NZ618977B2 - Formulations of fluorinated stilbene suitable for pet imaging - Google Patents

Abstract

Disclosed are formulations comprising a lipophilic Amyloid beta ligand stilbene, ethanol, a polyether, ascorbic acid and sodium ascorbate, specifically formulations which are capable to be administered parenterally e.g. intravenously, wherein the lipophilic Amyloid beta ligand stilbene is a fluorinated stilbene such as methyl-[4-((F)-2-{4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}-vinyl)-phenyl]-amine. Further, the invention is directed to a method for sterile filtration of formulations suitable for PET imaging of mammals. ted stilbene such as methyl-[4-((F)-2-{4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}-vinyl)-phenyl]-amine. Further, the invention is directed to a method for sterile filtration of formulations suitable for PET imaging of mammals.

Description

Formulations of fluorinated stilbene suitable for PET imaging Field of the ion The invention is directed to formulations of lipophilic Amyloid beta iigand stilbene and more particularly to formulations, which are capable to be administered parenterally e.g. intravenously, n the lipophilic Amyloid beta ligand stilbene is a fluorinated stiibene as d below. Further, the invention is directed to a method for sterile filtration of pharmaceuticai formulations pursuant to the invention le for PET imaging of s.

Background Stilbene useful for Positron Emission Tomography (PET) imaging of patient are known from WO2003/018070A1 and W020061066104A1. Stilbene are radiolabeled with 13F sotope whereas radiolabeiing occurred in organic solution in presence of the stilbene sor and [18F]. The stilbene sor can be in a dry condition and optionally has an inert pharmaceutically acceptable carrier and/or auxiliary substances added thereto and a reducing agent and optionally a chelator. The fluoro-radiolabeled stilbene (PET tracer) solution may contain any additive such as pH lling agents (e.g. acids, bases, s), stabilizers (e.g. ascorbic acid) or isotonizing agents (e.g. sodium chloride).

Ethanol, isopropanol, glycerol, and polyethylene glycol are well known as solubility- increasing excipients, W02001/68142.

Usually, PET supply centers produce on demand a hot stock solution comprising the pharmaceutical that is injected to the patient along the working clay. The hot stock solution must be stable and storable. Furthermore, a significant amount of newly synthesised PET tracer is lost during purification step(s) i.e. sterile filtration. Until now, there has been iittle published on formulations suitable for PET« pharmaceuticals.

Thus, there is a need for commercially acceptable suitable formulations comprising a PET agent, characterized in that the PET agent shows a low water solubility i.e. lipophilic PET agent, wherein the PET agent is an Amyloid beta ligand stilbene useful for PET imaging. it has been surprisingiy found that the d pharmaceutical formulation is chemically stable and can be stored at least for 8 hours and that this pharmaceutical formulation allows the sterile filtration using suitable filter material(s) t loss of activity. it has been found that fluoro-radiolabeled stilbene are solubilized and stabilized by the ation of present invention, Using this formulation, dilutions needed for adjustment of W0 2012/175641 activity can be made in a wide range of dilution ratios, allowing the precise adjustment for any t at any given time of the shelf life. it combines good local tolerability with easy applicability within the manufacturing process for the radiolabeled PET tracer.

Sterile filtration step is ary for providing a sterile parenteral pharmaceutical ation and the like for obtaining a suitable pharmaceutical solution for pharmaceutical use. Unfortunately, a critical loss of PET tracer is in many cases observed. Thus, there is a need for improving the purification steps leading to an increase of the radio—labelling yield.

It has been surprisingly found that the pharmaceutical formulation of the present invention is successfully used with a sterile filter reducing adsorption onto a sterile filter of the pharmaceutical.

The invention is directed to formulations of ilic Amyloid beta ligand stilbene and more particularly to formulations, which are capable to be administered parenterally e.g. enously, wherein the lipophilic Amyloid beta ligand stilbene is a isF-Iabeled pharmaceutical thereof. Further, the invention is directed to a method for sterile filtration of said pharmaceutical ation.

Detailed description The present invention concerns formulations comprising pharmaceuticals eg. radiotracer, wherein the pharmaceutical formulation is suitable for parenteral administration into mammals.

In a first aspect, the invention is directed to pharmaceutical formulations comprising: - Lipophilic Amyloid beta ligand stilbene and suitable salts thereof, - Ethanol, - Polyether, - Ascorbic acid, and - Sodium ascorbate.

