Method for preventing precipitation of injectable solution 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, and more particularly to a method for preventing precipitation of an injection solution containing p-boronophenylalanine during storage. [Background technology]

[0002] In recent years, boron neutron capture therapy (BNCT) has been attracting attention as a cancer treatment method using radioisotopes. 10 This is a treatment method in which a boron compound containing boron-10 is taken up by cancer cells, and then low-energy neutrons (e.g. epithermal neutrons) are irradiated to destroy the cancer cells locally through a nuclear reaction that occurs within the cells. In this treatment method, it is important to selectively accumulate the boron compound containing boron-10 in the cells of the cancer tissue in order to enhance the therapeutic effect, so it is necessary to develop a boron compound that can be selectively and reliably taken up by cancer cells.

[0003] Boron-containing compounds that have boron atoms or boron groups introduced into their basic skeletons have been synthesized as drugs for use in BNCT. Drugs actually used in clinical practice include p-boronophenylalanine (BPA) and mercaptoundecahydrododecaborate (BSH).

[0004] p-Boronophenylalanine is extremely poorly soluble at physiological pH.

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

[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. 6,169,076 [Patent Document 3] Patent No. 5345771 Summary of the Invention [Problem to be solved by the invention]

[0007] The blood boron concentration required for boron neutron capture therapy to be effective is limited, so it is desirable to prepare a stable formulation that maintains a constant BPA concentration so that the therapeutic effect can be maximized.

[0008] However, it was found that when the BPA concentration was kept constant while storing the injection for the period until administration, stability problems could arise and precipitation could occur.

[0009] Therefore, an object of the present invention is to provide a method for preventing precipitation of an injectable solution containing p-boronophenylalanine when stored over a wide range of temperatures, particularly when stored at low temperatures. [Means for solving the problem]

[0010] As a result of extensive research to solve the above problems, the inventors discovered that p-boronophenylalanine in an injection solution can be stabilized over a wide temperature range by adding a sugar alcohol or an antioxidant and changing the type of pH adjuster depending on changes in the pH value, thereby completing the present invention.

[0011] That is, the present invention provides the following method for preventing precipitation of an injection solution. [1] A method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutical acceptable salt thereof, comprising: A method for preventing precipitation, comprising preparing an injection solution containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and having a pH controlled to greater than 7.5 and not greater than 8.0. [2] A method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutical acceptable salt thereof, comprising: A method for preventing precipitation, comprising preparing an injection solution containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and containing at least one organic acid or a salt thereof, and having a pH controlled to 6.5 to 8.0. [3] The method for preventing precipitation according to [1] or [2], wherein the sugar alcohol is sorbitol or mannitol. [4] The method for preventing precipitation 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 method for preventing precipitation 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 terms of molar ratio to the content of p-boronophenylalanine. [6] The method for preventing precipitation according to any one of [2] to [5], wherein the organic acid is citric acid or lactic acid. [7] The method for preventing precipitation according to any one of [2] to [6], wherein the amount of the organic acid or a salt thereof is 0 to 8.3 w / v % of the injection solution. [8] Item 8. The method for preventing precipitation according to any one of Items 1 to 7, wherein the injection solution is an intravenous injection solution. Effect of the Invention

[0012] The present invention can provide a method for preventing precipitation of an injection solution for boron neutron capture therapy when stored over a wide temperature range, particularly when stored at low temperatures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0014] One aspect of the present invention is a method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, in which the pH of the injection solution is controlled to be greater than 7.4 and less than 8.0, preferably greater than 7.5 and less than 8.0.

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

[0016] [Injection solution for boron neutron capture therapy] (p-Boronophenylalanine or a pharma- ceutically acceptable salt thereof) The p-boronophenylalanine used in the present invention is not particularly limited, but the proportion of boron-10 among the boron atoms in the compound 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 (boron) contains isotopes of boron-10 and boron-11, with the ratio of boron-10 being 20% ​​and boron-11 being 80%. Therefore, prior to the production of an injectable solution 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 natural boron compounds are separated to produce highly concentrated boron-10. The boron used in the present invention may be concentrated to increase its concentration as boron-10, or a commercially available product may be used. Examples of commercially available products include 10 B Concentrated boric acid (manufactured by Stella Chemifa Co., Ltd.) can be used as the starting material.

