JP5150084B2 - Highly water-soluble p-boronophenylalanine-containing composition - Google Patents

Description

  The present invention relates to a boron-containing pharmaceutical composition, and more particularly to a boron-containing composition with increased water solubility for use as a boron source in boron neutron capture therapy.

Since the advent of neutron capture therapy in the United States in the 1930s (Locher GL. Biological effects and therapeutic possibilities of neutrons. Am J Roentgenol Radium Ther,
1936, 36, 1-13), while disruptive, potential of boron ⁽¹⁰ B) neutron capture therapy in the treatment of tumors is, study of the effects of animal and human against tumors, suitable for administering to a patient the formulation Each aspect of the development of small reactors (neutron sources) suitable for morphology and clinical use has been studied for many years.

Boron neutron capture therapy (BNCT) is a relatively low energy target that captures ¹⁰ B (which is an isotope occupying approximately 1/5 of natural boron) into a tumor mass. neutrons to cause a (thermal neutrons or epithermal neutrons) beam nuclear reactions ^{[10 B (n, αγ) 7} Li ] to the ¹⁰ B irradiation of, to destroy the tumor cells by α particles created thereby treating Is the method. The generated α particles have a large linear energy transfer (LET: energy lost on average per unit length of the range), and the range in the living body is approximately equivalent to one cancer cell. Since it is as short as 10 μm, only the cell containing ¹⁰ B that has undergone a nuclear reaction and cells adjacent thereto are destroyed. Therefore, if ¹⁰ B is taken into the tumor mass and focused on this and irradiated with thermal neutrons or the like from the outside of the body, it is possible to reliably destroy cancer cells with almost no damage to normal cells. . Treatment irradiation using boron neutron capture therapy has already been attempted in the United States from the 1950s to the beginning of the 1960s. In Japan, brain tumors were treated in 1968 and malignant melanomas in 1987. Irradiation was performed and cases have been accumulated since then.

  In order to be able to administer boron atoms to a patient in a necessary amount and to facilitate the transfer to cancer cells, it is necessary to prepare an aqueous solution of an appropriate boron-containing compound. As a compound suitable for this, p-boronophenylalanine (hereinafter also referred to as “BPA”) having a structure in which the para-position of phenylalanine is substituted with a dihydroboryl group,

It has been known. BPA includes L-BPA in which the phenylalanine moiety is the same type of configuration as natural L-phenylalanine, D-BPA that is D-type, and DL-BPA that is a racemate. It is mainly used because it is considered to be most easily taken up by tumor tissues such as malignant melanoma. BPA by itself is very poorly soluble at physiological pH, but for effective boron neutron capture therapy, a large amount of ¹⁰ B (for example, 30 g / 60 kg body weight in terms of BPA) is injected into the patient. As it turns out that is preferred, various methods have been attempted to improve the solubility of BPA in water. Among them, in particular, BPA and a monosaccharide (particularly fructose) are mixed in water, and the pH of the mixture is increased to 10 with a base (such as sodium hydroxide) and dissolved to form a BPA fructose complex. A method of readjusting to a physiological pH (7.4) with hydrochloric acid or the like is known (see Patent Document 1). In addition, water, a strong base (such as sodium hydroxide), and a monosaccharide such as fructose, a disaccharide or a polyol such as sorbitol are added to BPA to form a complex aqueous solution under basic conditions (pH 8 to 10). There is also known a method for producing a BPA complex solution by processing to return the pH to about 7.3 to 7.5 (see Patent Document 2). Fructose can be complexed to dissolve BPA in water to a concentration of about 2.6 w / v% at room temperature. In fact, this is used in clinical trials in patients with brain tumors and mesothelioma, A remarkable and tumor-selective effect is being obtained, and coupled with the development of a small reactor suitable for clinical use, there is a great expectation for the practical use of boron neutron capture therapy.

  However, the water solubility of the BPA fructose complex is insufficient. That is, for example, when an amount equivalent to 30 g of BPA is prepared as a complex aqueous solution with fructose at room temperature for a patient weighing 60 kg, the amount of the solution is at least about 1.2 L, which is an extremely large amount. Injecting this is inconvenient for the patient, and it is also inconvenient for medical institutions because it requires a long time for intravenous infusion of the aqueous solution to the patient prior to neutron irradiation to the tumor mass.

