JP7525094B2 - BPA formulation using ionic liquid and ionic liquid containing BPA as a constituent - Google Patents

Description

Article 30, paragraph 2 of the Patent Act applies 1. Publication name: Program and Abstracts of the 16th Japanese Society for Neutron Capture Therapy Academic Conference Publication date: August 15, 2019 2. Research meeting name: 16th Japanese Society for Neutron Capture Therapy Academic Conference Date held: September 7, 2019 Venue: Kyoto University Campus Uji Obaku Plaza

The present invention relates to an enhancer for use in radiation therapy that contains an ionic liquid and BPA, a labeling agent for imaging the distribution of BPA in the body using PET, and a pharmaceutical ingredient that contains a high concentration of BPA dissolved therein.

Boron neutron capture therapy (hereinafter referred to as "BNCT") for cancer is a radiotherapy that damages tumor cells with α particles and 7Li particles generated by the capture reaction between ^10B nuclei that have been incorporated into tumor tissue in advance and thermal neutron rays that have almost no effect on the living body. p-Boronophenylalanine (BPA) is known as a drug used in BNCT and is already in clinical use.

However, BPA has very poor solubility at physiological pH, which is a major practical problem. For this reason, methods known for promoting the dissolution of BPA include forming a fructose complex with BPA (Patent Document 1), adding monosaccharides or polyols to BPA in an alkaline solution and removing inorganic salts with an ion exchange resin (Patent Document 2), and adding sorbitol (Patent Document 3).

However, in the method described in Patent Document 1, the water solubility of the BPA-fructose complex is insufficient. For example, when preparing an aqueous solution of BPA-fructose complex with an amount equivalent to 30 g at room temperature for a patient weighing 60 kg, the amount of solution is at least about 1.2 L, which is an extremely large amount of liquid, and is problematic in practical use. In addition, compared with the fructose complex method, the sorbitol method described in Patent Document 3 does not improve solubility very much, and the method of adding a polyol and removing inorganic salts with an ion exchange resin described in Patent Document 2 improves solubility only about four times that of the fructose complex method. In addition, the method described in Patent Document 2 requires complicated operations and is not suitable for practical use, and the method described in Patent Document 1 has problems in terms of cytotoxicity.

Since 2000, ionic liquids have been used in the fields of catalysis and electrochemistry, and in the field of pharmaceuticals, they are used for the purpose of promoting percutaneous absorption, etc. (Non-Patent Document 1). In addition, in biomass-based research, it is known that choline-amino acid ionic liquids selectively solubilize lignin from rice straw (Non-Patent Document 2). In addition, a method for dissolving poorly soluble drugs using an ionic liquid composed of meglumine and fatty acids is known as a method for dissolving poorly soluble drugs (Patent Document 4).
However, the relationship between ionic liquids and boron preparations is completely unknown.

Yoshiro Tahara, Masahiro Goto, Drug Delivery System, Vol. 33, No. 4 (2018), pp. 303-310 Lorenzo Contrani, Biophysical Reviews, Vol. 10, No. 3 (2018), pp. 873-880

U.S. Patent No. 5,492,900 U.S. Patent No. 6,169,076 JP 2013-173804 A Patent No. 5468221

The present invention aims to provide a water-soluble preparation containing a high concentration of p-boronophenylalanine that is suitable for BNCT therapy.

The present invention relates to
[1] A liquid pharmaceutical composition comprising p-boronophenylalanine as an active ingredient and containing an ionic liquid;
[2] The liquid pharmaceutical composition according to [1], wherein the ionic liquid is an ionic liquid of a choline salt.
[3] The liquid pharmaceutical composition according to [1] or [2], wherein the ionic liquid of the choline salt is composed of a cation of 2-hydroxyethyltrimethylammonium hydroxide and an anion of an amino acid or citric acid.
[4] The pharmaceutical composition according to any one of [1] to [3], wherein the amino acid is glycine, serine, proline or phenylalanine.
[5] The liquid pharmaceutical composition according to any one of [1] to [4], characterized in that it contains p-boronophenylalanine at a boron concentration of 5,000 to 30,000 ppm.
[6] A potentiator for use in tumor radiation therapy, comprising the liquid pharmaceutical composition according to any one of [1] to [5] as an active ingredient.
[7] A potentiator according to [6], wherein the radiotherapy is neutron capture therapy.
[8] The liquid pharmaceutical composition according to any one of [1] to [5], which is used for imaging diagnosis by PET.