Preferably, the ion is directed to ceutical formulations comprising: - 0.03 GBq/mL to L Lipophilic Amyloid beta ligand stilbene when F is 18F or 0.01 pg/mL to 5 pg/mL Lipophiiic Amyloid beta ligand stilbene and suitable salts thereof, - 8% v/v to 25% v/v l, .. t0% wlv to 25% w/v Polyether, W0 2012/175641 _ 3 - - 0.01% to 3% w/v Ascorbic acid, and - 0.01% to 20% w/v Sodium ascorbate. ngophilic Amyloid beta ligand stilbene: The term stilbene as used herein, refers to compounds of formula A Y / \x R2 FormulaA wherein, X is selected from the group comprising C and N, 1O Y is selected from the group comprising C and N, R1 is NR3R4, preferably, R3 is ) alkyi, preferably, R4 is selected from the group comprising H and Boo (ted—butoxycarbonyl), R2 is selected from the group comprising (O-CH2)n-F, )nnOR5, OH, preferably, R5 is selected from the group comprising H, O-SOZ-Re, n is selected from the group comprising 1, 2, 3 and 4. preferably, R1 is NHCH3.andl or preferably, (O-CH2)n-F and,l or preferably, Y = C andil or preferably, X = C and! or preferably, n = 3 and/ or More ably, lipophilic Amyioid beta ligand stilbene is Methyl~[4—((F){4-[2—(2~propoxy-ethoxy)-ethoxyi—phenyl}-vinyl)—phenyl]—amine wherein F is fluorine atom that is 1BF or 19F and suitable salts thereof.

Even more preferably, Lipophilic Amyioid beta ligand stilbene is Methyl-[4-((F)—2—{4n[2~(2-propoxy-ethoxy)—ethoxy]-phenyl}-vinyl)-phenyl]—amine ing to Figure 1 below or Methyl—[4-(C3F)—2-{4—[2-(2—propoxy—ethoxy)*ethoxy]-phenyl}-vinyl)—phenyl]- amine according to Figure 2 below.

\ O oA/Owo/VF Methyl-[4-((F)-2—{4-[2-(2-propoxy-e thoxy)-ethoxy}—phenyl}-vinyl)-pheny t]—amine Fig. 1 Compound 1 O \ O o/\/O\/\o/\/F1B Methyl-[4-((F18)—2-{4-[2-(2-propoxy-e thoxy)»ethoxy]—phenyl}—vinyl)—pheny l]—amine Fig. 2 Compound 2 Preferably, the nd 1 according to Figure 1 or compound 2 ing to Figure 2 or a mixture thereof is present in the pharmaceutical formulation in an amount of about 0.01 ug/mL to 5 pg/mL, more ably in an amount of about 0.01 to 3.5 uglmL. Even more preferably, compound 1 or 2 or a mixture thereof is/are present in the pharmaceutical 1O formulation in an amount of about 3pg/mL.

When F is 18F, then the lipophiiic Amyloid beta ligand stiibene is a PET tracer present in the pharmaceutical formulation pursuant to the invention at the dose of 0.03 GBq/mL to 5GBqlmL, preferably 0.03GBq/mL to 3 GBq/mL.

Ethanol: in a preferred ment, ethanol is present in the pharmaceutical formulation in an amount of about 8% WV to 30% vlv. Preferabiy, the ethanol is present in a maximum amount of 25% v/v or 20% V/V. More preferably, the ethanol is present in an amount of about 10% Viv to 15% vlv, more preferably 15% Viv. Preferably, the ethanol is a 96% up to 100% ethanol.

Preferably, ethanol is in an amount of about 15% v/v.

Poiyether: in a preferred embodiment, the her is t in the pharmaceutical formulation in an amount of about 10% WA! to 25% w/v. ably, the polyether is present in an amount of W0 2012/175641 about 10% w/v to 20 % w/v, more preferabiy 20%wi'v. Polyether is preferably a thyiene glycol) (PEG), such as PEG 300, PEG 400 or PEG 1500.

Preferabiy, pclyether is PEG 400 in an amount of about 20% w/v. ic acid: in a preferred embodiment, ic acid is present in the pharmaceuticai formulation in an amount of 0.01% to 3% w/v. Preferably, ic acid is present in an amount of about 0.01% w/v to 1.5 % w/v, more preferably is present in an amount of about 0.44% w/v.

Sodium ascorbate: in a preferred embodiment, sodium ascorbate is present in the pharmaceutical formulation in an amount of 0.01% to 20% wlv. Preferably, sodium ascorbate is present in an amount of about 1.5% w/v to 5 % w/v, more preferably is present in an amount of about 2.88 % w/v.

Preferably, the invention is directed to pharmaceutical formulations comprising: - Lipophiiic Amyloid beta ligand stilbene and suitable saits f, ~ Ethanol, ~ Poiy(ethylene giycol), - Ascorbic acid, and - Sodium ascorbate.

More preferably, the invention is directed to pharmaceuticai ations sing: - Methyl-[4-((F){4~{2-(2-propoxy~ethoxy)—ethoxy]-phenyl}-vinyl)-phenyl1— amine or Methyinizi—(CaF)—2-{4—[2-(2-propoxy«ethoxy)—ethoxy]—phenyl}- vinyI)-phenyi]~amine or mixture thereof, and suitable salts thereof, - Ethanoi, - Pciy(ethylene glycol), - Ascorbic acid, and - Sodium ascorbate.