  In addition, as described above, the BPA fructose complex was obtained only by mixing BPA and fructose in water adjusted to be alkaline with sodium hydroxide or the like, and after confirming that the mixture was sufficiently stirred to form a complete solution. Thus, the pH is readjusted to a predetermined range near neutrality. In order to prepare such an aqueous solution as a preparation that can be administered to a patient, the entire dissolution operation including the pH adjustment step needs to be carried out in a strict aseptic environment. It is practically impossible to prepare an aqueous solution by the procedure. On the other hand, it is conceivable that an aqueous solution of a BPA fructose complex is freeze-dried and supplied to a medical institution as a powder. reference). For this reason, it is not practical to use a lyophilized powder of BPA fructose complex supplied to a medical institution and to restore it to an aqueous solution at the time of use. Therefore, the BPA fructose complex is commercialized and shipped in the form of an aqueous solution. The aqueous solution of BPA fructose complex is insufficient in water solubility as described above, so a large amount of water is required to prepare the aqueous solution, which increases the amount and weight of the packaging liquid when commercialized, which increases the cost of transportation and storage. It becomes a factor.

  Meanwhile, meglumine,

Is a basic compound and is used as a solubilizing agent that neutralizes and dissolves certain organic iodine contrast agents (amidotrizoic acid, adipiodone, iotalamic acid, metrizoic acid, iodamide, iotroxic acid, iodoxamic acid, and isoxaglic acid). However, all of these organic iodine contrast agents are acids having a 2,4,6-triiodobenzoic acid moiety, and a type in which an amino group and a carboxyl group form an inner salt like BPA. It is not a compound.
US Pat. No. 5,492,900 US Pat. No. 6,169,076

  In the above background, the present invention makes it possible to provide an aqueous solution having a pH near neutral by dissolving BPA in water at a higher concentration than conventional, and to obtain BPA obtained by such a method compared to conventional methods. An object is to provide an aqueous solution having a pH near neutrality that can be contained up to a high concentration.

  As a result of various studies aimed at achieving the above object, the present inventors have found that BPA can be present in a high concentration in an alkaline mixture obtained by adding meglumine and water to BPA, and this Even if acid is added to the aqueous solution and the pH is adjusted to near neutrality, BPA remains dissolved in a high concentration. Furthermore, the powder obtained by freeze-drying the aqueous solution thus neutralized is water and It has been found that when mixed, it dissolves easily and gives an aqueous solution containing BPA at the original high concentration. The present invention has been completed by further studies based on these findings. That is, the present invention provides the following.

1. A pharmaceutical composition comprising p-boronophenylalanine and meglumine.
2. The pharmaceutical composition according to 1 above, wherein the meglumine content relative to p-boronophenylalanine is at least 0.8 in molar ratio.
3. 3. The pharmaceutical composition according to 1 or 2 above, which is an aqueous solution having a pH near neutrality.
4). 4. The pharmaceutical composition according to 3 above, wherein the concentration of p-boronophenylalanine is at least 3 w / v%.
5. 3. The pharmaceutical composition according to 1 or 2 above, which is a dry preparation comprising p-boronophenylalanine and meglumine.
6). 6. The pharmaceutical composition according to 5 above, which gives an aqueous solution having a pH near neutral when reconstituted with water.
7). 7. The pharmaceutical composition according to any one of 1 to 6 above, which is an agent for boron neutron capture therapy.
8). 8. The pharmaceutical composition according to any one of 1 to 7 above, wherein p-boronophenylalanine is Lp-boronophenylalanine.
9. Production of an aqueous solution containing p-boronophenylalanine, comprising the steps of mixing p-boronophenylalanine and meglumine in water to form an aqueous solution, and adding an acid to the aqueous solution to adjust the pH to near neutral. Method.
10. 10. The production method according to 9 above, wherein the meglumine content relative to p-boronophenylalanine is at least 0.8 in molar ratio.
11. 11. The method according to 9 or 10 above, wherein the concentration of p-boronophenylalanine in the aqueous solution is at least 3 w / v%.
12 A method for producing a p-boronophenylalanine-containing composition, further comprising a step of lyophilizing a p-boronophenylalanine-containing aqueous solution obtained by any one of the above 9 to 11 production methods.
13. 13. The method according to any one of 9 to 12 above, wherein p-boronophenylalanine is Lp-boronophenylalanine.

