from said monomer or macromer.
108. The process according to claim 92, 93 or 94 wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 75% by weight.
109. The process according to claim 92, 93 or 94 wherein said at least one monomer or macromer is present in a range from about 0. 001 % by weight to about 60% by weight.
110. The process according to claim 97 wherein said polymer is selected from the group consisting of polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly (methyl methacrylate), poly (ethoxyethyl methacrylate), poly (hydroxyethylmethacrylate) ; poly (vinyl acetate) s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly (N-vinyl pyrrolidinone), poly (vinyl actetate), poly (vinyl alcohol), poly (hydroxypropyl methacrylamide), poly (caprolactone), poly (dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly (trimethylene carbonate) s, poly (butadiene), polystyrene, polyacrylonitrile, poly (chloroprene), neoprene, poly (isobutene), poly (isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly (chlorotrifluoroethylene), poly (vinyl chloride), poly (oxymethylene), poly (ethylene terephthalate), poly (oxyethylene) poly (oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharides, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.
111. The process according to claim 92 to 110 including physically or chemically modifying the inner surface of the mold upon which pre-selected morphologies are induced into the wall of the said product by inducing beading or spreading of the separated liquid phase.
112. The process according to claim 111 with molecules including silanating agents.
113. The process according to claim 92 to 112 including the step of removing the solvent and including repeating steps a) b) and c), at least once to produce a multi- layered product.
114. The process according to claim 92 to 113 including the step of removing the solvent and including repeating steps a), b) and c), and wherein said mixture includes particles in step a) to produce a multi-layered product with constituents embedded in the wall of the product, and wherein the constituents include one or a combination of cells, proteins, peptides, enzymes, genes, vectors, growth factors, hormones, nucleotides, therapeutics, drugs and carbohydrates.
115. The process according to claim 114 wherein said constituents are embedded directly in the wall of the product.
116. The process according to claim 114 wherein said constituents are embedded in microspheres or nanoparticles which are embedded in the wall of the product.
117. The process according to claim 92 to 116 wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to increase adherence of the product deposited thereon during rotation.
118. The process according to claim 92 to 1 16 wherein prior to filling up said mold with said mixture, said inner surface of said mold is treated in such a way so as to prevent adherence of the product deposited thereon during rotation.
119. A process of producing a product, comprising: a) inserting and securing a structure of pre-selected size and shape into an interior of a mold and filling the remaining interior of the mold with a mixture so that substantially all gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing the structure and the mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an outer surface of the structure; and c) forming the product by stabilizing the at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.
120. The process according to claim 119 wherein the mixture includes a solution of chitosan in aqueous acetic acid diluted with an equal volume of ethanol and mixed with a twofold molar excess of acetic anhydride, and wherein the product is chitin formed by phase separation using gelation and syneresis and deposited on the outside of the structure of pre-selected size and shape.
121. The process according to claim 120 wherein the solution of chitosan is 3% solution of chitosan in 2% aqueous acetic acid, and wherein the structure of preselected size and shape is removed from the mold and, including one of leaving the chitin product from the structure of pre-selected size and shape, removing the chitin product from the structure of pre-selected size and shape, and drying the chitin product by storage in air prior to the removal from the structure of pre-selected size and shape.
122. A product produced by a method comprising the steps of: filling an interior of a mold with a mixture so that substantially all visible gas bubbles are displaced therefrom, the mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold
; and forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.
123. The product according to claim 122 including removing said product from said mold.
124. The product according to claim 122 wherein said hollow mold is a cylindrical tube so that said product is a tube.
125. The product according to claim 122 wherein of said at least two components at least one is selected from the group consisting of the group of monomers and macromers and the other is at least one solvent, wherein said at least one of the phases that deposits onto the inner surface includes at least one of the monomer and macromer, and wherein the step of stabilizing said deposited phase includes gelation of the at least one of the monomer and macromer by polymerization thereof.
126. The product according to claim 125 wherein said phase separation agent is selected from the group consisting of solution immiscibility, polymer immiscibility, light, pH, initiation agents, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
127. The product according to claim 126 wherein said initiation agent is selected from the group consisting of free radical initiators, thermal and photo initiators, redox initiators, anionic, cationic or ring-opening initiators.
128. The product according to claim 125 wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.
129. The product according to claim 125 wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to a lumenal side, resulting in spotting on an outer wall surface.