Even more preferably, the invention is directed to pharmaceutical formulations comprising: - 0.03GBqlmi. to SGBqlmL Methyl-[4-((1BF)—2—{4-[2—(2-propoxy—ethoxy)- ethoxy}-phenyl}-vinyl)-phenyI]-amine and suitable salts thereof, - 8% v/v to 25% W l, - 10% w/v to 25% w/v Poiy(ethyiene glycci), - 0.01 % to 3% w/v Ascorbic acid, and - 0.01% to 20% wlv Sodium ascorbate.

Even more preferabiy, the invention is directed to pharmaceutical formulations comprising: - 5 _ 0.03GBquL to SGBq/mL Methyl-[4K18F){4~[2~(2~propoxy—ethoxy)- ]—phenyi}-vinyl)-phenyll-amine and suitable salts thereof, % v/v to 15% V/V Ethanol, % w/v to 20% w/v Poiy(ethyiene glycol), 0.01% to 1.5% wlv Ascorbic acid, and 1.5% to 5% w/v Sodium ascorbate.

Even more ably, the invention is directed to pharmaceutical formulations comprising: 0.03GBqlmL to 5GBq/mL Methyi-{4—(C3F)—2—{4-[2—(2-propoxy—ethoxy)- ethoxyI—phenyl}-vinyl)-phenyl]—amine and suitabie salts thereof, %v/v Ethanol, % wlv PEG 400, 0.44% w/v Ascorbic acid, and 2.88% w/v Sodium ascorbate.

Even more preferably, the invention is directed to pharmaceutical formulations comprising: 001 uglmL to 5 uglmi. MethyinI4-((F)-2—{4-[2-(2-propoxy-ethoxy)~ethoxy]— phenyl}-vinyl)—phenyl]-a-mine or mixture of Methyl-[4-((F)-2—{4-[2-(2- propoxy~ethoxy)-eth0xy]-phenyl}-vinyl)-phenyl]—amine and Methyl~[4-((1BF)- 2~{4-[2-(2-propoxy-ethoxy)-ethoxy}~phenyl}-vinyI)-phenyl]-amine, and suitable salts thereof, 8% vlv to 25% v/v Ethanol, % w/v to 25% w/v thylene glycol), 0.01% to 3% w/v ic acid, and 0.01% to 20% w/v Sodium ascorbate.

Even more preferably, the invention is directed to pharmaceutical formulations comprising: 0.01 pglmL to 5 pglmL Methyl-[4-((F)—2-{4-[2-(2~propoxy-ethoxy)»ethoxy}- phenyl}—vinyl)~phenyl]-amine or mixture of Methyl~[4-((F)~2—{4-[2-(2« pmpoxy-ethoxy)—ethoxyiaphenyi}-vinyl)-phenyl]-amine and Methyl-[4~((13F)« 2—{4-[2~(2-propoxy—ethoxy)-ethoxy}-phenyi}-vinyl)-phenyl]-amine, and suitable salts thereof, % v/v to 15%v/v l, % w/v to 20% w/v thyiene glycol), 0.01 % to 1.5% w/v Ascorbic acid, and 1.5% to 5% wlv Sodium ascorbate.

W0 2012/175641 _ 7 _ Even more preferably, the invention is directed to pharmaceutical formulations comprising: - 3 uglmL Methyi-[4-((F){4-[2-(2—propoxy—ethoxy)~ethoxy]-phenyl}-vinyi)— phenyll-amine or mixture of Methyl-[4-((F){4-[2-(2—propoxy—ethoxy)- ethoxy]-phenyl}~vinyl)-phenyi]—amine and Methyl-[4—((1sF)—2-{4-[2~(2~ y-ethoxy)-ethoxy]—phenyl}«vinyi)-phenyi]~amine, and suitable salts thereof, — 15%vlv Ethanol, - 20% w/v PEG 400, - 0.44% wlv ic acid, and - 2.88% w/v Sodium ate.

Preferably, the pharmaceutical formulation comprises a mixture of compounds 1 and 2 according to Figures 1 and 2 or a e of suitabie salts thereof.

The formulations of the t invention are pharmaceutical formulations suitable for parenteral administration into mammals for conducting PET imaging.

The ceutical formulation has a pH of about 4.5 to 8.5, preferably 5 to 6, which is le for injection in patient.

In a second aspect, the invention is directed to a method for preparing the pharmaceuticai formuiations of the present invention comprising a lipophilic Amyloid beta iigand stilbene by general Formula A, or the Figures 1 and 2 as set out below.

Lipophilic Amyloid beta ligand stilbene: The term stilbene as used in the second aspect, refers to compounds of formula A Y / \X R2 Formula A wherein, X is selected from the group comprising C and N, Y is selected from the group comprising C and N, R1 is NR3R“, preferably, R3 is (C1-C4) alkyl, preferabiy, R4 is selected from the group comprising H and Boo (tort-butoxycarbonyi), R2 is selected from the group comprising (O—CH2)n-F, (O—CH2)n—OR5, OH, preferably, R5 is selected from the group comprising H, O-SOQ-Re, n is ed from the group comprising 1, 2, 3 and 4. ably, R1 is NHCH3.andl or preferably, (O-CH2)n-F and;r or preferably, Y x C and! or 1O preferably, X = C and! or preferably, n = 3 ancllr or More preferably, lipophiiic Amyloid beta ligand stilbene is Methyl-{4-((F){4-[2-(2-propoxy-ethoxy)-—ethoxy]-phenyl}-vinyl)-phenyl]-amine wherein F is fluorine atom that is 18F or 19F and suitable salts f.

