WO1991009622A1 - Radiolabeled colloid compositions, their use and process for their preparation - Google Patents

Radiolabeled colloid compositions, their use and process for their preparation Download PDF

Info

Publication number
WO1991009622A1
WO1991009622A1 PCT/US1990/007522 US9007522W WO9109622A1 WO 1991009622 A1 WO1991009622 A1 WO 1991009622A1 US 9007522 W US9007522 W US 9007522W WO 9109622 A1 WO9109622 A1 WO 9109622A1
Authority
WO
WIPO (PCT)
Prior art keywords
iron
hydroxide
radionuclide
colloid
composition
Prior art date
Application number
PCT/US1990/007522
Other languages
French (fr)
Inventor
Jaime Simon
Lance A. Cooper
Kenneth Mcmillan
David A. Wilson
Original Assignee
The Dow Chemical Company
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 The Dow Chemical Company filed Critical The Dow Chemical Company
Priority to DE69033953T priority Critical patent/DE69033953T2/en
Priority to AT91903521T priority patent/ATE216596T1/en
Priority to CA002046308A priority patent/CA2046308C/en
Priority to EP91903521A priority patent/EP0460205B1/en
Publication of WO1991009622A1 publication Critical patent/WO1991009622A1/en

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
    • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • This invention relates to radiolabeled colloid compositions, to their use as a pharmaceutical and to a process for producing radioactive colloids.
  • the process concerns a radionuclide which is sorbed to a previously prepared colloid.
  • the radioactive colloid so produced is useful in the treatment of arthritis, especially rheumatoid arthritis.
  • Rheumatoid arthritis is a prevalent disease characterized by chronic inflammation of the synovial membrane lining the afflicted joint.
  • Current treatment methods for severe cases of rheumatoid arthritis include the removal of the synovial membrane, e.g., synovectomy.
  • Surgical synovectomy has many limitations including the risk of the surgical procedure itself, and the fact that a surgeon often cannot remove all of the membrane. The diseased tissue remaining eventually regenerates, causing the same symptoms which the surgery was meant to alleviate.
  • Radiation synovectomy is radiation-induced ablation of diseased synovial membrane tissue accomplished by injecting a radioactive compound into the diseased synovium.
  • a radioactive compound e.g., a radioactive compound that has been administered to the patient.
  • Early attempts to perform radiation synovectomy were limited by leakage of the radioactive compounds from the synovium and into surrounding healthy tissues. Significant leakage of the radioactive compound from the injection site exposed normal tissues to dangerous levels of radiation. Because of these limitations, new radiolabeled colloids were sought which would be kinetically inert and of a sufficient size to restrict leakage.
  • radioactive compounds of choice are those with relatively short half-lives, consequently, radioactive colloids prepared by the co-precipitation process have an extremely limited shelf life, and the ability of a physician and patient to schedule therapeutic procedures is highly dependent upon prompt supply and delivery of the products.
  • the present invention provides a process for the preparation of a radiolabeled colloid wherein an iron-hydroxide [Fe(II) or Fe(III)] colloid is produced prior to the addition of radionuclide.
  • This colloid may optionally be separated by size to remove fines and other small particles prior to the addition of the radionuclide which particles would be otherwise likely to leak from the sight of injection during treatment and cause injury to normal tissues.
  • a prepared iron-hydroxide colloid may be stored or shipped for on- site radionuclide addition.
  • the appropriate radionuclide is sorbed onto the colloid to quickly prepare the radionuclide-iron hydroxide colloid for use in therapeutic procedures such as radiation synovectomy.
  • the composition may be advantageously prepared from a kit where the colloid may be kept for a period of time, but the radionuclide portion may be supplied (to be added to the colloid) just prior to use.
  • This present sorption process minimizes the number of manipulations required with radioactive compounds.
  • the process also provides for the removal of undesirable fines and small particles which may leak from the site of injection. Further, this process provides for the preparation of a colloid which may be stored an indefinite period of time and shipped prior to the addition of radionuclides. The radioactive colloid then may be conveniently prepared by the physician just prior to therapeutic use.
  • the resulting product of this process comprises a radionuclide sorbed onto an iron-hydroxide colloid, as opposed to a radionuclide being entrapped within the matrix of a colloid, as in the products prepared by the prior co-precipitation procedure.
  • the radiolabeled colloid compositions of this invention comprise spherical aggregations of radioactive metal in iron- hydroxide particles. More specifically, the compositions of the present invention comprise iron- hydroxide and a radionuclide wherein greater than 50 of the radionuclide is contained within spherical aggregations of the iron hydroxide.
  • colloids prepared by the co-precipitation of iron and the radioactive metal are comprised of a homogeneous distribution of radioactive metal in needle-like crystals.
  • Radiolabeled colloids prepared by the sorption process of this invention remain in the synovium better than similar entrapped radionuclide formulations prepared by the co-precipitation processes.
  • the desired radioactive colloid composition is prepared by the steps of:
  • the iron-hydroxide may be either a solution of iron (II) or iron (III).
  • An iron hydroxide colloid is prepared by the precipitation of an iron solution such as iron (II) or iron (III) sulfate with an alkali metal hydroxide, such as sodium hydroxide. The precipitate is washed in a suitable buffer at neutral pH, such as borate buffer, centrifuged and decanted to form a slurry.
  • the particles of the colloid slurry may be sized prior to the addition of radioactive metal. Particles greater than approximately 1 to 3 ⁇ m have generally been found to be of a sufficient size to be 0 retained in the synovium of a joint. Particles of greater than 3 ⁇ m are preferred, and particles greater than 5 ⁇ m are more preferred. Such sizing may be accomplished by methods known in the art such as t - chromatographic separation, filtration, or differential centrifugation. The process employed may be optimized to remove particles of less than the desired size, or to more stringently separate out particles of a specific size range. A suitable radioactive metal may then be 0 sorbed to the prepared colloid particles.
  • Radioactive metals useful in radiation synovectomy include: Sm-153; Ho-166; In-155m; Gd-159; La-140; Lu-177; Yb-175; and Y- 90.
