WO2002020624A1 - Medicaments a liberation prolongee prepares par des techniques de traitement par fluides supercritiques - Google Patents

Medicaments a liberation prolongee prepares par des techniques de traitement par fluides supercritiques Download PDF

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Publication number
WO2002020624A1
WO2002020624A1 PCT/US2001/026383 US0126383W WO0220624A1 WO 2002020624 A1 WO2002020624 A1 WO 2002020624A1 US 0126383 W US0126383 W US 0126383W WO 0220624 A1 WO0220624 A1 WO 0220624A1
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WO
WIPO (PCT)
Prior art keywords
drugs
reactor
polymer
supercritical fluid
starting materials
Prior art date
Application number
PCT/US2001/026383
Other languages
English (en)
Inventor
Frederick S. Mandel
J. Don Wang
Steven M. Howdle
Kevin M. Shakesheff
Original Assignee
Ferro Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Ferro Corporation filed Critical Ferro Corporation
Priority to AU2001285242A priority Critical patent/AU2001285242A1/en
Publication of WO2002020624A1 publication Critical patent/WO2002020624A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/04—Specific aggregation state of one or more of the phases to be mixed
    • B01F23/043—Mixing fluids or with fluids in a supercritical state, in supercritical conditions or variable density fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/405—Methods of mixing liquids with liquids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/49—Mixing systems, i.e. flow charts or diagrams
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • 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
    • B01F27/90—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with paddles or arms 
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions

