WO2016087653A1 - Method of removing acetaldehyde from radioactive pharmaceuticals - Google Patents

Method of removing acetaldehyde from radioactive pharmaceuticals Download PDF

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Publication number
WO2016087653A1
WO2016087653A1 PCT/EP2015/078682 EP2015078682W WO2016087653A1 WO 2016087653 A1 WO2016087653 A1 WO 2016087653A1 EP 2015078682 W EP2015078682 W EP 2015078682W WO 2016087653 A1 WO2016087653 A1 WO 2016087653A1
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Prior art keywords
acetaldehyde
pharmaceutical
radioactive
aldehyde scavenger
composition according
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Ceased
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PCT/EP2015/078682
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French (fr)
Inventor
Torgrim Engell
Julian Grigg
Dimitrios Mantzilas
Dag M EVJE
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GE Healthcare Ltd
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GE Healthcare Ltd
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Priority to US15/532,938 priority Critical patent/US10660966B2/en
Priority to KR1020227036371A priority patent/KR102668112B1/en
Priority to KR1020177014839A priority patent/KR102458116B1/en
Priority to AU2015356971A priority patent/AU2015356971B2/en
Priority to BR112017010484-9A priority patent/BR112017010484B1/en
Priority to JP2017527839A priority patent/JP6842415B2/en
Priority to CN201580065805.7A priority patent/CN106999603B/en
Priority to EP15816682.7A priority patent/EP3226884B1/en
Application filed by GE Healthcare Ltd filed Critical GE Healthcare Ltd
Priority to RU2017116966A priority patent/RU2719399C2/en
Publication of WO2016087653A1 publication Critical patent/WO2016087653A1/en
Priority to IL252186A priority patent/IL252186B/en
Anticipated expiration legal-status Critical
Priority to US16/849,881 priority patent/US11389538B2/en
Priority to US17/838,638 priority patent/US11964020B2/en
Ceased legal-status Critical Current

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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
    • A61K51/02—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/082—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being a RGD-containing peptide
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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

