WO2002020645A2 - Polymer matrices prepared by supercritical fluid processing techniques - Google Patents
Polymer matrices prepared by supercritical fluid processing techniques Download PDFInfo
- Publication number
- WO2002020645A2 WO2002020645A2 PCT/US2001/026457 US0126457W WO0220645A2 WO 2002020645 A2 WO2002020645 A2 WO 2002020645A2 US 0126457 W US0126457 W US 0126457W WO 0220645 A2 WO0220645 A2 WO 0220645A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- reactor
- supercritical fluid
- polymers
- polymer
- poly
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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- B01F23/405—Methods of mixing liquids with liquids
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
- B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B7/00—Mixing; Kneading
- B29B7/80—Component parts, details or accessories; Auxiliary operations
- B29B7/86—Component parts, details or accessories; Auxiliary operations for working at sub- or superatmospheric pressure
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01F33/70—Mixers specially adapted for working at sub- or super-atmospheric pressure, e.g. combined with de-foaming
- B01F33/71—Mixers specially adapted for working at sub- or super-atmospheric pressure, e.g. combined with de-foaming working at super-atmospheric pressure, e.g. in pressurised vessels
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Definitions
- the invention relates to the use of supercritical fluid processing techniques to prepare polymer matrices suitable for use in orthopedic, pharmaceutical, and similar applications. Reference to Related Patent Applications.
- each of these inventions involves the discovery that an improved product can be made by (1) mixing desired ingredients in a reactor with a process medium that is, or can be made to become, a supercritical fluid, (2) mixing the ingredients in the reactor under supercritical fluid conditions to form a supercritical fluid slurry, and (3) releasing the pressure in the reactor in a controlled manner or discharging the reactor contents into a receiving vessel in a controlled manner.
- the resultant product is finely divided, porous particles that can be used in orthopedic or pharmaceutical applications.
- a source of calcium ions such as tribasic calcium phosphate or hydroxyapatite is mixed with a polymer such as poly-e-caprolactone (PCL) and a supercritical fluid such as carbon dioxide to form a porous, strong material that can be carved, molded, or poured into a suitable shape.
- PCL poly-e-caprolactone
- the polymer forms a matrix that provides support and structure for the calcium ions.
- the polymer is biosorbable, so that a porous calcium structure that simulates autogenic bone will be left in the body.
- a biologically active ingredient such as an antibiotic is mixed with a polymer such as PCL or polylactide-co-glycolide (PLGA) and a supercritical fluid such as carbon dioxide to form porous polymer particles that are infused with the biologically active ingredient.
- a polymer such as PCL or polylactide-co-glycolide (PLGA)
- PLGA polylactide-co-glycolide
- carbon dioxide a supercritical fluid such as carbon dioxide
- the polymer forms porous particles that provide a matrix, or carrier, for the biologically active ingredient.
- the characteristics of the polymer are such that the active ingredient will be released slowly into the patient over time through delayed dissolution or controlled diffusion.
- the process conditions particularly the temperature of the ingredients, the mixing time, and the manner in which (1) the supercritical fluid is released from the reactor or (2) the slurry is discharged from the reactor can be varied to control the size of the particles and the porosity thereof. Variations in the sizes of the particles and their porosity control the performance characteristics of the resultant products.
- a polymer matrix would be known that could be used to produce high strength orthopedic and pharmaceutical mixtures. Any such polymer matrix preferably would meet or exceed the performance characteristics of existing polymer matrices as described in the Polymer Matrices Patent and the Pharmaceutical Mixture Patent. Any such polymer matrix desirably would be very easy to manufacture.
- the present invention provides a new and improved polymer matrix and a process for its manufacture that can be used to make high strength orthopedic and pharmaceutical mixtures.
- the invention involves the discovery that a polymer matrix having strength gains of several orders of magnitude can be produced by blending, or alloying, known polymers.
- the resultant polymer matrices are homogeneous, have enhanced strength, and are not fractionated or degraded.
- Polymer matrices according to the invention are prepared by charging a reactor with starting materials that include two or more polymers.
- a process medium is added to the reactor.
- the process medium preferably is carbon dioxide which is supplied to the reactor in a supercritical state or which is heated and pressurized in the reactor to attain a supercritical state.
- the heated and pressurized ingredients are mixed in the reactor for a period of time sufficient to form them into a homogeneous, gas-saturated suspension, or supercritical fluid slurry. After the ingredients have been mixed adequately, the slurry either is left in the reactor or is discharged into a receiving vessel where the process medium is separated from the remainder of the materials and removed, leaving finely divided particles behind.