  • the preferred radioactive metals are Sm-153. Ho- 166, and In-155m.
  • the therapeutically effective amount 5 of radionuclide to be added will vary according to the radionuclide used due to its half-life and emissions.
  • the respective radionuclides can be produced in several ways.
  • a nuclide is bombarded with neutrons to obtain a nuclide with additional neutrons in its nucleus. For example:
  • the desired radionuclide can be prepared by irradiating an appropriate target, such as the metal oxide.
  • an appropriate target such as the metal oxide.
  • Another process of obtaining radionuclides is by bombarding nuclides with particles in a linear accelerator or cyclotron.
  • Yet another way of obtaining radionuclides is to isolate them from fission product mixtures. The process of obtaining the radionuclide is not critical to this invention.
  • sorption includes both absorption and adsorption.
  • a radionuclide is sorbed to the previously prepared iron- hydroxide colloid by mixing a radioactive metal with the colloid and then allowing the mixture to stand for a period of time ranging from 0 to 30 minutes, preferably 0.5 to 10 minutes.
  • a preferred ratio of iron to radionuclide in the final colloid product is greater than 1.0 (mole:mole); a more preferred ratio is greater than 10.0 (mole:mole) .
  • the amount of activity of the radionuclide is dependent upon the particular radionuclide used. The preferred activity is that which is sufficient, when injected into the synovium of a subject, to completely ablate the synovial membrane.
  • sufficient dose is a dose to deliver from 500 to 150,000 rads; a -more preferred sufficient dose of radioactivity is that to deliver from 2,000 to 50,000 rads, to the -synovial membrane.
  • a "therapeutically effective amount” of the present colloid will have a “sufficient dose” amount present.
  • fines, or very small particles are removed from the iron-hydroxide colloid, prior to the step of radionuclide sorption.
  • the sorbed radioactive colloids comprise spherical aggregations distributed within the crystalline structure containing the major portion of the radioactive metal. From 50 to 100 of the radionuclide may be within the spherical aggregations, preferably greater than 70%.
  • the sorbed radioactive colloids of this invention are useful in therapeutic procedures such as radiation synovectomy.
  • a therapeutically effective dose of the sorbed radioactive colloid is injected into the synovium of a subject suffering from rheumatoid arthritis.
  • the appropriate sufficient dose to be therapeutically effective of the sorbed radioactive colloid will vary according to the particular radionuclide, its specific activity and half- life, and the ratio of radioactive metal to iron- hydroxide colloid. In general, the sufficient dose will be that which provides from 500 to 150,000 rads to the synovial membrane.
  • the subject may be any animal in need of such treatment preferably a mammal, and more preferably a human.
  • the radioactive colloid may be challenged with excess metal chelators, such as diethylenetriaminepentaacetic acid (DTPA).
  • DTPA diethylenetriaminepentaacetic acid
  • An iron (II) solution was prepared by the addition of 0.5 ml of 0.2% (0.2 g/100 ml) ferrous sulfate to 5 ml of deionized water. To this solution was added 2 ml of 1.0M sodium hydroxide. The resulting precipitate was isolated by centrifugation, using a Model 2K centrifuge (International Equipment Co.) for 2.5 to 3 minutes at a speed setting of 45 on a scale from 0 to 50. The centrifuged pellet was washed first with 2 ml of water, and then with 2 ml of borate buffer, pH 7. The supernatant liquid was decanted to yield an iron-hydroxide slurry.
  • Model 2K centrifuge International Equipment Co.
  • Example 1 was added 30 ⁇ l of a Sm-153 solution in 0.1N HC1 (3x10 ⁇ ⁇ M Sm), which resulted in a solution containing approximately 8,000 counts per minute.
  • the amount of radiation was determined using a multichannel analyzer equipped with- a Nal well detector. The solution was stirred and allowed to stand for approximately five minutes at room temperature, and then was filtered through a 0.45 micron filter. The relative amount of Sm-153 in the filter paper and in the wash was determined by counting the radioactivity as described above. The results indicated that greater than 99% of the Sm-153 was associated with the iron-hydroxide colloid.
  • EXAMPLE A CHALLENGE OF Sm-153-IRON-HYDROXIDE COLLOID WITH DTPA
  • the filters containing the Sm-153-iron- hydroxide colloid prepared in Example 2 were challenged with excess chelator, DTPA, by flushing the filters with 0.3 ml of DTPA solution (3.3x10 "4 M, pH 7.5). The relative amount of radioactivity in the filter and in the wash was then determined. The results indicated that less than 0.2% of the Sm-153 was displaced from the iron-hydroxide colloid by the excess chelant treatment.
  • Example 2 was injected (100 ⁇ l) into the synovium of the stifle of the hind leg of a rabbit. Counts of the knee area were taken using a Nal scintillation detector over a 4 hour period. Greater than 99% of the injected dose of radioactivity remained in the synovium, with no leakage into surrounding tissues during this 4 hour period.
  • Example 2 The procedure of Example 2 was followed using the radioactive compound Ho-166 to prepare the radioactive colloid. The results indicated that greater than 99% of the Ho-166 was associated with the iron- hydroxide colloid.
  • EXAMPLE B CHALLENGE OF Ho-166-IRON-HYDROXIDE COLLOID WITH DTPA
  • Example 4 The Ho-166-iron hydroxide colloid prepared in Example 4 was challenged with DTPA as described in Example A. The results indicated less than 0.2% of the Ho-166 was displaced from the colloid by the addition of the excess chelator.
  • Example 4 was injected (100 ⁇ l) into the synovium of the stifle of the hind leg of a rabbit.
  • Ho-166-iron-hydroxide colloid was also prepared according to the co-precipitation process of Hnatowich et. al., J. Nucl. Med.19(3), 303-308 (1978), following the procedure described on page 305 of this article. This colloid was also injected (100 ⁇ l) into the synovium of the stifle of the hind leg of a rabbit.
  • Ho-iron-hydroxide colloid Samples of Ho-iron-hydroxide colloid were prepared according to the sorption process in Example 4 using only non-radioactive Ho-165. Ho-iron-hydroxide colloid was also prepared by the co-precipitation process in Example 5 using only non-radioactive Ho-165. The non-radioactive Ho-iron-hydroxide preparations were
  • the colloid prepared by each process was readily distinguishable by the distribution of the Ho metal.
  • Holmium (Ho) was distributed in a homogeneous manner
  • the new composition prepared by sorption of the holmium onto the previously prepared iron hydroxide was comprised of spherical aggregates of iron-hydroxide 0 which contained the majority of the holmium metal (approximately 80 to 90%).