  The present invention configured as described above can provide a high-concentration BPA aqueous solution exceeding 10 w / v%. Since this is about 4 times higher than the 2.6% w / v concentration obtained with BPA fructose complex, a significant reduction in the volume of boron-containing composition administered to patients in boron neutron capture therapy (1 / 4) is possible. This reduces the burden on the patient and is also advantageous to medical institutions through shortening the infusion time and storage space. Furthermore, the pharmaceutical composition obtained by the present invention can be reconstituted by easily dissolving it in distilled water for injection or a neutral buffer after making it into a dried product by freeze-drying or the like. It can also be supplied to a medical institution in the form of a solid formulation that does not contain, thereby making it possible to reduce transportation costs and storage costs. Further, the aqueous solution of the present invention has an advantage that the storage stability is remarkably high as compared with the BPA fructose complex aqueous solution.

  In the present invention, as p-boronophenylalanine (BPA), any of D-type, L-type, and DL-type configurations can be used with respect to the configuration of the phenylalanine moiety. However, taking into account that the uptake efficiency into cancer cells is higher in the L type than in the D type, the L type is most preferable, and then the DL type is preferable.

  In the composition of the present invention, there is no clear lower limit to the ratio of meglumine to BPA. However, in order to dissolve BPA at a particularly high concentration, the meglumine amount relative to the BPA amount is preferably 0.8 or more in molar ratio, and at this time, BPA can be dissolved to about 7 w / v%. More preferably, the meglumine amount relative to the BPA amount is 1.0 in terms of a molar ratio, and at this time, BPA can be dissolved to about 9 w / v%. Particularly preferably, the amount of meglumine with respect to the amount of BPA is 1.10 or more in molar ratio, and at this time, BPA can be dissolved to 10.4 w / v%. However, if a BPA concentration that is not so high (for example, 3 to 5 w / v%) is sufficient, the amount of meglumine can be reduced. On the other hand, there is no clear upper limit to the molar ratio of meglumine to BPA in terms of dissolving BPA in water at a high concentration, but the effect is not proportional even if excessive meglumine is added, so usually up to a molar ratio of 2.5 It is preferable to stop. Therefore, the meglumine amount relative to the BPA amount is usually set appropriately in the range of 0.8 to 2.5 in molar ratio, for example, 1.0 to 2.0, 1.10 to 1.5, etc. do it.

  The aqueous solution of the present invention can be easily prepared by mixing BPA and meglumine in water and adding an acid to the resulting alkaline aqueous solution to adjust the pH to near neutral. The temperature at which the aqueous solution is produced is not particularly limited, and can be simply carried out at room temperature, and does not require heating (60 ° C.) as in the production of the BPA fructose complex solution. After preparation of the aqueous solution of the present invention, filter sterilization can be performed as necessary.

  In the aqueous solution of the present invention, “substantially neutral pH” refers to the vicinity of the physiological pH of human blood (fluctuating around pH 7.4). Since the BPA meglumine aqueous solution of the present invention is considered to be a general administration method to be mixed and administered in an infusion solution, since it also receives a buffering effect by a buffer contained in the infusion solution, it is not necessary to strictly set pH 7.4, For example, pH 6.0 to pH 8.0 may be used, and this is included in “neutral pH” in the present invention. It has been found in the completion process of the present invention that the aqueous solution of the present invention has high stability near neutrality, and that the pH level near neutrality has little effect on stability. Accordingly, the pH of the aqueous solution of the present invention may be appropriately set in the vicinity of neutrality so as to be convenient for use as a product. For example, pH 6.2 to 8.0, which is closer to the physiological pH of blood, or pH 6. It may be 5 to 7.9, or even 6.5 to 7.7, but it is not essential to do so.