[0018] Here, the boron-10 measurement method can be performed by quadrupole ICP-MS (ICP-QMS) using a quadrupole mass analyzer, using an Agilent 7500 (manufactured by Agilent). The ICP-QMS used for the measurement is adjusted in accordance with JIS K0133.

[0019] The currently used form of p-boronophenylalanine is the L-form, and the present invention also preferably uses Lp-boronophenylalanine, but is not limited thereto. That is, the present invention also uses D-form or racemic p-boronophenylalanine containing both D-form and L-form.

[0020] Here, p-boronophenylalanine can be synthesized, for example, by known methods (e.g., 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. 5,157,149; Japanese Patent Publication No. 2000-212185; and Japanese Patent No. 2,979,139) 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, and salts with inorganic bases.

[0022] Examples of salts with organic acids include acetates, trifluoroacetates, fumarates, maleates, lactates, tartrates, citrates, and methanesulfonates. Examples of salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates. 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 injection solution used in the present invention, the content of p-boronophenylalanine or its salt relative to the total amount of the injection solution is appropriately set depending on the balance with other components. The total content of p-boronophenylalanine and / or its salt relative to the total amount of the injection 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 content of p-boronophenylalanine in the injectable solution of the present invention is within the above range, the amount of solution required for clinical application is adequate, the solution has good stability, and is highly effective when administered.

[0025] (Sugar alcohol) The sugar alcohol used in the present invention is not particularly limited as long as it is used as a component of injections in the pharmaceutical field. Although the sugar alcohol is 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 has been confirmed to be safe, may be preferably used, but is not limited thereto. That is, in the present invention, L-sorbitol or a mixture of L- and D-sorbitol may also be used.

[0027] As mannitol, D-mannitol, which is currently approved for use in pharmaceuticals and has been confirmed to be safe, may be preferably used, but is not limited thereto. That is, in the present invention, L-mannitol or a mixture of L-mannitol and D-mannitol may also be used.

[0028] The total content of sugar alcohols used in the injectable solution of the present invention varies depending on the amounts of other additives, 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%, based on 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 terms of molar ratio. When the amount of sugar alcohol is in this range, precipitation of p-boronophenylalanine can be suppressed, and the osmotic pressure ratio can be appropriately adjusted.

[0030] (Antioxidant) An antioxidant can be optionally used in the injection solution used in the present invention. The antioxidant is not particularly limited as long as it is used as a component of injections in the pharmaceutical field. The antioxidant is not limited, but is preferably one or more selected from the group consisting of sulfurous acid, hydrogen sulfite, pyrosulfite, nitrous acid, ascorbic acid, L-cysteine, thioglycolic acid, and salts thereof.

[0031] Here, examples of the salts of sulfurous acid, hydrogen sulfite, pyrosulfite, nitrous acid, 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, and ammonium salts.

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

[0033] The total content of the antioxidants used in the injectable solution of the present invention varies depending on the amounts 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%, based on the total amount of the injectable solution.

[0034] (water) The injection 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 a component of injections in the pharmaceutical field.

[0035] The content of water used in the injection solution of the present invention varies depending on the amounts of other additives, but is preferably 80 w / v% or more, more preferably 85 w / v% or more, and is preferably 95 w / v% or less, and even more preferably 94 w / v% or less, based on the total amount of the injection solution.

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

[0037] In order to ensure stability in and out of the body, the injection solution used in the present invention may contain various metal ions that may be contained in the body. Preferably, sodium ions are contained, and the concentration is not particularly limited, but is particularly preferably 130 mEq / L to 160 mEq / L. This numerical range close to the Na ion concentration range of body fluids is preferable so that the electrolyte balance between intracellular fluid and extracellular fluid is not significantly disrupted.

