L-4-boryl phenylalanine intravenous injection as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to an L-4-boryl phenylalanine intravenous injection as well as a preparation method and application thereof. According to the L-4-boryl phenylalanine intravenous injection disclosed by the invention, a glucose-low molecular dextran complexing agent (in a mass ratio of (3-5): 1) or a maltitol-polyethylene glycol 400 complexing agent (in a mass ratio of (2-4): 1) is used as a solubilizer to replace saccharides such as D-sorbitol, fructose and the like used in the prior art. The composite solubilizer provided by the invention not only can significantly improve the solubility of L-BPA, but also can enhance the stability of a preparation, and realizes room temperature preservation. According to the preparation method, an integrated process of ultrasonic-assisted dissolution, buffer pair adjustment and nanofiltration infiltration reduction is adopted, a traditional sodium hydroxide-hydrochloric acid adjustment system is avoided, the pH value is accurately controlled through a citric acid-sodium dihydrogen phosphate buffer pair, excessive ions are removed in cooperation with a nanofiltration technology, and a salt-free preparation process is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to L-4-boronylphenylalanine intravenous injection solution, its preparation method and application. Background Technology

[0002] L-4-boronophenylalanine (L-BPA) is a core boron drug ingredient clinically approved for use in boron neutron capture therapy (BNCT). It contains ¹ 0 B can undergo a nuclear reaction with thermal neutrons, precisely killing tumor cells. The basic principle of BNCT is to utilize ¹ 0 The nuclear reaction between boron and low-energy thermal (external) neutrons allows boron-containing drugs to selectively accumulate in tumor cells. When combined with an appropriate neutron source, this can achieve the goal of locally killing tumor cells without causing too much damage to normal tissues.

[0003] However, L-BPA has extremely low solubility in water, requiring the use of large amounts of sodium hydroxide for dissolution during formulation. After forming a complex with polyhydroxy sugars, hydrochloric acid is used to adjust the pH to an acceptable range. This process generates a large amount of excess sodium chloride, resulting in a high osmotic pressure and significant risks associated with its use. Current technologies primarily use sugars such as D-sorbitol and fructose as solubilizers. While this can improve the solubility of L-BPA, fructose-based L-boronylphenylalanine formulations currently suffer from extremely short shelf life and clinical acceptability issues. They typically require refrigeration at 2–8°C, failing to meet the requirements for room temperature storage. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide an L-4-boronylphenylalanine intravenous injection solution, its preparation method and application, so as to at least solve the problems of poor stability of existing L-BPA-containing preparations, which cannot meet the requirements for room temperature storage, and the problem of generating a large amount of excess sodium chloride in the preparation process.

[0005] The following is a summary of this disclosure to provide a basic understanding of some aspects. This summary is not intended to identify key or important elements, nor is it intended to limit the implementation or any aspects of the claims. Furthermore, this summary provides a simplified overview of some aspects that may be described in more detail in other parts of this disclosure.

[0006] The present invention solves the above-mentioned technical problems through the following technical means:

[0007] In a first aspect, embodiments of the present invention provide an L-4-boronylphenylalanine intravenous injection solution, comprising L-4-boronylphenylalanine and a composite solubilizer, wherein the composite solubilizer is a glucose-low molecular weight dextran composite or a maltitol-polyethylene glycol 400 composite.

[0008] Furthermore, the mass ratio of glucose to low molecular weight dextran in the glucose-low molecular weight dextran complex is (3-5):1; and / or, the mass ratio of maltitol to polyethylene glycol 400 is (2-4):1.

[0009] Furthermore, in the intravenous injection solution, the concentration of L-4-boronylphenylalanine is 2.0–5.5 w / v, and the concentration of the composite solubilizer is 2.0–7.0 w / v.

[0010] Furthermore, the intravenous injection solution also includes an antioxidant at a concentration of 0.01–0.6 w / v%, wherein the antioxidant is sodium bisulfite or sodium thiosulfate.

[0011] Furthermore, the intravenous injection solution uses a pH adjuster to control the pH value to 6.5–7.8, and the pH adjuster is a citrate-sodium dihydrogen phosphate buffer pair.

[0012] Furthermore, the osmotic pressure of the intravenous injection solution is 280–320 mOsm / kg.

