HK1197031B

HK1197031B - Preparations of fluorinated stilbene suitable for pet imaging

Info

Publication number: HK1197031B
Application number: HK14110500.6A
Authority: HK
Inventors: 卡尔斯腾．奥尔布里奇; 迈克尔．克劳斯; 安德里亚斯．伯克哈德; 安尼特．里克特; 雷纳．布劳恩
Original assignee: Life Molecular Imaging Limited
Priority date: 2011-06-21
Filing date: 2012-06-21
Publication date: 2017-04-07

Abstract

The invention is directed to formulations of lipophilic Amyloid beta ligand stilbene and more particularly to formulations which are capable to be administered parenterally e.g. intravenously, wherein the lipophilic Amyloid beta ligand stilbene is a fluorinated stilbene. Further, the invention is directed to a method for sterile filtration of formulations suitable for PET imaging of mammals pursuant to the invention.

Description

Formulations of fluorinated stilbene suitable for PET imaging

Technical Field

The present invention relates to formulations of lipophilic amyloid beta ligand stilbene, more particularly to formulations capable of parenteral administration such as intravenous injection, wherein the lipophilic amyloid beta ligand stilbene is a fluorinated stilbene as defined below. In addition, the present invention relates to a method for sterile filtration of a pharmaceutical formulation of the present invention suitable for PET imaging of mammals.

Background

Stilbene which can be used for Positron Emission Tomography (PET) imaging of patients are known from WO2003/018070A1 and WO2006/066104A 1. By using¹⁸The F radioisotope radiolabells the stilbene, however the radiolabelling is in the precursor of the stilbene and¹⁸F]in organic solution. The stilbene precursor may be in dry condition and optionally have inert pharmaceutically acceptable carriers and/or auxiliary substances added thereto, as well as reducing agents and optionally chelating agents. The fluoro-radiolabeled stilbene (PET tracer) solution may contain any additive such as pH controlling agents (e.g. acids, bases, buffers), stabilizers (e.g. ascorbic acid) or isotonicity agents (e.g. sodium chloride).

Ethanol, isopropanol, glycerol and polyethylene glycol are well known adjuvants for increasing solubility (WO 2001/68142).

Typically, PET supply centers produce hot stock solutions containing drugs on demand, which are injected into patients on a weekday. The hot stock solution must be stable and storable. Furthermore, a large amount of the novel synthetic PET tracer is lost in purification steps such as sterile filtration. To date, few formulations suitable for PET drugs have been disclosed.

Therefore, there is a need for a commercially acceptable suitable formulation comprising a PET agent characterized in that said PET agent exhibits low water solubility, i.e. a lipophilic PET agent, wherein said PET agent is amyloid beta ligand stilbene useful for PET imaging.

Surprisingly, it was found that the pharmaceutical formulation is chemically stable and can be stored for at least 8 hours and that the pharmaceutical formulation allows sterile filtration using a suitable filtration material without loss of activity.

It was found that fluoro-radiolabeled stilbene via the formulations of the present invention was soluble and stable. Using the formulation, the required dilution to modulate activity can be made over a wide range of dilution ratios, allowing precise modulation for any patient at any particular time during shelf life. It combines good local tolerance with ease of applicability in the manufacturing process of radiolabeled PET tracers.

A sterile filtration step is necessary to provide, inter alia, a sterile parenteral formulation for obtaining a suitable pharmaceutical solution for pharmaceutical use. Unfortunately, in many cases a large loss of PET tracer is observed. Therefore, there is a need for improved purification steps that can increase the radio-label yield.

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

SUMMARY

The present invention relates to formulations of lipophilic β amyloid ligand stilbene, more particularly to formulations capable of parenteral administration such as intravenous injection, wherein lipophilic β amyloid ligand stilbene is¹⁸F labeled drug. In addition, the invention relates to a method for sterile filtration of said pharmaceutical preparation.

Detailed Description

The present invention relates to a formulation comprising a drug, such as a radiotracer, wherein the pharmaceutical formulation is suitable for parenteral administration to a mammal.

In a first aspect, the present invention relates to a pharmaceutical formulation comprising:

lipophilic amyloid beta ligand stilbene and suitable salts thereof,

the reaction mixture of ethanol and water is added,

a polyether compound (I) having a polyether group,

ascorbic acid, and

sodium ascorbate.