[0038] (pH adjuster) The injection solution used in the present invention may contain, as necessary, an inorganic acid such as hydrochloric acid or phosphoric acid, or an alkaline component such as sodium hydroxide or potassium hydroxide, or other pH adjusters. Furthermore, it is also preferable to use an organic acid in addition to or instead of an inorganic acid. As the organic acid, it is preferable to use citric acid, acetic acid, trifluoroacetic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, or methanesulfonic acid, and it is more preferable to use citric acid or lactic acid.

[0039] The content of the pH adjuster used in the injection solution used in the present invention varies depending on the amount of other additives, but for example, in the case of an inorganic acid such as hydrochloric acid, the content is preferably 0.001 to 0.5 w / v%, 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 injection solution.

[0040] The content of the pH adjuster used in the injection solution used in the present invention will vary depending on the amounts of other additives, but for example, in the case of an organic acid 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%, relative to the total amount of the injection solution.

[0041] The content of the pH adjuster used in the injection solution used in the present invention will vary depending on the amounts of other additives, but for organic acids such as citric acid, the content 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%, relative to the total amount of the injection solution, particularly when the pH is in the range of 6.5 to 7.4 or around 7.5.

[0042] The inorganic alkaline 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 injection solution used in the present invention is preferably neutral to weakly alkaline, taking into consideration the balance between administration to the living 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 during storage at room temperature to low temperature, it is preferably in the range of more than pH 7.4 to 8.0 or less, and particularly preferably more than pH 7.5 to 7.8 or less. For adjusting the pH, a suitable pH regulator, buffer, etc. used in the technical field may be used as necessary.

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

[0045] [Other ingredients] If necessary, the injection solution used in the present invention may contain a buffer such as a phosphate buffer, a Tris-HCl buffer, an acetate buffer, a carbonate buffer, a citrate buffer, etc. These buffers may be useful for stabilizing the preparation or reducing irritation.

[0046] Furthermore, the injection solution of the present invention may contain other components that are generally used in the art, as necessary, as long as they are not contrary to the object of the present invention. Such components include additives that are generally 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 hydroxyethylcellulose and hydroxypropylmethylcellulose, 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 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 injection for intravenous injection, particularly an intravenous drip infusion solution.

[0048] Injectable solutions are prepared by dissolving, suspending or emulsifying a certain amount of active ingredient 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 an aqueous solvent (e.g., distilled water for injection, physiological saline, Ringer's solution, etc.) or an oily solvent (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.). In this case, additives such as solubilizing agents (e.g., sodium salicylate, sodium acetate, etc.), stabilizers (e.g., human serum albumin, etc.), and pain-relieving agents (e.g., benzyl alcohol, etc.) may be used as desired. Furthermore, antioxidants, colorants, and other additives may be added as necessary.

[0049] In addition, a "pharmaceutical acceptable carrier" can also be used. Examples of such substances include solvents, solubilizing agents, suspending agents, isotonicity agents, surfactants, soothing agents, etc. in liquid preparations. Furthermore, if necessary, preparation additives such as preservatives, colorants, etc. can also be used in the usual manner.

[0050] Suitable examples of the "solvent" include alcohol, propylene glycol, macrogol, etc.

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

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

[0053] Suitable examples of the "isotonicity agent" include glucose, sodium chloride, glycerin, and the like. Examples of the "surfactant" include sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and the like. Suitable examples of "soothing agents" include benzyl alcohol and the like.

[0054] Suitable examples of the "preservative" include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

[0055] [Manufacturing method of injection solution] The method for producing the injection solution used in the present invention is not particularly limited, but as an example, a pH adjuster such as sodium hydroxide, water, and p-boronophenylalanine can be mixed, and then a sugar alcohol can be added to prepare the injection solution. Here, during preparation, the order of adding the components can be important for more efficient production. Particularly preferably, a mixture of water and an alkaline component pH adjuster such as sodium hydroxide is first prepared, and then p-boronophenylalanine is added and stirred. Then, a sugar alcohol is added and dissolved, an acidic component pH adjuster is added, and the volume is adjusted with water to prepare the injection solution. By following such a protocol, each component can be efficiently dissolved in a short time, and an excellent injection solution can be efficiently prepared. The types and amounts of water, p-boronophenylalanine, sugar alcohol, and pH adjuster used in this step should conform to those described for the injectable solution for boron neutron capture therapy.

