JP2009051766A - LIQUID STATE COMPOSITION CONTAINING p-BORONOPHENYLALANINE AND SORBITOL - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid state composition containing p-boronophenylalanine, having an excellent solubility and stability. <P>SOLUTION: This liquid state composition containing p-boronophenylalanine and sorbitol is provided by setting 0.9 to 2 range of the molar ratio of content of the sorbitol to the content of the p-boronophenylalanine. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a liquid composition containing p-boronophenylalanine and sorbitol. Furthermore, this invention relates to the method of improving the stability of the liquid body containing p-boronophenylalanine by sorbitol.

In recent years, boron neutron capture therapy (BNCT) has attracted attention as a cancer treatment method using radioactive isotopes. In boron neutron capture therapy, a boron compound containing a boron 10 isotope ( ¹⁰ B) is taken into a cancer cell, irradiated with a low-energy neutron beam (for example, thermal neutron), and locally by a nuclear reaction occurring in the cell. It is a treatment method that destroys cancer cells. In this method of treatment, it is important to increase the therapeutic effect by selectively accumulating boron compounds containing 10B in cancer tissue cells. Therefore, a boron compound that is selectively and reliably taken up by cancer cells is developed. It is necessary to do.

  Conventionally, boron-containing compounds in which a boron atom or a boron atom group is introduced into a basic skeleton have been synthesized as drugs used for BNCT. Examples of drugs actually used in clinical practice include p-boronophenylalanine (BPA) and mercaptoundecahydrododecaborate (BSH).

Among these, BPA has extremely poor solubility at physiological pH, and its utilization form is limited.

In order to improve the solubility of BPA in water, a fructose complex of BPA is formed (for example, Patent Document 1), or a monosaccharide or polyol is added to BPA in an alkaline solution (such as in an aqueous sodium hydroxide solution) Attempts have been made to remove inorganic salts with an exchange resin for use (for example, Patent Document 2).
US Pat. No. 5,492,900 US Pat. No. 6,169,076

  However, in this way, liquids to which saccharides are added or alkali-treated have problems of stability and properties that are not suitable as injections.

  Accordingly, an object of the present invention is to provide a homogeneous liquid composition containing p-boronophenylalanine which has excellent stability and ensures safety as an injection.

  Another object of the present invention is to provide a method for improving the solubility and stability of a liquid containing p-boronophenylalanine (BPA).

  As a result of intensive studies to solve the above problems, the present inventors have improved the solubility of p-boronophenylalanine (BPA) in a liquid and its stability under certain conditions. The present inventors have found that it is suitable for ensuring safety and have completed the present invention.

  That is, the present invention is a liquid composition containing p-boronophenylalanine and sorbitol, wherein the content ratio of sorbitol is 0.9 in terms of molar ratio to the content of p-boronophenylalanine. To a composition in the range of 2 to 2.

  The p-boronophenylalanine may be Lp-boronophenylalanine, and the sorbitol may be D-sorbitol.

  The pH of the composition can be in the range of 6.5 to 7.5.

  The osmotic pressure ratio of the composition may range from 1 to 2 relative to physiological saline.

  The concentration of p-boronophenylalanine in the composition can be 2.0-8.0 W / V%.

  The sodium ion concentration in the composition can be in the range of 130 mEq / L to 160 mEq / L.

  The composition can be a pharmaceutical product.

  The composition may be selected from nasal drops, oral preparations, vaginal preparations, suppositories, and injections.

  The present invention also relates to a method for increasing the solubility and stability of a liquid containing p-boronophenylalanine and a metal ion with sorbitol.

  In the liquid composition containing p-boronophenylalanine and sorbitol of the present invention, p-boronophenylalanine is homogeneously dissolved in the solution by the action of sorbitol, and is excellent in stability. It has properties that are acceptable for administration.

  The liquid composition of the present invention may be aqueous, alcoholic, or any other liquid, but is preferably an aqueous liquid.

  The use of the liquid composition of the present invention is preferably used as a pharmaceutical, and particularly preferably used as a pharmaceutical for boron neutron capture therapy.

  The composition of the present invention contains p-boronophenylalanine and sorbitol.

  As p-boronophenylalanine, the L form is currently used, and Lp-boronophenylalanine can be preferably used in the present invention, but is not limited thereto. That is, racemic p-boronophenylalanine containing both D-form or both D-form and L-form can be used in the present invention.

