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.

Claims

1. A radiopharmaceutical composition comprising the following four components: (i) a radio-labelled compound comprising a .sup.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.

2. The radiopharmaceutical composition of claim 1, wherein the radio-labelled compound comprises [.sup.18F]FDG, [.sup.18F]FMAU, [.sup.18F]FMISO, [.sup.18F]FHBG, [.sup.18F]AV-45, [.sup.18F]AV-19, [.sup.18F]AV-1, [.sup.18F] Flutemetamol, [.sup.18F] Flurpiridaz, [.sup.18F]K5, [.sup.18F]HX4, [.sup.18F]W372, [.sup.18F]VM4-037, [.sup.18F]CP18, [.sup.18F]ML-10, [.sup.18F]T808, [.sup.18F]T807, 2-[.sup.18F]fluoromethyl-L-phenylalanine, or combinations thereof.

3. The radiopharmaceutical composition of claim 1, wherein the radio-labelled compound comprises a compound of Formula (I): ##STR00004## wherein A is selected from N(R.sup.7), S, O, C(═O), C(═O)O, NHCH.sub.2CH.sub.2O, a bond, or C(═O)N(R.sup.7); when present, B is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C.sub.1-C.sub.6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; when present, C is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C.sub.1-C.sub.6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; D is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C.sub.1-C.sub.6 alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; or C 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; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and Ware independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with an imaging moiety, and an imaging moiety; R.sup.8 is C.sub.1-C.sub.6 alkyl, optionally substituted with an imaging moiety; and E 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, C.sub.1-C.sub.6 alkyl optionally substituted with an imaging moiety, and heteroaryl; provided that at least one imaging moiety is present in Formula (I).

4. The radiopharmaceutical composition of claim 1, wherein the radio-labelled compound comprises flurpiridaz: ##STR00005##

5. The radiopharmaceutical composition of claim 1, wherein the radio-labelled compound is not [.sup.18F]FLT.

6. The radiopharmaceutical composition of claim 1, wherein the stabilizer comprises ascorbic acid and ethanol.

7. The radiopharmaceutical composition of claim 1, wherein the ethanol comprises up to 10% (v/v) ethanol in aqueous solution.

8. The radiopharmaceutical composition of claim 1, wherein the cyclodextrin comprises: α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, or pharmaceutically acceptable derivatives or combinations thereof.

9. The radiopharmaceutical composition of claim 1, wherein the cyclodextrin comprises β-cyclodextrin.

10. The radiopharmaceutical composition of claim 1, wherein the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin (HPbCD).

11. The radiopharmaceutical composition of claim 1, wherein the radiopharmaceutical composition comprises a biocompatible carrier.

12. The radiopharmaceutical composition of claim 1, wherein the radiopharmaceutical composition is in a form suitable for mammalian administration.

13. The radiopharmaceutical composition of claim 1, wherein the stabilizer comprises ascorbic acid and ethanol, the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin (HPbCD) and the radio-labelled compound comprises flurpiridaz.

14. The radiopharmaceutical composition of claim 13, wherein the ascorbic acid is in an amount from about 1 to about 100 mg/mL, the ethanol is in an amount from about 2 to about 10% (v/v) and the HPbCD is in an amount of from about 1 to about 100 mg/mL.

15. A radiopharmaceutical composition comprising cyclodextrin as a co-stabilizer.

16. The composition of claim 15, further comprising a radio-labelled compound, wherein the radio-labelled compound is not [.sup.18F]FLT.

17. A method of imaging a subject using the radiopharmaceutical composition of claim 1.

18. A method of positron emission tomography (PET) imaging using the radiopharmaceutical composition of claim 1.

19. A method of preparation of a radiopharmaceutical composition comprising the following four components: (i) a radio-labelled compound as defined in any preceding claim; (ii) ethanol; (iii) a stabilizer of the radio-labelled compound as defined in any preceding claim; and (iv) a cyclodextrin as defined in any preceding claim.

20. A kit for the preparation of a radiopharmaceutical composition, comprising: (i) a precursor compound for the production of a radio-labelled compound as defined in any preceding claim; (ii) ethanol; (iii) a stabilizer of the radio-labelled compound as defined in any preceding claim; and (iv) a cyclodextrin as defined in any preceding claim.

Description

[0044] FIG. 1 shows the results of radiochemical purity (RCP) testing of various radiopharmaceutical compositions as a function of radioactive concentration (RAC).

[0045] FIG. 2 shows the results of radiochemical purity (RCP) testing of various radiopharmaceutical compositions as a function of ascorbic acid concentration.

[0046] As shown in FIG. 1, the RCP is more stable over 10 hours when HPbCD is present in the ascorbic acid formulation than without HPbCD.

[0047] The radiostability of [.sup.18F]flurpiridaz is equal or better when prepared with 30 mg/mL ascorbic acid and 40 mg/mL HPbCD than when prepared with 50 mg/mL ascorbic acid without HPbCD. The HPbCD also improves the aqueous solubility of flurpiridaz and reduces the risk of incompatibility with consumer materials (e.g., tubing, sterilising filters, syringes etc.).

