+

WO1997001304A1 - Particules d'apatite radiomarquees contenant un ion paramagnetique - Google Patents

Particules d'apatite radiomarquees contenant un ion paramagnetique Download PDF

Info

Publication number
WO1997001304A1
WO1997001304A1 PCT/US1996/010808 US9610808W WO9701304A1 WO 1997001304 A1 WO1997001304 A1 WO 1997001304A1 US 9610808 W US9610808 W US 9610808W WO 9701304 A1 WO9701304 A1 WO 9701304A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
composition
apatite
group
hydroxyapatite
Prior art date
Application number
PCT/US1996/010808
Other languages
English (en)
Inventor
James W. Brodack
Edward A. Deutsch
Karen E. Deutsch
Original Assignee
Mallinckrodt Medical, Inc.
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.)
Filing date
Publication date
Application filed by Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Publication of WO1997001304A1 publication Critical patent/WO1997001304A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/183—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an inorganic material or being composed of an inorganic material entrapping the MRI-active nucleus, e.g. silica core doped with a MRI-active nucleus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates in general to a radiolabeled paramagnetic compound for the simultaneous therapy and imaging of an individual afflicted with inflammatory arthropathy.
  • the primary disadvantage of this technique has been the unacceptable radiation doses to non-target organ systems due to leakage of radioactive material from the cavity and difficulty in delivering a ⁇ -particle of the appropriate energy for the size joint being treated.
  • the chemical nature of current radiation synovectomy agents is such that leaked materials tend to be retained by liver, spleen and lymph nodes.
  • the leakage problem is often due either to the difficulty of formulating the correct particle size or to lack of a tight binding of the nuclide to the particle.
  • Another disadvantage is the use of radionuclides that do not have the appropriate beta energy to treat the inflamed synovium.
  • Brodack et al. describe a radiation synovectomy composition comprised of a radiolabeled insoluble compound, preferably hydroxyapatite, that solves these problems.
  • the MRI agent and the radiation synovectomy agent are typically chemically distinct and have different chemical and biological properties, e.g., distribution in the joint, one cannot be certain that the image obtained from the MRI agent accurately represents the effect of the synovectomy agent and that relevant or accurate data are being provided.
  • the present invention provides methods and compositions for improved medical diagnostic imaging and therapy for the treatment of diseases such as rheumatoid arthritis.
  • the compositions are derived from apatite particles including, but not limited to, hydroxyapatite (sometimes referred to as
  • hydroxylapatite fluoroapatite, iodoapatite, carbonate-apatite, and mixtures and derivatives thereof.
  • fluoroapatite includes pure fluoroapatite as well as mixtures of fluoroapatite, hydroxyapatite, iodoapatite, and carbonate-apatite.
  • hydroxyapatite, iodoapatite, and carbonate- apatite are intended to include the pure and mixed forms. Since hydroxyapatite is a natural bone constituent, it is well tolerated and generally safe.
  • compositions of the present invention contain a paramagnetic species incorporated into the apatite particles to improve magnetic resonance contrast and a radionuclide capable of providing a therapeutic dose of radioactivity.
  • the apatite particles may also be fluorinated to form stable, fluoroapatite compositions useful for 19 F imaging. Incorporating a paramagnetic metal species in fluoroapatite or hydroxyapatite particles may reduce 1 F and proton relaxivity, thereby enhancing MRI, MRS, or MRSI.
  • Also disclosed is a combination diagnostic /therapeutic composition and methods of performing medical diagnostic and therapeutic procedures which involve administering to a warm-blooded animal an amount of the above- described apatite particles containing a diagnostically effective amount of the paramagnetic ion and a therapeutically effective amount of the radionuclide and then performing the medical treatment and diagnostic procedures.
  • a radiation synovectomy composition to treat inflamed synovia of people afflicted with rheumatoid arthritis and permit imaging of the afflicted joint by MRI; the provision of a composition that permits evaluation of proper distribution of the particles in the inflamed synovia by MRI; the provision of a composition that permits the effect of the radiation to be evaluated and monitored during its course of activity by MRI; and the provision of a composition that by the nature of the labelling process, .any in vivo decomposition that generates joint leakage produces radioactive materials in a form that clear rapidly from the body.
  • the present invention provides methods and compositions for improved medical diagnostic imaging and therapy for inflammation arthropathy, including rheumatoid arthritis.
  • medical diagnostic imaging includes magnetic resonance imaging ("MRI"), magnetic resonance spectroseopy (“MRS”), magnetic resonance spectroseopy imaging (“MRSI”) and therapy includes radiation synovectomy.
  • the compositions of the present invention are derived from apatite or apatite-like particles.
  • the radiation synovectomy aspect of the composition is useful for treating, e.g., by ablation, the inflamed synovium of a synovial joint of a person suffering from inflammatory arthropy, such as rheumatoid arthritis. It comprises a radionuclide or radionuclide complex bound to a substantially insoluble particle as the radiation synovectomy agent in a sufficient amount to provide satisfactory synovectomy when administered with a pharmaceutically acceptable radiation synovectomy vehicle.
  • the radionuclide is a beta emitter that would substantially ablate or destroy the diseased synovium, but will not significantly damage underlying articular cartilages or overlying skin.
  • the radionuclide complex is substantially kinetically stable, but should degradation lead to leakage from the joint after adminish ation, the radioactive material will rapidly clear from the body.
  • a substantially kinetically stable complex as known to those skilled in the art is a complex which under normal biological conditions is kinetically stable, but not necessarily 100 percent kinetically stable in each and every patient application since biological systems vary somewhat.
  • the necessary stability of the complex is determinant upon the half- life of the radioisotope being used. After the isotope has decayed to the point of being insignificant, the stability of the complex is no longer important.
  • the particle size of the agent is of sufficient size such that there is essentially little or no leakage of the intact radionuclide complex-particle unit from the synovial joint after administration.
  • the size and properties of the particle can be defined and controlled before it is bound to the radionuclide complex resulting in an agent having good synovectomy properties. Also, the binding of the radionuclide complex can be controlled resulting in better reproductivity and more complete binding and better in vivo clearance.
  • the radiation agent comprises a substantially insoluble particle which is of suitable size as to not substantially leak from the joint after administration.
  • the size may be from approximately 0.5 to 40 microns.
  • These particles are preferably biodegradable (but can also be degradable by other mechanisms) and not prone to aggregation under the conditions used to prepare or store the radiation synovectomy agent.
  • the particle should have a density of approximately 0.7 to 3.5 gm/ml, preferably from 0.7 to 2.0 gm/ml, and should be suspendable in pharmaceutically acceptable vehicles.
  • hydroxyapatite(s) shall include materiak known as hydroxyapatite(s) and also as hydroxylapatite(s). These two terms have been used previously in the literature to refer to the same materials.
  • hydroxyapatites for this application include matrix prepared from the bones and or teeth of animals and matrix prepared by inorganic synthesis, each being more amorphous than crystalline in composition. This includes caldunv-hydroxy- hexaphosphate (3(Ca 3 (P0 4 )2)Ca(OH) 2 ; also given as.2[Ca s (P0 4 ) 3 OH ⁇ ).
  • the invention comprises a composition comprising an apatite particle having the following general formula:
  • M is a paramagnetic ion or stoichiometric mixture of metal ions having a valence of 2+ or 3+
  • X is a simple anion
  • Y is a tetrahedral oxyanion, carbonate, tetrahedral anion, or mixtures thereof
  • m is from 1-10
  • Z is a ⁇ -emitting radionuclide(carrier-free or carrier-added).
  • Possible metal ions which can be used in the apatite particles of the present invention include: chro ⁇ um(ILI), manganese(II), iron(LI), iron(fll), praseodymium( ⁇ i), neodymium(III), samarium(HI), ytterbium(Iflj, gadolinium(i ⁇ ), terbium(HI), dysprosium(ITI), holmium(lTI), erbium(LII), or mixtures of these with each other or with alkali or alkaline earth metals.