[0056] [Method to prevent precipitation of injection solutions] One of the methods for preventing precipitation of an injection solution of the present invention is a method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, sugar alcohol, and a pH adjuster, in which the pH of the injection solution is controlled to more than 7.4 and not more than 8.0, where the types and amounts of water, p-boronophenylalanine, sugar alcohol, and pH adjuster are the same as those described for the injection solution for BNCT.

[0057] Another aspect of the present invention is a method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, the pH adjuster containing an organic acid or a salt thereof, and controlling the pH of the injection solution to 6.5 to 8.0. The types and amounts of water, p-boronophenylalanine, sugar alcohol, and pH adjuster are the same as those described for the injection solution for boron neutron capture therapy.

[0058] Here, "prevention of precipitation" means prevention of precipitation when stored at various temperatures. That is, in particular, it includes prevention of precipitation when stored at room temperature or lower, suitable for storage, for example, 30°C or lower, preferably 25°C or lower. For example, but not limited to, precipitation may be prevented when stored at around 5°C. Here, prevention of precipitation includes, for example, complete suppression of white turbidity when visually observed, reduction of the degree of white turbidity, and extension of the time until white turbidity appears. In addition, under storage means storage for at least 6 hours or more, preferably 24 hours or more, and more preferably 2 days or more. In some cases, it may be stored for a long period, such as one week or one month.

[0059] [Neutron capture therapy] (Administration) The injection solution used in the present invention is preferably used as an intravenous infusion, and particularly preferably as an intravenous infusion used in boron neutron capture therapy. Neutron capture therapy is a treatment method using powerful particle beams (alpha beams, 7Li particles) generated by the nuclear reaction between boron 10 taken up in tumor cells and neutrons, and the injection solution used in the present invention is particularly convenient for use in this method.

[0060] Prior to irradiation, the injection solution of the present invention can be administered to a subject or animal in advance, adjusted so that boron-10 accumulates in the tumor, and then epithermal neutron radiation can be irradiated. Alternatively, prior to irradiation, the injection solution of the present invention can be administered to a subject or animal in advance, adjusted so that boron-10 accumulates in the tumor, and then epithermal neutron radiation can be irradiated while continuing the administration. The dosage of the injection solution of the present invention is not particularly limited, but can be controlled to achieve a preferred intracellular boron concentration. Such a dosage is set depending on the type and progression of the tumor to be applied, the age and weight of the subject, etc., but when the injection solution of the present invention is used for intravenous administration, it is administered by drip infusion into a vein at a rate of 200 to 500 ml per hour for 1.5 to 4.0 hours, preferably 2.0 to 3.6 hours. It is particularly preferable that the timing of administration is continuously performed from before the start of neutron irradiation until the start of irradiation.

[0061] For example, but not limited to, for a brain tumor patient or a head and neck cancer patient, it is effective to adjust the BPA concentration to 150 to 250 mg / kg / hour, more preferably 200 mg / kg / hour, and after administration for preferably 1.5 to 3 hours, more preferably 2 hours, the BPA is then reduced in speed to preferably 80 to 120 mg / kg / hour, more preferably 100 mg / kg / hour, and the reduced speed administration is continued for a maximum of 0.5 to 1.5 hours, preferably a maximum of 1 hour, while irradiating the patient with epithermal neutrons.

[0062] Thus, the injection liquid used in the present invention is preferably used in neutron capture therapy. The target disease is not limited, but solid cancer is preferable, and cancer (epithelial tumor) developed from epithelial cells is particularly preferable. Representative examples include skin cancer including melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, uterine cancer, ovarian cancer, and head and neck cancer (oral cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, etc.). Alternatively, sarcoma developed from non-epithelial cells may be the target. Representative examples include osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, liposarcoma, and angiosarcoma. In addition to these, brain tumors such as glioma, primary central nervous system malignant lymphoma, meningioma, pituitary adenoma, neurilemmoma, and craniopharyngioma may be the target diseases for treatment. Not only primary or single cancer, but also cancer that has spread to individual organs, metastatic cancer, and intractable cancer may be the target.

