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WO2003059325A1 - Compositions a administration par voie magnetique - Google Patents

Compositions a administration par voie magnetique Download PDF

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Publication number
WO2003059325A1
WO2003059325A1 PCT/US2003/000489 US0300489W WO03059325A1 WO 2003059325 A1 WO2003059325 A1 WO 2003059325A1 US 0300489 W US0300489 W US 0300489W WO 03059325 A1 WO03059325 A1 WO 03059325A1
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Prior art keywords
biologically active
composition
particle
magnetic
iron
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PCT/US2003/000489
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English (en)
Inventor
Gilles Hugues Tapolsky
Yuhua Li
Sarah Nicole Failing
Scott Raymond Rudge
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FeRx Inc
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FeRx Inc
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Priority to AU2003214812A priority Critical patent/AU2003214812A1/en
Publication of WO2003059325A1 publication Critical patent/WO2003059325A1/fr
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Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis

Definitions

  • Targeted delivery systems have been developed based on antibodies or peptides linked to chemotherapeutic compounds, magnetic microparticles, magnetic liposomes, and regional therapy based on local injections. Also, particulate, implantable systems based on metallic or polymeric micro- or millimetric cylinders, biodegradable wafers, osmotic devices, and polymeric solutions forming a solid precipitate once injected parenterally have been used for a local treatment by local placement or injection.
  • magnetic microparticle technologies are based on lipid, polymeric or other appropriate matrices that contain iron oxide (usually as magnetite or hematite) as the magnetic targeting material.
  • iron oxide usually as magnetite or hematite
  • the necessity of enclosing both the magnetic material and the biologically active compound(s) within a polymeric matrix or lipid vesicle is well known, as the presence of the matrix makes possible the delivery of increased quantities of the biologically active compound above that which could be accomplished by use of the iron oxide particles alone.
  • the biologically active compound(s) need to be released from the particles and vesicles by either diffusion through the matrix, degradation of the particle over time, or any other mechanism leading to the still active biological compound being at the desired site at sufficient concentrations for a sufficient period of time.
  • ferrocarbon particles have been used for targeted delivery. These particles comprise iron and carbon composite particles, wherein the iron provides magnetic susceptibility and the carbon carries the drug. The presence of carbon, even in low quantities, is required for delivering biologically active compounds. While these particles overcome previous deficiencies, as with other targeted delivery systems, both a targeting moiety and a carrier moiety are present within the particles. Until now, methods for associating biologically active compounds directly with the magnetic material were not known.
  • the present invention relates to a single component capable of carrying a biologically active compound in relevant quantities to a specific site.
  • the magnetic particles have the general properties of having Curie temperatures (Tc) greater than the normal human body temperature (37°C), having high magnetic saturation (> approximately 20 Am 2 /kg), and being ferromagnetic or ferrimagnetic.
  • the magnetic particles include iron oxides such as Jacobsite (MnFe 2 0 ), Trevorite (NiFe 2 0 4 ), iron sulfides such as Pyrrhotite (Fe 7 S 8 ), and Greigite (Fe S 4 ), ceramics such as Aliiico 5, Alnico 5 DG, Sm 2 Co 17 , SmCo 5 and NdFeB, as well as metals and alloys, such as iron (Fe), cobalt (Co), nickel (Ni), awaruite (Ni 3 Fe) and wairauite (CoFe).
  • iron oxides such as Jacobsite (MnFe 2 0 ), Trevorite (NiFe 2 0 4 ), iron sulfides such as Pyrrhotite (Fe 7 S 8 ), and Greigite (Fe S 4 ), ceramics such as Aliiico 5, Alnico 5 DG, Sm 2 Co 17 , SmCo 5 and NdFeB, as well as metal
  • the magnetic particles and the magnetically susceptible compositions of the instant invention are the iron oxides magnetite (Fe 3 0 4 ), hematite ( ⁇ Fe 2 0 3 ), and maghemite ( ⁇ Fe 2 0 3 ).
  • Each of the magnetic particles can have added to its chemical formula specific impurities that may or may not alter the magnetic propreties of the material. Doped ferromagnetic or ferrimagentic materials within the above limits of Curie temperatures and magnetic saturation values are considered to be within the scope of the instant invention.
  • the term "metal particles” as used herein refers to paritcles formed from the metals and alloys listed above, while the term “metallic iron particles” refers to those formed from iron alone. Such particles are available commercially.
  • a magnetically susceptible composition comprising a magnetic particle that has attached thereon a biologically active compound.
  • a magnetically susceptible composition for the manufacture of a medicament, wherein said composition comprises a magnetic particle having attached thereon a biologically active compound.
  • a magnetically susceptible composition for ex vivo diagnostic imaging comprising: a) providing a combination of a biological material and a magnetically susceptible composition that comprises a magnetic particle having attached thereon a biologically active compound; b) applying a magnetic field to said combination; and c) analyzing said biological material to provide a diagnosis.