Definitions

  • the present invention relates to methods for removing or controlling the formation of aldehydes, and for their quantification.
  • the present invention relates to a method for removing and/or controlling and/or quantifying the formation of acetaldehyde.
  • Acetaldehyde is often found in the final formulation of a radioactive pharmaceutical. The rate of acetaldehyde formation increases with increased radioactivity. There are several sources for formation of acetaldehyde; ethanol is one of the most important sources. Acetaldehyde is most likely formed by oxidation of ethanol. This oxidation increases in a radioactive environment. In a worst case scenario formation of acetaldehyde might limit the maximum possible radiochemical concentration (RAC) and hence both the number of patient doses and product shelf- life. Further, acetaldehyde levels increase in time over the shelf-life of a radioactive pharmaceutical. As such, the level of acetaldehyde cannot be controlled by the manufacturing process of the radioactive pharmaceutical itself.
  • RAC radiochemical concentration
  • the present invention provides a method of quantifying and/or removing and/or controlling the level of acetaldehyde to be within acceptable limits (i.e. 120 ⁇ g/10 ⁇ ; Muller et al, Regulatory Toxicology and Pharmacology, 44, (2006), 198- 211) in a final radioactive pharmaceutical formulation.
  • the present invention provides a method of quantifying and/or removing and/or controlling the level of acetaldehyde during a radioactive pharmaceutical's shelf- life by introducing an aldehyde scavenger.
  • the present method of the invention may also be used to measure and remove other by-products (e.g. other aldehydes, ketones) found in final radioactive pharmaceutical formulation.
  • the method of the invention can specifically by used for determination for quality control (QC) purposes of trace amounts of acetaldehyde in radioactive pharmaceutical formulations as an alternative to gas chromatography (GC).
  • QC quality control
  • GC gas chromatography
  • Measurement of residual acetaldehyde by GC is complicated by the presence of ethanol in pharmaceutical formulations due to its relatively large peak, and the method of the present invention overcomes this problem. It can also be used for determination of acetaldehyde in ethanol. Derivatives arriving from reaction between amino xy and aldehyde or ketone can be designed to be a molecule which will increase both sensitivity and separation.
  • the level of acetaldehyde in a method of the invention By quantifying and/or removing and/or controlling the formation of acetaldehyde by a method of the invention, the level of acetaldehyde in a
  • RAC radiochemical concentration
  • the present invention permits simplification and improvement for quality control (QC)-methods for determination of trace amounts of aldehydes and ketones found in various pharmaceutical formulations.
  • Figure 1 shows the effect on RCP of the Fluciclatide ( 18 F) Injection, by quench with aldehyde scavenger AH111695.
  • the present invention provides a method for quantifying and/or removing and/or controlling acetaldehyde formation in a pharmaceutical formulation.
  • the present invention provides a method comprising the step of combining an aldehyde scavenger with a pharmaceutical formulation.
  • the present invention provides a method comprising the step of combining an aldehyde scavenger with a pharmaceutical formulation wherein the pharmaceutical formulation comprises a radioactive pharmaceutical and a solvent.
  • the present invention provides a composition comprising an aldehyde scavenger, a radioactive pharmaceutical and a solvent.
  • the aldehyde scavenger may be any molecule that has an amino-oxy terminus.
  • the amino-oxy functional group is known to be extremely reactive allowing near full conversion of e.g. acetone in a concentration of 1 ppm at room temperature.
  • the aldehyde scavenger can quantify and/or control acetaldehyde levels and/or thereby permit removal of acetaldehyde from a pharmaceutical formulation until the levels are within acceptable industry standard limits.
  • the aldehyde scavenger can equally be applied to other by-products (e.g. other aldehydes such as fluorobenzaldehyde (FBA), ketones) found in a pharmaceutical formulation.
  • FBA fluorobenzaldehyde
  • the aldehyde scavenger is the following compound (herein also referred to as "AH111695"; Mol. Wt. 1709.92):
  • the acetaldehyde scavenger may be presented to the pharmaceutical formulation in a variety of manners.
  • the acetaldehyde scavenger may be presented to the pharmaceutical formulation in a variety of manners.
  • the acetaldehyde scavenger may be presented to the pharmaceutical formulation in a variety of manners.
  • acetaldehyde scavenger may be presented as:
  • the aldehyde scavenger may also be added as an excipient in a pre-made formulation vial.