130. The product according to claim 122 wherein said at least two components includes at least one polymer dissolved in at least one solvent, and wherein said mixture is composed of at least two solutions, wherein said at least one of the phases that deposits on the inner surface includes at least the polymer, and wherein the step of stabilizing said deposited phase includes gelation thereof.
131. The product according to claim 130 wherein said phase separation agent is selected from the group consisting of solution immiscibility, light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
132. The product according to claim 130 wherein gelation is achieved by exposure to an agent selected from the group consisting of light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
133. The product according to claim 130 wherein the product has a wall morphology that includes a porous structure, a gel structure or overlapping regions of porous/gel structure.
134. The product according to claim 130 wherein the product has a wall morphology that includes a predominantly gel morphology with porous channels running from a periphery to alumenal side, resulting in spotting on an outer wall surface.
135. The product according to claim 122 wherein said product is a multilayered product produced by repeating steps a), b) and c), at least once to produce a multi- layered product.
136. The product according to claim 125 wherein the wall structure is used as the reservoir for the delivery of the methotrexate.
137. The product according to claim 130 wherein the wall structure is used as the reservoir for the delivery of the methotrexate.
138. The product according to claim 130 wherein the solution contains particles containing pre-selected constituents, and wherein the product includes said particles are distributed either uniformly or in a gradient within the wall structure of the product.
139. The process according to claim 126 including a step of inserting an object into the mold to be coated with wherein said object is coated with said at least one of the phases which is stabilized on said object.
140. The process according to claim 92 wherein the object is selected from the group consisting of meshes, scaffolds, stents, coils, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for abdominal aortic aneurysms and esophageal scaffolds and fibers that occupy a periphery of the mold.
141. The product according to claim 92 wherein the process includes a step of inserting an object into the mold to be coated with wherein said product includes said object being coated with said at least one of the phases and which is stabilized on said object.
142. The process according to claim 94 wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
143. The process according to claim 94 wherein said step c) by stabilizing said at least one of the phases deposited onto the inner surface of the mold is achieved by one or a combination of gelation, exposure of the phase to light, change in pH, change in temperature, creation of a chemical product within the mold, changes in cationic and/or anionic concentrations, electric and magnetic fields.
144. The product produced in accordance with claim 92 for use as a coronary artery bypass graft, vascular graft, artificial fallopian tubes, a drainage implant for glaucoma, a drainage implant for the lacrymal duct, artificial tissues such as intestines, ligaments, tendons, nerve guidance channels, ureter and urethra replacements, aural drainage tubes, abdominal/gastrointestinal structural replacements, stents for aortic aneurysms, esophageal scaffolds, composite catheters, shunts, delivery matrices, coatings applied to pacemaker leads, implantable sensor wire leads, wires for interventional cardiology, and biosensors.
145. A process of producing a product, comprising: a) partially filling an interior of a mold with a mixture comprising at least two components which can be phase separated by a phase separation agent into at least two phases; b) rotating said mold containing said mixture at an effective rotational velocity so that under rotation at least one of the phases deposits onto an inner surface of the mold ; and c) forming said product by stabilizing said at least one of the phases deposited onto the inner surface of the mold; wherein the product is capable of acting as a reservoir for a drug comprising methotrexate, and is capable of limiting the rate of dissolution of said drug from said reservoir.
146. The process according to claim 145 wherein the mixture is a solution comprising at least one polymer which is biodegradable and selected from the group of polysaccharides ; polyesters, polycarbonates, polyesterethers, polyesterurethanes, polyanhydrides, polypeptides, proteins and derivatives thereof.
147. The process according to claim 100 wherein said cylindrical tube is filled with more than one distinct monomer/macromer formulation in a sequential manner so as to create a polymer tube product comprised of graded wall composition.
148. The process according to claim 147 wherein said distinct monomer/macromer formulations are introduced into the cylindrical hollow mold in a graded manner using a commercially available gradient-making apparatus, syringe pumps, or custom controlled liquid delivery apparatus.
149. The depot according to claim 25 wherein the impregnated polymer comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate), poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), polyCcaprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharide, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.