Preferably, the present invention relates to a pharmaceutical formulation comprising:

when F is¹⁸F, from 0.03GBq/mL to 5GBq/mL lipophilic β amyloid ligand stilbene or from 0.01 μ g/mL to 5 μ g/mL lipophilic β amyloid ligand stilbene and suitable salts thereof,

8% v/v to 25% v/v ethanol,

10% w/v to 25% w/v of a polyether,

0.01% to 3% w/v ascorbic acid, and

0.01% to 20% w/v sodium ascorbate.

Lipophilic β amyloid ligand stilbene:

the term stilbene, as used herein, refers to a compound of formula A:

wherein the content of the first and second substances,

x is selected from the group consisting of C and N,

y is selected from the group consisting of C and N,

R¹is NR³R⁴，

Preferably, R³Is (C)₁-C₄) An alkyl group, a carboxyl group,

preferably, R⁴Selected from the group consisting of H and Boc (t-butyloxycarbonyl),

R²is selected from (O-CH)₂)_n-F、(O-CH₂)_n-OR⁵、OH，

Preferably, R⁵Selected from H, O-SO₂-R⁶

n is selected from 1, 2, 3 and 4.

Preferably, R¹Is NHCH₃And/or

Preferably, (O-CH)₂)_nF and/or

Preferably, Y ═ C and/or

Preferably, X ═ C and/or

Preferably, n is 3 and/or

More preferably, the lipophilic amyloid beta ligand stilbene is:

methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethyl]-phenyl } -vinyl) -phenyl]Amines and suitable salts thereof, in which F is a fluorine atom¹⁸F or¹⁹F。

Even more preferably, the lipophilic β amyloid ligand stilbene is methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] ethoxy as depicted in FIG. 1 below]-phenyl } -vinyl) -phenyl]-amine or methyl- [4- (a) as depicted in figure 2 below¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-an amine.

Methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -phenyl } -vinyl) -phenyl ] -amine

FIG. 1 Compound 1

Methyl- [4- (A)¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amines

FIG. 2 Compound 2

Preferably, compound 1 depicted in figure 1 or compound 2 depicted in figure 2, or a mixture thereof, is present in the pharmaceutical formulation in an amount of about 0.01 to 5 μ g/mL, more preferably, in an amount of about 0.01 to 3.5 μ g/mL. Even more preferably, compound 1 or compound 2, or a mixture thereof, is present in the pharmaceutical formulation in an amount of about 3 μ g/mL.

When F is¹⁸F, the lipophilic β amyloid ligand stilbene is a PET tracer, which is present in the pharmaceutical formulation of the invention at a dose of 0.03 to 5GBq/mL, preferably 0.03 to 3 GBq/mL.

Ethanol:

in a preferred embodiment, the ethanol is present in the pharmaceutical formulation in an amount of about 8% to 30% v/v. Preferably, ethanol is present in a maximum amount of 25% v/v or 20% v/v. More preferably, ethanol is present in an amount of about 10% v/v to 15% v/v, more preferably 15% v/v. Preferably, the ethanol is 96% up to 100% ethanol. Preferably, ethanol is in an amount of about 15% v/v.

Polyether:

in a preferred embodiment, the polyether is present in the pharmaceutical formulation in an amount of about 10% w/v to 25% w/v. Preferably, the polyether is present in an amount of 10% w/v to 20% w/v, more preferably 20% w/v. The polyether is preferably poly (ethylene glycol) (PEG), such as PEG300, PEG400, or PEG 1500.

Preferably, the polyether is PEG400 in an amount of about 20% w/v.

Ascorbic acid:

in a preferred embodiment, the ascorbic acid is present in the pharmaceutical formulation in an amount of 0.01% to 3% w/v. Preferably, the ascorbic acid is present in an amount of 0.01% to 1.5% w/v, more preferably, 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% w/v. Preferably, the sodium ascorbate is present in an amount of about 1.5% w/v to 5% w/v, more preferably, in an amount of about 2.88% w/v.

lipophilic amyloid beta ligand stilbene and salts thereof,

the reaction mixture of ethanol and water is added,

a poly (ethylene glycol) having a high degree of polymerization,

ascorbic acid, and

sodium ascorbate.