  • Radioactive pharmaceuticals such as PET tracers are commonly transferred off an automated synthesis machine (e.g.
  • the aldehyde scavenger can be a part of this pre-filled formulation vial as an excipient.
  • the aldehyde scavenger may also be added as an excipient to a clinical vial.
  • the pharmaceutical formulation, as described herein, is dispensed into different vials after formulation. If the aldehyde scavenger is solid particles, it cannot be dispensed since this dispensing includes sterile filtration. The solution to this is to present the scavenger as an excipient in the clinical vial (patient vial).
  • the imines formed in a reaction between an amino xy and an aldehyde can be detected down to below 0.2 ⁇ g/ml equal to 0.1 nanomol e.g. for the PET tracer fluciclatide described herein by UV (the sensitivity by mass spectrometry would be even higher).
  • the obtained molecule 3 can be analysed either by GC or HPLC. Separation of 3 from 2 is regarded as simple because of the great difference in polarity.
  • AHl 11930 illustrated below is the product between the aldehyde scavenger AHl 11695 described herein and acetaldehyde:
  • AHl 11930 is formed during synthesis of fluciclatide described herein and is found in the crude reaction mixture in various amounts depending on the content of acetaldehyde e.g. in the ethanol used during process. AHl 11930 is typically reduced less to than 1-2 ⁇ / ⁇ 1 over the final purification step. The amount of AH111930 in the final product is determined by the QC HPLC method during release of
  • AH111930 quantified and compared with release analysis.
  • AH111930 might have a response at 216 nm lower than fluciclatide used as standard, but the response ratio between the two can be determined and AH111585 still be used as the standard.
  • a pharmaceutical formulation shall refer to any final radioactive pharmaceutical formulation.
  • the pharmaceutical formulation is in a form suitable for mammalian administration, by which is meant a formulation which is sterile, pyrogen- free, lacks compounds which produce toxic or adverse effects, and is formulated at a biocompatible pH (approximately pH 4.0 to 10.5).
  • Such formulations lack particulates which could risk causing emboli in vivo, and are formulated so that precipitation does not occur on contact with biological fluids (e.g. blood).
  • biological fluids e.g. blood
  • Such formulations also contain only biologically compatible excipients, and are preferably isotonic.
  • a pharmaceutical formulation comprises a radioactive pharmaceutical and a solvent, each as described herein.
  • a pharmaceutical formulation may be made by any means known in the art including, but not limited to, automated synthesis machines (e.g. FASTlabTM).
  • a radioactive pharmaceutical may comprise any radio labelled compound suitable for in vitro or in vivo imaging.
  • said radio labelled compound is suitable for in vivo imaging.
  • a radioactive pharmaceutical is suitably provided in a form suitable for mammalian administration, and assists in providing clearer images in the region or organ of interest than could be obtained by imaging the mammalian subject alone.
  • the radioactive pharmaceutical is a positron emission tomography (PET) tracer.
  • PET positron emission tomography
  • the radioactive pharmaceutical is a 18 F PET tracer.
  • suitable 18 F PET tracers include, but are not limited to, [ 18 F]fluciclatide, [ 18 F]flutemetamol, and [ 18 F]GE180:
  • the 18 F PET tracer is [ 18 F] flutametamol.
  • [ 18 F]GE180 are described in WO 2010109007 A2, WO 2011117421 Al and WO 2012080349 Al .
  • the 18 F PET tracer is [ 18 F]GE180.
  • the solvent can comprise any organic solvent known in the art suitable for use in a pharmaceutical formulation.
  • the solvent comprises an alcohol.
  • the solvent is ethanol, isopropanol or a bioalcohol.
  • the solvent is ethanol.
  • the deviation between the HPLC and GC results is due to the higher sensitivity of the HPLC method over the GC method.
  • the results indicate a complete quench of acetaldehyde was achieved by the addition of the aldehyde scavenger AHl 11695.
  • the quenched sample of Fluciclatide ( 18 F) Injection was also analysed for the content of the radio impurity 4-[ 18 F]fluorobenzaldehyde ([ 18 F]FBA) and the results were compared with an unquenched sample.
  • the results showed that aldehyde scavenger AHl 11695 reacted with [ 18 F]FBA to form [ 18 F] fluciclatide removing the [ 18 F]FBA radio impurity from the product.
  • Figure 1 clearly demonstrates the efficacy of the method in controlling aldehyde formation: (1) bottom trace is Fluciclatide ( 18 F) Injection quenched with aldehyde scavenger AHl 11695 after 9 hours; (2) middle trace is a blank; and (3) the top trace is Fluciclatide ( 18 F) Injection unquenched i.e., without addition of aldehyde scavenger AHl 11695, after 9 hours.