Even more preferably, Lipophilic Amyloid beta ligand stilbene is Methyl-[4-((F)~2—{4-[2—(2-propoxy~ethoxy)-ethoxy}~phenyl}-vinyl)—phenyl]-amine according to Figure 1 below or Methyl—{4—(C8F)—2-{4~[2—(2-propoxy—ethoxy)-ethoxy]—phenyi}-vinyl)-phenyl]— amine according to Figure 2 below.

O \ O O/VOWO/VF Methy|~[4—((F)-2—{4-[2-(2-propoxy-e thoxy)-ethoxy}-phenyl}-vinyi)-pheny ne Fig. 1 Compound 1 O \ O 0/\/0\/\o/\/F1B Methyl-[4-((F18)-2—{4—[2—(2-propoxy~e -ethoxy]—phenyl}-vinyl)—pheny l]-amine Fig. 2 Compound 2 W0 2012/175641 2012/062034 , g _ Preferably, the lipophilic Amyloid beta ligand stilbene is a Methyl-[4-((F)—2—{4—{2—(2-propoxy- ethoxy)—ethoxy]-phenyl}-vinyl)-phenyl}—amine wherein F is fluorine atom that is 1E’F or 19F or mixture thereof.

The method comprises the steps of: - iisation of lipophilic Amyloid beta ligand stilbene in ethanoi, - Adding the l on of first step into a mixture of polyether, ascorbic acid, and sodium ascorbate. ments disclosed above for lipophilic Amyloid beta ligand stilbene according to the general Formula A, and the Figures 1 and 2, ethanol, polyether, ascorbic acid, and sodium ascorbate are included within the below context of a method for preparation.

Preferably, the method comprises the steps of: ‘15 - Solubilisation of Methyl-[4-((F){4-{2-(2—propoxy-ethoxy)—ethoxy]-phenyl}-vinyl)—phenyl]~amine or mixture of Methyl—[4—((F){4-[2-(2-propoxy-ethoxy)~ethoxy]—phenyl}—vinyl)~ phenyl]—amine and Methyl-[4463F)~2~{4—[2-(2-propoxy-ethoxy)-ethoxy1—phenyl}- vinyl)~phenyl]-amine in ethanol, and - Adding the l on of first step into a mixture of polyether, ascorbic acid, and sodium ascorbate.

More preferably, the method comprises the steps of: - Solubilisation of 3 ug/mLof Methyl-[4-((F)~2—{4—[2-(2—propoxy-ethoxy)—ethoxy]-phenyl}-vinyl)-phenyl]—amine or mixture of Methyl-[4-((F)—2—{4—{2—(2~propoxy-ethoxy)—ethoxy]-phenyi}—vinyl)~ phenyl]-amine and Methyl—[4—((1BF)-2—{4-[2—(2—propoxy-ethoxy)~ethoxy}-phenyl}- -pheny|]-amine in ethanol, and - Adding the ethanol solution of first step into a mixture of PEG 400, ic acid, and sodium ascorbate resulting in a final concentration of 15% vlv ethanol, 20% wlv PEG 400, 0.44% wlv ascorbic acid, and 2.88% w/v sodium ascorbate.

In a third aspect, the invention is directed to a method for sterile filtration of the pharmaceutical formulations of the present invention comprising a lipophiiic Amyloid beta ligand stilbene according to the general Formula A, and according to Figures 1 and 2 as set out below.

W0 2012/175641 Ligoghilic Amyloid beta ligand stilbene: The term stilbene as used in the third aspect, refers to compounds of formula A Y / \X R2 Formula A wherein, X is ed from the group comprising C and N, Y is selected from the group comprising C and N, R1 is NR3R4, preferably, R3 is (C1-C4) alkyi, ably, R4 is selected from the group comprising H and Boo butoxycarbonyl), R2 is selected from the group comprising )n-F, (O-CH2)n-OR5, OH, preferably, R5 is selected from the group comprising H, Rs, n is selected from the group comprising 1, 2, 3 and 4. preferably, R1 is NHCH3.andl or preferably, (O-CH2)n—F and/ or preferably, Y = C and! or preferably, X = C and! or preferably, n = 3 and! or More preferably, lipophilic Amyloid beta ligand stiibene is Methyl-[4-((F)-2—{4—[2-(2-propoxy-ethoxy)~ethoxy]—phenyi}-vinyI)-phenyl]—amine wherein F is fluorine atom that is 18F or 19F and suitable salts thereof.

