METHOD FOR REMOVING ACETALDEHYDE

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.

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: ##STR00006##

4. A method according to claim 1, wherein the pharmaceutical 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 4, wherein the radioactive pharmaceutical is a .sup.18F PET tracer.

7. A method according to claim 4, wherein the radioactive pharmaceutical is elected from the group of compounds comprising: ##STR00007##

8. A method according to claim 4, 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 scavenger has the following structure: ##STR00008##

14. A composition according to claim 11, wherein the radioactive pharmaceutical is a positron emission tomography (PET) tracer.

15. A composition according to claim 11, wherein the radioactive pharmaceutical is a .sup.18F PET tracer.

16. A composition according to claim 15, wherein the radioactive pharmaceutical is selected from the group of compounds comprising: ##STR00009##

17. A composition according to claim 11, 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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 shows the effect on RCP of the Fluciclatide (.sup.18F) Injection, by quench with aldehyde scavenger AH111695.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] 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.

[0010] 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.

[0011] The present invention provides a method for quantifying and/or removing and/or controlling acetaldehyde formation in a pharmaceutical formulation.

[0012] The present invention provides a method comprising the step of combining an aldehyde scavenger with a pharmaceutical formulation.

[0013] 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

[0014] 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.

[0015] 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.

[0016] In an embodiment of the invention, the aldehyde scavenger is the following compound (herein also referred to as “AH111695”; Mol. Wt. 1709.92):

##STR00001##

[0017] 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:

[0018] (i) a free aminoxy-containing excipient in the pharmaceutical formulation;

[0019] (ii) a solid-phase material containing the bound aminoxy-containing functionality through which the pharmaceutical formulation will be passed;

[0020] (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;

[0021] (iv) part of a cartridge/filtering unit as part of the dispensing fluid path used to dispense just prior to clinical use;

[0022] (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

[0023] (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.

[0024] 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.

[0025] 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).

[0026] In the context of the quantification embodiment of the invention it should be noted that the imines formed in a reaction between an aminoxy 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:

##STR00002##

[0027] 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.

[0028] AH111930 illustrated below is the product between the aldehyde scavenger AH111695 described herein and acetaldehyde:

##STR00003##

[0029] AH111930 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. AH111930 is typically reduced less to than 1-2 μg/ml over the final purification step. The amount of AH111930 in the final product is determined by the QC HPLC method during release of Fluciclatide (.sup.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

[0030] 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

[0031] According to the invention a radioactive pharmaceutical may comprise any radiolabelled compound suitable for in vitro or in vivo imaging. In one embodiment of the invention said radiolabelled 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 .sup.18F PET tracer. Non-limiting examples of suitable .sup.18F PET tracers include, but are not limited to, [.sup.18F]fluciclatide, [.sup.18F]flutemetamol, and [.sup.18F]GE180:

##STR00004##

[0032] Methods suitable for production of [.sup.18F]fluciclatide and formulations comprising [.sup.18F]fluciclatide are described in WO 2004080492 A1, WO 2006030291 A2, WO 2012076697 A1 and US 20130209358 A1. In one embodiment of aspects of the present invention the .sup.18F PET tracer is [.sup.18F]fluciclatide.

[0033] Methods suitable for production of [.sup.18F]flutametamol and formulations comprising [.sup.18F]flutametamol are described in WO 2007020400 A1, WO 2009027452 A2 and WO 2011044406 A2. In one embodiment of aspects of the present invention the .sup.18F PET tracer is [.sup.18F]flutametamol.

[0034] Methods suitable for production of .sup.18F]GE180 and compositions comprising [.sup.18F]GE180 are described in WO 2010109007 A2, WO 2011117421 A1 and WO 2012080349 A1. In one embodiment of aspects of the present invention the .sup.18F PET tracer is [.sup.18F]GE180.

Solvent

[0035] 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.

[0036] 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

[0037] In an experiment to analyse the content of acetaldehyde in a Fluciclatide (.sup.18F) Injection sample using HPLC, the acetaldeyde was derivatized to an UV absorbing fluciclatide analogue AH111930 using AH111695 (Scheme 1).

##STR00005##

[0038] After 10 hours of decay, 0.5 ml sample of Fluciclatide (.sup.18F) Injection was mixed with 0.5 ml of aqueous 1.6 mM AH111695/77.2 mM aniline HCl and heated to 60° C. for 30 min. The molar content of AH111930 was determined by HPLC and the amount of acetaldehyde quenched by AH111695 was found to be 7.6 μg/ml. In contrast, the amount of acetaldehyde in a control sample that was unquenched (i.e., no aldehyde scavenger AH111695 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 AH111695.

[0039] The quenched sample of Fluciclatide (.sup.18F) Injection was also analysed for the content of the radio impurity 4-[.sup.18F]fluorobenzaldehyde ([.sup.18F]FBA) and the results were compared with an unquenched sample. The results showed that aldehyde scavenger AH111695 reacted with [.sup.18F]FBA to form [.sup.18F]fluciclatide removing the [.sup.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 AH111695, the RCP increased to 94.5% (cis and trans isomers combined). Overlays of the radio chromatograms before and after quench are shown in FIG. 1. The two major radioimpurities are shown where [.sup.18F]FBA was not detected in the quenched sample.

[0040] FIG. 1 clearly demonstrates the efficacy of the method in controlling aldehyde formation: (1) bottom trace is Fluciclatide (.sup.18F) Injection quenched with aldehyde scavenger AH111695 after 9 hours; (2) middle trace is a blank; and (3) the top trace is Fluciclatide (.sup.18F) Injection unquenched i.e., without addition of aldehyde scavenger AH111695, after 9 hours.