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

  Here, p-boronophenylalanine is synthesized by, for example, a known method (for example, HR Synder, AJ Reedy, WMJ Lennarz, J. Am. Chem. Soc. 1958, 80, 835: C. Malan, C. Morin, SYNLETT, 1996, 167: U.S. Pat. No. 5,157,149: JP 2000-212185 A: and Japanese Patent No. 2979139).

  The content of sorbitol used in the liquid composition of the present invention is 0.9 to 2 in molar ratio to the amount of p-boronophenylalanine, although it depends on the amount of other additives. It is a range. More preferably, it is in the range of 1.1 to 1.5. If the amount of sorbitol added is reduced, the allowable pH range for solubility is narrow and may precipitate in the body. Increasing the amount added increases the osmotic pressure ratio. Moreover, this range is preferable also from a viewpoint of making use of the effect as a solubilizing agent and improving economical efficiency.

  The content of p-boronophenylalanine in the composition of the present invention is appropriately determined depending on its kind and the kind of the component to be blended, but is usually 2.0-8.0 W / V%. If the blending amount is small, a large volume of liquid is required for clinical application, which is inconvenient. On the other hand, when the blending amount is large, the solution stability tends to be insufficient, and the osmotic pressure ratio becomes large, which is inconvenient as an injection.

  The pH of the liquid composition of the present invention is preferably a neutral pH in consideration of administration to a living body. More specifically, it is in the range of 6.5 to 7.5, particularly preferably around 7.4. For adjusting the pH, an appropriate pH adjusting agent (hydrochloric acid, sodium hydrogen carbonate, etc.) used in the art and a buffering agent may be used as necessary.

  The osmotic pressure ratio of the liquid composition of the present invention is not particularly limited, but is preferably in the range of 1 to 2 in comparison with physiological saline. More preferably, it is in the range of 1.1 to 1.4. When it is within this range, in the case of an injection, pain can be reduced and administration time can be shortened.

  In the liquid composition of the present invention, various metal ions that may be contained in a living body may be appropriately contained in order to achieve stability inside and outside the living body. Preferably, sodium ions are contained, and the concentration thereof is not particularly limited, but is particularly preferably from 130 mEq / L to 160 mEq / L. This numerical range close to the Na ion concentration range of the body fluid is preferable so that the electrolyte balance between the intracellular fluid and the extracellular fluid is not greatly lost.

  If necessary, a buffering agent such as a phosphate buffer, a Tris-HCl buffer, an acetate buffer, a carbonate buffer, or a citrate buffer may be added to the liquid composition of the present invention. These buffers may be useful for stabilizing the formulation or reducing irritation.

  Furthermore, the composition of the present invention can contain other components that are usually used in the technical field, if necessary, as long as the object of the present invention is not adversely affected. As such components, additives usually used in liquid, especially aqueous compositions, for example, preservatives such as benzalkonium chloride, potassium sorbate, chlorohexidine hydrochloride, stabilizers such as sodium edetate, hydroxyethyl cellulose , Thickeners such as hydroxypropylmethylcellulose, isotonic agents such as sodium chloride, potassium chloride, glycerin, sucrose, glucose, surfactants such as polysorbate 80, polyoxyethylene hydrogenated castor oil, sodium chloride, potassium chloride, Examples thereof include isotonic agents such as glycerin and pH adjusting agents such as hydrochloric acid and sodium hydroxide.

  When the liquid composition of the present invention is a pharmaceutical used for boron neutron therapy, it can take the form of nasal drops, oral preparations, vaginal preparations, suppositories, injections, and the like.

  That is, when the liquid composition of the present invention is used as a pharmaceutical product, it can be administered orally by a liquid or the like, or it can be administered parenterally by an injection such as intraarterial injection, intravenous injection or intramuscular injection, a suppository, or a transdermal preparation. It may be a form. The parenteral administration includes intravenous, intramuscular, subcutaneous, intra-tissue, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal administration, and the like.

  “Liquid composition for oral administration” includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and generally used inert solvents such as purified water, Contains ethanol. In addition to the inert solvent, this composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, corrigents, fragrances, and preservatives.