  There is no limitation in particular in the BPA density | concentration in the aqueous solution of this invention, It can set suitably. However, it is generally preferable that the concentration is higher than that of a conventional aqueous solution of BPA fructose complex. This is because the amount of the aqueous solution to be administered to the patient can be reduced. Accordingly, the BPA concentration is preferably set to 3.0% or more, for example.

  The acid added to bring pH close to neutral after mixing BPA with water and meglumine to form an aqueous solution is not particularly limited as long as it is suitable for that purpose and can be used for pharmaceuticals. One preferred acid that is commonly used is hydrochloric acid.

The pharmaceutical composition of the present invention does not exclude the inclusion of components other than BPA, water, and meglumine unless the pharmaceutical composition of the present invention has a substantial adverse effect on its stability (solubility, storage stability). (For HCl, Cl ^-) conjugate base of acid added during pH adjustment but as a matter of course assumes that contained, may for example, be used for the fine adjustment at the time of preparation of pH otherwise carbonate A component derived from a pH adjusting agent such as sodium hydrogen may be contained.

  The pharmaceutical composition of the present invention may be supplied as a product in the form of an aqueous solution. Alternatively, the pharmaceutical composition of the present invention may be supplied as a solid preparation in which a BPA meglumine aqueous solution is dried and the dried product is enclosed in a packaging for dissolution. Although it is convenient to use lyophilization for drying the aqueous BPA meglumine solution, the drying method is not particularly limited as long as it is a method that can supply a sterile preparation suitable for injection by other methods. Freeze-dried The pharmaceutical composition of the present invention has high temporal stability even in the form of a freeze-dried product, and when used, it is easily converted into an aqueous solution form by adding distilled water for injection and shaking by hand. And can be restored.

Hereinafter, the present invention will be described in more detail with reference to comparative examples and examples, but the present invention is not intended to be limited to the examples. In addition, all the BPA used below were synthesized by a conventional method using boron obtained by concentrating the ratio of ¹⁰ B with respect to the total boron from about 20% to 95% of natural (made by Stella Chemifa Corporation). Since the mass number of boron does not affect the chemical properties, the results obtained in the examples apply to BPA containing ¹⁰ B in any proportion.

[Comparative Example 1] Preparation of BPA fructose aqueous solution A BPA fructose complex aqueous solution was prepared as follows. Based on prior studies, the total volume of the aqueous solution is approximately the minimum amount of BPA that can be completely dissolved in water at room temperature using fructose (thus the amount that can be set to the highest concentration of BPA when prepared at room temperature). ) That is, 30 g of L-BPA and 66.7 g of fructose were added to 900 mL of water, and 166 mL of 1 mol / L sodium hydroxide was added and dissolved while stirring at room temperature (pH 9 at the completion of dissolution). The mixture was allowed to stand at room temperature for 30 minutes to form a BPA fructose complex, adjusted to pH 7.2 with 1 mol / L hydrochloric acid and sodium bicarbonate (total liquid volume 1240 mL), and then filtered through a 0.22 μm filter. The BPA concentration of the obtained aqueous solution is 2.4 w / v%.

[Example 1] Preparation of aqueous solution of BPA meglumine 30 g of L-BPA and 42.2 g of meglumine were dissolved in water to make 250 mL (meglumine / BPA = 1.5 (mol / mol)). 6 mol / L hydrochloric acid was added to adjust to pH 7.0, water was added to make a total liquid volume of 300 mL, and then filtered through a 0.22 μm filter. It was confirmed that a complete aqueous solution containing no insoluble matter was obtained. The BPA concentration of the obtained aqueous solution is 10 w / v%.

[Comparative Example 2 and Examples 2-9]
The formulations shown in Table 1 were prepared in the same manner as in Comparative Example and Example 1, except that the sodium hydroxide aqueous solution used for the preparation of the BPA fructose complex aqueous solution was 8 mol / L and hydrochloric acid used for readjustment of pH was 6 mol / L. According to the above, BPA fructose complex aqueous solution and BPA meglumine aqueous solution having various concentrations and two meglumine / BPB ratios (molar ratio, 1.5 and 2.5) were prepared. For each aqueous solution, after confirmation of appearance properties and measurement of BPA concentration by HPLC, 1 mL each was sealed in a glass vial for stability stability test and stored at 40 ° C. for 4 weeks under light shielding, appearance properties, pH and BPA Each content was observed and measured. The results are shown in Tables 1 and 2. In addition, the following conditions were used for the measurement of BPA by HPLC.