150. The depot according to claim 26 wherein the coated polymer comprises a member of the group consisting of: polyacrylates, polysulfone, peptide sequences, proteins and derivatives, oligopeptides, degradable polymer, collagen, gelatin, elastin, fibrin, fibronectin, laminin, polymethacrylates such as but not limited to poly(methyl methacrylate), poly(ethoxyethyl methacrylate),- poly(hydroxyethylmethacrylate); polyvinyl acetate)s polyacetates, polyesters, polyamides, polycarbonates, polyanhydrides, polyamino acids including poly(N-vinyl pyrrolidinone), polyvinyl actetate), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic acid, polylactic acid, copolymers of lactic and glycolic acids, and poly(trimethylene carbonate)s, poly(butadiene), polystyrene, polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene), poly(isoprene), polypropylene, polytetrafluoroethylene, poly(vinylidene fluoride), poly(chlorotrifluoroethylene), polyvinyl chloride), poly(oxymethylene), poly(ethylene terephthalate), poly(oxyethylene) poly(oxyterephthaloyl), polyamides, cellulose, polysulfones, carbohydrates, polysaccharides and modified polysaccharids, such as hyaluronic acid, sodium hyaluronate, alginate, dextran and modified dextran, such as dextran-acrylates, including dex-lactate-HEMA, dex-GMA, dex-HEMA, agarose, chitosan and derivatives thereof; chitin, and mixtures thereof; starch, starch derivatives, cellulose and derivatives.
151. A compound according to claim 1 further comprising a stabilizer.
152. A compound according to claim 151 wherein the stabilizer is polycaprolactone fibers.
PCT/CA2006/000805 2005-05-17 2006-05-17 Depot for sustained and controlled delivery of methotrexate WO2006122414A1 (en)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070269487A1 (en) * 2006-03-31 2007-11-22 Forsight Labs, Llc Drug Delivery Methods, Structures, and Compositions for Nasolacrimal System
GB2448871A (en) * 2007-04-30 2008-11-05 Inion Ltd Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds
WO2009035387A1 (en) * 2007-09-14 2009-03-19 Softcure Pharmaceuticals Ab A medicament prepared using methotrexate and suitable for topical administration, for the treatment of a lower gastrointestinal tract inflammatory disease
CN103169951A (en) * 2013-03-15 2013-06-26 中国人民解放军第四军医大学 Gel microcapsule with cell recruitment function and preparation method thereof
US9216054B2 (en) 2010-11-04 2015-12-22 Mayo Foundation For Medical Education And Research Esophageal mucosectomy systems, devices and methods
CN105193620A (en) * 2014-06-09 2015-12-30 吴旭东 Drug-decocting machine provided with micromolecule generator
CN105713152A (en) * 2016-01-22 2016-06-29 黄淮学院 Polyethylene glycol bipolymer with endothelial cell selectivity and preparation method and application method of composite coating
US9427396B2 (en) 2008-06-27 2016-08-30 Ucl Business Plc Magnetic microbubbles, methods of preparing them and their uses
US9610271B2 (en) 2011-08-29 2017-04-04 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
CN106674443A (en) * 2016-12-23 2017-05-17 浙江工业大学 Glucan-poly(hydroxyethyl methacrylate) based continuous bed cryogel separation medium and preparation method thereof
CN107118299A (en) * 2017-06-27 2017-09-01 郑鑫 Environment-friendly acrylic elastomer resin and preparation method thereof
US9770414B2 (en) 2010-05-13 2017-09-26 Pacira Pharmaceuticals, Inc. Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent
US9974685B2 (en) 2011-08-29 2018-05-22 Mati Therapeutics Drug delivery system and methods of treating open angle glaucoma and ocular hypertension

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4797282A (en) * 1985-04-18 1989-01-10 Merck Patent Gesellschaft Mit Beschrankter Haftung Drug depot containing cytostatics
EP0350246A2 (en) * 1988-07-05 1990-01-10 Takeda Chemical Industries, Ltd. Sustained release microcapsule for water soluble drug
US5292515A (en) * 1990-09-28 1994-03-08 Hydro Med Sciences, A Division Of National Patent Development Corporation Manufacture of water-swellable hydrophilic articles and drug delivery devices
CN1208612A (en) * 1997-08-15 1999-02-24 安徽中人科技有限责任公司 Sustained release and implantation type methotrexate medicine and method for preparing same
US6001386A (en) * 1995-09-27 1999-12-14 University Of Kentucky Research Foundation Implantable controlled release device to deliver drugs directly to an internal portion of the body