FIG. 1 shows the results of ¹ H-NMR of the choline-serine ionic liquid. FIG. 2 shows the FT-IR results of the choline-serine ionic liquid. FIG. 3 shows the result of ¹ H-NMR of the choline-proline ionic liquid. FIG. 4 shows the FT-IR results of the choline-proline ionic liquid. FIG. 5 shows the results of ¹ H-NMR of the choline-glycine ionic liquid. FIG. 6 shows the FT-IR results of the choline-glycine ionic liquid. FIG. 7 shows the results of ¹ H-NMR of the choline-phenylalanine ionic liquid. FIG. 8 shows the results of FT-IR of the choline-phenylalanine ionic liquid. FIG. 9 shows the results of ¹ H-NMR of the choline-citrate ionic liquid. FIG. 10 shows the results of FT-IR of the choline-citrate ionic liquid. FIG. 11 shows the cell viability for BPA dissolved in an ionic liquid and for BPA dissolved using fructose.

The p-boronophenylalanine used in the present invention may be any boronophenylalanine (BPA) in which phenylalanine is labeled with boron ( ^10B ), but also includes derivatives of boronophenylalanine that utilize the properties of BPA. Derivatives of boronophenylalanine include fluoroboronophenylalanine (FBPA), a compound in which BPA is labeled with the radioactive nuclide ^18F in order to image the distribution of BPA in the body using PET.
The optical isomer of p-boronophenylalanine may be any of the L-form, D-form, L-form and D-form diastereomers, with the L-form being particularly preferred.

A liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient refers to a liquid pharmaceutical composition whose main medicinal effect is to utilize the accumulation of p-boronophenylalanine in tumor cells and to destroy only cancer cells using alpha particles (helium ions) of high-LET radiation generated by the nuclear reaction of boron ( ^10B ) with thermal neutrons.

An ionic liquid is a salt that exists as a liquid over a wide temperature range, and refers to a liquid consisting of only ions. Examples of cations in ionic liquids include ammonium, imidazolium, choline, sulfonium, pyrazolium, pyridinium, pyrrolidinium, and phosphonium, and examples of anions combined with these cations include CH ₃ COO ^- , CF ₃ COO ^- , NO ³ - , Br ^- , and Cl ^- . When meglumine is used as the cation, fatty acids such as oleic acid, decanoic acid, and isostearic acid can be used as suitable anions.

In the present invention, it is preferable that the ionic liquid used in the present invention is an ionic liquid in which the cation is a choline salt, which is highly safe. If the ionic liquid used in the present invention is an ionic liquid in which the cation is a choline salt, the anions described above can be used, but it is preferable to use a choline-amino acid ionic liquid or a choline-citrate ionic liquid, which uses an amino acid as the anion.

Examples of choline, which is the cation of the choline-amino acid ionic liquid, include N,N,N-trimethylethanolammonium, 2-hydroxy-N,N,N-trimethylethane-1-ammonium, and 2-hydroxyethyltrimethylammonium hydroxide. Examples of amino acids used as anions include glycine, phenylglycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, lysine, arginine, aspartic acid, asparagine, glutamic acid, glutamine, or ornithine, and derivatives thereof, with serine, proline, phenylalanine, and glycine being preferred.

Examples of choline, which is the cation of the choline-citrate ionic liquid, include N,N,N-trimethylethanolammonium, 2-hydroxy-N,N,N-trimethylethane-1-ammonium, etc., and citric acid and its derivatives are used as the anion.

The liquid pharmaceutical composition of the present invention refers to a liquid composition in which poorly soluble p-boronophenylalanine is dissolved, which is used for the above-mentioned medical applications, and is characterized in that it contains p-boronophenylalanine at a boron concentration of 5000 ppm or more, 5000 to 30000 ppm, preferably 10000 to 30000 ppm, and particularly preferably 12000 to 20000 ppm, at room temperature.
The ionic liquid contained in the liquid composition may be entirely made up of an ionic liquid, or may be dispersed in water as necessary.

The pH of the liquid composition of the present invention is preferably near neutral, taking into consideration administration to a living body. More specifically, it is in the range of 6.5 to 7.5, and particularly preferably near 7.4. If necessary, a suitable pH regulator used in the art (such as hydrochloric acid or sodium bicarbonate), buffer, etc. may be used to adjust the pH.

The osmotic pressure ratio of the liquid composition of the present invention is not particularly limited, but is preferably within the range of 1 to 2 relative to physiological saline. More preferably, it is within the range of 1.1 to 1.4. When it is within this range, in the case of an injection, it is possible to reduce pain and shorten the administration time.