Abstract

Radiolabeled colloid compositions, a process for their preparation, and their use in the treatment of rheumatoid arthritis are disclosed. A radionuclide of Sm-135, Ho-166, In-155m, Y-90, Gd-159, La-140, Lu-177 or Yb-175 is sorbed to a previously prepared iron-hydroxide colloid. The radiolabeled colloid compositions are comprised of spherical aggregations containing greater than 50 % of the radioactive metal in iron-hydroxide particles.

Description

RADIOLABELED COLLOID COMPOSITIONS, THEIR USE AND PROCESS FOR THEIR PREPARATION
This invention relates to radiolabeled colloid compositions, to their use as a pharmaceutical and to a process for producing radioactive colloids. The process concerns a radionuclide which is sorbed to a previously prepared colloid. The radioactive colloid so produced is useful in the treatment of arthritis, especially rheumatoid arthritis.
Rheumatoid arthritis is a prevalent disease characterized by chronic inflammation of the synovial membrane lining the afflicted joint. Current treatment methods for severe cases of rheumatoid arthritis include the removal of the synovial membrane, e.g., synovectomy. Surgical synovectomy has many limitations including the risk of the surgical procedure itself, and the fact that a surgeon often cannot remove all of the membrane. The diseased tissue remaining eventually regenerates, causing the same symptoms which the surgery was meant to alleviate.
Radiation synovectomy is radiation-induced ablation of diseased synovial membrane tissue accomplished by injecting a radioactive compound into the diseased synovium. Early attempts to perform radiation synovectomy were limited by leakage of the radioactive compounds from the synovium and into surrounding healthy tissues. Significant leakage of the radioactive compound from the injection site exposed normal tissues to dangerous levels of radiation. Because of these limitations, new radiolabeled colloids were sought which would be kinetically inert and of a sufficient size to restrict leakage.
The preparation of a radioactive colloid by a co-precipitation process is disclosed in U.S. Patent 4,752,464. This process entraps a radionuclide in an iron hydroxide matrix. While compounds as described in U.S. Patent 4,752,464 are useful for radiation synovectomy, their process of preparation is cumbersome in that it requires many chemical manipulations with highly radioactive compounds. The radioactive colloid particles produced by the co-precipitation process are of varied sizes and include sizes which will leak from the site of injection. Further, the radioactive compounds of choice are those with relatively short half-lives, consequently, radioactive colloids prepared by the co-precipitation process have an extremely limited shelf life, and the ability of a physician and patient to schedule therapeutic procedures is highly dependent upon prompt supply and delivery of the products.
Therefore, a process for preparing radiolabeled colloids for use in the treatment of rheumatoid arthritis, which would be safe and easy to practice, which would produce colloid particles of a uniform size- distribution, and which would enable on-site addition of radionuclide and hence be cost saving and more convenient for use by the daily practitioner, is still needed.
The present invention provides a process for the preparation of a radiolabeled colloid wherein an iron-hydroxide [Fe(II) or Fe(III)] colloid is produced prior to the addition of radionuclide. This colloid may optionally be separated by size to remove fines and other small particles prior to the addition of the radionuclide which particles would be otherwise likely to leak from the sight of injection during treatment and cause injury to normal tissues.
By the process of this invention, a prepared iron-hydroxide colloid may be stored or shipped for on- site radionuclide addition. Immediately prior to use, the appropriate radionuclide is sorbed onto the colloid to quickly prepare the radionuclide-iron hydroxide colloid for use in therapeutic procedures such as radiation synovectomy. Thus, the composition may be advantageously prepared from a kit where the colloid may be kept for a period of time, but the radionuclide portion may be supplied (to be added to the colloid) just prior to use.
This present sorption process minimizes the number of manipulations required with radioactive compounds. The process also provides for the removal of undesirable fines and small particles which may leak from the site of injection. Further, this process provides for the preparation of a colloid which may be stored an indefinite period of time and shipped prior to the addition of radionuclides. The radioactive colloid then may be conveniently prepared by the physician just prior to therapeutic use.