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Abstract

A method for removing or controlling or quantifying the presence of aldehydes, in particular acetaldehyde, is described. Such a method is useful in prolonging the shelf life of a pharmaceutical product.

Description

METHOD OF REMOVING ACETALDEHYDE FROM RADIOACTIVE PHARMACEUTICALS
FIELD OF THE INVENTION
The present invention relates to methods for removing or controlling the formation of aldehydes, and for their quantification. In particular, the present invention relates to a method for removing and/or controlling and/or quantifying the formation of acetaldehyde.
BACKGROUND OF THE INVENTION
Acetaldehyde is often found in the final formulation of a radioactive pharmaceutical. The rate of acetaldehyde formation increases with increased radioactivity. There are several sources for formation of acetaldehyde; ethanol is one of the most important sources. Acetaldehyde is most likely formed by oxidation of ethanol. This oxidation increases in a radioactive environment. In a worst case scenario formation of acetaldehyde might limit the maximum possible radiochemical concentration (RAC) and hence both the number of patient doses and product shelf- life. Further, acetaldehyde levels increase in time over the shelf-life of a radioactive pharmaceutical. As such, the level of acetaldehyde cannot be controlled by the manufacturing process of the radioactive pharmaceutical itself.
Thus there exists a need in the art for a method of quantifying and/or removing and/or controlling the formation of acetaldehyde in order to ensure that acetaldehyde levels remain within acceptable limits in order to prolong the shelf life of the radioactive pharmaceutical. The present invention answers such a need. SUMMARY OF THE INVENTION
The present invention provides a method of quantifying and/or removing and/or controlling the level of acetaldehyde to be within acceptable limits (i.e. 120 μg/10 μΐ; Muller et al, Regulatory Toxicology and Pharmacology, 44, (2006), 198- 211) in a final radioactive pharmaceutical formulation. In particular, the present invention provides a method of quantifying and/or removing and/or controlling the level of acetaldehyde during a radioactive pharmaceutical's shelf- life by introducing an aldehyde scavenger. The present method of the invention may also be used to measure and remove other by-products (e.g. other aldehydes, ketones) found in final radioactive pharmaceutical formulation.
The method of the invention can specifically by used for determination for quality control (QC) purposes of trace amounts of acetaldehyde in radioactive pharmaceutical formulations as an alternative to gas chromatography (GC).
Measurement of residual acetaldehyde by GC is complicated by the presence of ethanol in pharmaceutical formulations due to its relatively large peak, and the method of the present invention overcomes this problem. It can also be used for determination of acetaldehyde in ethanol. Derivatives arriving from reaction between amino xy and aldehyde or ketone can be designed to be a molecule which will increase both sensitivity and separation.
By quantifying and/or removing and/or controlling the formation of acetaldehyde by a method of the invention, the level of acetaldehyde in a
pharmaceutical formulation, as defined herein, can remain within acceptable standard limits and thus an increased radiochemical concentration (RAC) may be achieved which in turn may maximize the number of patient doses from a single batch of a radioactive pharmaceutical formulation. The present invention permits simplification and improvement for quality control (QC)-methods for determination of trace amounts of aldehydes and ketones found in various pharmaceutical formulations.
These and other aspects of the invention will become apparent from the following detailed description of the preferred embodiments, taken in conjunction with the Figure.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the effect on RCP of the Fluciclatide (18F) Injection, by quench with aldehyde scavenger AH111695.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
To more clearly and concisely describe and point out the subject matter of the claimed invention, definitions are provided hereinbelow for specific terms used throughout the present specification and claims. Any exemplification of specific terms herein should be considered as a non-limiting example. The terms "comprising" or "comprises" have their conventional meaning throughout this application and imply that the agent or composition must have the essential features or components listed, but that others may be present in addition. The term 'comprising' includes as a preferred subset "consisting essentially of which means that the composition has the components listed without other features or components being present.
The present invention provides a method for quantifying and/or removing and/or controlling acetaldehyde formation in a pharmaceutical formulation.
The present invention provides a method comprising the step of combining an aldehyde scavenger with a pharmaceutical formulation.
