US3863004A - Denatured macroprotein with divalent tin for tagging with technetium-99m and method of preparation - Google Patents
Denatured macroprotein with divalent tin for tagging with technetium-99m and method of preparation Download PDFInfo
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- US3863004A US3863004A US236159A US23615972A US3863004A US 3863004 A US3863004 A US 3863004A US 236159 A US236159 A US 236159A US 23615972 A US23615972 A US 23615972A US 3863004 A US3863004 A US 3863004A
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- denatured
- divalent tin
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- 238000000034 method Methods 0.000 title claims abstract description 44
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 title claims abstract description 33
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 title claims abstract description 23
- 229940056501 technetium 99m Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title description 7
- 239000002245 particle Substances 0.000 claims abstract description 42
- 210000004072 lung Anatomy 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 239000000243 solution Substances 0.000 claims abstract description 21
- 239000007853 buffer solution Substances 0.000 claims abstract description 15
- 229940102213 injectable suspension Drugs 0.000 claims abstract description 11
- 239000004005 microsphere Substances 0.000 claims abstract description 11
- 229910001432 tin ion Inorganic materials 0.000 claims abstract description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 33
- 108090000623 proteins and genes Proteins 0.000 claims description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 9
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 239000001119 stannous chloride Substances 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 description 32
- 102000009027 Albumins Human genes 0.000 description 20
- 108010088751 Albumins Proteins 0.000 description 20
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 18
- 229910052713 technetium Inorganic materials 0.000 description 13
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000008351 acetate buffer Substances 0.000 description 6
- 235000019445 benzyl alcohol Nutrition 0.000 description 6
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 238000009206 nuclear medicine Methods 0.000 description 3
- 238000003303 reheating Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100400378 Mus musculus Marveld2 gene Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000004980 dosimetry Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 108010013207 macro aggregates of albumin Proteins 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- RCIVOBGSMSSVTR-UHFFFAOYSA-L stannous sulfate Chemical compound [SnH2+2].[O-]S([O-])(=O)=O RCIVOBGSMSSVTR-UHFFFAOYSA-L 0.000 description 1
- JEHASHUIFUSSAI-UHFFFAOYSA-N sulfanylidenetechnetium Chemical compound [Tc]=S JEHASHUIFUSSAI-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229910000375 tin(II) sulfate Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- An improved composition suitable for tagging with technetium-99m and use in lung scanning procedures consists essentially of an injectable suspension in buffer solution of particles of a denatured macroprotein having divalent tin bound thereto.
- the macroprotein has a molecular weight of at least about 20,000.
- a method for preparing the inject-able suspension by treating macroaggregates or mierospheres of a denatured macroprotein with a solution containing divalent tin ions is also provided.
- Macroaggregated macroproteins have found use as carriers for radionuclides useful in diagnostic radioscanning techniques.
- such proteins for example human serum albumin labeled or tagged with a radionuclide, have been used in the diagnosis of pulmonary circulatory defects.
- radioactive macroprotein particles must be labeled with a gamma emitting radionuclide and be within a prescribed size range.
- the labeled particles must also be non-toxic and biodegradable, i.e., physically or chemically removable from the lungs in a relatively short period.
- Macroaggregated human serum albumin tagged with iodine-131 has become widely used for perfusion lung scanning. While the biological properties of this scanning agent are excellent, an important objection to its use arises from the decay scheme of iodine-l 3 I. In the course of decay, iodine-131 emits a beta particle, its gamma rays are difficult to collimate effectively, and it has an 8-day physical half-life. As a result of these characteristics, a patient receiving an injection of iodine- 13l-tagged albumin is exposed to a high radiation dose, not only to the lungs but to other organs such as the thyroid gland as well.
- a radionuclide which may advantageously be substituted for iodine-131 in lung scanning is technetium- 99m which emits only gamma rays which can be easily collimated, and has a physical half-life of only 6 hours.
- technetium- 99m which emits only gamma rays which can be easily collimated, and has a physical half-life of only 6 hours.
- an aqueous solution of albumin can be dispersed in hot, waterimmiscible oil to precipitate the albumin in the form of microspheres.
- the most common has involved first tagging a solution of albumin with technetium and then precipitating to form the solid albumin in particles ofthe desired size. Where this method is utilized, however, an immediate microscopic examination of the particles must be made to assure their proper size, and purification is required to remove unreacted technetium from the suspension.
- sterility tests cannot be completed on the denatured and precipitated protein before it is used in human patients.
- a technetium sulfur colloid is formed in the presence of denatured albumin microspheres causing the spheres to become tagged with the technetium.
- labeling is not very efficient by this method, and several washes of the protein particles are required to remove the unbound technetium.
- the tagged microspheres produced by this method are prone to stick together and it becomes necessary to disperse the resulting agglomerates by an appropriate technique such as ultrasonic treatment, immediately prior to injection into a patient.
- the bond between the technetium and the microspheres is somewhat labile, and if the suspension is allowed to stand unused for as little as an hour or so after preparation, both the purification and ultrasonic treatment must be repeated before injection.
- technetium-tagged albumin has not been found generally useful as a lung scanning agent, despite its desirable radiation properties.
- the present invention is directed to a composition suitable for tagging with technetium-99m and use in lung scanning procedures.
- composition consists essentially of an injectable suspension in a buffer solution of particles of a denatured macroprotein having divalent tin bound thereto, the macroprotein having a molecular weight of at least about 20,000.