  • Typical simple anions which can be used in the apatite particles of the present invention include: OH “ , P, Br I " , - ⁇ [COs 2 ], or mixtures thereof.
  • the paramagnetic metal species is incorporated into the apatite particles to improve magnetic resonance contrast.
  • the apatite particles may also be fluorinated to form stable, nontoxic fluoroapatite compositions useful for 19 F imaging.
  • the presence of a paramagnetic metal species in fluoroapatite or hydroxyapatite particles may reduce 19 F and proton relaxivity, thereby enhancing MRI, MRS, or MRSI.
  • hydroxyapatite having the formula Ca 10 (PO 4 ) 6 (OH) 2
  • Apatites in which the OH " is replaced with simple anions, including F “ , Br “ , I ' , or Vi[C0 3 2" ] may be prepared by modifying the process for preparing hydroxyapatite.
  • Apatite derivatives in which calcium is replaced by a paramagnetic metal ion may also be prepared and used within the scope of the present invention.
  • Stoichiometric pure hydroxyapatite has a Ca:P ratio of 1.67:1.
  • the major impurity found in hydroxyapatite is tricalcium phosphate, Ca 3 (P0 4 ) 2 , known as "TCP".
  • This impurity can be detected by deviation from the 1.67:1 Ca:P ratio (for large amounts of impurity) or by X-ray diffraction for impurity levels down to 1 percent.
  • Stoichiometric hydroxyapatite is prepared by adding an ammonium phosphate solution to a solution of calcium /ammonium hydroxide. To minimize the amount of TCP formed, it is important to have. excess calcium throughout the addition process.
  • Apatite Particles for MRI Applications encompasses the detection of certain atomic nuclei (those possessing magnetic dipole moments) utilizing .magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography ("CT") in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail.
  • CT X-ray computed tomography
  • the hydrogen atom having a nucleus consisting of a single unpaired proton, has the strongest magnetic dipole moment of any nucleus. Since hydrogen occurs in both water and lipids, it is abundant in the human body. Therefore, MRI is most commonly used to produce images based upon the distribution density of protons and/or the relaxation times of protons in organs and tissues. Other nuclei having a net magnetic dipole moment also exhibit a nuclear magnetic resonance phenomenon which may be used in magnetic resonance applications. Such nuclei include carbon-13 (six protons and seven neutrons), fluorine-19 (9 protons and 10 neutrons), sodium-23 (11 protons and 12 neutrons), and phosphorus-31 (15 protons and 16 neutrons).
  • the nuclei under study in a sample e.g. protons, 19 F, etc.
  • RF radio-frequency
  • the resonance frequency of the nuclei depends on the applied magnetic field.
  • nuclei with appropriate spin when placed in an applied magnetic field align in the direction of the field.
  • B expressed generally in units of gauss or Tesla (IO 4 gauss)
  • these nuclei precess at a frequency, F, of 42.6 MHz at a field strength of 1 Tesla.
  • F a frequency
  • an RF pulse of radiation will excite the nuclei and can be considered to tip the net magnetization out of the field direction, the extend of this rotation being determined by the pulse, -duration and energy.
  • the nuclei "relax" or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency.
  • T. is the spin-lattice relaxation time or longitudinal relaxation time, that is, the time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field.
  • T 2 is the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
  • the relaxation times T- and T 2 are influenced by the environment of the nuclei (e.g., viscosity, temperature, and the like). These two relaxation phenomena are essentially mechanisms whereby the initially imparted radio-frequency energy is dissipated to the surrounding environment.
  • the rate of this energy loss or relaxation can be influenced by certain other nuclei or molecules (such as nitroxide radicals) which are paramagnetic.
  • Chemical compounds incorporating paramagnetic nuclei or molecules may substantially alter the T x and T 2 values for nearby nuclei having a magnetic dipole moment. The extent of the paramagnetic effect of the given chemical compound is a function of the environment within which it finds itself.
  • paramagnetic ions of elements with an atomic number of 21 to 29, 42 to 44 and 58 to 70 have been found effective as MRI contrasting agents.
  • suitable paramagnetic ions include chromium(III), manganese(II), iron(II), iron(III), cobalt(II), nickel(H), copper(H), praseodymium(III), neodymium(III), samarium(III), gadolinium(III), dysprosium(HT), and ytterbium(HI).
  • Paramagnetic metal ions may be incorporated into the apatite structure by replacement of calcium sites.
  • Apatite doping in the range from about 1% to 100% is possible, depending upon the particular metal species, in most cases, apatite doping with metal ions in the range from about 1% to 25% is expected.
  • the preferred metals from a toxicity and efficacy viewpoint are iron and manganese. With iron doped hydroxyapatite particles, any iron released from metabolized or solubilized particles would join the body's pool of iron, with calcium and phosphate also going to their respective body pools.
  • Manganese is preferred because of its higher relaxivity properties and affinity for liver tissue. Moreover, the liver has a clearance mechanism for manganese, thereby reducing residual toxicity.
  • Metal doped hydroxyapatite is prepared by mixing a basic (pH 12) phosphate solution with a calcium/paramagnetic metal solution at native pH.
  • the calcium/paramagnetic metal solution could be basic (pH 12) if the solution also contains a ligand to prevent hydrolysis of the paramagnetic metal.
  • the ligand could either be left in the hydroxyapatite matrix or "ashed out” by sintering the hydroxyapatite between 200°C and 1100°C. Any strong chelating ligands may be used, such as polyamino polycarboxylic acid derivatives which are well known in the art.
  • Antioxidants such as gentisic acid and ascorbic acid, added during apatite particle synthesis may also be used to prevent metal ion oxidation.
  • Reducing agents such as NaBH 4 , have been found * to reduce metal; ions that are unintentionally , oxidized during apatite particle synthesis.
  • Paramagnetic apatite particles may also be prepared by adsorbing paramagnetic metal ions onto the particle surface.
  • manganese can be surface-adsorbed to hydroxyapatite particles by taking a slurry of hydroxyapatite, adding Mn(N0 3 ) 2 and applying energy, such as ultrasonic power or heat, to the resulting mixture.
  • the resulting mixture can be separated by either centrifugation and decantation or by filtration.
  • the resulting solid is washed with large amounts of water to remove excess manganese. The same procedure may be used with other paramagnetic cations.
  • the amount of manganese adsorbed onto the particle surface is in the range from about 0.1% to about 10%.
  • Such particles exhibit very high relaxivities and rapid liver enhancement in magnetic resonance imaging studies.
  • Paramagnetic metal species may also be adsorbed onto apatite particle surfaces through the use of bifunctional coating agents.
  • bifunctional coating agents are chelating agents having one or more phosphonate groups capable of adsorption to the apatite particle surface.
  • One currently preferred bifunctional coating agent is the functionalized poiyphosphonate diethylenetri-aminepenta(methylenephosphonic acid), abbreviated DETAPMDP, having the following structure:
  • the bifunctional coating- agent may form complexes with paramagnetic metal ions. These particles also exhibit very high relaxivities and rapid liver enhancement in magnetic resonance imaging studies.
  • the concentration of nuclei to be measured is not sufficiently high to produce a detectable MR signal.
  • a fluorine source since 19 F is present in the body in very low concentration, a fluorine source must be administered to a subject to obtain a measurable MR signal. Signal sensitivity is improved by administering higher concentrations of fluorine or by coupling the fluorine to a suitable "probe" which will concentrate in the body tissues of interest. High fluorine concentration must be balanced against increased tissue toxicity. It is also currently believed that a fluorine agent should desirably contain magnetically equivalent fluorine atoms in order to obtain a clear, strong signal.
  • Fluoroapatites useful as 19 F imaging agents, are prepared by replacing the OH " with stoichiometric or non-stoichiometric quantities of F " .
  • Fluoroapatites may also be synthesized with organic phosphate esters using the procedures described by M. Okazaki, "Fluoridated Hydroxyapatites Synthesized With Organic Phosphate Ester," Biomaterials, Vol. 12, pp. 46-49, (1991). It is currently believed that all of the fluorine atoms in fluoroapatite are chemically and magnetically equivalent. Since fluoroapatite has a high molar content of identical fluorine atoms, it may be advantageously used as a low concentration 19 F MRI agent. Fluoroapatite may also be doped with paramagnetic metal species, as described above, to reduce 19 F and proton relaxivity, thereby enhancing MRI, MRS, or MRSI. Controlling the Particle Size and Aggregation