  • a kit for administering a biologically active substance comprising: a) a first receptacle comprising a unit dose of magnetic particles; and b) a second receptacle comprising a solution comprising one or more biologically active compounds.
  • a method for local regional therapy comprising: a) intra-arterial injection of a magnetically responsive composition comprising a magnetic particle having attached thereon a biologically active compound; and b) establishment of an external magnetic field adjacent to a desired target region.
  • a method for increasing the concentration of a biologically active compound at an in vivo site comprising: a) injecting into a patient a magnetically responsive composition comprising a magnetic particle having attached thereon a biologically active compound; and b) establishing an external magnetic field adjacent to the in vivo site where said increased concentration is desired.
  • a process for producing a magnetically susceptible composition comprising attaching a biologically active compound onto a magnetic particle.
  • a method for local regional therapy comprising: a) intravenous injection of a magnetically responsive composition comprising a magnetic particle having attached thereon a biologically active compound; and b) establishment of an external magnetic field adjacent to a desired target region.
  • a composition made by the process comprising attaching a biologically active compound onto a magnetic iron particle.
  • a magnetically susceptible composition comprising a magnetic iron particle having attached thereon a biologically active compound, whereby the composition is produced by a process comprising high-energy milling of said magnetic iron particle.
  • magentic particle is selected from the group consisting of iron, nickel, awaruite, wairauite, pyrrhotite, greigite, troilite, yttrium iron garnet, Alnico 5, Alnico 5 DG, Sm 2 C ⁇ 7 , SmCos and NdFeB particles.
  • magentic particle is selected from the group consisting of iron, nickel, awaruite, wairauite, pyrrhotite, greigite, troilite, yttrium iron garnet, Alnico 5, Alnico 5 DG, Sm 2 C ⁇ 7 , SmCos and NdFeB particles.
  • Another examplary group of the above embodiments occurs when the magnetic particle of the embodiment is selected from magnetic particles composed of iron, nickel, awaruite, wairauite, pyrrhotite, greigite, troilite, and yttrium iron garnet particles.
  • Yet another examplary embodiment of the above embodiments occurs when the magnetic particle is an iron particle. Yet another examplary embodiment of the above embodiments occurs when the magnetic particle is a wairauite (CoFe) particle. Another exemplary group of the above embodiments occurs when the magnetic particles are those that have a magnetic saturation value of approximately 100 AmVkg. Yet another exemplary group of of the above embodiments occurs when the magnetic particle of any of the above embodiments is ferrimagnetic.
  • magnetic particles of the present invention have a surface area less than 50 m 2 /g, well below values that would be considered useful for an adsorption/desorption process, hi particular, surface areas of iron particles measured by a surface area analyzer, for example BET, are less than 50 mVg and would have been considered too small to allow the adsorption of diagnostic or therapeutic quantities of pharmaceutical compounds in general, and especially of large macromolecules. Additionally, modification of the particle size of the magnetic iron would not have been considered to provide useful alternatives. For example, use of larger particles might preclude intravenous administration, while use of smaller particles might not yield sufficient magnetic susceptibility. Thus, iron particles would not have been considered as potential carriers to deliver therapeutically relevant quantities of biologically active compounds. Indeed, for the same reasons, none of the otlier instant magnetic particles would have been considered as potential carriers of biologically active compounds.
  • a useful delivery technology should be inert biologically, and ideally biocompatible or biodegradable.
  • Magnetic particles would, at first, not be considered as the ideal biologically inert system because of toxicity concerns.
  • the iron particles of the present invention are surprisingly biocompatible. The most likely reason for " this is a slow in vivo absorption process.
  • Figure 1 is a Scanning Electron Microscope (SEM) picture of metallic iron particles (unprocessed).
  • Figure 2 is the size distribution of the iron particles (unprocessed) using a light scattering technique.
  • Figure 3 shows the attachment efficiency of rhenium radical onto unprocessed and processed iron particles.
  • Figure 4 shows the stability in human plasma of the attached rhenium radical onto two different types of particles.
  • Figure 5 is a Scanning Electron Microscope (SEM) picture of metallic iron particles after a high-energy milling treatment.
  • Figure 6 shows the stability of Yttrium 90 attached to iron particles in human plasma at 37°C as a function of time.
  • Figure 7 shows the stability of rhenium radical attached to iron particles (processed and unprocessed) as a function of time.
  • the present invention relates to a single component capable of carrying a biologically active compound in relevant quantities to a specific site.
  • This combination of magnetic particles and one or more biologically active agents attached thereto is referred to herein as a "magnetically susceptible composition”.
  • the magnetic particles have the general properties of having Curie temperatures (Tc) greater than the normal human body temperature (37°C), having high magnetic saturation (> approximately 20 AnVVkg), and being ferromagnetic or ferimagnetic.