<HPLC measurement conditions>
Column used: Mightysil RP-18 GP 250-4.6 (5μm) Kanto Chemical Co., Inc.
Mobile phase: Water: Acetonitrile: Trifluoroacetic acid = 800: 200: 1
Column temperature: Constant temperature flow rate around 25 ° C .: 0.5 mL / min Injection volume: 5 μL
Detection wavelength (UV): 232 nm
Detection wavelength (photodiode array detector: PDA): 200 to 400 nm

<Stability: Appearance properties>
As shown in Table 1, all aqueous solutions were colorless and clear at the time of preparation. During the stability acceleration test at 40 ° C., the BPA fructose complex aqueous solution of Comparative Example 2 was clear but slightly yellow at the time of 2 weeks after the start of the test, and the same was observed in the subsequent observation. Each of the BPA meglumine aqueous solutions of Examples 2 to 9 maintained a clear and colorless and clear appearance property at 2 weeks after the start of the test, and remained clear and colorless or slightly at 3 weeks after the start of the test. It was yellowish and similar at 4 weeks. Regarding the stability of the appearance properties, there was no difference due to the difference in meglumine / BPA ratio (1.5 and 2.5).

<Stability: pH>
Table 2 shows the pH stability test results of each aqueous solution. The pH of the aqueous BPA fructose complex solution of Comparative Example 2 continued to decrease over time from 7.20 at the start of the test, and to 6.97 after 4 weeks. In contrast, the BPA meglumine aqueous solution of Example 2 containing the same concentration of BPA did not show a decrease in pH over time, and the same was true for the BPA meglumine aqueous solutions of Examples 3 to 9 having higher concentrations. Met. There was no difference in pH stability due to the difference in meglumine / BPA ratio (1.5 and 2.5).

<Stability: BPA content>
The time course of the BPA content in each aqueous solution after storage at 40 ° C. for 4 weeks is shown in Table 2 as the residual ratio relative to the content at the start of the test. In the aqueous solution of Comparative Example 2, the BPA content decreased to 96.2% at the start of the test. On the other hand, in each aqueous solution of Examples 2-9, the fall was not seen substantially but the BPA density | concentration was maintained stably.

  As described above, the BPA meglumine aqueous solution is superior to the BPA fructose complex in the stability of the appearance properties when stored at 40 ° C. In addition, while the pH of the aqueous BPA fructose complex solution decreases with time under the same conditions, the pH of the aqueous BPA meglumine solution is stable and does not show a decrease. Furthermore, with respect to the stability of BPA in an aqueous solution under the same conditions, the BPA fructose complex aqueous solution shows a clear decrease in BPA content with time, whereas the BPA meglumine aqueous solution has a substantial decrease in BPA content. It turned out not to be seen. These indicate that the stability of the BPA meglumine aqueous solution is significantly higher than that of the BPA fructose aqueous solution.

[Comparative Example 3 and Examples 10-15]
In the same manner as above, according to the formulation shown in Table 3, BPA fructose complex aqueous solution and pH 6.0, 7.0 and 8.0, containing 10.4 w / v% BPA near the upper limit concentration, and two ways A BPA meglumine aqueous solution having a meglumine / BPB ratio (molar ratio of 1.5 and 2.0) was prepared. For each aqueous solution, after confirmation of appearance properties and measurement of BPA concentration by HPLC, 1 mL each was sealed in a glass vial for stability and severe testing, and stored for up to 2 weeks at 50 ° C and 60 ° C under light shielding conditions. The appearance properties, pH and BPA content were observed and measured every week. The results are shown in Tables 3 and 4.

