US3743714A - Novel carrier preparations for injectable radioactive compositions - Google Patents

Novel carrier preparations for injectable radioactive compositions Download PDF

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Publication number
US3743714A
US3743714A US00095271A US3743714DA US3743714A US 3743714 A US3743714 A US 3743714A US 00095271 A US00095271 A US 00095271A US 3743714D A US3743714D A US 3743714DA US 3743714 A US3743714 A US 3743714A
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gelatin
solution
sterile
sodium thiosulfate
acid
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Expired - Lifetime
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US00095271A
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English (en)
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M Deutsch
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CIS RADIOPHARMACEUTICALS Inc
CIS RADIOPHARMACEUTICALS INC US
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CIS RADIOPHARMACEUTICALS Inc
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    • 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
    • A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
    • 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
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • FIGA A first figure.
  • radioisotopes must, of necessity, have a rather short half life since it is not desirable for radio active materials to remain in the system of a patient for any substantial length of time. Since the half life of most of these isotopes is of the order of hours it is customary to prepare a suitable carrier composition and mix it with the radio tracer immediately before diagnostic administration to the patient.
  • colloidal sulfur has a tendency to accumulate in the liver and spleen and, to a lesser extent to the lungs, and colloidal ferric hydroxide has a tendency to accumulate in the lungs.
  • technetium-99 has a remarkable ability to be absorbed upon colloidal sulfur having a particular size up to 2.0 microns, although the best results are achieved by using a particular size less than 1.2 microns.
  • indium-113 has a tendency to be absorbed on ferric hydroxide in colloidal form.
  • the standard technique of preparing the colloidal sulfur comprises the provision of an aqueous solution containing gelatin and sodium thiosulfate to which is added an aqueous solution of radio tracer such as sodium pertechnetate, acid is then added and the solution heated briefly, suitably in boiling Water to convert the sodium thiosulfate into colloidal sulfur. The solution is then cooled and substantially neutralized with a physiologically acceptable base.
  • kits for this purpose which have been provided heretofore comprise an aqueous solution of gelatin and sodium thiosulfate, a source of acid and a source of base, suitably compounded with a buffer.
  • a further disadvantage of the provision of an aqueous solution of gelatin and sodium thiosulfate is that such a combination has poor stability and short shelf life. Upon standing at ambient temperatures for substantial periods of time, aqueous solutions of sodium thiosulfate have a tendency to decompose into compounds which will not form a sulfur colloid.
  • the present invention comprises the provision of a mixture of gelatin and sodium thiosulfate in readily soluble form together with means for adding acid and means for adding base thereto.
  • a solution of gelatin is prepared by suspending it in pyrogen-free, substantially particle-free distilled water, steam sterilizing the suspension and cooling the resultant solution.
  • a solution of sodium thiosulfate suitably sodium thiosulfate pentahydrate in cool, pyrogen-free distilled water which is then filtered through a Millipore filter into a clean sterile vessel.
  • Calculated quantities of each of these solutions are then transferred into sterile containers, frozen, and freezedried using aseptic technique.
  • the containers are then sealed, suitably using a puncturable scalable closure such 0 as a rubber cap or rubber stopper.
  • a puncturable scalable closure such 0 as a rubber cap or rubber stopper.
  • These are also prepared sterile, pyrogen-free solutions of acid and also of base, suitably the base being in the presence of a buifer, which are each packaged into sterile means for introduction thereof into the sterile containers charged with the freeze-dried mixtures of gelatin and sodium thiosulfate. It has been found suitable to utilize disposable plastic syringes for the purpose.
  • an aqueous solution of the radio tracer for example sodium pertechnetate is injected into the container charged with the freeze-dried gelatin and sodium thiosulfate, suitably using a syringe, mixing the components together, adding the requisite quantity of acid, remixing and heating at an elevated temperature for a short time.
  • the colloidal sulfur having the radio tracer absorbed thereon is thus produced.
  • the mixture is cooled and the base, suitably containing the buffer, is then injected to adjust the pH to the appropriate value.
  • the composition is then injected into the subject patient.
  • the principle is also applicable to other injectable colloidal carriers for example to colloidal ferric hydroxide.
  • ferric ethylate which may be readily hydrolyzed, suitably, but not necessary, in an alkaline environment to produce salt free colloidal ferric hydroxide, upon which a radio tracer, such as induim-113 is absorbed.
  • FIG. 1 is an elevational cross sectional view of a sterile container for the gelatin and thiosulfate.
