DE2115066A1 - Packing unit for radioactive identification media - Google Patents

Description

M 2y A

PATENT LAWYERS Dr.-lng. HANS RUSCHKE Dipi.-Ifio.fi:- h / AGULAR

EtMi ,, 33
Auflustö-Viktcria-Siraß «eg

Minnesota Mining and Manufacturing Company, Saint Paul,

Minnesota 55101 (V.St.ν.Α.)

Packaging unit for radioactive identification media

The invention applies to a packaging unit for radioactive eii Identifying biodegradable microparticles for the medical diagnosis. In particular, the invention relates to a simplified method for labeling biodegradable microparticles using a special reaction container that contains all the necessary components for such a With the exception of the short half-life, labeling contains radionuclides.

They are currently radioactive in hospitals and clinics labeled microparticles because the desired radioactive emission of these particles is useful for diagnostic, prophylactic and therapeutic purposes. Such labeled microparticles can be injected into the bloodstream, for example

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and later excreted from the lungs again. then a suitable device for examining uci- lun ^ je verv / ends with which a silo, the lungs on one. Oscilloscope, on paper, on a photographer or the like. If there are no such germinated particles in the lungs, the doctor can conclude that there is no proper circulation in the lung concerned. If a tumor has developed in the body, it requires a high concentration of blood if the tumor is vascular. The marked microparticles would ^{seek to concentrate in tumor 1} for a long time.

The radioactive nuclide commonly used to identify particles is radio-technetium (^^ ^m Tc), which can be obtained from a commercial generator commonly found in most hospitals and clinics. Currently, the components used to identify the particles are kept separate from one another outside the container in which the identification is to be carried out. Dry microparticles are suspended in a detergent and ir: ':', water, and technetium and sodium thiosulphate, a reducing reagent, ^{is required for labeling with - ^ m} TG, after which an acid is added to support the labeling v / ird. All these components mentioned are kept separate from one another outside of the ampoule in which the mixture takes place. After the labeling reaction, not all of the radio technecium remains adhering to the particles, but rather some of it remains in the solution. It is undesirable to inject unbound technetium into the body as it migrates to other locations in the body so that the lungs cannot properly ground and also parts of the body can be exposed to an undesirable dose of radiation. The unbound technetium must therefore be separated from the labeled microparticles. This is done in the way that after the beads or particles have settled, the excess reaction products and the technetium are poured off or balanced. This is difficult to do as hieroei is part of the

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.: u :: v :::::; eia :: ... i: en Fertil · el is also drawn. ". ^ ';...'. T ,: \ ± \ ::: - oj ~, -zll: el in a filter bowl; iio ze aorej-OSEen or need to be drawn. However throw -j-.uch i :. In this case, all components for identifying the particles are kept separate from one another outside the filter area. As far as the applicant is aware, there is currently no - ..; Packaging unit with which micrO particles can be radioactively calibrated.

The invention provides a packaging system with whose IIiix · .-: bloaegv ^ Iie -.jare microparticles with aia radioactive Kikiio ge ^ enr :: -. <They: ^ xet v; ei'den, wooei a special reaction .? container is used that contains all the necessary components ... u ::; Ke: i:. „Calibrate apart from the nuclide. The Ver-ackungsei:.: Uit ue-ic?: It generally from a Beaälx · iuit at least one ... ciie ^ jii _ ^ nue, ύ / αε a ia container arranged porous I-'ilti ⁱ -; "l ; ". ttj, uie no Benalter in a first uiiC. a second allotment subdivided from an Anzc.nl of pharmaseutiseh unbev.Ler.I: llo.; 3: i microarticles in the first division, from mindeeci:. :: a ^ üi Ko ::: izeici: now £ sre £. genzinmittel in the bank una from ei: io; - means, :: iit cle ::; the open end of a Benälters zeitxveilig vei'i'O-.losser. is, una the a hollow needle of a syringe on-: ie. "::: .- j :: l: ar. ::,.:. a liquid is introduced into the container v: ir.i. uiiw. κ- it also removes the radioactively identified particles may be::.

Z-. de ϊ.ΐΐο Department can be registered for supporting the suspension four Iiikrop ^ rtikel a non-ragiei-end and non-toxic wetting agent., ^ ei use of radio-Te-oknetiurn oefir. ^ et them :, i :: dex "first department a reducing agent serving as a marking agent, while a solid source for hydrogen ions is arranged in the "multiple division".