  • apatite particle size Various techniques are available to control the apatite particle size. For example, slower mixing rates (introduction of the precipitating -anion or cation), larger solution volumes, higher reaction temperatures, and lower concentrations generally result in smaller particles.
  • sonication during precipitation, turbulent flow or impingement mixers, homogenization, and pH modification may be used to control particle size.
  • Procedures for preparing monodispersed colloidal particles that are known in the art may be adapted for preparing submicron apatite particles.
  • mechanical means such as computer controlled autoburets, peristaltic pumps, and syringes, may also be used to control the release of precipitating ions.
  • autoburets are capable of releasing solutions at rates as low as 10 ⁇ L/minute. In the future cis computer controlled equipment improves, it is expected that even slower release rates may be obtained. Due to the small size and nature of apatite particles, they tend to aggregate. Particle aggregation may be reduced by coating the particles. Although the reasons apatite particles aggregate is not fully understood, it has been found that several different coating agents are able to inhibit particle aggregation.
  • apatite particles may be stabilized by treatment with coating agents such as di- and polyphosphonate-containing compounds, such as hydroxyethyldiphosphonate (HEDP), pyrophosphate, aminophosphonates; carboxylates and polycarboxylate-containing compounds such as oxalates and citrates; alcohols and polyalcohol-containing compounds; phosphates and polyphosphate-containing compounds; sulfates and sulfate- containing compounds; sulfonates and sulfonate-containing compounds; and biomolecules such as peptides, proteins, antibodies, and lipids.
  • coating agents such as di- and polyphosphonate-containing compounds, such as hydroxyethyldiphosphonate (HEDP), pyrophosphate, aminophosphonates; carboxylates and polycarboxylate-containing compounds such as oxalates and citrates; alcohols and polyalcohol-containing compounds; phosphates and polyphosphate-containing compounds; sulf
  • Stabilized apatite particles are desirable for in vivo use as medical diagnostic imaging agents.
  • Apatite particle can also be stabilized by addition of small amounts of calcium sequestering anions, such as citrate and oxalate. Such anions, which coordinate calcium, may effectively stabilize small apatite particles.
  • particle relaxivity is enhanced by allowing more water accessible to the particle surface. By limiting particle size and increasing the available surface area, improved relaxivity is observed.
  • conventional particle coating techniques may also be used in the manufacturing processes of the present invention. Typical coating techniques are identified in International Publication Numbers WO 85/02772, WO 91/02811, and European Publication Number EP 0343934, which are incorporated by reference.
  • agglomerated particles may be disrupted by mechanical or chemical means and then coated with polymers such as carbohydrates, proteins, and synthetic polymers.
  • Dextran having a molecular weight in the range from about 10,000 to about 40,000 is one currently preferred coating material.
  • Albumin and surfactants, such as tween 80, have also been used to reduce particle aggregation.
  • One common characteristic of useful apatite coating agents is their ability to modify the particle surface charge, or zeta potential.
  • the currently preferred mechanical means for disrupting or subdividing agglomerated particles is sonication, but other means such as heating, other forms of particle energization, such as irradiation, and chemical -means, such as pH modification or combinations of these types of treatment, such as pH ; modification combined with sonication may be used.
  • Functionalized Apatite Particles Apatite particles may be prepared with coating agents containing reactive functional groups such as amine, active ester, alcohol, and carboxylate. Polyethylene glycols (PEG) and derivatized PEG's may also be used as coating agents. Such functional groups may be used to couple apatite particles to paramagnetic metal chelates, to organ or tissue specific peptides or proteins, and to antibodies.
  • HEDP derivative An example of one possible coating agent having a reactive functional group is the following HEDP derivative:
  • HEDP derivative an example of one possible coating agent having a reactive functional group is the following HEDP derivative:
  • HEDP derivative an example of one possible coating agent having a reactive functional group.
  • hydroxyapatite or hydroxyapatite-like matrix the particle size thereof becomes important. This is because of reports that hydroxyapatite particles may become phagocytosed and solubilized by synovial fibroblasts. In particular, it is believed that the hydroxyapatite particles are first solubilized by phagocytosis and then dissolved in the acidic environment of secondary lyposomes.
  • the rate of solubilization of the hydroxyapatite should optimally be much slower than the half-life of the radioisotope used in the radiation synovectomy agent. In this manner, the radioisotope may completely decay before dissolution of the hydroxyapatite particle. It has been determined that the rate of solubilization and dissolution of hydroxyapatite is a function of particle size, wherein smaller particles are more quickly phagocytosed and dissolved than larger particles. Studies have suprisingly shown that there is no significant lower limit on particle size.
  • Maximum particle size is approximately 40 microns. If particles are too large, e.g. greater than 40 microns, the particles can not be surrounded by cells and will not be easily phagocytosed and dissolved. This can disadvantagously cause dead fibrous areas too occur in the synovium.
  • hydroxyapatite particles when using hydroxyapatite particles as the particles of the radiation synovectomy agent according to the present invention, it is desirable that the hydroxyapatite particles have a particle size of 0.5 to 40 microns.
  • the radioisotopes that can be used are those that emit beta particles and are such that after adrrtinistration will ablate the diseased synovium but will not significantly damage the underlying articular cartilage or overlying skin. These isotopes should have an average beta energy between 0.25 - 2.75 Mev, with or without an imageable gamma ray, with mean soft tissue penetration of about .0.70 and 25.0. mm, and with a half-life of between 0.05 and 700 hours.
  • beta ernitting isotopes examples include 198-Au, 188-Re, 186-Re, 177-Lu, 176m-Lu, 175-Yb, 169-Er, 166-Ho, 165-Dy, 156-Sm, 153-Sm, 115m-In, 105-Rh, 90-Y, 51-Cr, 77-As, 67-Cu and 32-P, in addition to others of the lanthanide group such as, 141-Ce, 144-Pr, 147-Nd, 148-Pm, 152-Eu, 153-Gd, 157-Tb and 170-Tm.
  • the isotope would either have an imageable gamma ray or could be doped with an isotope that would contain an imageable gamma ray.
  • This doping isotope could be of the same or different element providing that its chemistry is sufficiently similar to the beta emitting isotope so that its biodistribution in the present use would be close or identical to the beta emitter.
  • Preferred isotopes include: 186-Re, 188-Re, 90-Y, 153-Sm, 77-As, 105-Rh, 177-Lu, 176m-Lu and 166-Ho.
  • the radionuclide complexes that can be used are those that are stable before and after administration to the synovium joint. Additionally, if such complex leaks from the joint it will be rapidly cleared from the body. This will be the case even if the complex becomes separated from the insoluble particle.
  • the complexes are formed by complexing the radionuclide under complexing conditions with a suitable ligand to provide a complex with the foregoing properties.
  • Ligands that can be used are preferably polydentate, i.e., containing more than two coordinating atoms per ligand molecule.
  • a coordinating atom is defined as one that has a free pair of electrons which can be bonded to the radionuclide.
  • This atom is preferably separated by two or more atoms from any other coordinating atom.
  • the coordinating atoms are chosen from nitrogen, oxygen, sulfur, phosphorus or carbon with nitrogen c d /or oxygen and /or sulfur being the preferred coordinating atoms.
  • chelates include all phosphonate carboxylate and amine carboxylate ligahds, citrate, MAG 3 (mercaptoacetylglycylglycylglycine), all polycarboxylic acid-amine ligands especially DTPA (diethylenetri- arriinepentaacetic acid), e.g., EDTA (ethylenediamine-tetraacetic acid), DADS (N,N'-bis(mercaptoacetamido)-e ylenediamine arid C0 2 -DADS N,N'- bis(mercaptoacetamido)-2,3-diaminopropanoic acid) and their derivatives (see European Application 0173424 and US Patent 4,673,562), mono- and poly- phosphonates, BATs (N,N'-bis(2-mercapto-ethyl)ethylene-diamine) and derivatives (see European Applications 0163119 and 0200211), thio
  • Examples of preferred phosphonate ligands include but are not limited to those specified in U.S. Patents Numbered 4,234,562; 3,983,227; 4,497,744; 4,233,284; 4,232,000; 4,229,427; and 4,504,463; preferably HEDP (hydroxyethyldiphosphonate), PYP (pyrophosphate), EDTMP (ethylenediaminetetramethylphosphate), and HMDP (hydroxymethylenediphosphonate).