- Figure 1 is a schematic view of apparatus suitable for practicing the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENT
- FIG. 1 apparatus for practicing the present invention is indicated generally by the reference numeral 10.
- the apparatus 10 is described in U.S. Patent 5,399,597, entitled Method of Preparing Coating Materials, issued March 21 , 1997 to Frederick S. Mandel, et al. Reference also is made to U.S.
- Patent 5,399,597 entitled Method of Preparing Coating Materials, issued March 21 , 1995 to Frederick S. Mandel, et al.
- U.S. Patent 5,698,163 entitled Control System for Processes Using Supercritical Fluids, issued December 16, 1997 to Frederick s. Mandel, for a description of a control system for the apparatus 10. Additional details of the apparatus 10 can be found in U.S. Patent 6,054,103, entitled Mixing System for Processes Using Supercritical Fluids, issued to Frederick S. Mandel; U.S. application serial no. 09/315,616, entitled Delivery System for Processes Using Supercritical Fluids, filed May 20, 1999 by Frederick S. Mandel; and U.S. Patent 5,993,747, entitled Mixing System for Processes Using Supercritical Fluids, issued November 30,
- the apparatus 10 includes a reactor 12 that is connected by conduit 13 to a receiving vessel 14.
- a conduit 15 connects the reactor 12 to a source 16 of a process medium such as liquid carbon dioxide.
- the process medium preferably is fed under pressure into reactor 12 using a compressor or liquid pump 18.
- the receiving vessel 14 is connected by conduit 20 to a return tank 22.
- the return tank 22 is connected by conduit 24 to the source 16 of the process medium.
- Reactor 12 includes, preferably at its base, a valve 26 for facilitating the emptying of the contents of the reactor 12 into the receiving vessel 14.
- a conduit 28 connects the top portion of the reactor 12 to conduit 20.
- a control valve 30 is included in conduit 28.
- a compressor 32 is included in conduit 20.
- Compressor 32 compresses and transfers gas emanating from the reactor 12 or the receiving vessel 14 into the return tank 22.
- Reactor 12 includes a sealable opening or access port (not shown) that permits material to be charged into the reactor 12.
- Reactor 12 also includes a mechanical stirring device 34 for mechanically agitating and stirring the contents of reactor 12 so as to form a homogeneous mixture.
- the access port is equipped with a quick-opening, breech-lock system that requires no hand tools to open and close.
- reactor 12 preferably includes a feed port having a valve (not shown) that facilitates the quick addition of minor amounts of material (e.g., polymer) to the reactor 12 once it has been pressurized.
- Reactor 12 and receiving vessel 14 preferably are made of stainless steel. However, it will be appreciated that a number of alternative materials may be utilized, such as, for example, nickel-coated carbon steel or carbon steel vessels having chemically inert inserts or liners. A particularly desirable reactor 12 is shown in U.S. Patent 6,054,103, referred to previously.
- conduit 13 The length of conduit 13 is minimized as much as possible.
- Conduit 13 can be in the form of a constant-diameter tubing.
- an orifice can be disposed in the conduit 13 just prior to receiving vessel 14.
- a header 36 can be disposed in conduit 13 just prior to receiving vessel 14.
- the header 36 includes a nozzle having multiple openings through which the . homogeneous mixture is sprayed. Any number of nozzle openings may be employed to spray the slurry.
- the selection of the proper nozzle will be a function of various parameters, such as, for example, the pressure employed in reactor 12, the size of particles and flow rates desired, and the starting materials and process medium being used.
- an orifice in the conduit 13 or the openings in a spray nozzle in the header 36 have a diameter of from about 0.001 inch to about 1 inch, preferably from about 0.005 inch to about 0.5 inch, and more preferably from about 0.01 inch to about 0.1 inch.
- suitable spray nozzles are hydraulic atomizing nozzles sold by Spraying Systems Co. of Wheaton, 111. Reference is made to application serial no. 09/315,616, referred to previously, for a disclosure of a particularly desirable control valve 26 and header 36.
- Mechanical stirring device 34 comprises an electric motor 38 that drives a mixer 40.
- Mixer 40 may comprise any number of conventional mixing devices.
- the selection of the proper mixer will be a function of various parameters, such as, for example, the size of motor 38, the materials being mixed, the configuration of the reactor 12, the process medium being utilized and the pressure employed in vessel 12.
