Method to prevent precipitation of an injectable solution containing p-voronophenylalanine

Abstract

The present invention aims to provide a method for preventing precipitation during the storage of an injectable solution for boron neutron capture therapy. The present invention provides a method for preventing precipitation of an injectable solution for boron neutron capture therapy to be administered by intravenous drip infusion, comprising p-voronophenylalanine or a pharmaceutically acceptable salt thereof; a sugar alcohol; and a pH adjuster, wherein the pH is 6.5 to 8.0 and the osmotic pressure ratio is 1.0 to 1.8.

Description

Technology Field

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

[0002] Recently, Boron Neutron Capture Therapy (BNCT) is attracting attention as a cancer treatment method using radioisotopes. Boron Neutron Capture Therapy uses the Boron-10 isotope ( 10 This is a treatment method in which a boron compound containing B) is introduced into cancer cells and irradiated with low-energy neutron rays (e.g., thermal extraneutrons) to locally destroy cancer cells through nuclear reactions occurring within the cells. In this treatment method, since it is important to selectively accumulate a boron compound containing boron 10 in the cells of the cancer tissue to enhance the therapeutic effect, it is necessary to develop a boron compound that is selectively and reliably introduced into cancer cells.

[0003] Boron-containing compounds with boron atoms or boron atomic groups introduced into the basic framework are being synthesized as agents used in BNCT. Agents currently used in actual clinical practice include p-voronophenylalanine (BPA) and mercaptoundecahydrodecarborate (BSH).

[0004] p-voronophenylalanine has very poor solubility at physiological pH.

[0005] In order to improve the solubility of p-voronophenylalanine in water, methods are being attempted such as generating a fructose complex of BPA (e.g., Patent Document 1), or adding a monosaccharide or polyol to p-voronophenylalanine in an alkaline solution (e.g., an aqueous sodium hydroxide solution) and removing the inorganic salt using an ion exchange resin (e.g., Patent Document 2).

[0006] In addition, other techniques to improve the solubility of p-voronophenylalanine are also proposed (Patent Document 3). Prior art literature

[0007] Patent Document 1: U.S. Patent No. 5,492,900 Patent Document 2: U.S. Patent No. 6,169,076 Patent Document 3: Japanese Patent No. 5,345,771 The problem to be solved

[0008] The concentration of boron in the blood at the time of administration required to be effective as boron neutron capture therapy is limited. Accordingly, it is required to prepare a formulation with excellent stability while maintaining a constant BPA concentration to maximize the therapeutic effect.

[0009] However, it has been revealed that maintaining a constant BPA concentration during the period leading up to administration and storing the product as an injectable can lead to stability issues and precipitation.

[0010] Accordingly, the object of the present invention is to provide a method for preventing precipitation of an injectable preparation containing p-voronophenylalanine under storage over a wide temperature range, including particularly under low-temperature storage. means of solving the problem

[0011] As a result of conducting in-depth research to solve the above problem, the inventors discovered that p-voronophenylalanine in an injectable solution can be stabilized over a wide temperature range by including a sugar alcohol or an antioxidant and changing the type of pH adjuster according to changes in pH value, and thus completed the present invention.

[0012] That is, the present invention provides a method for preventing precipitation of an injectable solution as described below.

[0013] [1]

[0014] A method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof,

[0015] A method for preventing precipitation comprising preparing an injectable solution containing p-voronophenylalanine 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.

[0016] [2]

[0017] A method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof,

[0018] A method for preventing precipitation, comprising preparing an injectable solution containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and containing at least one organic acid or its salt, with the pH controlled to 6.5 to 8.0.

[0019] [3]

[0020] The above sugar alcohol is sorbitol or mannitol, a method for preventing precipitation as described in [1] or [2].

[0021] [4]

[0022] A precipitation prevention method described in any one of [1] to [3], wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v%.

[0023] [5]

[0024] A precipitation prevention method described in any one of [1] to [4], wherein the content ratio of the above sugar alcohol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-voronophenylalanine.

[0025] [6]

[0026] A method for preventing precipitation described in any one of [2] to [5], wherein the organic acid is citric acid or lactic acid.

[0027] [7]

[0028] A method for preventing precipitation described in 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.