WO2001085417A1 (en) * 2000-05-12 2001-11-15 Dalton Paul D Method of producing structures using centrifugal forces
US20030036794A1 (en) * 1995-06-07 2003-02-20 Cook Incorporated Coated implantable medical device
WO2004060346A2 (en) * 2002-12-30 2004-07-22 Angiotech International Ag Drug delivery from rapid gelling polymer composition
WO2004071736A2 (en) * 2003-02-13 2004-08-26 Matregen Corp. Method of producing structures using centrifugal forces

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4797282A (en) * 1985-04-18 1989-01-10 Merck Patent Gesellschaft Mit Beschrankter Haftung Drug depot containing cytostatics
EP0350246A2 (en) * 1988-07-05 1990-01-10 Takeda Chemical Industries, Ltd. Sustained release microcapsule for water soluble drug
US5292515A (en) * 1990-09-28 1994-03-08 Hydro Med Sciences, A Division Of National Patent Development Corporation Manufacture of water-swellable hydrophilic articles and drug delivery devices
US20030036794A1 (en) * 1995-06-07 2003-02-20 Cook Incorporated Coated implantable medical device
US6001386A (en) * 1995-09-27 1999-12-14 University Of Kentucky Research Foundation Implantable controlled release device to deliver drugs directly to an internal portion of the body
CN1208612A (en) * 1997-08-15 1999-02-24 安徽中人科技有限责任公司 Sustained release and implantation type methotrexate medicine and method for preparing same
WO2001085417A1 (en) * 2000-05-12 2001-11-15 Dalton Paul D Method of producing structures using centrifugal forces
WO2004060346A2 (en) * 2002-12-30 2004-07-22 Angiotech International Ag Drug delivery from rapid gelling polymer composition
WO2004071736A2 (en) * 2003-02-13 2004-08-26 Matregen Corp. Method of producing structures using centrifugal forces

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DALTON P.D. ET AL.: "Creating porous tubes by centrifugal forces for soft tissue application", BIOMATERIALS, vol. 22, no. 19, 1 October 2001 (2001-10-01), pages 2661 - 2669, XP004296086 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8795711B2 (en) * 2006-03-31 2014-08-05 Mati Therapeutics Inc. Drug delivery methods, structures, and compositions for nasolacrimal system
US9849082B2 (en) 2006-03-31 2017-12-26 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
US20070269487A1 (en) * 2006-03-31 2007-11-22 Forsight Labs, Llc Drug Delivery Methods, Structures, and Compositions for Nasolacrimal System
US10300014B2 (en) 2006-03-31 2019-05-28 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
GB2448871A (en) * 2007-04-30 2008-11-05 Inion Ltd Modulation of inflammatory and immune responses in the treatment of inflammation using substituted heterocyclic compounds
WO2009035387A1 (en) * 2007-09-14 2009-03-19 Softcure Pharmaceuticals Ab A medicament prepared using methotrexate and suitable for topical administration, for the treatment of a lower gastrointestinal tract inflammatory disease
US9427396B2 (en) 2008-06-27 2016-08-30 Ucl Business Plc Magnetic microbubbles, methods of preparing them and their uses
US10028911B2 (en) 2010-05-13 2018-07-24 Pacira Pharmaceuticals, Inc. Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent
US9770414B2 (en) 2010-05-13 2017-09-26 Pacira Pharmaceuticals, Inc. Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent
US9216054B2 (en) 2010-11-04 2015-12-22 Mayo Foundation For Medical Education And Research Esophageal mucosectomy systems, devices and methods
US9974685B2 (en) 2011-08-29 2018-05-22 Mati Therapeutics Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
US9610271B2 (en) 2011-08-29 2017-04-04 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
CN103169951A (en) * 2013-03-15 2013-06-26 中国人民解放军第四军医大学 Gel microcapsule with cell recruitment function and preparation method thereof
CN103169951B (en) * 2013-03-15 2015-03-04 中国人民解放军第四军医大学 Gel microcapsule with cell recruitment function and preparation method thereof
CN105193620A (en) * 2014-06-09 2015-12-30 吴旭东 Drug-decocting machine provided with micromolecule generator
CN105713152A (en) * 2016-01-22 2016-06-29 黄淮学院 Polyethylene glycol bipolymer with endothelial cell selectivity and preparation method and application method of composite coating
CN106674443A (en) * 2016-12-23 2017-05-17 浙江工业大学 Glucan-poly(hydroxyethyl methacrylate) based continuous bed cryogel separation medium and preparation method thereof
CN107118299A (en) * 2017-06-27 2017-09-01 郑鑫 Environment-friendly acrylic elastomer resin and preparation method thereof

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