WO1993022260A1 - Radiolabelled compound formulations - Google Patents
Radiolabelled compound formulations Download PDFInfo
- Publication number
- WO1993022260A1 WO1993022260A1 PCT/GB1993/000869 GB9300869W WO9322260A1 WO 1993022260 A1 WO1993022260 A1 WO 1993022260A1 GB 9300869 W GB9300869 W GB 9300869W WO 9322260 A1 WO9322260 A1 WO 9322260A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- rcp
- organic compound
- dye
- control
- Prior art date
Links
Classifications
-
- 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
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
- C07B63/04—Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- 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
- radiochemicals to experimental systems, such as protein or nucleic acid manipulation.
- 32-P radiolabelled nucleotides are often sold as buffered aqueous solutions shipped in dry ice and sold for storage by the customer at -20oC. It would be a significant advantage, both to the shipper and to the customer, if the radiolabelled nucleotides could be supplied at ambient temperature and stored in an
- radiolabelled organic chemical might be used.
- the invention provides a composition
- a composition comprising an organic compound labelled with a ⁇ -emitting radionuclide, said radiolabelled organic compound being subject to radiolytic
- a stabiliser selected from tryptophan, paraaminobenzoate, indoleacetate, luminol, and the group of azoles which are compounds having a 5-membered ring with at least two ring nitrogen atoms directly bonded to one another.
- the invention provides a composition comprising a solution of an organic compound
- the invention is mainly concerned with radiolabelled organic compounds which are supplied, shipped and stored in solution, usually aqueous
- compositions in the solid state e.g. those produced by lyophilising or otherwise drying liquid compositions.
- the invention is applicable to radiolabelled organic compounds which are subject to radiolytic self-decomposition, for example: amino acids, steroids, lipids, fatty acids, peptides, carbohydrates, proteins, and particularly nucleotides, thionucleotides,
- nucleosides and nucleic acids.
- the nature of the ⁇ -emitting radionuclide is not critical; 3-H and 14-C are possible, but 32-P, 35-S and 33-P are preferred.
- the stabiliser is preferably selected from L- and D-tryptophan; para-aminobenzoate which term is used to include the free acid and salts and esters thereof; indoleacetate which term is used to include the free acid and salts and esters thereof; luminol (3-aminophthalhydrazide); and the group of azoles which are compounds having a 5-membered ring with at least two ring nitrogen atoms directly bonded to one another. Such compounds preferably have the structure
- Y and Z may represent N or one of X, Y and Z may represent S, the remaining X, Y and Z representing C,
- R 5 represents -OH, -SH, -H. -COOH, -NH 2 , -CH 3 attached to the ring directly or via a chain of up to 10 carbon atoms, or two adjacent members of R 1 , R 2 , R 3 , R 4 and R 5 may together constitute an aromatic ring.
- R 5 will or will not be present depending on the nature of X, Y and Z and on the positions of the two double bonds.
- Examples of classes of azole compounds are azole compounds
- the concentration of stabiliser is sufficient to reduce radiolytic decomposition of the radiolabelled organic compound, while not being so high as to materially interfere with the reaction systems where the
- radiolabelled organic compound is to be used.
- Preferred concentrations in liquid compositions are in the range of 1 mM to 1M, particularly 10 to 100 mM. Used in these concentrations, the preferred compounds have proved effective stabilisers particularly for nucleotides.
- the dye is preferably selected from
- Sulphorhodamine B Xylene Cyanol, Azocarmine B and New Coccine.
- Other possible dyes include Orange G, Tartrazine, Safranin O, Methyl Green, Bromophenol Blue, Eosin, Evans Blue, Brilliant Blue G, Bromocresol Green, Ponceau S, Carmoisine Red, Remazol Red RB, Sandoz
- concentration of the dye should be sufficient to visibly colour the solution, but not so high as to materially interfere with the reaction systems into which the radiolabelled organic compound is to be introduced.