  As “injection for parenteral administration”, a certain amount of an active ingredient is dispersed into a dispersant (for example, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservative (for example, , Methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, glucose, etc.) and the like, and aqueous solvents (eg, distilled water for injection, physiological saline) Water, Ringer's solution, etc.) or an oily solvent (for example, olive oil, sesame oil, cottonseed oil, corn oil and other vegetable oils, propylene glycol, etc.) and the like. At this time, additives such as a solubilizing agent (for example, sodium salicylate, sodium acetate, etc.), a stabilizer (for example, human serum albumin), a soothing agent (for example, benzyl alcohol, etc.) may be used as desired. Furthermore, you may contain an antioxidant, a coloring agent, etc. and another additive as needed.

  A “pharmaceutically acceptable carrier” can also be used. Examples of such substances include solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like in liquid preparations. If necessary, formulation additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, gelling agents and the like can be used according to a conventional method.

  Preferable examples of the “antioxidant” include sulfite and ascorbic acid. Preferable examples of the “isotonic agent” include glucose, sodium chloride, glycerin, D-mannitol and the like.

  Preferable examples of the “solubilizing agent” include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. .

  Preferable examples of the “solvent” include water for injection, alcohol, propylene glycol, macrogol and the like.

  Preferable examples of the “suspending agent” include hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Examples of the “surfactant” include sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like.
Preferable examples of the “soothing agent” include benzyl alcohol and the like.

  Preferable examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

  EXAMPLES The present invention will be described in more detail with reference to the following examples, but these do not limit the scope of the present invention.

  Liquid compositions were prepared by the methods shown in the following examples and comparative examples, respectively. Then, stability evaluation was performed about these liquid compositions. The stability evaluation was mainly performed using the following models and conditions as standard conditions for the severe drug stability test based on the ICH guidelines.

  That is, the light severe storage conditions are 25 ° C. ± 2 ° C./amb H / D65 lamp (instant illuminance: 5000 Lux · hr), after 600,000 Lux · hr and 1.2 million Lux · hr light irradiation, visual observation of properties, pH Measurement (781 type, manufactured by Metronome Shibata), osmotic pressure ratio measurement (OM6060 type, manufactured by ARAKRAY), and BPA concentration measurement (high-performance liquid chromatograph LaChromElite L2000 series, manufactured by Hitachi High-Technologies) were performed and compared with those at the start of the test.

  On the other hand, in the thermal severe test, at 60 ° C ± 2 ° C / ambH / dark place, the storage device: ADP300 (manufactured by Yamato Kagaku) is placed for 1 week, 2 weeks, and 4 weeks. Visual observation of properties, pH measurement (781 type metronome shibata), osmotic pressure ratio measurement (OM6060 type ARAKRAY), BPA concentration measurement (high-performance liquid chromatograph LaChromElite L2000 series, Hitachi High-Technologies) and comparison with the start of the test did.

  Here, the measurement conditions by HPLC are as follows.

Column used: Atlantis T3 (3 μm, 4.6 × 150 mm) manufactured by Waters Mobile phase: water / methanol / trifluoroacetic acid (950: 50: 1)
Column temperature: constant temperature around 40 ° C Flow rate: 1.0 mL / min Injection volume: 5 μL
Detection wavelength: 223nm
Detection wavelength (photodiode array detector: PDA): 200 to 360 nm

[Example 1]
(Preparation of BPA sorbitol aqueous solution)
A 3 w / v% BPA sorbitol aqueous solution was prepared as follows. That is, first, 82.9 mL of water was added to 15.0 mL of a 1 mol / l sodium hydroxide aqueous solution and stirred. L-BPA 3.00 g and D-sorbitol 3.15 g were added and stirred at room temperature for 30 minutes to completely dissolve. 1.22 mL of 1 mol / l hydrochloric acid was added at room temperature to adjust to pH 7.4, and 0.88 mL of water was added to make a total volume of 100 mL. Subsequently, it filtered with the 0.2 micrometer filter.

[Example 2]
An aqueous BPA sorbitol solution was prepared in the same manner as in Example 1 except that the sorbitol / BPA ratio (molar ratio) was adjusted to 1.5.

Example 3
An aqueous BPA sorbitol solution was prepared in the same manner as in Example 1 except that the sorbitol / BPA ratio (molar ratio) was adjusted to 1.75.