The liquid composition of the present invention may contain various metal ions, such as sodium and magnesium, contained in living bodies, if necessary, in order to increase the stability of the composition both in and out of the body. In the case of sodium ions, the concentration is preferably in a numerical range close to the range of sodium ion concentrations in body fluids so as not to significantly disrupt the electrolyte balance between intracellular fluid and extracellular fluid.

If necessary, a buffer such as a phosphate buffer, a Tris-HCl buffer, an acetate buffer, a carbonate buffer, or a citrate buffer may be added to the liquid composition of the present invention. These buffers may be useful for stabilizing the formulation or reducing irritation.

Furthermore, the composition of the present invention may contain additives that are permitted as additives for liquid preparations under the Pharmaceutical and Medical Devices Act, if necessary. Such additives include additives that are normally used in liquid, particularly aqueous, compositions, such as preservatives such as benzalkonium chloride, potassium sorbate, and chlorhexidine hydrochloride, stabilizers such as sodium edetate, thickeners such as hydroxyethyl cellulose and hydroxypropyl methylcellulose, isotonicity agents such as sodium chloride, potassium chloride, glycerin, sucrose, and glucose, surfactants such as polysorbate 80 and polyoxyethylene hydrogenated castor oil, isotonicity agents such as sodium chloride, potassium chloride, and glycerin, and pH adjusters such as hydrochloric acid and sodium hydroxide.

When the liquid composition of the present invention is a pharmaceutical product used in BNCT, the method of administration of the liquid pharmaceutical composition, which contains p-boronophenylalanine as an active ingredient and an ionic liquid, may be any method that delivers p-boronophenylalanine to the vicinity of the tumor, but is preferably intravenous, intraperitoneal, or transdermal administration. In addition, when the liquid composition of the present invention is a diagnostic pharmaceutical product used in PET, intravenous administration is used as the administration method.

In the case of administration methods involving direct injection into the body, such as intravenous administration or intraperitoneal administration, dispersants such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, preservatives such as methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, and isotonicity agents such as sodium chloride, glycerin, D-mannitol, and glucose are added as necessary to p-boronophenylalanine dissolved in an ionic liquid, and the mixture is diluted with a water-soluble solvent such as distilled water for injection, physiological saline, or Ringer's solution to produce a liquid pharmaceutical composition for intravenous or intraperitoneal administration, which contains p-boronophenylalanine as an active ingredient and an ionic liquid.

When p-boronophenylalanine is to be delivered to the vicinity of a tumor by transdermal administration, a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient and an ionic liquid for transdermal administration is produced by adding, as necessary, dispersants such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, preservatives such as methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, and isotonicity agents such as sodium chloride, glycerin, D-mannitol, and glucose, and dissolving, suspending, or emulsifying the mixture in a vegetable oil such as olive oil, sesame oil, cottonseed oil, or corn oil, or an oily solvent such as propylene glycol.

In addition, in the manufacturing process of the above pharmaceutical composition, additives such as solubilizing agents, for example, sodium salicylate, sodium acetate, etc., stabilizers, for example, human serum albumin, etc., and soothing agents, for example, benzyl alcohol, etc., may be used as desired, and further, if approved by the Pharmaceutical and Medical Device Act, antioxidants, colorants, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, preservatives, and gelling agents may be used as necessary.

Furthermore, a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient and an ionic liquid may be diluted, if necessary, with a water-soluble agent such as distilled water for injection, physiological saline, or Ringer's solution, or with a pharmaceutical lotion or cream at the time of treatment.
The liquid pharmaceutical composition of the present invention, which contains p-boronophenylalanine as an active ingredient and an ionic liquid, can be produced by the following production method.

1. Synthesis of choline-anion ionic liquid The synthesis of choline-anion ionic liquid was carried out as follows, with reference to the method of Chowdhry et al. (Chowdhry et al., Molecular Pharmaceutics, Vol. 15, No. 6 (2018) pp. 2484-2488).

Regarding the anion, a compound to be used as the anion is dissolved in water to prepare a 0.1 mol to 0.01 mol, preferably 0.05 mol, aqueous solution.
The compound used as the anion may be any compound that is a source of anions such as CH ₃ COO-, CF ₃ COO-, NO ₃ -, Br-, Cl-, etc., but in the present invention, amino acids or citric acid and derivatives thereof can be used. Examples of amino acids include glycine, phenylglycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, lysine, arginine, aspartic acid, asparagine, glutamic acid, glutamine, or ornithine, and derivatives thereof, but it is preferable to use serine, proline, phenylalanine, or glycine.