- the invention is further directed to a process for preparing the composition. In this process, particles of a denatured macroprotein are contacted with a solution containing a water-soluble salt of divalent tin causing divalent tin to be bound to the macroprotein. The macroprotein having divalent tin bound thereto is then washed and suspended in buffer solution.
- the macroprotein constituent of the composition of the invention is preferably denatured human serum albumin, a protein which is particularly suitable for use in lung scanning. It will be understood, however, that any denatured macroprotein having a molecular weight of at least about 20,000 may have divalent tin bound thereto in accordance with the invention to render it more susceptible to labeling with a radioactive isotope of technetium.
- the particles of the protein constituent of the composition of the invention are characterized as macroaggregates.
- Macroaggregatcs are considered to be particles of irregular form having an average diameter of between about 5 and about 80 microns.
- the mean size of the particles is preferably between about l5 and about 30 microns.
- the improved susceptibility of the suspended protein macroaggregates to tagging with technetium99m relates to the divalent tin which is bound to the protein.
- a suspension of serum albumin treated with divalent tin in accordance with the invention is subsequently treated with a solution containing heptavalent technetium-99m, for example a solution of sodium pertechnetate, upwards of 90% of the technetium is rapidly and firmly bound to the serum protein.
- human serum albumin or other appropriate macroprotein is first denatured and then precipitated to form particles of the desired size.
- Various methods are known to the art for producing macroaggregates 'or microspheres of denatured protein. While any of these methods may be successfully used, excellent results have been obtained using a method wherein a dilute aqueous solution of human serum albumin is first heated at a temperature of about '70l00C., preferably about 85C., to denature the protein, then cooled to a temperature on the order of l8-22C., preferably about 20C.
- the albumin is then precipitated by slowly adding a dilute acid, approximately 0.1N, until the pH is about 4.8-5.2, i.e., the isoelectric pH of the protein being about 4.9.
- Hydrochloric acid is preferred for use in adjusting the pH to precipitate the denatured protein.
- other mineral acids or acetic acid may also be employed.
- the particle size of the macroaggregates thus precipitated is typically in the range of 5-80 microns with a mean particle size of -30 microns.
- the integrity of the precipitated aggregates is further improved if the suspension is reheated for a short period of time following precipitation.
- the reheating temperature is of approximately the same order as the denaturing temperature.
- the macroaggregated albumin particles are separated from the suspension, washed and resuspended in a fresh buffer solution having essentially the same pH as the isoelectric pH of the protein (i.e.,
- a convenient buffer solution is an acetate buffer having a pH of 4.9 (0.052N sodium acetate and 0.02N hydrochloric acid).
- Binding of the protein aggregates with divalent tin is effected by adding to the protein suspension an aqueous solution containing stannous ions. Contact of the macroaggregates with stannous ions causes divalent tin to become bound to the protein.
- stannous chloride is preferred because of its solubility and greater stability, although other watersoluble stannous salts, such as stannous sulfate. may also be used. lt is necessary. however. to employ a divalent tin solution since tetravalent tin ions are not effective.
- stannous ions are available for binding to the protein if the mixture of the protein suspension and stannous salt solution contains approximately 3 mg. of stannous ions per mg. of macroaggregates. With such proportions, binding of divalent tin to the protein molecule occurs quickly at room temperature and appears to be substantially complete in about 15 minutes or so. For optimum results, however, the mixture containing stannous ions and protein should be allowed to stand for a longer time, preferably about 24 hours. After the treatment period is complete, the aggregates are separated from the liquid phase, washed with and rcsuspended in fresh buffer solution. After resuspcnsion, the macroaggregates may be stored for a substantial period at 4C.
- the precipitation and tin-binding steps of the process are combined into a single step.
- the stannous salt is dissolved in the dilute acid used to precipitate the heat-denatured protein thus eliminating one step of the above-described process. Whichever procedure is followed, the same end result is realized, i.e., the preparation of a suspension of precipitated de natured protein particles having divalent tin bound thereto.
- the resulting suspensions have a shelf life of approximately 60 days when stored at 4C. before such characteristics as particle integrity and susceptability to radionuclide tagging begin to deteriorate. If 60 days of storage are significantly exceeded, the tagging efficiency normally falls off to the extent that the product should be discarded.
- the shelf life of the macroaggregate suspensions may be extended beyond 60 days by freezing the suspension and storing it in the frozen state.
- the shelf life of the frozen suspension has been found to extend to approximately 4 months or longer. Storage in the frozen state has not generally been attractive, however, since the macroaggregate particles tend to clump together during subsequent thawing and form agglomerates which are too large for use in lung scanning procedures.
- an antiagglomerating agent such as propylene glycol, glycerin, gelatin or sucrose.
- the preferred antiagglomerating agent is propylene glycol. Agglomeration of the macroprotein particles is effectively prevented by inclusion of the anti-agglomerating agent in the suspension immediately prior to freezing.
- a suitable preservative is also advisable.
- the addition of approximately 1% by weight of benzyl alcohol to the initial protein solutions or to the finished suspensions of the invention has been found acceptable and effective.
- Other nontoxic bacte riostatic preservatives may be substituted for benzyl alcohol.
- the tin-treated protein of the suspension is conveniently and easily tagged with technetium-99m by adding the sodium pertechnetate eluate from a technetium generator directly to the suspension.