[0029] [8]

[0030] A method for preventing precipitation described in any one of [1] to [7], wherein the above-mentioned injection solution is an intravenous injection solution. Effects of the invention

[0031] According to the present invention, a method for preventing precipitation of an injectable solution for boron neutron capture therapy under storage over a wide temperature range, including particularly under low-temperature storage, can be provided. Specific details for implementing the invention

[0032] In this specification, the unit "mass%" has the same meaning as "g / 100g". "w / v%" has the same meaning as "g / 100ml".

[0033] One embodiment of the present invention is a method for preventing precipitation of an injectable solution for boron neutron capture therapy, comprising p-voronophenylalanine 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, preferably greater than 7.5 and less than or equal to 8.0.

[0034] Another aspect of the present invention is a method for preventing precipitation of an injectable solution for boron neutron capture therapy, comprising p-voronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH adjuster comprises an organic acid or a salt thereof and controls the pH of the injectable solution to 6.5 to 8.0.

[0035] [Injectable solution for boron neutron capture therapy]

[0036] (p-voronophenylalanine or pharmaceutically acceptable salts thereof)

[0037] The p-voronophenylalanine 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.

[0038] In natural boron (boron), boron-10 and boron-11 exist as isotopes, with boron-10 present in a ratio of 20% and boron-11 in an 80% ratio. Therefore, prior to the preparation of the injectable solution containing p-voronophenylalanine according to the present invention, boron with a mass number of 10 (boron-10) is concentrated. To this end, boron-10 and boron-11 are selected from natural boron compounds, and highly concentrated boron-10 is prepared. The boron used in the present invention may be concentrated by increasing the concentration of boron-10, and commercially available products may also be used. Examples of commercially available products include, 10 B. Concentrated boric acid (Stellar Chemifa) can be used as a starting material.

[0039] At this time, the measurement of boron 10 can be performed using the quadrupole ICP-MS (ICP-QMS) method utilizing a quadrupole mass spectrometer with an Agilent 7500 (Agilent). The ICP-QMS used for measurement is adjusted in accordance with JIS K0133.

[0040] The p-voronophenylalanine currently in use is the L-form, and while the L-p-voronophenylalanine may be preferably used in the present invention, it is not limited thereto. That is, the D-form, or a racemic form of p-voronophenylalanine containing both the D-form and the L-form, may also be used in the present invention.

[0041] At this time, p-voronophenylalanine can be used by synthesizing it by known methods, for example (e.g., HRSynder, AJReedy, WMJLennarz, J.Am.Chem.Soc., 1958, 80, 835; C.Malan, C.Morin, SYNLETT, 1996, 167; U.S. Patent No. 5157149; Japanese Patent Publication No. 2000-212185; and Japanese Patent No. 2979139).

[0042] In this case, the salt is not particularly limited as long as it is pharmacologically acceptable. Examples of salts of p-voronophenylalanine include salts with organic acids, salts with inorganic acids, salts with organic bases, salts with inorganic bases, etc.

[0043] Examples of salts with organic acids include acetates, trifluoroacetates, fumarates, maleates, lactates, tartrates, citrates, methanesulfonates, etc. Examples of salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc. Examples of salts with organic bases include salts with triethanolamine, etc. Examples of salts with inorganic bases include ammonium salts, sodium salts, potassium salts, calcium salts, magnesium salts, etc.

[0044] In the injectable solution used in the present invention, the content of p-voronophenylalanine or its salt relative to the total amount of the injectable solution is appropriately set according to the balance with other components. The total content of p-voronophenylalanine and / or its salt relative to the total amount 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%.

[0045] When the content of p-voronophenylalanine in the injectable solution of the present invention is within the above range, it is administered in an appropriate volume when applied in clinical practice, has good solution stability, and also has excellent efficacy upon administration.

[0046] (sugar alcohol)

[0047] The sugar alcohols used in the present invention are not particularly limited as long as they are used as components of injectables in the pharmaceutical field. The sugar alcohols are not limited, but monosaccharide sugar alcohols are preferred, and sorbitol and / or mannitol are particularly preferred.

[0048] As for sorbitol, D-sorbitol, which is currently approved for use as a pharmaceutical and whose safety has been confirmed, may be preferably used, but is not limited thereto. That is, in the present invention, L-sorbitol, or a mixture of L-sorbitol and D-sorbitol may be used.

[0049] As for mannitol, D-mannitol, which is currently approved for use as a pharmaceutical and whose safety has been confirmed, 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 be used.

[0050] The total content of sugar alcohol used in the injectable solution of the present invention varies depending on the amount 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% with respect to the total amount of the injectable solution.