- An example of a suitable mixer 40 is a Cowles blade mixer sold by Indco, Inc. of New Albany, Indiana. Reference is made to U.S. Patent 6,054,103, referred to previously, for a disclosure of a particularly effective mixer 40. It will be appreciated that the present invention preferably provides for both distributive and dispersive mixing.
- Apparatus 10 is employed in accordance with the present invention by first charging the starting materials for the pharmaceutical that one desires to produce into the reactor 12. Reactor 12 then is sealed and isolated. The process medium from source 16 then is fed into reactor 12 via conduit 15 until a suitable quantity has been introduced into reactor 12. A critical temperature can be attained by heating reactor 12, heating the liquid/gas stream as it enters reactor 12, by agitating reactor 12, or by combinations of these techniques. The pressure and temperature in reactor 12 converts the process medium into a supercritical fluid.
- Reactor 12 is maintained at an internal temperature of about -85°C. to about 200°C.
- a temperature of about 15°C. to about 160°C. is employed, and preferably about 20°C. to about 150°C, and more preferably about 31 °C. to about 100°C.
- the particular temperature utilized will be a function of various variables such as, for example, the gas utilized, the composition of the starting materials, the pressures employed and equipment configurations. Pressure from about 350 psi to about 20,000 psi may be utilized.
- a pressure of about 550 psi to about 7000 psi is utilized, and preferably about 950 psi to about 5000 psi, and more preferably about 1080 psi to about 4500 psi.
- the particular pressure utilized will be a function of such variables as the temperature of the reactor 12 and the particular process medium utilized.
- motor 38 is energized and the starting materials and the supercritical fluid are thoroughly mixed to form a homogeneous, gas-saturated suspension, otherwise referred to as a supercritical fluid slurry.
- reactor 12 is held below the melting point of the materials being processed.
- the temperature in reactor 12 preferably is in the range of from about 5 degrees below the T g (i.e., glass transition temperature) of at least one of the materials being processed up to about the melting point of such one material.
- T g i.e., glass transition temperature
- melting point means the temperature at which the material become wholly fluid. It is believed that a supercritical fluid will suppress the T g of most materials.
- reactor 12 may be equipped with heat exchangers or other suitable heating/cooling means.
- the starting materials are mixed in reactor 12 for a period of about 1 to about 480 minutes, preferably about 5 to about 300 minutes and more preferably from about 30 to about 240 minutes.
- the viscosity of the supercritical fluid slurry is a function of the temperature and the density of the process medium.
- valve 30 is opened in order to depressurize reactor 12 and permit the flow of gaseous process medium into return tank 22.
- the recycled process medium is made available for purposes of reuse by being transferred via conduit 24 to conduit 15.
- receiving vessel 14 is held at a constant pressure.
- the pressure in receiving vessel 14 is lower than that in the reactor 12 so that the slurry enters receiving vessel 14 at a very high rate.
- Receiving vessel 14 is maintained at a starting temperature of about -85°C. to about 220°C, preferably about -18°C. to about 160°C., and more preferably about 0°C. to about 130°C.
- receiving vessel 14 is maintained at a temperature below the melting point of the materials being processed.
- Receiving vessel 14 is maintained at a pressure of about 0 psi to about 5000 psi, preferably about 100 psi to about 2000 psi, and more preferably about 150 psi to about 1000 psi.
- the particular pressure and temperature utilized in receiving vessel 14 are a function of various variables, such as the particular process medium utilized and the composition of the starting materials.
- the present invention uses a process medium that is capable of achieving a supercritical state.
- supercritical fluid means a material that at specific temperatures and pressures no longer displays the properties of either a gas or a liquid.
- potential supercritical fluids suitable for use with the present invention include carbon dioxide, water, nitrous oxide, methane, ethane, ethylene, propane, pentane, benzene, methanol ethanol, isopropanol, various fluorocarbons such as cholrotrifluoromethane and monofluoromethane, toluene, pyridine, cyclohexane, decalin, cyclohexanol, o- xylene, and tetralin.
- C0 2 carbon dioxide
- Carbon dioxide is preferred because it is non- toxic, nonflammable, reasonably priced, and is easily separated or removed from the constituents used in making pharmaceuticals at the contemplated temperatures and pressures. Therefore, there will be no residual C0 2 in the finished products that could contribute to toxicity problems when contacted by a patient. Also, the critical temperature of C0 2 is sufficiently low that the biologically active materials used in the process will not be affected adversely.