- Generators suitable for preparation of the eluate are commercially available. For example, one such generator is described in Shumate US. Pat. No. 3,535,085, dated October 20, 1970.
- binding of the technetium to the protein occurs spontaneously and quickly with an efficiency of 95% or more.
- about 30 minutes are allowed to optimize the specific activity of the tagged suspension.
- the mechanism of tagging is not clear but it involves oxidation of the divalent tin to the tetravalent state with concomitant reduction of the heptavalent technetium to a lower valency. Tetravalent tin remains attached to the protein. Within minutes of the addition of the technetium eluate thereto, the suspension of tagged albumin may be intravenously injected directly into animals or humans without any further treatment.
- the effectiveness of lung scanning is optimized by using sufficient eluate to provide a tagged suspension having a specific activity of up to approximately 20 mci TcO /mg. of the macroaggregated albumin.
- the lungs of a subject contain 90% or more of the injected technetium-99m.
- the presence or absence of a pathological condition is then determined by radioscanning the lungs of the patient and comparing the emission pattern thereof with a standard pattern.
- the tagged denatured albumin is eliminated from the subjects lungs at a rate corresponding to a biological half life of approximately 510 hours.
- the suspensions of the tin-treated albumin macroaggregates may be stored for substantial periods of time while still retaining their potency. Then, when desired, they may be tagged with technetium merely by adding a solution containing sodium pertechnetate for immediate use as a lung scanning agent without further treatment.
- the invention thus obviates the costly, timeconsuming and difficult procedures which have heretofore been necessary.
- EXAMPLE 1 A solution containing fresh human serum albumin (500 mg.) in a 1% by weight aqueous solution of benzyl alcohol (45 cc.) was heated for minutes at 85C. with slow stirring to denature the protein. The solution was then transferred to a cold water bath, and when the temperature had reached l8-22C. 2 ml. of 0.085N hydrochloric acid solution was slowly added over a period of about 3 minutes with rapid stirring. The pH of the resulting suspension of precipitated albumin was 4.8 to 5.2. The suspension was then reheated to 83C. for 5 minutes with slow stirring, causing the precipitated albumin aggregates to become more compact and less subject to fragmentation.
- the particle size analysis of the precipitated macroaggregates indicated the size range to be 5-80 microns, with a mean of 15-30 microns.
- the macroaggregates were collected by centrifugation and resuspcndcd in 30 ml. of an acetate buffer solution having a pH of 4.8 (0.052N sodium acetate and 0.02N hydrochloric acid).
- EXAMPLE 2 To the suspension produced in Example 1 was added 0.6 ml. ofa 1N HCl solution containing 50 mg. of stannous chloride per ml. This is equivalent to approximately 3 mg. of divalent tin per I00 mg. of albumin. The pH of the resulting mixture was 4.04.l. Two ml. of a 0.4M sodium acetate solution was added, and the mixture allowed to incubate for 24 hours. After the incubation period was complete, the protein macroaggregates were washed three times by centrifugation, with resuspension in 30 ml. of fresh acetate buffer following each washing. The treated particles were finally resuspended in 50 ml. of pH 4.8 acetate buffer containing 1% by weight benzyl alcohol.
- the resulting suspensions may be stored at 4C. or frozen as previously described. If they are to be stored at 4C., the suspensions are diluted 1:5 with acetate buffer (pH 4.8) containing 1% benzyl alcohol. If theyare to be frozen the suspensions are diluted I15 with acetate buffer (pH 4.8) containing 1% benzyl alcohol and 8-16% propylene glycol, for example.
- a composition suitable for rapid tagging with technetium-99m and use in lung scanning procedures consisting essentially of an injectable suspension in a buffer solution of particles of denatured macroprotein having divalent tin bound thereto, said macroprotein having a molecular weight of at least about 20,000.
- composition as set forth in claim 1 wherein said macroprotein comprises particles of macroaggregated human serum albumin.
- composition as set forth in claim 1 wherein the size of the particles is substantially between about 5 and about microns.
- composition as set forth in claim 4 wherein the mean size of said particles is between about 15 and about 30 microns.
- composition as set forth in claim 1 including macroprotein particles in the form of microspheres.
- an antiagglomerating agent selected from the group consisting of propylene glycol, sucrose, glycerin and gelatin.
- a process for preparing a buffered injectable sus pension of particles of denatured macroprotein suitable for rapid tagging with technetium-99m and use in lung scanning procedures comprising the steps of:
Abstract
An improved composition suitable for tagging with technetium-99m and use in lung scanning procedures consists essentially of an injectable suspension in buffer solution of particles of a denatured macroprotein having divalent tin bound thereto. The macroprotein has a molecular weight of at least about 20,000. A method for preparing the injectable suspension by treating macroaggregates or microspheres of a denatured macroprotein with a solution containing divalent tin ions is also provided.
Description
United States Patent 1 [1 1 Wolfangel I DENATURED MACROIROTEIN WITH DIVALENT TIN FOR TAGGING WITH TECHNETIUM-99M AND METHOD OF PREPARATION [75] Inventor: Robert G. Wolfangel, St. Louis. Mo.
[73] Assignee: Mallinckrodt Chemical Works. St.
Louis. Mo.
[22] Filed: Mar. 20, 1972 [2]] App]. No; 236.159
OTHER PUBLICATIONS Lin et al., Journal of Nuclear Medicine, Vol. 12. No. 5 (1971) pp. 204-21]. Eckelman et al.. Journal of Nuclear Medicine, Vol.