Intended by the term "Kennzeicnnungsreagenzmittel" a material oezeicimct \; ground that oeviirkt that either the Mikrc-;.. ^: - tik- l ede · al-.i to identify uer Mil-zropc- .. Tikel. used.

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Accept a radionuclide for adhering the radioactive iluklide ¹ to the 'flikropartikel appropriate state. A labeling reagent consists, for example, of sodium thiosulfate, which serves as a reducing agent, the purpose of which is to reduce the original pertechnetate to a usable lower oxidation form of the technology, the reduction taking place in the presence of an acid. In this case, both the reducing agent and a source of hydrogen ions must be provided in the packaging unit. In the same way, sodium paratoluene-chlorosulfonamide, an oxidizing agent, is used as a characterizing reagent with radio-iodine to oxidize the iodide to a usable form, which oxidation takes place in the presence of suitable buffer substances, which together with the oxidizing agent are constituents of the Packing unit are. On the other hand, no labeling reagents are required when radioiron or radioindium is used, although in this case too, the use of a labeling reagent is preferable in order to ensure that the best results are achieved. Such a labeling reagent can be made of ferric chloride if suitable buffers are present. The mechanical processes that take place in these characterization reactions are not yet known, but it is known that when certain radionuclides are used, identification reagents are required, as will be described later.

The invention will now be reviewed in detail. In the accompanying drawing is the

1 shows a side view, partly drawn as a section, of a packaging unit according to iZrfindu.ng,

Fig. 2 is a section through the packaging unit along the line 2-2 in Fig. 1 and the

3 shows a section through the packaging unit along the line 3-3 in Fig. 1.

As can be seen in particular from Fig.l, one ordered preferred embodiment of the invention 10 from a

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elongated bottle 18, which at both ends with a neck 1-7 and 27 is provided, in which the stoppers Io and 29 for closing of the bottle. In the neck on the one A porous, e.g. sintered filter plate 22 is inserted into one end of the container, marked with A. The plate 22 consists preferably made of a glass frit and carries a large number of biodegradable microparticles 19 on the side 23, which labeled with a radionuclide and put into the body for Should be injected for diagnostic purposes and the like.

In a usable embodiment, the illustrated Bottle in the middle has an outside diameter of 25 mm and at the neck an outside diameter of about 17 mm. The diameter the filter plate is therefore approximately 13 mm. Depending on The dimensions of the Bottle can of course be changed. The diameter of the filter plate 22 must of course be dimensioned so that it is at the edge is completely fused with the bottle or ampoule. The thickness of the plate is preferably about 2.5 mm since at this thickness the microbeads are retained while, on the other hand, the saline solution introduced into the container during the marking can flow freely through the plate. The pores of the filter plate have a V / eite of approximately 5.5 to 6.5 microns (0.0055 to 0.0065 mm). In addition to sintered glass, the fine-pored filter plate 22 can also be made from others suitable materials are made, e.g. from Pr ^ O / zellan, Metal, plastic and the like. · The material used should not react with the contents of the bottle, and the width the pores should be sized so that the microparticles through the pores cannot migrate through.

A large number of acidic resin particles 24 are deposited directly on the plate 22, which are intended to give off hydrogen ions, which generate an acidic solution that is necessary for a complete labeling reaction is required. The resin particles are held at the point of use by a packing material 2υ, which in turn is retained at the "point of use" by a pharmaceutical rubber stopper 29.

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At the other end, marked B, the container is also closed in the neck by a pharmaceutical rubber stopper Io, which is vexed with a jSiia cut. This incision 15 is intended to form a space for generating a reduced pressure in the bottle during the manufacture of the packaging unit. Other suitable means can also be used to generate such a reduced pressure, so that a specially designed stopper does not need to be provided. The stoppers are sealed in the bottle by aluminum caps 12 and 50 which are pressed onto the bottle. In the central compartment 12 of the bottle is a small capsule 20 containing, if necessary or desired, a reducing reagent for the labeling reaction and a wetting agent to aid in the suspension of the microparticles.

