US3872226A - Tc{14 99m albumin aggregates with stannous tin and denatured albumin - Google Patents

Tc{14 99m albumin aggregates with stannous tin and denatured albumin Download PDF

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Publication number
US3872226A
US3872226A US265849A US26584972A US3872226A US 3872226 A US3872226 A US 3872226A US 265849 A US265849 A US 265849A US 26584972 A US26584972 A US 26584972A US 3872226 A US3872226 A US 3872226A
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Prior art keywords
albumin
macroaggregates
solution
macroaggregate
stannous
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Thomas Albert Haney
Gerald Anthony Bruno
Janeth Bartlett
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Priority to BE786566D priority Critical patent/BE786566A/xx
Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US265849A priority patent/US3872226A/en
Priority to CA147,372A priority patent/CA1011653A/en
Priority to CH1081472A priority patent/CH563776A5/xx
Priority to SE7209504A priority patent/SE417896B/xx
Priority to FR7226238A priority patent/FR2146437B1/fr
Priority to IT51655/72A priority patent/IT1048987B/it
Priority to NLAANVRAGE7210027,A priority patent/NL178130C/xx
Priority to DE2235681A priority patent/DE2235681A1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • 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
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/081—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the protein being an albumin, e.g. human serum albumin [HSA], bovine serum albumin [BSA], ovalbumin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1255—Granulates, agglomerates, microspheres
    • 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