  • the magnetic particles include iron oxides such as Jacobsite (MnFe 2 0 4 ), Trevorite (NiFe 2 0 ), iron sulfides such as Pyrrhotite (Fe 7 S 8 ), and Greigite (Fe 4 S 4 ), ceramics such as Alnico 5, Alnico 5 DG, Sm 2 Co 17 , SmCo 5 and NdFeB, as well as metals and alloys, such as iron (Fe), cobalt (Co), nickel (Ni), awaruite (Ni 3 Fe) and wairauite (CoFe).
  • iron oxides such as Jacobsite (MnFe 2 0 4 ), Trevorite (NiFe 2 0 ), iron sulfides such as Pyrrhotite (Fe 7 S 8 ), and Greigite (Fe 4 S 4 ), ceramics such as Alnico 5, Alnico 5 DG, Sm 2 Co 17 , SmCo 5 and NdFeB, as well
  • iron oxides magnetite Fe 3 0 4
  • hematite Fe 2 0 3
  • maghemite ⁇ Fe 2 0 3
  • Each of the magnetic particles can have added to its chemical formula specific impurities that may or may not alter the magnetic propreties of the material.
  • Doped ferromagnetic or ferrimagentic materials within the above limits of Curie temperatures and magnetic saturation values are considered to be within the scope of the instant invention.
  • the term "metal particles” as used herein refers to paritcles formed from the metals and alloys listed above, wlwar the term “metallic iron particles” refers to those formed from iron alone. Such particles are available commercially.
  • One examplary group of the instant embodiments encompassing the magnetically susceptible compositions occurs when in any of the instant embodiments the magentic particle is selected from the group consisting of iron, nickel, awaruite, wairauite, pyrrhotite, greigite, troilite, yttrium iron garnet, Alnico 5, Alnico 5 DG, Sm 2 Co , SmCo 5 and NdFeB particles.
  • Another examplary group of the instant embodiments occurs when the magnetic particle is selected from the group consisting of iron, nickel, awaruite, wairauite, pyrrhotite, greigite, troilite, and yttrium iron garnet particles.
  • Another group of instant embodiments occurs when the particles for use in the instant embodiments are those that have a magnetic saturation value of approximately 100 Am 2 /kg or above.
  • Yet another exemplary group of instant embodiments occurs when the particles are ferrimagnetic.
  • iron particles possess superior magnetic susceptibility.
  • a preferred magnetic particle for the various embodiments of the invention described herein is an iron particle.
  • Yet another preferred magnetic particle for the various embodiments of the invention described herein is wairauite (CoFe).
  • iron particles is meant to include any biocompatible, metallic iron particles, essentially free of carbon.
  • the term “essentially free of carbon” refers to, for example, less than 1% by mass of carbon.
  • the term refers to, for example, 0.9%, 0.8, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% and the like. It also refers to, for example, carbonyl iron powder.
  • metallic iron is meant to include any magnetically susceptible iron composition having less than about 10-20% by weight iron oxide(s). This also includes a metallic iron phase that is a single solid phase, or a single solid solution, comprised primarily of metallic iron, preferably greater than about 75%. Unlike previous compositions having iron components comprised primarily of iron oxide, the amount of iron oxide in the compositions of the present invention is limited to impurities and thus is present in a small amount. Such iron particles possess superior magnetic susceptibility.
  • the "magnetic susceptibility" of the particles is the degree of responsiveness of a sample of the particles to a magnetic field, wherein lack of magnetic susceptibility correlates to an absence of response to a magnetic field.
  • This responsiveness may be affected for example, by the components present in the magnetic composition.
  • the responsiveness lends the particle the ability to be localized in an organism with an externally applied magnetic field.
  • the ability to be localized is affected by the route of administration, by the resulting depth of the particles in the body and/or strength of the magnetic field.
  • biologically active is meant to include any compound having in vivo and ex vivo diagnostic and/or therapeutic properties.
  • the terms “a” and “one” are both meant to be interpreted as “one or more" and "at least one.”
  • the method used to produce the magnetically susceptible composition uses magentic particles that are essentially ree from organic and inorganic impurities, hi the case of the instant iron particles, for particles that are mainly metallic iron are used. For example, the addition of extreme heat or the use of certain chemical processes that result in iron oxidation are not necessary.
  • the iron may be raw, or subjected to processing such as high-energy milling or gas phase treatments.
  • the state and nature of the particle surface is not critical to the attachment efficiency. However, the particle surface may be optimized, for example, to enhance attachment, bioavailability and targeting efficiency, and/or to increase surface area without change to the overall particle size. Because the "carrier" is a magnetic particle rather than an additional component, the particles display an extremely high level of magnetic susceptibility, wlangle at the same time exhibiting imexpected but excellent attachment efficiency.