- process media may be used to produce pharmaceuticals in accordance with the principles of the present invention, care must be taken not to utilize starting materials that are soluble in the process medium at operating temperatures and pressures. If the starting materials are soluble in the process medium, it will not be possible to transfer the starting materials to the receiving vessel 14 without losing some of the starting materials to the storage tank 22, which would be a very undesirable result.
- Starting materials that are used in the present invention are polymers that have a low melting temperature and which are capable of being formed into microscopic particles having suitable porosity to accept a biologically active material. Because the pharmaceuticals produced by the present invention are intended for use in the human body, potentially harmful additives such as pigments, flow control agents, extenders, and the like should not be used.
- thermoplastic thermoset
- Polymers suitable for use in controlled drug release are discussed in K. Ulrich, et al., Polymeric Systems for Controlled Drug Release,
- polymers are suitable for use with the present invention.
- suitable polymers include polyesters, polyorthoesters, polyanhydrides, polyamides, and phosphorous-containing polymers. It has been found that hydroxy-methyl cellulose and derivative-type polymers (e.g., hydroxy propyl cellulose) and polylactide-co-glycolide (e.g., Medisorb 8515 DL High I.V.) function well as part of the present invention.
- hydroxy-methyl cellulose and derivative-type polymers e.g., hydroxy propyl cellulose
- polylactide-co-glycolide e.g., Medisorb 8515 DL High I.V.
- suitable polymers as specified in the Polymer Article include polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol, polyethylene-vinyl acetate, polyenol-ketone, polyacrylic acid, polycarbophil, polyacrylamides, poly-N- isopropyl acrylamide, polyacrylates, polyethylene glycol, polyglycolic acid, polylactic acid, poly-e-caprolactone, poly-3-hydroxybutyrate, polyortho esters,
- polyanhydrides polyamino acids, pseudo-polyamino acids, polyamide-enamines, polyamido amines, polyurethanes, azopolymers, polydimethylsiloxane, and polyphosphazenes.
- Biologically active ingredients suitable for use with the present invention include inorganic or organic molecules, peptides, proteins, oligosaccharides,
- the biologically active ingredients can include compounds that treat the following:
- Infections antiviral drugs, antibacterial drugs, antifungal drugs, and anthelmintics.
- Cardiovascular system positive inotropic drugs, diuretics, anti- :0 arrhythmic drugs, beta-ad renoceptor blocking drugs, calcium channel blockers, sympathomimetics, anticoagulants, anti-platelet drugs, fibrinolytic drugs, and lipid-Iowering drugs.
- Gastro-intestinal system antacids, antispasmodics, ulcer-healing drugs, anti-diarrhoeal drugs, and laxatives.
- Central nervous system hupnotics and anxiolytics, anti-psychotics, antidepressants, central nervous system stimulants, appetite suppressants, drugs used to treat nausea and vomiting, analgesics, anti-epileptics, drugs used in parkinsonism, and drugs used in substance dependence.
- Malignant disease and immunosuppresion cytotoxic drugs, immune response modulators, and sex hormones and antagonists of malignant diseases.
- Respiratory system bronchodilators, corticosteroids, cromoglycate and related therapy, antihistamines, respiratory stimulants, pulmonary surfactants, and systemic nasal decongestants.
- Musculoskeletal and joint diseases drugs used in rheumatic diseases, and drugs used in neuromuscular disorders.
- Pharmaceuticals produced in accordance with the present invention can be fabricated into tablets, powders, granules, capsules, suppositories, pessaries, colloidal suspensions, matrices, gels, micro-particles, monoliths, pastes, and creams.
- the pharmaceuticals can be administered by pulmonary, oral, rectal, parenteral, epicutaneous, or mucosal routes. Delivery of active ingredients may be accomplished via a series of methods including modified release via polymer biosorption or enhanced release via extended surface area. Active drugs have been placed in biosorption matrices at as little as 0.5% to 99%. The levels have been modified to below percolation threshold to well above.
- C0 2 gas is utilized as a process medium
- C0 2 is charged to or utilized in reactor 12 so as to provide from about 1.0% by weight to about 99.0% by weight C0 2 and from about 99.0% by weight to about 1.0% by weight starting materials, preferably from about 20% by weight to about 80% by weight C0 2 and from about 80% by weight to about 20% by weight starting materials, and more preferably from about 40% by weight to about 60% by weight C0 2 and from about 60% by weight to about 40% by weight starting materials.
