US-20260124326-A1 - USE OF CYCLODEXTRINS AS A RADIOSTABILIZER

Abstract

The present invention provides a radiopharmaceutical composition comprising the following four components: (i) a radio-labelled compound; (ii) ethanol; (iii) a stabilizer of the radio-labelled compound; and (iv) a cyclodextrin. The present invention also provides a radiopharmaceutical composition comprising: (i) a radio-labelled compound; (ii) a stabilizer of the radio-labelled compound, wherein the stabilizer comprises: ascorbic acid, aspartic acid, cysteine, maleic acid, gentisic acid, glutathione, glutamic acid, mannitol, nicotinamide, calcium chloride, N-t-butyl-alpha-phenylnitrone (PBN), tartaric acid, para-aminobenzoic acid (pABA), chloride ions or salts or combinations thereof; and (iii) a cyclodextrin.

Inventors

• Kristine Opsvik WIKENE
• IMTIAZ Ahmed KHAN
• Graeme McRobbie

Assignees

• GE HEALTHCARE LIMITED

Dates

Publication Date

20260507

Application Date

20251218

Priority Date

20191021

Claims (4)

1. 1 . A stable radiopharmaceutical composition suitable for mammalian administration comprising: [ 18 F] flurpiridaz; about 30 to about 50 mg/mL ascorbic acid; about 40 to about 50 mg/mL hydroxypropyl-beta-cyclodextrin (HPbCD); and ethanol; wherein the pH of the stable radiopharmaceutical composition is 4.5 to 9.5.
2. 2 . A method of imaging a subject in need thereof, comprising: intravenously administering the stable radiopharmaceutical composition of claim 1 ; and acquiring an at least one image from the subject after the administration.
3. 3 . A method of positron emission tomography (PET) imaging in a subject in need thereof, comprising intravenously administering the radiopharmaceutical composition of claim 1 ; and acquiring at least one PET image from the subject after the administration.
4. 4 . A method of positron emission tomography (PET) imaging in a subject in need thereof, comprising: intravenously administering a stable radiopharmaceutical composition having a pH of 4.5 to 9.5 and comprising: [ 18 F] flurpiridaz: about 30 to about 50 mg/mL ascorbic acid; a cyclodextrin; about 2% to about 10% (v/v) ethanol; and a biocompatible carrier selected from the group consisting of pyrogen-free water; isotonic saline and phosphate buffer; and acquiring at least one PET image from the subject after the administration.

Description

FIELD OF THE INVENTION The present invention generally relates to radiopharmaceutical compositions, which comprise a radio-labelled compound and are stabilized with a stabilizer and cyclodextrin as a co-stabilizer. The invention also relates to the use of such radiopharmaceutical compositions in methods of imaging a subject using the radiopharmaceutical compositions. Also described are methods and kits for the preparation of the radiopharmaceutical compositions. BACKGROUND TO THE INVENTION Stabilizers are needed in radiopharmaceutical preparations to reduce the formation of radioimpurities during their shelf life. Conventional radiopharmaceuticals contain a radiopharmaceutical, a gas, and a formulation that contains a solvent and a stabilizer. Commonly used stabilizers include ethanol, sodium ascorbate, ascorbic acid, maleic acid, gentisic acid and calcium chloride among others. Cyclodextrins have previously been used to improve the solubility of poorly water soluble substances. DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a radiopharmaceutical composition comprising the following four components: (i) a radio-labelled compound comprising a 18F-labelled radiopharmaceutical, or a pharmaceutically acceptable salt thereof; (ii) ethanol; (iii) a stabilizer of the radio-labelled compound wherein said stabilizer comprises ascorbic acid; and (iv) a co-stabilizer of the radio-labelled compound wherein said co-stabilizer is a cyclodextrin. The following subject-matter is provided in combination with the aspect provided above and the additional aspects provided below. The term radiopharmaceutical has its conventional meaning, and refers to a radioactive compound suitable for in vivo mammalian administration for use in diagnosis or therapy. The radiopharmaceutical compositions described herein may comprise components as described in US2013129623. The radio-labelled compound comprises a 18F-labelled radiopharmaceutical, or a pharmaceutically acceptable salt thereof. Examples of such 18F-labelled radiopharmaceuticals include [18F]FDG, [18F]FMAU, [18F]FMISO, [18F]FHBG, [18F]AV-45, [18F]AV-19, [18F]AV-1, [18F] Flutemetamol, [18F] Flurpiridaz, [18F]K5, [18F]HX4, [18F]W372, [18F]VM4-037, [18F]CP18, [18F]ML-10, [18F]T808, [18F]T807, 2-[18F]fluoromethyl-L-phenylalanine, or combinations thereof. Preferably, the radio-labelled compound is not [18F]FLT. The radio-labelled compound may comprise a compound of Formula (I): wherein A is selected from N(R7), S, O, C(═O), C(═O) O, NHCH2CH2O, a bond, or C(═O)N(R7);when present, B is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety;when present, C is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety;D is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; orC and D, together with the atom to which they are attached, form a three- or four-membered carbocyclic ring;G is halo or haloalkyl;n is 0, 1, 2, or 3;R1, R2, R3, R4, R5, R6 and R7 are independently selected from hydrogen, C1-C6 alkyl optionally substituted with an imaging moiety, and an imaging moiety;R8 is C1-C6 alkyl, optionally substituted with an imaging moiety; andE is selected from a bond, carbon, and oxygen, provided that when E is a bond, B and C are absent and D is selected from aryl and heteroaryl, and provided that when E is oxygen, B and C are absent and D is selected from hydrogen, alkoxyalkyl, aryl, C1-C6 alkyl optionally substituted with an imaging moiety, and heteroaryl;provided that the imaging moiety comprises 18F and at least one imaging moiety is present in Formula (I). Substituent A of Formula (I) may be O. R8 may be tert-butyl. G may be chloro. Compounds of Formula (I) and how to obtain them can be found for example in WO2005079391A2, the contents of which is incorporated herein by reference. The radio-labelled compound may comprise flurpiridaz, which has the following structure: By the term “stabilizer” it is specifically meant radio-stabilizer, which is a compound that inhibits degradation reactions, such as redox processes, by trapping highly-reactive free radicals, such as oxygen-containing free radicals arising from the radiolysis of water. The stabilizers of the invention protect the radio-labelled compound(s) from radiolysis and therefore lower/prevent a drop in the purity of the radio-labelled compound(s) over their shelf life. By the term “co-stabilizer” is meant a compound that enhances the desired effects of the stabilizer. Radiochemical purity (RCP) is determined using radio TLC or HPLC and can be defined as the ratio of the (radio-labelled) drug substance peak to the total (radio-labelled) peaks in the chromatogram. If one manufactures a radiopharmaceutical with high radioactive concentra