The resulting product of this process comprises a radionuclide sorbed onto an iron-hydroxide colloid, as opposed to a radionuclide being entrapped within the matrix of a colloid, as in the products prepared by the prior co-precipitation procedure. The radiolabeled colloid compositions of this invention comprise spherical aggregations of radioactive metal in iron- hydroxide particles. More specifically, the compositions of the present invention comprise iron- hydroxide and a radionuclide wherein greater than 50 of the radionuclide is contained within spherical aggregations of the iron hydroxide. In contrast, colloids prepared by the co-precipitation of iron and the radioactive metal are comprised of a homogeneous distribution of radioactive metal in needle-like crystals. Radiolabeled colloids prepared by the sorption process of this invention remain in the synovium better than similar entrapped radionuclide formulations prepared by the co-precipitation processes.
Specifically, the desired radioactive colloid composition is prepared by the steps of:
(a) preparing an iron-hydroxide colloid by precipitating an iron solution with an alkali metal hydroxide; and
(b) sorbing onto the iron-hydroxide colloid a radionuclide.
The iron-hydroxide may be either a solution of iron (II) or iron (III). An iron hydroxide colloid is prepared by the precipitation of an iron solution such as iron (II) or iron (III) sulfate with an alkali metal hydroxide, such as sodium hydroxide. The precipitate is washed in a suitable buffer at neutral pH, such as borate buffer, centrifuged and decanted to form a slurry.
If desired, the particles of the colloid slurry may be sized prior to the addition of radioactive metal. Particles greater than approximately 1 to 3 μm have generally been found to be of a sufficient size to be 0 retained in the synovium of a joint. Particles of greater than 3 μm are preferred, and particles greater than 5 μm are more preferred. Such sizing may be accomplished by methods known in the art such as t- chromatographic separation, filtration, or differential centrifugation. The process employed may be optimized to remove particles of less than the desired size, or to more stringently separate out particles of a specific size range. A suitable radioactive metal may then be 0 sorbed to the prepared colloid particles. Radioactive metals useful in radiation synovectomy include: Sm-153; Ho-166; In-155m; Gd-159; La-140; Lu-177; Yb-175; and Y- 90. The preferred radioactive metals are Sm-153. Ho- 166, and In-155m. The therapeutically effective amount 5 of radionuclide to be added will vary according to the radionuclide used due to its half-life and emissions.
The respective radionuclides can be produced in several ways. In a nuclear reactor, a nuclide is bombarded with neutrons to obtain a nuclide with additional neutrons in its nucleus. For example:
Ho-165 + neutron → Ho-166 + gamma Typically the desired radionuclide can be prepared by irradiating an appropriate target, such as the metal oxide. Another process of obtaining radionuclides is by bombarding nuclides with particles in a linear accelerator or cyclotron. Yet another way of obtaining radionuclides is to isolate them from fission product mixtures. The process of obtaining the radionuclide is not critical to this invention.
The term "sorption" includes both absorption and adsorption. In the process of this invention, a radionuclide is sorbed to the previously prepared iron- hydroxide colloid by mixing a radioactive metal with the colloid and then allowing the mixture to stand for a period of time ranging from 0 to 30 minutes, preferably 0.5 to 10 minutes. A preferred ratio of iron to radionuclide in the final colloid product is greater than 1.0 (mole:mole); a more preferred ratio is greater than 10.0 (mole:mole) . The amount of activity of the radionuclide is dependent upon the particular radionuclide used. The preferred activity is that which is sufficient, when injected into the synovium of a subject, to completely ablate the synovial membrane. For this use "sufficient dose" is a dose to deliver from 500 to 150,000 rads; a -more preferred sufficient dose of radioactivity is that to deliver from 2,000 to 50,000 rads, to the -synovial membrane. A "therapeutically effective amount" of the present colloid will have a "sufficient dose" amount present.
In one embodiment of this invention, fines, or very small particles are removed from the iron-hydroxide colloid, prior to the step of radionuclide sorption. -1-
The sorbed radioactive colloids comprise spherical aggregations distributed within the crystalline structure containing the major portion of the radioactive metal. From 50 to 100 of the radionuclide may be within the spherical aggregations, preferably greater than 70%.
The sorbed radioactive colloids of this invention are useful in therapeutic procedures such as radiation synovectomy. In this procedure, a therapeutically effective dose of the sorbed radioactive colloid is injected into the synovium of a subject suffering from rheumatoid arthritis. The appropriate sufficient dose to be therapeutically effective of the sorbed radioactive colloid will vary according to the particular radionuclide, its specific activity and half- life, and the ratio of radioactive metal to iron- hydroxide colloid. In general, the sufficient dose will be that which provides from 500 to 150,000 rads to the synovial membrane. The subject may be any animal in need of such treatment preferably a mammal, and more preferably a human.
To test the kinetic stability or lability of the radionuclide-collo.id, the radioactive colloid may be challenged with excess metal chelators, such as diethylenetriaminepentaacetic acid (DTPA). The failure of excess chelator to displace the radioactive metal from the colloid is evidence that the colloid is stable and inert, and thus suited for use in radiation synovectomy.