Example 4
A 2.5 w / v BPA sorbitol aqueous solution was prepared as follows. That is, first, 171.5 mL of water was added to 25.0 mL of 1 mol / l sodium hydroxide aqueous solution and stirred. L-BPA 5.00g and D-sorbitol 6.562g were added, and it stirred for 30 minutes at room temperature, and melt | dissolved completely. 2.1 mL of 1 mol / l hydrochloric acid was added at room temperature to adjust the pH to 7.4, and 0.1751 g of sodium chloride and 1.4 mL of water were added to make a total volume of 200 mL. Subsequently, it filtered with the 0.2 micrometer filter.

Example 5
A BPA sorbitol aqueous solution was prepared in the same manner as in Example 4 except that the sorbitol / BPA ratio (molar ratio) was adjusted to 1.75.

Example 6
A BPA sorbitol aqueous solution was prepared in the same manner as in Example 4 except that the sorbitol / BPA ratio (molar ratio) was adjusted to 2.0.

[Comparative Example 1]
Preparation of L-BPA-fructose aqueous solution
4.84 g of L-BPA and 10.76 g of fructose were added to 145 mL of water, and 26.9 mL of 1 mol / l sodium hydroxide was added and dissolved while stirring at room temperature. 4.4 mL of 1 mol / l hydrochloric acid was added to adjust the pH to 7.4, and 23.6 mL of water was added to make the volume 200 mL. Subsequently, it filtered with the 0.2 micrometer filter.

[Comparative Example 2]
Preparation of L-BPA-fructose aqueous solution
4.84 g of L-BPA and 10.76 g of fructose were added to 145 mL of water, and 26.9 mL of 1 mol / l sodium hydroxide was added and dissolved while stirring at room temperature. While adjusting with 1 mol / l hydrochloric acid or 7% aqueous sodium hydrogen carbonate, the volume was adjusted to 200 mL and adjusted to pH 7.9. Subsequently, it filtered with the 0.2 micrometer filter.

Table 1 shows the results of optical severe storage tests on the aqueous solutions of Examples 1 to 3 and Comparative Example 1.

  As a result, in the light stress test, no significant changes in pH, osmotic pressure ratio and content were confirmed in any of the preparations of Examples and Comparative Examples, but the stability was equivalent to that of the fructose preparation used in clinical research. It was.

Table 2 shows the results of the thermal severe test performed on the aqueous solutions of Examples 4 to 6 and Comparative Example 2.

  As a result, in the thermal stability test, in the property observation, the change in color was large in the comparative example, and the change in the component was also inferred from the appearance, but no such change was seen in the aqueous solutions of the examples. It was. Furthermore, in the comparative example, the results show the instability of the solution, such as the osmotic pressure ratio also changing with time and the BPA concentration changing, but such changes are found in the aqueous solutions of the examples. Was found, indicating that the solution was stable. That is, the fructose preparation has a significant color change and the BPA concentration is greatly reduced, whereas the liquid composition containing sorbitol has a small change in concentration and is stable.

  Moreover, although the dissolution concentration is shown by the measurement of HPLC, the solubility of BPA in water is 1.6 g / L, and in comparison with that, the solubility of BPA increases dramatically in the solution of the example. It is confirmed that Judging comprehensively the results of solubility, heat severity and light severity, it was found that the liquid composition containing sorbitol of the present invention was excellent in stability and liquid homogeneity.

Claims (9)

A liquid composition containing p-boronophenylalanine and sorbitol, wherein the content ratio of sorbitol is within a range of 0.9 to 2 in terms of molar ratio with respect to the content of p-boronophenylalanine. There is a composition. The composition according to claim 1, wherein p-boronophenylalanine is Lp-boronophenylalanine and sorbitol is D-sorbitol. The composition according to claim 1 or 2, wherein the pH is in the range of 6.5 to 7.5. The composition according to any one of claims 1 to 3, wherein the osmotic pressure ratio is in the range of 1 to 2 in comparison with physiological saline. The composition according to any one of claims 1 to 4, wherein the concentration of p-boronophenylalanine is 2.0-8.0 W / V%. The composition according to any one of claims 1 to 5, wherein the sodium ion concentration is in the range of 130 mEq / L to 160 mEq / L. The composition according to any one of claims 1 to 6, which is a pharmaceutical product. The composition according to any one of claims 1 to 7, which is selected from nasal drops, oral preparations, vaginal preparations, suppositories, and injections. A method for enhancing the solubility and stability of a liquid containing p-boronophenylalanine and a metal ion by sorbitol.