- Preferred dye concentrations are from 20 to 3000 ⁇ g/ml, particularly 50 to 400 ⁇ g/ml; that is to say approximately (depending on the
- the dyes do have a mild stabilising effect, in addition to providing colour.
- the colour of compositions containing these dyes does fade with time, possibly due to radiolytic rupture of double bonds of the ring structures of the dyes. While this fading does not render the
- compositions unworkable it may nevertheless be
- the radiolabelled organic compound composition includes both the dye and the stabiliser.
- the stabiliser helps to prevent the dye from fading.
- the dye improves the visibility of the radiochemical.
- the dye and the stabiliser may act synergistically to improve the stability of the radiolabelled organic compound.
- compositions of this invention may contain buffers.
- the nature of the buffer is not critical to the invention, but standard commercial diluents for nucleotides consisting of an aqueous buffered solution stabilised by 2-mercaptoethanol or dithiothreitol are preferred systems. These are the systems that are used in the examples below. But other systems have been tested and shown to be equally effective.
- Radiolabelled nucleotides and other organic compounds are conventionally shipped and stored at -20oC or below, requiring the use of dry ice.
- compositions according to this invention are suitable for shipment and storage either at 4oC (on ice) or more preferably at ambient temperature.
- compositions were made up and tested for stability.
- Some of the tabulated experimental data refers to batches of dCTP labelled with 32 Phosphorus, but the stabilising compounds were also tested with the other 32 Phosphorus alpha-labelled nucleotides dATP, dGTP and dTTP.
- Stability testing was therefore carried out for 21 days to approximate the length of customer usage.
- test results are expressed as absolute percentage incorporation of the nucleotide compared with a control formulation, from the same batch, based on the above diluent without further added stabiliser or dye and stored at RT or +4oC or -20.C.
- the radiochemical purity of the labelled nucleotide was measured after storage for various intervals, using thin layer chromatography plates which were subsequently scanned using a Raytek RITA scanner. This is reported as RCP.
- Formulations were tested in various nucleic acid assays and manipulations: Sanger dideoxy sequencing using T7, Taq and Klenow DNA polymerase enzymes, random primed and nick translated DNA
- Probes generated as above were used in genomic hybridisations for single copy
- Biochem. 137, 266-267 (1984)) was selected as providing a stringent and representative test of radiolabelled organic compound stability and activity for the dNTPs: 5'end labelling was selected as the principal test for 32 P gamma-labelled ATP.
- RCP refers to the radiochemical purity of the sample
- SB, XY, AB and NC are Sulphorhodamine B,
- pABA is para-aminobenzoate.
- IAA is indoleacetic acid.
- 2ME is 2-mercaptoethanol and DTT is dithiothreitol.
- Storage conditions designated +40/RT/+4 indicate that the nucleotide was stored at +40oC for 24 hours, then at room temperature (RT; 21-24oC) for 48 hours before being stored at +4oC for the remainder of the test period.
- Control samples consist of Amersham International's current selling nucleotide formulation, without the addition of any further stabiliser or dye.
- the 32P labelled nucleotide (dCTP) was used at a specific activity of 3000 Ci/mmol and a concentration of 10 mCi/ml. 1 mCi lots were used for tests. Unless otherwise stated, the formulation used was an aqueous buffered diluent stabilised by 2-mercaptoethanol.
- Formulations containing the two dyes Sulphorhodamine B and Xylene Cyanol were made up and tested under different temperature storage conditions. Both dyes are seen to have a minor stabilising effect at +4oC.
- Formulations containing the stabiliser pABA K at the normal concentration of 50 mM and the dye New Coccine were tested.
- the dye was used at a final molarity of 3.5 ⁇ 10 -4 mol/l (equivalent to
- Sulphorhodamine B at 200 ⁇ g/ml). Storage was at RT, 37oC or 42-45oC for either 1, 2 or 3 days as indicated, to test the robustness of the dye. After this period, all pots were stored at +4oC for the remainder of the test period.
