DE2329168A1 - PHARMACEUTICAL PREPARATION MADE OF MACRO-AGGREGATED HUMAN SERUM ALBUMIN LABELED WITH 99M TECHNETIUM - Google Patents

Description

ΡΑΤΕΝΤΛΝ \ Λ / Ϊ! .Τε £ O Z CJ I Ό

Dr.-Ing. HANS ⁰ USCHKE Dip! .- In. '. OLAf- "RUSTMKE Dipl.-ir.g- HANiT; R'jjCHXE

1 BERLIN 33 AugusteViKtoria Strasse 65.

M 5285

Dr.Ve/Q.

MEDI - Physics Inc., Emeryville, California, V.St.A.

Pharmaceutical preparation made from macroaggregated human serural albumin labeled ^{with 99 m -Technetium}

The invention relates in general terms to marked with 99 ^m -Technetium pharmaceutical preparations which are suitable for scintigraphic organ imaging and more particularly to an improved macro-aggregate of with 99m-technetium labeled human serum albumin (MSA), which is especially suitable for lung imaging.

The main aim of the invention is to produce a macroaggregate from MSA labeled directly with 99m-technetium a particle size suitable for lung imaging.

Another object of the invention is to provide a process for the direct production of technetium-labeled MSA macroaggregates with a predetermined particle size business fen, in which the 99m technetium firmly attached to a macroaggregated MSA-tin-II-complex is bound.

It is still another object of the invention to provide a packaged tin-II-MSA base reagent for making the labeled macroaggregate and a simple method of using the reagent

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with the generally available physiological 99m-technetium peptide salt solutions. ^r

Further objects and features of the invention are the following description of preferred embodiments of the marked Macroaggregate, the packaged reagent, and the methods of making the labeled macroaggregate and the packaged Remove reagent.

Although it is known that albumin is reduced with 99m technetium labeled and then heat aggregated into particle sizes suitable for lung imaging the previously known 99m technetium label is not firmly bound to MSA, but has been easily detached or removed from it. eluted. The aggregation of already labeled MSA led to a broad particle size distribution, which is due to the radioactivity and the short half-life are not easily limited or to an optimal size for a particular one Application could be discontinued.

In contrast, the 99m-technetium-labeled macroaggregate of the invention is made directly using an already macroaggregated MA-tin-II basic reagent, its particles an optimal size for a special application, e.g. for lung imaging. The reagent will simply a generally available physiological 99ro-technetium pertechnetate solution to form a suitable one Way labeled complex added. The radioactive component is tightly bound and does not come out of the particulate easily Complex dissolved or eluted. The packaged reagent prepared by the above method has a Service life on the order of at least three to four Months. The suspended particulate complex of the described reagent and the final pharmaceutical preparation

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ORIGINAL INSPECTED

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sen mainly a particle size in the range from iü to 90 μίτι, with no particles larger than 100 μπι are. However, the particles can be easily adjusted to any predetermined particle size range.

The reagent contains a physiological solution of a particulate A complex of macroaggregated MSA and divalent tin, which is produced by the following process:

200 ml of 0.1 normal acetate buffer and 1800 ml of normal physiological saline solution are introduced into a macroaggregation flask, the solution mixture is brought to the boiling point heated, and nitrogen gas is passed through the mixed solution after it has cooled, to oxygenate to remove. The aggregation flask is closed and sterilized. After the mixed solution has cooled down At room temperature, 1 g of human serum albumin (low salt, USP) in 4 ml (250 mg / ml) is added to the solution in the aggregation flask dispersed, and the contents of the flask are then mixed thoroughly. The pH obtained is slightly above the isoelectric Point of MSA, i.e. at 5.2 to 5.4. The flask is then immersed in a boiling salt water bath at 108 ° C and held there for 8 minutes with constant stirring to add the albumin to form a macroaggregate dispersion coagulate.

Remove the flask from the bath and add 200 ml from 1 to 10 mmol of tin (II) chloride colloid in pyrogen-free Water is added and the contents of the flask are cooled with continued stirring. 10 minutes after adding the tin (II) colloid the aggregation flask is placed in an ice bath and, with continued stirring, is allowed to cool to room temperature accelerated. The tin (II) colloid forms a complex with the MSA and is bound by the individual macro-aggregated MSA telecommunications.