  • HEDP hydroxyethyldiphosphonate
  • PYP pyrophosphate
  • EDTMP ethylenediaminetetramethylphosphate
  • HMDP hydroxymethylenediphosphonate
  • ligands include MAG 3 , DTPA, BAT, DADS and PnAO type ligands which have been modified so that they are bifunctional, i.e., can coordinate the radionuclide and also be coupled to the particle.
  • Preferred complexes include a citrate/hydroxyapatite or hydroxyapatite-like matrix complexed with 186-Re, 188-Re, 105-Rh, 153-Sm or 156-Sm.
  • the composition of this invention can be prepared by attaching or binding to the paramagnetic-containing particle the desired isotope under standard conditions for attachment. This involves coupling a ligand (either with or without a radioactive atom) to the particle with or without the presence of a spacer between the two units. Generally, the coupling can be done by any group (s) attached to the ligand that is (are) not crucial for complexing the radioisotope in a stable manner.
  • This coupling portion of the ligand may consist of any group that can easily and specifically bind covalently to functional groups on the particle or that may simply adsorb very strongly to the surface of the particle.
  • Examples of the covalent coupling would include amino-carboxylate, carboxylate or phosphonate ligands which would combine with Ca + at or near the surface of the particle, activated esters of carboxylic acids which would combine covalently to amine groups, to sylates and acid halides which would combine with OH groups and maleimides which would combine with thiol groups, with the thiol, amine and OH groups assumed to be at or near the surface of the particle.
  • Step one a particle of the optimal size, (e.g., 1-10 microns, 5-50 microns) and composition (e.g., hydroxyapatite, hydroxyapatite-like matrix, albumin, polycarbonate, cellulose, glass, latex) and having appropriate residues (amines, hydroxyls, hydroxide, phosphate, carboxylates, thiols) is selected.
  • Step two a radioisotope (of the appropriate nuclear characteristics) which has been incorporated into a ligand (i.e., a radionuclide complex) is covalently bonded to the particle.
  • a ligand is covalently bonded to one of the previously described particles. Thereafter, one of the previously described radioisotopes is incorporated into the covalently bonded complexing ligand, after the radionuclide has been treated in such a way, e.g., using a transfer ligand such as citrate or tartarate to facilitate transfer of the radionuclide to the ligand, to make it bind more readily to the ligand.
  • a transfer ligand such as citrate or tartarate
  • compositions of this invention may be used in any pharmaceutically acceptable vehicle.
  • suitable for injection such as aqueous buffer solutions, e.g., (trishydroxymethyl)aminomethane and its salts, phosphate, citrate, bicarbonate, e.g., sterile water for injection, physiological saline and balanced ionic solutions containing chloride and /or bicarbonate salts of normal blood plasma cations such as calcium, sodium, potassium, magnesium.
  • aqueous buffer solutions e.g., (trishydroxymethyl)aminomethane and its salts, phosphate, citrate, bicarbonate, e.g., sterile water for injection, physiological saline and balanced ionic solutions containing chloride and /or bicarbonate salts of normal blood plasma cations such as calcium, sodium, potassium, magnesium.
  • Other buffer solutions are described in Remington's Practice of Pharmacy, 11th Edition, for example on page 170.
  • the vehicle may contain stabilizers, antioxidants and other adjuncts
  • Stabilizers include gelatin or other materials in stabilizing amounts to prevent aggregation of the particles, antioxidants in antioxidant amounts such as reducing sugars (e.g., fructose, or free acid or metal salts of gentisic acid) ascorbic acid and other adjuvants such as reducing agents, preferably stannous salts, intermediate exchange ligands in exchange amounts such as metal salts of tartrate, gluconate or citrate as well as bulking agents in bulking amounts such as lactose.
  • the composition may be formulated in a one-step procedure as a lyophilized kit where the radioisotope solution is injected for reconstitution or as an autoclaved or radiation sterilized solution which is then treated with the radioisotope.
  • the ligand has already been attached to the paramagnetic-containing particle before lyophilization or autoclaving.
  • the product may be formulated in a two-step scheme where the radioisotope is bound to the ligand and then this complex with or without purification as necessary is combined with the paramagnetic-containing particles to give the final composition. Any of these steps may require heating and any of the intermediates or final products may require purification before use.
  • the radiolabeled, paramagnetic-containing apatite particles of this invention are preferably formulated for parenteral administration.
  • parenteral formulations advantageously contain a sterile aqueous solution or suspension of treated apatite particles according to this invention.
  • Various techniques for preparing suitable pharmaceutical solutions and suspensions are known in the art.
  • Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • compositions of this invention are used in a conventional manner with regard to its magnetic resonance imaging applications.
  • the compositions are administered in a sufficient amount to provide adequate visualization, to a warm-blooded animal by direct injection into the joint to be treated and imaged, then the animal is subjected to the MRI procedure.
  • Such doses may vary widely, but are readily determined by one of ordinary skill in the art.
  • the amount of the radionuclide in the pharmaceutically acceptable vehicle also varies with the particular use. A sufficient amount is present to provide satisfactory radiation synovectomy. This amount will vary with the physical properties of the isotope being used. For example, when using 186-Re for radiation synovectomy of the hip, a sufficient amount is 2 to 5 mCi and preferably from 3 to 4 mCi.
  • the amount used is approximately 10-20 mCi.
  • the composition is administered so that preferably it remains substantially in the joint for 20 half-lifes of the isotope although shorter residence times are acceptable as long as the leakage of the radionuclide is small and the leaked radionuclide is rapidly cleared from the body.
  • the compositions may be used in the usual way for radiation synovectomy procedures. For example, in the case of the treatment of a knee- joint, a sufficient amount of the radiation synovectomy composition to provide adequate radiation synovectomy is injected into the synovial cavity of the knee.
  • Strict asepsis is essential.
  • the area to be aspirated and/or injected should be cleansed and prepped as for a spinal tap.
  • the injection site is selected by first obtaining radiographs in two planes with the joint position at the injection angle. These are used to correlate easily palpable bony landmarks as a guide for needle placement. Major nerves, vessels and tendons should be avoided. Extensor surfaces are the preferred injection sites. The specific area of the joint to be injected is then marked with firm pressure by a ballpoint pen which has the writing tip retracted. This will leave an impression lasting 10 to 30 minutes. The area is carefully cleansed with Betadine solution and the injection site is anesthetized with 1% xylocaine. The injection needle is then inserted through the ballpoint impression, using care to avoid hitting the cartilage. Following insertion, the needle position may be checked by MRI contrast imaging.
  • the joint is then imaged to assure distribution throughout the joint space. This is an important precaution, because loculated distribution is probably a common cause of treatment failure.
  • the joint is then splinted or the patient confined to bed rest for 48 hours to minimize leakage from the joint space (in the case of 165 Dy- macroaggregates, 7 hours bed rest is deemed sufficient.)
  • the knee is the easiest joint to inject. Tiie patient should be in a supine position with the knee fully extended. The puncture is made 1 to 2 cm medial to the medial margin of the patella using an 18-gauge by 1.5 in. needle directed slightly interiorly and toward the joint space. The joint space should be entered and easily aspirated. If osteophytes make this approach difficult, the knee may- be injected with the patient sitting and the knee fixed. In this case, the needle is placed beneath the distal border of the patella and directed straight. posteriorly or slightly superiorly toward the joint cavity.
  • the joint In most cases after the joint has been injected, it is either (1) moved to allow homogeneous distribution of the radiation synovectomy agent and then immobilized and shielded with appropriate radioactive shielding for a period of time related to the half-life of the isotope or (2) simply immobilized and shielded without working the joint.
  • the calcium nitrate solution pH was adjusted to a pH of 11 with ammonium hydroxide.
