Method for preventing precipitation of injectable solutions containing p-boronophenylalanine

Abstract

To provide a method for preventing precipitation caused by the storage of an injection solution for boron neutron capture therapy.SOLUTION: The present invention provides a method for preventing precipitation of an injection solution for boron neutron capture therapy, the injection solution containing: p-boronophenylalanine or a pharmaceutically acceptable salt thereof; a sugar alcohol; and a pH adjusting agent, having a pH of 6.5 to 8.0 and an osmotic pressure ratio of 1.0 to 1.8, and being to be administered by intravenous drip injection.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for preventing precipitation of an injection solution containing p-boronophenylalanine. More specifically, the present invention relates to a method for preventing precipitation during storage of an injection solution containing p-boronophenylalanine.

Background Art

[0002] In recent years, as a cancer treatment method using radioactive isotopes, boron neutron capture therapy (BNCT) has attracted attention. Boron neutron capture therapy is a treatment method in which a boron compound containing boron-10 isotope ( 10 10B) is incorporated into cancer cells, and low-energy neutron rays (for example, epithermal neutrons) are irradiated to locally destroy cancer cells by a nuclear reaction occurring inside the cells. In this treatment method, it is important to selectively accumulate a boron compound containing boron-10 in the cells of cancer tissue in order to enhance the treatment effect. Therefore, it is necessary to develop a boron compound that is selectively and surely incorporated into cancer cells.

[0003] As a drug used for BNCT, boron-containing compounds in which a boron atom or a boron atomic group is introduced into the basic skeleton have been synthesized. Drugs actually used in clinical practice include p-boronophenylalanine (BPA) and mercaptoundecahydrododecaborate (BSH).

[0004] p-Boronophenylalanine has extremely poor solubility at physiological pH.

[0005] In order to improve the solubility of p-boronophenylalanine in water, methods such as generating a fructose complex of BPA (for example, Patent Document 1) or adding a monosaccharide or polyol to p-boronophenylalanine in an alkaline solution (such as an aqueous sodium hydroxide solution) and removing inorganic salts with an ion exchange resin for use (for example, Patent Document 2) have been attempted.

[0006] Furthermore, other techniques for improving the solubility of p-boronophenylalanine have also been proposed (Patent Document 3). [Patent Document 1] U.S. Patent No. 5,492,900 [Patent Document 2] U.S. Patent No. 6169076 [Patent Document 3] Patent No. 5345771 [Overview of the project] [Problems that the invention aims to solve]

[0007] The blood boron concentration required for boron neutron capture therapy to be effective is limited. Therefore, it is desirable to prepare a highly stable formulation while maintaining a constant BPA concentration to maximize the therapeutic effect.

[0008] However, it was found that maintaining a constant BPA concentration while storing the drug as an injectable solution until administration can lead to stability issues and precipitation.

[0009] Therefore, the object of the present invention is to provide a method for preventing the precipitation of an injectable solution containing p-boronophenylalanine, particularly under storage conditions in a wide range of temperatures, including low-temperature storage. [Means for solving the problem]

[0010] The inventors of this invention conducted extensive research to solve the above problems and, as a result, discovered that p-boronophenylalanine in an injectable solution can be stabilized over a wide temperature range by including sugar alcohols and antioxidants, and by changing the type of pH adjuster in response to changes in pH value, thus completing the present invention.

[0011] In other words, the present invention provides a method for preventing precipitation of the following injectable solutions. [1] A method for preventing precipitation of an injectable boron neutron capture therapy solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, A method for preventing precipitation, comprising preparing an injectable solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH is controlled to be greater than 7.5 and less than or equal to 8.0. [2] A method for preventing precipitation of an injectable boron neutron capture therapy solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, A method for preventing precipitation, comprising preparing an injectable solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and containing at least one organic acid or a salt thereof, with the pH controlled to 6.5-8.0. [3] The precipitation prevention method according to [1] or [2], wherein the sugar alcohol is sorbitol or mannitol. [4] A method for preventing precipitation according to any one of the following [1] to [3], wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v%. [5] The precipitation prevention method according to any one of [1] to [4], wherein the content of the sugar alcohol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-boronophenylalanine. [6] The precipitation prevention method according to any one of [2] to [5], wherein the organic acid is citric acid or lactic acid. [7] The precipitation prevention method according to any one of [2] to [6], wherein the amount of the organic acid or its salt is 0 to 8.3 w / v% of the injection solution. [8] The precipitation prevention method according to any one of items 1 to 7, wherein the injectable solution is an intravenous injection solution. [Effects of the Invention]

[0012] The present invention can provide a method for preventing precipitation of an injection for boron neutron capture therapy during storage in a wide temperature range, including especially under cryopreservation.