[ Jan. 28, 1975 12. No. 11 (197]) pp. 707-710.
Morcellet. Use of TinTc 99rn-Nuclear Sci. Abs. Vol 24. No 4.. p. 617. Feb. 28. 1970. Item No. 6078. Charamza. Chemical Abstracts. Vol. 72. 1970 p.86, Item No. 87066.
De Paoli. Nuclear Sci. Abs.. Vol. 20. No. 23 Dec. 15. 1966. Item No, 43390 Albumin Macroaggregatcs etc."
Primary Examiner-Benjamin R. Padgett Attorney, Agent. or FirmKocnig. Senniger, Powers. and Leavitt ABSTRACT An improved composition suitable for tagging with technetium-99m and use in lung scanning procedures consists essentially of an injectable suspension in buffer solution of particles of a denatured macroprotein having divalent tin bound thereto. The macroprotein has a molecular weight of at least about 20,000. A method for preparing the inject-able suspension by treating macroaggregates or mierospheres of a denatured macroprotein with a solution containing divalent tin ions is also provided.
14 Claims, No Drawings DENATURED MACROPROTEIN WITH DIVALENT TIN FOR TAGGING WITH TECHNETIUM-99M AND METHOD OF PREPARATION BACKGROUND OF THE INVENTION This invention relates to the field of radiopharmaceutical diagnostic testing and more particularly to an injectable suspension of solid particulate denatured macroprotein suitable for tagging with technetium-99m and use in lung scanning procedures.
Macroaggregated macroproteins have found use as carriers for radionuclides useful in diagnostic radioscanning techniques. In particular, such proteins, for example human serum albumin labeled or tagged with a radionuclide, have been used in the diagnosis of pulmonary circulatory defects. The distribution in the lungs of radioactively labeled protein macroaggregates, as determined by isotope radioscanning, indicates the presence or absence of certain pathological conditions.
To be useful in lung scanning, radioactive macroprotein particles must be labeled with a gamma emitting radionuclide and be within a prescribed size range. The labeled particles must also be non-toxic and biodegradable, i.e., physically or chemically removable from the lungs in a relatively short period.
Macroaggregated human serum albumin tagged with iodine-131 has become widely used for perfusion lung scanning. While the biological properties of this scanning agent are excellent, an important objection to its use arises from the decay scheme of iodine-l 3 I. In the course of decay, iodine-131 emits a beta particle, its gamma rays are difficult to collimate effectively, and it has an 8-day physical half-life. As a result of these characteristics, a patient receiving an injection of iodine- 13l-tagged albumin is exposed to a high radiation dose, not only to the lungs but to other organs such as the thyroid gland as well.
A radionuclide which may advantageously be substituted for iodine-131 in lung scanning is technetium- 99m which emits only gamma rays which can be easily collimated, and has a physical half-life of only 6 hours. Chiefly on the basis of favorable dosimetry profiles, a host of technetium-99m labeled particles have been prepared and used in lung scanning. A comprehensive review of the present state of knowledge in this field was published by G. V. Taplin and N. S. MacDonald in Seminars in Nuclear Medicine, Vol. I, No. 2 (April), 1971, pages 132-52.
The safety, convenience and effectiveness of the lung scanning techniques employing technetium-99m have heretofore been limited, however, by problems associated with the preparation of technetium-tagged albumin. To prepare serum albumin for use in lung scanning, it must be both denatured and precipitated in the form of macroaggregates or microspheres of a particular range of particle size. To prepare the albumin in such form, a solution of albumin is typically heated to denature the protein after which the solution is cooled and the albumin precipitated by adjusting the pH to the isoelectric point (approximately pH 4.9). Particles of the desired size are obtained by suitable control of both pH and temperature. Alternatively, an aqueous solution of albumin can be dispersed in hot, waterimmiscible oil to precipitate the albumin in the form of microspheres. Of the several known methods for tagging protein particles with technetium-99m, the most common has involved first tagging a solution of albumin with technetium and then precipitating to form the solid albumin in particles ofthe desired size. Where this method is utilized, however, an immediate microscopic examination of the particles must be made to assure their proper size, and purification is required to remove unreacted technetium from the suspension. Moreover. because of the short half-life of technetium-99m, sterility tests cannot be completed on the denatured and precipitated protein before it is used in human patients.
In an alternative method for preparing technetium- 99m tagged macroaggregates, a technetium sulfur colloid is formed in the presence of denatured albumin microspheres causing the spheres to become tagged with the technetium. However, labeling is not very efficient by this method, and several washes of the protein particles are required to remove the unbound technetium. Also, the tagged microspheres produced by this method are prone to stick together and it becomes necessary to disperse the resulting agglomerates by an appropriate technique such as ultrasonic treatment, immediately prior to injection into a patient. Furthermore, the bond between the technetium and the microspheres is somewhat labile, and if the suspension is allowed to stand unused for as little as an hour or so after preparation, both the purification and ultrasonic treatment must be repeated before injection.
As a consequence of the various disadvantages outlined above, technetium-tagged albumin has not been found generally useful as a lung scanning agent, despite its desirable radiation properties.
SUMMARY OF THE INVENTION Among the objects of the present invention may be noted the provision of an improved composition which may be readily and efficiently tagged with technetium- 99m to produce an injectable suspension for use in lung scanning procedures; the provision of such a composition which can be stored for substantial periods of time without degradation, be tagged with technetium-99m and then used for injection without particle size examination, ultrasonic treatment or purification; and the provision of processes for preparing the composition. Other objects and features will be in part apparent and in part pointed out hereinafter.
