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"Automated Method"

Abstract: The present invention provides an automated method for the preparation of 99mTc radiopharmaceutical compositions, together with disposable cassettes for use in the method. The use of an automated synthesizer apparatus in the preparation of 99mTc radiopharmaceuticals is also described. Also described is the use of kits for the preparation of 99mTc radiopharmaceuticals in the method and disposable cassettes of the present invention.

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Patent Information

Application #
Filing Date
28 March 2008
Publication Number
27/2008
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

GE HEALTHCARE LIMITED
AMERSHAM PLACE, LITTLE CHALFTONT, BUCKINGHAMSHIRE HP79NA, ENGLAND.

Inventors

1. NIGEL ANTHONY POWELL
GE HEALTHCARE LIMITED, THE GROVE CENTRE, WHITE LION ROAD, AMERSHAM, BUCKINGHAMSHIRE HP7 9LL, GREAT BRITAIN.
2. PETER STEWART WEISNER
GE HEALTHCARE LIMITED, THE GROVE CENTRE, WHITE LION ROAD, AMERSHAM, BUCKINGHAMSHIRE HP7 9LL, GREAT BRITAIN.
3. IAN ANTHONY SARGEANT
GE HEALTHCARE LIMITED, THE GROVE CENTRE, WHITE LION ROAD, AMERSHAM, BUCKINGHAMSHIRE HP7 9LL, GREAT BRITAIN.
4. TORGRIM ENGELL
GE HEALTHCARE AS, NYCOVEIEN 2, POSTBOKS 4220, N-0401 OSLO, NORWAY.
5. JOHN HENRIK JOHANSEN
GE HEALTHCARE AS, NYCOVEIN 2, POSTBOKS 4220, N-0401 OSLO, NORWAY.