  • FIG. 2 is a top plan view of the container of FIG. 1 showing crimp seal in place.
  • FIG. 3 is a top plan view of the container of FIG. 1 showing rubber seal exposed.
  • FIGS. 4 and 5 are injection means for acid, and base with buffer.
  • all of the components utilized should be, where available, clean and sterile. And all water used for solvating components should be pyrogen-free and substantially particlefree.
  • the galatin solution is prepared by suspending gelatin in water and allowing it to imbibe water for a short period of time, thereafter the glutinous suspension is sealed suitably by crimp sealing, and heat sterilized suitably by steam sterilization which, not only sterilizes the suspension but causes the gelatin to dissolve.
  • the amount of water utilized to dissolve the gelatin is in no way critical, however, it has been found convenient to utilize concentrations of the order of 60 to 100 grams of gelatin per litre of water. Gelatin suspensions of this concentration will pick up the optimal amount of water at ambient temperature in about to about 20 minutes, longer immersion is therefore unnecessary.
  • the sodium thiosulfate suitably in the form of the pentahydrate, is dissolved in water at ambient temperature or below.
  • the temperature is not critical, however it must be recognized that the solubility at low temperatures is less than that at higher temperatures and that temperatures above ambient are not favored in order to include the premature decomposition of the sodium thiosulfate into colloidal sulfur.
  • the pentahydrate is preferred as the most readily available form, sodium thiosulfate with other degrees of hydration may of course be employed, similarly potassium thiosulfate may also be employed but the sodium salt is preferred for reasons of cost.
  • the solution is then filtered through a Millipore filter in order to remove particulate matter and bacteria.
  • concentration of sodium thiosulfate is not critical at this point, it has been found convenient to utilize the concentrations from about 3 to about 8 grams of thiosulfate per litre of water. It has also been found convenient to utilize a filter having ca. 0.8 micron apertures, this removes all bacteria.
  • portions of the gelatin solution and the thiosulfate solution are then transferred into small sterile containers 10, suitable clean sterile serum vials. It has been found convenient to transfer amounts of solutions corresponding to from about 4 to about 40 mg. of gelatin, preferably about 8 mg. of gelatin and from about 1 to about 4 mg. preferably about 2.5 mg. of sodium thiosulfate pentahydrate into each vial.
  • the vials are then frozen and freeze-dried using standard aseptic techniques.
  • the vials are then sealed utilizing a puncturable, resealable closure such as a rubber stopper or similar elastomeric closure which is then sealed suitably by crimp sealings.
  • the vial 10 thus contains a layer 19 of freeze dried gelatin/thiosulfate mixture.
  • the dual sealing device comprises a puncturable rubber stopper 12 which is covered by a metallic crimp seal cap 14 which comprises a retaining portion 16 and a removable center plate 18. This center plate 18 is removed immediately prior to use permit sterile injection into vial 10.
  • the other components of the kit are then prepared.
  • the acid utilized should be one which contains a physiologically acceptable anion. While not limiting the invention thereto, it is generally preferred to utilize an aqueous solution of phosphoric acid or hydrochloric acid suitably about 0.5 to about 0.15 N acid being utilized, acid of about 0.1 N being preferred.
  • the acid is then place in a sterile means for introducing the said acid into the sterile container containing the freeze-dried mixture of gelatin and sodium thiosulfate.
  • disposable plastic syringes have been found specially suitable. Where the foregoing quantities of gelatin and sodium thiosulfate have been employed, 5 ml. syringes containing 2 ml. of acid have been found especially useful.
  • Typical syringes 20 and 30 are shown in FIGS. 4 and 5 and comprise respectively barrel portions 22 and 32 fitted with plungers 24 and 34 and needle portions 26 and 36.
  • the acid 28 and base 38 components are located in the portion of barrels 22 and 32 between plungers 24 and 34 and needles 26 and 36.
  • a base having physiologically acceptable cations and anions preferably though not criticially, a physiologically acceptable buffer.
  • bases which may be used are potassium or sodium hydroxides or carbonates.
  • a buffer the commonly used sodium or potassium dihydrogen phosphate may be employed.
  • bases having a concentration from about 0.05 to about 0.15 N preferably about 0.1 N.
  • the buffer which is, of course, dissolved in the same solution containing the base may be of a strength of between about 0.1 to about 0.2 M suitably about 0.15 M.
  • the typical ratio of quantities of components used in the combination of the present invention may be summarized as from about 4 to about 40 milligrams, suitably about 8 milligrams of gelatin, from about 1 to about 4 milligrams suitably about 2.5 milligrams of sodium thiosulfate pentahydrate initially charged, with which are packaged from about 1 to about 5 ml.
  • each of acid solution containing from about 0.1 to about 0.3, suitably about 0.2 milliequivalants of acid and of base solution containing from about 0.15 to about 0.35 suitably about 0.28 milliequivalants of base in the presence of about 0.2 to about 0.4 suitably 3.3 millimoles of buffer.
  • the radio tracer utilized with this injectable composition is usually obtained in the form of an aqueous solution of a salt.