[0063] The present invention includes the following embodiments of the method for preventing precipitation of an injection solution. (1) A method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutical acceptable salt thereof, comprising: A method for preventing precipitation, comprising preparing an injection solution containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and having a pH controlled to greater than 7.5 and not greater than 8.0. (2) The method for preventing precipitation according to the above (1), wherein the pH adjuster contains at least hydrochloric acid, and the amount of the hydrochloric acid is 0.001 to 0.5 w / v %. (3) The method for preventing precipitation according to (1) or (2), wherein the sugar alcohol is sorbitol or mannitol. (4) The method for preventing precipitation 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 method for preventing precipitation according to any one of (1) to (4), wherein the content of the sugar alcohol is in a range of 0.9 to 3.0 in terms of molar ratio to the content of p-boronophenylalanine. (6) The method for preventing precipitation according to any one of (1) to (5), which contains at least an organic acid or a salt thereof, and the organic acid is citric acid or lactic acid. (7) The method for preventing precipitation according to any one of (1) to (6), wherein the injection solution is an intravenous injection solution. (8) The method for preventing precipitation according to any one of (1) to (7), wherein the injection solution is an intravenous injection solution for BNCT for treating head and neck cancer or brain tumor. (9) The method for preventing precipitation according to any one of (1) to (8), wherein the injection solution is for intravenous administration 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 injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutical acceptable salt thereof, comprising: A method for preventing precipitation, comprising preparing an injection solution containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and containing at least one organic acid or a salt thereof, and having a pH controlled to 6.5 to 8.0. (11) The method for preventing precipitation according to (10), wherein the sugar alcohol is sorbitol or mannitol. (12) The method for preventing precipitation according to any one of (10) and (11), wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v %. (13) The method for preventing precipitation according to any one of (10) to (12), wherein the content of the sugar alcohol is in a range of 0.9 to 3.0 in terms of molar ratio to the content of p-boronophenylalanine. (14) The method for preventing precipitation according to any one of (10) to (13), wherein the organic acid is citric acid or lactic acid. (15) The method for preventing precipitation according to any one of (10) to (14), wherein the amount of the organic acid or a salt thereof is 0 to 8.3 w / v % of the injection solution. (16) The method for preventing precipitation according to any one of (10) to (15), wherein the injection solution is an intravenous injection solution. (17) The method for preventing precipitation according to any one of (10) to (16), wherein the injection solution is an intravenous injection solution for BNCT for treating head and neck cancer or brain tumor. (18) The method for preventing precipitation according to any one of (10) to (17), wherein the injection solution is for intravenous administration at a rate of 200 to 500 ml per hour for a period of 1.5 to 4.0 hours, preferably for a period of 2.0 to 3.6 hours. EXAMPLES

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

[0065] (Production example) Prior to the production of an injection solution containing p-boronophenylalanine (BPA; L-form is used here) of the present invention, boron with a mass number of 10 (boron-10) was concentrated. 10 96% concentrated boric acid (manufactured by Stella Chemifa Co., Ltd.) was used. Using the obtained highly concentrated boron 10, p-boronophenylalanine (BPA) was produced by a conventional method.

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

[0067] (Preparation of BPA-mannitol aqueous solution) A BPA sorbitol aqueous solution was prepared in the same manner as the BPA sorbitol aqueous solution, except that mannitol was used instead of sorbitol.

[0068] (Preparation of BPA sugar alcohol aqueous solution) An aqueous solution was prepared in the same manner as the BPA sorbitol aqueous solution, except that mannitol was also present in addition to sorbitol.