  • An ammonium phosphate solution was prepared by adding 0.396 g (NH 4 ) 2 HP0 4 to 5 mL of deionized water.
  • the pH of the ammonium phosphate solution was adjusted to a pH of 11 with ammonium hydroxide.
  • the ammonium phosphate solution was injected into the calcium nitrate solution and vigorously stirred. The resulting precipitated particles were examined under a microscope and estimated to have particle sizes greater than 10 ⁇ m.
  • Example 2 Preparation of Hydroxyapatite Hydroxyapatite particles were prepared according to the procedure of Example !, except that the pH of the calcium nitrate solution was not adjusted to pH' 11.*. The ammonium phosphate solution was injected into the calcium nitrate solution and vigorously stirred. The resulting precipitated particles were examined under a microscope and estimated to have particle sizes greater than 10 ⁇ m.
  • a metal ion solution was prepared by adding 1.18 g Ca(N0 3 ) 2 *»4H 2 0 and 0.202 g Fe(N0 3 ) 3 • 9H 2 0 to 20 mL deionized water.
  • An ammonium phosphate solution was prepared by adding 0.396 g (NH 4 ) 2 HP0 4 to 5 mL of deionized water. The pH of the ammonium phosphate solution was adjusted to 11 with ammonium hydroxide. The ammonium phosphate solution was injected into the metal ion solution and vigorously stirred. The resulting precipitated particles were examined and found to have particle sizes greater than 10 ⁇ m.
  • Fluoroapatite is prepared by mixing 5 mL of a 0.58 M solution of calcium fluoride with 10 mL of a 0.17 M ammonium phosphate solution at native pH. The calcium fluoride solution is dripped into a vigorously stirred ammonium phosphate solution over 30 minutes. The resulting precipitated particles are examined under a microscope and estimated to have particle sizes of approximately 1 ⁇ m.
  • Fluoroapatite is prepared by mixing 5 mL of a 0.58 M solution of calcium nitrate with 10 mL of solution containing 0.17 M ammonium phosphate and 0.17 M ammonium fluoride. The calcium nitrate solution is dripped into a vigorously stirred ammonium phosphate and ammonium fluoride solution over 30 minutes. The resulting precipitated particles are examined under a microscope and estimated to have particle sizes of approximately 1 ⁇ m.
  • Fluoroapatite doped with a paramagnetic metal ion is prepared according to the procedure of Example 5, except that the calcium fluoride solution also contains 0.058 M manganese nitrate. .
  • the calcium fluoride/manganese nitrate solution is dripped into a vigorously • stirred ammonium phosphate solution over 30 minutes. The resulting precipitated particles are examined under a microscope and estimated to have, particle sizes of approximately 1 ⁇ m.
  • Iodoapatite is prepared by mixing 5 mL of a 0.58 M solution of calcium iodide with 10 mL of a 0.17 M ammonium phosphate solution at native pH. The calcium iodide solution is dripped into a vigorously stirred ammonium phosphate solution over 30 minutes. The resulting precipitated particles are examined under a microscope and estimated to have particle sizes of approximately 1 ⁇ m.
  • Example 9 Preparation of Iodoapatite
  • Iodoapatite is prepared by mixing 5 mL of a 0.58 M solution of calcium nitrate with 10 mL of solution containing 0.17 M ammonium phosphate and 0.17 M ammonium iodide. The calcium nitrate solution is dripped into a vigorously stirred ammonium phosphate and ammonium iodide solution over 30 minutes. The resulting precipitated particles are examined under a microscope and estimated to have particle sizes of approximately 1 ⁇ m.
  • Carbonate-doped hydroxyapatite particles are prepared according to the procedure of Example 3, except that calcium carbonate was used instead of • calcium nitrate.
  • the ammonium phosphate solution is dripped using a computer controlled autoburet into a vigorously stirred calcium carbonate solution over 30 minutes.
  • the resulting precipitated particles were examined under a microscope and estimated to have submicron particle sizes.
  • An ammonium phosphate solution was prepared by dissolving 10.56 grams (NH 4 ) 2 HP0 4 in 200 mL of D.I. water. To this was added 100 mL of concentrated NH 4 OH with stirring. A white precipitate formed which was . dissolved by addition of 150 mL of H z O.
  • This solution was stirred for 3 hours at room temperature and then added dropwise (over 2 hours) via a peristaltic pump (Masterflex) to a 1000 mL three-neck round bottom flask fitted with a dry ice/ isopropanol condenser on top of a standard water-jacketed condenser containing a solution of 31.5 grams Ca(N0 3 ) 2 *»4H 2 0 in 500 mL of H 2 0 in boiling water stirred rapidly with a mechanical stirrer. Reflux was continued for two hours after addition was complete and the mixture was allowed to cool to room temperature with stirring overnight. The reaction mixture was centrifuged at 2300 rpm and the nearly-clear supernatant discarded.
  • the resulting white, pelleted solid was slurried with water and completely broken up by means of a vortex mixer. The mixture was again centrifuged and the cloudy supernatant collected. The washing was repeated two separate times. All three washings were saved as was the remaining solid in the centrifuge tubes.
  • the calcium /phosphorous ratio and particle size of the washed particles is summarized below:
  • This material was prepared according to the procedure of Example 11 except that a Mn(II) (as Mn(N0 3 ) 2 »H 2 0) was substituted mole-for-mole for Ca.
  • Mn(II) as Mn(N0 3 ) 2 »H 2 0
  • the reaction mixture was centrifuged at 2300 rpm and the nearly-clear supernatant discarded.
  • the resulting off-white, pelleted solid was slurried with water and completely broken up by means of a vortex mixer.
  • the mixture was again centrifuged md the cloudy supernatant collected.
  • the washing procedure was repeated two times. All three washings were saved as was the remaining solid in the centrifuge tubes.
  • the particle size of the particles in the supernatant increased and the percentage of particles in the supernatant decreased (i.e., less cloudy supernatant). Solids from supernatants could be concentrated by further centrifugation at 7000 rpm.
  • the average particle size was 449 nm with a standard deviation of 171 nm.
  • Manganese containing hydroxyapatite particles were prepared by the following general procedure (Mn/Ca mole ratios of ⁇ 0.33 can be used):
  • the reaction mixture was then divided among six 50mL plastic centrifuge tubes and centrifuged for 15 minutes at 2400 rpm. The procedure was repeated with the remainder of the reaction mixture. The almost clear supernatant was discarded and the solid in each tube resuspended to 50 mL of volume with D.I. water and re-centrifuged. The milky wash was set aside and the solid washed twice more. The three washes were combined and then centrifuged at 7000 rpm for 30 minutes. The particles remained pelleted and the clear supernatant was decanted. The solid was resuspended in water and re-centrifuged three more times at 7000 rpm discarding the supernatant after each washing.
  • Manganese containing hydroxyapatite particles were prepared by the following general procedure. A procedure is described for particles containing
  • This solution was degassed for 2 hours (argon bubbling) with stirring and then added dropwise (over 2 hours) via a peristaltic pump (Masterflex) to a solution of 1.27 grams Mn(N0 3 ) 2 »H 2 0 and 14.5 grams Ca(N0 3 ) 2 »4H 2 0 in 200 mL of H z O that had also been deaerated for 2 hours with argon as it was stirred rapidly with a mechanical stirrer. Argon bubbling was continued during the addition. The reaction mixture was stirred for an additional 2 hours as the Ar bubbling continued.
  • the pH of the hydroxyapatite slurry was adjusted from 9.50 to 8.70 with 80 mL of 0.5 N HCl.
  • 2.1 g of Mn(N0 3 ) 2 -XH 2 0 in 5 mL of H z O was added to the hydroxyapatite mixture and stirred for four hours.
  • the reaction mixture became light brown in color.
  • the reaction mixture was divided among six 50 mL plastic centrifuge tubes and centrifuged for 15 minutes at 2400 rpm. The supernatant was deep purple and clear.
  • the solid residue was washed/centrifuged three times with 50 mL volumes of water per tube and the three washes combined. The combined washes were centrifuged at 7000 rpm for 20 minutes. The solid pellets were washed/centrifuged three additional times discarding the supernatant after each centrifuge run.
  • the white solid residue was suspended in 15 mL of D.I. H z O then subjected to routine analyses.
  • Example 15 The general procedure is the same as in Example 15. Before addition of the additional Mn(N0 3 ) 2 , however, the reaction mixture was pH adjusted from 9.8 to a lower pH (7.5-9.5) and the mixture then centrifuged, the resulting solid washed with D.I. water, the Mn(N0 3 ) 2 added with stirring under argon bubbling, the resultant mixture centrifuged and the solid washed with water. In the final step the HEDP was added to the slurried solid and then the excess washed away with the supernatant during centrifugation.
  • the reaction mixture was stirred for an additional 2 hours as the argon bubbling continued.
  • the pH of the reaction mixture was adjusted from 9.8 to 9.0 with 3 N HCl with rapid stirring and argon bubbling.