During the production of the packaging unit, sterile microparticles are suspended in an inert volatile solvent, for example in a mixture of diethyl ether and 1,1,2-trichloro-1,2,2-trifluoroethane, many last-mentioned Suostanz under the name "Freon II3" is available, the mixture preferably consisting of 1 / p ether and 2/5 Fr-eon. The suspension is aseptically filled into an empty sterile bottle from the open end B. The Afcher-Freon Gemiscii is aspirated at end A at 23, the microparticles, the diameter of which is generally about 15 to 30 microns (0.015 to 0.030 mm), and which are retained by the porous glass frit or plate 22, whose pores are smaller than the microparticles. The sterile capsule 20 is then introduced into the department through 3, and the bottle is briefly closed on the linde B with a rubber stopper Id. The bottle is then turned over so that the end A is now open, and the sterile acid resin particles 24, which are held by the packing material 26 at the point of use, are now entered into the compartment through the end A. Thereafter, the bottle is sealed and at the end A by a plug provided with a Aluminiuuikappe "Finally, by the end of the bottle through the like in a weak vacuum of about 1/5 generated at, after which

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aas iSno.e 3 if a cap is used. The Hi kr σ particles However, they do not need to be deposited on the plate 22 although this is preferable because the particles do the best dispensed in a known volume of solvent and not by weighing. The Mikropaiükel could be loose in a container ode ^. · be entered in the capsule.

Both the Ir. The shape of the bottle or ampoule shown in Fig. 1 is preferred, but this can also be made longer, shorter, wider or thinner, where the only important thing is that the bottle at least 'at one end is open so that the liquids in question can be filled in and the liquids scv: ie the marked microparticles can be removed. In addition to glass, the bottle can also be made of other materials that are sterilizable, non-reactive, non-toxic and resistant to relatively high temperatures, for example from polytetrafluoroethylene (Teflon). Glass, however, is v · r ^ u._ie.; ^ N, since the identification reaction can be observed, and cowardly, because glass is chemically inert and pharmaceutically uiioederii lion.

The microparticles that can be used for long periods of time are siiiv; eesonde / e compositions and represent a physiologically harmless, solid and at body temperature in water ii ;, wecentliohen insoluble material, which can be iv.etabolisiert or degi'ad'ie.'t in a way in which no toxic residues formed by the material in the body fluids, such as serum, plasma, lymph and the like (anscneineiiQ ciurcn3nz; iT.ie or other metabolic mechanisms) is made soluble in such a metabolization or other degradation of these substances soluble. Suitable materials for the special susceptibility consist of physiologically inactive substances, such as albumin, gelatin, hemoglobin and dergieiciiei: or also polysaccharides, such as amylose, inulin, glycogen and starch , or made from material that contains a :: physiologiscAi harmless><Lichen carrier ','v; ie ice: J: yo.i "-o :: id, silver iodide or the like. According to the.; Marking *.". he particles are resistant to leaching of the nac.io::uclide oeira Sintaucxicii in water with

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37 ° C for at least 15 minutes.

Purely diagnostic purposes or treatments where ax ~ Radionuclides have to be directed to a specific point in the body, the material is finely ground and the size of the Particles are sorted to a narrow size range limited, which corresponds to the particular purpose. The narrow size ranges of particles can have an average diameter of 0.5 to 1000 microns (0.005 up to 1.0 mm), whereDei the fourth in the selected size ranges by no more than plus or minus 20.5 of the mean differ.

They are preferably spherical or substantially Spherical particles are used because they are more uniform and more easily controlled in terms of radionuclide content and the time of elimination from the body. For diagnostic purposes, spherical bodies have a diameter from 0.5 to 60 microns (0.0005 - Ο, ΟόΟ mm) as best proved suitable. For certain therapeutic purposes, larger spherical particles with a diameter of up to 1 mm can be used be used. Since spherical or roughly conical bodies are more easily controlled because of the uniform dimensions can be with respect to the Radionucliugeiialt and to the At the time of elimination from the body, these bodies are also preferable because they are the size of neon an o.ie .jeite from Body ducts, such as arteries, capillaries, etc. be adjusted the course of which through a healthy body can be predicted and the location of the particles can be determined must be with certainty. The total weight of the for Microbeads preferably used for the purposes of the invention can contain about 0.1 to 50 mg, while the size of the individual Microbeads can be approximately 0.5 to 100 microns (0.0005-0.1 mm).

The solid source of the hydrogen ions is used to acidify the radioactive nuclide solution which migrates through the porous filter plate into the container in which the capsule is arranged, v. ^r hen radio technetium is used. Acidification is essential to support the labeling reaction, anyway

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the exact mechanism is not known. As an example of a solid acid material that can be used, a strongly acidic cation exchange resin is used called, which is composed of nuclear sulfonic acid exchange groups attached to a styrene-divinylbenzene polymer lattice attached, which material is commercially available under the designation "Dowex 50x8". It can too other types of strongly acidic resins can be used. As an example, a resin is given which has methylene sulfone groups on a contains phenolic grating. Instead of the acidic resin, crystalline acids can also be used, e.g. Trichloroacetic acid, citric acid, potassium bisulJä> etc.