  • ABSTRACT Disclosed herein are aggregatess comprising coprecipitated Tc-99m, ionic tin and denatured albumin.
  • the aggregates of this invention can be utilized in the imaging of lungs to determine the conditin of pulmonary vessels.
  • Tc-99m for clinical scintiscanning stems both from its physical and from its chemical properties. Its short half-life, of 6 hr., coupled with an absence of primary B-emission, result in very low radiation doses to tissues. The high activities that can therefore be administered shorten the time required for a scan and enable several views of an organ to be examined.
  • the low energy of its 'y-emission, 140 KeV enables a picture to be obtained with a focusing collimator, of virtually a surface layer a few cm in thickness. This due partly to improved resolution, and partly to reduction of the contribution of radiation from deeper structures by self-absorption.
  • technetium can be prepared in a variety of chemical forms and can be complexed with proteins.
  • Tc-99m complexed with macroaggregated human albumin for lung scanning has been described.
  • Tc-99m0 is reduced with hydrochloric acid and ammonium thiocyanate.
  • a protein precipitate which retained more than 95 percent of the Tc-99m, was formed when the solution of reduced technetium was added to the human serum albumin.
  • Specific activity is such that the required dose of radioactivity can be carried on less than 1.5 mg. of albumin.
  • This invention relates to the tagging of human serum albumin with the radioactive isotope, Tc-99m, without carrying on numerous reactions and heating procedures. It has been discovered that aggregates of albumin and stannous chloride can be treated with Tc-99m, and the resulting suspension formed can be injected intravenously into the body.
  • the aggregates formed by the present invention contains what is known in the art as macroaggregated human serum albumin.
  • the process of this invention comprises adding stannous halide (e.g., stannous chloride, stannous iodide, stannous bromide, etc.) to an acidified solution of human serum albumin, adjusting the pH to the isoelectric point of albumin to form macroaggregates, removing the macroaggregate supernatant thus formed, resuspending the macroaggregates formed in a solution suitable for injection to a specific concentration which may or may not then be dehydrated and adding Tc-99m solution to form radioactive tagged macroaggregates.
  • stannous halide e.g., stannous chloride, stannous iodide, stannous bromide, etc.
  • macroaggregate as utilized in this description means a particle having a size of from about 5 to 100 microns with the preferred size being from about 30 to 50 microns.
  • the macroaggregates of this invention are formed utilizing human serum albumin which is denatured.
  • the denatured albumin of this invention is known in the art as first stage denatured albumin and can be prepared by any known means.
  • One manner in which the albumin can be prepared is by heating normal serum albumin (NSA) followed by making it alkaline.
  • NSA normal serum albumin
  • Human normal serum albumin is to be utilized when the test is to be performed in humans and appropriate animal serum is utilized when the test is performed on cows, dogs, rats, and so forth.
  • the NSA is heated to a temperature of from between about 55 to 95 degrees Centigrade, but more preferably from between about to degrees Centigrade for from 15 to 60 minutes, depending on the quantity of albumin utilized.
  • the larger quantities of albumin requiring longer periods of time than smaller quantities.
  • an organic base such as sodium acetate, acetic acid buffer solution, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide), or alkali metal bicarbonate (e.g., sodium bicarbonate)
  • alkali metal hydroxide e.g., sodium hydroxide
  • alkali metal bicarbonate e.g., sodium bicarbonate
  • the albumin may be denatured by adjusting the pH to about 8, wherein an acid is used to adjust the pH to about 4.5 to 6, or the albumin may be denatured by adjusting the pH to about 2, wherein a base is employed to reach a pH of about 4.5 to 6.
  • the pH change is generally accompanied by warming to insure adequate denaturization.
  • the preferred manner in preparing the albumin of this invention is by utilizing commercially available human serum albumin having preservatives and antifoam agents therein.
  • This material is adjusted to a pH of from about 1.00 to 3.0, but preferably to about 1.50 to about 2.00 utilizing a strong inorganic acid, e.g., sulfuric acid, hydrochloric acid, etc.
  • Stannous halide dissolved in a chloride acid solution is then added to the reaction mixture.
  • the ratio of stannous ions to albumin should be from about 1:2 to 1:20. The most outstanding results being achieved when the ratio of stannous ions to albumin is about 115.
  • the requisite amount of stannous halide in an acid medium such as hydrochloric acid is added.
  • the pH of this solution should be about 1.0 to 2.0 but preferably about 1.1 to 1.3.
  • the solution is then adjusted to the isoelectric point of denatured albumin which is about pH 5.3 but could reasonably fall within 4.8 to 5.8.
  • Particulate matter is thus formed which have become known in the art as macroaggregates.
  • heat is applied to the solution for a period of from to 45 minutes with from 10 to 20 minutes being the preferred period of time.
  • the temperature to be applied is from about 75 to 85C with the preferred range being from 78 to 81C.
  • the macroaggregates thus formed are then washed with distilled water, saline solution or a reducing agent such as a sulfonic acid salt solution.
  • the particles are then resuspended in water for injection, saline, or a solution containing a suitable reducing agent such as dextrose, salt of sulfonic acid, and so forth.
  • the macroaggregates can also be dehydrated if desired, since this appears to enhance the stability of the stannous ion.
  • the preferred method of dehydration is lyophilzation although other standard methods may be employed.
  • albumin to form the macroaggregates of this invention
  • other proteins such as globulin may be utilized.
  • alpha, beta or gamma globulins can be utilized with fibrinogen being one of the most preferred globulins.
  • Such dosage units are prepared so that a single intravenous injection when administered to a mammal of about 70 kg of body weight will deliver about 1 to 5 millicuries of Technetium-99m, preferably about 3 millicuries.
  • aqueous solution preferably a saline solution
  • the amount of radioactivity desired is the governing factor in how much Technetium-99m is to be utilized.
  • Measurement of chemical quantities of Technetium is impractical as it is present in varying amounts depending on the activity of the generator and when it was last eluded.
  • the reaction proceeds equally well by reversing the addition of reagents in solution to Technetium99m.
  • a stannous salt of a mineral acid is generally utilized in the practice of this invention, preferably a halide, such as stannous chloride, stannous bromide, stannous iodide, etc.
  • HSA Human Serum Albumin
  • Benzyl Alcohol 0.9 ml
  • Propylene Glycol 2.0 ml
  • Antifoam AF ca. 2 drops
  • Water for Injection ml 0.1N HCl q.s. ad pH 1.75 1.1 ml SnCl '2H- O 100 mg 0.5M Acetate Buffer q.s. ad pH 5.1 20 ml
  • the human serum albumin, benzyl alcohol, propylene glycol, antifoam, and water for injection are combined and mixed. After the mixture is adjusted to 1.75 with the 0.1N HCl, stannous chloride is added and mixed.
  • the 0.5M acetate buffer is added with mixing to form macroaggregates and the mixture heated in a C (i 15C.) water bath for 40 minutes while constantly being stirred. The mixture is centrifuged and the supernatant discarded. To further purify the macroaggregates, water for injection is mixed with macroaggregates, the mixture again centrifuged and the supernatant discarded. The denatured macroaggregated human serum albumin is suspended in ml of water for injection and refrigerated (ca. 5C).
  • Each preparation is tested for radiochemical binding and the amount of the injected dose that located in the lungs and liver of rats. After the preparations are made, exactly 0.25 ml is injected into the external jugular vein of rats. Three rats are used per preparation. After a resident time of 15 minutes in the rats, they are sacrificed and the percent of the injected dose in the lungs and liver determined. To determine the radiochemical binding, a count rate on the remainder of each formulation is made. They are then centrifuged and a count rate taken on the decanted supernatants only. The percent radiochemical binding is determined as follows:
  • the human serum albumin, water for injection, and 0.lN HCl are combined and mixed for minutes at 79C. (ca. 325 oscillations/min)
  • the 2.5% stannous chloride solution is added and the pH adjusted to 5.1- 5.2 with the IM acetate buffer solution (ca. 30 ml).
  • the mixture is again heated with mixing for 20 minutes at 79C. (ca. 325 oscillations/min).
  • the mixture is centrifuged and the supernatant discarded.
  • To wash the macroaggregates. water for injection is mixed with the macroaggregates, the mixture again centrifuged, and the supernatant discarded. This washing step is repeated then the macroaggregates suspended in 100 ml of water for injection and refrigerated.
  • Table II Macroaggregated HSA Suspension (Ex. No. 2) 1 ml Tc-99m (from generator) l ml Water for Injection 8 ml "/1 In ected Dose in Rat Lungs 108* "z ln ected Dose in Rat Liver 057* Average of three rats.
  • This table illustrates the binding ability of the ionictin macroaggregate.
  • EXAMPLE 6 15 minutes with agitation after which the agiation is stopped and the aggregates allowed to settle.
  • the aggregates are resuspended in water for injection after the volume needed to give the desired denatured albumin concentration of 0.75 mg/cc is determined based a chemical analysis. Based on the calculated final volume, the amount of normal human serum albumin necessary to make the product a 0.5% solution with respect to this carrier is determined.
  • Vials preferably silicon are filled and the contents lyophilized to dryness. Before the vials are sealed they are flooded with nitrogen.
  • the radioactive concentration may range from .5 millicuries per ml to 200 millicuries per ml; generally, however one adjusts the solution so as to add I to 3 ml of the Tc-99m solution having a radioactive concentration of l to 10 millicuries per ml.
  • a macroaggregate in accordance with claim 1 being from about 5 to 100 microns in dimension.
  • a process for preparing macroaggregates of claim 1 which comprises complexing denatured albumin with a stannous salt, adjusting the pH of the reaction solution to from between about 4.8 to 5.8 to form macroaggregates and adding an aqueous Tc-99m solution thereto.
  • a process for preparing macroaggregates in accordance with claim 1 which comprises adding Technetium-99m to a reaction vial containing macroaggregates of denatured albumin and stannous tin.
  • a method for scanning the lungs the pulmonary system which comprises injecting intravenously the macroaggregate of claim 1 in a pharmaceutically acceptable vehicle and scanning the lungs and pulmonary system.
  • a method for scanning the lungs and pulmonary system which comprises injecting intravenously the macroaggregates of claim 8 in a pharmaceutically acceptable vehicle and scanning the lungs and pulmonary UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,872,226