  • 1.27 g Mn(N0 3 ) 2 * » H 2 0 in 25 mL of deaerated H z O was added in one portion to the reaction slurry, followed, after 60 minutes, by centrifugation and one washing of the resultant solid (via vortex mixing and recentrifugation).
  • the resulting solution was stirred for 3 hours at room temperature.
  • Into a 3-neck IL round bottom flask equipped with a water cooled and low temperature condenser sequence (dry ice/isopropanol), mechanical stirrer and rubber septum were placed 19.4 g of Ca(N0 3 ) 2 »4H 2 0 in 468 mL of D.I. water.
  • the solution was heated to reflux.
  • the phosphate mixture was added to the rapidly stirred calcium nitrate solution dropwise with a peristaltic pump over one hour. The heat was removed when the addition was complete and the reaction mixture cooled to room temperature.
  • the hydroxylapatite slurry was stirred overnight at room temperature.
  • the pH of the reaction mixture was decreased from 9.53 to 8.50 with 169 ml of IN HCl.
  • Manganese nitrate, Mn(N0 3 ) 2 -xH 2 0 (2.10 g) was added to the hydroxyapatite mixture and stirred for 1 hour and 15 minutes. The color of the slurry became pale tan. The mixture was then centrifuged at 2400 rpm for 15 minutes. The clear colorless supernatant was discarded and the solid washed/centrifuged with 3-50 mL aliquots of water at 2400 rpm for 15 minutes per run. Half of the solid residue was suspended in 200 mL of D.I.
  • the HEDP treated hydroxyapatite fraction was divided among six 50 mL plastic centrifuge tubes and centrifuged for 15 minutes at 2400 rpm. The supernatant was deep purple and slightly cloudy. The solid residue was suspended in H z O and centrifuged at 7000 rpm for 30 minutes. The supernatant was discarded and the solid pellet washed/centrifuged three more times at 7000 rpm. The purified hydroxyapatite was suspended in approximately 30 mL of D.I. water then characterized. The results of the analyses are listed below. HEDP treated untreated size (average diameter, nm): 216 34,100 relaxivity (mMolar "1 sec "1 ): 38.3 0.78
  • Mn-Doped Hydroxyapatite Particles Having a Functionalized Coating Agent This example describes the general preparation of hydroxyapatite particles having a functionalized coating agent.
  • the particles are prepared by adding 0.1-100 mole % of an appropriate coating agent to a slurry of Mn(II) substituted hydroxyapatite with 0.1-100 mole % Mn based on the Ca used in the reaction. The mixture is stirred from 1 to 360 minutes at temperatures in the range from 4°C to 100°C and the solid separated from the supernatant by centrifugation. The resulting solid is collected or subjected to repeated washings with water to remove excess ions and coating agent.
  • the solid after resuspension in water, may be treated with a metal salt (0.01-10 mole% based on Ca in the preparation). This is especially appropriate if the coating agent contains a pendant chelating group to capture and hold tightly the metal (when subjected to in vitro and /or in vivo solutions).
  • the resultant solid is separated by centrifugation and washed 3 timer with water to remove loosely attached coating agent or free metal/coating agent complex.
  • Calcium hydroxyapatite was prepared by the following procedure then treated with.the functionalized poiyphosphonate, dieth * ylene * triamine- penta(methylene-phosphonic acid), abbreviated DETAPMDP and having the following structure:
  • a basic ammonium phosphate solution was prepared using 6.34 g of (NH 4 ) 2 HP0 4 in 120 mL of D.I. water. Concentrated ammonium hydroxide (60 mL) was added followed by 90 ml of D.I. water. The mixture was stirred for 4 hours at room temperature.
  • a solution of 19.0 g of Ca(N0 3 ) 2 « 4H 2 0 in 468 mL of D.I. water was placed in a 3-neck IL round bottom flask.
  • the reaction setup included a mechanical stirrer, water cooled and low temperature (dry ice /isopropanol) condenser arrangement, and a rubber septum.
  • the solution was heated to reflux with rapid stirring.
  • the basic phosphate solution was added dropwise with a peristaltic pump over one hour. The heat was removed after the addition was complete and the reaction mixture stirred overnight at room temperature.
  • the reaction mixture was divided among six 50 mL plastic centrifuge tubes and centrifuged at 2400 rpm for 15 minutes. The clear supernatant was discarded and the solid residue suspended in 50 mL of D.I. per tube and centrifuged at 2400 rpm.
  • the milky suspension was decanted and set aside. The solid was washed/centrifuged twice more and the three washes combined. The milky suspension was re-centrifuged at 7000 rpm for 30 minutes. The clear supernatant was discarded and the solid pellet resuspended and centrifuged three additional times at 7000 rpm. The purified pellet was then suspended in 15 mL od D.I. water and analyzed. The following results were obtained.
  • Example 14 The procedure according to Example 14 is used except that 0.1-100 mole % arsenate is substituted for the phosphate. For example, 9.51 grams
  • Example 14 The procedure according to Example 14 is used except that 0.1-100 mole percent vanadate is substituted for the phosphate. For example, 9.51 grams
  • Example 23 Preparation at 100°C of Mn-Doped Fluoroapatite Particles
  • Manganese fluoroapatite was prepared by the following general procedure. Into a 5-neck IL round bottom flask equipped with a mechanical stirrer, water cooled reflux condenser, adapter for pH electrode, and two rubber septa for addition of reagents were placed 10.3 g of Mn(OAC) 2 »4H 2 0 in 200 mL of D.I. water. The solution was degassed with heavy argon bubbling for 30 minutes. A solution of ammonium fluoride, NH 4 F (0.3 g) in 50 mL of D.I.
  • a stabilizer gentisic acid
  • a reductant stannous
  • a transfer agent citrate
  • 188-Re or 186-Re as perrhenate was injected into the vial.
  • This solution was heated for 15 to 30 minutes in a boiling water bath.
  • the contents of the vial were removed with a syringe and injected into a second vial which contains the Mn-hydroxyapatite particles prepared in Example 4 in an appropriate buffer solution.
  • the contents of the second vial were heated so as to effect covalent bonding of the metal chelate complex to the particle.
  • Quality controls were performed on the contents of this second vial.
  • the radiolabeled Mn-hydroxyapatite. articles were suspended in a solution that is physically acceptable for injection.
  • a radiorhenium-HEDP complex was prepared by adding an aliquot of radiorhenium to a solution that contains ⁇ 10 mg HEDP, ⁇ 3 mg of SnCl 2 , and ⁇ 10 mg of gentisic acid. This solution was heated in either an autoclave at 120°C, or a boiling water bath (or heating block) at 100°C for 15 min. to 1 hour, or in a microwave oven for 2 minutes. An aliquot of this solution was added to a slurry that contains from 10 to 100 mg of Mn-hydroxyapatite particles ⁇ described in Example 4 which have been suspended in water to which a 1% dispersant such as Triton-X,
  • Tween-80 has been added.
  • the slurry was stirred at room temperature for up to 30 rninutes before the particles were collected and washed by centrifugation and /or filtration.
  • the particles were resuspended in an injectable matrix prior to use as a synovectomy agent.
  • Mn-hydroxyapatite particles as described in Example 4 were slurried with 600 ⁇ l Citrate solution (25 mg/ml) for up to 30 minutes. The particles were removed by centrifugation or filtration and washed to remove the excess ligand. The ligand bonded particles were then added to a solution containing 200 ⁇ l of 153 SmCl 3 . After the formation of the ligand bonded particle-radioisotope composition the particles are collected and washed by centrifugation and /or filtration. The particles were resuspended in an injectable matrix prior to use as a synovectomy agent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Nanotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Radiology & Medical Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention se rapporte à des procédés et à des compositions pour améliorer l'imagerie de diagnostic médical et la thérapie pour le traitement de l'arthrite rhumatoïde. Les compositions sont dérivées de particules d'apatite comprenant, sans caractère limitatif, l'hydroxyapatite, la fluoroapatite, l'idioapatite, le carbone-apatite et leurs mélanges et dérivés. Lesdites compositions contiennent une espèce paramagnétique incorporée dans les particules d'apatite afin d'améliorer le contraste de la résonance magnétique et un radionuclide capable de fournir une dose thérapeutique de radioactivité. L'invention se rapporte aussi à une composition de combinaison diagnostique/thérapeutique et à des procédés pour établir un diagnostic médical et appliquer des procédures thérapeutiques, impliquant l'administration à un mammifère à sang chaud d'une quantité suffisante pour un diagnostic de l'ion paramagnétique et une quantité efficace thérapeutiquement du radionuclide et ensuite pour effectuer le traitement médical et les procédures de diagnostic.
PCT/US1996/010808 1995-06-29 1996-06-25 Particules d'apatite radiomarquees contenant un ion paramagnetique WO1997001304A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49664595A 1995-06-29 1995-06-29
US08/496,645 1995-06-29