  • the magnetic particles can be processed to change their shape, size, surface area, and surface chemistry before biologically active compounds are attached to them.
  • Many different processes can be used to increase and to optimize either the magnetic susceptibility of the particles or the resulting amount of the biologically active compounds that can be attached to the particles.
  • raw particles such as iron can undergo gas phase treatment or activation, milling, thermal activation, chemical vapor deposition of functional groups or any of a variety of P T/US03/00489 other techniques apparent to any person skilled in the art. (See, for example, Reynoldson, R.W. 'The use of fluidized bed reactors for chemical vapor deposition, thermochemical diffusion treatment on ferrous and non-ferrous alloys" Heat Treatment of Metals. 28(1).
  • the magnetic particles may be milled, as described below.
  • This milling step could result in particles with higher magnetic moment because of the particles' deformation during the process.
  • the deformation leads to elongation of the particles, such that, when in the presence of a magnetic field, magnetic poles are established on the most spatially distant ends of the particles.
  • the spatial separation could lead to a quantitatively higher magnetic moment induced in the particle, giving it superior targeting capabilities compared to an equivalent mass of perfectly spherical magnetic particles. It could also lead to improvements in the particle's attachment efficiency with the biologically active material to be carried.
  • the magnetic particles used in the various aspects of the instant magnetically susceptible compositions have a size of less than about 1 mm, preferably between 0.1 and 20 microns, and most preferably between 0.2 and 5 microns.
  • the magnetic material such as iron used for making the particles is essentially chemically pure, free of carbon, with higher than about 75% magnetic material, more preferably higher than about 85% magnetic material, and most preferably higher than about 95%>.
  • the magnetic material used for making the particles also typically contains less than about 20% iron oxides, more preferably less than about 10% > , and most preferably less than about 5%.
  • a number of considerations are involved in determining the size of carrier particles to be used for any specific diagnostic and/or therapeutic situation.
  • the choice of particle size is determined in part by technological constraints inherent in producing the magnetic particles such as iron under 0.2 micron in size.
  • relatively large particle sizes can cause desirable or undesirable embolization of blood vessels during injection either mechanically or by facilitating clot formation by physiological mechanisms.
  • the dispersion may coagulate, which makes injections more difficult, and the rate at which biologically active compounds desorb from the magnetic particles in the targeted pathological zones may decrease.
  • the size of the magnetic particles should be less than 50 microns, preferably less than 30 microns, and more preferably less than 10 microns. Generally, 03 00489 the particles have an average size in the range of 0.2 to 5 microns with 99% of the particles below 10 microns. These size ranges are exemplary of the embodiments of the instant invention that encompass an iron particle. Any person having ordinary skill in the art can readily determine the size range of particles to be used for any given application and route of admimstration. The size of the resulting particles can be controlled by the size of the magnetic particles used, or by typical size selection processes that may be employed before or after the biologically active compounds have been attached.
  • the particles may be raw iron particles or processed iron particles.
  • use of either raw or processed iron particles can affect the adsorption, precipitation, or labeling of biologically active compounds onto the magnetic particles, as well as affecting the stability as a function of time and the magnetic susceptibility.
  • processes may be used singly or in combination. Processes that may be employed include milling, chemical vapor deposition, or gas phase treatment. Otlier suitable processes are apparent to those having skill within the art. These processes are useful in manipulating the other magnetic particles, as well.
  • the high-energy milling process consists of combining the magnetic powder with a liquid, for example ethanol, in a canister containing grinding balls.
  • the liquid serves as a lubricant during the milling process and also inhibits the oxidation of the powder, an especially important consideration when fabricating the instant magnetic particles.
  • the canisters are then placed in a laboratory planetary mill of the type characteristically used in metallurgy (/. e. , mill made by Fritsch, Germany). Other types of mills producing similar results may also be employed.
  • the mill is run for an appropriate time (generally between 1 and 10 hours) at speeds, for example, between 100 and 1000 rpm. At the end of the cycle, the magnetic particles are collected.
  • the particles may be re- suspended and homogenized if desired.
  • the magnetic particles are dried by any suitable technique, allowing for the protection of the particles against oxidation, or in the case of yttrium iron garnet, for example, against further oxidation. This process results hi elongation of particles, rendering them more magnetically susceptible due to increased pole separation, and larger surface area per mass of magnetic substance.
  • Another process includes subjecting the particles to a gas phase treatment.
  • iron particles may be placed in a quartz container within an oven. Hydrogen may be used to replace air in the oven and the temperature is then raised for example, to about 300°C. The iron particles are left in this environment for about 2 hours. At the end of the cycle, the temperature is lowered and hydrogen is replaced by nitrogen. Once the iron particles' temperature has been returned to room temperature, they are collected and packaged. This process results in an increase in the roughness of the magnetic particle surface, leading to enhanced attachment of the biologically active compound.