[0051] With respect to the amount of p-voronophenylalanine, the amount of sugar alcohol is in a molar ratio 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. If the amount of sugar alcohol is in this range, the precipitation of p-voronophenylalanine can be suppressed and the osmotic pressure ratio can be appropriately adjusted.

[0052] (Antioxidant)

[0053] The antioxidant used in the present invention may optionally be an antioxidant. As long as it is used as a component of an injectable in the pharmaceutical field, it is not particularly limited. As for the antioxidant, it is not limited, but it is preferable that it be one or more selected from the group consisting of sulfur dioxide, hydrogen sulfite, pyrosulfite, nitrous acid, ascorbic acid, L-cysteine, thioglycolic acid, and salts thereof.

[0054] In this case, the salts of sulfurous acid, hydrogen sulfite, pyrosulfite, nitrous acid, ascorbic acid, L-cysteine, or thioglycolic acid may include, for example, 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. In addition, salts with organic bases such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine may also be used. Particularly preferably, they are sodium salts, potassium salts, or ammonium salts.

[0055] Particularly preferred as an antioxidant used in the present invention is one or more selected from the group consisting of sodium sulfite, dry sodium sulfite, potassium sulfite, calcium sulfite, sodium bisulfite, potassium bisulfite, ammonium bisulfite, sodium pyrosulfite, and potassium pyrosulfite.

[0056] The total content of the antioxidant used in the injectable solution of the present invention varies depending 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%, more preferably 0.01 to 0.6 w / v%, and most preferably 0.01 to 0.03 w / v% with respect to the total amount of the injectable solution.

[0057] (water)

[0058] 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 can be used as a component of an injectable in the pharmaceutical field.

[0059] The water content used in the injectable solution of the present invention varies depending on the amount of other additives, but is preferably 80 w / v% or more, more preferably 85 w / v% or more, preferably 95 w / v% or less, and more preferably 94 w / v% or less with respect to the total amount of the injectable solution.

[0060] (Osmotic pressure ratio)

[0061] The osmotic pressure ratio of the injectable solution of the present invention is not particularly limited, but it is preferably within the range of 1.0 to 1.8 relative to physiological saline. More preferably, it is within the range of 1.1 to 1.5. In this range, in the case of large-volume intravenous injection, it is possible to reduce pain, avoid the onset of phlebitis, or shorten the administration time.

[0062] In the injectable solution used in the present invention, various metal ions that are acceptable to be appropriately present in the body may be included to ensure stability inside and outside the body. Preferably, sodium ions are included, and while the concentration is not particularly limited, 130 mEq / L to 160 mEq / L is particularly preferred. A numerical range close to the Na ion concentration range of body fluids is preferred so that the electrolyte balance between intracellular and extracellular fluids is not significantly disrupted.

[0063] (pH adjuster)

[0064] In the injectable solution used in the present invention, pH adjusting agents such as inorganic acids like hydrochloric acid and phosphoric acid, or alkaline components such as sodium hydroxide and potassium hydroxide, may be appropriately added as needed. In addition, it is also desirable to use organic acids in addition to or instead of inorganic acids. As for organic acids, 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 even more preferable to use citric acid or lactic acid.

[0065] The content of the pH adjuster used in the injectable solution used in the present invention varies depending on the amount of other additives, but with respect to the total amount of the injectable solution, for example, in the case of an inorganic acid such as hydrochloric acid, it 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%.

[0066] The content of the pH adjuster used in the injectable solution used in the present invention varies depending on the amount of other additives, but with respect to the total amount of the injectable solution, for example, in 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%, more preferably 0 to 0.18 w / v%, and most preferably 0 to 0.08 w / v%.

[0067] The content of the pH adjuster used in the injectable solution used in the present invention varies depending on the amount of other additives, but with respect to the total amount of the injectable solution, particularly when the pH is in the range of 6.5 to 7.4 or around 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%, more preferably 0.03 to 0.18 w / v%, and most preferably 0.05 to 0.08 w / v%.

[0068] As for inorganic alkali components such as sodium hydroxide, 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 more preferably 0.01 to 0.65 w / v%.

[0069] (pH)

[0070] The pH of the injectable solution used in the present invention is preferably neutral to slightly alkaline, taking into account 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 perspective of preventing precipitation during storage from room temperature to low temperature ranges, it is preferably in the range of greater than 7.4 to 8.0, and particularly preferably in the range of greater than 7.5 to 7.8. For pH adjustment, suitable pH adjusters, buffers, etc., used in the relevant technical field may be used as needed.