Publications (1)

Publication Number Publication Date
WO1997001304A1 true WO1997001304A1 (fr) 1997-01-16

Family

ID=23973545

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/010808 WO1997001304A1 (fr) 1995-06-29 1996-06-25 Particules d'apatite radiomarquees contenant un ion paramagnetique

Country Status (1)

Country Link
WO (1) WO1997001304A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029034A1 (fr) * 1998-11-12 2000-05-25 Nycomed Amersham Plc Produits et procedes
WO2001028587A3 (fr) * 1999-10-18 2002-01-03 Ferx Inc Porteurs magnetiques cibles composes de fer et de matieres poreuses pour l'administration ciblee d'agents biologiquement actifs
WO2001062895A3 (fr) * 2000-02-24 2002-02-28 Xcyte Therapies Inc Stimulation et concentration simultanees de cellules
US6797514B2 (en) 2000-02-24 2004-09-28 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
US6867041B2 (en) 2000-02-24 2005-03-15 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
EP1526171A1 (fr) * 2000-02-24 2005-04-27 Xcyte Therapies, Inc Stimulation et concentration simultanées de cellules
WO2005079867A2 (fr) * 2004-02-20 2005-09-01 Algeta As Particules d'hydroxyapatite emettrices de rayons alpha
JP2007528373A (ja) * 2004-02-20 2007-10-11 アルゲッタ エイエス α放射性ヒドロキシアパタイト粒子
WO2008017944A3 (fr) * 2006-08-11 2008-06-12 Mds Canada Inc Composition appareillage et méthode servant pour l'imagerie
US7541184B2 (en) 2000-02-24 2009-06-02 Invitrogen Corporation Activation and expansion of cells
US7572631B2 (en) 2000-02-24 2009-08-11 Invitrogen Corporation Activation and expansion of T cells
KR100912343B1 (ko) 2002-05-21 2009-08-14 후지쯔 가부시끼가이샤 금속 수식 애퍼타이트 함유막의 형성 방법, 여기에사용되는 코팅액, 및 금속 수식 애퍼타이트 함유막으로피복된 부위를 갖는 전자 기기
EP2177232A3 (fr) * 2003-02-28 2010-04-28 The European Atomic Energy Community (EURATOM), represented by the European Commission Activation et production de particules radiomarquées
US7977095B2 (en) 2003-05-08 2011-07-12 Life Technologies Corporation Generation and isolation of antigen-specific T cells
FR2957913A1 (fr) * 2010-03-26 2011-09-30 Commissariat Energie Atomique Nouvelle iodoapatite, son procede de preparation et ses utilisations
US20140227177A1 (en) * 2002-07-02 2014-08-14 Universiteit Utrecht Holding B.V. Scanning Suspension Comprising a Particle with a Diameter of at least 1 Micrometer
WO2016001871A1 (fr) * 2014-07-02 2016-01-07 Universidade Católica Portuguesa Filtres uv, procédé de production de ceux-ci et leur utilisation dans des compositions, en particulier des écrans solaires
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation
IT201900004673A1 (it) * 2019-03-28 2020-09-28 Consiglio Nazionale Ricerche Filtro solare fisico comprendente idrossiapatite o idrossiapatite modificata ottenuto da rifiuti dell’industria ittica e acquacoltura, processo per la sua produzione e composizioni fotoprotettive che lo comprendono