[0013] Secondly, embodiments of the present invention also provide a method for preparing L-4-boronylphenylalanine intravenous injection solution, the preparation method comprising the following steps:

[0014] Weigh out L-4-boronylphenylalanine, composite solubilizer, and antioxidant, respectively. The composite solubilizer is a glucose-low molecular weight dextran composite or a maltitol-polyethylene glycol 400 composite.

[0015] At 30–60°C, L-4-boronylphenylalanine was added to water for injection and dissolved by sonication for 10–15 minutes. Then, a composite solubilizer and an antioxidant were added in sequence, and sonication was continued until the mixture was completely dissolved.

[0016] Add a pH adjuster to adjust the pH to 6.5–7.8 to obtain a mixed solution;

[0017] A nanofiltration membrane with a molecular weight cutoff of 100–200 Da was used to treat the mixture under a pressure of 0.3–0.5 MPa. The osmotic pressure was adjusted to 280–320 mOsm / kg to obtain the nanofiltrate.

[0018] The nanofiltration solution was filtered and sterilized to obtain L-4-boronylphenylalanine intravenous injection solution, which was then dispensed and sealed in glass bottles.

[0019] Further, the concentration of L-4-boronylphenylalanine is 2.0–5.5 w / v, the concentration of the composite solubilizer is 2.0–7.0 w / v, and the concentration of the antioxidant is 0.01–0.6 w / v.

[0020] Further, the mass ratio of glucose to low molecular weight dextran in the glucose-low molecular weight dextran complex is (3-5):1; and / or, the mass ratio of maltitol to polyethylene glycol 400 is (2-4):1; and / or, the antioxidant is sodium bisulfite or sodium thiosulfate; and / or, the pH adjuster is a citrate-sodium dihydrogen phosphate buffer pair.

[0021] Thirdly, the embodiments of the present invention also provide the application of the L-4-boronylphenylalanine intravenous injection solution described in the first aspect above, or the L-4-boronylphenylalanine intravenous injection solution prepared by the preparation method described in the second aspect, in the preparation of BNCT therapeutic drugs for head and neck cancer or glioma.

[0022] One or more technical solutions provided in the embodiments of the present invention have at least the following technical effects or advantages:

[0023] (1) This invention utilizes the hydrogen bonds and hydrophobic interactions formed between glucose and L-BPA molecules to improve drug solubility. At the same time, low molecular weight dextran inhibits L-BPA crystallization through steric hindrance, thereby improving the stability of room temperature storage.

[0024] (2) On the other hand, based on the stabilization mechanism of polyol structure, maltitol and L-BPA form a stable complex, and polyethylene glycol 400 is used as a co-solvent to further improve solubility. It is expected to achieve a shelf life of 1-4 years, which is significantly better than existing fructose preparations.

[0025] (3) Compared with the complex process of using a large amount of sodium hydroxide to dissolve BPA and then using hydrochloric acid to adjust the pH, the present invention simplifies the preparation process by using ultrasound-assisted dissolution and buffer pair adjustment: On the one hand, the 20-40kHz ultrasound generates microjets through cavitation effect, which can break up drug aggregates and is suitable for preparing suspensions with particle size < 200nm, significantly improving dissolution efficiency; on the other hand, the citrate-sodium dihydrogen phosphate buffer pair is used to adjust the pH to 7.2-7.8, avoiding the generation of a large amount of sodium chloride, reducing the osmotic pressure of the preparation, and improving the safety of medication; furthermore, nanofiltration membrane (molecular weight cutoff 100-200Da) is used to perform nanofiltration at a pressure of 0.3-0.5MPa to remove excess sodium ions and control the osmotic pressure to 280-320mOsm / kg, which meets the requirements for intravenous injection.

[0026] (4) Compared with the existing technology which requires refrigeration at 2-8°C, the present invention achieves a technological breakthrough in room temperature (20-25°C) storage through a composite solubilizing system and optimized pH control. According to stability study data, after 24 months of storage at room temperature, the content retention rate of the injection solution of the present invention is >95%, the pH change is <0.3, and there is no visible precipitation. Detailed Implementation

[0027] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0028] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0029] In this invention, w / v% means the mass (in grams) of solute per 100 ml of solution.