  • 03 00489 is a gas phase treatment.
  • the biologically active compound may be introduced to the raw magentic particles or to particles that have been processed, if desired to form the instant magnetically susceptible compositions
  • Various methods of attachment that is, labeling, adsorbing and/or precipitating
  • biologically active compounds are known in the art.
  • the specific parameters used in these processes will depend upon the character and quality of the surface of the magnetic particles as well as that of the biologically active compound(s), and the properties of the solutions employed.
  • any person having ordinary skill in the art may easily identify an appropriate method for introduction of the desired biologically active compound(s).
  • any person having ordinary skill in the art may easily identify an appropriate method for introduction of the desired biologically active compound(s).
  • an appropriate method for introduction of the desired biologically active compound(s) See, for example, Harrison, RG, Todd, PW, Rudge, SR and Petrides, DP, Bioseparation Science and Engineering. Chapters 8,9, and 10, Oxford University Press, New York, 2003.
  • a redox reaction would be a good choice for labeling magnetic particles ⁇ vith rhenium oxides.
  • the magnetic particles may be incubated with the biologically active compound in a medium, for example, water, buffer, or solvent to form the instant magnetically susceptible compositions.
  • a medium for example, water, buffer, or solvent to form the instant magnetically susceptible compositions.
  • the medium should not include compounds that are likely to solubilize the magnetic particles.
  • the amount of incubation time may be determined in the feasible and reasonable range of about 5 to about 90 minutes, and preferably in the range of about 15 to about 60 minutes.
  • the incubation temperature may be determined in accordance with the stability of the desired biologically active compounds. The incubation times and temperatures may be adjusted to obtain the highest efficiency.
  • Additional methods include the addition of solvent, such as ethanol, addition of salt or change of pH so as to induce precipitation, evaporation, or reduction of volume.
  • Another possible method may include lowering the temperature of the solution in which the biologically active compound is present so as to induce precipitation or crystallization of the compound. Any person having ordinary skill in the art would be familiar with the appropriate methods involved in attachement and would be able to adjust the methods accordingly without undue experimentation.
  • Chemicals may be introduced to the process, for example, in order to alter the solubility of the biologically active compounds, to induce precipitation (for instance, a redox reaction), or to facilitate attachment onto the particles (for example, pH modification, or adjustment of the hydropliilicity-lipophilicity balance of the solution).
  • the magnetic particles may be optionally washed, dried, recovered, sterilized and or filtered. Routine methods of packaging and storing may be employed.
  • the raw or processed dried particles such as iron may be packaged in appropriate container closure system, for example, one enabling unit dosage forms. Packaging under nitrogen, argon or other inert gas is preferred to limit the oxidation of particles such as iron.
  • the iron particles must be stored so as to prevent oxidation.
  • the particles may be stored "wet," the liquid should not be aqueous.
  • ethanol or DMSO may be employed. (See, for example, Kibbe, AH, Handbook of Pharmaceutical Excipients.
  • the particles may be sterilized by any appropriate means, keeping in mind that methods relying on moist heat, such as by autoclave, may tend to lead to midersirable oxidation or futher oxidation of the particles.
  • the excipients may be prepared in dry form, and one or more dry excipients are packaged together with a unit dose of the carrier particles.
  • a wide variety of excipients may be used, for example, to enhance precipitation or release of the biologically active compound.
  • the type and amount of appropriate dry excipients can readily be determined by any person having ordinary skill in the art.
  • the excipients can be selected from a viscosity agent or a tonicifier, or both.
  • Viscosity agents are, for example, biodegradable polymers such as carboxymethylcellulose, PVP, polyethylene glycol (PEG), and the tike.
  • Tonicifiers include sodium chloride, amiitol, dextrose, lactose, and other agents used to impart the same osmolarity to the reconstituted solution.
  • the package or kit containing both the dry excipients and dry magentic particles such as iron is formulated to be mixed with the liquid contents of a vial containing a unit dose of the biologically active compound.
  • Liquid agents could be used as excipients just prior to use of the particles.
  • Such liquid agents could be soybean oil, rapeseed oil, or an aqeous based polymer solution composed of the polymers as listed above.
  • liquid solutions could be a tonicifier, such as Ringer's solution, 5% dextrose solution, physioligical saline.
  • a combination of liquid excipients and tonicifiers can be used. (See, for example, Kibbe, AH, Handbook of Pharmaceutical Excipients. American Pharmaceutical Association, Washington, DC, 2000).
  • the biologically active compound attaches to the magnetic particles according to a protocol developed for each compound, thus forming a magnetically controllable composition containing a diagnostic and/or therapeutic amount of a biologically active compound attached to the magnetic particles and being suitable for ex vivo or in vivo therapeutic and/or diagnostic as well as ex vivo diagnostic use.