In essence, therefore, the present invention is directed to a composition suitable for tagging with technetium-99m and use in lung scanning procedures. The
'composition consists essentially of an injectable suspension in a buffer solution of particles of a denatured macroprotein having divalent tin bound thereto, the macroprotein having a molecular weight of at least about 20,000. The invention is further directed to a process for preparing the composition. In this process, particles of a denatured macroprotein are contacted with a solution containing a water-soluble salt of divalent tin causing divalent tin to be bound to the macroprotein. The macroprotein having divalent tin bound thereto is then washed and suspended in buffer solution.
DESCRIPTION OF THE PREFERRED EMBODIMENTS It has now been discovered that an injectable suspension ofa denatured and precipitated macroprotein having divalent tin bound thereto may be prepared and stored without degradation for substantial periods prior to use. Even more significantly, it has been found that the macroprotein of the suspension may be quickly and easily tagged with technetium-99m and that the resulting suspension of the tagged protein may be safely and effectively used in lung scanning techniques without particle size determination. ultrasonic treatment or purification for the removal of unbound technetium. Thus, the relatively cumbersome and time-consuming techniques previously required are avoided and both the cost of preparing a suitable suspension for use in lung scanning procedures and the risks associated with its use are minimized.
The macroprotein constituent of the composition of the invention is preferably denatured human serum albumin, a protein which is particularly suitable for use in lung scanning. It will be understood, however, that any denatured macroprotein having a molecular weight of at least about 20,000 may have divalent tin bound thereto in accordance with the invention to render it more susceptible to labeling with a radioactive isotope of technetium.
The particles of the protein constituent of the composition of the invention are characterized as macroaggregates. Macroaggregatcs are considered to be particles of irregular form having an average diameter of between about 5 and about 80 microns. Where the protein particles are intended for use as lung scanning agents, the mean size of the particles is preferably between about l5 and about 30 microns.
The improved susceptibility of the suspended protein macroaggregates to tagging with technetium99m relates to the divalent tin which is bound to the protein. When a suspension of serum albumin treated with divalent tin in accordance with the invention is subsequently treated with a solution containing heptavalent technetium-99m, for example a solution of sodium pertechnetate, upwards of 90% of the technetium is rapidly and firmly bound to the serum protein.
In the practice of the invention, human serum albumin or other appropriate macroprotein is first denatured and then precipitated to form particles of the desired size. Various methods are known to the art for producing macroaggregates 'or microspheres of denatured protein. While any of these methods may be successfully used, excellent results have been obtained using a method wherein a dilute aqueous solution of human serum albumin is first heated at a temperature of about '70l00C., preferably about 85C., to denature the protein, then cooled to a temperature on the order of l8-22C., preferably about 20C. The albumin is then precipitated by slowly adding a dilute acid, approximately 0.1N, until the pH is about 4.8-5.2, i.e., the isoelectric pH of the protein being about 4.9. Hydrochloric acid is preferred for use in adjusting the pH to precipitate the denatured protein. However, other mineral acids or acetic acid may also be employed. The particle size of the macroaggregates thus precipitated is typically in the range of 5-80 microns with a mean particle size of -30 microns. The integrity of the precipitated aggregates is further improved if the suspension is reheated for a short period of time following precipitation. Preferably the reheating temperature is of approximately the same order as the denaturing temperature.
After reheating, the macroaggregated albumin particles are separated from the suspension, washed and resuspended in a fresh buffer solution having essentially the same pH as the isoelectric pH of the protein (i.e.,
pH 4.9). A convenient buffer solution is an acetate buffer having a pH of 4.9 (0.052N sodium acetate and 0.02N hydrochloric acid).
Binding of the protein aggregates with divalent tin is effected by adding to the protein suspension an aqueous solution containing stannous ions. Contact of the macroaggregates with stannous ions causes divalent tin to become bound to the protein. For this purpose, stannous chloride is preferred because of its solubility and greater stability, although other watersoluble stannous salts, such as stannous sulfate. may also be used. lt is necessary. however. to employ a divalent tin solution since tetravalent tin ions are not effective.
Sufficient stannous ions are available for binding to the protein if the mixture of the protein suspension and stannous salt solution contains approximately 3 mg. of stannous ions per mg. of macroaggregates. With such proportions, binding of divalent tin to the protein molecule occurs quickly at room temperature and appears to be substantially complete in about 15 minutes or so. For optimum results, however, the mixture containing stannous ions and protein should be allowed to stand for a longer time, preferably about 24 hours. After the treatment period is complete, the aggregates are separated from the liquid phase, washed with and rcsuspended in fresh buffer solution. After resuspcnsion, the macroaggregates may be stored for a substantial period at 4C.
In an alternative embodiment of the invention, the precipitation and tin-binding steps of the process are combined into a single step. Following this alternative, the stannous salt is dissolved in the dilute acid used to precipitate the heat-denatured protein thus eliminating one step of the above-described process. Whichever procedure is followed, the same end result is realized, i.e., the preparation of a suspension of precipitated de natured protein particles having divalent tin bound thereto.