Even more preferably, Lipophilic Amyloid beta ligand stiibene is Methyl~[4-((F)-2—{4—{2—(2-propoxy-ethoxy)~ethoxy]—phenyl}-vinyi)—phenyI]—amine according to Figure 1 below or Methyl-[4-((1aF)~2-{4—[2-(2-propoxy—ethoxy)-ethoxy]-phenyl}-vinyl)-phenyl]— amine according to Figure 2 below.

WO 75641 _ 1 1 - Methyl-[4-((F){4-[2~(2-propoxy-e thoxy)~ethoxy]-pheny|}-vinyI)-pheny |}~amirie Fig. 1 Compound 1 C \ O owe/saw Methyl—[4—((F18){4-[2-(2-propoxy~e thoxy)—ethoxy]—phenyl}-vinyE)-pheny I]—amine Fig. 2 Compound 2 Preferably, the lipophilic d beta ligand stilbene is Methyl-[4-((F)—2-{4~[2—(2-propoxyethoxy xy]-phenyI}—vinyl)-pheny|1~amine wherein F is fluorine atom that is 18F or 19F or e thereof. it was surprisingly found that the tion onto sterile filter is strongly decreased when the pharmaceutical formulation of the present invention is used. The sterile filter can be standard sterile filter used for radiotracer filtration. Such sterile filters are well known in the art.

The method for sterile filtration of the pharmaceutical formulations of the present invention comprises the step of giving the pharmaceutical formulation of the present invention onto a sterile filter.

The ilic Amyloid beta ligand stilbene according to the general Formula A, and the Figures 1 and 2 as described above are hydrophobic substances and the claimed ceutical formulations allow the dissolution of the substances at the required doses. It is well known and acknowledged that hydrophobic filters have an ty for hydrophobic substances. It was surprisingly found that the pharmaceutical formulations of the present invention prevent this adsorption and allows a high yield sterile filtration.

Preferably, the method for sterile filtration of the pharmaceutical formulations of the present invention comprises the step of giving the pharmaceutical formulation of the present invention onto polytetrafiuoroethyiene (PTFE) sterile filter e.g. Sartorius Minisart 0.2 pm (Order number 16596) or Polyvinyiidene Fluoride (PVDF) sterile filter e.g. ore Millex 0,2 pm SLGV033RS.

More preferably, the hydrophobic filter is polytetrafluoroethylene (PTFE) e filter.

Optionally, the sterile filtration method is preceded by the preparation of the pharmaceutical formulation of the present invention. 1O Embodiments disclosed above for the iipophiiic Amyloid beta ligand stilbene ing to general Formula A, and the Figures 1 and 2, ethanol, polyether, ascorbic acid, and sodium ascorbate are also included within the below context of the fourth, fifth and sixth aspect as follows: Lipoghilic Amyioid beta ligand stilbene: The term stilbene as used within the context of the below fourth, fifth, and sixth aspect of the invention, refers to compounds of formula A Y\/ 2 X R Formula A wherein, X is selected from the group comprising C and N, Y is selected from the group sing C and N, R‘ is NR3R4, preferably, R3 is ) alkyl, preferably, R4 is selected from the group comprising H and Boo (iert—butoxycarbonyl), R2 is selected from the group comprising (O—CH2)n-F, (O-CH2)n-OR5, OH, preferably, R5 is selected from the group sing H, 0R6, n is selected from the group comprising 1, 2, 3 and 4. preferably, R1 is NHCH3.ahd/ or preferably, )n~F and! or preferably, Y = C and] or W0 2012/175641 preferabiy, X = C and! or ably, n = 3 andir or More preferably, lipophilic Amyloid beta ligand stiibene is Methyi~[4-((F)—2—{4-[2«(2-propoxy-ethoxy)-ethoxy]-phenyl}—vinyl)-phenyf]—amine wherein F is fluorine atom that is "’F or19F and suitable salts thereof.

Even more preferably, Lipophilic Amyloid beta iigand stilbene is Methyl-[4-((F)-2—{4-[2—(2-propoxy-ethoxy)—ethoxy]-phenyl}—vinyI)-pheny|}-amine according to Figure 1 below or Methyl«[4~((1SF){4—[2-(2—propoxy~ethoxy)-ethoxy]—phenyl}-viny|)-phenyl]— amine according to Figure 2 below.

O0/\/0\/\\O/\\/F Methyl-[4-((F)-2—{4—[2—(2—pr0poxy-e thoxy)—ethoxy]—phenyl}-vinyl}-pheny lI-amine Fig. 1 Compound 1 O o/\/O\/\o/\/F13 Methyl-{4((F18)—2-{4—[2-(2-propoxy-e thoxy}-ethoxy]-phenyl}—vinyi)—pheny IE—amine Fig.2 Compoundz In a fourth aspect, the invention is directed to the use of the pharmaceutical formulations of the present invention for the manufacture of a suitable PET imaging formulation for parenteral administration to s. in a fifth aspect, the invention is directed to the use of the pharmaceutical ations of the present invention for the cture of a suitable radiotherapy medicament for parenteral administration to mammals.