- the materials in receiving vessel 14 are a collection of homogeneous, uniformly sized particles. In the unlikely event that any oversize particles or an agglomeration of particles (foam) are contained in receiving vessel 14, the product must be rejected.
- the amount of carbon dioxide absorbed and hence the amount of polymer swelling is proportional to temperature and pressure.
- the swelling could be as much as 66% or greater. This swelling leaves a large void volume within- the polymer.
- the rate of degassing or depressurization can influence the pore size of the particles as well as the size of the particles themselves.
- the depressurization is accomplished b way of controlled release from the receiving vessel 14 and a variable rate can be set.
- the density of the swollen polymer usually is equalized to that of the supercritical fluid density of the process medium. This permits the starting materials to be suspended in a mixture of equivalent density.
- a range of materials can be produced that possess high surface areas with relatively low surface areas as well.
- the high surface area materials will give an immediate dosage of the biologically active material whereas the low surface area materials will require significant biosorption before release of the biologically active material to the host system. Rapid or slow degassing of the mixture can further induce additional control of the formulation's release characteristics.
- the apparatus 10 has been described as including various components downstream of the reactor 12 such as the conduit 13, receiving vessel 14, flush valve 26, etc., it is possible to produce acceptable product according to the invention without any such components. Suitable product can be prepared merely by mixing the supercritical fluid slurry in the reactor 12 and then releasing the internal pressure in a controlled manner.
- pore sizes will range between 1-400 microns, with
- Reactor 12 was filled with 5.4 pounds of liquid C0 2 from source 16.
- the source 16 of C0 2 is a standard commercial source maintained at a temperature of about -18°C. and a pressure of about 300 psi.
- the reactor 12 was heated to 38°C at a pressure of 2050 psi, thereby rendering the C0 2 a supercritical fluid.
- the starting materials and supercritical fluid were maintained under these conditions while being mixed for 60 minutes using agitation device 34.
- the mixer 40 was rotated at a rate of 200 rpm. After 60 minutes, the temperature was raised to 65°C resulting in a pressure of 3700 psi. The contents were stirred for another 30 minutes before the C0 2 was released and pressure returned to ambient. A homogeneous polymer blend was produced.
- the starting materials consisted of 95% PCL and 5% PVA.
- the starting materials consisted of 67% PCL and 33% PVA.
- Acceptable product was produced in each experiment. Suitable material ranges for the polymer starting materials are 1-99% for a given polymer and 1-99% for the other polymer.
- the pressure in the reactor 12 can be varied between 290-14,500 psi, the temperature can vary between 0- 127°C, and the mixing rate can vary between 1-200 rpm.
- the process of the invention can be used to produce mixtures suitable for orthopedic applications.
- the polymer blend from Example 1 was pulverized and mixed with hydroxyapatite (HA) in a ratio of 70% polymer alloy to 30% HA.
- the mixture was charged into a one-gallon reactor 12.
- Reactor 12 was filled with 5.5 pounds of liquid C0 2 from source 16.
- the reactor 12 was heated to 38°C at a pressure of 1600 psi, thereby rendering the C0 2 a supercritical fluid.
- the starting materials and supercritical fluid were maintained under these conditions while being mixed for 60 minutes using agitation device 34.
- the mixer 40 was rotated at a rate of 145 rpm. After 60 minutes, the temperature was raised to 65°C resulting in a pressure of 3000 psi.
- EXAMPLE 4 Several mixtures of zinc stearate and calcium stearate in a 50:50 ratio were premixed and charged into a one-gallon reactor 12 that was filled with C0 2 from source 16. The materials were mixed for 60 minutes or more at a temperature of 120°C and a pressure of approximately 3000 psi. Thereafter, the flush valve 26 was opened and the mixture was transferred through the conduit 13. The mixture was atomized into the vessel 14 to produce a finely divided powder. Although the ingredients in this Example were not polymers perse, the experiment demonstrates the usefulness of the blending concept.