[0071] Meanwhile, the injectable solution used in the present invention can select a free pH between 6.5 and 8.0, and can also ensure stability including inhibition of precipitation under storage from room temperature to low temperature ranges. Accordingly, it is particularly desirable to use an organic acid or its salt as a pH adjuster for acidic components. In particular, when the pH is approximately 6.5 to 7.4, depending on the composition, an organic acid is used as an essential component as a pH adjuster, and it is possible to prevent or inhibit precipitation even when stored for, for example, one week at 5°C, or in some cases for more than one month, preferably more than three months.

[0072] [Other ingredients]

[0073] Buffers such as phosphate buffer, Tris hydrochloride buffer, acetic acid buffer, carbonate buffer, and citrate buffer may be added to the injectable solution used in the present invention as needed. Such buffers may be useful for stabilizing the formulation or reducing irritation.

[0074] The injectable solution of the present invention may also contain, as necessary, other components commonly used in the relevant technical field, provided that such components do not contradict the purpose of the present invention. Examples of such components include additives commonly used in liquids, particularly aqueous compositions, such as preservatives like benzalkonium chloride, potassium sorbate, and chlorhexidine hydrochloride; stabilizers like sodium edeticate; thickeners like hydroxyethylcellulose and hydroxypropylmethylcellulose; isotonic agents like sodium chloride, potassium chloride, glycerin, sucrose, and glucose; surfactants like polysorbate 80 and polyoxyethylene hardened castor oil; isotonic agents like sodium chloride, potassium chloride, and glycerin; and pH adjusters like sodium hydroxide.

[0075] When the injectable solution of the present invention is used as a pharmaceutical product, it may be in the form of an intravenous injectable solution. In particular, it may be an intravenous drip infusion solution.

[0076] As an injectable solution, a certain amount of an active ingredient is prepared by dissolving, suspending, or emulsifying it in an aqueous solvent (e.g., distilled water for injection, physiological saline solution, 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, polyoxyethylenedioxide 60, polyethylenedioxide 60, polyethylenedioxide glycol, etc.), a preservative (e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonic agent (e.g., sodium chloride, propylparaben, benzyl alcohol, etc.). At this time, additives such as a solubilizing agent (e.g., sodium salicylate, sodium acetate, etc.), a stabilizer (e.g., human serum albumin, etc.), or an analgesic (e.g., benzyl alcohol, etc.) may also be used as desired. In addition, antioxidants, coloring agents, or other additives may be included as needed.

[0077] In addition, "pharmaceuticalally acceptable carriers" may be used. Examples of such substances include solvents, solubilizing agents, suspending agents, isotonic agents, surfactants, analgesics, etc., in liquid formulations. Furthermore, if necessary, formulation additives such as preservatives and coloring agents may be used in accordance with the Commercial Code.

[0078] Preferable examples of "solvents" include, for instance, alcohol, propylene glycol, macrogol, etc.

[0079] Examples of solubilizing aids include polyethylene glycol, propylene glycol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

[0080] Preferred examples of "suspending agents" include, for instance, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0081] Desirable examples of "isotonic agents" include, for example, glucose, sodium chloride, glycerin, etc.

[0082] Examples of "surfactants" include sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.

[0083] Desirable examples of "analgesics" include, for instance, benzyl alcohol.

[0084] Preferable examples of "preservatives" include, for instance, para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.

[0085] [Method for manufacturing an injectable solution]

[0086] The method for preparing the injectable solution used in the present invention is not particularly limited, but as an example, a pH adjuster such as sodium hydroxide, water, and p-voronophenylalanine can be mixed, and then a sugar alcohol can be added to prepare the solution. At this time, the order in which the components are added may be important for more efficient preparation. Particularly preferably, a mixture of water and an alkaline pH adjuster such as sodium hydroxide is prepared first, followed by the addition of p-voronophenylalanine and stirring. Afterward, a 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 this protocol, each component can be dissolved efficiently in a short time, and an excellent injectable solution can be prepared efficiently.

[0087] At this time, the types and amounts of water, p-voronophenylalanine, sugar alcohol, and pH adjuster are in accordance with the amounts specified in the injectable solution for boron neutron capture therapy.

[0088] [Method to prevent precipitation of injectable solutions]

[0089] One of the methods for preventing precipitation of an injectable solution of the present invention is a method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine 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. At this time, the types and amounts of water, p-voronophenylalanine, sugar alcohol, and pH adjuster are in accordance with the amounts specified in the injectable solution for BNCT.