Definitions

  • the invention relates to the use of supercritical fluid processing techniques to prepare mixtures of pharmaceuticals with various polymeric excipients, particularly for the purpose of producing controlled-release pharmaceuticals.
  • Description of the Prior Art There is a continuing need for high quality pharmaceuticals, particularly pharmaceuticals whose active ingredient can be released gradually over an extended period of time or at a specific time during treatment.
  • the phase "controlled-release” will be used herein to describe techniques to modify the rate at which active ingredients are released. Such techniques include delayed dissolution and diffusion control.
  • controlled-release pharmaceuticals have been known for some time, they suffer from various drawbacks.
  • One type of controlled-release pharmaceutical relies on micro encapsulation.
  • micro encapsulation a very small particle or droplet of an active ingredient to be dispensed into a patient forms a core material that is coated with or embedded in an inert shell.
  • the core material is released from the shell through erosion, permeation, or rupture of the shell. Variations in the thickness or material of the shell can be used to control the rate or timing with which the core material is released from the shell.
  • Micro encapsulation processes are very difficult and time-consuming to perform and often produce a large quantity of material that is out of specification. Although attempts have been made to improve micro encapsulation processes, certain difficulties remain. For example, in the process disclosed in U.S.
  • liposomes are produced by dissolving certain of the ingredients in solvents such as methanol, ethanol, and acetone.
  • solvents such as methanol, ethanol, and acetone.
  • solvents such as methanol, ethanol, and acetone.
  • solvents such as methanol, ethanol, and acetone.
  • a micro encapsulation process is disclosed that avoids the use of solvents, but the disclosed process still produces micro capsules which are believed to inherently suffer from a lack of consistency, and which therefore cannot release a drug into a patient at a uniform rate over a long period of time.
  • Another type of controlled-release pharmaceutical is a microscopic particle that is infused with an active ingredient.
  • Such particles can be manufactured easier than micro capsules, and they have the potential to produce more uniform and predictable drug release.
  • Numerous techniques are known to manufacture such particles, such techniques being exemplified by U.S. 5,424,076, U.S. 5,851 ,453, and U.S. 5,874,029, among others.
  • Each of the referenced techniques relies on a solvent of some type to dissolve various ingredients, with the solvent being removed at a later stage of the process.
  • the solvent is completely removed from the particles prior to completion of the manufacturing process, the use of such solvents causes the process to be more expensive and difficult to perform than desired.
  • a process would be known that would produce microscopic particles that would release an active ingredient into a patient at a uniform rate over a long and predictable period of time. Any such process desirably would be easy to practice and would avoid the use of solvents completely.
  • the present invention provides an effective technique for the manufacture of controlled-release pharmaceuticals.
  • Pharmaceutical mixtures according to the invention are prepared by charging a reactor with starting materials that include a biologically active ingredient and a polymer.
  • 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.
  • 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.
  • the finely divided, engineered polymer particles are infused with the biologically active ingredient and can be incorporated into tablets, capsules, or the like for ingestion by patients.
  • the pore sizes are designed to optimize the drug delivery profile.
  • the sizes of the particles and the sizes of the pores can be controlled very accurately in order to dispense a known quantity of drugs or other biologically active ingredients at a uniform rate into a patient over a predictably long period of time. Due to the low temperature of the process, there will be little or no diminution of biologic ' activity of the biologically active ingredient.
  • Figure 1 is a schematic view of apparatus suitable for practicing the present invention.
  • 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
  • Patent 5,698,163 entitled Control System for Processes Using Supercritical
  • 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
  • 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, III. 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.
  • 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 a heat exchanger 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 While the slurry is being transferred to receiving vessel 14, receiving vessel 14 is held at a constant pressure. Preferably 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. As with reactor 12, in order to maintain the desired temperature in receiving vessel 14, a heat exchanger or other cooling/heating device may be necessary. Preferably, 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.
  • Examples of potential supercritical fluids suitable for use with the present invention include carbon dioxide and nitrous oxide. The critical properties for these compounds are set forth below. The present invention contemplates the use of these compounds either by themselves or in combination.
  • 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 problems when used as pharmaceuticals. Also, the critical temperature of C0 2 is sufficiently low that the biologically active materials used in the process will not be affected adversely.
  • 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. Categories of acceptable polymers include thermoplastic, thermoset, or a combination of both. Polymers suitable for use in controlled drug release are discussed in K. Ulrich, et al., Polymeric Systems for Controlled Drug Release, Journal of the American Chemical Society (1999)("the Polymer Article”). It is believed that such polymers are suitable for use with the present invention.
  • polyesters As noted in the Polymer Article, categories of 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 IN.) 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 IN.
  • polymers as specified in the Polymer Article include polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol, polyethylene-vinyl acetate, polyenol-ketone, polyacrylic acid, polycarbophil, polyacrylamides, poly- ⁇ - 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.
  • Bioly active ingredients suitable for use with the present invention include inorganic or organic molecules, peptides, proteins, oligosaccharides, carbohydrates, nucleic acids, steroidals, and small molecules such as aspirin, morphine, steroids, anti-diarrheals, anti-diabetics, etc.
  • 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- arrhythmic drugs, beta-ad renoceptor blocking drugs, calcium channel blockers, sympathomimetics, anticoagulants, anti-platelet drugs, fibrinolytic drugs, and lipid-lowering drugs.
  • Gastro-intestinal system antacids, antispasmodics, ulcer-healing drugs, anti-diarrheals drugs, and laxatives.
  • Central nervous system hypnotics 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.
  • Pharmaceutical mixtures 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 can be placed in biosorption matrices at concentrations from 0.5% to 99%. The levels can be modified from below percolation threshold to well above. For the high threshold materials, many of the biosorbable polymers have from 25 to 100% pore interconnectivity which provides an additional mechanism for drug release.
  • 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, engineered polymer 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 byway 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.
  • atomization is carried out, 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.
  • use of the components downstream of the reactor 12, particularly orifices or nozzles in the conduit 13, enables accurate control of particle size to be attained more easily. Because the particle size can be controlled accurately, pharmaceuticals having predictable, desired characteristics can be produced easily.
  • the C0 2 was released from reactor 12 until ambient pressure was attained. During pressure release, the reactor 12 was cooled with water. The reactor 12 was opened to yield a cake composed of finely divided particles, each containing 50% enzyme and 50% polymer.
  • Suitable material ranges for the enzyme starting material are 1-99% and 1-99% for the polymer starting material (PCL or PLGA).
  • 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 1-150 rpm.
  • EXAMPLE 2 A series of experiments were conducted to vary the ratio of enzyme to polymer. Catalase to PLGA (RG755) ratios from 5:95 to 40:60 were tested. In each experiment, the mixture was charged into a 250 ml TEFLON beaker that was placed into a one-gallon reactor 12. Reactor 12 was filled with liquid C0 2 from source 16.
  • the filled reactor 12 was heated to 38°C and pressurized to pressures within the range of 1800-2200 psi, thereby rendering the C0 2 a supercritical fluid.
  • the starting materials and supercritical fluid were maintained under these conditions while being mixed for 30 minutes using agitation device 34.
  • the mixer 40 was rotated at a rate of about 80 rpm.
  • water was turned on to cool the system as C0 2 was released from the reactor 12 until ambient pressure was attained.
  • the reactor 12 was opened to yield a monolithic, porous product.
  • Suitable material ranges for the catalase enzyme starting material are 1- 99% and 1-99% for the PCL/PLGA polymer starting material.
  • 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 1-150 rpm.
  • Reactor 12 was sealed, filled with 6.3 pounds of liquid C0 2 from source 16, and heated to 50°C at a pressure of 2770 psi, thereby rendering the C0 2 a supercritical fluid.
  • the starting materials and supercritical fluid were maintained under these conditions while being mixed for 75 minutes using agitation device
  • PLGA Medium Absorb 8515 DL High I.V.
  • Reactor 12 was sealed, filled with 6.4 pounds of liquid C0 2 from source 16, and heated to 40°C at a pressure of 3400 psi, thereby rendering the C0 2 a supercritical fluid.
  • the starting materials and supercritical fluid were maintained under these conditions while being mixed for one hour using agitation device 34.
  • the mixer 40 was rotated at a rate of 55 rpm. Thereafter, the flush valve 26 was opened and the mixture was transferred through the conduit 13 (heated to 50°C). The mixture was atomized into the vessel 14 to produce 4.5 grams of finely divided powder. Controlled release studies were conducted on the recovered product.
  • Suitable material ranges for the sodium fluorescein starting material are 1-99% and 1-99% for the PCL/PLGA polymer starting material.
  • 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 1-150 rpm.
  • An anti-cancer drug (Gooserlein Acetate) and a biodegradable PLGA
  • Reactor 12 was sealed, filled with 6.4 pounds of liquid C0 2 from source 16, and heated to 40°C at a pressure of 3100 psi, thereby rendering the C0 2 a supercritical fluid.
  • the starting materials and supercritical fluid were maintained under these conditions while being mixed for one hour using agitation device 34.
  • the mixer 40 was rotated at a rate of 108 rpm. Thereafter, the flush valve 26 was opened and the mixture was transferred through the conduit 13 (heated to
  • the mixture was atomized into the vessel 14 to produce a finely divided powder.
  • Suitable material ranges for the anti-cancer starting material are 1-36% and 64-99% for the PLGA polymer starting material.