- Formulations containing two different dyes and two different stabilisers were tested. Both dyes were used at a concentration of 400 ⁇ g/ml.
- L-Tryptophan and potassium p-aminobenzoate were used at concentrations of 25 mM and 50 mM respectively.
- a formulation containing 50 mM pABA K + was stored at RT, 37oC or 42-45oC for either 1, 2 or 3 days to test the robustness of the stabiliser.
- Formulations containing different stabilisers were made up with and without 400 ⁇ g/ml of
- nucleotide used in testing was 35 S dATP at a concentration of 10 mCi/ml. All the stabilising compounds were used at a
- DTT Dithiothreitol
- radioactive concentration of the dCTP was 10 mCi/ml. All samples contained 5 mM 2-mercaptoethanol. Storage conditions were +40/RT/+4 except for the -20oC control.
- Formulations containing stabiliser and/or dye were tested on dATP (alpha-35S) nucleotide solutions which were at 10 mCi/ml radioactive concentration.
- the labelling on the table shows the stabiliser and/or dye present in each sample including their respective concentrations. Storage conditions were +40/RT/+4 except for the -20oC control.
- Stabilisers were tested on dATP (alpha 35S) nucleotide solutions. All the samples were pH 10.0 and the radioactive concentration was 10 mCi/ml. All samples contained 20 mM DTT. Storage conditions were +40/RT/+4, except for the first two controls which were stored at -20oC.
- Stabilisers were tested on 33P gamma-labelled ATP. All samples contained 0.1% 2-mercaptoethanol. The radioactive concentration was 5 mCi/ml. All samples were stored at +4oC except the one control sample stored at -20oC, (there was no temperature cycling).
- Stabilisers were tested on 35S labelled methionine. All samples contained 0.1% 2-mercaptoethanol. The radioactive concentration was 34 mCi/ml. All samples were stored at +4oC except the first Control sample which was stored at -20oC.
- the stabilisers provided some stabilisation compared with the RT control sample. All samples performed well. The 14C half-life is very long (5730 years) and because of this, 14C-labelled compounds would be expected to be more stable. Long-term stability studies would be expected to show that the samples containing stabilisers have a significant stability improvement compared with controls.
- stabilisers does not reduce the stability of L-(5-3H) Proline and (8-14C) ATP.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK93911868T DK0594837T4 (en) | 1992-04-30 | 1993-04-27 | Radiolabelled compound preparations |
AU42665/93A AU655548B2 (en) | 1992-04-30 | 1993-04-27 | Radiolabelled compound formulations |
JP05515158A JP3117719B2 (en) | 1992-04-30 | 1993-04-27 | Formulation of radiolabeled compounds |
EP93911868A EP0594837B2 (en) | 1992-04-30 | 1993-04-27 | Radiolabelled compound formulations |
CA002105402A CA2105402C (en) | 1992-04-30 | 1993-04-27 | Radiolabelled compound formulations |
DE69301300T DE69301300T3 (en) | 1992-04-30 | 1993-04-27 | FORMULATIONS OF RADIO-MARKED CONNECTIONS |
US08/107,733 US5494654A (en) | 1992-04-30 | 1993-04-27 | Radiolabelled compound formulations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92303905 | 1992-04-30 | ||
EP92303905.1 | 1992-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993022260A1 true WO1993022260A1 (en) | 1993-11-11 |
Family
ID=8211352