Abstract
Description
Claims
Priority Applications (3)
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US12/027,728 US8568766B2 (en) | 2000-08-24 | 2008-02-07 | Peptides and peptide mimetics to treat pathologies associated with eye disease |
US13/804,161 US20130295042A1 (en) | 2000-08-24 | 2013-03-14 | Peptides and Peptide Mimetics to Treat Pathologies Associated With Eye Disease |
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US10/187,215 Continuation-In-Part US7144862B2 (en) | 2000-08-24 | 2002-06-28 | Orally administered peptides to ameliorate atherosclerosis |
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US10/273,386 Continuation-In-Part US7166578B2 (en) | 2000-08-24 | 2002-10-16 | Orally administered peptides synergize statin activity |
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Cited By (4)
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5508060A (en) * | 1993-02-11 | 1996-04-16 | Minnesota Mining And Manufacturing Company | Method of polymer impregnation |
US5800758A (en) * | 1997-09-16 | 1998-09-01 | Kimberly-Clark Worldwide, Inc. | Process for making microporous films with improved properties |
US6005013A (en) * | 1995-08-14 | 1999-12-21 | Massachusetts Institute Of Technology | Gear throttle as a nucleation device in a continuous microcellular extrusion system |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6005162A (en) | 1988-04-20 | 1999-12-21 | Norian Corporation | Methods of repairing bone |
DE4029969A1 (en) | 1989-09-21 | 1991-04-04 | Asahi Optical Co Ltd | METHOD FOR PRODUCING BONE PROSTHESES |
DE4041563A1 (en) * | 1990-12-22 | 1992-06-25 | Sanol Arznei Schwarz Gmbh | METHOD FOR PRODUCING ACTIVE MICROPARTICLES FROM HYDROLYTICALLY DEGRADABLE POLYMERS |
AU678788B2 (en) | 1992-11-02 | 1997-06-12 | Ferro Corporation | Method of preparing coating materials |
US5554382A (en) * | 1993-05-28 | 1996-09-10 | Aphios Corporation | Methods and apparatus for making liposomes |
GB9313642D0 (en) * | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
AU5717296A (en) | 1995-05-10 | 1996-11-29 | Ferro Corporation | Control system for processes using supercritical fluids |
US5989289A (en) | 1995-10-16 | 1999-11-23 | Sdgi Holdings, Inc. | Bone grafts |
US5874029A (en) * | 1996-10-09 | 1999-02-23 | The University Of Kansas | Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent |
US5766637A (en) * | 1996-10-08 | 1998-06-16 | University Of Delaware | Microencapsulation process using supercritical fluids |
GB9800936D0 (en) | 1997-05-10 | 1998-03-11 | Univ Nottingham | Biofunctional polymers |
US5993747A (en) | 1997-06-25 | 1999-11-30 | Ferro Corporation | Mixing system for processes using supercritical fluids |
US6054103A (en) | 1997-06-25 | 2000-04-25 | Ferro Corporation | Mixing system for processes using supercritical fluids |
-
2000
- 2000-09-08 US US09/658,251 patent/US6521258B1/en not_active Expired - Lifetime
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- 2001-08-24 WO PCT/US2001/026457 patent/WO2002020645A2/en active Application Filing
- 2001-08-24 AU AU2001285255A patent/AU2001285255A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5508060A (en) * | 1993-02-11 | 1996-04-16 | Minnesota Mining And Manufacturing Company | Method of polymer impregnation |
US6005013A (en) * | 1995-08-14 | 1999-12-21 | Massachusetts Institute Of Technology | Gear throttle as a nucleation device in a continuous microcellular extrusion system |
US5800758A (en) * | 1997-09-16 | 1998-09-01 | Kimberly-Clark Worldwide, Inc. | Process for making microporous films with improved properties |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7641917B2 (en) | 2001-05-30 | 2010-01-05 | Csir | Method of encapsulating an active substance |
US7605252B2 (en) | 2002-11-14 | 2009-10-20 | Dharmacon, Inc. | siRNA targeting kinase insert domain receptor (KDR) |
EP1605984B1 (en) * | 2003-03-27 | 2011-09-21 | Regentec Ltd | Porous matrix |
US10232087B2 (en) | 2003-03-27 | 2019-03-19 | Locate Therapeutics Limited | Porous matrix |
KR20190007091A (en) * | 2010-10-22 | 2019-01-21 | 어퀘스티브 테라퓨틱스, 인크. | Manufacturing of small film strips |
KR102005223B1 (en) | 2010-10-22 | 2019-07-29 | 어퀘스티브 테라퓨틱스, 인크. | Manufacturing of small film strips |
Also Published As
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US6521258B1 (en) | 2003-02-18 |
WO2002020645A3 (en) | 2002-07-18 |
AU2001285255A1 (en) | 2002-03-22 |
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