An aqueous solution of choline in an amount equal to the amount of the anion is added to the aqueous anion solution, and the mixture is stirred at 15°C to 25°C, preferably at room temperature, for 12 to 36 hours, preferably 24 hours. Water is then removed using an evaporator or the like at 100°C to 140°C, preferably 120°C, in an oil bath or the like. The desired ionic liquid can be obtained by gradually cooling the resulting liquid.

Examples of choline used as a cation include N,N,N-trimethylethanolammonium, 2-hydroxy-N,N,N-trimethylethane-1-ammonium, and 2-hydroxyethyltrimethylammonium hydroxide. Choline may be dissolved in water as a solid, or a commercially available aqueous choline solution [2-hydroxyethyltrimethylammonium hydroxide (47-50% aqueous solution)] may be used.

2. Method for producing a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient and containing an ionic liquid At room temperature, p-boronophenylalanine is added to the choline anion ionic liquid, to which pure water has been added as necessary, and stirred to dissolve. The final concentration of p-boronophenylalanine is adjusted to 5,000 to 30,000 ppm. If necessary, the pharmaceutical formulation additives are added to produce a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient and containing an ionic liquid.

The p-boronophenylalanine used in the present invention may be any boronophenylalanine (BPA) in which phenylalanine is labeled with boron ( ¹⁰ B), and a commercially available product may also be used.

When synthesizing p-boronophenylalanine, it may be synthesized by referring to the known methods described in JP-A-11-255773, JP-A-2000-212185, and U.S. Patent No. 5,157,149.

The optical isomer of p-boronophenylalanine may be any of the L-isomer, D-isomer, L-isomer and D-isomer diastereomers, with the L-isomer being particularly preferred. The pure water to be added may be, for example, commercially available MILLi-QWater (trade name) commercially available pure water.

Below is shown a prescription example of a liquid pharmaceutical composition that contains p-boronophenylalanine as an active ingredient and an ionic liquid.
Formulation Example 1
Ionic liquid containing BPA 36 μL
tween80 15μL
Ethanol 60 μL
PBS 469 μL
Citric acid dissolved in PBS 20 μL (1 g/25 mL)

Example 1
1-1 Choline-serine ionic liquid Commercially available pharmaceutical high-purity serine (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved as an anion in pure water (trade name: Milli-QWater, manufactured by Merck Millipore Co., Ltd.) to a final concentration of 0.05 mol. As a cation, 12.0 ml of a choline aqueous solution (2-hydroxyethyltrimethylammonium hydroxide, 47-50% aqueous solution: manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the anion in an amount equivalent to that of the anion, and the mixture was stirred at room temperature for 24 hours. After stirring, the mixture was transferred to an oil bath, heated to a temperature of 120° C., and the water was removed using an evaporator, and then gradually cooled to room temperature.
To chemically confirm the formation of the choline-serine ionic liquid, a sample was characterized by ¹ H NMR (FIG. 1) and FT-IR (FIG. 2).
The ¹ H NMR measurement results were consistent with the literature values, and FT-IR confirmed the asymmetric stretching of carboxylate appearing around 1555-1593 cm ⁻¹ , confirming the formation of a choline-serine ionic liquid.

1-2 p-Boronophenylalanine-Containing Choline-Serine Ionic Liquid Composition A solution was prepared by adding 100 μL of pure water (product name: Milli-Q Water, manufactured by Merck Millipore) to 338.1 mg of choline-serine ionic liquid.
p-Boronophenylalanine was added to the solution and stirred. Undissolved p-boronophenylalanine was removed, and the concentration of dissolved p-boronophenylalanine was measured by measuring the boron concentration, which was 17672.245 ppm.

Example 2
2-1 Choline-proline ionic liquid Commercially available pharmaceutical high-purity proline (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in pure water (trade name: Milli-QWater, manufactured by Merck Millipore Co., Ltd.) as an anion to a final concentration of 0.05 mol. As a cation, 12.0 ml of a choline aqueous solution (2-hydroxyethyltrimethylammonium hydroxide, 47-50% aqueous solution: manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the anion in an amount equivalent to that of the anion, and the mixture was stirred at room temperature for 24 hours. After stirring, the mixture was transferred to an oil bath, heated to a temperature of 120° C., and water was removed with an evaporator, and then gradually cooled to room temperature to obtain a choline proline ionic liquid.