[0090] Another aspect of the present invention is a method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, wherein the pH adjuster comprises an organic acid or a salt thereof, and the pH of the injectable solution is controlled to 6.5 to 8.0. In this case, the types and amounts of water, p-voronophenylalanine, sugar alcohol, and pH adjuster are in accordance with the amounts specified in the injectable solution for boron neutron capture therapy.

[0091] In this case, "prevention of precipitation" means preventing precipitation when stored at various temperatures. That is, it includes preventing precipitation when stored at temperatures ranging from room temperature, which is particularly suitable for storage, to low temperatures, for example, 30°C or lower, preferably 25°C or lower. For example, although not limited to, precipitation may be prevented when stored at around 5°C. In this case, prevention of precipitation includes, for example, complete suppression of visible turbidity, as well as a reduction in the degree of turbidity and an extension of the time until turbidity appears. Furthermore, "preservation" means storing for at least 6 hours, preferably 24 hours, and more preferably 2 days. In some cases, it may involve long-term storage, such as for one week or one month.

[0092] Neutron Capture Therapy

[0093] (administration)

[0094] The injectable solution used in the present invention is preferably used as a drip intravenous injectable, and in particular, it is preferably used as a drip intravenous injectable for boron neutron capture therapy. Neutron capture therapy is a method of treatment using a powerful particle beam (alpha rays, 7Li particles) generated by a nuclear reaction between boron-10 and neutrons introduced into tumor cells, and the injectable solution used in the present invention can be particularly suitable for use in this method.

[0095] Prior to irradiation, the injectable solution of the present invention may be administered to a subject or animal in advance to induce Boron 10 accumulation in the tumor, and then extrathermal neutron radiation may be performed. Alternatively, prior to irradiation, the injectable solution of the present invention may be administered to a subject or animal in advance to induce Boron 10 accumulation in the tumor, and then extrathermal neutron radiation may be performed while continuing additional 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. This dosage is set according to the type or stage of the tumor to be applied, the age or weight of the subject, etc., but 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 that the timing of the administration start be performed continuously from before the start of neutron irradiation until the irradiation.

[0096] For example, but not limited to, for a patient with a brain tumor or head and neck cancer, it is also effective to adjust the BPA concentration to preferably 150 to 250 mg / kg / hour, more preferably 200 mg / kg / hour, and after administering it preferably for 1.5 to 3 hours, more preferably 2 hours, then administer it at a reduced dose preferably to 80 to 120 mg / kg / hour, more preferably 100 mg / kg / hour, and while performing the reduced dose for up to 0.5 to 1.5 hours, preferably up to 1 hour, irradiate with extrathermal neutrons.

[0097] The injectable solution used in the present invention is preferably used in this manner, particularly for neutron capture therapy. The target disease is not limited, but it is preferably a solid tumor, and particularly preferably a cancer arising from epithelial cells (epithelial tumor). Representative examples include skin cancer including malignant melanoma, lung cancer, breast cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, and head and neck cancer (oral cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, etc.). Alternatively, a sarcoma arising from non-epithelial cells may also be a target. Representative examples include osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, liposarcoma, and angiosarcoma. In addition to these, brain tumors such as glioma, primary malignant lymphoma of the central nervous system, meningioma, pituitary adenoma, schwannoma, and craniopharyngioma may be the target diseases for treatment. It can target not only initial and solitary cancers, but also cancers that have spread to individual organs, metastatic cancers, and intractable cancers.

[0098] The present invention includes each embodiment of a method for preventing precipitation of an injectable solution described below.

[0099] (1)

[0100] A method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof,

[0101] A method for preventing precipitation comprising preparing an injectable solution containing p-voronophenylalanine 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.

[0102] (2)

[0103] The precipitation prevention method described in (1), wherein the above pH adjusting agent contains at least hydrochloric acid, and the amount of the above hydrochloric acid is 0.001 to 0.5 w / v%.

[0104] (3)

[0105] A method to prevent precipitation described in (1) or (2), wherein the sugar alcohol is sorbitol or mannitol.

[0106] (4)

[0107] A precipitation prevention method described in any one of claims (1) to (3), wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v%.

[0108] (5)

[0109] A precipitation prevention method described in any one of claims (1) to (4), wherein the content ratio of the sugar alcohol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-voronophenylalanine.