More preferably, the present invention relates to a pharmaceutical formulation comprising:

methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethyl]-phenyl } -vinyl) -phenyl]-amine or methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]Amines or mixtures thereof and suitable salts of the above,

the reaction mixture of ethanol and water is added,

a poly (ethylene glycol) having a high degree of polymerization,

ascorbic acid, and

sodium ascorbate.

Even more preferably, the present invention relates to a pharmaceutical formulation comprising:

methyl- [4- (L) 0.03GBq/mL to 5GBq/mL¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-an amine and suitable salts thereof,

8% v/v to 25% v/v ethanol,

10% w/v to 25% w/v of poly (ethylene glycol),

0.01% to 3% w/v ascorbic acid, and

0.01% to 20% w/v sodium ascorbate.

methyl- [4- (L) 0.03GBq/mL to 5GBq/mL¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amines and suitable salts thereof

10% v/v to 15% v/v ethanol,

10% w/v to 20% w/v of poly (ethylene glycol),

0.01% to 1.5% w/v ascorbic acid, and

1.5% to 5% w/v sodium ascorbate.

15% v/v of ethanol, with the proviso that,

20% w/v of PEG400,

0.44% w/v ascorbic acid, and

2.88% w/v sodium ascorbate.

0.01 μ g/mL to 5 μ g/mL of methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]Mixtures of amines and suitable salts of the above,

8% v/v to 25% v/v ethanol,

10% w/v to 25% w/v of poly (ethylene glycol),

0.01% to 3% w/v ascorbic acid, and

0.01% to 20% w/v sodium ascorbate.

10% v/v to 15% v/v ethanol,

10% w/v to 20% w/v of poly (ethylene glycol),

0.01% to 1.5% w/v ascorbic acid, and

1.5% to 5% w/v sodium ascorbate.

Even more preferably, the present invention relates to a pharmaceutical composition comprising:

3 μ g/mL of methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]Mixtures of amines and suitable salts of the above,

15% v/v of ethanol, with the proviso that,

20% w/v of PEG400,

0.44% w/v ascorbic acid, and

2.88% w/v sodium ascorbate.

Preferably, the pharmaceutical formulation comprises a mixture of compound 1 and compound 2 of figures 1 and 2 or a mixture of suitable salts of the foregoing.

The formulations of the present invention are pharmaceutical formulations suitable for parenteral administration to a mammal for PET imaging.

The pharmaceutical formulation has a pH of about 4.5 to 8.5, preferably 5 to 6, which is suitable for injection into a patient.

In a second aspect, the present invention relates to a process for the preparation of a pharmaceutical formulation according to the present invention comprising a lipophilic amyloid beta ligand stilbene of general formula a or figures 1 and 2 as described below.

Lipophilic β amyloid ligand stilbene:

the term stilbene, as used in the second aspect, refers to a compound of formula a:

wherein the content of the first and second substances,

x is selected from the group consisting of C and N,

y is selected from the group consisting of C and N,

R¹is NR³R⁴，

Preferably, R³Is (C)₁-C₄) An alkyl group, a carboxyl group,

R²is selected from (O-CH)₂)_n-F、(O-CH₂)_n-OR⁵、OH，

Preferably, R⁵Selected from H, O-SO₂-R⁶

n is selected from 1, 2, 3 and 4.

Preferably, R¹Is NHCH₃And/or

Preferably, (O-CH)₂)_nF and/or

Preferably, Y ═ C and/or

Preferably, X ═ C and/or

Preferably, n is 3 and/or

More preferably, the lipophilic amyloid beta ligand stilbene is:

FIG. 1 Compound 1

FIG. 2 Compound 2

Preferably, the lipophilic β amyloid ligand stilbene is methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amines in which F is a fluorine atom¹⁸F or¹⁹F, or mixtures of the foregoing.

The method comprises the following steps:

dissolving lipophilic amyloid beta ligand stilbene in ethanol,

adding the ethanol solution obtained in the first step into a mixture of polyether, ascorbic acid and sodium ascorbate

The preparation method includes the following embodiments of the lipophilic amyloid beta ligand stilbene, ethanol, polyether, ascorbic acid and sodium ascorbate as disclosed in general formula a above and depicted in fig. 1 and 2.

Preferably, the method comprises the steps of:

methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethyl]-phenyl } -vinyl) -phenyl]-amine or methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-aminesIs dissolved in ethanol, and

the ethanol solution of the first step is added to a mixture of polyether, ascorbic acid and sodium ascorbate.