<Stability: Appearance properties>
As is apparent from Table 3, at 50 ° C., the BPA fructose complex aqueous solution (pH 7.2) of Comparative Example 3 turned yellow after storage for 1 week from colorless at the start of the test, and turned brown after 2 weeks. On the other hand, the BPA meglumine aqueous solutions of Examples 11 and 14 having the same pH were colorless or slightly yellow after storage for 1 week at 50 ° C., and became slightly yellow even after storage for 2 weeks. I stopped at. At 60 ° C., the aqueous solution of Comparative Example 3 turned brown after storage for 1 week, whereas the aqueous solutions of Examples 11 and 14 remained colorless or slightly yellow even after storage for 1 week at 60 ° C. It was only tinged, and even after being stored for 2 weeks, it was only slightly yellow or yellow. In addition, no difference was observed in the appearance properties of the aqueous solutions of Examples 11 and 14 for any temperature and storage period.

Regarding the aqueous solution of pH 6, in the aqueous solution of Example 10 (meglumine / BPA = 1.5 (mole / mole)), white crystals were slightly precipitated when stored at 50 ° C. and 60 ° C. for 1 and 2 weeks. However, all the solutions were colorless or slightly yellowish. In the aqueous solution of Example 13 having the same pH (meglumine / BPA = 2.0 (mol / mol)), it was stored at 50 ° C. and 60 ° C. for 1 week and 2 weeks, and the appearance was similar to that of Examples 11 and 14 at pH 7. The properties were similar.
Further, for the aqueous solution at pH 8, both the aqueous solution of Example 12 (meglumine / BPA = 1.5 (mol / mol)) and the aqueous solution of Example 15 (meglumine / BPA = 2.0 (mol / mol)) were both 60 After 1 and 2 weeks storage at 50 ° C. and 60 ° C. of aqueous solutions of pH 11 Examples 11 and 14 except that slight white to slightly yellow deposits were observed after 2 weeks storage at 0 ° C. It was equivalent to the appearance property.

<Stability: pH>
As shown in Table 4, the pH of the aqueous solution of Comparative Example 3 significantly decreased from the initial value of 7.22 to 6.54 when stored at 50 ° C. for 2 weeks, and 6.12 when stored at 60 ° C. for 2 weeks. It declined further greatly. On the other hand, the pH of the aqueous solution of Example 11 slightly decreased from 7.06 to 7.17 at the initial value after storage at 50 ° C. for 2 weeks, and to 7.18 after storage at 60 ° C. for 2 weeks. It was only rising. Further, the pH of the aqueous solution of Example 14 only increased from the initial value of 7.19 to 7.30 after storage at 50 ° C. for 2 weeks, and no change in pH was observed after storage at 60 ° C. for 2 weeks. It was.

Regarding the aqueous solution of pH 6, the pH of the aqueous solution of Example 10 was changed from the initial value of 5.99 to 6.37 after storage at 50 ° C. for 2 weeks, and to 6.18 after storage at 60 ° C. for 2 weeks, respectively. It stopped to rise somewhat. Further, the pH of the aqueous solution of Example 13 slightly varies from 6.02 to 6.11 after storage at 50 ° C. for 2 weeks and to 5.96 after storage at 60 ° C. for 2 weeks. Stopped.
Regarding the aqueous solution of pH 8, the pH of the aqueous solution of Example 12 was changed from the initial value of 8.05 to 8.18 when stored at 50 ° C. for 2 weeks, and to 8.07 when stored at 60 ° C. for 2 weeks. Only a slight rise. In addition, the pH of the aqueous solution of Example 15 slightly varies from an initial value of 8.11 to 8.22 when stored at 50 ° C. for 2 weeks, and to 8.09 when stored at 60 ° C. for 2 weeks. Stopped.

<Stability: BPA content>
Further, Table 4 shows the time course of the BPA content of each aqueous solution as the residual ratio with respect to the content at the start of the test. The BPA residual rate of the aqueous solution of Comparative Example 3 decreased to 90.1% and 73.8% by storage for 1 week and 2 weeks at 50 ° C., respectively, whereas the aqueous solutions of Examples 10 to 15 decreased. The BPA residual ratio was about 95 to 98% after storage at 50 ° C. for 1 week, and was almost the same after storage at 50 ° C. for 2 weeks. Moreover, the BPA residual rate of the aqueous solution of Comparative Example 3 extremely decreased to 35.9% and 29.4%, respectively, by storage at 60 ° C. for 1 week and 2 weeks. The BPA residual ratio was about 88 to 93% after storage at 60 ° C. for 1 week, and 51 to 75% after storage at 60 ° C. for 2 weeks. The residual ratio of the aqueous solution of Comparative Example 3 at the corresponding temperature condition and storage period, respectively. The level was significantly higher than

  As described above, even in the stability test results under severe temperature conditions of 50 ° C. and 60 ° C., the BPA meglumine aqueous solution has a significantly higher stability (appearance property, pH) than the BPA fructose complex aqueous solution at pH 6-8. , BPA content).