  • the radio tracers utilizable with these compositions is sodium pertechnetate.
  • the quantity of radio tracer utilized with the aforementioned quantities of composition is of the order of about 1 to about 10 millicuries.
  • the radio tracer solution is injected into the sealed containers containing the freeze-dried gelatin and sodium thiosulfate mixture.
  • the components are thoroughly mixed to provide a solution, and the acid components added thereto.
  • the components are then thoroughly mixed again, suitably by shaking, and heating for a short period of time to produce the colloidal sulfur solution having absorbed thereon the radio tracer.
  • Example 1 Preparation of gelatin-sodium thiosulfate component.- There is prepared a suspension of l g. of gelatin in 12.5 ml. of pyrogen-free substantially particle-free distilled water. The mixture is allowed to stand for minutes, transferred to a crimp-sealed serum vial, steam sterilized, and cooled.
  • 250 mg. of sodium thiosulfate pentahydrate is dissolved in 50 ml. of pyrogen-free distilled water at ambient temperature, and filtered through a Millipore filter (0.8 micron aperture) into a clean sterile vial.
  • 0.1-ml. portions of the gelatin solution and 0.5-ml. portions of the thiosulfate solution respectively are combined in a series of clean sterile vials, frozen, freeze-dried, and stoppered with rubber stoppers which are crimp sealed in place.
  • Example 2 Preparation of the acid and base components.--(a) A 0.111 N solution of hydrochloric acid is prepared in a sterile pyrogen-free water and 2-ml. portions thereof transferred to disposable plastic syringes of 2.5-ml. capacity.
  • Example 3 Preparation of injectable composition.lnto a vial containing freeze-dried gelatin and freeze-dried-sodium thiosulfate as prepared in accordance with Example 1, there is injected l-ml. of a sterile pyrogen-free, substantially carrier-free solution of sodium pertechnetate. The contents are mixed thoroughly, the contents of the syringe prepared in accordance with Example 2(a) are added, the contents again mixed and placed in a vigorously boiling water bath for three minutes, cooled, and the contents of the syringe of Example 2(b) added.
  • a process for the preparation of an injectable carrier for radioisotopes which comprises the steps of:
  • step (b) freeze-drying the solution of step (a),
  • step (c) adding to the freeze-dried product of step (b) an aqueous solution containing the radioisotopes to be utilized, and mixing thoroughly,
  • step (d) adding to the solution of step (c) an aqueous solution of a strong acid containing a physiologically acceptable anion and mixing thoroughly,
  • step (e) heating the mixture of step (d) at a temperature of between 90 and about 100 C. for a short time to produce a colloidal sulfur solution with the colloidal particles being of a size less than 2 microns, preferably less than 1.2 microns, and having absorbed thereon the radioisotope, and
  • step (f) cooling the colloidal solution of step (e) and neutralizing with a base containing physiologically acceptable anions and cations in the presence of a physiologically acceptable butter.
  • a process according to claim 1 comprising the steps of (a) suspending gelatin in pyrogen-free, substantially particle free water,
  • a process according to claim 2 comprising the additional steps of (a) adding to said sterile container an aqueous pyrogen-free solution of an injectable water soluble composition comprising radioisotopes,
  • radioisotope tracer is a water soluble salt comprising technetium-99.
  • a kit for the preparation of injectable radioisotope solutions comprising (a) a sterile container comprising a freeze-dried mixture of gelatin and sodium thiosulfate,
  • a sterile means for introducing a base having physiologically acceptable anions and cations and a physiologically acceptable buffer into said sterile container, said sterile means containing said base and said buffer wherein the relatives quantities of acid, butter, and base are such that when mixed with each other and the contents of the sterile container, there will be produced a colloidal solution having a pH of between 6.0 and 6.5 and wherein the ratio of components is from about 4 to about 40 mg. of gelatin relative to between about 1 to about 4 mg.
  • the base is aqueous potassium or sodium hydroxide or carbonate
  • said buffer is sodium or potassium dihydrogen phosphate.
  • kits according to claim 7 wherein (a) the sterile container contains 8 mg. of gelatin and 2.5 mg. of sodium thiosulfate, both components having been freeze-dried, the weights being measured prior to freeze-drying, (b) a first sterile introducing means containing 2 ml. of 0.11 N hydrochloric acid in pyrogen-free water, (c) a second sterile introducing means containing 2 ml. of a pyrogen-free aqueous solution of 0.139 mM. sodium hydroxide and 0.163 mM. of sodium dihydrogen phosphate monohydrate.
  • a process for the preparation of an injectable carrier for radioisotopes comprising the steps of:
  • step (c) adding to the freeze dried product of step (b) an aqueous solution containing the radioisotopes to be utilized and mixing thoroughly,
  • step (d) adding to the solution of step (c) a base containing a physiologically acceptable anion and cation and mixing thoroughly,
  • step (f) cooling the colloidal solution of step (e) and adding thereto an acid containing a physiologically acceptable anion in the presence of a physiologically acceptable buffer to bring the pH into the region from about 7 to 8.