Specification

Automated Method, Field of the Invention., The present invention provides an automated method for the preparation of 99mTc radiopharmaceutical compositions, together with disposable cassettes for use in the method. The use of an automated synthesizer apparatus in the preparation of 99mTc radiopharmaceuticals is also described. Also described is the use of kits for the preparation of 99mTc radiopharmaceuticals in the method and disposable cassettes of the present invention. Background to the Invention. Automated methods for the preparation of radiopharmaceuticals which comprise a positron-emitting radioisotope for positron emission tomography (PET) are well-established [D.Alexoff, in "Handbook of Radiopharmaceuticals", M.J.Welch & C.S.Redvanly (Eds.), pages 283-305 Wiley (2003)]. WO 02/051447 describes an automated synthesizer apparatus for the preparation of radiopharmaceuticals, which incorporates a disposable module containing pre-metered amounts of chemical reagents. The device is said to be particularly useful for the short half-life positron-emitting radioisotopes 11C, 13N, 15O and 18F. For 99m Tc radiopharmaceuticals, the conventional wisdom developed over many years is that the user obtains a sterile supply of 99mTc as 99mTc-pertechnetate in saline from a 99Mo/ 9mTc radioisotope generator, and uses that radioactive eluate to reconstitute lyophilised, non-radioactive kits to generate the desired radiopharmaceutical directly in a ready-to-inject form. These steps are typically carried out manually, although efforts have been made to investigate automated radiopharmaceutical dispensing (APD) [Solanki, Hosp.Pharmac., 7(4), 94-98 (2000)]. Automated elution of 99Mo/99mTc radioisotope generators is described in US 4,625,118 and US 5,580,541. Fisco et al [Lab.RobotAutomat., 6(4), 159-165 (1994)] disclosed the use of a robotic system for the automated kit reconstitution and quality control of the 99mTc radiopharmaceutical Cardiotec™. Ensing [Dev.Nucl.Med., 22, 49-54 (1992)] reviewed efforts to automate radiopharmaceutical kit preparations in hospital radiopharmacies, including automated reconstitution of non-radioactive kits. Prior art approaches have therefore focused on either the automated reconstitution of either 99mTc generators or 99mTc kits, always with the conventional kit as the basis for the chemistry involved. This has the drawback that, if multiple doses are required on a regular basis, the only option is to process large numbers of kits, with each kit requiring a separate QC check on radiochemical purity (RCP), This means that the same process steps may need to be replicated many times over, which is inefficient, and that the volume and number of containers and apparatus made radioactive as a result of the operations is relatively high. Whilst automation is recognised as having the potential to reduce operator radiation dose, prior art automated processes have also been reported to be much slower than the manual counterpart, which makes them less attractive [Solanki, Hosp.Pharmac., 7(4), 94-98 (2000)]. There is therefore a need for an automated approach which is fast, more flexible, less constrained by existing kit chemistry, and which can generate larger batch sizes in a more efficient manner. The Present Invention. The present invention provides an automated method for the preparation of 99mTc radiopharmaceutical compositions, together with disposable cassettes for use in the method. The method is particularly suitable for use in conjunction with "automated synthesizer" apparatus which are commercially available, but currently used primarily for the preparation of short-lived PET radiopharmaceuticals. The method is particularly useful where large numbers of unit patient doses are required on a regular basis, such as in a radiopharmacy serving either multiple hospitals or a single large hospital. This permits a single determination of RCP. The present invention also permits the preparation of sterile 99mTc radiopharmaceuticals which are not amenable to preparation via the conventional kit approach, due to eg. the need to use non-aqueous solvents or where undesirable non-biocompatible impurities cannot easily be removed within the ambit of the kit approach. The method can be readily adapted to use 99Mo-raolybdate in solution as the source of 99mTc-pertechnetate, as opposed to the conventional 99Mo/99mTc generator. The use of a radioactive starting material in solution makes automation of the processes involved more straightforward, and thus avoids the complexities of the prior art needed to automate generator elution. The cassettes of the present invention contain the non-radioactive chemicals necessary for a given 99mTc radiopharmaceutical preparation, and may optionally also include the necessary radioactive precursor chemicals. These cassettes make the present method more flexible than prior art approaches. Use of the cassettes in the preparation of 99mTc radiopharmaceuticals is also described. The present invention also provides the use of automated synthesizer apparatus for 99mTc radiopharmaceutical preparation, plus the use of sterile, non-radioactive kits in the present claimed method of preparation. Detailed Description of the Invention. In a first aspect, the present invention provides an automated method for the preparation of a sterile, 99mTc radiopharmaceutical composition which comprises a 9 mTc metal complex in a biocompatible carrier medium, wherein said method comprises: (i) provision of a precursor which comprises a solution of 99mTc- pertechnetate; (ii) provision of a supply of a non-radioactive ligand, wherein said ligand forms a metal complex with 99mTc; (iii) provision of a supply of a reductant capable of reducing technetium from the Tc(VII) oxidation state to a lower technetium oxidation state; (iv) complexation of the ligand with 99mTc by microprocessor-controlled transfer of separate aliquots of said precursor and ligand to a reaction vessel and mixing therein, with optional heating, and optionally in the presence of an amount of said reductant effective to reduce said aliquot of 99rnTc-pertechnetate precursor; (v) when the 99mTc complex product from step (iv) is already in a biocompatible carrier medium it is used directly in step (vi), otherwise the product of step (iv) is either dissolved in a biocompatible carrier medium or the solvent used in step (iv) is removed and the residue re-dissolved in a biocompatible carrier medium; (vi) optionally carrying out one or more of the following additional processes: purification; pH adjustment; solvent removal and re-dissolution in a biocompatible solvent to give the desired 99mTc radiopharmaceutical composition; (vii) either maintaining sterility during steps (i) to (vi) so that the mTc metal complex from step (vi) is already sterile, or subjecting the9 mTc metal complex from step (vi) to either terminal sterilisation or sterile filtration to give the desired 99mTc-radiopharmaceutical. The "biocompatible carrier medium" is a fluid, especially a liquid, in which the 99mTc metal complex is suspended or dissolved, such that the composition is physiologically tolerable, ie. can be administered to the mammalian body without toxicity or undue discomfort. The biocompatible carrier medium is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (eg. salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (eg. sorbitol or mannitol), glycols (eg. glycerol), or other non-ionic polyol materials (eg. polyethyleneglycols, propylene glycols and the like). The biocompa.tible carrier medium may also comprise biocompatible organic solvents such as ethanol. Such organic solvents are useful to solubilise more lipophilic compounds or formulations. Preferably the biocompatible carrier medium is pyrogen-free water for injection, isotonic saline or an aqueous ethanol solution. As