The invention will be further clarified by consideration of the following examples, which are intended to be purely exemplary of the method of the invention.
EXAMPLE 1. PREPARATION OF IRON-HYDROXIDE COLLOID
An iron (II) solution was prepared by the addition of 0.5 ml of 0.2% (0.2 g/100 ml) ferrous sulfate to 5 ml of deionized water. To this solution was added 2 ml of 1.0M sodium hydroxide. The resulting precipitate was isolated by centrifugation, using a Model 2K centrifuge (International Equipment Co.) for 2.5 to 3 minutes at a speed setting of 45 on a scale from 0 to 50. The centrifuged pellet was washed first with 2 ml of water, and then with 2 ml of borate buffer, pH 7. The supernatant liquid was decanted to yield an iron-hydroxide slurry.
EXAMPLE 2. SORPTION OF Sm-153 TO THE IRON-HYDROXIDE COLLOID
To the 0.3 ml iron-hydroxide slurry prepared in
Example 1 was added 30 μl of a Sm-153 solution in 0.1N HC1 (3x10~^M Sm), which resulted in a solution containing approximately 8,000 counts per minute. The amount of radiation was determined using a multichannel analyzer equipped with- a Nal well detector. The solution was stirred and allowed to stand for approximately five minutes at room temperature, and then was filtered through a 0.45 micron filter. The relative amount of Sm-153 in the filter paper and in the wash was determined by counting the radioactivity as described above. The results indicated that greater than 99% of the Sm-153 was associated with the iron-hydroxide colloid. EXAMPLE A. CHALLENGE OF Sm-153-IRON-HYDROXIDE COLLOID WITH DTPA
The filters containing the Sm-153-iron- hydroxide colloid prepared in Example 2 were challenged with excess chelator, DTPA, by flushing the filters with 0.3 ml of DTPA solution (3.3x10"4M, pH 7.5). The relative amount of radioactivity in the filter and in the wash was then determined. The results indicated that less than 0.2% of the Sm-153 was displaced from the iron-hydroxide colloid by the excess chelant treatment.
EXAMPLE 3. INJECTION OF Sm-153-IRON-HYDROXIDE COLLOID INTO RABBIT SYNOVIUM
The Sm-153-iron hydroxide colloid prepared in
Example 2 was injected (100 μl) into the synovium of the stifle of the hind leg of a rabbit. Counts of the knee area were taken using a Nal scintillation detector over a 4 hour period. Greater than 99% of the injected dose of radioactivity remained in the synovium, with no leakage into surrounding tissues during this 4 hour period.
EXAMPLE 4. PREPARATION OF Ho-166-IRON-HYDROXIDE COLLOID
The procedure of Example 2 was followed using the radioactive compound Ho-166 to prepare the radioactive colloid. The results indicated that greater than 99% of the Ho-166 was associated with the iron- hydroxide colloid. EXAMPLE B. CHALLENGE OF Ho-166-IRON-HYDROXIDE COLLOID WITH DTPA
The Ho-166-iron hydroxide colloid prepared in Example 4 was challenged with DTPA as described in Example A. The results indicated less than 0.2% of the Ho-166 was displaced from the colloid by the addition of the excess chelator.
EXAMPLE 5. INJECTION OF Ho-166-IRON-HYDROXIDE COLLOID INTO RABBIT SYNOVIUM
The Ho-166-iron hydroxide colloid prepared in
Example 4 was injected (100 μl) into the synovium of the stifle of the hind leg of a rabbit.
Ho-166-iron-hydroxide colloid was also prepared according to the co-precipitation process of Hnatowich et. al., J. Nucl. Med.19(3), 303-308 (1978), following the procedure described on page 305 of this article. This colloid was also injected (100 μl) into the synovium of the stifle of the hind leg of a rabbit.
As in Example 3> counts of the knee areas over a 4 hour period were taken. Results for the sorbed- radioactive colloid indicated that greater than 99% of the radioactivity remained in the synovium, with no leakage into surrounding tissues. In contrast, results for the colloid prepared by an "entrapment" co- precipitation process indicated only 95% of the activity remained in the synovium after 4 hours of treatment. EXAMPLE C. COMPARISON OF PHYSICAL CHARACTERISTICS OF SORBED-HOLMIUM COLLOID VERSUS CO- PRECIPITATED HOLMIUM COLLOID.
Samples of Ho-iron-hydroxide colloid were prepared according to the sorption process in Example 4 using only non-radioactive Ho-165. Ho-iron-hydroxide colloid was also prepared by the co-precipitation process in Example 5 using only non-radioactive Ho-165. The non-radioactive Ho-iron-hydroxide preparations were
10 viewed in a transmission electron microscope. The colloid prepared by each process was readily distinguishable by the distribution of the Ho metal. Holmium (Ho) was distributed in a homogeneous manner
-j- throughout the needle-like crystals of the colloid prepared by the co-precipitation process . In contrast, the new composition prepared by sorption of the holmium onto the previously prepared iron hydroxide was comprised of spherical aggregates of iron-hydroxide 0 which contained the majority of the holmium metal (approximately 80 to 90%).
Other embodiments of the invention will be apparent to those skilled in the art from a 5 consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims. 0