In a sixth aspect, the inventors have found a method for obtaining pharmaceutical formulations nt to the invention that can be easiiy integrated into the pharmaceutical ses ted by automated devices known in the art.

W0 2012/175641 - 14 The method for the preparation of a sterile filtered pharmaceutical formulation comprises the steps of: - Obtaining a radiotracer via an automated device for pharmaceutical use, - Purification of the racer using phase-extraction cartridges or s, wherein the radiotracer is eluted with a composition sing ethanol, optionally solubilisation of radiotracer in ethanol, - Adding the ethanol eluat into a mixture of poiyether, ascorbic acid, and sodium ascorbate for obtaining the pharmaceuticai formulations of the present invention and - Sterile filtration of the ceutical formulation according to the present invenfion.

The radiotracer is preferably a lipophiiic Amyloid beta ligand stilbene according to the general Formula A, and the Figures 1 and 2, and more ably Methyl-[Ii-((1aF){4-[2—(2-propoxy— ethoxy)-ethoxy}—pheny|}—vinyl)-phenyl]—amine, and ethanol, poiyether, ascorbic acid, and sodium ascorbate as d above.

The sterile filter is a polytetrafluoroethyiene (PTFE) or Polyvinylidene Fluoride (PVDF) steriie filter. Preferably, the sterile filter is trafluoroethylene (PTFE) sterile filter.

The invention is also directed to: - A device for the preparation of the pharmaceutical formulations pursuant to the invention, wherein the radiotracer is preferably obtained via an automated device for pharmaceuticai use.

Definitions The terms used throughout the entire specification and within the claims of the t invention are defined below but are not limiting the scope of the invention. ble salts" of the compounds according to the ion include salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesuiphonic acid, ethanesuiphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disul-phonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. ble salts" of the compounds according to the invention atso include salts of customary bases, such as, by way of example and by way of preference, alkaii metal saits (for example W0 2012/175641 sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamlne, diethanolamine, triethanolamine, dlcyclohexylamine, dimethylaminoethanol, procaine, zylamine, N- methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

“Halogen" means , iodo, Fluoro and Bromo. Preferably, n means lodo or Bromo.

The terms "polyether/polyethers” refer to compounds with more than one ether group. In particular, said term refers to polymers which contain the ether onal group in their main chain. While the term generally refers to polymers like polyethylene glycol and polypropylene glycol, low lar compounds such as the crown ethers may mes be included. in this regard, the term “glycol" refers to low to medium range molar mass polymers.

A “pharmaceutical or radiotracer" is a compound suitable for use in medical applications such as nuclear imaging, chemotherapy and the like. Pharmaceuticals are generally provided in a pharmaceutically~acceptable carrier. PET tracer is a racer.

A “suitable pharmaceutical formulation” is rendered suitable for pharmaceutical use by adjusting the pH, concentration or other al characteristics of pharmaceutical preparation well known in the art.

The sions “chemically stable, stability” in accordance with the t invention reflects a concentration interval of the compounds according to general Formula A and compounds according to the Figures 1 or 2 or a mixture thereof or suitable salts thereof as claimed for the provided pharmaceutical formulations of at least 95% to 105%, preferably 98% to 105% after at least 12 hours storage relative to the respective concentration after preparation pursuant to the invention, further characterized in that the respective solutions remain clear without any visible particles after said at least 12 hours storage. The term “concentration interval of compound 2" as used herein is corrected for the decay of ne— Further, the sions "chemically stable, stability" in accordance with the present ion refer to pharmaceutical formulations comprising the compound according to Figure W0 2012/175641 2, characterized in that said formulations provides the compound 2 with a radiochemical purity of >93%, preferably >95%.

The term “storage” refers to storage conditions from 0°C to 40°C, preferabiy, to storage conditions from 10°C to 40°C, more preferably to ambient storage conditions of 25 +l— 10°C.

The terms “parenteral/parenterally" refer to the introduction of a medication or pharmaceutical formulation pursuant to the invention into the subject or patient to be administered for PET imaging via a route other than the gastro-intestinal tract, in particular via infusion intravenously, injection or impiantation.

Unless otherwise specified, when generally referring in the specification and the accompanied claims to “compound! nds” or und/ compounds" of Formula A, and the Figures 1 and 2 according to the present invention as well as when ing to any pharmaceutical composition or formuiation thereof in the specification and the accompanied claims per se all of the corresponding hydrates, es, salts, and xes thereof are ‘15 included.

W0 2012/175641 2012/062034 _ 17 _ Abbreviations '.18.

Experimental data Example 1. Compounds 1 (fluoro-iabeted) and 2 (fluoro-radiolabeted) Compound 1 021H26FN03 359.43 g/mol Compound 2 C21H2618FNO3 358.43 g/mol Example 2. Formulations comprising Iipophilic Amyloid beta ligand stilbene l procedure To mimic the manufacturing procedure in the radio pharmacy department the following ure was developed.