[0110] (6)

[0111] A method for preventing precipitation described in any one of claims (1) to (5), comprising at least an organic acid or its salt, wherein the organic acid is citric acid or lactic acid.

[0112] (7)

[0113] A method for preventing precipitation described in any one of claims (1) to (6), wherein the above injection solution is an intravenous injection solution.

[0114] (8)

[0115] A method for preventing precipitation described in any one of claims (1) to (7), wherein the above injection solution is an intravenous injection solution for BNCT for the treatment of head and neck cancer or brain tumor.

[0116] (9)

[0117] A method for preventing precipitation described in any one of claims (1) to (8), wherein the above injection solution is to be administered intravenously by drip 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.

[0118] (10)

[0119] A method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof,

[0120] A method for preventing precipitation, comprising preparing an injectable solution containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof, a sugar alcohol, and a pH adjuster, and containing at least one organic acid or its salt, with the pH controlled to 6.5 to 8.0.

[0121] (11)

[0122] The above sugar alcohol is sorbitol or mannitol, a method for preventing precipitation described in (10).

[0123] (12)

[0124] A precipitation prevention method described in either claim (10) or (11), wherein the concentration of the sugar alcohol is 2.6 to 6.5 w / v%.

[0125] (13)

[0126] A precipitation prevention method described in any one of claims (10) to (12), wherein the content ratio of the sugar alcohol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-voronophenylalanine.

[0127] (14)

[0128] A method for preventing precipitation described in any one of claims (10) to (13), wherein the organic acid is citric acid or lactic acid.

[0129] (15)

[0130] A method for preventing precipitation described in any one of claims (10) to (14), wherein the amount of the organic acid or its salt is 0 to 8.3 w / v% of the injection solution.

[0131] (16)

[0132] A method for preventing precipitation described in any one of claims (10) to (15), wherein the above injection solution is an intravenous injection solution.

[0133] (17)

[0134] A method for preventing precipitation described in any one of claims (10) to (16), wherein the above injection solution is an intravenous injection solution for BNCT for the treatment of head and neck cancer or brain tumor.

[0135] (18)

[0136] A method for preventing precipitation described in any one of claims (10) to (17), wherein the above injection solution is to be administered intravenously by drip at a rate of 200 to 500 ml per hour for 1.5 to 4.0 hours, preferably 2.0 to 3.6 hours.

[0137] [Example]

[0138] The present invention will be described in more detail below by providing examples, but these do not limit the scope of the invention.

[0139] (Manufacturing Example)

[0140] Prior to the preparation of the injectable solution containing p-voronophenylalanine (BPA; L-form used herein) of the present invention, boron having a mass number of 10 (boron 10) was concentrated 10 B 96% concentrated boric acid (Stella Chemifasa) was used. Using the obtained highly concentrated boron 10, p-voronophenylalanine (BPA) was prepared by the standard method.

[0141] [Reference Example, Example]

[0142] (Preparation of BPA Sorbitol Aqueous Solution)

[0143] An aqueous solution containing 2.5 w / v% to 5.0 w / v% of BPA, and D-sorbitol, sodium bisulfite, or sodium pyrosulfite was prepared as follows. Specifically, 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 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 the total volume 200 ml. Subsequently, the solution was filtered through a 0.2 μm filter.

[0144] (Preparation of BPA Mannitol Aqueous Solution)

[0145] Instead of sorbitol, mannitol was used to prepare the solution in the same manner as the BPA sorbitol aqueous solution.

[0146] (Preparation of BPA sugar alcohol solution)

[0147] An aqueous solution was prepared by using mannitol in combination with sorbitol, in the same manner as the BPA sorbitol aqueous solution.

[0148] <Stability Test 1>

[0149] Stability evaluations were performed using the following equipment or conditions as standard conditions for harsh stability testing of pharmaceuticals based primarily on ICH guidelines.

[0150] First, as stability test 1, a storage test at 40°C was performed. In this storage test, the liquids were stored for 2 and 4 weeks at 40°C ± 2°C, 75 ± 5% RH, in a dark place, in a storage device: LH21-13M (Nagano Science Co., Ltd.), and samples were taken of each liquid to measure BPA concentration, Tyr concentration, Phe concentration, and Ac-BPA concentration (high-speed liquid chromatograph NexeraX2 series, Shimadzu Corporation), and compared with the values ​​at the start of the test.

[0151] At this time, the measurement conditions by HPLC are as follows.