With the solid source of the hydrogen ions, there is a mobile » les V / as s only available off ion that is made with a sodium ion the saline solution is exchangeable, which is introduced into the container Contains radionuclide. Sodium ions react with the resin, leaving a chemically equivalent amount of hydrogen ions is released. The amount of released hydrogen ions, acidifying the radionuclide-containing saline solution is made by the Determined amount of resin used. Purely for most uses 100 to 500 mg of resin per bottle or ampoule are sufficient. The resin particles should preferably be spherical or approximately spherical, so that they have a relatively uniform surface for the ion exchange have so that the delivery takes place with an even flow. The diameter of the pearls should be around 50-1000 microns preferably 500-700 microns.

After the resin has been added to the bottle at A, the resin is removed from a small amount of one at the point of use Packing material 26 held. This material can be made of glass wool, cotton, plastic, or from a Schwarnmaterial of some other porous material, or the packing can also be omitted entirely. The pack is useful in that it assures leakage from the bottle. Prevented during the manufacture of the packaging unit and furthermore the resin is evenly distributed over the surface. Besides that secures the pack that between the plug 29 and the resin 24 a space for the introduction of the radionuclide containing

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Solution is available.

When using radio-technetium, the capsule 20 basically contains sodium thiosulfate and a wetting agent, e.g. a detergent. The Natriurntniosuifat supports the Labeling reaction as a reducing agent, while the wetting agent suspends the microbeads supported so that uniform labeling is carried out. The reducing agent assists the reduction aes - ^ "'TcO;, the state in which technetium is generally enlightened oei Presence of an acid. The remaining components in the capsule are generally inert and can be made up of different types pharmaceutical additives generally used in the manufacture Used by tablets and pills, v / ie fillers (Lactones), binders (polyvinylpyrrolidone) and lubricants (benzoic acid). The dimensions and the composition the capsule or Taolette with the reagents can be changed turn, or hatriuasuifate crystals will turn the tablet replaced or by a mixture of sodium thiosulfe ^ t and one inert filler, such as lactose.

The cleaning agent to be used preferably for the purposes of the invention consists of poloxaien, which is a nonionic sufactan of poly (oxyethylene), poly (oxpropylene) and polymer (o;: ethylene) polymer available from Wyandotte . Gheinical Co. under the name "Pluronic F-68" relative v / can ground As another example of a cleaning agent (detergent) which is useful, is cited a mixture of P3lyo: cethylenäther oiler with oily partly esters Sorbitolanr4 ^r dr -ide, v / elcnes · material commercially available under the name "Polysorbate cio" is available. also, various other detergents may be used provided that they do not interfere ungiftxg .are and labeling reaction.

The sodium thiosulphate content of the agent tablet can be 0.5 mg to 10 mg. Instead aes lia & riu-athiosalfates, other oekannte reagent vei v / endefc wez'deii, for example thioacetamide, tin, zinc and zinnnaltige Cnloriae, although the sodium thiosulfate for his performance in Kenujeiehnungs-

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re '- :; tior. before-.ra ^ iei-eri is. If instead of ues radio-tecrinetiums anuore itaaioniklific- vei '-'.- ienaet, then become anaeric according to requirement? appropriate reagent agents are used. For example, degenerate iladio-iodine is an O;: idierur.tgs:; ii'ctel, «sB Natriuni-pai-a-toluenoül ·" · -suli'onamicl, weloiies Macerie.l under 'the · Designation "chloramine T" er ^ älilie, * ist, and fei'üer are used in Radiceii? 3-un.,. Iiadio-iiiciiuia Pui "f ersal.se, like sodium-.ii ^ rai-ogeii-pi.osu ;: ^ '*; uiv ^ DinatriunihydrogenpXiOspIiat together with " ^: .ί3ο..ο1ι1 · '- · Ι-. · vervreiiaet. In some cases, in which eg. Radioeifien and 7; aoio-inuiur: i vei'vreYicet wi ^ -d, is the use an .ivji-Vw-nr ^ .iittels wahlii'ei, oowoiil for most purposes the Verv.'eiiäun ^: a Keagenzrittel is preferable. VJird Lein J \ eagen.;: jittel bon.it ^ t, ^ .3. in the case of radionuclides, such as already ei-wILint, the kciin ^ eioiinung are carried out by U .'.- i-uj ^ -en der-IHI'i-cpa. -: liv: o cntiiindest, ε 'das, -: a wetting agent, solid acidic or ode_' ie / uierde Suostanzen were used as components of the allied.