The resulting suspensions have a shelf life of approximately 60 days when stored at 4C. before such characteristics as particle integrity and susceptability to radionuclide tagging begin to deteriorate. If 60 days of storage are significantly exceeded, the tagging efficiency normally falls off to the extent that the product should be discarded.
The shelf life of the macroaggregate suspensions may be extended beyond 60 days by freezing the suspension and storing it in the frozen state. The shelf life of the frozen suspension has been found to extend to approximately 4 months or longer. Storage in the frozen state has not generally been attractive, however, since the macroaggregate particles tend to clump together during subsequent thawing and form agglomerates which are too large for use in lung scanning procedures.
This problem is overcome by incorporating into the suspension between about 8% and about 16% by weight of an antiagglomerating agent such as propylene glycol, glycerin, gelatin or sucrose. The preferred antiagglomerating agent is propylene glycol. Agglomeration of the macroprotein particles is effectively prevented by inclusion of the anti-agglomerating agent in the suspension immediately prior to freezing.
To prevent bacterial growth in the suspension, the addition of a suitable preservative is also advisable. For this purpose, the addition of approximately 1% by weight of benzyl alcohol to the initial protein solutions or to the finished suspensions of the invention has been found acceptable and effective. Other nontoxic bacte riostatic preservatives may be substituted for benzyl alcohol.
The tin-treated protein of the suspension is conveniently and easily tagged with technetium-99m by adding the sodium pertechnetate eluate from a technetium generator directly to the suspension. Generators suitable for preparation of the eluate are commercially available. For example, one such generator is described in Shumate US. Pat. No. 3,535,085, dated October 20, 1970. When the eluate and suspension are mixed, binding of the technetium to the protein occurs spontaneously and quickly with an efficiency of 95% or more. Preferably, about 30 minutes are allowed to optimize the specific activity of the tagged suspension. The mechanism of tagging is not clear but it involves oxidation of the divalent tin to the tetravalent state with concomitant reduction of the heptavalent technetium to a lower valency. Tetravalent tin remains attached to the protein. Within minutes of the addition of the technetium eluate thereto, the suspension of tagged albumin may be intravenously injected directly into animals or humans without any further treatment.
The effectiveness of lung scanning is optimized by using sufficient eluate to provide a tagged suspension having a specific activity of up to approximately 20 mci TcO /mg. of the macroaggregated albumin. Five minutes after injection, the lungs of a subject contain 90% or more of the injected technetium-99m. The presence or absence of a pathological condition is then determined by radioscanning the lungs of the patient and comparing the emission pattern thereof with a standard pattern.
The tagged denatured albumin is eliminated from the subjects lungs at a rate corresponding to a biological half life of approximately 510 hours.
Thus, the suspensions of the tin-treated albumin macroaggregates may be stored for substantial periods of time while still retaining their potency. Then, when desired, they may be tagged with technetium merely by adding a solution containing sodium pertechnetate for immediate use as a lung scanning agent without further treatment. The invention thus obviates the costly, timeconsuming and difficult procedures which have heretofore been necessary.
The following examples illustrate the invention.
EXAMPLE 1 A solution containing fresh human serum albumin (500 mg.) in a 1% by weight aqueous solution of benzyl alcohol (45 cc.) was heated for minutes at 85C. with slow stirring to denature the protein. The solution was then transferred to a cold water bath, and when the temperature had reached l8-22C. 2 ml. of 0.085N hydrochloric acid solution was slowly added over a period of about 3 minutes with rapid stirring. The pH of the resulting suspension of precipitated albumin was 4.8 to 5.2. The suspension was then reheated to 83C. for 5 minutes with slow stirring, causing the precipitated albumin aggregates to become more compact and less subject to fragmentation. The particle size analysis of the precipitated macroaggregates indicated the size range to be 5-80 microns, with a mean of 15-30 microns. After reheating, the macroaggregates were collected by centrifugation and resuspcndcd in 30 ml. of an acetate buffer solution having a pH of 4.8 (0.052N sodium acetate and 0.02N hydrochloric acid).
EXAMPLE 2 To the suspension produced in Example 1 was added 0.6 ml. ofa 1N HCl solution containing 50 mg. of stannous chloride per ml. This is equivalent to approximately 3 mg. of divalent tin per I00 mg. of albumin. The pH of the resulting mixture was 4.04.l. Two ml. of a 0.4M sodium acetate solution was added, and the mixture allowed to incubate for 24 hours. After the incubation period was complete, the protein macroaggregates were washed three times by centrifugation, with resuspension in 30 ml. of fresh acetate buffer following each washing. The treated particles were finally resuspended in 50 ml. of pH 4.8 acetate buffer containing 1% by weight benzyl alcohol.
The resulting suspensions may be stored at 4C. or frozen as previously described. If they are to be stored at 4C., the suspensions are diluted 1:5 with acetate buffer (pH 4.8) containing 1% benzyl alcohol. If theyare to be frozen the suspensions are diluted I15 with acetate buffer (pH 4.8) containing 1% benzyl alcohol and 8-16% propylene glycol, for example.
ln view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
As various changes could be made in the above methods and products without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
What is claimed is:
1. A composition suitable for rapid tagging with technetium-99m and use in lung scanning procedures consisting essentially of an injectable suspension in a buffer solution of particles of denatured macroprotein having divalent tin bound thereto, said macroprotein having a molecular weight of at least about 20,000.
2. A composition as set forth in claim 1 wherein the pH of said buffer solution is approximately the isoelec tric pH of said denatured macroprotein.