indicated above, the pH of the biocompatible carrier medium for intravenous injection is suitably in the range 4.0 to 10.5. The term "microprocessor-controlled" has its conventional meaning. Thus, the term "microprocessor" as used herein, refers to a computer processor contained on an integrated circuit chip, such a processor may also include memory and associated circuits. The microprocessor is designed to perform arithmetic and logic operations using logic circuitry that responds to and processes the basic instructions that drive a computer. The microprocessor may also include programmed instructions to execute or control selected functions, computational methods, switching, etc. Microprocessors and associated devices are commercially available from a number of sources, including, but not limited to: Cypress Semiconductor Corporation, San Jose, California; IBM Corporation; Applied Microsystems Corporation, Redmond, Washington, USA; Intel Corporation and National Semiconductor, Santa Clara, California. With regard to the present invention, the microprocessor provides a programmable series of reproducible steps involving eg. transfer of chemicals, heating, filtration etc. The microprocessor of the present invention also preferably records batch production data (eg. reagents used, reaction conditions, radioactive materials etc). This recorded data is useful to demonstrate GMP compliance for radiopharmaceutical manufacture. The microprocessor is also preferably linked to a barcode reader to permit facile selection of reaction conditions for a given production run, as described below. The term "oxidation state" has its conventional meaning in inorganic chemistry. By the term "lower technetium oxidation state" is meant Tc(-I) to Tc(VI). Preferred oxidation states for the ligand metal complex with 99mTc are in the range Tc(0) to Tc(V), and are most preferably chosen from Tc(I), Tc(III) and Tc(V). Technetium complexes of ligands having an oxidation state Tc(VII) are, however, known. For such complexes a reductant may not be necessary. For technetium complexes of oxidation state Tc(-I) to Tc(VI), the reductant is expected to be an essential feature of the method of the present invention. The oxidation state of the technetium in 99mTc-pertechnetate is Tc(VII). The "reductant" of the present invention is suitable for reduction of Tc(VII) pertechnetate to lower oxidation states of technetium, ie. the oxidation state of technetium in the metal complex of 99mTc with the ligand. Suitable such reductants are known in the art [Clarke, Coord Chem. Rev., 78, 253-331 (1987) and references therein]. It is also envisaged that the reduction could be carried out using an electrolytic cell, which could form an additional feature of the cassette of the present invention. Such electrolytic cells have the advantage of providing controlled reduction conditions, with the need to add chemical reductants. The reductant of the present invention does not have to be biocompatible, since the flexibility of the method means that non-biologically compatible reductants can subsequently be removed. Biocompatible reductants are, however, preferred. By the term ''biocompatible reductant" is meant a reducing agent suitable for reduction of Tc(VII) pertechnetate to lower oxidation states of technetium, which is non-toxic at the required dosage and hence suitable for administration to the mammalian body, especially the human body. Suitable such reductants include: sodium dithionite, sodium bisulphite, ascorbic acid, formamidine sulphinic acid, stannous ion, Fe(II) or Cu(I). The biocompatible reductant is preferably a stannous salt such as stannous chloride or stannous tartrate. The reductant of the present invention may be supplied in solid (eg. lyophilised) or solution form. When used hi solid form, a known amount of reductant is suitably provided in a vial or container, and dissolved in a suitable solvent prior to use, as part of the automated method. When used in solution form, this has the advantage that the reductant concentration is known and hence the microprocessor-controlled delivery of the right amount of reductant simplifies to the delivery of a specific volume or aliquot of reductant solution. The reductant solution is preferably in a biocompatible carrier medium, as defined above. Sterile solutions of stannous in biocompatible carrier media are expected to be sufficiently stable in the absence of air in a suitable container to have a useful shelf-life for use in the cassette of the present invention. The term "ligand" as used herein has its conventional meaning in inorganic chemistry, ie. a compound which forms a complex with a metal, in this instance technetium. By the term "metal complex" is meant a coordination complex of the metal ion with one or more ligands. It is strongly preferred that the technetium metal complex is "resistant to transchelation", ie. does not readily undergo ligand exchange with other potentially competing ligands for the 99mTc coordination sites. Potentially competing ligands include other excipients in the preparation in vitro (eg. radioprotectants, antimicrobial preservatives or sterilising agents such as alcohols used in the preparation), or endogenous compounds in vivo (eg. glutathione, transferrin or plasma proteins). Suitable ligands for use in the present invention which form technetium complexes resistant to transchelation include: chelating agents, where 2-6, preferably 2-4, metal donor atoms are arranged such that chelate rings result (by having a non- coordinating backbone of either carbon atoms or non-coordinating heteroatoms linking the metal donor atoms), preferably 5- or 6-membered chelate rings; or monodentate ligands which comprise donor atoms which bind strongly to the technetium, such as carbon monoxide (CO), isonitriles, phosphines, thiols or diazenides. Examples of donor atom types which bind well to technetium as part of chelating agents are: amines, thiols, amides, oximes and phosphines. Phosphines form such strong metal complexes that even monodentate or bidentate phosphines form suitable technetium complexes. The linear geometry of isonitriles and dia/enides is such that they do not lend themselves readily to incorporation into chelating agents, and are hence typically used as monodentate ligands. Examples of suitable isonitriles include simple alkyl isonitriles such as tert-butylisonitrile, and ether-substituted isonitriles such as mibi (i.e. l-isocyano-2-methoxy-2-methylpropane). Examples of suitable phosphines include Tetrofosmin, and monodentate phosphines such as tris(3-methoxypropyl)phosphine. Examples of suitable diazenides include the HYNIC series of ligands i.e. hydrazine-substituted pyridines or nicotinamides. Examples of suitable chelating agents for technetium which form metal complexes resistant to transchelation include, but are not limited to: (i) diaminedioximes of formula: (Formula Removed) where E1-E6 are each independently an R' group; each R' is H or C1-10 alkyl, C3-10 alkylaryl, C2-10alkoxyalkyl, C1-10hydroxyalkyl5 C1-10 fluoroalkyl, C2-10 carboxyalkyl or C1-10aminoalkyl, or two or more R' groups together with the atoms to which they are attached form a carbocyclic, heterocyclic, saturated or unsarurated ring; and Q is a bridging group of formula -(J)r ; where f is 3, 4 or 5 and each J is independently --O-, -NR'- or -C(R')i- provided that -(J)f- may contain a maximum of one J group which is— O- or -NR'-. Preferred Q groups are as follows: Q = -(CH2)(CHR')(CH2)- ie. propyleneamine oxime or PnAO derivatives; Q = -(CH2)2(CHR')(CH2)2- ie. pentyleneamine oxime or PentAO derivatives; Q = -(CH2)2NR'(CH2)2-. E1 to E6 are preferably chosen from: Ci-3 alky'l, alkylaryl alkoxyalkyl, hydroxyalkyl, fluoroalkyl, carboxyalkyl or aminoalkyl. Most preferably, each E! to E6 group is CH3. Q is preferably -(CH2)(CHR')(CH2)- , -