[0030] The L-4-boronylphenylalanine intravenous injection solution of this invention uses a glucose-low molecular weight dextran complex (mass ratio (3-5):1) or a maltitol-polyethylene glycol 400 complex (mass ratio (2-4):1) as a solubilizer, replacing sugars such as D-sorbitol and fructose used in the prior art. The composite solubilizer of this invention not only significantly improves the solubility of L-BPA but also enhances the stability of the formulation, enabling room temperature storage. The preparation method of this invention employs an integrated process of "ultrasound-assisted dissolution + buffer pair adjustment + nanofiltration osmosis reduction," avoiding the traditional sodium hydroxide-hydrochloric acid adjustment system. It precisely controls the pH value through a citrate-sodium dihydrogen phosphate buffer pair, and uses nanofiltration technology to remove excess ions, achieving a salt-free preparation process.

[0031] Specifically, the L-4-boronylphenylalanine intravenous injection solution of the present invention comprises L-4-boronylphenylalanine and a composite solubilizer, wherein the composite solubilizer is a glucose-low molecular weight dextran composite agent or a maltitol-polyethylene glycol 400 composite agent. In a specific implementation, the L-4-boronylphenylalanine intravenous injection solution comprises 2.0–5.5 w / v% L-4-boronylphenylalanine, 2.0–7.0 w / v% of the composite solubilizer, and 0.01–0.6 w / v% of an antioxidant. The mass ratio of glucose to low molecular weight dextran in the glucose-low molecular weight dextran composite solubilizer is (3–5):1; the mass ratio of maltitol to polyethylene glycol 400 in the composite solubilizer is (2–4):1; and the antioxidant is sodium bisulfite or sodium thiosulfate. The L-4-boronylphenylalanine intravenous injection solution of the present invention uses a citrate-sodium dihydrogen phosphate buffer pair as a pH adjuster to control the pH value of the intravenous injection solution to 6.5-7.8.

[0032] The preparation method of the L-4-boronylphenylalanine intravenous injection solution of the present invention is as follows:

[0033] Weigh out L-4-boronylphenylalanine, a compound solubilizer, and an antioxidant separately. Add L-4-boronylphenylalanine to water for injection at 30–60℃. Set the ultrasonic power to 200–300W and the frequency to 20–40kHz for ultrasonic-assisted dissolution for 10–15 minutes. Then add the compound solubilizer and antioxidant sequentially, and continue ultrasonication until complete dissolution. Adjust the pH to 6.5–7.8 with a pH adjuster to obtain a mixture. Use a nanofiltration membrane with a molecular weight cutoff of 100–200 Da to perform nanofiltration on the mixture at a pressure of 0.3–0.5 MPa, adjusting the osmotic pressure to 280–320 mOsm / kg to obtain the nanofiltrate. Filter the nanofiltrate to remove bacteria to obtain L-4-boronylphenylalanine intravenous injection solution, which is then dispensed and sealed in glass vials.

[0034] The purity of L-4-boronylphenylalanine used in this invention is ≥99%,¹ 0 B abundance ≥99%, and the water used for injection meets the requirements of the 2025 edition of the Chinese Pharmacopoeia.

[0035] The L-4-boronylphenylalanine intravenous injection solution and its preparation method of the present invention will be described in detail below through specific embodiments:

[0036] Example 1

[0037] The preparation method of L-4-boronylphenylalanine intravenous injection solution in this embodiment is as follows:

[0038] (1) Weigh out 30g of L-4-boronylphenylalanine, 22.5g of glucose, 7.5g of low molecular weight dextran (40kDa), and 0.3g of sodium sulfite. Mix the glucose and low molecular weight dextran to obtain a composite solubilizer. In this example, citrate-disodium hydrogen phosphate buffer (pH 4.0) (Pharmacopoeia) is used as a pH adjuster.

[0039] (2) Add 800 mL of water for injection to the mixing tank, turn on the stirrer, set the speed to 250 rpm, and control the temperature at 45℃. Then add L-4-boronylphenylalanine, turn on the ultrasonic device, set the ultrasonic power to 250 W and the frequency to 30 kHz, and use ultrasonic-assisted dissolution for 12 min. Then add the composite solubilizer and antioxidant, and continue ultrasonic stirring under the same conditions until completely dissolved.