Claims

1. A process for preparing a radioactive colloid composition, comprising the steps of:
(a) preparing an iron-hydroxide colloid by precipitating an iron solution with an alkali metal hydroxide; and
(b) sorbing onto the iron-hydroxide colloid a radionuclide.
2. The process of Claim 1, wherein the iron solution of step (a) is a solution comprising iron (II).
3. The process of Claim 1, wherein the iron solution of step (a) is a solution comprising iron (III).
4. The process of Claim 1, wherein the radionuclide of step (b) is Sm-153, Ho-166, In-115m, Y-90, Gd-159, La-140, Lu-177 or Yb-175.
5. The process of Claim 4, wherein the radionuclide of step (b) is Sm-153, Ho-166 or In-115m.
6. The process of Claim 1, wherein said sorbing is accomplished by preparing a mixture of a radionuclide with the iron-hydroxide colloid wherein the mixture is further permitted to stand for a period of up to 30 minutes.
7. The process of Claim 1, including the additional step of filtering the iron-hydroxide colloid formed in step (a) prior to step (b).
8. The process of Claim 7, wherein the colloid retained for use is greater than 3μm.
0 9. The process of Claim 8, wherein the colloid retained for use is greater than 5μm.
10. A composition comprising iron-hydroxide and a radionuclide wherein greater than 50% of the .. radionuclide is contained within spherical aggregations of the iron hydroxide.
11. The composition of Claim 10, wherein said spherical aggregations contain greater than 70% of the n radionuclide.
12. The composition of Claim 10, wherein the iron-hydroxide is iron (II)-hydroxide.
13. The composition of Claim 10, wherein the 5 iron-hydroxide is iron- (III)-hydroxide.
14. The composition of Claim 10, wherein the radionuclide is Sm-153, Ho-166, In-115m, Y-90, Gd-159, La-140, Lu-177 or Yb-175. 0
15. The composition of Claim 14, wherein the radionuclide is Sm-153, Ho-166 or In-115m.
16. The composition of Claim 10, wherein the ratio of iron to radionuclide is greater than 1.0.
17. The composition of Claim 16, wherein the ratio of iron to radionuclide is greater than 10.0.
18. A method for the treatment of arthritis comprising sorbing a radionuclide onto a previously prepared iron-hydroxide colloid; and administering to a subject in need of such treatment a therapeutically effective amount of the composition thus formed.
19. A method for the treatment of arthritis comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising iron-hydroxide and a radionuclide wherein greater than 50% of the radionuclide is contained within spherical aggregations of the iron- hydroxide.
20. The method of Claim 19, wherein said spherical aggregations contain greater than 70% of the radionuclide.
21. The method of Claim 19, wherein the iron hydroxide is iron (II) hydroxide.
22. The method of Claim 19, wherein the iron hydroxide is iron (III) hydroxide.
23- The method of Claim 19, wherein the radionuclide 'is Sm-153, Ho-166, In-115m, Y-90, Gd-159, La-140, Lu-177 or Yb-175.
24. The method of Claim 23, wherein the radionuclide is Sm-153, Ho-166 or In-115m.
25. The method of Claim 19, wherein said arthritis is rheumatoid arthritis.
26. The method of Claim 19, wherein said administering is to the synovium of a joint of the subject.
27. The method of Claim 19, wherein said subject is a human.
28. The method of Claim 19, wherein the therapeutically effective amount of the composition is a sufficient dose of radioactivity that is able to deliver from 500 to 150,000 rads.
29. The method of Claim 28, wherein the therapeutically effective amount of the composition is a sufficient dose of radioactivity that is able to deliver from 2,000 to 50,000 rads.
30. A composition as defined in any one of Claims 10 to 17 for use as a pharmaceutical.
31. A composition as defined in any one of Claims 10 to 17 for use in the treatment of arthritis,
PCT/US1990/007522 1989-12-27 1990-12-18 Radiolabeled colloid compositions, their use and process for their preparation WO1991009622A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DE69033953T DE69033953T2 (en) 1989-12-27 1990-12-18 COLLOIDAL RADIO-MARKED COMPOSITIONS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF
AT91903521T ATE216596T1 (en) 1989-12-27 1990-12-18 COLLOIDAL RADIOM LABELED COMPOSITIONS, THEIR USE AND METHOD FOR THEIR PRODUCTION
CA002046308A CA2046308C (en) 1989-12-27 1990-12-18 Radiolabeled colloid compositions, their use and process for their preparation
EP91903521A EP0460205B1 (en) 1989-12-27 1990-12-18 Radiolabeled colloid compositions, their use and process for their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/458,049 US5061476A (en) 1989-12-27 1989-12-27 Radiolabeled colloid compositions and method for preparing same
US458,049 1989-12-27

Publications (1)

Publication Number Publication Date
WO1991009622A1 true WO1991009622A1 (en) 1991-07-11

Family

ID=23819152

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/007522 WO1991009622A1 (en) 1989-12-27 1990-12-18 Radiolabeled colloid compositions, their use and process for their preparation

Country Status (7)