To chemically confirm the formation of the choline-proline ionic liquid, a sample was characterized by ¹ H NMR (FIG. 3) and FT-IR (FIG. 4).
The ^1H NMR measurement results were consistent with literature values (Duanjiang Tao et al., Journal of Chemical Engineering Data, 2013, Vol. 58, pp. 1542-1548; Koudry et al., Molecular Pharmaceuticals, 2018, Vol. 15, No. 6, pp. 2484-2488), and a unique peak was confirmed in FT-IR, confirming the production of choline-serine ionic liquid.

2-2 p-Boronophenylalanine-Containing Choline-Proline Ionic Liquid Composition 100 μL of pure water (product name: Milli-Q Water, manufactured by Merck Millipore) was added to 297.5 mg of the choline-proline ionic liquid to prepare a solution.
p-Boronophenylalanine was added to the solution and stirred. Undissolved p-boronophenylalanine was removed, and the concentration of dissolved p-boronophenylalanine was measured by boron concentration measurement, which was 12500.139 ppm.

Example 3
3-1 Choline-glycine ionic liquid Commercially available pharmaceutical high-purity glycine (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in pure water (trade name: Milli-Q Water, manufactured by Merck Millipore Co., Ltd.) as an anion to a final concentration of 0.05 mol. As a cation, 12.0 ml of a choline aqueous solution (2-hydroxyethyltrimethylammonium hydroxide, 47-50% aqueous solution: manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the anion so as to be equivalent to the amount of the choline aqueous solution, and the mixture was stirred at room temperature for 24 hours. After stirring, the mixed solution was transferred to an oil bath, heated to a temperature of 120°C, and water was removed with an evaporator, and then gradually cooled to room temperature to obtain a choline glycine ionic liquid.

To chemically confirm the formation of the choline-proline ionic liquid, a sample was characterized by ¹ H NMR (FIG. 5) and FT-IR (FIG. 6).
The ^1H NMR measurement results were consistent with literature values (Duanjiang Tao et al., Journal of Chemical Engineering Data, 2013, Vol. 58, pp. 1542-1548; Koudry et al., Molecular Pharmaceuticals, 2018, Vol. 15, No. 6, pp. 2484-2488), and a unique peak was confirmed in FT-IR, confirming the production of choline-serine ionic liquid.

3-2 p-Boronophenylalanine-Containing Choline-Glycine Ionic Liquid Composition 100 μL of pure water (product name: MilLi-Q Water, manufactured by Merck Millipore) was added to 321.0 mg of choline-glycine ionic liquid to prepare a solution.
p-Boronophenylalanine was added to the solution and stirred. Undissolved p-boronophenylalanine was removed, and the concentration of dissolved p-boronophenylalanine was measured by measuring the boron concentration, which was 7171.876 ppm.

Example 4
4-1 Choline-phenylalanine ionic liquid Commercially available pharmaceutical high-purity phenylalanine (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in pure water (trade name: Milli-Q Water, manufactured by Merck Millipore Co., Ltd.) as an anion to a final concentration of 0.05 mol. 12.0 ml of a choline aqueous solution (2-hydroxyethyltrimethylammonium hydroxide, 47-50% aqueous solution: manufactured by Tokyo Chemical Industry Co., Ltd.) was added as an equivalent amount as the cation, and the mixture was stirred at room temperature for 24 hours. After the stirring was completed, the mixed solution was transferred to an oil bath, heated to a temperature of 120°C, and water was removed with an evaporator, and then gradually cooled to room temperature to obtain a choline phenylalanine ionic liquid.

To chemically confirm the formation of the choline-phenylalanine ionic liquid, a sample was characterized by ¹ H NMR (FIG. 7) and FT-IR (FIG. 8).
The ^1H NMR measurement results were consistent with literature values (Duanjiang Tao et al., Journal of Chemical Engineering Data, 2013, Vol. 58, pp. 1542-1548; Koudry et al., Molecular Pharmaceuticals, 2018, Vol. 15, No. 6, pp. 2484-2488), and a unique peak was confirmed in FT-IR, confirming the production of choline-serine ionic liquid.

4-2 p-Boronophenylalanine-Containing Choline-Phenylalanine Ionic Liquid Composition A solution was prepared by adding 100 μL of pure water (product name: Milli-Q Water, manufactured by Merck Millipore) to 280.9 mg of the choline-glycine ionic liquid.
p-Boronophenylalanine was added to the solution and stirred. Undissolved p-boronophenylalanine was removed, and the concentration of dissolved p-boronophenylalanine was measured by measuring the boron concentration, which was 7342.104 ppm.