[0040] (3) Add pH adjuster to adjust pH to about 7.4, add water for injection to make up to 1000 mL, control the temperature at 45℃, and continue stirring for 30 min to obtain the mixture.

[0041] (4) The mixed solution was transferred to a nanofiltration device and nanofiltration was performed using a nanofiltration membrane with a molecular weight cutoff of 150 Da at a pressure of 0.4 MPa. The osmotic pressure of the mixed solution was monitored in real time and adjusted to 300 mOsm / kg. The solution was then filtered through 0.45 μm and 0.22 μm microporous membranes and sterilized to obtain L-4-boronylphenylalanine intravenous injection solution. The solution was dispensed into 100 ml glass bottles under sterile conditions and sealed by stoppering and capping.

[0042] Example 2

[0043] The preparation method of L-4-boronylphenylalanine intravenous injection solution in this embodiment is as follows:

[0044] (1) Weigh out 25g of L-4-boronylphenylalanine, 20g of maltitol, 10g of polyethylene glycol 400, and 0.25g of sodium thiosulfate. Mix maltitol and polyethylene glycol 400 to obtain a composite solubilizer. In this example, citrate-disodium hydrogen phosphate buffer (pH 4.0) (Pharmacopoeia) is used as a pH adjuster.

[0045] (2) Add 800 mL of water for injection to the mixing tank, turn on the stirrer, set the speed to 200 rpm, and control the temperature at 35℃. Then add L-4-boronylphenylalanine, turn on the ultrasonic device, set the ultrasonic power to 200 W and the frequency to 25 kHz, and use ultrasonic-assisted dissolution for 15 min. Then add the composite solubilizer and antioxidant, and continue ultrasonic stirring under the same conditions until completely dissolved.

[0046] (3) Add pH adjuster to adjust pH to about 7.6, add water for injection to make up to 1000mL, control the temperature at 35℃, and continue stirring for 40min to obtain the mixture.

[0047] (4) The mixed solution was transferred to a nanofiltration device and nanofiltration was performed using a nanofiltration membrane with a molecular weight cutoff of 100 Da at a pressure of 0.3 MPa. The osmotic pressure of the mixed solution was monitored in real time and adjusted to 290 mOsm / kg. The solution was then filtered through 0.45 μm and 0.22 μm microporous membranes and sterilized to obtain L-4-boronylphenylalanine intravenous injection solution. The solution was dispensed into 250 ml glass bottles under sterile conditions and sealed by stoppering and capping.

[0048] Example 3

[0049] The preparation method of L-4-boronylphenylalanine intravenous injection solution in this embodiment is as follows:

[0050] (1) Weigh out 50g of L-4-boronylphenylalanine, 37.5g of glucose, 12.5g of low molecular weight dextran (40kDa), and 0.5g of sodium sulfite. Mix the glucose and low molecular weight dextran to obtain a composite solubilizer. In this example, citrate-disodium hydrogen phosphate buffer (pH 4.0) (Pharmacopoeia) is used as a pH adjuster.

[0051] (2) Add 800 mL of water for injection to the mixing tank, turn on the stirrer, set the speed to 250 rpm, and control the temperature at 55℃. Then add L-4-boronylphenylalanine, turn on the ultrasonic device, set the ultrasonic power to 300 W and the frequency to 40 kHz, and use ultrasonic-assisted dissolution for 10 min. Then add the composite solubilizer and antioxidant, and continue ultrasonic stirring under the same conditions until completely dissolved.

[0052] (3) Add pH adjuster to adjust pH to about 7.3, add water for injection to make up to 1000 mL, control the temperature at 55℃, and continue stirring for 30 min to obtain the mixture.

[0053] (4) The mixed solution was transferred to a nanofiltration device and nanofiltration was performed using a nanofiltration membrane with a molecular weight cutoff of 150 Da at a pressure of 0.4 MPa. The osmotic pressure of the mixed solution was monitored in real time and adjusted to 315 mOsm / kg. The solution was then filtered through 0.45 μm and 0.22 μm microporous membranes and sterilized to obtain L-4-boronylphenylalanine intravenous injection solution. The solution was dispensed into 100 ml glass bottles under sterile conditions and sealed by stoppering and capping.