More preferably, the method comprises the steps of:

3 μ g/mL of methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-the mixture of amines is dissolved in ethanol, and

the ethanol solution of the first step was added to a mixture of PEG400, ascorbic acid and sodium ascorbate to give a final concentration of 15% v/v ethanol, 20% w/v PEG400, 0.44% w/v ascorbic acid and 2.88% w/v sodium ascorbate.

In a third aspect, the present invention relates to a method for sterile filtration of a pharmaceutical formulation of the present invention comprising a lipophilic amyloid beta ligand stilbene of general formula a or fig. 1 and 2 as described below.

Lipophilic β amyloid ligand stilbene:

the term stilbene, as used in the third aspect, refers to a compound of formula A:

wherein the content of the first and second substances,

x is selected from the group consisting of C and N,

y is selected from the group consisting of C and N,

R¹is NR³R⁴，

Preferably, R³Is (C)₁-C₄) An alkyl group, a carboxyl group,

R²is selected from (O-CH)₂)_n-F、(O-CH₂)_n-OR⁵、OH，

Preferably, R⁵Selected from H, O-SO₂-R⁶

n is selected from 1, 2, 3 and 4.

Preferably, R¹Is NHCH₃And/or

Preferably, (O-CH)₂)_nF and/or

Preferably, Y ═ C and/or

Preferably, X ═ C and/or

Preferably, n is 3 and/or

More preferably, the lipophilic amyloid beta ligand stilbene is:

FIG. 1 Compound 1

FIG. 2 Compound 2

Preferably, the lipophilic β amyloid ligand stilbene is methyl- [4- ((F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy ] -ethoxy]-phenyl } -vinyl) -phenyl]-amines in which F is a fluorine atom¹⁸F or¹⁹F or mixtures of the above.

It was surprisingly found that the adsorption on the sterile filter is significantly reduced when using the pharmaceutical formulation of the present invention. The sterile filter may be a standard sterile filter for radiotracer filtration. Such sterile filters are well known in the art.

The method of sterile filtration of a pharmaceutical formulation of the present invention comprises the step of applying a pharmaceutical formulation of the present invention to a sterile filter.

The lipophilic amyloid beta ligand stilbene described in general formula a and figures 1 and 2 described above is a hydrophobic substance and the pharmaceutical formulation allows the substance to be dissolved at the required dose. It is well known and accepted that hydrophobic filters have an affinity for hydrophobic substances. It was surprisingly found that the pharmaceutical formulations of the present invention avoid such adsorption and allow sterile filtration in high yields.

Preferably, the method of sterile filtration of a pharmaceutical formulation of the invention comprises the step of applying a pharmaceutical formulation of the invention to a Polytetrafluoroethylene (PTFE), such as Sartorius Minisart0.2 μm (product number 16596) or a polyvinylidene 1, 1-difluoroethylene (PVDF) sterile filter, such as Millipore Millex0.2 μmSLCV 033 RS.

More preferably, the hydrophobic filter is a Polytetrafluoroethylene (PTFE) sterile filter.

Optionally, sterile filtration is performed prior to preparation of the formulation of the invention.

Included in the following contents of the fourth, fifth and sixth aspects are embodiments of the lipophilic amyloid beta ligand stilbene, ethanol, polyether, ascorbic acid and sodium ascorbate as disclosed above general formula a and described in figures 1 and 2.

Lipophilic β amyloid ligand stilbene:

the term stilbene as used in the context of the following fourth, fifth and sixth aspects of the invention refers to compounds of formula A:

wherein the content of the first and second substances,

x is selected from the group consisting of C and N,

y is selected from the group consisting of C and N,

R¹is NR³R⁴，

Preferably, R³Is (C)₁-C₄) An alkyl group, a carboxyl group,

R²is selected from (O-CH)₂)_n-F、(O-CH₂)_n-OR⁵、OH，

Preferably, R⁵Selected from H, O-SO₂-R⁶

n is selected from 1, 2, 3 and 4.

Preferably, R¹Is NHCH₃And/or

Preferably, (O-CH)₂)_nF and/or

Preferably, Y ═ C and/or

Preferably, X ═ C and/or

Preferably, n is 3 and/or

More preferably, the lipophilic amyloid beta ligand stilbene is:

FIG. 1 Compound 1

FIG. 2 Compound 2

In a fourth aspect, the present invention relates to the use of said pharmaceutical formulation for the preparation of a suitable PET imaging formulation suitable for parenteral administration to a mammal.