[0048] As shown in FIG. 2, reduction in RCP is observed over 4 to 10 h when [.sup.18F]flurpiridaz is formulated with 30 to 50 mg/mL ascorbic acid (pH ˜6) with or without 40-47 mg/mL HPbCD. All samples contain ca. 7% (v/v) ethanol and are held under 0-21% (v/v) oxygen headspace gas.

[0049] The invention is described with reference to the following non limiting examples.

EXAMPLE 1: RADIOSYNTHESIS OF [.SUP.18.F]FLURPIRIDAZ WITH SPE PURIFICATION

[0050] [.sup.18F]fluoride (ca. 200 GBq) was produced using a GE Medical Systems PETtrace cyclotron with a silver target via the [.sup.18O](p,n) [.sup.18F] nuclear reaction. Total target volumes of 3.2-4.8 mL were used. The radiofluoride was trapped on a Waters QMA cartridge (pre-conditioned with carbonate), and the fluoride was eluted with a solution of tetrabutylammnonium hydrogen carbonate (22 mg) in water (100 μL) and acetonitrile (400 μL). Nitrogen was used to drive the solution off the QMA cartridge to the reaction vessel. The [.sup.18F]fluoride was dried for ca. 15 minutes at 110-120° C. under a steady stream of nitrogen and vacuum. The precursor (10.2 mg) in MeCN (1.7 mL) was added to the dried [.sup.18F]fluoride and the reaction mixture was heated at 110 C for 3 minutes. The crude product was then hydrolysed with a solution of NaOH (2 M, 2.3 mL). The hydrolysed crude product was then loaded onto a tC18 SPE cartridge (Waters, product number WAT036800) and purified using the method described below.

[0051] The SPE cartridge was washed with ascorbic acid (21 mL) to wash away the acetonitrile, NaOH and hydrophilic chemical and radiochemical impurities. Then the SPE cartridge was washed with a 40% acetonitrile solution in water (11.9 mL) to remove the hydroxy impurity. After this, the first SPE cartridge was connected in series to a second SPE cartridge (Waters, product number WAT036800) and the two were washed in series with 40% acetonitrile solution in water (22.2 mL) followed by a stream of nitrogen to transfer [.sup.18F]Flurpiridaz onto the second cartridge and trap the more lipophilic chemical and radiochemical impurities on the first SPE cartridge. The second SPE cartridge was washed with a 40% acetonitrile solution in water (5.1 mL) followed by ascorbic acid (21 mL) to remove the acetonitrile. The product was then eluted off the second SPE cartridge with a 45% ethanolic solution (9 mL, first 2 mL not collected) to elute [.sup.18F]Flurpiridaz into the product vial.

[0052] The first 45 mL product vial was composed of water (42 mL), ethanol (3 mL), calcium disodium edetate (0.25 mg/mL), ascorbic acid (50 mg/mL) and sodium hydroxide (7.5 mg/mL). The second 45 mL product vial was composed of water (42 mL), ethanol (3 mL), calcium disodium edetate (0.25 mg/mL), ascorbic acid (50 mg/mL), hydroxypropyl-beta-cyclodextrin (45 mg/mL; HPbCD) and sodium hydroxide (7.5 mg/mL).

[0053] The non-decay corrected yield was 41-44%, resulting in a product with an RAC of ca. 1800 MBq/mL (Table 1). The RCP of the final product was 96-98%.

[0054] After 2 hours the RCP decreased by 0.8-1.4% with the formulation vial not containing HPbCD or 0.3-0.4% with the formulation vial containing HPbCD (Table 1). After 4 hours the RCP decreased by 1.1-1.7% with the formulation vial not containing HPbCD or 0.6% with the formulation vial containing HPbCD. As the specification for RCP was 95% at end of shelf-life (8-10 hours), the batch failed when HPbCD was excluded from the formulation.

[0055] Furthermore, when HPbCD is used in the formulation, the starting activity can be increased to 350 GBq with a product RAC of ca. 2500 MBq/mL. The RCP is 96-98% with a ca. 0.5-1.3% decrease in RCP over 8-10 hours.

TABLE-US-00001 TABLE 1 Representative formulated products of [.sup.18F]Flurpiridaz with and without hydroxypropyl-beta-cyclodextrin (HPbCD). Starting RAC activity (MBq/ [.sup.18F]fluoride RCP Formulation (MBq) mL) T = 0 h T = 4 h T = 0 h T = 4 h Without HPbCD 190279 1742 <0.3 0.4 97.4 95.7 Without HPbCD 200127 1911 0.3 0.5 96.1 95.0 With HPbCD 202606 1976 <0.3 <0.3 97.7 97.1 With HPbCD 202902 1971 <0.3 <0.3 97.4 96.8

[0056] As shown above, the present inventors have found that the use of cyclodextrin as co-stabilizer improves the radiostability of a radiopharmaceutical composition compared to using a conventional radiostabilizer alone, e.g. ascorbic acid, or radiostabilizing system, e.g. ascorbic acid and ethanol.