Documents

Application Documents

# Name Date
1 2589-DELNP-2008-AbandonedLetter.pdf 2017-04-08
1 2589-DELNP-2008-Form-3-(22-07-2010).pdf 2010-07-22
2 2589-DELNP-2008_EXAMREPORT.pdf 2016-06-30
2 2589-DELNP-2008-Correspondence-Others-(22-07-2010).pdf 2010-07-22
3 2589-delnp-2008-pct-304.pdf 2011-08-21
3 2589-delnp-2008-Correspondence Others-(14-08-2012).pdf 2012-08-14
4 2589-delnp-2008-pct-237.pdf 2011-08-21
4 2589- delnp-2008-Correspondence-Others-(06-03-2012).pdf 2012-03-06
5 2589-delnp-2008-pct-220.pdf 2011-08-21
5 2589-DELNP-2008-Correspondence-Others-(17-02-2012).pdf 2012-02-17
6 2589-delnp-2008-pct-210.pdf 2011-08-21
6 2589-DELNP-2008-Form-3-(17-02-2012).pdf 2012-02-17
7 2589-delnp-2008-pct-101.pdf 2011-08-21
7 2589-delnp-2008-abstract.pdf 2011-08-21
8 2589-delnp-2008-gpa.pdf 2011-08-21
8 2589-delnp-2008-claims.pdf 2011-08-21
9 2589-delnp-2008-form-5.pdf 2011-08-21
9 2589-delnp-2008-correspondence-others.pdf 2011-08-21
10 2589-delnp-2008-description (complete).pdf 2011-08-21
10 2589-delnp-2008-form-3.pdf 2011-08-21
11 2589-delnp-2008-form-1.pdf 2011-08-21
11 2589-delnp-2008-form-2.pdf 2011-08-21
12 2589-DELNP-2008-Form-18.pdf 2011-08-21
13 2589-delnp-2008-form-1.pdf 2011-08-21
13 2589-delnp-2008-form-2.pdf 2011-08-21
14 2589-delnp-2008-description (complete).pdf 2011-08-21
14 2589-delnp-2008-form-3.pdf 2011-08-21
15 2589-delnp-2008-correspondence-others.pdf 2011-08-21
15 2589-delnp-2008-form-5.pdf 2011-08-21
16 2589-delnp-2008-claims.pdf 2011-08-21
16 2589-delnp-2008-gpa.pdf 2011-08-21
17 2589-delnp-2008-abstract.pdf 2011-08-21
17 2589-delnp-2008-pct-101.pdf 2011-08-21
18 2589-DELNP-2008-Form-3-(17-02-2012).pdf 2012-02-17
18 2589-delnp-2008-pct-210.pdf 2011-08-21
19 2589-DELNP-2008-Correspondence-Others-(17-02-2012).pdf 2012-02-17
19 2589-delnp-2008-pct-220.pdf 2011-08-21
20 2589-delnp-2008-pct-237.pdf 2011-08-21
20 2589- delnp-2008-Correspondence-Others-(06-03-2012).pdf 2012-03-06
21 2589-delnp-2008-pct-304.pdf 2011-08-21
21 2589-delnp-2008-Correspondence Others-(14-08-2012).pdf 2012-08-14
22 2589-DELNP-2008_EXAMREPORT.pdf 2016-06-30
22 2589-DELNP-2008-Correspondence-Others-(22-07-2010).pdf 2010-07-22
23 2589-DELNP-2008-Form-3-(22-07-2010).pdf 2010-07-22
23 2589-DELNP-2008-AbandonedLetter.pdf 2017-04-08