Mode for Carrying Out the Invention

[0013] In this specification, the unit “mass %” is synonymous with “g / 100 g”. “w / v %” is synonymous with “g / 100 ml”.

[0014] One aspect of the present invention is a method for preventing precipitation of an injection for boron neutron capture therapy, which contains p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and controls the pH of the injection to exceed 7.4 and be 8.0 or less, preferably exceed 7.5 and be 8.0 or less.

[0015] Another aspect of the present invention is a method for preventing precipitation of an injection for boron neutron capture therapy, which contains p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH adjuster contains an organic acid or a salt thereof, and controls the pH of the injection to be 6.5 to 8.0.

[0016] [Injection for Boron Neutron Capture Therapy] (p-Boronophenylalanine or a Pharmaceutically Acceptable Salt Thereof) The p-boronophenylalanine used in the present invention is not particularly limited, but among the boron atoms in the compound, the proportion of boron-10 is preferably 75% or more, more preferably 80% or more, even more preferably 90% or more, and particularly preferably 95% or more.

[0017] Natural boron contains boron-10 and boron-11 as isotopes, with boron-10 present at a ratio of 20% and boron-11 at 80%. Therefore, prior to the production of the injection preparation containing p-boronophenylalanine of the present invention, boron with a mass number of 10 (boron-10) is concentrated. For this purpose, boron-10 and boron-11 in the natural boron compound are separated to produce highly concentrated boron-10. The boron used in the present invention may be concentrated to increase its concentration, or a commercially available product may be used. As commercially available products, for example, 10 B enriched boric acid (manufactured by Stella Chemifa Corporation) can be used as a starting material.

[0018] Here, as a method for measuring boron-10, it can be carried out by the quadrupole type ICP-MS (ICP-QMS) method using Agilent 7500 (manufactured by Agilent) and the quadrupole mass spectrometry section. The ICP-QMS used for measurement is adjusted in accordance with JIS K0133.

[0019] As p-boronophenylalanine, the currently used one is the L-form, and in the present invention, L-p-boronophenylalanine can be preferably used, but it is not limited thereto. That is, p-boronophenylalanine in the form of the D-form or a racemic form containing both the D-form and the L-form can also be used in the present invention.

[0020] Here, p-boronophenylalanine can be synthesized by a known method (for example, H.R. Synder, A.J. Reedy, W.M.J. Lennarz, J. Am. Chem. Soc., 1958, 80, 835: C. Malan, C. Morin, SYNLETT, 1996, 167: U.S. Patent No. 5157149: JP 2000-212185 A: and Patent No. 2979139) and used.

[0021] Here, the salt is not particularly limited as long as it is pharmacologically acceptable. Examples of salts of p-boronophenylalanine include salts with organic acids, salts with inorganic acids, salts with organic bases, salts with inorganic bases, and the like.

[0022] Examples of salts with organic acids include acetate, trifluoroacetate, fumarate, maleate, lactate, tartrate, citrate, and methanesulfonate. Examples of salts with inorganic acids include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Examples of salts with organic bases include salts with triethanolamine. Examples of salts with inorganic bases include ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts.

[0023] In the injectable solution used in the present invention, the content of p-boronophenylalanine or its salt relative to the total volume of the injectable solution is appropriately set in balance with other components. The total content of p-boronophenylalanine and / or its salt relative to the total volume of the injectable solution is not particularly limited, but is preferably 2.0 to 5.5 w / v%, more preferably 2.5 to 5.0 w / v%, and even more preferably 2.5 to 4.0 w / v%.

[0024] When the p-boronophenylalanine content in the injectable solution of the present invention is within the above range, it settles into an appropriate volume when applied clinically, exhibits good solution stability, and provides excellent efficacy upon administration.