30G881 / 1Ü79

The contents of the flask are then, with continued stirring, the solution containing the suspended tin (II) macroaggregated MSA particles contains, through a blood transfusion filter (pore size 200 to 260 μκι) and. then through a filter made of corrosion-resistant Steel (pore size 100 μm) placed in a sterile settling flask, which is flushed with filtered nitrogen. The supernatant fluid is drawn off and normal physiological Saline solution using aseptic techniques. The particles are resuspended in the solution and can then settle again, and this washing process is repeated.

After washing, so much normal saline becomes added that a particle density of 200,000 to 300,000 / ml is obtained. The suspension of the macroaggregates in Physiological saline solution is supplied in nitrogen-purged sterile ampoules that are free of oxygen and others oxidizing agents are packaged.

An immediately marked macroaggregate that is used for lung imaging is suitable, is from the described tin-II macroaggregated MSA reagent made in a simple four step process and then ready for injection. In the first stage, using an aseptic technique, enough 99m technetium pertechnetate is obtained in normal physiological Saline solution taken into a syringe so that an amount of radioactivity is obtained that is useful for the Use in a single patient is suitable. This amount is generally on the order of 2 to 3 MCi. In a second stage, an ampoule is filled with the Tin-II macroaggregated MSA reagent is opened aseptically and enough reagent is poured into the same syringe as the pertechnetate contains, added so that a final ratio of 3 parts by volume of reagent to 1 part by volume of pertechnetate solution

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given is. The 99m-Teohnetium is replaced by the tin-II-ions reduces and immediately marks the particulate tin-II macroaggregated MSA complex. In a third stage, a small volume of air is drawn into the syringe and becomes then shake the syringe well for 10 seconds to ensure complete mixing. In a last one In the fourth stage, the macroaggregate, which is now appropriately marked, is kept in an incubator at room temperature. It can then be slowly administered to the patient by intravenous injection.

The marking takes place with an efficiency of over 90 ^ instead, so that processing is not necessary. The labeling efficiency is generally determined by the concentration of the reagent is not affected. About $ 90 of the marked Particles have a diameter between 10 and 90 μm. If the marked macroaggregate (particle size over 10 μm) is injected intravascularly, it initially remains in the first arterial capillary that it reaches, and the relative distribution of the macroaggregate is a measure of the relative blood flow to the relevant vascular systems a special vascular system is blocked, as can be observed in the lungs after a pulmonary embolism, then shows the tissue with an insufficient blood supply does not have an accumulation of radioisotope, in contrast to the surrounding normal perfused tissue. The labeled macroaggregate of the invention has thus been found to be a useful means of detection the lung flow and to a lesser extent also for the evaluation of other organs in which the aggregate is added to the afferent blood supplied.

The above examples and the methods described are only intended to illustrate the invention. The examples and the procedures can be modified within the scope of the invention.

Claims 3 03881/1079

ORIGINAL INSPECTED

Claims (5)

2o ^ i) 168 - 6 claims (ly) Reagent for making one labeled with 99m technetium Macro-aggregate with the addition of 99m technetium pertechnetations in normal physiological saline solution to the Reagent, characterized in that the reagent is a physiological Solution of a particulate complex containing macroaggregated human serum albumin and divalent ones Contains tin. 2.) Reagent according to claim 1, characterized in that the particulate complex has a particle size that mainly is within the range of 10 to 90 μαι and 100 μπι does not exceed. 3.) Process for the preparation of the reagent according to claim / L or 2, characterized in that one is a dispersion of human serum albumin in physiological saline solution heated so that the albumin coagulates into macroaggregates, a hydrolyzed tin (II) chloride solution with the warm Dispersion of the macroaggregate with the formation of a complex of the tin (II) ions mixed with each particle of the macroaggregate and in this solution only the particulate tin (II) macroaggregate complex with a predetermined range of particle sizes retains. 4.) Unit marked with 99 "i-technetium for the scinitigraphic Organ mapping, characterized in that it is a physiological solution of a particulate complex which contains macroaggregated human serum albumin, divalent tin and 99m technetium. 5.) Marked unit according to claim 4, characterized in that 3ÖS88 1/1079 net that the particulate complex has a particle size has, which μπι mainly in the range of 10 to 90 lies and does not exceed 100 μπι » 309881/1079