Pharmaceutical formulations

Abstract

The present invention relates to a pharmaceutical composition comprising a radiohybrid agent containing a silicon-fluoride and a chelating group wherein either the fluorine is .sup.18F or the chelating group contains a chelated radioactive metal, wherein the composition has a pH of 4.0-6.0 and further comprises: 0.1-200 mM citrate buffer; 1-100 mg/mL ethanol; and 5-10 mg/mL sodium chloride.

Claims

1. A pharmaceutical composition comprising a radiohybrid agent containing a silicon-fluoride group and a chelating group, wherein either the fluorine of the silicon-fluoride group is .sup.18F or the chelating group contains a chelated radioactive metal, wherein the radiohybrid agent is: ##STR00054## or an isomer or salt thereof, wherein M.sup.3+ is a chelated radioactive or non-radioactive metal, and wherein the composition has a pH of 4.0-6.0 and further comprises: a) 0.1-200 mM citrate buffer; and b) 1-100 mg/mL ethanol; and c) 5-10 mg/mL sodium chloride.

2. The pharmaceutical composition as defined in claim 1 comprising 1-15 mM citrate buffer.

3. The pharmaceutical composition as defined in claim 1 comprising 5-50 mg/mL ethanol.

4. The pharmaceutical composition as defined in claim 1 that has a pH of 4.5 to 5.5.

5. The pharmaceutical composition as defined in claim 1 wherein the citrate buffer is prepared from citric acid and sodium hydroxide, or sodium citrate and hydrochloric acid.

6. The pharmaceutical composition as defined in claim 5, wherein 1-3 mg/mL citric acid and 0.5-1.0 mg/mL sodium hydroxide are used to prepare the citrate buffer.

7. The pharmaceutical composition as defined in claim 1 wherein M.sup.3+ is a chelated radioactive metal and the fluorine is .sup.19F.

8. The pharmaceutical composition as defined in claim 1 wherein the chelated metal is selected from the cations of: Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th or Er.

9. The pharmaceutical composition as defined in claim 1 wherein the fluorine is .sup.18F and M.sup.3+ is a chelated non-radioactive metal.

10. The pharmaceutical composition as defined in claim 8 wherein the chelated metal cation is radioactive and is a positron emitting isotope.

11. The pharmaceutical composition as defined in claim 1 that has an end of synthesis (EOS) radioactive concentration (RAC) of 5-200 mCi/mL.

12. The pharmaceutical composition as defined in claim 1 comprising 10 mM citrate buffer, 50 mg/mL ethanol, 7.2 mg/mL sodium chloride, and that is pH 5.

13. The pharmaceutical composition as defined in claim 1, which is diluted with sodium chloride solution prior to administration.

14. The pharmaceutical composition as defined in claim 13 comprising 1.1 mM (?10%) citrate buffer, 5.3 mg/mL (?10%) ethanol, 8.8 mg/mL (?10%) sodium chloride, and which has a pH of 4.5 to 5.5.

15. A method of imaging and/or diagnosing cancer comprising administering a composition according to claim 1 to a patient in need thereof.

16. A method of diagnosis, imaging or prevention of neoangiogenesis/angiogenesis comprising administering a composition according to claim 1 to a patient in need thereof.

17. A method of imaging and/or diagnosing cancer comprising administering a composition according to claim 1 to a patient in need thereof wherein the cancer is prostate, breast, lung, colorectal or renal cell carcinoma.

18. A method of producing a composition as defined claimed in claim 1, the method comprising: preparing a formulation comprising the radiohybrid agent, the citrate buffer, and the ethanol, wherein the formulation has a pH of 4.0-6.0 and a citrate concentration of at least 10 mM, and diluting the citrate concentration of the formulation with sodium chloride.