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
US265849A 1971-07-20 1972-06-23 Tc{14 99m albumin aggregates with stannous tin and denatured albumin Expired - Lifetime US3872226A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BE786566D BE786566A (fr) 1971-07-20 Agregats a base de tc-99m et d'albumine
US265849A US3872226A (en) 1971-07-20 1972-06-23 Tc{14 99m albumin aggregates with stannous tin and denatured albumin
CA147,372A CA1011653A (en) 1971-07-20 1972-07-18 Tc-99m albumin aggregates
SE7209504A SE417896B (sv) 1971-07-20 1972-07-19 Vattenhaltig suspension av makroaggregat, merkta med teknetium 99-m, till anvendning vid avsokning av lungorna och lungsystemet samt forfarande for framstellning av suspensionen
CH1081472A CH563776A5 (enrdf_load_stackoverflow) 1971-07-20 1972-07-19
FR7226238A FR2146437B1 (enrdf_load_stackoverflow) 1971-07-20 1972-07-20
IT51655/72A IT1048987B (it) 1971-07-20 1972-07-20 Procedimento per la preparazione di aggregati macroscopici a base di tecnezio 99m albumina e stagno stannoso e prodotto ottenuto
NLAANVRAGE7210027,A NL178130C (nl) 1971-07-20 1972-07-20 Werkwijze voor de bereiding van een radioactief technetium-albuminepreparaat.
DE2235681A DE2235681A1 (de) 1971-07-20 1972-07-20 Macroaggregate aus albumin, technetium99m und zinn(ii)-ionen, verfahren zu ihrer herstellung und ihre verwendung als radioindikatoren bei der untersuchung von organen