Country Link
US (1) US5061476A (en)
EP (1) EP0460205B1 (en)
JP (1) JP3155273B2 (en)
AT (1) ATE216596T1 (en)
CA (1) CA2046308C (en)
DE (1) DE69033953T2 (en)
WO (1) WO1991009622A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995016463A1 (en) * 1992-09-23 1995-06-22 The Dow Chemical Company Radioactive compositions and their use for radiation ablation treatment
EP0730871A1 (en) * 1995-03-10 1996-09-11 Korea Atomic Energy Research Institute Radioactive chitosan complex and the use thereof for radiation therapy
EP0730870A1 (en) * 1995-03-10 1996-09-11 Korea Atomic Energy Research Institute Radioactive chitosan complex and its macroaggregates for use in internal radiation therapy and their preparation method
EP0734725A2 (en) * 1995-03-27 1996-10-02 IMMUNO Aktiengesellschaft Adjuvants containing colloidal iron compounds
US5762903A (en) * 1995-03-10 1998-06-09 Korea Atomic Energy Research Institute Radioactive chitosan complex for radiation therapy
CN100450553C (en) * 2006-11-16 2009-01-14 沈阳 Degradable radioactive sponge and its making process

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5137709A (en) * 1991-02-15 1992-08-11 The Dow Chemical Company Layered mixed metal hydroxides for the stabilization of radioactive colloids
US5268129A (en) * 1991-02-15 1993-12-07 The Dow Chemical Company Layered mixed metal hydroxides for the stabilization of radioactive colloids
US5429582A (en) * 1991-06-14 1995-07-04 Williams; Jeffery A. Tumor treatment
US5924973A (en) 1996-09-26 1999-07-20 The Trustees Of Columbia University In The City Of New York Method of treating a disease process in a luminal structure
WO1998019740A1 (en) * 1996-11-05 1998-05-14 Duke University Radionuclide production using intense electron beams
WO2000029501A1 (en) 1998-11-18 2000-05-25 Emory University Radioactive coating solutions, methods, and substrates
ES2671622T3 (en) 2011-12-21 2018-06-07 Iso Therapeutics Group Llc Compositions and radioactive methods for therapeutic use
JP2016520650A (en) * 2013-06-05 2016-07-14 アール−エヌエーヴィ・エルエルシー Treatment of immune, inflammatory and osteoarthritis with tin-117m
KR20160113496A (en) * 2015-03-20 2016-09-29 이화여자대학교 산학협력단 Inorganic polymer hybrid colloid compound and method for preparing the same

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4752464A (en) * 1985-06-07 1988-06-21 Cadema Medical Products, Inc. Treatment of arthritis, including rheumatoid arthritis, with radioactive isotopes
US4758429A (en) * 1985-11-04 1988-07-19 Gordon Robert T Method for the treatment of arthritis and inflammatory joint diseases
US4849209A (en) * 1985-06-07 1989-07-18 Cadema Medical Products, Inc. Treatment of arthritis, including rheumatoid arthritis with 166 Holmium radionuclide
US4889707A (en) * 1988-01-29 1989-12-26 The Curators Of The University Of Missouri Composition and method for radiation synovectomy of arthritic joints
US4897254A (en) * 1984-09-21 1990-01-30 The Dow Chemical Company Radioactive compositions for the treatment of calcific tumors
US4898724A (en) * 1984-06-04 1990-02-06 The Dow Chemical Company Organis amine phosphonic acid complexes for the treatment of calcific tumors
US4906450A (en) * 1987-03-26 1990-03-06 Ephraim Lieberman Treatment of arthritis, including rheumatoid arthritis, with the radionuclide, tin SN-121
US4915932A (en) * 1987-10-14 1990-04-10 Australian Nuclear Science & Technology Organisation Macroaggregates for radiation synovectomy
US4970062A (en) * 1989-05-30 1990-11-13 The United States Of America As Represented By The United States Department Of Energy Colloid labelled with radionuclide and method

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU900222D0 (en) * 1990-01-22 1990-04-28 Peter Teleki Process for giving 5b-10, 45rh-103 isotops to ferrofluidic ferric oxide, advantageous stopping vital functions of cancerous cells
WO1991015240A1 (en) * 1990-04-11 1991-10-17 Teleki Peter Method of preparing an iron oxide composition for therapeutic treatment of a living body and iron oxide composition

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4898724A (en) * 1984-06-04 1990-02-06 The Dow Chemical Company Organis amine phosphonic acid complexes for the treatment of calcific tumors
US4897254A (en) * 1984-09-21 1990-01-30 The Dow Chemical Company Radioactive compositions for the treatment of calcific tumors
US4752464A (en) * 1985-06-07 1988-06-21 Cadema Medical Products, Inc. Treatment of arthritis, including rheumatoid arthritis, with radioactive isotopes
US4849209A (en) * 1985-06-07 1989-07-18 Cadema Medical Products, Inc. Treatment of arthritis, including rheumatoid arthritis with 166 Holmium radionuclide
US4758429A (en) * 1985-11-04 1988-07-19 Gordon Robert T Method for the treatment of arthritis and inflammatory joint diseases
US4906450A (en) * 1987-03-26 1990-03-06 Ephraim Lieberman Treatment of arthritis, including rheumatoid arthritis, with the radionuclide, tin SN-121
US4915932A (en) * 1987-10-14 1990-04-10 Australian Nuclear Science & Technology Organisation Macroaggregates for radiation synovectomy
US4889707A (en) * 1988-01-29 1989-12-26 The Curators Of The University Of Missouri Composition and method for radiation synovectomy of arthritic joints
US4970062A (en) * 1989-05-30 1990-11-13 The United States Of America As Represented By The United States Department Of Energy Colloid labelled with radionuclide and method