Formulation 1 containing Compound 1: Ascorbic acid and sodium ate were weighed together. Then, water and PEG were added and the mixture was stirred. The lipophilic d beta ligand stilbene compound 1 was weighted and dissolved in ethanol. This on was added to the mixture of polyether, ascorbic acid, sodium ascorbate and water and the preparation was mixed.

Com-oundi Ethanol 96% P0! eth lene I col PEG 400 Ascorbic acid Sodiumascorbate ad 10 mL Since solutions of sttlbene are sensitive to light, the solutions were stored under light protection.

WO 75641 .. 19 _ Example 3. Stability of Formulation ising HCi salt of nd 1 for 12 hours at room temperature (RT) Formulation 1 was ed containing 3 ug/mL of Compound 1 (according to 3.3 pglmL HCI sait of compound 1). The assay was analysed after preparation and after 12 hours storage according to the short shelf iife of PET imaging , typically ed between 6 and 10 hours. Eight individual batches were prepared and analysed for assay.

Table 1 indicates the results of stability testing after 12 hours of n = 8 individually manufactured batches.

Tab. 1 Content of Comound 1 after 12h stora- e at three different stora- e conditions Storage Visual Content of Compound 1 mutation in % condition inspection in % after 12 h (min. — max.) (min. — max.)1 prior filtration ' after filtration (Minisart HY 0.2 pm) clear solution, 98.9 97.0 no visible (97.4 ... 100.1) (95.6 —- 97.8) particles 1 concentration after 12 hours relative to the respective concentration after preparation which was in a range of2.97 to 3.14 pgi’mL.

Minisart HY 0.2 pm is a steriie filter with PTFE hydrophobic membrane.

The assay of compound 1 stays within the 95% to 105% interval within 12 hours observation time and there is no trend of a reduction over time. Compound 1 can be considered to be chemicatly stable in the formulation.

WO 75641 - 20 Example 4. Hydrophobic filters and adsorption Formulation 1 comprising compound 1 was prepared as indicated above and filtered using selected sterile filters. Adsorption of compound 1 was determined by measuring the concentration of Compound 1 before and after filtration of 10 ml. of Formulation 1 and uent calculation of the adsorption. Table 2 tes the results of tion experiments using different s.

Tab. 2 Compound 1 filter adsorption MinisartH‘gh F'W Pall HP2002 Millex CV Minisart HY Minisart 02 pm 0.22 pm 0.2 pm SRP25 0.2 (Sartorius (Millipore) (Sartorius urn Stedim) Stedim) (Sartorius Stedim) 16532 HP2002 SLGV033RS HYK 17575 Filter Polyether— Versapor® R PVDF PTFE PTFE membrane sulfone hydrophobic hydrophobic hydrophobic hydrophobic hydrophobic material that was rendered hydrophilic by modification.

Filtrate(%) 63.91MB 85.8i03 _4.0+0.7_8.8:l:0.6_94+0.3 tion 36 1 % 142 % Only the filter units containing PTFE and PVDF show a low amount of compound 1 adsorbed onto the filter material.

Example 5. Adsorption and formulation composition using nd 1 Formulation 1 was prepared as described in Example 2. Formulation 2 and Standard Formulation were analogically prepared to the method described in Example 1.

Tab. 3 Composition of formulations tested . Standard Formulation 1 Compound 1 30.0 pg 30.0 3.19 Ethanol 96% Ascorbic aCld 0.044 g - - 21 ..

Sodium ascorbate 0.288 g 0.288 g _ PEG 400 2.0 g lsotonic saline - 8 5 ml solution ad‘iOml ad10m| ad10 ml Tab. 4 Filter adsorption of different formulations using Minisart HY filter (art.no. HYK), Formulation 1 Formulation 2 Standard Formulation Filtrate (%) 98.8 i 0.6 74.7 i 6 42.8 i 2.4 Adsorption 25.3 % 57.2 % Tab. 5 Filter adsorption of ent formutations using Millex GV filter (art.no.SLGV033RS), Formulation 1 Formulation 2 Standard Formulation Filtrate (%) 55.9 :i: 2.3 40.8 1r 0.8 Adsorption 6.0 % 44.1 % 59.2 % _ 22 -

Claims (15)

Claims 1.

1. A pharmaceutical ation comprising: - Lipophilic Amyloid beta ligand stilbene and suitable salts thereof, - Ethanol, - Polyether, - Ascorbic acid, and - Sodium ascorbate.

2. The pharmaceutical formulation according to claim 1 wherein the lipophilic Amyloid beta ligand stilbene is —{4~((F)—2-{4-[2-(2-propoxy~ethoxy)-ethoxy]-phenyl}- vinyl)-phenyl]-amine or mixture of IV]ethyl-[4-((F){4-[2-(2-propoxy~ethoxy)-ethoxy]- }-vinyl)-phenyl]—amine and Methyl-[4-((18F)—2-{4-[2-(2-propoxy-ethoxy)~ethoxy]— 15 phenyl}—Vinyl)-phenyl}-amine, and suitable salts thereof.