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US00095271A 1970-12-04 1970-12-04 Novel carrier preparations for injectable radioactive compositions Expired - Lifetime US3743714A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4300569A (en) * 1977-06-17 1981-11-17 Merck & Co., Inc. Red blood cell labelling kit
US4540410A (en) * 1982-11-16 1985-09-10 Serono Pharmaceutical Partners Lyophilized compositions, preparation and use thereof
US5326532A (en) * 1993-02-25 1994-07-05 E. I. Du Pont De Nemours And Company Apparatus for chemically processing toxic materials
US6225611B1 (en) 1999-11-15 2001-05-01 Hull Corporation Microwave lyophilizer having corona discharge control
US20080172902A1 (en) * 2006-06-20 2008-07-24 Octapharma Ag Lyophilisation targeting defined residual moisture by limited desorption energy levels
US20180213819A1 (en) * 2017-01-27 2018-08-02 Food & Beverage Innovations, Llc Device and methods for preparation of gelatin-based products

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2024007B (en) * 1978-06-30 1983-04-27 Gordon R T Cancer-treating composition containing inductively heatable particles

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4300569A (en) * 1977-06-17 1981-11-17 Merck & Co., Inc. Red blood cell labelling kit
US4540410A (en) * 1982-11-16 1985-09-10 Serono Pharmaceutical Partners Lyophilized compositions, preparation and use thereof
US5326532A (en) * 1993-02-25 1994-07-05 E. I. Du Pont De Nemours And Company Apparatus for chemically processing toxic materials
US6225611B1 (en) 1999-11-15 2001-05-01 Hull Corporation Microwave lyophilizer having corona discharge control
US20080172902A1 (en) * 2006-06-20 2008-07-24 Octapharma Ag Lyophilisation targeting defined residual moisture by limited desorption energy levels
US8769841B2 (en) 2006-06-20 2014-07-08 Octapharma Ag Lyophilisation targeting defined residual moisture by limited desorption energy levels
US20180213819A1 (en) * 2017-01-27 2018-08-02 Food & Beverage Innovations, Llc Device and methods for preparation of gelatin-based products
US10842168B2 (en) * 2017-01-27 2020-11-24 Jevo Ip, Llc Device for preparation of gelatin-based products
US11700864B2 (en) 2017-01-27 2023-07-18 Jevo Ip, Llc Methods for preparation of gelatin-based products

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FR2116420A1 (enExample) 1972-07-13
DE2160009A1 (de) 1972-06-29
FR2116420B1 (enExample) 1974-07-19

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