19. The pharmaceutical composition as defined in claim 1 wherein the metal is 68 Ga.

20. The pharmaceutical composition as defined in claim 1 wherein the fluorine is .sup.18F and the metal is .sup.68Ga.

Description

Example 1

(1) The Gallium chelate of Compound rh-PSMA-7.3 was prepared as previously described in WO2019/020831 and EP19154500.3:

(2) rhPSMA-7.3 (D-Dap, (S)-DOTA-GA):

(3) ##STR00053##

(4) Fmoc-D-Dap(Dde)-OH (2.0 eq.) was pre-activated in a mixture of HOAt (2.0 eq.), TBTU (2.0 eq.) and 2,4,6-trimethylpyridine (6.7 eq.) in DMF and added to the resin-bound peptide for 2.5 h. Orthogonal Dde-deprotection was done using imidazole and hydroxylamine hydrochloride dissolved in a mixture of NMP and DMF for 3 h. SiFA-BA (1.5 eq.) was reacted with the free amine of the side chain with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (4.5 eq.), as activation reagents in DMF for 2 h. After Fmoc-deprotection (20% piperidine in DMF (v/v, 8 mL/g resin) for 5 min and subsequently for 15 min, afterwards, the resin was washed thoroughly with DMF (8?5 mL/g resin)), (R)-DOTA-GA(tBu).sub.4 (2.0 eq.) was conjugated with HOAT (2.0 eq.), TBTU (2.0 eq.) and 2,4,6-trimethylpyridine (6.7 eq.) in DMF for 2.5 h. Cleavage from the resin with simultaneous deprotection of acid labile protecting groups was performed in TFA (The fully protected resin-bound peptide was dissolved in a mixture of TFA/TIPS/water (v/v/v; 95/2.5/2.5) and shaken for 30 min. The solution was filtered off and the resin was treated in the same way for another 30 min. Both filtrates were combined, stirred for additional 5 h and concentrated under a stream of nitrogen. After dissolving the residue in a mixture of tert-butanol and water and subsequent lyophilisation the crude peptide was obtained). .sup.natGa-complexation of the peptide was carried out. The peptide (1.0 eq.) was dissolved in a 3:1 (v/v) mixture of tBuOH in H.sub.2O and an aqueous solution of Ga(NO.sub.3).sub.3 (3.5 eq.) was added. After heating the resulting mixture for 30 min at 75? C. the peptide was purified by RP-HPLC.

(5) .sup.18F-Labeling

(6) Aqueous .sup.18F.sup.? was passed through a SAX cartridge (Sep-Pak Accell Plus QMA Carbonate light), which was preconditioned with 10 mL of water. After drying with 10 mL of air, water was removed, by rinsing the cartridge with 10 mL of anhydrous acetonitrile followed by 20 mL of air. .sup.18F was eluted with 100 ?mol of [K.sup.+?2.2.2]OH.sup.? dissolved in 500 ?L of anhydrous acetonitrile. Before labelling, 30 ?mol of oxalic acid in anhydrous acetonitrile (1 M, 30 ?L) were added. This mixture was used as a whole or aliquot for fluorination of 10-25 nmol of PSMA-SiFA (1 mM in anhydrous DMSO). The resulting reaction mixture was incubated for 5 minutes at room temperature. For purification of the tracer, a Sep-Pak C18 light cartridge, preconditioned with 10 mL EtOH, followed by 10 mL of H.sub.2O was used. The labelling mixture was diluted with 9 mL PBS (pH 3) and passed through the cartridge followed by 10 mL of H.sub.2O. The peptide was eluted with 500 ?L of a 4:1 mixture (v/v) of EtOH in water. Radiochemical purity of the labelled compound was determined by radio RP-HPLC and radio-TLC (Silica gel 60 RP-.sup.18F.sub.254s, mobile phase: 3:2 mixture (v/v) of MeCN in H.sub.2O supplemented with 10% of 2 M aqueous NaOAc and 1% of TFA).

(7) Alternatively [.sup.18F]rhPSMA-7.3 may be prepared on an automated synthesis module by isotopic exchange between [.sup.18F]fluoride ion and [.sup.18F]rhPSMA-7.3 as follows:

(8) Fluorine-18 in the form of [.sup.18F]fluoride ion is prepared from .sup.18O(p,n).sup.18F nuclear reaction in a cyclotron by irradiation of .sup.18O-enriched water with protons. [.sup.18F]fluoride is first immobilised on an ion exchange resin to allow for recovery of .sup.18O-enriched water. [.sup.18F]fluoride is then eluted with a solution of Cryptand 222 and potassium carbonate in acetonitrile and water. The eluate is transferred into the reaction vessel and evaporated by heating under a flow of nitrogen. [.sup.19F]rhPSMA-7.3 in solution of DMSO, acetonitrile and acetic acid is added to the reaction vessel and reacted with nucleophilic [.sup.18F]fluoride for at least 1 min to form [.sup.18F]rhPSMA-7.3. The crude solution of [.sup.18F]rhPSMA-7.3 is diluted with water and purified by hydrophobic solid phase extraction. Impurities are removed by washing the cartridge with water. [.sup.18F]rhPSMA-7.3 is eluted with an ethanol-water solution and formulated by diluting with an isotonic formulation buffer. The formulated solution is sterilised by filtration through a 0.2 ?m filter.