The present invention provides a method comprising the step of combining an aldehyde scavenger with a pharmaceutical formulation wherein the pharmaceutical formulation comprises a radioactive pharmaceutical and a solvent.
The present invention provides a composition comprising an aldehyde scavenger, a radioactive pharmaceutical and a solvent.
ALDEHYDE SCAVENGER
According to the invention, the aldehyde scavenger may be any molecule that has an amino-oxy terminus. The amino-oxy functional group is known to be extremely reactive allowing near full conversion of e.g. acetone in a concentration of 1 ppm at room temperature.
According to the invention, the aldehyde scavenger can quantify and/or control acetaldehyde levels and/or thereby permit removal of acetaldehyde from a pharmaceutical formulation until the levels are within acceptable industry standard limits. According to the invention, the aldehyde scavenger can equally be applied to other by-products (e.g. other aldehydes such as fluorobenzaldehyde (FBA), ketones) found in a pharmaceutical formulation.
In an embodiment of the invention, the aldehyde scavenger is the following compound (herein also referred to as "AH111695"; Mol. Wt. 1709.92):
Figure imgf000005_0001
According to the invention, the acetaldehyde scavenger may be presented to the pharmaceutical formulation in a variety of manners. For example, the
acetaldehyde scavenger may be presented as:
(i) a free aminoxy-containing excipient in the pharmaceutical formulation;
(ii) a solid-phase material containing the bound aminoxy-containing functionality through which the pharmaceutical formulation will be passed;
(iii) part of a cartridge/filtering unit as part of the dispensing fluid path used during the initial dispensing of the individual dose/QC/micro/retained sample vials;
(iv) part of a cartridge/filtering unit as part of the dispensing fluid path used to dispense just prior to clinical use;
(v) part of a cartridge/filtering unit that the pharmaceutical formulation is passed through when filling the syringe for patient dose administration soon after manufacture of the radiotracer; and/or
(vi) a cartridge/filtering unit that the pharmaceutical formulation is passed through when filling the syringe for patient dose administration just prior to clinical use.
According to the invention, the aldehyde scavenger may also be added as an excipient in a pre-made formulation vial. Radioactive pharmaceuticals such as PET tracers are commonly transferred off an automated synthesis machine (e.g.
FASTlab™) and into a pre-filled formulation vial to make the formulated production. According to this aspect of the invention, the aldehyde scavenger can be a part of this pre-filled formulation vial as an excipient.
According to the invention, the aldehyde scavenger may also be added as an excipient to a clinical vial. The pharmaceutical formulation, as described herein, is dispensed into different vials after formulation. If the aldehyde scavenger is solid particles, it cannot be dispensed since this dispensing includes sterile filtration. The solution to this is to present the scavenger as an excipient in the clinical vial (patient vial).
In the context of the quantification embodiment of the invention it should be noted that the imines formed in a reaction between an amino xy and an aldehyde can be detected down to below 0.2 μg/ml equal to 0.1 nanomol e.g. for the PET tracer fluciclatide described herein by UV (the sensitivity by mass spectrometry would be even higher). 0.1 nanomol acetaldehyde corresponds to 0.0048 μg/ml acetaldehyde or 0.0048 ppm = 4.8 ppb acetaldehyde. Below is illustrated a model reaction for quantification of acetaldehyde:
Figure imgf000006_0001
3
Molecular Weight: 192,21
The obtained molecule 3 can be analysed either by GC or HPLC. Separation of 3 from 2 is regarded as simple because of the great difference in polarity.
AHl 11930 illustrated below is the product between the aldehyde scavenger AHl 11695 described herein and acetaldehyde:
Figure imgf000006_0002
E-AH111930
AHl 11930 is formed during synthesis of fluciclatide described herein and is found in the crude reaction mixture in various amounts depending on the content of acetaldehyde e.g. in the ethanol used during process. AHl 11930 is typically reduced less to than 1-2 μ /ηι1 over the final purification step. The amount of AH111930 in the final product is determined by the QC HPLC method during release of
Fluciclatide (18F) Injection. All unreacted AH111695 is removed during purification and hence acetaldehyde will remain unreacted if formed post-purification. The amount of acetaldehyde formed during storage of the pharmaceutical formulation can be determined by adding some AH111695 to a sample and heat for 10 min. The sample can then be analysed using the QC HPLC method and the content of
AH111930 quantified and compared with release analysis. AH111930 might have a response at 216 nm lower than fluciclatide used as standard, but the response ratio between the two can be determined and AH111585 still be used as the standard.
PHARMACEUTICAL FORMULATION