[0054] Example 4

[0055] The preparation method of L-4-boronylphenylalanine intravenous injection solution in this embodiment is as follows:

[0056] (1) Weigh out 55g of L-4-boronylphenylalanine, 58.5g of glucose, 11.5g of low molecular weight dextran (40kDa), and 6.0g of sodium sulfite. Mix the glucose and low molecular weight dextran to obtain a composite solubilizer. In this example, citrate-disodium hydrogen phosphate buffer (pH 4.0) (Pharmacopoeia) was used as a pH adjuster.

[0057] (2) Add 800 mL of water for injection to the mixing tank, turn on the stirrer, set the speed to 250 rpm, and control the temperature at 60℃. Then add L-4-boronylphenylalanine, turn on the ultrasonic device, set the ultrasonic power to 300 W and the frequency to 40 kHz, and use ultrasonic-assisted dissolution for 14 min. Then add the composite solubilizer and antioxidant, and continue ultrasonic stirring under the same conditions until completely dissolved.

[0058] (3) Add pH adjuster to adjust pH to 7.8, add water for injection to make up to 1000 mL, control the temperature at 60℃, and continue stirring for 30 min to obtain the mixture.

[0059] (4) The mixed solution was transferred to a nanofiltration device and nanofiltration was performed using a nanofiltration membrane with a molecular weight cutoff of 200 Da at a pressure of 0.5 MPa. The osmotic pressure of the mixed solution was monitored in real time and adjusted to 320 mOsm / kg. The solution was then filtered through 0.45 μm and 0.22 μm microporous membranes and sterilized to obtain L-4-boronylphenylalanine intravenous injection solution. The solution was dispensed into 100 ml glass bottles under sterile conditions and sealed by stoppering and capping.

[0060] Example 5

[0061] The preparation method of L-4-boronylphenylalanine intravenous injection solution in this embodiment is as follows:

[0062] (1) Weigh out 20g of L-4-boronylphenylalanine, 16g of maltitol, 4g of polyethylene glycol 400, and 0.1g of sodium thiosulfate. Mix maltitol and polyethylene glycol 400 to obtain a composite solubilizer. In this example, citrate-disodium hydrogen phosphate buffer (pH 4.0) (Pharmacopoeia) is used as a pH adjuster.

[0063] (2) Add 800 mL of water for injection to the mixing tank, turn on the stirrer, set the speed to 200 rpm, and control the temperature at 30℃. Then add L-4-boronylphenylalanine, turn on the ultrasonic device, set the ultrasonic power to 220 W and the frequency to 25 kHz, and use ultrasonic-assisted dissolution for 13 min. Then add the composite solubilizer and antioxidant, and continue ultrasonic stirring under the same conditions until completely dissolved.

[0064] (3) Add pH adjuster to adjust pH to 6.5, add water for injection to make up to 1000 mL, control the temperature at 30℃, and continue stirring for 40 min to obtain the mixture.

[0065] (4) The mixed solution was transferred to a nanofiltration device and nanofiltration was performed using a nanofiltration membrane with a molecular weight cutoff of 150 Da at a pressure of 0.4 MPa. The osmotic pressure of the mixed solution was monitored in real time and adjusted to 280 mOsm / kg. The solution was then filtered through 0.45 μm and 0.22 μm microporous membranes and sterilized to obtain L-4-boronylphenylalanine intravenous injection solution. The solution was dispensed into 250 ml glass bottles under sterile conditions and sealed by stoppering and capping.

[0066] Comparative Example 1

[0067] The preparation of the L-4-boronylphenylalanine intravenous injection solution in this comparative example is as follows:

[0068] Weigh out 30g of L-4-boronylphenylalanine and 31.5g of D-sorbitol. Add 800mL of water for injection to a mixing vessel, start stirring at 250rpm and maintain the temperature at 55℃. Then add L-4-boronylphenylalanine and add 10wt% sodium hydroxide solution dropwise while stirring until L-4-boronylphenylalanine is completely dissolved. Then add D-sorbitol and stir until completely dissolved. Adjust the pH of the mixed solution to 7.8 with hydrochloric acid, add water to make up to 1000mL, stir and mix well. Filter through 0.45μm and 0.22μm microporous membranes and sterilize to obtain L-4-boronylphenylalanine intravenous injection solution.