Je nac: c-Ci .. "-oi'v.-eiiaeueri RaGionukiiä can the or the rea- ^ or. J..ittel them. Ii. Dar eisuei. Or- the av.'eiten department or in ociüen Äoteilun ^ ci: oei'iaUeii in de ± preferred embodiment ;; i ... aS. as I "enn.:eichiiuncsreagen3;:iittel acting llatriurnthio-Duli'at in dex-". it 21 oszeialuieten ersöer. Abctsilun ^ provided, v; ä.: U'e2iG aie :: v; eite department the pesticide source -er, / as s first offionen or the acidic Kai * c c. ~ Removes, so that the solution acidified-'t viii ' d, \ -iem \ <: \ iese ::; it de;., heageiuraittel got into 3si'führung, "irä als Kei: n.: ei3hm; nr; srea _; 5er: zr.iittel Natriurr.-para-toluen -chlorsi; lfonar.: iö. used, so ίζεηη it is provided in every division, preferably in the first division, while aie Faffersabsran ;. sial: gl ielifalis in Jeaar department, but before - .. jugsvföioe ir. eier: ; .ei ^ :; Department may be located.Ss is a characteristic de; Zrfizi-auii ^ * that all reagents, ga.n ^ same '. vr ^ lejier kind, Ei ^: .:.: ^ borrowed i: i a · Verpaolr.:.r.retention are included.

Dar zu ::: K6:; "reijh :: en der ϊ-iikrcperien; jenutz; te liadicnuclid ;: ira c ^ c a :: [: ev; erjlij.ien G-nerator received in the Ti ^ hnii; as "a: vr" be :: -_ ■! 2h: ier- becomes. V. "ie already stated, he know ;; i: ..?: e :: n.-eie: r; en v ::; I-Iiirrcpartikein u the following

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radioactive materials are used, namely hadio-iodine, radio-iron, radio-technetium, radio-indium and other suitable radionuclides together with suitable reagents. The use of radio-technetium (^ Tc) is preferable because of its gamma emission energy and because it is generally available. The technetium is taken from the generator in such a way that a salt solution is passed through the generator, which transports the ^^ ^m Tc from the generator into a collecting container. The saline solution containing the radio-technetium is then withdrawn from the container using a syringe.

If the particles are to be labeled, the needle will of the syringe containing the radio-technetium in the saline solution, inserted through the rubber stopper 29 into the end a of the bottle at 28. The reduced pressure in the bottle that was created during manufacture sucks the radio-technetium solution over the resin and through the glass frit into division 21 in to a regular extent. The ion exchange between the resin and the isotopic saline solution can be represented by the following formula:

+ NaCl + H ⁺ resin ~>'- ^ TcO ^ + HCL + Na resin, where

an acidic solution is generated. By determining the width of the needle and the vacuum, the .Btrömurig can be regulated via the resin will. At a pressure of 1/5 at approximately 10 ml of the Solution passed over the resin in approximately 45 seconds. These The flow velocity is important because the sodium ions exchange when the radio-technetium flows over the resin takes place in the salt solution with the hydrogen ions in the resin. If the solution migrates too quickly over the resin, no proper result occurs between the sodium ions and the hydrogen ions Exchange. The flow velocity must therefore be regulated will.

The bottle containing the radio-technetium in the compartment in which the tablet or capsule is located can be immersed in an ultrasonic bath in order to prevent the suspension of the ^{microbeads on the 7} glass frit.

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support and promote the dissolution of the tablet. At the dissolution the tablet will contain the sodium thiosulfate and the detergent released. The bottle is then immersed in warm, preferably boiling water and can be shaken, so that the labeling reaction takes place completely. The bottle is then cooled, after which the unreacted radio-technetium and the solution containing the used reagents is removed from the bottle at A, with the labeled microbeads behind the porous filter plate 22 on its side lag behind. A saline solution or other solution used as a vehicle or a means for injections and containing a Detergent containing can be introduced into the compartment 21 through the end B for the suspension and injection of the marked Microbeads, or the microbeads can be washed once and several times with saline solution before injecting, which saline solution is removed after washing, as already mentioned.