According to the invention a pharmaceutical formulation shall refer to any final radioactive pharmaceutical formulation. In one embodiment the pharmaceutical formulation is in a form suitable for mammalian administration, by which is meant a formulation which is sterile, pyrogen- free, lacks compounds which produce toxic or adverse effects, and is formulated at a biocompatible pH (approximately pH 4.0 to 10.5). Such formulations lack particulates which could risk causing emboli in vivo, and are formulated so that precipitation does not occur on contact with biological fluids (e.g. blood). Such formulations also contain only biologically compatible excipients, and are preferably isotonic. According to the invention a pharmaceutical formulation comprises a radioactive pharmaceutical and a solvent, each as described herein. A pharmaceutical formulation may be made by any means known in the art including, but not limited to, automated synthesis machines (e.g. FASTlab™).
RADIOACTIVE PHARMACEUTICAL
According to the invention a radioactive pharmaceutical may comprise any radio labelled compound suitable for in vitro or in vivo imaging. In one embodiment of the invention said radio labelled compound is suitable for in vivo imaging. To be suitable for in vivo imaging a radioactive pharmaceutical is suitably provided in a form suitable for mammalian administration, and assists in providing clearer images in the region or organ of interest than could be obtained by imaging the mammalian subject alone. In a preferred embodiment, the radioactive pharmaceutical is a positron emission tomography (PET) tracer. In a preferred embodiment, the radioactive pharmaceutical is a 18F PET tracer. Non- limiting examples of suitable 18F PET tracers include, but are not limited to, [18F]fluciclatide, [18F]flutemetamol, and [18F]GE180:
Figure imgf000008_0001
[18F]fiuciclatide
Figure imgf000008_0002
[ 18F]flutametamo 1
Figure imgf000008_0003
Methods suitable for production of [18F]fluciclatide and formulations comprising [18F]fiuciclatide are described in WO 2004080492 Al, WO 2006030291 A2, WO 2012076697 Al and US 20130209358 Al . In one embodiment of aspects of the present invention the 18F PET tracer is [18F]fluciclatide. Methods suitable for production of [18F]flutametamol and formulations comprising [18F] flutametamol are described in WO 2007020400 Al, WO
2009027452 A2 and WO 2011044406 A2. In one embodiment of aspects of the present invention the 18F PET tracer is [18F] flutametamol.
Methods suitable for production of [18F]GE180 and compositions comprising
[18F]GE180 are described in WO 2010109007 A2, WO 2011117421 Al and WO 2012080349 Al . In one embodiment of aspects of the present invention the 18F PET tracer is [18F]GE180.
SOLVENT
According to the invention, the solvent can comprise any organic solvent known in the art suitable for use in a pharmaceutical formulation. In a preferred embodiment, the solvent comprises an alcohol. In a preferred embodiment, the solvent is ethanol, isopropanol or a bioalcohol. In a preferred embodiment, the solvent is ethanol.
This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims. All patents and patent applications mentioned in the text are hereby incorporated by reference in their entireties, as if they were individually incorporated.
Example 1
In an experiment to analyse the content of acetaldehyde in a Fluciclatide (18F) Injection sample using HPLC, the acetaldeyde was derivatized to an UV absorbing fluciclatide analogue AH111930 using AH111695 (Scheme 1). Scheme 1
Figure imgf000010_0001
AHl 11965
Figure imgf000010_0002
Figure imgf000010_0003
After 10 hours of decay, 0.5 ml sample of Fluciclatide (18F) Injection was mixed with 0.5 ml of aqueous 1.6 mM AHl 11695/77.2 mM aniline HCl and heated to 60 °C for 30 min. The molar content of AHl 11930 was determined by HPLC and the amount of acetaldehyde quenched by AHl 11695 was found to be 7.6 μ^ιηΐ. In contrast, the amount of acetaldehyde in a control sample that was unquenched (i.e., no aldehyde scavenger AHl 11695 was added) was later determined by GC analysis to be 6.9 μg. The deviation between the HPLC and GC results is due to the higher sensitivity of the HPLC method over the GC method. The results indicate a complete quench of acetaldehyde was achieved by the addition of the aldehyde scavenger AHl 11695. The quenched sample of Fluciclatide (18F) Injection was also analysed for the content of the radio impurity 4-[18F]fluorobenzaldehyde ([18F]FBA) and the results were compared with an unquenched sample. The results showed that aldehyde scavenger AHl 11695 reacted with [18F]FBA to form [18F] fluciclatide removing the [18F]FBA radio impurity from the product. This had a profound effect on the radiochemical purity (RCP). Analysis of 9 hours unquenched sample gave a RCP of 92.5% (initial RAC 1030 MBq/ml). After addition of aldehyde scavenger AHl 11695, the RCP increased to 94.5% (cis and trans isomers combined). Overlays of the radio chromatograms before and after quench are shown in Figure 1. The two major radio impurities are shown where [18F]FBA was not detected in the quenched sample.
Figure 1 clearly demonstrates the efficacy of the method in controlling aldehyde formation: (1) bottom trace is Fluciclatide (18F) Injection quenched with aldehyde scavenger AHl 11695 after 9 hours; (2) middle trace is a blank; and (3) the top trace is Fluciclatide (18F) Injection unquenched i.e., without addition of aldehyde scavenger AHl 11695, after 9 hours.