[0069] <Stability test 1> Stability evaluation was mainly performed using the following equipment and conditions as standard conditions for severe pharmaceutical stability testing based on ICH guidelines.

[0070] First, a storage test at 40°C was conducted as stability test 1. In this storage test, the liquids were stored in a storage device: LH21-13M (Nagano Science) at 40°C ± 2°C, 75 ± 5% RH, and in a dark place for 2 weeks and 4 weeks, and samples were taken from each liquid to measure the BPA concentration, Tyr concentration, Phe concentration, and Ac-BPA concentration (High-performance liquid chromatograph NexeraX2 series, Shimadzu Corporation) and compared with the concentrations at the start of the test.

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

[0072] Representative examples of the results of stability evaluation 1 are shown in Tables 1 and 2. The remaining amount of BPA in the tables indicates the amount of BPA remaining after 4 weeks of storage, assuming the amount of BPA used in production in stability test 1 to be 100%. In addition, although not shown in the tables, the initial tyrosine amount was evaluated as an index showing the state of BPA decomposition in the early stages due to the coexistence of components other than BPA in the composition. [Table 1] (The percentages of BPA and additives refer to w / v%.)

[0073] As shown in Table 1, all of the compositions of the examples showed good stability. In addition, when the BPA concentration was set to 2.5 to 4.0 w / v% and sodium bisulfite was used as an antioxidant, similar good stability was also shown. 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%, and the type and concentration of the antioxidant were examined under the same conditions, compositions showing similar good stability were obtained.

[0074] [Table 2] (The percentages of BPA and additives refer to w / v%.)

[0075] In the case of the compositions in Table 2, in the storage test, it was found that the aqueous solution of the example retained more than 99% of the BPA even after 4 weeks or more. In the observation of the retention properties, no change in color or appearance of the ingredients was observed.

[0076] Comprehensively judging the results of the solubility and storage tests, it was found that the injection solutions containing sorbitol or mannitol of the examples had excellent stability when stored at 40°C at a pH of 7.4 to 7.8, and also had excellent liquid homogeneity.

[0077] [Examples and 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 to dissolve. 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 the total volume 100 ml.

[0078] <Stability test 2> The BPA sorbitol aqueous solution thus prepared 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 place, and the presence or absence of cloudiness and the time until cloudiness 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 0.15w / v%

[0080] As a result, it was found that in the low pH range, adjusting the pH with hydrochloric acid alone may cause cloudiness during low-temperature storage. On the other hand, adding citric acid could suppress cloudiness 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 to dissolve. 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 the total volume 50 ml. [Table 4]

[0082] As a result, when hydrochloric acid was used, clouding sometimes occurred during storage at 5°C. Here, it was found that when citric acid was added instead of hydrochloric acid at pH 6.8, clouding occurred during storage, but the occurrence was delayed. Thus, it was found that the occurrence of clouding can be completely prevented or the time for it to occur can be delayed, or suppressed, by adding citric acid instead of hydrochloric acid.

Claims

1. A method for preventing precipitation of an injection solution for boron neutron capture therapy containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, comprising: A method for preventing precipitation at low temperatures, comprising preparing an injection solution containing p-boronophenylalanine or a pharma- ceutically acceptable salt thereof, sorbitol, and a pH adjuster, the pH adjuster containing at least one organic acid or a salt thereof, and the pH being controlled to 6.5 to 7.

5.

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

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

4. The method for preventing precipitation according to any one of claims 1 to 3, wherein the low temperature is 5°C ± 3°C.

5. The method for preventing precipitation according to any one of claims 1 to 4, wherein the content of sorbitol is in the range of 0.9 to 3.0 in terms of molar ratio to the content of p-boronophenylalanine.

6. The method for preventing precipitation according to any one of claims 1 to 5, wherein the organic acid is citric acid or lactic acid.

7. The method for preventing precipitation according to any one of claims 1 to 6, wherein the amount of the organic acid or its salt is 0.01 to 8.3 w / v % of the injection solution.

8. The method for preventing precipitation according to any one of claims 1 to 7, wherein the injection solution is an intravenous injection solution.

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