[0152] Column used: Mightysil RP-18GP (5 μm, 4.6 × 150 mm) Kanto Kagaku Co.

[0153] Mobile phase: 0.05 mol / L sodium dihydrogen phosphate solution (pH 2.5) / methanol (95:5)

[0154] Column temperature: A constant temperature around 40℃

[0155] Flow rate: Approx. 0.8 ml / min

[0156] Injection volume: 10 μl

[0157] Detection wavelength: 223 nm

[0158] Representative examples of the results of Stability Evaluation 1 are shown in Tables 1 and 2. In the tables, the BPA residual amount represents the amount of BPA remaining after 4 weeks of storage, assuming the amount of BPA used in manufacturing for Stability Test 1 is 100%. Additionally, although not shown in the tables, the initial amount of tyrosine was evaluated as an indicator representing the initial BPA degradation status when components other than BPA are used in combination in the composition.

[0159] BPA concentration Additive 1 Additive 2 Actual osmotic pressure ratio Actual pH BPA residue after 4 weeks Reference Example 1 2.5% Sorbitol 2.625% Sodium pyrosulfite 0.01% 1.0 7.4 Over 99% Example 1 1.0 7.6 Example 2 1.0 7.8 Reference Example 2 3.5% Sorbitol 3.675% 1.5 7.4 Example 3 1.4 7.6 Example 4 1.4 7.8 Reference Example 3 4.0% Sorbitol 4.2% 1.7 7.4 Example 5 1.6 7.6 Example 6 1.6 7.8 Reference Example 4 3.0% Sorbitol 3.15% Sodium bisulfite 0.01% 1.2 7.4 Over 99% Example 7 1.2 7.6 Example 8 1.2 7.8 Reference Example 5 3.0% Sorbitol 4.7% 1.6 7.4 Example 9 1.5 7.6 Example 10 1.5 7.8 Reference Example 6 3.0% Sorbitol 5.75% 1.8 7.4 Example 11 1.7 7.6 Example 12 1.8 7.8

[0160] (The % of BPA and additives refers to w / v%)

[0161] As shown in Table 1, the composition of any of the examples exhibited good stability. In addition, when sodium bisulfite was used as an antioxidant with a BPA concentration of 2.5 to 4.0 w / v%, it exhibited good stability. 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%, the type and concentration of the antioxidant were verified under the same conditions, and a composition exhibiting good stability was obtained.

[0162] Examples BPA concentration Additive 1 Additive 2 Actual osmotic pressure ratio Actual pH BPA residue after 4 weeks Example 13 2.5% Mannitol 2.625% Sodium bisulfite 0.01% 1.0 7.8 Over 99% Reference Example 7 2.5% Mannitol 5.35% Sodium bisulfite 0.01% 1.6 7.4 Example 14 2.5% Mannitol 5.35% Sodium bisulfite 0.01% 1.6 7.6 Example 15 2.5% Mannitol 5.35% Sodium bisulfite 0.01% 1.6 7.8

[0163] (The % of BPA and additives refers to w / v%)

[0164] In the compositions of Table 2, it was found that in the preservation test, more than 99% of the BPA was retained in the aqueous solution of the example even after 4 weeks or more. No change in color was observed in the observation of retention characteristics, and no change in composition was observed in the observation of appearance.

[0165] Based on a comprehensive assessment of the results of solubility and preservation tests, it was found that the injectable solution containing sorbitol or mannitol of the example has excellent stability at pH 7.4 to 7.8 and excellent homogeneity of the liquid during storage at 40°C.

[0166] [Examples, Comparative Examples]

[0167] (Preparation of BPA Sorbitol Aqueous Solution)

[0168] 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, stirred, and dissolved. 0.02 g of sodium bisulfite was added, and at room temperature, an appropriate amount of 1 mol / l hydrochloric acid or 1 mol / l citric acid was added, the pH was adjusted, and water was added to make the total volume 100 ml.

[0169] <Stability Test 2>

[0170] The BPA sorbitol aqueous solution adjusted in this manner was used in Stability Test 2. In this test, a storage test was conducted at 5°C. In this storage test, the solution was left standing 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.