Claims

1. A method for quantifying, removing or controlling acetaldehyde formation in a pharmaceutical formulation comprising the step of combining an aldehyde scavenger with a pharmaceutical formulation.
2. A method according to claim 1, wherein the aldehyde scavenger is any molecule that has an amino -oxy terminus.
3. A method according to claim 1, wherein the aldehyde scavenger has the following structure:
Figure imgf000012_0001
4. A method according to any one of claims 1-3, wherein the drug formulation comprises a radioactive pharmaceutical and a solvent.
5. A method according to claim 4, wherein the radioactive pharmaceutical is a positron emission tomography (PET) tracer.
6. A method according to claim 5, wherein the radioactive pharmaceutical is a 18F PET tracer.
7. A method according to claim 6, wherein the radioactive pharmaceutical isselected from the group of compounds comprising:
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
8. A method according to any one of claims 4-7, wherein the solvent comprises an alcohol.
9. A method according to claim 8, wherein said alcohol is selected form the group comprising ethanol, isopropanol and a bioalcohol.
10. A method according to claim 9, wherein said alcohol is ethanol.
11. A composition comprising an aldehyde scavenger, a radioactive
pharmaceutical and a solvent.
12. A composition according to claim 11, wherein the aldehyde scavenger is any molecule that has an amino -oxy terminus.
13. A composition according to claim 11, wherein the aldehyde scaveng following structure:
Figure imgf000014_0001
14. A composition according to any one of claims 11-13, wherein the radioactive pharmaceutical is a positron emission tomography (PET) tracer.
15. A composition according to any one of claims 11-14, wherein the radioactive pharmaceutical is a 18F PET tracer.
16. A composition according to claim 15, wherein the radioactive pharmaceutical is selected from the group of compounds comprising:
Figure imgf000015_0001
[18F]fluciclatide;
Figure imgf000015_0002
[18F]flutametamol; and,
Figure imgf000015_0003
[18F]GE180.
17. A composition according to any one of claims 11-16, wherein the solvent comprises an alcohol.
18. A composition according to claim 17, wherein said alcohol is ethanol, isopropanol or a bioalcohol.
19. A composition according to claim 18, wherein said alcohol is ethanol.
PCT/EP2015/078682 2014-12-04 2015-12-04 Method of removing acetaldehyde from radioactive pharmaceuticals Ceased WO2016087653A1 (en)

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JP2017527839A JP6842415B2 (en) 2014-12-04 2015-12-04 How to remove acetaldehyde from radiopharmaceuticals
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10660966B2 (en) 2014-12-04 2020-05-26 Ge Healthcare Limited Method for removing acetaldehyde
CN115698118A (en) * 2020-05-26 2023-02-03 佛莱恩股份公司 Liquid formulations comprising aldehyde scavengers