[0025] (Sugar alcohol) The sugar alcohol used in the present invention is not particularly limited as long as it is used as an ingredient in injectable drugs in the pharmaceutical field. Although not limited, monosaccharide sugar alcohols are preferred, and sorbitol and / or mannitol are particularly preferred.

[0026] As sorbitol, D-sorbitol, which is currently approved for use in pharmaceuticals and whose safety has been confirmed, can preferably be used, but is not limited to this. In other words, in the present invention, the L-isomer or a mixture of the L-isomer and the D-isomer can also be used.

[0027] As mannitol, D-mannitol, which is currently approved for use in pharmaceuticals and whose safety has been confirmed, can preferably be used, but is not limited to this. In other words, in the present invention, the L-isomer or a mixture of the L-isomer and the D-isomer can also be used.

[0028] The total sugar alcohol content used in the injectable solution of the present invention depends on the amount of other additives added, but is preferably 2.0 to 7.0 w / v%, more preferably 2.6 to 6.5 w / v%, and even more preferably 2.6 to 4.2 w / v%, relative to the total amount of the injectable solution.

[0029] The amount of sugar alcohol relative to the amount of p-boronophenylalanine is preferably in the range of 0.9 to 3.0, more preferably 0.9 to 2.0, and even more preferably 1.1 to 1.5 in molar ratio. When the amount of sugar alcohol is within this range, the precipitation of p-boronophenylalanine can be suppressed and the osmotic pressure ratio can be appropriately adjusted.

[0030] (Antioxidant) The injectable solution used in the present invention may optionally contain antioxidants. The antioxidant is not particularly limited as long as it is used as a component of injectable preparations in the pharmaceutical field. While not limited, the antioxidant is preferably one or more selected from the group consisting of sulfurous acid, bisulfite, pyrosulfite, nitrite, ascorbic acid, L-cysteine, thioglycolic acid, and salts thereof.

[0031] Here, examples of salts of sulfurous acid, bisulfite, pyrosulfite, nitrite, ascorbic acid, L-cysteine, or thioglycolic acid include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and inorganic bases such as aluminum salts and ammonium salts. Furthermore, salts with organic bases such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine can also be used. Particularly preferred are sodium salts, potassium salts, or ammonium salts.

[0032] Particularly preferred antioxidants used in the present invention are one or more selected from the group consisting of sodium sulfite, anhydrous sodium sulfite, potassium sulfite, calcium sulfite, sodium bisulfite, potassium bisulfite, ammonium bisulfite, sodium pyrosulfite, and potassium pyrosulfite.

[0033] The total content of the antioxidant used in the injectable solution of the present invention depends on the amount of other additives, but is preferably 0.005 to 2.0 w / v%, more preferably 0.005 to 1.5 w / v%, even more preferably 0.005 to 1.2 w / v%, even more preferably 0.01 to 0.6 w / v%, and most preferably 0.01 to 0.03 w / v% relative to the total amount of the injectable solution.

[0034] (water) The injectable solution used in the present invention further contains water. The water used in the present invention is not particularly limited as long as it is used as an ingredient in injectable preparations in the pharmaceutical field.

[0035] The water content used in the injectable solution of the present invention depends on the amount of other additives added, but is preferably 80 w / v% or more, more preferably 85 w / v% or more, preferably 95 w / v% or less, and even more preferably 94 w / v% or less, relative to the total amount of the injectable solution.

[0036] (Osmotic pressure ratio) The osmotic pressure ratio of the injectable solution of the present invention is not particularly limited, but it is preferably in the range of 1.0 to 1.8 relative to physiological saline. More preferably, it is in the range of 1.1 to 1.5. When it is within this range, in the case of large-volume intravenous injection, it is possible to reduce pain, avoid the onset of phlebitis, and shorten the administration time.

[0037] The injectable solution used in the present invention may contain various metal ions that are naturally present in the body, as appropriate, in order to ensure its stability both inside and outside the body. Preferably, it contains sodium ions, and although its concentration is not particularly limited, 130 mEq / L to 160 mEq / L is particularly preferred. This numerical range is preferred because it is close to the range of Na ion concentrations in body fluids, so as not to significantly disrupt the electrolyte balance between intracellular and extracellular fluids.