If microbeads smaller than 6 microns are to be identified, which are used e.g. to examine the liver, so the procedure described above is used with the exception that the supernatant is not withdrawn through the end A. Rather, a suitable buffer substance, such as sodium dihydrogen phosphate, is introduced into compartment 21 through end B along with disodium hydrogen phosphate to reduce the acidity of the reaction to neutralize. The small microbeads are then introduced into this buffer solution.

With a slight modification of the packaging unit shown in FIG. 1, it can be equipped with its own ^ " ¹¹¹ Tc generator, so that the user does not have to resort to a commercial generator. Such a complete packaging unit would be useful for researchers, whose clinical volume is not large enough to justify the purchase of a special "^ ⁰¹ Tc generator. For this purpose approximately 100 mg of alumina grains are placed between the resin 24 and the packing 26. About 5 to 100 millicuries, and preferably about 20 millicuries) ₂ MoO ~ 9 ^ytrv rc0. (Ammonium molybdate) are obtained by means of a

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Pipette applied to the top of this aluminum oxide and dried. The amount of animoniura molybdate must be sufficient to produce an effective amount of radio-technetium for labeling. The bottle is then closed at end A, after which the bottle is evacuated through end 3 and closed. The needle of a syringe containing approximately 10 ml of saline solution was then pushed through the rubber stopper at A, after which the vacuum (1/5 at) in the bottle allowed the saline solution over the aluminum oxide, over the resin 2-r and through the porous filter plate 22 Sucks into the center located department 21 to a controlled extent. As the salt solution migrates over the aluminum oxide, the Na- ³ ^ ¹¹¹ TeO _{1 is} removed from the absorbed (NEW J ^ '-' MoO ^, which remains immobile.

When the salt solution, the Na ^ ^"ra Tc0 ^ containing üoer- aas acidic resin flows, so HCl is obtained, enters the department so that acidified Na ^ ¹¹¹ TCOH. Through the porous filter plate 22. The packaging unit is AARM Inder- already ue advertised Used wisely.

Not only labeled alburrine microparticles have been used for clinical diagnosis and the like, but labeled colloidal sulfur (sulfur colloid) has also been used. Since the same reactants were used in each case, the labeled colloidal sulfur can be produced in such a way that the packaging unit according to the invention is used without the microparticles. The same procedure is used as for marking microbeads except that the supernatant is not removed but a buffer solution is added to neutralize the reaction, after which the "^ ^m Tc colloidal sulfur is ready to use. However, it is preferable To use albumin microparticles of human serum because of their constant size and physical stability.

Some examples are described below, However, to which the invention is not restricted, all values given being based on weight, unless nothing otherwise stated.

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- 15 Example 1

Means odnei 'hypodermic Naoei were injected 4 ml albumin in about 1 liter of vegetable oil (Baurawollsamenöl) which at about JO - 50 "*' was heated C. The speed of stirring uestir.imt the final size of the spherical :: material obtained under. use of a container which is higher than ijreit v / a ·, and a hypoderniscnen needle, 25 Deim Uvrühren were initoels a ό-enj Propellerrürirwerks with rotational "a :: l vo :: i; QQ ü / i.- .. Iiri microbeads ait a Durcnmesser of un-, xähr 10 - ^ O Kikroii obtained by heating at 110 - 150 ° C v.'urde the stirring continued ice dea of the microbeads _L; esa ;;; te V / asse: - entfex * was nt This has been determined, • .lass removed from the mixture a small number of beads .. vmrde found ivj, ο ο they still kieorig were or not, ae to: .. SntiVrrien the Fifth. " As se rs xfurden the particles are filtered out of the oil and washed in diethyl ether. Albumin ::; il: ro2->alder2; · were obtained.

^s , P

Ξε V7 was a Vei'pacloingseiniieit sum radioactive labeling according to the £ rfi :: dun _fo · in the following terms: sterile alournin microbeads of the human serum were suspended in 200 ml of a mixture of diethyl ether and 1,1,2- trichloro-1,2,2-trifluoroethane (1/3 ether and 2/3 sthan). To '■} mg obtain about microbeads zn, v; 1 ml urde aogesogen mixture and aseptically ooensteilende into an empty sterile bottle after at Pig.l;:; End of B entered. The ether and A'thangemixture was sucked off at the opposite Enae A. The microbeads uit a diameter of 15-30 microns were obtained from-the porous glass frit restrained, the pores having a width of 5> 5 SSIS c, ^l j microns. A sterile reagent tablet was inserted through the end of B, after which the bottle rit briefly at the end 3; closed with a rubber stopper. The *

Reagent tablet had the following composition:

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ο, 55 mg 67, 2 mg ο, 3 mg Is bo mg 0 mg

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Sodium thio sulfate lactose

non-ionic sifactant of poly (oxyethylene), poly (oxpropylene) and poly (oxethylene) polymers
(Pluronic F-68)

Polyvinyl pyrrolidone benzoic acid

The hardness was 4.5 kg (Strong Gobb Test) and the solution time was 2-4 minutes.