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1993/000869 WO1993022260A1 (en) | 1992-04-30 | 1993-04-27 | Radiolabelled compound formulations |
Country Status (10)
Country | Link |
---|---|
US (1) | US5494654A (en) |
EP (1) | EP0594837B2 (en) |
JP (1) | JP3117719B2 (en) |
AT (1) | ATE132842T1 (en) |
AU (1) | AU655548B2 (en) |
CA (1) | CA2105402C (en) |
DE (1) | DE69301300T3 (en) |
DK (1) | DK0594837T4 (en) |
ES (1) | ES2081717T5 (en) |
WO (1) | WO1993022260A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2727687A1 (en) * | 1994-12-02 | 1996-06-07 | Isotopchim Sarl | Stabilisation of radioactively marked organic cpds. |
WO1997001520A1 (en) * | 1995-06-28 | 1997-01-16 | E.I. Du Pont De Nemours And Company | Composition and method for stabilizing radiolabeled organic compounds |
WO1998055154A1 (en) * | 1997-06-03 | 1998-12-10 | Coulter Pharmaceutical, Inc. | Radioprotectant for peptides labeled with radioisotope |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5686058A (en) * | 1992-04-30 | 1997-11-11 | Amersham International Plc | Radiolabelled nucleotide formulations stored in an unfrozen state |
HU225723B1 (en) * | 2001-03-21 | 2007-07-30 | Izotop Intezet Kft | Method for covering of plastic material |
HUP0101921A2 (en) * | 2001-05-10 | 2004-01-28 | Izotóp Intézet Kft | Radiolabelled nucleotid containing preparations and process for producing thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4390517A (en) * | 1979-12-19 | 1983-06-28 | New England Nuclear Corporation | Method, composition and kit for stabilizing radiolabeled compounds |
US4411881A (en) * | 1982-07-12 | 1983-10-25 | New England Nuclear Corporation | Composition and method for stabilizing radiolabeled compounds using thiocarbonylated diethylenetriamines |
US4451451A (en) * | 1981-10-30 | 1984-05-29 | Amersham International Plc | Radiopharmaceutical composition based on technetium-99m and reagent for making it |
US4793987A (en) * | 1985-04-26 | 1988-12-27 | Amersham International Plc | Stabilized radiolabelled compounds |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3261747A (en) * | 1964-05-08 | 1966-07-19 | Spencer L Commerford | Stabilized iodine labeled 2'-deoxy-5-iodouridine |
US3673410A (en) * | 1969-06-25 | 1972-06-27 | John H Waite | Method of examination of cell samples using a radioactively tagged dye |
US4095950A (en) * | 1976-06-11 | 1978-06-20 | Bio-Dynamics, Inc. | Method for the chromatographic analysis of a technetium-containing mixture |
JPS59125062A (en) * | 1982-12-29 | 1984-07-19 | Toshiba Corp | Column type immunoanalysis method |
JPS6132291A (en) * | 1984-07-24 | 1986-02-14 | Sony Corp | Memory device |
US4966854A (en) * | 1986-02-12 | 1990-10-30 | Linus Pauling Institute Of Science And Medicine | Radio labelled dye composition for detecting proteins in gels |
US5101020A (en) * | 1986-02-12 | 1992-03-31 | Linus Pauling Institute Of Science And Medicine | Novel radio labeled dyes for detecting proteins in gels |
JPS63118661A (en) * | 1986-11-07 | 1988-05-23 | Hitachi Ltd | Nucleic acid base sequence determination instrument |
JPH0235100U (en) * | 1988-08-30 | 1990-03-06 | ||
US4880615A (en) * | 1988-11-25 | 1989-11-14 | Merck & Co., Inc. | Stabilized radiopharmaceutical compositions |
US5262175A (en) * | 1989-05-10 | 1993-11-16 | Solanki Kishor K | Stabilization of radiopharmaceutical compositions |
US5093105A (en) * | 1991-04-09 | 1992-03-03 | Merck Frosst Canada, Inc. | Radiopharmaceutical bacteriostats |