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12194506B2 (en) 2015-07-16 2025-01-14 Sortera Technologies, Inc. Sorting of contaminants
US12017255B2 (en) 2015-07-16 2024-06-25 Sortera Technologies, Inc. Sorting based on chemical composition
US11969764B2 (en) 2016-07-18 2024-04-30 Sortera Technologies, Inc. Sorting of plastics
US12280403B2 (en) 2015-07-16 2025-04-22 Sortera Technologies, Inc. Sorting based on chemical composition
US12290842B2 (en) 2015-07-16 2025-05-06 Sortera Technologies, Inc. Sorting of dark colored and black plastics
US12551931B2 (en) 2015-07-16 2026-02-17 Sortera Technologies, Inc. Classifying of materials with contaminants

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992010747A1 (en) * 1990-12-13 1992-06-25 Genentech, Inc. Container system for storage stable pharmaceuticals
WO2012076697A1 (en) * 2010-12-09 2012-06-14 Ge Healthcare Limited Radiotracer compositions

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MC2260A1 (en) * 1990-06-18 1993-04-26 Dow Chemical Co RADIOPHARMACEUTICAL FORMULATIONS, THEIR METHOD OF ADMINISTRATION AND THEIR PREPARATION PROCESS
EP1379297B1 (en) * 2001-04-13 2006-10-04 Trasis S.A. Process and device for preparing radiopharmaceutical products for injection
JP2004073377A (en) 2002-08-13 2004-03-11 Takeda Chem Ind Ltd Method for stabilizing effective component
US20050267222A1 (en) 2002-10-22 2005-12-01 Dainippon Pharmaceutical Co. Ltd. Stabilized composition
GB0305704D0 (en) 2003-03-13 2003-04-16 Amersham Plc Radiofluorination methods
GB0410448D0 (en) 2004-05-11 2004-06-16 Hammersmith Imanet Ltd Purification methods
GB0420344D0 (en) 2004-09-14 2004-10-13 Amersham Plc Diagnostic compounds
GB0516564D0 (en) 2005-08-12 2005-09-21 Ge Healthcare Ltd Fluorination process
CN101790387B (en) 2007-08-30 2013-03-20 通用电气健康护理有限公司 Radiopharmaceutical composition
EP2195037A2 (en) * 2007-09-10 2010-06-16 GE Healthcare UK Limited Radiofluorination methods
RU2474435C2 (en) * 2007-11-07 2013-02-10 Джи-И Хелткер БВ Stabilisation of radiopharmaceutical compositions
GB0905328D0 (en) 2009-03-27 2009-05-13 Ge Healthcare Ltd Indole derivatives
SG182378A1 (en) 2009-10-08 2012-08-30 Ge Healthcare Ltd Purification method
WO2011117421A1 (en) 2010-03-26 2011-09-29 Ge Healthcare Limited Tricyclic indole derivatives as pbr ligands
GB201021263D0 (en) 2010-12-15 2011-01-26 Ge Healthcare Ltd Solid phase extraction method
GB201202420D0 (en) 2012-02-13 2012-03-28 Ge Healthcare Ltd Radiotracer compositions
EP2920148B1 (en) * 2012-11-16 2019-06-12 The Regents of the University of California Pictet-spengler ligation for protein chemical modification
WO2016087653A1 (en) 2014-12-04 2016-06-09 Ge Healthcare Limited Method of removing acetaldehyde from radioactive pharmaceuticals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992010747A1 (en) * 1990-12-13 1992-06-25 Genentech, Inc. Container system for storage stable pharmaceuticals
WO2012076697A1 (en) * 2010-12-09 2012-06-14 Ge Healthcare Limited Radiotracer compositions

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10660966B2 (en) 2014-12-04 2020-05-26 Ge Healthcare Limited Method for removing acetaldehyde
US11389538B2 (en) 2014-12-04 2022-07-19 Ge Healthcare Limited Method for removing acetaldehyde
US11964020B2 (en) 2014-12-04 2024-04-23 Ge Healthcare Limited Method for removing acetaldehyde
CN115698118A (en) * 2020-05-26 2023-02-03 佛莱恩股份公司 Liquid formulations comprising aldehyde scavengers

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