  • Any suitable sterilization technique may be employed.
  • iron particles may be P T/US03/00489 sterilized using gamma or electron irradiation or dry heat and the aqueous solution of excipients may be sterilized by autoclave.
  • the resulting particles having attached thereon one or more biologically active compounds may be used alone or incorporated into a delivery system.
  • Suitable delivery systems will be apparent to any person possessing ordinary skill in the art. Without limitation, examples of useful delivery systems include matrices, capsules, slabs, microspheres, and liposomes. Conventional excipients may be incorporated into any of the formulations.
  • a diagnostic and/or therapeutic amount of a biologically active compound attached to the magnetic particles will be determined by any person having ordinary skill in the art as that amount necessary to effect diagnosis and/or treatment of a particular disease or condition, taking into account a variety of factors such as the patient's weight, age, and general health, and the nature and severity of the disease.
  • one dose of the magnetically susceptible composition will deliver a unit dose of the biolgically active compound.
  • Magnetic particles provide superior delivery of biologically active compounds to specific sites in the body under the h fluence of a magnetic field as a result of the combination of the high magnetic susceptibility of the microparticles and the biologically active compound carrying capability of the magnetic particle.
  • the particles have a significantly higher magnetic susceptibility due to the use of metallic magnetic iron instead of iron oxides.
  • Magnetic susceptibility of iron oxides, for similar size and shape particles can be as much as ten times lower than pure metallic magnetic iron particles. Consequently, magnetic iron particles can be targeted more efficiently and at greater depths within the body than iron oxide based particles, with less sophisticated magnet technology, and if desired, without requiring a carrier component such as a polymer matrix.
  • the instant magnetically susceptible compositions of the invention may also be used ex vivo.
  • biological material may be extracted from a patient and dispersed in a slurry.
  • the magnetic particles having attached thereon a biologically active compound may be present in the test container either before or after the biological material is dispersed.
  • Application of a magnetic field separates the biological material related to the disease due to the material's "recognition" of the biologically active compoimd attached to the metallic magnetic particle. For example, this recognition may be via binding.
  • any useful diagnostic and/or therapeutic compound may be attached to the magnetic particles such as iron for guided delivery to a target site.
  • biologically active also includes compounds used for diagnostic purposes and having no apparent physiological, therapeutic effect. Bifunctional compounds having both diagnostic and therapeutic properties are also contemplated.
  • Biologically active compounds that can be attached to the magnetic particles are, for example, but not limited to muscarinic receptor agonists and antagonists; anticholinesterase agents; catelcholamines, sympatliomimetic drugs, and andrenergic receptor antagonists; serotonin receptor agonists and antagonists; local and general anesthetics; anti-migraine agents such as ergotamine, caffeine, sumatriptan and the like; anti-epileptic agents; agents for the treatment of central nervous system degenerative disorders; opiod analgesics and antagonists; anti-inflammatory agents, including anti-asthmatic drugs; lnstamine and bradykinin antagonists, lipid-derived autocoids; nonsteroidal antiinflamatory agents and anti-gout agents; anti-diuretics such as vassopressin peptides; inhibitors of the renin-angiotensin system such as angiotensin converting enzyme inliibitors; agents used in the treatment of myo
  • L-asparaginase biological response modifiers
  • biological response modifiers such as interferon-alpha
  • platinum coordination compounds such as the estrogens, progestins, and the adrenocorticosteriods
  • hormones and antagonists such as the estrogens, progestins, and the adrenocorticosteriods
  • antibodies immunomdulators including both immunosuppressive agents as well as hmnunostimulants; hematopoietic growth factors, anticoagulant, thrombolytic and antiplatelet agents; thyroid hormone, anti-thyroid agents, androgen receptor antagonists; adrenocortical steroids, insulin, oral hypoglycemic agents, agents affecting calcification and bone turnover as well as otlier therapeutic and diagnostic hormones, vitamins, minerals blood products biological response modifiers, diagnostic imaging agents, as well as paramagnetic and radioactive particles
  • Other biologically active substances may include, but are not limited to monoclonal or other antibodies, natural or synthetic genetic material and pro
  • genetic material refers generally to nucleotides and polynucleotides, including nucleic acids, RNA and DNA of either natural or synthetic origin, including recombinant, sense and antisense RNA and DNA.
  • Types of genetic material may include, for example, genes carried on expression vectors, such as plasmids, phagemids, cosmids, yeast artificial chromosomes, and defective (helper) viruses, antisense nucleic acids, both single and double stranded RNA and DNA and analogs thereof. Also included are proteins, peptides and other molecules formed by the expression of genetic material.
  • the biologically active compounds for the instant compositions may also be radioisotopes.
  • radioisotopes are chemical compounds or elements that emit alpha, beta or gamma radiation and that are useful for diagnostic and/or therapeutic purposes.