-
1993
- 1993-04-27 US US08/107,733 patent/US5494654A/en not_active Expired - Lifetime
- 1993-04-27 DE DE69301300T patent/DE69301300T3/en not_active Expired - Lifetime
- 1993-04-27 EP EP93911868A patent/EP0594837B2/en not_active Expired - Lifetime
- 1993-04-27 WO PCT/GB1993/000869 patent/WO1993022260A1/en active IP Right Grant
- 1993-04-27 JP JP05515158A patent/JP3117719B2/en not_active Expired - Lifetime
- 1993-04-27 CA CA002105402A patent/CA2105402C/en not_active Expired - Lifetime
- 1993-04-27 AU AU42665/93A patent/AU655548B2/en not_active Expired
- 1993-04-27 DK DK93911868T patent/DK0594837T4/en active
- 1993-04-27 ES ES93911868T patent/ES2081717T5/en not_active Expired - Lifetime
- 1993-04-27 AT AT93911868T patent/ATE132842T1/en active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4390517A (en) * | 1979-12-19 | 1983-06-28 | New England Nuclear Corporation | Method, composition and kit for stabilizing radiolabeled compounds |
US4451451A (en) * | 1981-10-30 | 1984-05-29 | Amersham International Plc | Radiopharmaceutical composition based on technetium-99m and reagent for making it |
US4411881A (en) * | 1982-07-12 | 1983-10-25 | New England Nuclear Corporation | Composition and method for stabilizing radiolabeled compounds using thiocarbonylated diethylenetriamines |
US4793987A (en) * | 1985-04-26 | 1988-12-27 | Amersham International Plc | Stabilized radiolabelled compounds |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 111, no. 11, 11 September 1989, Columbus, Ohio, US; abstract no. 93463b, K. NAGAI 'APPARATUS FOR BASE SEQUENCE DETERMINATION IN NUCLEIC ACIDS' page 388 ;column 1 ; * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2727687A1 (en) * | 1994-12-02 | 1996-06-07 | Isotopchim Sarl | Stabilisation of radioactively marked organic cpds. |
WO1997001520A1 (en) * | 1995-06-28 | 1997-01-16 | E.I. Du Pont De Nemours And Company | Composition and method for stabilizing radiolabeled organic compounds |
US5738836A (en) * | 1995-06-28 | 1998-04-14 | E. I. Du Pont De Nemours And Company | Composition for stabilizing radiolabeled organic compounds |
US5843396A (en) * | 1995-06-28 | 1998-12-01 | Nen Life Science Products, Inc. | Method for stabilizing radiolabeled organic compounds by adding a separate stabilizing compound |
WO1998055154A1 (en) * | 1997-06-03 | 1998-12-10 | Coulter Pharmaceutical, Inc. | Radioprotectant for peptides labeled with radioisotope |
US5961955A (en) * | 1997-06-03 | 1999-10-05 | Coulter Pharmaceutical, Inc. | Radioprotectant for peptides labeled with radioisotope |
US6338835B1 (en) | 1997-06-03 | 2002-01-15 | Coulter Pharmaceutical, Inc. | Radioprotectant for peptides labeled with radioisotope |
Also Published As
Publication number | Publication date |
---|---|
EP0594837B1 (en) | 1996-01-10 |
DE69301300D1 (en) | 1996-02-22 |
AU655548B2 (en) | 1994-12-22 |
JP3117719B2 (en) | 2000-12-18 |
US5494654A (en) | 1996-02-27 |
DE69301300T3 (en) | 2000-07-27 |
JPH06502729A (en) | 1994-03-24 |
AU4266593A (en) | 1993-11-29 |
CA2105402A1 (en) | 1993-10-31 |
DK0594837T4 (en) | 2000-03-27 |
EP0594837A1 (en) | 1994-05-04 |
DE69301300T2 (en) | 1996-05-23 |
ATE132842T1 (en) | 1996-01-15 |
DK0594837T3 (en) | 1996-04-09 |
EP0594837B2 (en) | 1999-12-08 |
CA2105402C (en) | 2000-04-04 |
ES2081717T5 (en) | 2000-02-16 |
ES2081717T3 (en) | 1996-03-16 |
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