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Arthritis and Rheumatism, Volume 20, Number 7, issued 1977, SLEDGE et al., "Experimental Radiation Synovectomy by 165Dy Ferric Hydroxide Macroaggregate", see pages. 1334-1342. *
Arthritis and Rheumatism, Volume 29, Number 2, issued 1986, SLEDGE et al., "Treatment of Rheumatoid Synovitis of the Knee with Intraarticular Injection of Dyspropium 165-Ferric Hydroxide Macroaggregates", see pages 153-159. *
Clinical Orthopedics and Related Research, Volume 182, Number 7, issued 1984, SLEDGE et al., "Intra-articular Radiation Synovectomy", see pages. 37-40. *
Journal of Nuclear Medicine, Volume 19, Number 3, issued 1978, HNATOWICH et al., "Dyspropium-165 Ferric Hydroxide Macroaggregates for Radiation Synovectomy", see pages 303-308. *
Journal of the American Medical Association, Volume 253, issued 1985, DOEPEL., "Radionuclide Therapy for Arthritic Knees", see pages 744-745. *
Nuclear Medicine, issued 1986 SPOORAN et al., "Synovectomy of the Knee with 90Y", see pages. 441-445. *
ROSENTHAL, L., Therapy in Nuclear Medicine, R. SPENCER, ed., published 1978, by Gruen and Stratton(New York), See Chapter 12 entitled "Use of Radiocolloids for Intra-articular Therapy for Synovitis", pages 147-153. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995016463A1 (en) * 1992-09-23 1995-06-22 The Dow Chemical Company Radioactive compositions and their use for radiation ablation treatment
EP0730871A1 (en) * 1995-03-10 1996-09-11 Korea Atomic Energy Research Institute Radioactive chitosan complex and the use thereof for radiation therapy
EP0730870A1 (en) * 1995-03-10 1996-09-11 Korea Atomic Energy Research Institute Radioactive chitosan complex and its macroaggregates for use in internal radiation therapy and their preparation method
US5762903A (en) * 1995-03-10 1998-06-09 Korea Atomic Energy Research Institute Radioactive chitosan complex for radiation therapy
EP0734725A2 (en) * 1995-03-27 1996-10-02 IMMUNO Aktiengesellschaft Adjuvants containing colloidal iron compounds
EP0734725B1 (en) * 1995-03-27 2003-07-09 Bio-Products & Bio-Engineering Aktiengesellschaft Adjuvants containing colloidal iron compounds
CN100450553C (en) * 2006-11-16 2009-01-14 沈阳 Degradable radioactive sponge and its making process

Also Published As

Publication number Publication date
EP0460205B1 (en) 2002-04-24
US5061476A (en) 1991-10-29
ATE216596T1 (en) 2002-05-15
JP3155273B2 (en) 2001-04-09
DE69033953T2 (en) 2002-10-17
EP0460205A4 (en) 1993-07-28
DE69033953D1 (en) 2002-05-29
CA2046308A1 (en) 1991-06-28
CA2046308C (en) 2000-11-28
JPH04505023A (en) 1992-09-03
EP0460205A1 (en) 1991-12-11

Similar Documents

Publication Publication Date Title
EP0460205B1 (en) Radiolabeled colloid compositions, their use and process for their preparation
KR100671387B1 (en) The Preparation And Use Of Radium-223 To Target Calcified Tissues For Pain Palliation, Bone Cancer Therapy, And Bone Surface Conditioning
AU652813B2 (en) Layered mixed metal hydroxides for the stabilization of radioactive colloids
AU657641B2 (en) Macrocyclic aminophosphonic acid complexes, their preparation, formulations and use
CA2109208C (en) Radiolabeled metal-binding protein for the treatment of arthritis
AU625644B2 (en) Bone marrow suppressing agents
EP0164843B1 (en) Organic amine phosphonic acid complexes for the treatment of calcific tumors
US6149889A (en) Radioactive particles and methods for preparing same
US10596277B2 (en) High purity therapeutic bone agents
EP0225409A1 (en) Organic amine phosphonic acid complexes for the treatment of calcific tumors
EP0176288A1 (en) Aminocarboxylic acid complexes for the treatment of calcific tumors
US5268129A (en) Layered mixed metal hydroxides for the stabilization of radioactive colloids
Hansard Effects of hydrobiotites upon strontium-89 and cesium-137 retention by ruminant animals.
Ferro-Flores et al. 153 Sm metallic-hydroxide macroaggregates: an improved preparation for radiation synovectomy
Saraswathy et al. Radiochemical and biological studies, including in non-human primates, towards indigenous development of 153 Sm-EDTMP for metastatic bone pain palliation
SARASWATHY et al. RADIOCHEMICAL AND BIOLOGICAL STUDIES, XA0102697 INCLUDING IN NON-HUMAN PRIMATES, TOWARDS INDIGENOUS DEVELOPMENT OF 153Srn-EDTMP FOR METASTATIC BONE PAIN PALLIATION
AU624283B2 (en) Organic amine phosphonic acid complexes
Saraswathy et al. Radiochemical and biological studies, including in non-human primates, towards indigenous development of {sup 153} Sm-EDTMP for metastatic bone pain palliation
WO1995016463A1 (en) Radioactive compositions and their use for radiation ablation treatment

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 FR GB GR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 2046308

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1991903521

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1991903521

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1991903521

Country of ref document: EP