In a fifth aspect, the invention relates to the use of said pharmaceutical formulation in the manufacture of a suitable radiotherapeutic medicament suitable for parenteral administration to a mammal.

In a sixth aspect, the inventors have found a method for obtaining the pharmaceutical formulation of the invention, which can be easily integrated into pharmaceutical processes carried out by automated devices known in the art.

A method of preparing a sterile filtered pharmaceutical formulation comprising the steps of:

the radioactive tracer is acquired by an automated means for pharmaceutical use,

purifying the radiotracer using a solid phase extraction cartridge or a solid phase extraction column, wherein the radiotracer is eluted with an ethanol-containing composition, optionally the radiotracer is dissolved in ethanol,

adding the ethanol eluate to a mixture of polyether, ascorbic acid and sodium ascorbate to obtain the pharmaceutical formulation of the invention, and

the pharmaceutical formulation of the present invention is sterile filtered.

The radiotracer is preferably a lipophilic β amyloid ligand stilbene of general formula A and depicted in FIGS. 1 and 2, and more preferably methyl- [4- (2)¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -ethyl) -phenyl]Amine, ethanol, polyether, ascorbic acid and sodium ascorbate are as defined above.

The sterile filter is a Polytetrafluoroethylene (PTFE) or polyvinylidene fluoride (PVDF) sterile filter. Preferably, the sterile filter is a Polytetrafluoroethylene (PTFE) sterile filter.

The invention also relates to:

apparatus for preparing a pharmaceutical preparation of the invention, wherein the radiotracer is preferably obtained by pharmaceutical automation.

Definition of

The terms used throughout the specification and claims of the present invention are defined as follows, without limiting the scope of the invention.

Suitable salts of the compounds of the invention include salts of mineral acids, carboxylic acids and sulfonic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate, naphthalenedisulfonate, acetate, trifluoroacetate, propionate, lactate, tartrate, malate, citrate, fumarate, maleate and benzoate.

"suitable salts" of the compounds of the invention also include salts of customary bases, such as, by way of example and illustration, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, diphenylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperazine.

"halogen" is chlorine, iodine, fluorine and bromine. Preferably, the halogen is iodine or bromine.

The term "polyether/polyethers" refers to compounds having more than one ether group. In particular, the term refers to polymers that contain the ether functionality in their backbone. Although the term generally refers to polymers such as polyethylene glycol and polypropylene glycol, low molecular weights such as crown ethers may sometimes be included.

In this regard, the term "ethylene glycol" refers to polymers in the low to medium molecular weight range.

A "drug or radiotracer" is a compound suitable for use in medical applications such as nuclear imaging, chemotherapy, and the like. The drug is typically provided in a pharmaceutically acceptable carrier. The PET tracer is a radioactive tracer.

An "appropriate pharmaceutical formulation" is adapted for pharmaceutical use by adjusting the pH, concentration, or other physical properties of the pharmaceutical formulation as is well known in the art.

The expression "chemically stable, stability" according to the present invention is in response to the concentration interval between the compound of formula a according to the present invention and the compound of figure 1 or figure 2 or a mixture or a suitable salt thereof, which requires that after at least 12 hours of storage the pharmaceutical formulation is provided at least at 95% to 105%, preferably at 98% to 105%, relative to the respective concentration after preparation according to the present invention, and further characterized in that after said at least 12 hours of storage the respective solution remains clear without any visible particles. Wherein the term "concentration interval of Compound 2" is used in the pair¹⁸The attenuation of F is corrected.

In addition, the expression "chemically stable or stable" according to the present invention refers to a pharmaceutical formulation comprising the compound depicted in fig. 2, characterized in that said formulation provides compound 2 with a radioactive purity of > 93%, preferably > 95%.

The term "storage" means storage conditions from 0 ℃ to 40 ℃, preferably storage conditions from 10 ℃ to 40 ℃, more preferably peripheral storage conditions of 25+/-10 ℃.

The term "parenteral" means that the medicament or pharmaceutical preparation of the invention is introduced into a subject or patient to be administered for PET imaging by a route other than the gastrointestinal tract, in particular by intravenous infusion, injection or implantation.