<Examples 16 to 19>
According to the formulation shown in Table 5, a BPA meglumine aqueous solution having a meglumine / BPA ratio of 1.10 to 1.25 was prepared in the same manner as described above. The aqueous solutions of all Examples were colorless and clear. These aqueous solutions were subjected to a severe test at 50 ° C. for 1 week. As a result, as shown in Table 5, the appearance properties, pH, and BPA residual ratio all showed excellent stability equivalent to that seen in each aqueous solution of the pH 7 example.

<Examples 20 and 21> Lyophilized preparation In the same manner as described above, BPA meglumine aqueous solutions shown in Table 6 were prepared and lyophilized by a conventional method. After that, when the lyophilized powder was added with an amount of distilled water necessary for the original liquid and shaken, it was easily dissolved to restore a colorless and transparent aqueous solution. This indicates that the BPA meglumine-containing composition of the present invention can be supplied as a product even in the form of a lyophilized powder for the purpose of adding water during use to form an aqueous solution.

The present invention makes it possible to provide a high-concentration BPA aqueous solution that can significantly reduce the amount of boron-containing composition administered to a patient in boron neutron capture therapy. The present invention also makes it possible to provide a lyophilized powder that provides an aqueous BPA solution that is advantageous in terms of transportation and storage compared to an aqueous solution.

Claims (16)

p- borono Ri phenylalanine and greens contain meglumine, meglumine content relative p- boronophenylalanine is Ru least 0.8 der molar ratio, pharmaceutical compositions.   The meglumine content with respect to p-boronophenylalanine is 0.8-2.5 by molar ratio, The pharmaceutical composition of Claim 1. The pharmaceutical composition according to claim 2, wherein the meglumine content relative to p-boronophenylalanine is 1.1 to 2.5 in molar ratio. The pharmaceutical composition according to any one of claims 1 to 3, which is an aqueous solution having a pH of 6.0 to 8.0 .   The pharmaceutical composition of claim 4, which is an aqueous solution having a concentration of p-boronophenylalanine of at least 3 w / v%.   The pharmaceutical composition according to any one of claims 1 to 3, which is a dry preparation comprising p-boronophenylalanine and meglumine. The pharmaceutical composition according to claim 6, which gives an aqueous solution of pH 6.0 to pH 8.0 when reconstituted with water.   The pharmaceutical composition according to any one of claims 1 to 7, which is an agent for boron neutron capture therapy.   The pharmaceutical composition according to any one of claims 1 to 8, wherein p-boronophenylalanine is Lp-boronophenylalanine. A p- boronophenylalanine- containing aqueous solution comprising the steps of mixing p- boronophenylalanine and meglumine in water to form an aqueous solution, and adding an acid to the aqueous solution to adjust the pH to 6.0 to pH 8.0. Manufacturing method.   The process according to claim 10, wherein the meglumine content relative to p-boronophenylalanine is at least 0.8 in molar ratio.   The manufacturing method of Claim 10 whose meglumine content with respect to p-boronophenylalanine is 0.8-2.5 by molar ratio. The manufacturing method of Claim 12 whose meglumine content with respect to p-boronophenylalanine is 1.1-2.5 by molar ratio. The method according to any one of claims 10 to 13 , wherein the concentration of p-boronophenylalanine in the aqueous solution is at least 3 w / v%. A method for producing a p-boronophenylalanine-containing composition, further comprising a step of lyophilizing a p-boronophenylalanine-containing aqueous solution obtained by the production method according to any one of claims 10 to 14 . The method according to any one of claims 10 to 15 , wherein the p-boronophenylalanine is Lp-boronophenylalanine.