Example 5
5-1 Choline-citric acid ionic liquid Commercially available pharmaceutical citric acid (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in pure water (trade name: Milli-Q Water, manufactured by Merck Millipore Co., Ltd.) as an anion to a final concentration of 0.05 mol. As a cation, 12.0 ml of a choline aqueous solution (2-hydroxyethyltrimethylammonium hydroxide, 47-50% aqueous solution: manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the anion in an amount equivalent to that of the anion, and the mixture was stirred at room temperature for 24 hours. After stirring, the mixed solution was transferred to an oil bath, heated to a temperature of 120° C., and water was removed with an evaporator, and then gradually cooled to room temperature to obtain a choline-citric acid ionic liquid.

To chemically confirm the formation of the choline-citrate liquid, samples were characterized by ¹ H NMR (FIG. 9) and FT-IR (FIG. 10).
The ^1H NMR measurement results were consistent with literature values (Duanjiang Tao et al., Journal of Chemical Engineering Data, 2013, Vol. 58, pp. 1542-1548; Koudry et al., Molecular Pharmaceuticals, 2018, Vol. 15, No. 6, pp. 2484-2488), and a unique peak was confirmed in FT-IR, confirming the production of choline-serine ionic liquid.

5-2 p-Boronophenylalanine-Containing Choline-Citrate Ionic Liquid Composition 100 μL of pure water (product name: Milli-Q Water, manufactured by Merck Millipore) was added to the choline-citrate ionic liquid to prepare a solution.
p-Boronophenylalanine was added to the solution and stirred. Undissolved p-boronophenylalanine was removed, and the concentration of dissolved p-boronophenylalanine was measured by measuring the boron concentration, which was 10656.333 ppm.

Test Example 1 Comparison of Cytotoxicity Between p-Boronophenylalanine-Containing Choline Serine Ionic Liquid and p-Boronophenylalanine Fructose Complex (BPA-Flu) The following experiment was carried out to compare the cytotoxicity of BPA-IL and BPA-Flu.
V79-379A cells (Chinese hamster lung, fibroblasts: 5000 cells/well) were cultured in a _CO2 incubator for 24 hours (5000 cells/well). 10 μL each of BPA-IL and BPA-FLU (boron concentration 7.8125 ppm to 4000 ppm) was added to the cell culture medium and cultured for another hour. 60 minutes after adding 10 μL of CCK-8 solution to the _CO2 incubator, the cell viability at each concentration of BPA-IL and BPA-FLU was measured by measuring the absorbance at 450 nm (FIG. 9).

As a result, the IC ₅₀ of BPA-FLU was 633.3 ppm, whereas that of BPA-IL was 1215 ppm, indicating that the composition of the present invention is safer than conventional compounds.

The present invention provides a safe enhancer for tumor radiation therapy and a diagnostic drug for PET that contains high-concentration p-boronophenylalanine.

Choline: choline aqueous solution Ionic Liquids: choline-serine ionic liquid BPA-IL: choline-serine liquid containing p-boronophenylalanine BPA-Flu: p-boronophenylalanine fructose complex (a) choline, (b) choline-serine ionic liquid, (c) L-serine (d) choline-proline ionic liquid, (e) L-proline (f) choline-glycine ionic liquid, (g) L-glycine (h) choline-phenylalanine ionic liquid, (i) L-phenylalanine (j) choline-citrate ionic liquid, (k) citric acid

Claims (6)

A liquid pharmaceutical composition comprising p-boronophenylalanine as an active ingredient, and an ionic liquid composed of a cation which is any one of N,N,N-trimethylethanolammonium, 2-hydroxy-N,N,N-trimethylethane-1-ammonium, and 2-hydroxyethyltrimethylammonium hydroxide, and an anion which is any one of glycine, serine, proline, phenylalanine, and citric acid . 2. The liquid pharmaceutical composition according to claim 1, comprising p-boronophenylalanine at a boron concentration of 5000 ppm or more. 2. The liquid pharmaceutical composition according to claim 1 , comprising p-boronophenylalanine at a boron concentration of 5,000 ppm to 30,000 ppm. A potentiator for use in tumor radiation therapy, comprising the liquid pharmaceutical composition according to any one of claims 1 to 3 as an active ingredient. The enhancer according to claim 4 , wherein the radiation therapy is neutron capture therapy. 4. The liquid pharmaceutical composition according to claim 1, which is used for diagnostic imaging using PET.