(9) Dilution if applicable is performed using an isotonic sodium chloride solution for injection.

(10) Batches of material were prepared in either a citrate buffer made from sodium citrate+HCl or a citrate buffer made from citric Acid+NaOH.

(11) Radio-stability was measured in phosphate and citrate buffers at various pH levels to compare the level of the correct 18FSi compound and the decomposed free 18F:

(12) TABLE-US-00001 HPLC G-49 .sup.18F- TLC t = 0 h TLC t = 6 h t = 6 h rhPSMA [.sup.18F][.sup.natGa]- [.sup.18F] [.sup.18F][.sup.natGa]- [.sup.18F] Impurity ?[.sup.18F] Sample in 50% pH rhPSMA- Fluoride rhPSMA- Fluoride @ 2.6 min Fluoride [%] # ethanol diluent t = 0 h 7.3 [%] [%] 7.3 [%] [%] [Area] (t6h-t0) 1 0.5 mL none 8.0 96.1 3.9 93.2 6.8 0.406 2.9 2 0.1 mL 0.6 mL 0.23M 6.5 98.1 1.9 96.8 3.1 0.314 1.2 phosphate buffer pH 6.0 3 0.1 mL 0.6 mL 7.5 97.7 2.3 96.25 3.75 0.138 1.5 phosphate buffer pH 7.0 4 0.1 mL 0.6 mL 0.2M 5.0 97.7 2.3 97.3 2.7 0.119 0.4 citrate buffer pH 5.0 5 0.1 mL 0.6 mL 0.2M 6.0 98.4 1.6 97.5 2.5 0.191 0.9 citrate buffer pH 8.0 6 0.1 mL 0.6 mL 0.2M 7.5 97.8 2.2 95.7 4.3 0.084 2.1 citrate buffer pH 7.0

(13) The most stable formulation was pH 5.0 in citrate buffer. Increasing the pH in citrate buffer gave an increase in the amount of free 18F (which is presumably displaced by OH). At the same pH (6.0) phosphate buffer gives a less stable product than citrate buffer.

(14) Radiochemical and chemical purity was assessed for various formulations containing citrate buffer or citrate buffered saline (Table 1).

(15) TABLE-US-00002 TABLE 1 Radiochemical and chemical purity of various formulations Radiochemical [.sup.18F]fluoride Radioactivity purity by HPLC impurity by Chemical concentration (%) TLC (%) purity (%) at EOS T = T = T = Entry (mCl/mL) Formulation pH T0 10 h T0 10 h T0 10 h 1 27 100 mM citrate 5.0 98.6 98.7 1.6 1.5 98.6 96.9 buffer, 5% ethanol 2 26 100 mM citrate 5.5 99.5 99.5 1.9 2.5 99.1 96.7 buffer, 5% ethanol 3 12 100 mM citrate 6.0 99.5 >99.5 1.2 1.5 N/A N/A buffer, 5% ethanol 4 51 100 mM citrate 6.5 99.5 >99.5 <1.0 1.4 N/A N/A buffer, 5% ethanol 5 56 10 mM citrate 5.0 98.7 98.9 1.2 1.1 98.3 96.7 buffered saline, 5% ethanol 6 34 10 mM citrate 6.0 99.3 99.6 1.0 1.9 99.6 98.8 buffered saline, 5% ethanol

(16) Upon dilution with sodium chloride solution for injection (0.9% w/v), the pH of the formulation (entry 5, Table 1: 10 mM citrate buffered saline, 5% ethanol) is maintained:

(17) TABLE-US-00003 TABLE 2 Formulation after dilution of Table 1, entry 5 with sodium chloride solution dilution citrate buffer Sodium chloride Ethanol Entry factor (mM) (mg/mL) (mg/mL) pH 1 1 10 7.2 50.0 5.0 2 1.8 5.6 8.0 27.8 5.0 3 3 3.3 8.4 16.7 5.0 4 5 2.0 8.6 10.0 5.0 5 7 1.4 8.7 7.1 5.1 6 9.4 1.1 8.8 5.3 5.1