3. A composition as set forth in claim 1 wherein said macroprotein comprises particles of macroaggregated human serum albumin.
4. A composition as set forth in claim 1 wherein the size of the particles is substantially between about 5 and about microns.
5. A composition as set forth in claim 4 wherein the mean size of said particles is between about 15 and about 30 microns.
6. A composition as set forth in claim 1 including macroprotein particles in the form of microspheres.
7. A composition as set forth in claim 1 wherein the buffer solution contains between about 8 and about l6 by weight of an antiagglomerating agent selected from the group consisting of propylene glycol, sucrose, glycerin and gelatin.
8. A process for preparing a buffered injectable sus pension of particles of denatured macroprotein suitable for rapid tagging with technetium-99m and use in lung scanning procedures comprising the steps of:
contacting particles of a denatured macroprotein with a solution containing a water-soluble salt of divalent tin causing divalent tin to be bound to said macroprotein;
washing the macroprotein having divalent tin bound thereto with a buffer solution; and
12. A process as set forth in claim 8 wherein said macroprotein is in the form of macroaggregates.
13. A process as set forth in claim 8 wherein said macroprotein is in the form of microspheres.
14. A process as set forth in claim 8 wherein said macroprotein is prepared by precipitating denatured macroprotein in an acid medium at a pH approximately the isoelectric pH of said protein.
Claims (13)
- 2. A composition as set forth in claim 1 wherein the pH of said buffer solution is approximately the isoelectric pH of said denatured macroprotein.
- 3. A composition as set forth in claim 1 wherein said macroprotein comprises particles of macroaggregated human serum albumin.
- 4. A composition as set forth in claim 1 wherein the size of the particles is substantially between about 5 and about 80 microns.
- 5. A composition as set forth in claim 4 wherein the mean size of said particles is between about 15 and about 30 microns.
- 6. A composition as set forth in claim 1 including macroprotein particles in the form of microspheres.
- 7. A composition as set forth in claim 1 wherein the buffer solution contains between about 8 % and about 16 % by weight of an antiagglomerating agent selected from the group consisting of propylene glycol, sucrose, glycerin and gelatin.
- 8. A process for preparing a buffered injectable suspension of particles of denatured macroprotein suitable for rapid tagging with technetium-99m and use in lung scanning procedures comprising the steps of: contacting particles of a denatured macroprotein with a solution containing a water-soluble salt of divalent tin causing divalent tin to be bound to said macroprotein; washing the macroprotein having divalent tin bound thereto with a buffer solution; and thereafter suspending in a buffer solution the macroprotein having divalent tin bound thereto.
- 9. A process as set forth in claim 8 wherein said macroprotein is human serum albumin.
- 10. A process as set forth in claim 8 wherein said solution containing divalent tin ions is a solution of stannous chloride.
- 11. A process as set forth in claim 10 wherein said solution contains approximately 3 mg. of divalent tin for each 100 mg. of macroprotein.
- 12. A process as set forth in claim 8 wherein said macroprotein is in the form of macroaggregates.
- 13. A process as set forth in claim 8 wherein said macroprotein is in the form of microspheres.
- 14. A process as set forth in claim 8 wherein said macroprotein is prepared by precipitating denatured macroprotein in an acid medium at a pH approximately the isoelectric pH of said protein.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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US236159A US3863004A (en) | 1972-03-20 | 1972-03-20 | Denatured macroprotein with divalent tin for tagging with technetium-99m and method of preparation |
GB1188673A GB1409176A (en) | 1972-03-20 | 1973-03-13 | Protein composition for labelling with technetium-99m and method of preparation |
IL41767A IL41767A (en) | 1972-03-20 | 1973-03-13 | Injectable composition for tagging with technetium-99m and its preparation |
AU53375/73A AU472255B2 (en) | 1972-03-20 | 1973-03-16 | Improved composition for tagging with technetium-99m and method of preparation |
DE19732314059 DE2314059A1 (en) | 1972-03-20 | 1973-03-19 | IMPROVED SUBSTANCE FOR MARKING WITH TECHNETIUM-99M AND METHOD OF MANUFACTURING IT |
NL7303842A NL7303842A (en) | 1972-03-20 | 1973-03-19 | |
BE1004909A BE796962A (en) | 1972-03-20 | 1973-03-19 | IMPROVED TECHNETIUM-99M LABELING COMPOSITION AND PREPARATION PROCESS |
IT48899/73A IT989625B (en) | 1972-03-20 | 1973-03-20 | PROCESS FOR PREPARING A COMPOSITION FOR LABELING WITH TECNETIO 99M AND RELATED COMPOSITION |
FR7309886A FR2182880B1 (en) | 1972-03-20 | 1973-03-20 | |
JP3253773A JPS5328971B2 (en) | 1972-03-20 | 1973-03-20 |
Applications Claiming Priority (1)
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US236159A US3863004A (en) | 1972-03-20 | 1972-03-20 | Denatured macroprotein with divalent tin for tagging with technetium-99m and method of preparation |
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US (1) | US3863004A (en) |