  • One factor used in selecting an appropriate radioisotope is that the half-life be long enough so that it is still detectable or therapeutic at the time of maximum uptake by the target, but short enough so that deleterious radiation with respect to the host is minimized. Selection of an appropriate radioisotope would be readily apparent to one having ordinary skill in the art. Generally, alpha and beta radiation are considered useful for local therapy.
  • Examples of useful compounds include, but are not limited to 32 P, ls6 Re, Re, 123 I, 125 I, 131 I, 90 Y, 166 Ho, 153 Sm, 142 Pr, 143 Pr, 149 Tb, 161 Tb, In, 77 Br, 212 Bi, 213 Bi, 223 Ra, 210 Po, 195 Pt, 195m Pt, 255 Fm, 1S5 Dy, 109 Pd, 121 Sn, 127 Te, 103 Pd, 177 Lu, and 211 At.
  • the radioisotope generally exists as a radical within a salt, although exceptions such as iodine and radium exist wherein the radical is not in ionic form.
  • the useful diagnostic and therapeutic radioisotopes may be used alone or in combination.
  • Radioisotopes that may be employed include, but are not limited to 99 Tc, 142 Pr, 161 Tb, 1S ⁇ Re 5 and 1S8 Re.
  • otlier diagnostically useful compounds are metallic ions including, but not limited to nl In, 97 Ru, 67 Ga, 68 Ga, 72 As, 89 Zr, and 201 TI.
  • paramagnetic elements that are particularly useful in magnetic resonance imaging and electron spin resonance techniques include, but are not limited to 157 Gd, 55 Mn, 162 Dy, 52 Cr, and 56 Fe.
  • the methods of use for the instant magnetically susceptible compositions include methods for localized in vivo or ex vivo diagnosis and/or therapeutic treatment providing a magnetic particle having attached thereto one or more biologically active compounds selected for efficacy in diagnosing and/or treating the disease, and magnetically guiding the particle to a desired location in the body of a patient.
  • Such magnetically susceptible compositions containing said magnetic particles may be introduced enterally or parenterally, by any conventional route of administration.
  • the particles attached to the biologicaly active compound(s) may be injected by inserting delivery means such as a catheter or needle into an artery within a short distance from a body site to be treated and at a branch or branches, preferably the most immediate, to a network of arteries carrying blood to the site.
  • the particles are injected through the delivery means into the blood vessel.
  • a magnetic field is established exterior to the body and adjacent to the target site, and having sufficient field strength to guide a substantial quantity of the injected particles to, and retain the substantial quantity of the particles at the site.
  • the magnetic field is of sufficient strength to draw the particles into the soft tissue at the site adjacent to the network of vessels, thus avoiding substantial embolization of any of the vessels by the carrier particles, should embolization be undesirable for the particular treatment/diagnosis.
  • One example of such a magnet would be to use either a DC electromagnet or permanent magnent of sufficient size and strength to produce 100 gauss of magnetic flux at the target site of the magnetically susceptible compositions.
  • the magnets discussed in Mitchiner et al, U. S. Pat. No. 6,488,615, issued Dec. 3, 2002, are suitable for use with the instant invention.
  • the imaging is performed while the particles attached to the biogically active compound(s)are captured at the target site, and in some cases before and/or after.
  • Imaging modalities and methods are well-known to any person having ordinary skill in the art.
  • the magnetic field Once the magnetic field is removed, the particles remain at the site for a period of time and then slowly biodegrade. The magnetic field may be applied one or more times in order to guide the particles to one or more desired sites.
  • Iron particles can be treated with different gases and plasma to increase the surface roughness in order to enhance the binding affinity of biologically active compounds. For example, 4 g of iron particles in a quartz container are placed in an oven. The particles are heated to 300°C i a flow of t ⁇ trahigh-pririty ammonium. (NH 3 ) at 25 mL/min. After treatment for 3 h, the samples are cooled to room temperature and NH 3 is replaced with N 2 .
  • Iron particles (mean diameter of 1.09 ⁇ m with 99% of the population smaller than 2.34 ⁇ m; see Figures 1 and 2) were used to carry out a protocol based upon the reduction of perrhenate with tin chloride.
  • a tin chloride solution (20 mg/mL SnCl 2 ) was prepared by dissolving 20.1 mg SnCl 2 hi 0.5 mL of 0.2 N HC1, and then by adding 0.5 mL 0.9% saline; the mixture was vortexed until dissolution.
  • Raw iron particles (20 mg, Alfa Aesar, 1-3 ⁇ m) were weighed out in three tubes each. For each sample, we added:
  • Results show that the labeling (attachment) efficiency and stability of the iron particles was very good. Stability of the labeling or adsorption is important when a radioisotope is to be delivered to the specific site in the body. One would like to mmimize the activity present hi the systemic circulation in order to minimize side effects by keeping the activity bound or adsorbed onto the particles over time.