[0038] (pH adjuster) The injectable solution used in the present invention may optionally contain pH adjusters such as inorganic acids like hydrochloric acid and phosphoric acid, or alkaline components like sodium hydroxide and potassium hydroxide. Furthermore, it is preferable to use organic acids in addition to or instead of inorganic acids. Preferred organic acids include citric acid, acetic acid, trifluoroacetic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, or methanesulfonic acid, with citric acid or lactic acid being even more preferable.

[0039] The pH adjusting agent content used in the injectable solution used in the present invention depends on the amount of other additives, but for inorganic acids such as hydrochloric acid, the content is preferably 0.001 to 0.5, more preferably 0.001 to 0.10 w / v%, and even more preferably 0.001 to 0.03 w / v%, relative to the total amount of the injectable solution.

[0040] The content of the pH adjusting agent used in the injectable solution used in the present invention depends on the amount of other additives, but relative to the total amount of the injectable solution, for example, with respect to organic acids such as citric acid, it is preferably 0 to 8.3 w / v%, more preferably 0 to 1.7 w / v%, even more preferably 0 to 0.56 w / v%, even more preferably 0 to 0.18 w / v%, and most preferably 0 to 0.08 w / v%.

[0041] The content of the pH adjusting agent used in the injectable solution used in the present invention depends on the amount of other additives added, but in relation to the total amount of the injectable solution, especially when the pH is in the range of 6.5 to 7.4 or 7.5, for organic acids such as citric acid, it is preferably 0 to 8.3 w / v%, more preferably 0.01 to 1.7 w / v%, even more preferably 0.02 to 0.56 w / v%, even more preferably 0.03 to 0.18 w / v%, and most preferably 0.05 to 0.08 w / v%.

[0042] The inorganic alkali component, such as sodium hydroxide, is preferably 0 to 2.20 w / v%, more preferably 0.01 to 1.50 w / v%, even more preferably 0.01 to 0.86 w / v%, and even more preferably 0.01 to 0.65 w / v%.

[0043] (pH) The pH of the injectable solution used in the present invention is preferably in the neutral to slightly alkaline range, taking into consideration the balance between administration to the body and stability. More specifically, it is in the range of 6.5 to 8.0, and in particular, from the viewpoint of preventing precipitation under storage at room temperature to low temperature range, it is preferably in the range of pH above 7.4 to 8.0, and especially preferably around pH above 7.5 and 7.8. To adjust the pH, appropriate pH adjusting agents, buffering agents, etc., used in the art may be used as needed.

[0044] On the other hand, the injectable solution used in the present invention can be freely selected between pH 6.5 and 8.0 while also ensuring stability, including suppression of precipitation during storage at room temperature to low temperatures. For this purpose, it is preferable to use an organic acid or a salt thereof as the pH adjuster for the acidic component. In particular, when the pH is around 6.5 to 7.4, depending on the composition, an organic acid can be made an essential component as a pH adjuster, and precipitation can be prevented or suppressed even when stored at 5°C for a week, or in some cases for a month or more, preferably for three months or more.

[0045] [Other ingredients] The injectable solution used in the present invention may optionally contain buffers such as phosphate buffer, Tris-HCl buffer, acetate buffer, carbonate buffer, or citrate buffer. These buffers may be useful for stabilizing the formulation or reducing its irritancy.

[0046] Furthermore, the injectable solution of the present invention may, as necessary, contain other components commonly used in the art, provided that they do not contradict the objectives of the present invention. Such components include additives commonly used in liquid, particularly aqueous, compositions, such as preservatives like benzalkonium chloride, potassium sorbate, and chlorohexidine hydrochloride; stabilizers like sodium edetate; thickeners like hydroxyethylcellulose and hydroxypropyl methylcellulose; isotonic agents like sodium chloride, potassium chloride, glycerin, sucrose, and glucose; surfactants like polysorbate 80 and polyoxyethylene hydrogenated castor oil; isotonic agents like sodium chloride, potassium chloride, and glycerin; and pH adjusters like sodium hydroxide.

[0047] When the injectable solution of the present invention is used as a pharmaceutical product, it may be in the form of an injectable solution for intravenous injection. In particular, it may be an intravenous drip infusion solution.