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US16445671A 1971-07-20 1971-07-20
US265849A US3872226A (en) 1971-07-20 1972-06-23 Tc{14 99m albumin aggregates with stannous tin and denatured albumin

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BE (1) BE786566A (enrdf_load_stackoverflow)
CA (1) CA1011653A (enrdf_load_stackoverflow)
CH (1) CH563776A5 (enrdf_load_stackoverflow)
DE (1) DE2235681A1 (enrdf_load_stackoverflow)
FR (1) FR2146437B1 (enrdf_load_stackoverflow)
IT (1) IT1048987B (enrdf_load_stackoverflow)
NL (1) NL178130C (enrdf_load_stackoverflow)
SE (1) SE417896B (enrdf_load_stackoverflow)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992513A (en) * 1975-01-07 1976-11-16 Atomic Energy Of Canada Limited Labelled phospholipid material colloidially dispersed and sized to localize at preselected organs
US4024233A (en) * 1972-06-05 1977-05-17 Medi-Physics, Inc. 99M-technetium labeled macroaggregated human serum albumin pharmaceutical
US4042677A (en) * 1974-08-29 1977-08-16 Union Carbide Corporation Technetium-99m labeled radiodiagnostic agents and method of preparation
US4057617A (en) * 1975-05-15 1977-11-08 Abramovici J Method of labeling proteins with technetium
US4087516A (en) * 1976-03-19 1978-05-02 The Radiochemical Centre Limited Body scanning agent
US4187285A (en) * 1977-12-16 1980-02-05 E. R. Squibb & Sons, Inc. Microaggregated albumin
US4406876A (en) * 1980-10-14 1983-09-27 Research Foundation Of The State Univ. Of New York Sulfur free small-particle production of technetium sulfur colloid
US4410507A (en) * 1981-08-28 1983-10-18 Solco Basel Ag Process for the preparation of physiologically degradable, colloidal radioisotope carriers and their use
US4424200A (en) 1979-05-14 1984-01-03 Nuc Med Inc. Method for radiolabeling proteins with technetium-99m
US5208007A (en) * 1988-11-22 1993-05-04 Board Of Regents Of The University Of Oklahoma Isotopic tracer composition and method for making and using same
WO2002067997A1 (en) * 2001-02-28 2002-09-06 Bracco Diagnostics Inc. Manufacturing process to control particle size
US20040122516A1 (en) * 2002-12-20 2004-06-24 Fogarty Thomas J. Biologically implantable prosthesis and methods of using the same