At the above end A, 200 mg of sterile resin "Dowex 50" were applied to the glass frit and by means of a made of cotton packing material held. The end A of the bottle was then opened using a pharmaceutical Rubber stopper closed and provided with a cap. The bottle was then evacuated to a pressure of 1/3 atm and provided with a flap.

Example 3

The labeling bottle produced according to Example 2 was used to label albumin microbeads of human serum with radio-technetium (Na- ^ ¹¹¹ TcO.). The needle of a syringe containing 6 ml (approximately 12 millicuries) of Na 1 ¹⁷¹ TcO ₂ in saline solution (obtained from a commercial generator) was inserted into the glass bottle containing the resin. The vacuum (about 1/3 at) is wrong; Inside the bottle, the Na- ^ ¹¹¹ Tcon solution was drawn over the Dowex resin, through the glass frit and into the center of the bottle, where the reagent tablet was. The bottle was then shaken and treated in an ultrasonic bath for 2 minutes to dissolve the tablet and release the sodium thiosulfate and detergent. Thereafter, the bottle was taken out of the ultrasonic bath and immersed in boiling water for β minutes to complete the labeling reaction, after which the bottle was cooled with tap water for 2 minutes. The solution containing the unreacted Na - ^ TcO ^ and spent reagent was then ^{removed by syringe through the ^ n <} ^ ^e A of the bottle, at which; End A is the resin

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and the pack uefinü. The labeled microbeads remained behind the Olas frit and back on it. 6 ml of an isotonic SC..en Saline solution, the 0.05) 'Polysoruat 60 (an Oenisch from. Polyo: ethylene-Uthcr of mixed partial oil esters of sorbitol anhydrides) were introduced into the membrane through the anaeric-3 nd, marked 3, around the marked microbeads to suspend again.

The marked microbeads were then examined in mice, for what purpose the saline solution containing polysorbate 60 and containing 0.1 ng of the ^{microbeads marked with 1} Tc (approximately 0.2 millicuries) was withdrawn and inserted into the tail veins of white white mice was injected. the mice were 'killed epäter 50 minutes and dissected. the activity of ^ Tc ^in! s was geinessen in nurnpi "in the lungs and in the leoer the animal. From the data obtained, the ^ ^ta To wux'de distribution in mice _m calculated. One to three mice were used to test each packaging unit.

In the table below, the term percent uptake relates to the effectiveness of the germ drawing while dii "other parameters, SiCN on the distribution of ^ ^rn Tc in the vast mice HALOE hour NaCN injection of microbeads marked bezienen. The data were obtained using 12 packaging units.

Table I.

average + Normal deviation (Per unit) Percent inclusion 79.0 5.7 Percent in the lungs 77.0 5.7 Percent in the liver 5, ο 1.2 Percent in the trunk 12.2 4, b Lung / liver ratio 14.1 4.4 Be i s ρ i e 1 4 -

It was an animal study ähr.lich Example 3 carried out using a nacli Example 2 prepared bottle except> that 350 mg Dowex resin and

1098 & 1M85Q

COPY

BATH ORIGINAL

211.5068

10 ml of Na ^ ¹¹¹ TcO ₂ J Jun & efUiir 20 Milliourio) are used. The Heagenzmittol tablet had the following composition

Sodium thiosulfate lactose

non-ionic Sux-fukbano of Poly (o / .Uthylen), Poly (oxpx-opylen), ν and poly (oxutylene) polymer

(Pluronic F-υό) Po.lyvinylpyiTolidone Benzoestiure

1.00 mg, 0 ulf ;,

The spiked microbeads were washed with 100 g, which contained 0.05 ',' * polysoroate oO, a gel made from the ingredients of the mixed partial oil esters of the soi'bitol anhydrides, which solution was poured into the bottle oei B and drained off . Several 10 ml of a iaotoniBonen Sal ^ lcisunt, (which contained 0.05 ','> polysorbate ÖO) was introduced into aia Plaaoho dux-cjn H, and the solution of the labeled microbeads was examined in mice as in the example } . Fourteen packaging units were used and the results below were obtained