[0048] The injectable solution is manufactured by dissolving, suspending, or emulsifying a certain amount of the active ingredient in an aqueous solvent (e.g., distilled water for injection, physiological saline, Ringer's solution, etc.) or an oily solvent (e.g., vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.) together with a dispersant (e.g., polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonic agent (e.g., sodium chloride, glycerin, D-mannitol, glucose, etc.). In this process, additives such as solubilizers (e.g., sodium salicylate, sodium acetate, etc.), stabilizers (e.g., human serum albumin, etc.), and analgesics (e.g., benzyl alcohol, etc.) may be used as desired. Furthermore, antioxidants, colorants, and other additives may be included as needed.

[0049] Furthermore, "pharmaceutically acceptable carriers" may be used. Examples of such substances in liquid formulations include solvents, solubilizers, suspending agents, isotonic agents, surfactants, and analgesics. In addition, if necessary, preservatives, colorants, and other formulation additives may be used in accordance with conventional methods.

[0050] Suitable examples of "solvents" include, for example, alcohols, propylene glycol, and macrogol.

[0051] Examples of solubilizers include polyethylene glycol, propylene glycol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0052] Suitable examples of "suspending agents" include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0053] Suitable examples of "isotonic agents" include, for example, glucose, sodium chloride, glycerin, and the like. Examples of "surfactants" include sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate. Suitable examples of "pain-relieving agents" include, for example, benzyl alcohol.

[0054] Suitable examples of "preservatives" include, for example, para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

[0055] [Manufacturing method for injectable solutions] The method for producing the injectable solution used in the present invention is not particularly limited, but as an example, it can be prepared by mixing a pH adjuster such as sodium hydroxide, water, and p-voronophenylalanine, and then adding a sugar alcohol. Here, the order in which the components are added may be important for more efficient production. Particularly preferably, a mixture of water and an alkaline pH adjuster such as sodium hydroxide is prepared first, then p-voronophenylalanine is added and stirred. After that, the sugar alcohol is added and dissolved, an acidic pH adjuster is added, and the volume is adjusted with water to prepare the injectable solution. By following such a protocol, each component can be dissolved efficiently in a short time, and an excellent injectable solution can be prepared efficiently. The type and amount of water, p-boronophenylalanine, sugar alcohol, and pH adjuster used at this time shall be in accordance with the amounts specified for the Boron Neutron Capture Therapy Injectable Solution.

[0056] [Method for preventing precipitation of injectable solutions] One method for preventing precipitation of an injectable solution according to the present invention is a method for preventing precipitation of an injectable solution for boron neutron capture therapy, which contains p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH of the injectable solution is controlled to be greater than 7.4 and less than or equal to 8.0. Here, the types and amounts of water, p-boronophenylalanine, sugar alcohol, and pH adjuster are in accordance with the amounts described for the injectable solution for BNCT.

[0057] Another aspect of the present invention is a method for preventing precipitation of an injectable boron neutron capture therapy solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH adjuster contains an organic acid or a salt thereof, and controls the pH of the injectable solution to 6.5 to 8.0. The type and amount of water, p-boronophenylalanine, sugar alcohol, and pH adjuster in this case are in accordance with the amounts described for the injectable boron neutron capture therapy solution.

[0058] Here, "precipitation prevention" means preventing precipitation when stored at various temperatures. In particular, it includes preventing precipitation when stored at room temperature to low temperatures suitable for storage, for example, below 30°C, preferably below 25°C. For example, although not limited to, precipitation may be prevented when stored at around 5°C. Here, precipitation prevention includes, for example, complete suppression of visible clouding, reduction of the degree of clouding, and extension of the time until clouding appears. Also, here, "storage" means storage for at least 6 hours, preferably 24 hours, and more preferably 2 days. In some cases, it may be storage for a long period, such as a week or a month.

[0059] [Neutron Capture Therapy] (Administration) The injectable solution used in the present invention is preferably used as an intravenous infusion, and is particularly preferably an intravenous infusion used in boron neutron capture therapy. Neutron capture therapy is a treatment method that uses a powerful particle beam (alpha particles, 7Li particles) generated by a nuclear reaction between boron-10 taken up by tumor cells and neutrons, and the injectable solution used in the present invention can be used particularly favorably in this method.