3. The pharmaceutical formulation according to claim 1 or 2 and d as follows: 0.0BGBquL to SGBq/mL Methyl—{4-((18F){4—[2-—(2vpropoxy-ethoxy)-ethoxy]- phenyl}-vinyl)~phenyl]-amine, 20 8% v/v to 25% V/V Ethanol, 10% wlv to 25% w/v Poly(ethylene glycol), 0.01% to 3% wlv ic acid, and 0.01% to 20% WW Sodium ascorbate.

25 The pharmaceutical formulation according to claim 3 and defined as follows: ODSGBqlmL to l. Methyl-{4-((18F)-2~{4-[2-(2—propoxy-ethoxy)-ethoxyl- phenyl}-vinyl)-phenyi]—amine, 15%vlv Ethanol, 20% WA! PEG 400, 30 0.44% w/v Ascorbic acid, and 2.88% w/v Sodium ascorbate.

5. The pharmaceutical formulation according to claim 1 or 2 defined as follows 0.01 pglmL to 5 ug/mL Methyl—[4-((F)-2—{4-[2-(2-propoxy—ethoxy)—ethoxy]-phenyl}- 35 vinyl)~phenyl]~amine or mixture of Methyl-[4-((F){4-[2-(2-propoxy«ethoxy)« ethoxy]-phenyl}-vinyl)-phenyl]-amine and -[4-((18F){4-[2-(2-propoxyethoxy )-ethoxy]-phenyl}-vinyl)-phenyl]-amine, and suitable salts thereof, - 8% v/v to 25% v/v Ethanol, - 10% w/v to 25% w/v Poly(ethylene glycol), 5 - 0.01% to 3% w/v Ascorbic acid, and - 0.01% to 20% w/v Sodium ascorbate.

6. The pharmaceutical formulation according to claim 5 and defined as follows - 3 µg/mLMethyl-[4-((F){4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}-vinyl)-phenyl]- 10 amine or mixture of Methyl-[4-((F){4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}- vinyl)-phenyl]-amine and Methyl-[4-((18F){4-[2-(2-propoxy-ethoxy)-ethoxy]- phenyl}-vinyl)-phenyl]-amine, and suitable salts thereof, - 15%v/v Ethanol, - 20% w/v PEG 400, 15 - 0.44% w/v Ascorbic acid, and - 2.88% w/v Sodium ascorbate.

7. A method for obtaining the pharmaceutical ation according to claims 1 to 6 comprising the steps of 20 - Solubilisation of lipophilic Amyloid beta ligand stilbene in ethanol, - Adding the ethanol solution of first step into a mixture of polyether, ascorbic acid, and sodium ascorbate.

8. The method according to claim 7 comprising the steps of 25 - Solubilisation of 3 µg/mL of Methyl-[4-((F){4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}-vinyl)-phenyl]-amine or mixture of Methyl-[4-((F){4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}-vinyl)-phenyl]- amine and Methyl-[4-((18F){4-[2-(2-propoxy-ethoxy)-ethoxy]-phenyl}-vinyl)- phenyl]-amine in ethanol and 30 - Adding the ethanol solution of first step into a mixture of PEG 400, ic acid, and sodium ascorbate resulting in a final tration of 15% v/v l, 20% w/v PEG 400, 0.44% w/v ascorbic acid, and 2.88% w/v sodium ascorbate.

9. A method for sterile tion of the pharmaceutical formulation according to claims 1 to 35 6, wherein the ceutical formulation is given onto a polytetrafluoroethylene (PTFE) or Polyvinylidene Fluoride (PVDF) sterile filter.

10. A method for the preparation of a sterile filtered ceutical ation comprising the steps: - Obtaining a radiotracer through an automated device for pharmaceutical use, - Purification of the radiotracer using a solid-phase-extraction cartridges or column, 5 wherein the radiotracer is eluted with a composition comprising ethanol, optionally solubilisation of radiotracer in ethanol, - Adding the ethanol eluat into a mixture of polyether, ascorbic acid, sodium ascorbate and water for obtaining the pharmaceutical formulation according to theclaims 1 to 6 and 10 - Sterile filtration of the pharmaceutical formulation, - wherein the radiotracer is a lipophilic Amyloid beta ligand stilbene and the e filter is a polytetrafluoroethylene (PTFE) or Polyvinylidene Fluoride (PVDF) sterile filter. 15

11. A method ing to claim 9 or 10, wherein the sterile filter is a polytetrafluoroethylene (PTFE) sterile filter.

12. A pharmaceutical formulation according to claim 1, substantially as herein described or exemplified.

13. A method ing to claim 7, substantially as herein described or exemplified.

14. A method ing to claim 9, substantially as herein described or exemplified. 25

15. A method according to claim 10, substantially as herein described or exemplified.