Unless otherwise indicated, when reference is made to "compound" or "compound" of formula a and figures 1 and 2 according to the invention in general in the description or in the appended claims and to any pharmaceutical composition or formulation thereof in the description and in the appended claims, the invention itself includes all corresponding hydrates, solvates, salts and complexes thereof.

Abbreviations

GBq	Giga beckelel
		RT	At room temperature
PBS	Phosphate buffer salt
		PET	Positron emission tomography
WFI	Water for injection

Detailed Description

Experimental data

EXAMPLE 1 Compound 1 (Fluorolabelled) and Compound 2 (Fluororadiolabelled)

Example 2 formulations comprising lipophilic amyloid beta ligand stilbene

General procedure

To simulate the manufacturing process of the radiopharmaceuticals, the following procedure was developed.

Formulation 1 containing compound 1:

ascorbic acid and sodium ascorbate were weighed together. Then, water and PEG were added and the mixture was stirred. Compound 1 was taken as lipophilic amyloid beta ligand stilbene and dissolved in ethanol. This solution was added to a mixture of polyether, ascorbic acid, sodium ascorbate and water, and the formulations were then mixed.

Composition (I)	Preparation 1
		Compound 1	30μg
96% ethanol	1.5mL
		Polyethylene glycol (PEG 400)	2g
Ascorbic acid	0.044g
		Ascorbic acid sodium salt	0.288g
Water (W)	Adding to 10mL
		pH	About 5.5

Since solutions of stilbene are sensitive to light, the solutions are stored protected from light.

Example 3 stability of formulations containing the hydrochloride salt of Compound 1 over 12 hours at room temperature

Preparation 1 containing 3. mu.g/mL of Compound 1 (3.3. mu.g/mL of the hydrochloride salt of Compound 1) was prepared. In terms of short shelf life storage of the PET imaging tracer, the assay is performed after preparation and the assay is performed after 12 hours, typically expected at 6 to 10 hours. Eight separate batches were prepared and analyzed for content.

TABLE 1 content of Compound 1 after 12 hours storage under three different storage conditions

1 was in the range of 2.97 to 3.14. mu.g/mL after 12 hours relative to the respective concentration after preparation.

MinisartHY0.2 μm is a sterile filter with PTFE hydrophobic membrane.

The content of compound 1 remained between 95% and 105% during the observation period of 12 hours and showed no decrease over time. Compound 1 is believed to be chemically stable in the formulation.

Example 4 hydrophobic Filter and adsorption

Formulation 1 comprising compound 1 was prepared as described above and filtered using a sterile filter of choice. Adsorption of compound 1 was determined by measuring the concentration of compound 1 before and after filtration for 10mL of formulation 1 and subsequent adsorption calculations. Table 2 shows the results of the adsorption tests using different filters.

Table 2 compound 1 filter adsorption (n ═ 6)

Filter units comprising only PTFE and PVDF showed a low amount of compound 1 adsorbed on the filter material.

Example 5 formulation composition for adsorption and use of Compound 1

Formulation 1 was prepared as described in example 2. Formulation 2 and the standard formulation were prepared similarly as described in example 1.

Table 3 composition of the test formulations

TABLE 4 Filter adsorption of different formulations using MinisartHY Filter (order No. 16596-HYK)

	Preparation 1	Preparation 2	Standard formulation
				Filtrate (%)	98.8±0.6	74.7±6	42.8±2.4
Adsorption	1.2％	25.3％	57.2％

TABLE 5 Filter adsorption of different formulations using Millex GV Filter (order number SLGV033RS)

	Preparation 1	Preparation 2	Standard formulation
				Filtrate (%)	94.0±0.7	55.9±2.3	40.8±0.8
Adsorption	6.0％	44.1％	59.2％

Claims

1. A pharmaceutical formulation comprising:

lipophilic amyloid beta ligand stilbene and salts thereof,

8% v/v to 25% v/v ethanol,

10% w/v to 25% w/v polyethylene glycol,

0.01% to 3% w/v ascorbic acid, and

0.01% to 20% w/v sodium ascorbate;

wherein the lipophilic amyloid beta ligand stilbene is selected from the group consisting of:

methyl radical-[4-((¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-an amine or a salt thereof,

wherein X is selected from C and N; y is selected from C and N; r¹Is NR³R⁴，R³Is (C)₁-C₄) Alkyl radical, R⁴Selected from H and t-butyloxycarbonyl; r²Is (O-CH)₂)_n-¹⁸F and n are selected from 1, 2, 3 and 4.