[0060] Prior to irradiation, the injectable solution of the present invention can be administered to the subject or animal in advance to adjust the concentration of boron-10 in the tumor, and then epithermal neutron irradiation can be performed. Alternatively, prior to irradiation, the injectable solution of the present invention can be administered to the subject or animal in advance to adjust the concentration of boron-10 in the tumor, and then epithermal neutron irradiation can be performed while continuing the administration. The dosage of the injectable solution of the present invention is not particularly limited, but can be controlled to achieve a desirable intracellular boron concentration. Such a dosage is set according to the type and stage of the tumor to be treated, the age and weight of the subject, etc. When the injectable solution of the present invention is used for intravenous administration, it is administered intravenously by drip infusion at a rate of 200 to 500 ml per hour for 1.5 to 4.0 hours, preferably for 2.0 to 3.6 hours. It is particularly preferable to start administration continuously from before the start of neutron irradiation until the start of irradiation.

[0061] For example, but not limited to, for patients with brain tumors or head and neck cancer, it is also effective to adjust the BPA concentration to preferably 150-250 mg / kg / hour, more preferably 200 mg / kg / hour, administer it for preferably 1.5-3 hours, more preferably 2 hours, and then administer it at a reduced rate to preferably 80-120 mg / kg / hour, more preferably 100 mg / kg / hour, and irradiate with epithermal neutron beams while performing this reduced administration for a maximum of 0.5-1.5 hours, preferably a maximum of 1 hour.

[0062] The injectable solution used in the present invention is, as described above, particularly preferred for neutron capture therapy. The target diseases are not limited, but are preferably solid tumors, and especially preferably cancers arising from epithelial cells (epithelial tumors). Typical examples include skin cancers, including melanoma, lung cancer, breast cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, and head and neck cancers (oral cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, etc.). Alternatively, sarcomas arising from non-epithelial cells may also be targeted. Typical examples include osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, liposarcoma, and angiosarcoma. In addition to these, gliomas, primary central nervous system lymphomas, meningiomas, pituitary adenomas, schwannomas, craniopharyngiomas, and other brain tumors may be targeted for treatment. Not only newly diagnosed and solitary cancers, but also cancers that have spread to individual organs, metastatic cancers, and refractory cancers can be targeted.

[0063] The present invention includes various embodiments of the methods for preventing precipitation of injectable solutions, as listed below. (1) A method for preventing precipitation of an injectable boron neutron capture therapy solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, A method for preventing precipitation, comprising preparing an injectable solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH is controlled to be greater than 7.5 and less than or equal to 8.0. (2) The precipitation prevention method according to (1) above, wherein the pH adjusting agent contains at least hydrochloric acid, and the amount of hydrochloric acid is 0.001 to 0.5 w / v%. (3) The precipitation prevention method according to (1) or (2), wherein the sugar alcohol is sorbitol or mannitol. (4) The precipitation prevention method according to any one of (1) to (3), wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v%. (5) The precipitation prevention method according to any one of (1) to (4), wherein the content of the sugar alcohol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-boronophenylalanine. (6) A method for preventing precipitation according to any one of (1) to (5), comprising at least an organic acid or a salt thereof, wherein the organic acid is citric acid or lactic acid. (7) The precipitation prevention method according to any one of (1) to (6), wherein the injectable solution is an intravenous injection solution. (8) The precipitation prevention method according to any one of (1) to (7), wherein the injectable solution is an intravenous injection solution for BNCT for the treatment of head and neck cancer or brain tumor. (9) The precipitation prevention method according to any one of (1) to (8), wherein the injection solution is to be administered intravenously by drip infusion at a rate of 200 to 500 ml per hour for a period of 1.5 to 4.0 hours, preferably 2.0 to 3.6 hours. (10) A method for preventing precipitation of an injectable boron neutron capture therapy solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, A method for preventing precipitation, comprising preparing an injectable solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and containing at least one organic acid or a salt thereof, with the pH controlled to 6.5-8.0. (11) The precipitation prevention method according to (10), wherein the sugar alcohol is sorbitol or mannitol. (12) The precipitation prevention method according to either (10) or (11), wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v%. (13) The precipitation prevention method according to any one of (10) to (12), wherein the content of the sugar alcohol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-boronophenylalanine. (14) The precipitation prevention method according to any one of (10) to (13), wherein the organic acid is citric acid or lactic acid. (15) The precipitation prevention method according to any one of (10) to (14), wherein the amount of the organic acid or its salt is 0 to 8.3 w / v% of the injection solution. (16) The precipitation prevention method according to any one of (10) to (15), wherein the injectable solution is an intravenous injection solution. (17) The precipitation prevention method according to any one of (10) to (16), wherein the injectable solution is an intravenous injection solution for BNCT for the treatment of head and neck cancer or brain tumor. (18) The precipitation prevention method according to any one of (10) to (17), wherein the injection solution is to be administered intravenously by drip infusion at a rate of 200 to 500 ml per hour for a period of 1.5 to 4.0 hours, preferably 2.0 to 3.6 hours. [Examples]