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Abstract

L'invention concerne des médicaments à libération prolongée préparés par mélange de produits de départ et d'un milieu de traitement dans un réacteur de manière à former une bouillie de fluides supercritiques. Les matériaux de départ comprennent un principe biologiquement actif et un polymère. Le milieu de traitement est, de préférence, du dioxyde de carbone, lequel est fourni au réacteur à l'état supercritique ou chauffé et mis sous pression dans le réacteur afin d'atteindre un état supercritique. Après avoir été mélangée durant un certain laps de temps, la bouillie est, soit maintenue dans le réacteur, soit déversée dans un récipient. Le milieu de traitement est séparé des autres matériaux puis, retiré, laissant derrière lui des particules fines. Ces particules consistent en des particules poreuses de polymère infusées avec l'ingrédient biologiquement actif. Les particules fines peuvent être incorporées dans des comprimés, dans des capsules, ou dans des articles analogues pour que des patients puissent les ingérer.
PCT/US2001/026383 2000-09-08 2001-08-23 Medicaments a liberation prolongee prepares par des techniques de traitement par fluides supercritiques WO2002020624A1 (fr)

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AU2001285242A AU2001285242A1 (en) 2000-09-08 2001-08-23 Controlled-release pharmaceuticals prepared by supercritical fluid processing techniques

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US65824900A 2000-09-08 2000-09-08
US09/658,249 2000-09-08

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009672A1 (fr) * 2002-07-19 2004-01-29 Nektar Therapeutics Uk Ltd Polyalkylene glycols, derives et conjugues de ceux-ci sous forme particulaire
WO2004096280A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau et procede de preparation de cette derniere
WO2004096281A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau presentant une excellente propriete d'elution, procedes de preparation de cette derniere
US7641917B2 (en) 2001-05-30 2010-01-05 Csir Method of encapsulating an active substance
WO2017128184A1 (fr) * 2016-01-28 2017-08-03 深圳市博恩实业有限公司 Dispositif de traitement de pâte et de colloïde industriel avant utilisation
CN108379562A (zh) * 2018-03-20 2018-08-10 苏州杰纳生物科技有限公司 一种聚合物纳米佐剂及其制备方法和用途

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US5399597A (en) * 1992-11-02 1995-03-21 Ferro Corporation Method of preparing coating materials

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US5399597A (en) * 1992-11-02 1995-03-21 Ferro Corporation Method of preparing coating materials

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7641917B2 (en) 2001-05-30 2010-01-05 Csir Method of encapsulating an active substance
WO2004009672A1 (fr) * 2002-07-19 2004-01-29 Nektar Therapeutics Uk Ltd Polyalkylene glycols, derives et conjugues de ceux-ci sous forme particulaire
WO2004096280A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau et procede de preparation de cette derniere
WO2004096281A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau presentant une excellente propriete d'elution, procedes de preparation de cette derniere
US8101207B2 (en) 2003-04-29 2012-01-24 Kowa Co., Ltd. Composition containing medicine extremely slightly soluble in water and method for preparation thereof
US8105630B2 (en) 2003-04-29 2012-01-31 Kowa Co., Ltd. Composition containing medicine extremely slightly soluble in water being excellent in eluting property and method for preparation thereof
WO2017128184A1 (fr) * 2016-01-28 2017-08-03 深圳市博恩实业有限公司 Dispositif de traitement de pâte et de colloïde industriel avant utilisation
CN108379562A (zh) * 2018-03-20 2018-08-10 苏州杰纳生物科技有限公司 一种聚合物纳米佐剂及其制备方法和用途

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