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1389809A (en) * 1972-06-05 1975-04-09 Medi Physics Inc 99m-technetium labeled macroaggregated human serum albumin pharmaceutical
FR2281134A1 (fr) * 1974-08-06 1976-03-05 Commissariat Energie Atomique Procede de marquage au 99m technetium
US3987157A (en) * 1974-08-29 1976-10-19 Union Carbide Corporation Technetium 99-m labeled radio-diagnostic agents employing stannous tartrate and method of preparation
GB1534956A (en) * 1975-05-15 1978-12-06 Ermans A Method of labeling proteins with technetium
US4062933A (en) * 1975-05-27 1977-12-13 Mallinckrodt, Inc. Colloidal compositions with protective agents suitable for radioactive labeling
US4094965A (en) * 1977-04-01 1978-06-13 New England Nuclear Corporation Diagnostic agents containing albumin and method for making same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725295A (en) * 1971-07-20 1973-04-03 Atomic Energy Commission Technetium labeling

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725295A (en) * 1971-07-20 1973-04-03 Atomic Energy Commission Technetium labeling

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024233A (en) * 1972-06-05 1977-05-17 Medi-Physics, Inc. 99M-technetium labeled macroaggregated human serum albumin pharmaceutical
US4042677A (en) * 1974-08-29 1977-08-16 Union Carbide Corporation Technetium-99m labeled radiodiagnostic agents and method of preparation
US3992513A (en) * 1975-01-07 1976-11-16 Atomic Energy Of Canada Limited Labelled phospholipid material colloidially dispersed and sized to localize at preselected organs
US4086330A (en) * 1975-01-07 1978-04-25 The Atomic Energy Of Canada Limited Labelled phospholipid spheres for organ visualization
US4057617A (en) * 1975-05-15 1977-11-08 Abramovici J Method of labeling proteins with technetium
US4087516A (en) * 1976-03-19 1978-05-02 The Radiochemical Centre Limited Body scanning agent
US4187285A (en) * 1977-12-16 1980-02-05 E. R. Squibb & Sons, Inc. Microaggregated albumin
US4424200A (en) 1979-05-14 1984-01-03 Nuc Med Inc. Method for radiolabeling proteins with technetium-99m
US4406876A (en) * 1980-10-14 1983-09-27 Research Foundation Of The State Univ. Of New York Sulfur free small-particle production of technetium sulfur colloid
US4410507A (en) * 1981-08-28 1983-10-18 Solco Basel Ag Process for the preparation of physiologically degradable, colloidal radioisotope carriers and their use
US5208007A (en) * 1988-11-22 1993-05-04 Board Of Regents Of The University Of Oklahoma Isotopic tracer composition and method for making and using same
WO2002067997A1 (en) * 2001-02-28 2002-09-06 Bracco Diagnostics Inc. Manufacturing process to control particle size
US6730286B2 (en) 2001-02-28 2004-05-04 Bracco Diagnostics, Inc. Manufacturing process to control particle size
US20040122516A1 (en) * 2002-12-20 2004-06-24 Fogarty Thomas J. Biologically implantable prosthesis and methods of using the same

Also Published As

Publication number Publication date
FR2146437B1 (enrdf_load_stackoverflow) 1976-07-02
SE417896B (sv) 1981-04-27
NL178130B (nl) 1985-09-02
NL178130C (nl) 1986-02-03
NL7210027A (enrdf_load_stackoverflow) 1973-01-23
IT1048987B (it) 1980-12-20
FR2146437A1 (enrdf_load_stackoverflow) 1973-03-02
CA1011653A (en) 1977-06-07
CH563776A5 (enrdf_load_stackoverflow) 1975-07-15
BE786566A (fr) 1973-01-22
DE2235681A1 (de) 1973-02-08

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