[0064] The present invention will be described in more detail below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0065] (Manufacturing example) Prior to the preparation of the injectable solution containing p-boronophenylalanine (BPA; L-isomer is used here) of the present invention, boron with a mass number of 10 (boron-10) was concentrated. 10 B96% concentrated boric acid (manufactured by Stella Chemifa) was used. Using the obtained highly concentrated boron-10, p-boronophenylalanine (BPA) was produced by a conventional method.

[0066] [Reference examples, examples] (Preparation of BPA sorbitol aqueous solution) Aqueous solutions containing 2.5 w / v% to 5.0 w / v% BPA, D-sorbitol, and sodium bisulfite or sodium pyrosulfite were prepared as follows: First, 5 g to 10 g of BPA was suspended in a solution of 1.05 to 2.08 g of sodium hydroxide dissolved in 175 ml of water. 5.25 to 13.0 g of D-sorbitol was added and stirred until dissolved. 0.02 g of sodium bisulfite or sodium pyrosulfite was added and dissolved, and 1.22 ml of 1 mol / l hydrochloric acid (at pH 7.6) or an appropriate amount was added to adjust the pH, and water was added to make a total volume of 200 ml. Then, the solution was filtered through a 0.2 μm filter.

[0067] (Preparation of BPA mannitol aqueous solution) Instead of sorbitol, mannitol was used, and the solution was prepared in the same manner as the BPA sorbitol aqueous solution.

[0068] (Preparation of BPA sugar alcohol aqueous solution) In addition to sorbitol, mannitol was also added, and an aqueous solution was prepared in the same manner as the BPA sorbitol aqueous solution.

[0069] <Stability Test 1> Stability evaluation was primarily performed using the following models and conditions, which are standard conditions for severe drug stability testing based on ICH guidelines.

[0070] First, as stability test 1, a storage test was conducted at 40°C. In this storage test, the solution was stored at 40°C ± 2°C, 75 ± 5% RH, and in the dark in a storage device: LH21-13M (manufactured by Nagano Science) for 2 weeks and 4 weeks. Samples of the solution were taken from each sample, and the BPA concentration, Tyr concentration, Phe concentration, and Ac-BPA concentration (high-performance liquid chromatograph Nexera X2 series, manufactured by Shimadzu Corporation) were measured and compared with the values ​​at the start of the test.

[0071] The measurement conditions for HPLC are as follows: Column used: Mightysil RP-18GP (5μm, 4.6×150mm), manufactured by Kanto Chemical Co., Ltd. Mobile phase: 0.05 mol / L sodium dihydrogen phosphate reagent (pH 2.5) / methanol (95:5) Column temperature: Constant temperature around 40°C Flow rate: approx. 0.8ml / min Injection volume: 10μl Detection wavelength: 223nm

[0072] Tables 1 and 2 show typical examples of the results of Stability Evaluation 1. In the table, the BPA residue amount represents the amount of BPA remaining after 4 weeks of storage, with the amount of BPA used in manufacturing set to 100% in Stability Test 1. Although not shown in the table, the initial tyrosine amount was also evaluated as an indicator of the initial BPA degradation due to the coexistence of components other than BPA in the composition. [Table 1] (The percentages for BPA and additives mean w / v%)

[0073] As shown in Table 1, all of the example compositions exhibited good stability. Similarly, good stability was also observed when the BPA concentration was set to 2.5-4.0 w / v% and sodium bisulfite was used as the antioxidant. Furthermore, when the BPA concentration was set to 2.5 w / v% and the sorbitol concentration was increased to 5.35 w / v% and 6.5 w / v%, compositions exhibiting similar good stability were obtained when the type and concentration of the antioxidant were tested under the same conditions.