[0069] The L-4-boronylphenylalanine intravenous injection solutions prepared in Examples 1-5 and the L-4-boronylphenylalanine intravenous injection solution prepared in Comparative Example 1 were subjected to quality testing. The test results are shown in Table 1.

[0070] Table 1 Quality Inspection Results

[0071] Sample source pH value Osmotic pressure (mOsm / kg) L-BPA content (labeled amount) Bacterial endotoxins (EU / mL) Aseptic examination Exterior color Example 1 7.4 300 99.5 0.3 Complies with relevant regulations for intravenous injection solutions Colorless and transparent liquid Example 2 7.6 290 98.8 0.2 Complies with relevant regulations for intravenous injection solutions colorless clear liquid Example 3 7.3 315 99.2 0.4 Complies with relevant regulations for intravenous injection solutions colorless clear liquid Example 4 7.8 320 99.0 0.3 Complies with relevant regulations for intravenous injection solutions colorless clear liquid Example 5 6.5 280 97.6 0.2 Complies with relevant regulations for intravenous injection solutions colorless clear liquid Comparative Example 7.8 450 98.5 0.3 Complies with relevant regulations for intravenous injection solutions colorless clear liquid

[0072] The stability of the L-4-boronylphenylalanine intravenous injection solutions prepared in Examples 1 and 2, and the L-4-boronylphenylalanine intravenous injection solution prepared in Comparative Example 1, was tested under the following conditions: 40℃±2℃, RH 75%±5%. The stability of the L-4-boronylphenylalanine intravenous injection solutions was tested after 6 months. The results are shown in Table 2.

[0073] Table 2. Stability test results after 6 months

[0074] Sample source Content retention rate pH changes Visible sediment Related material growth Example 1 96.8% 0.15 none 0.8% Example 2 97.5% 0.12 none 0.6% Comparative Examples 92.3% 0.35 slight 1.8%

[0075] The stability of L-4-boronylphenylalanine intravenous injection was tested after 12 months at 25℃±2℃ and RH 60%±5%. The results are shown in Table 3.

[0076] Table 3. Stability test results after 12 months

[0077] Sample source Content retention rate pH changes Visible sediment Related material growth Example 1 98.6% 0.08 none 0.3% Example 2 99.1% 0.06 none 0.2% Comparative Examples 95.2% 0.25 have 1.2%

[0078] The stability of L-4-boronylphenylalanine intravenous injection was tested after 24 months at 20-25℃. The results are shown in Table 4.

[0079] Table 4. Stability test results after 24 months

[0080] sample Content retention rate pH changes Visible sediment Related material growth Example 1 96.2% 0.25 none 0.9% Example 2 97.8% 0.20 none 0.7% Comparative Examples 89.5% 0.45 obvious 2.5%

[0081] As can be seen from Tables 2, 3 and 4, the L-4-boronylphenylalanine intravenous injection solutions prepared in Examples 1 and 2 are significantly superior to the traditional sorbitol system in all stability indicators. In particular, under room temperature storage conditions, the content retention rate is increased by 6-8 percentage points and the growth of related substances is reduced by 1.5-1.8 percentage points. Therefore, it is shown that the L-4-boronylphenylalanine intravenous injection solution of the present invention can maintain high stability under room temperature storage conditions.

[0082] Before administration of the L-4-boronylphenylalanine intravenous injection solution of the present invention, tumor uptake should be assessed by 18F-BPA PET imaging to screen suitable patients. During administration, vital signs such as blood pressure and heart rate should be monitored, and continuous administration should be ensured from before the start of neutron irradiation until the irradiation period. When the L-4-boronylphenylalanine intravenous injection solution of the present invention is used for BCNT treatment, the recommended administration method is as follows:

[0083] Initial dose: 150–250 mg / kg / hour, administered via intravenous infusion over 1.5–3 hours; maintenance dose: 80–120 mg / kg / hour, administered via intravenous infusion over 0.5–1.5 hours, with a total administration time of 2.0–4.0 hours.