  • Iron particles can also be labeled with Yttrium 90.
  • Yttrium 90 there is no addition of tin chloride to oxidize the biologically active compound.
  • the labeling is obtained by direct adsorption of the 90 Y +3 onto the iron particles. The adsorption was performed as follows: 20 mg of iron particles in 1.5 mL were placed in a screw cap tube, and 100 ⁇ L of an ammonium acetate buffer with ⁇ 0.5 mCi 90 YC1 3 was added (NEN Perkin-Elmer). The tubes were incubated at 37 °C for 30 min on a ⁇ liermomixer at 1400 rpm.
  • Example 8 Binding of Tumor Necrosis Factor ⁇ (TNF ⁇ )
  • TNF ⁇ is a 17 kDa cytokine that can induce hemorrhagic necrosis of cancerous cells and tumors.
  • Carrier-free TNF ⁇ was suspended in water at neutral pH. 200 ⁇ L of TNF ⁇ solution was mixed with 1 mg of iron particles. The iron particles were incubated with the TNF ⁇ for 1 hour at room temperature on a plate shaker. After incubation, the particles were separated using a magnet, and the supernatants were removed. The particles were washed twice with 200 ⁇ L PBS at pH 7.4 for 1 mg of iron, and the wash supernatants were saved for analysis.
  • TNF ⁇ The desorption of TNF ⁇ from the particles was tested by addmg 200 ⁇ L plasma to the particles and incubating the plate at 37°C with shaking. The plasma was changed at 30 min, 1 hr, 2 hr, and 4 hrs to give a semi-dynamic desorption curve. The concentrations of TNF ⁇ in samples were measured using ELISA plate.
  • An in vitro magnetic capture test has been designed to assess the percentage of the test material captured by the magnetic field.
  • the test material is in suspension in a 10%> w PEG (polyethylene glycol) water solution.
  • the test material suspension is pumped into tubing positioned in front of a 39Hpennanent magnet (Magnet Sales & Mfrg., Culver City, CA; Dexter Corp., Richardson, TX) capable of producing 0-0.7 tesla (0-7,000 gauss).
  • the inner diameter of the tube is between 0.5 and 10 mm.
  • the magnet can be moved away from the tube in order to change the flux of the magnetic field (gauss; tesla) applied on the test material in suspension. With the magnet positioned 4 cm away from the tubing and a magnetic field of about 0.1 tesla (1 kgauss), 99% of the test material was captured by the magnetic field.

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Abstract

L'invention concerne des particules magnétiques biocompatibles, biodégradables, servant à l'administration par voie magnétique de composés bioactifs à des fins diagnostiques ou thérapeutiques, in vivo et ex vivo. Ces particules possèdent, d'une part, d'excellentes caractéristiques de marquage, en termes d'efficacité et de stabilité et, d'autre part, une sensibilité magnétique supérieure à celle des compositions actuellement utilisées pour l'administration par voie magnétique d'agents diagnostiques et thérapeutiques.
PCT/US2003/000489 2002-01-09 2003-01-07 Compositions a administration par voie magnetique Ceased WO2003059325A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105903030A (zh) * 2016-04-22 2016-08-31 山西大学 一种酯化胆酸/Fe3O4磁性纳米复合体及其制备方法和应用

Citations (4)

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Publication number Priority date Publication date Assignee Title
US4345588A (en) * 1979-04-23 1982-08-24 Northwestern University Method of delivering a therapeutic agent to a target capillary bed
US5122418A (en) * 1985-12-09 1992-06-16 Shiseido Company Ltd. Composite powder and production process
US5411730A (en) * 1993-07-20 1995-05-02 Research Corporation Technologies, Inc. Magnetic microparticles
US5651989A (en) * 1993-01-29 1997-07-29 Magnetic Delivered Therapeutics, Inc. Magnetically responsive composition for carrying biologically active substances and methods of production and use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4345588A (en) * 1979-04-23 1982-08-24 Northwestern University Method of delivering a therapeutic agent to a target capillary bed
US5122418A (en) * 1985-12-09 1992-06-16 Shiseido Company Ltd. Composite powder and production process
US5651989A (en) * 1993-01-29 1997-07-29 Magnetic Delivered Therapeutics, Inc. Magnetically responsive composition for carrying biologically active substances and methods of production and use
US5411730A (en) * 1993-07-20 1995-05-02 Research Corporation Technologies, Inc. Magnetic microparticles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105903030A (zh) * 2016-04-22 2016-08-31 山西大学 一种酯化胆酸/Fe3O4磁性纳米复合体及其制备方法和应用
CN105903030B (zh) * 2016-04-22 2019-01-15 山西大学 一种酯化胆酸/Fe3O4磁性纳米复合体及其制备方法和应用

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