JP (1) | JPS5328971B2 (en) |
AU (1) | AU472255B2 (en) |
BE (1) | BE796962A (en) |
DE (1) | DE2314059A1 (en) |
FR (1) | FR2182880B1 (en) |
GB (1) | GB1409176A (en) |
IL (1) | IL41767A (en) |
IT (1) | IT989625B (en) |
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Cited By (20)
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US3968221A (en) * | 1972-05-05 | 1976-07-06 | Medi-Physics, Inc. | 99M-Technetium labeled tin colloid radiopharmaceuticals |
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 |
US4057617A (en) * | 1975-05-15 | 1977-11-08 | Abramovici J | Method of labeling proteins with technetium |
US4226846A (en) * | 1977-04-01 | 1980-10-07 | New England Nuclear Corporation | Albumin microaggregates for radioactive scanning of reticuloendothelial systems |
US4337240A (en) * | 1978-04-20 | 1982-06-29 | New England Nuclear Corporation | Denatured albumin complexes for radioscintigraphic imaging and evaluation of reticuloendothelial systems |
US4338248A (en) * | 1979-08-29 | 1982-07-06 | Nihon Medi-Physics Co., Ltd. | 2-Oxopropionaldehyde bis(thiosemicarbazone) protein derivatives, and their production and use |
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 |
US4462980A (en) * | 1981-01-05 | 1984-07-31 | Novo Industri A/S | Stabilized plasmin compositions and method for preparation thereof |
US4880616A (en) * | 1984-10-26 | 1989-11-14 | Nihon Medi-Physics Co., Ltd | Stable stannous chloride composition for labeling with radioactive technetium |
US5013720A (en) * | 1986-05-06 | 1991-05-07 | Abbott Laboratories | SAP-6-Val proteins and methods |
US5071965A (en) * | 1988-07-19 | 1991-12-10 | Mallinckrodt Medical, Inc. | Novel tc-99m complexes |
US5096696A (en) * | 1990-02-05 | 1992-03-17 | The Research Foundation Of State University Of New York | Binding of radiolabeled albumin fragments to fibrin clots |
US5116596A (en) * | 1986-12-10 | 1992-05-26 | Hoechst Aktiengesellschaft | Process for the preparation of an organ-specific substance labeled with technetium-99m |
US5300281A (en) * | 1991-02-15 | 1994-04-05 | The Dow Chemical Company | Radiolabeled compositions containing a calcific matrix and their use for treatment of arthritis |
US6022525A (en) * | 1991-04-10 | 2000-02-08 | Quadrant Healthcare (Uk) Limited | Preparation of diagnostic agents |
WO2002067997A1 (en) * | 2001-02-28 | 2002-09-06 | Bracco Diagnostics Inc. | Manufacturing process to control particle size |
WO2004091581A1 (en) * | 2003-04-16 | 2004-10-28 | Boehringer Ingelheim International Gmbh | Radioactively marked microparticles, method for the production thereof and use of the same |
US20050181758A1 (en) * | 2004-02-13 | 2005-08-18 | Nokia Corporation | Generating charging information in a communication system |
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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 |
GB1535847A (en) * | 1976-03-19 | 1978-12-13 | Radiochemical Centre Ltd | Technetium-99m labelled tin colloid for body scanning |
US4094965A (en) * | 1977-04-01 | 1978-06-13 | New England Nuclear Corporation | Diagnostic agents containing albumin and method for making same |
JPS5645790U (en) * | 1979-09-17 | 1981-04-24 | ||
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- 1973-03-19 BE BE1004909A patent/BE796962A/en unknown
- 1973-03-19 DE DE19732314059 patent/DE2314059A1/en not_active Withdrawn
- 1973-03-19 NL NL7303842A patent/NL7303842A/xx unknown
- 1973-03-20 IT IT48899/73A patent/IT989625B/en active
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Publication number | Priority date | Publication date | Assignee | Title |
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US3968221A (en) * | 1972-05-05 | 1976-07-06 | Medi-Physics, Inc. | 99M-Technetium labeled tin colloid radiopharmaceuticals |
US4024233A (en) * | 1972-06-05 | 1977-05-17 | Medi-Physics, Inc. | 99M-technetium labeled macroaggregated human serum albumin pharmaceutical |
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 |
US4226846A (en) * | 1977-04-01 | 1980-10-07 | New England Nuclear Corporation | Albumin microaggregates for radioactive scanning of reticuloendothelial systems |
US4337240A (en) * | 1978-04-20 | 1982-06-29 | New England Nuclear Corporation | Denatured albumin complexes for radioscintigraphic imaging and evaluation of reticuloendothelial systems |
US4338248A (en) * | 1979-08-29 | 1982-07-06 | Nihon Medi-Physics Co., Ltd. | 2-Oxopropionaldehyde bis(thiosemicarbazone) protein derivatives, and their production and use |
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 |
US4462980A (en) * | 1981-01-05 | 1984-07-31 | Novo Industri A/S | Stabilized plasmin compositions and method for preparation thereof |
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Also Published As
Publication number | Publication date |
---|---|
FR2182880A1 (en) | 1973-12-14 |
DE2314059A1 (en) | 1973-10-04 |
GB1409176A (en) | 1975-10-08 |
JPS4954517A (en) | 1974-05-27 |
FR2182880B1 (en) | 1976-04-09 |
IL41767A0 (en) | 1973-05-31 |
AU472255B2 (en) | 1976-05-20 |
JPS5328971B2 (en) | 1978-08-17 |
AU5337573A (en) | 1974-09-19 |
IT989625B (en) | 1975-06-10 |
IL41767A (en) | 1976-06-30 |
NL7303842A (en) | 1973-09-24 |
BE796962A (en) | 1973-09-19 |
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