[0084] The L-4-boronylphenylalanine intravenous injection of the present invention is suitable for the treatment of inoperable locally advanced or recurrent head and neck cancer, and also for the treatment of malignant glioma.

[0085] The foregoing description includes examples from this specification. Of course, for the purposes of describing this specification, it is impossible to describe every conceivable combination of components or methods; however, those skilled in the art will understand that many other combinations and arrangements are possible. Therefore, this specification is intended to cover all such changes, modifications, and variations that fall within the spirit and scope of the appended claims. Furthermore, with regard to the use of the term "comprising" in the detailed description or claims, the term is intended to be inclusive in a manner similar to the term "including," as interpreted when "comprising" is used as a transitional word in the claims.

[0086] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. An L-4-borono-phenylalanine intravenous solution, characterized in that, The L-4-borono-phenylalanine and a complex solubilizer, which is a glucose-low molecular dextran complexing agent or a maltitol-polyethylene glycol 400 complexing agent.

2. The L-4-borono-phenylalanine intravenous solution of claim 1, wherein, The mass ratio of glucose and low molecular dextran in the glucose-low molecular dextran complexing agent is (3-5):1; and / or, the mass ratio of maltitol-polyethylene glycol 400 is (2-4):

1.

3. The L-4-borono-phenylalanine intravenous solution of claim 1, wherein, The concentration of the L-4-borono-phenylalanine in the intravenous injection solution is 2.0-5.5 w / v%, and the concentration of the complex solubilizer is 2.0-7.0 w / v%.

4. The L-4-borono-phenylalanine intravenous solution of claim 3, wherein, The intravenous injection solution further comprises an antioxidant, which is sodium bisulfite or sodium thiosulfate, with a concentration of 0.01-0.6 w / v%.

5. The L-4-borono-phenylalanine intravenous solution of claim 1, wherein, The pH value of the intravenous injection solution is controlled to be 6.5-7.8 using a pH adjuster, which is a citric acid-sodium phosphate buffer pair.

6. The L-4-borono-phenylalanine intravenous solution of claim 1, wherein, The osmotic pressure of the intravenous injection solution is 280-320 mOsm / kg.

7. Process for the preparation of L-4-borono-phenylalanine intravenous solutions, characterized in that, The preparation method comprises the following steps: L-4-borono-phenylalanine, a complex solubilizer, and an antioxidant are weighed respectively, and the complex solubilizer is a glucose-low molecular dextran complexing agent or a maltitol-polyethylene glycol 400 complexing agent; The L-4-borono-phenylalanine is added into water for injection at 30-60°C, and is dissolved by ultrasonic wave for 10-15 min, then the complex solubilizer and the antioxidant are added in sequence, and the ultrasonic wave is continued until complete dissolution; A pH adjuster is added to adjust the pH value to 6.5-7.8, to obtain a mixed solution; The mixed solution is subjected to nanofiltration treatment under a pressure of 0.3-0.5 MPa using a nanofiltration membrane with a molecular weight cut-off of 100-200 Da, so as to adjust the osmotic pressure to 280-320 mOsm / kg, to obtain a nanofiltration solution; The nanofiltration solution is filtered and sterilized to obtain the L-4-borono-phenylalanine intravenous injection solution, which is sealed in glass bottles.

8. The preparation method according to claim 7, characterized in that, The concentration of the L-4-borono-phenylalanine is 2.0-5.5 w / v%, the concentration of the complex solubilizer is 2.0-7.0 w / v%, and the concentration of the antioxidant is 0.01-0.6 w / v%.

9. The preparation method according to claim 8, characterized in that, The mass ratio of glucose and low molecular dextran in the glucose-low molecular dextran complexing agent is (3-5):1; And / or, the mass ratio of maltitol-polyethylene glycol 400 is (2-4):1; And / or, the antioxidant is sodium bisulfite or sodium thiosulfate; And / or, the pH adjuster is a citric acid-sodium phosphate buffer pair.

10. The use of the L-4-borono-phenylalanine intravenous injection solution according to claims 1-6 or prepared by the preparation method of claims 7-9 in the preparation of a BNCT treatment drug for head and neck cancer or brain glioma.