T able II

Average £ normal deviation

percent recording To, 6 3, 1 percent in the lungs 02.9 1, 1 percent in the liver 2, 2 percent in the fuselage 11.6 ■ 5 ' Behavior . Lungs / liver 10.3

Claims

109841/1850

BATH ORIGINAL

Claims (1)

211506Θ - 19 claims 1. Packing unit for radioactive labeling of D: ia. \ ^: Na ^ eutisch harmless microparticles for medical diagnosis and the like, characterized by a container open at least at one end, by in: container arranged porous filter plate, which the container in a first and second compartments, divided by a large number of pharmaceutically acceptable microparticles in the first compartment, by at least one identification reagent in the container to support the identification reaction and by means for short-term use.: e: i of the mentioned open end and for receiving I the Holnaael a syringe with which a liquid is entered into the container and the radioactively marked r-Iik_-oparti]: el are removed from the container. d. Varpaekan ^ unit according to claim 1, characterized in that the germ cell dissolving reagent consists of a reducing agent located in the first division. ';: ■. Packaging unit according to claim 2, characterized in that the reducing agent consists of sodium thiosulphate. 4. Packaging unit according to claim jj, characterized in that that the packaging unit is also in the second Department is equipped with a pesticide source for hydrogen ions. 5. Packaging unit according to claim 4, characterized in that that said solid source for hydrogen ions consists of a strongly acidic cation exchange resin composed of nuclear sulfonic acid exchange groups which is bonded with a styrene-divinylbenzene polymer lattice ■ are. 109841Π8Β0 BATH ORIGINAL 2115086 6. Packaging unit according to claim 4, characterized in that that the packing unit in the second department is additionally provided with a packing material that prevents movement of the solid source of the hydrogen ions. 7. Packaging unit according to claim M-, characterized in that the reducing agent, together with pharmaceutically acceptable additives, forms a labeling reagent in tablet form. 8. Packaging unit according to claim ^r ( characterized in that said tablet consists of a reducing agent to support the labeling reaction and of a non-reactive and non-toxic wetting agent to support the suspension of the microparticles when a liquid is introduced into the container. 9. Packaging unit according to claim 8, characterized in that that said wetting agent consists of a non-ionic surfactant of poly (oxethylene), poly (oxpropylene), and poly (oxethylene) polymer. 10. Packing unit in which a radionuclide is produced, which are then labeled pharmaceutically acceptable microparticles, characterized by at least one at one end, open container, through one in the container transversely arranged porous filter plate which divides the container into a first and a second compartment by a Large number of pharmaceutically acceptable microparticles in the first compartment, through a solid source for hydrogen ions arranged in the second compartment one lying on the solid source of the hydrogen ions Layer of granular alumina, with an effective amount of ammonium molybdate to produce an effective amount Radio-technetiums on the aluminum oxide layer, by a 'reagent tablet in the said first compartment, those from a reducing reactant to assist the labeling reaction and a non-reacting one 109841/1850 ^f 'BAD O "*" and non-toxic illuminants to support the suspension the microparticle exists when a Liquid is introduced, and by means for briefly closing said open ends, the de hollow needle a syringe for introducing a liquid into the container. Method for radioactive labeling of pharmaceutically harmless microparticles, characterized in that, that (a) introducing a solution into the second compartment of the packaging unit, the radio tecnnetium contains, 'λ polygamy packaging unit has a generally elongated tank which is open at the two opposite hands, one mounted in the container cross glass frit which the container divided into a first and a second compartment, a large number of pharmaceutically safe and biodegradable microbeads in the first compartment and a solid source for hydrogen ions in the second compartment, (b) the solution through the solid source of hydrogen ions is passed through hindu for acidification, (c) the packaging unit for complete implementation the labeling reaction is heated, g (d). that the unreacted radio-technetium and consumed Supernatans containing reagent is removed and (e) the labeled microparticles are isolated. 12. The method according to claim 11, characterized in that In addition, the acidified solution is shaken and stirred to suspend the microparticles and the reagent tablet to be resolved according to process stage (b), and that the packaging unit after the Vex process stage (c) is cooled. Br. - BATH ORIGINAL 109841/1850