2. The pharmaceutical formulation of claim 1, wherein the lipophilic β amyloid ligand stilbene is methyl- [4- ((s) (b)) b¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [ 4-(s) ((s))¹⁹F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]Mixtures of amines and salts of the above.

3. A pharmaceutical formulation according to claim 1 or 2, which is defined as follows:

methyl- [4- (L) 0.03GBq/mL to 5GBq/mL¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-an amine, in which the amine is a hydrogen atom,

8% v/v to 25% v/v ethanol,

10% w/v to 25% w/v polyethylene glycol,

0.01% to 3% w/v ascorbic acid, and

0.01% to 20% w/v sodium ascorbate.

4. A pharmaceutical formulation according to claim 3, which is defined as follows:

15% v/v of ethanol, with the proviso that,

20% w/v of polyethylene glycol 400,

0.44% w/v ascorbic acid, and

2.88% w/v sodium ascorbate.

5. A pharmaceutical formulation according to claim 1 or 2, which is defined as follows:

0.01 to 5 [ mu ] g/mL of methyl- [4- (A/B)¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [ 4-(s) ((s))¹⁹F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]Mixtures of amines and salts of the above,

8% v/v to 25% v/v ethanol,

10% w/v to 25% w/v polyethylene glycol,

0.01% to 3% w/v ascorbic acid, and

0.01% to 20% w/v sodium ascorbate.

6. A pharmaceutical formulation according to claim 5, which is defined as follows:

3 μ g/mL of methyl- [4- (A/B)¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [ 4-(s) ((s))¹⁹F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]Mixtures of amines and salts of the above,

15% v/v of ethanol, with the proviso that,

20% w/v of polyethylene glycol 400,

0.44% w/v ascorbic acid, and

2.88% w/v sodium ascorbate.

7. A method of obtaining a pharmaceutical formulation according to any one of claims 1 to 6, comprising the steps of:

dissolving lipophilic amyloid beta ligand stilbene in ethanol,

adding the ethanol solution in the first step into a mixture of polyethylene glycol, ascorbic acid and sodium ascorbate;

methyl- [4- (A)¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-an amine or a salt thereof,

8. The method of claim 7, comprising the steps of:

3 mug/mL of methyl- [4- (a)¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine or methyl- [ 4-(s) ((s))¹⁹F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-amine and methyl- [ 4-(s) ((s))¹⁸F) -2- {4- [2- (2-propoxy-ethoxy) -ethoxy]-phenyl } -vinyl) -phenyl]-the mixture of amines is dissolved in ethanol, and

the ethanol solution of the first step was added to a mixture of polyethylene glycol 400, ascorbic acid and sodium ascorbate to a final concentration of 15% v/v ethanol, 20% w/v polyethylene glycol 400, 0.44% w/v ascorbic acid and 2.88% w/v sodium ascorbate.

9. The method for sterile filtering of a pharmaceutical formulation according to any one of claims 1 to 6, wherein said pharmaceutical formulation is applied to a Polytetrafluoroethylene (PTFE) sterile filter or a polyvinylidene 1, 1-difluoroethylene (PVDF) sterile filter.

10. The filtration method of claim 9, wherein the pharmaceutical formulation is applied to a Polytetrafluoroethylene (PTFE) sterile filter.

11. A method of preparing a sterile filtered pharmaceutical formulation comprising the steps of:

purifying the radiotracer using a solid phase extraction cartridge or a solid phase extraction column, wherein the radiotracer is eluted with an ethanol-containing composition,

adding the ethanol eluate obtained from the purification step to a mixture of polyethylene glycol, ascorbic acid and sodium ascorbate to obtain the pharmaceutical preparation of any one of claims 1 to 6, and

the pharmaceutical formulation is subjected to sterile filtration,

wherein the radiotracer is a lipophilic amyloid beta ligand stilbene and the sterile filter is a Polytetrafluoroethylene (PTFE) sterile filter or a polyvinylidene 1, 1-difluoroethylene (PVDF) sterile filter;

12. The method of claim 11, wherein the sterile filter is a Polytetrafluoroethylene (PTFE) sterile filter.