[0074] [Table 2] (The percentages for BPA and additives mean w / v%)

[0075] In the storage tests for the compositions shown in Table 2, it was found that in the aqueous solutions of the examples, BPA was retained at almost 99% or more even after more than 4 weeks. Observation of the retention properties showed no changes in color or appearance of the components.

[0076] Based on a comprehensive assessment of the solubility and storage test results, it was found that the injectable solutions containing sorbitol or mannitol in the examples had a pH of 7.4-7.8, exhibited excellent stability at 40°C, and also demonstrated excellent homogeneity of the solution.

[0077] [Examples, Comparative Examples] (Preparation of BPA sorbitol aqueous solution) An aqueous solution containing 3 w / v% BPA, D-sorbitol, and sodium bisulfite was prepared as follows: First, 0.62 g of sodium hydroxide was added to 87 ml of water and stirred. 3 g of BPA was suspended. 3.15 g of D-sorbitol was added and stirred until dissolved. 0.02 g of sodium bisulfite was added, and an appropriate amount of 1 mol / l hydrochloric acid or 1 mol / l citric acid was added at room temperature to adjust the pH, and water was added to make a total volume of 100 ml.

[0078] <Stability Test 2> The BPA sorbitol aqueous solution prepared in this manner was subjected to Stability Test 2. In this test, it was subjected to a storage test at 5°C. In this storage test, it was left to stand at 5°C ± 3°C / ambH / dark, and the presence or absence of turbidity and the time until turbidity occurred were measured. The results are shown in Table 3.

[0079] [Table 3] Comparative examples 1 and 3: HCl 0.13w / v% Comparative example 2: HCl 0.09w / v% Example: Citric acid 0.15 w / v%

[0080] The results showed that in the low pH range, adjustment with hydrochloric acid alone could result in turbidity during low-temperature storage. On the other hand, adding citric acid suppressed turbidity during low-temperature storage.

[0081] Next, an aqueous solution containing 3 w / v% BPA, D-sorbitol, and sodium bisulfite was prepared as follows: First, 0.32 g of sodium hydroxide was added to 43 ml of water and stirred. 1.50 g of BPA was suspended. 1.575 g of D-sorbitol was added and stirred until dissolved. 0.01 g of sodium bisulfite was added, and an appropriate amount of 1 mol / l hydrochloric acid or 1 mol / l citric acid was added at room temperature to adjust the pH, and water was added to make a total volume of 50 ml. [Table 4]

[0082] As a result, when hydrochloric acid was used, turbidity sometimes occurred during storage at 5°C. However, it was found that when citric acid was used instead of hydrochloric acid at pH 6.8, although turbidity still occurred during storage, its occurrence was delayed. Thus, it was found that using citric acid instead of hydrochloric acid can completely prevent or delay the occurrence of turbidity.

Claims

1. A method for preventing precipitation of an injectable boron neutron capture therapy solution containing p-boronophenylalanine or a pharmaceutically acceptable salt thereof, comprising p-boronophenylalanine or a pharmaceutically acceptable salt thereof, sorbitol, and citric acid or a salt thereof, A method for preventing precipitation at low temperatures of 5°C ± 3°C, which includes preparing an injectable solution with a controlled pH of 6.5 to 7.

5.

2. The precipitation prevention method according to claim 1, wherein the injection solution further contains one or more selected from the group consisting of sodium sulfite, anhydrous sodium sulfite, potassium sulfite, calcium sulfite, sodium bisulfite, potassium bisulfite, ammonium bisulfite, sodium pyrosulfite, and potassium pyrosulfite.

3. The precipitation prevention method according to claim 1 or 2, wherein the concentration of the sorbitol is 2.6 to 6.5 w / v%.

4. The precipitation prevention method according to any one of claims 1 to 3, wherein the content of sorbitol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-boronophenylalanine.

5. The precipitation prevention method according to any one of claims 1 to 4, wherein the amount of citric acid or its salt is 0.01 to 8.3 w / v% of the injection solution.

6. The precipitation prevention method according to any one of claims 1 to 5, wherein the injectable solution is an intravenous injection solution.

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