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5320824A (en) * 1989-10-12 1994-06-14 Mallinckrodt Medical, Inc. Radionuclide labelled particles useful for radiation synovectomy
US5342609A (en) * 1991-10-22 1994-08-30 Mallinckrodt Medical, Inc. Microfluidization of calcium/oxyanion-containing particles
US5520904A (en) * 1995-01-27 1996-05-28 Mallinckrodt Medical, Inc. Calcium/oxyanion-containing particles with a polymerical alkoxy coating for use in medical diagnostic imaging

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5320824A (en) * 1989-10-12 1994-06-14 Mallinckrodt Medical, Inc. Radionuclide labelled particles useful for radiation synovectomy
US5342609A (en) * 1991-10-22 1994-08-30 Mallinckrodt Medical, Inc. Microfluidization of calcium/oxyanion-containing particles
US5520904A (en) * 1995-01-27 1996-05-28 Mallinckrodt Medical, Inc. Calcium/oxyanion-containing particles with a polymerical alkoxy coating for use in medical diagnostic imaging

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029034A1 (fr) * 1998-11-12 2000-05-25 Nycomed Amersham Plc Produits et procedes
JP2005200426A (ja) * 1999-10-18 2005-07-28 Ferx Inc 磁気標的化キャリア
WO2001028587A3 (fr) * 1999-10-18 2002-01-03 Ferx Inc Porteurs magnetiques cibles composes de fer et de matieres poreuses pour l'administration ciblee d'agents biologiquement actifs
AU772755B2 (en) * 1999-10-18 2004-05-06 Ferx Incorporated Magnetic targeted carrier composed of iron and porous materials for the targeted delivery of biologically active agents
US7541184B2 (en) 2000-02-24 2009-06-02 Invitrogen Corporation Activation and expansion of cells
EP1526171A1 (fr) * 2000-02-24 2005-04-27 Xcyte Therapies, Inc Stimulation et concentration simultanées de cellules
US6905874B2 (en) 2000-02-24 2005-06-14 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
US6797514B2 (en) 2000-02-24 2004-09-28 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
US6867041B2 (en) 2000-02-24 2005-03-15 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
WO2001062895A3 (fr) * 2000-02-24 2002-02-28 Xcyte Therapies Inc Stimulation et concentration simultanees de cellules
US7572631B2 (en) 2000-02-24 2009-08-11 Invitrogen Corporation Activation and expansion of T cells
KR100912343B1 (ko) 2002-05-21 2009-08-14 후지쯔 가부시끼가이샤 금속 수식 애퍼타이트 함유막의 형성 방법, 여기에사용되는 코팅액, 및 금속 수식 애퍼타이트 함유막으로피복된 부위를 갖는 전자 기기
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation
US9731037B2 (en) * 2002-07-02 2017-08-15 Universitair Medisch Centrum Utrecht Scanning suspension comprising a particle with a diameter of at least 1 micrometer
US20140227177A1 (en) * 2002-07-02 2014-08-14 Universiteit Utrecht Holding B.V. Scanning Suspension Comprising a Particle with a Diameter of at least 1 Micrometer
EP2177232A3 (fr) * 2003-02-28 2010-04-28 The European Atomic Energy Community (EURATOM), represented by the European Commission Activation et production de particules radiomarquées
US7977095B2 (en) 2003-05-08 2011-07-12 Life Technologies Corporation Generation and isolation of antigen-specific T cells
JP2007528373A (ja) * 2004-02-20 2007-10-11 アルゲッタ エイエス α放射性ヒドロキシアパタイト粒子
US8142758B2 (en) 2004-02-20 2012-03-27 Algeta As Alpha-emitting hydroxyapatite particles
WO2005079867A3 (fr) * 2004-02-20 2006-03-16 Algeta As Particules d'hydroxyapatite emettrices de rayons alpha
WO2005079867A2 (fr) * 2004-02-20 2005-09-01 Algeta As Particules d'hydroxyapatite emettrices de rayons alpha
EP2054894A2 (fr) * 2006-08-11 2009-05-06 MDS (Canada) Inc. Composition appareillage et méthode servant pour l'imagerie
EP2054894A4 (fr) * 2006-08-11 2012-11-21 Nordion Canada Inc Composition appareillage et méthode servant pour l'imagerie
WO2008017944A3 (fr) * 2006-08-11 2008-06-12 Mds Canada Inc Composition appareillage et méthode servant pour l'imagerie
EP3355314A1 (fr) * 2006-08-11 2018-08-01 Biocompatibles Uk Ltd. Appareil de composition et procédé à utiliser en imagerie p.e.t.
FR2957913A1 (fr) * 2010-03-26 2011-09-30 Commissariat Energie Atomique Nouvelle iodoapatite, son procede de preparation et ses utilisations
WO2016001871A1 (fr) * 2014-07-02 2016-01-07 Universidade Católica Portuguesa Filtres uv, procédé de production de ceux-ci et leur utilisation dans des compositions, en particulier des écrans solaires
US10314772B2 (en) 2014-07-02 2019-06-11 Universidade Catolica Portuguesa UV-filters, method of producing the same and their use in compositions, in particular sunscreens
IT201900004673A1 (it) * 2019-03-28 2020-09-28 Consiglio Nazionale Ricerche Filtro solare fisico comprendente idrossiapatite o idrossiapatite modificata ottenuto da rifiuti dell’industria ittica e acquacoltura, processo per la sua produzione e composizioni fotoprotettive che lo comprendono
WO2020193750A1 (fr) * 2019-03-28 2020-10-01 Consiglio Nazionale Delle Ricerche Écran solaire physique comprenant de l'hydroxyapatite ou de l'hydroxyapatite modifiée obtenue à partir de déchets de pêcheries et d'aquaculture, procédé pour sa production et compositions photoprotectrices le comprenant

Similar Documents

Publication Publication Date Title
US5609850A (en) Treated apatite particles for ultrasound imaging
WO1997001304A1 (fr) Particules d'apatite radiomarquees contenant un ion paramagnetique
US5320824A (en) Radionuclide labelled particles useful for radiation synovectomy
US5948384A (en) Particulate agents
WO1994023649A1 (fr) Particules traitees contenant du calcium/des oxyanions pour l'imagerie medicale diagnostique
US10918746B2 (en) Radioactive compositions and methods for their therapeutic use
KR100190957B1 (ko) 방사성 키토산 착물, 방사성 키토산 응집입자 및 방사성키토산 착물 제조용 키트, 그리고 그들의 제조방법 및 용도
US20040131543A1 (en) Radiopharmaceuticals and radioactive microspheres for locoregional ablation of abnormal tissues
US5560901A (en) Radionuclide labelled particles useful for radiation synovectomy
Häfeli et al. Magnetically targeted microspheres for intracavitary and intraspinal Y-90 radiotherapy
Vimalnath et al. Formulation, characterization and bio-evaluation of Holmium-166 labeled agglomerated iron oxide nanoparticles for treatment of arthritis of knee joints
EP0563042B1 (fr) Particules a marquage par radionucleide utilisees en synovectomie par rayonnement
Kumar et al. Fullerene-based nanostructures: a novel high-performance platform technology for magnetic resonance imaging (MRI)
Macklis MAGNETICALLY TARGETED MICROSPHERES FOR INTRACAVITARY AND INTRASPINAL Y-90 RADIOTHERAPY

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载