[0171] HCl citric acid pH Stirring time after pH adjustment situation Comparative Example 1 3.5 ml(mmol) 0 ml(mmol) 6.8 40 min Check for turbidity after stirring is finished. Comparative Example 2 2.5 ml(mmol) 0 ml(mmol) 7.0 180 min After stirring is finished, check for clarity → After storing at 5℃ for 7 days, check for cloudiness Comparative Example 3 3.5 ml(mmol) 0 ml(mmol) 6.5 10 min Check for turbidity after stirring is finished. Example 16 0 ml(mmol) 0.8 ml(mmol) 7.1 Check for clarity after storing at 5℃ for 7 days. Example 17 0 ml(mmol) 0.8 ml(mmol) 7.2 Check for clarity after storing at 5℃ for 7 days. Example 18 0 ml(mmol) 0.8 ml(mmol) 7.4 Check for clarity after storing at 5℃ for 7 days.

[0172] Comparative Examples 1, 3: HCl 0.13 w / v%

[0173] Comparative Example 2: HCl 0.09 w / v%

[0174] Example: Citric acid 0.15 w / v%

[0175] As a result, it was found that in the low pH range, adjustment using only hydrochloric acid sometimes resulted in turbidity during low-temperature storage. On the other hand, by adding citric acid, turbidity during low-temperature storage could be suppressed.

[0176] Next, an aqueous solution containing 3 w / v% BPA, D-sorbitol, and sodium bisulfite was prepared as follows. Specifically, 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, stirred, and dissolved. 0.01 g of sodium bisulfite was added, and at room temperature, an appropriate amount of 1 mol / l hydrochloric acid or 1 mol / l citric acid was added, the pH was adjusted, and water was added to make the total volume 50 ml.

[0177] Test Example 1 Test Example 2 Test Example 3 pH 6.8 7.2 7.6 hydrochloric acid 19 hours 66 hours No cloudiness for up to 90 hours

[0178] As a result, when hydrochloric acid was used, cloudiness occurred during storage at 5°C. At this time, it was found that when citric acid was added instead of hydrochloric acid at pH 6.8, cloudiness occurred during storage, but its occurrence was delayed. Thus, it was found that by adding citric acid instead of hydrochloric acid, the occurrence of cloudiness could be completely prevented or suppressed, such as by delaying the time.

Claims

Claim 1 A method for preventing precipitation of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof at low temperatures comprises preparing an injectable solution containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof, sorbitol, hydrochloric acid, and an antioxidant, wherein the pH is controlled to be greater than 7.5 and less than or equal to 8.0, wherein the low temperature is 5℃±3℃, the antioxidant is one or more selected from the group consisting of sodium sulfite, dry sodium sulfite, potassium sulfite, calcium sulfite, sodium bisulfite, potassium bisulfite, ammonium bisulfite, sodium pyrosulfite, and potassium pyrosulfite, and the concentration is 0.01 to 1.2 w / v%, the concentration of p-voronophenylalanine or a pharmaceutically acceptable salt thereof is 2.0 to 5.5 w / v%, and the concentration of sorbitol is A method for preventing precipitation, wherein the amount is 2.6 to 6.5 w / v%, and the content ratio of the sorbitol is in the range of 0.9 to 3.0 in molar ratio with respect to the content of p-voronophenylalanine. Claim 2 A method for preventing precipitation at low temperature of an injectable solution for boron neutron capture therapy containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof, comprising preparing an injectable solution containing p-voronophenylalanine or a pharmaceutically acceptable salt thereof, sorbitol, an organic acid, and an antioxidant, wherein the pH is controlled to 6.5 to 7.5, wherein the low temperature is 5℃±3℃, the antioxidant is one or more selected from the group consisting of sodium sulfite, dry sodium sulfite, potassium sulfite, calcium sulfite, sodium bisulfite, potassium bisulfite, ammonium bisulfite, sodium pyrosulfite, and potassium pyrosulfite, and the concentration is 0.01 to 1.2 w / v%, the concentration of p-voronophenylalanine or a pharmaceutically acceptable salt thereof is 2.0 to 5.5 w / v%, and the concentration of sorbitol is A method for preventing precipitation, wherein the content of the sorbitol is 2.6 to 6.5 w / v%, the molar ratio of the sorbitol is in the range of 0.9 to 3.0 with respect to the content of p-voronophenylalanine, and the organic acid is citric acid, lactic acid, or a salt thereof. Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 A method for preventing precipitation according to paragraph 2, wherein the amount of the organic acid or its salt is 0.01 to 8.3 w / v% of the injection solution. Claim 8 A method for preventing precipitation according to claim 1 or 2, wherein the injection solution is an intravenous injection solution.

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