BPA freeze-dried preparation and preparation method

Abstract

The present invention provides a method for preparing a BPA lyophilized preparation, comprising a liquid preparation process and a freeze drying process; wherein the liquid preparation process comprises: (1) dissolving BPA and a polyol in an aqueous solution by using an alkali to obtain a clear solution; (2) adjusting the clear solution to 7.5 < pH ≤ 8.5 by using an acid to obtain a BPA solution; and the freeze drying process comprises: (3) packaging the BPA solution and freeze drying it under a vacuum degree of 10 to 20 Pa to obtain the lyophilized preparation. The BPA lyophilized preparation prepared by the method has good stability and a low impurity content.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a BPA freeze-dried preparation and a preparation method thereof. Background Art

[0002] Boron Neutron Capture Therapy (BNCT) is a method of using boron-containing 10 B) The drug has a high capture cross section for thermal neutrons. 10 B(n,α) 7 Li neutron capture and nuclear fission reaction production 4 He and 7 The average energy of the two charged particles is about 2.33 MeV, with high linear energy transfer (LET) and short range. The linear energy transfer and range of alpha particles are 150 keV / μm and 8 μm respectively. 7 The range of Li heavy-charged particles is 175keV / μm and 5μm. The total range of the two particles is approximately equivalent to the size of a cell. Therefore, the radiation damage caused to the organism can be limited to the cellular level. When boron-containing drugs selectively accumulate in tumor cells and are combined with appropriate neutron radiation sources, they can achieve the purpose of locally killing tumor cells without causing too much damage to normal tissues.

[0003] 4-Borate-phenylalanine (BPA) is a kind of 10 B. Since BPA is poorly soluble in water, it is generally necessary to add a cosolvent and dissolve it under the action of a strong acid or alkali, and then adjust it to a physiological pH. After sterilization, it is made into a sterile injection solution for use in patients or animals. The solution needs to be prepared on the spot. The cumbersome preparation process makes the drug extremely inconvenient in clinical use, and the sterility cannot be guaranteed, which limits its application. Patent CN103100094B discloses a freeze-drying process for L-BPA. After mixing L-BPA and cosolvent fructose, L-BPA is dissolved and freeze-dried for 22-26 hours under vacuum. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing a BPA freeze-dried preparation and a BPA preparation prepared by the method, wherein the preparation prepared by the method has good stability and a small impurity content.

[0005] In a first aspect, the present invention provides a method for preparing a BPA freeze-dried preparation, comprising a liquid preparation process and a freeze-drying process; wherein

[0006] The preparation process includes: (1) dissolving BPA and polyol in an aqueous solution by using an alkali to obtain a clear solution; (2) adjusting the clear solution to pH 7.5 < pH ≤ 8.5 by using an acid to obtain a BPA solution;

[0007] The freeze-drying process includes: (3) packaging the BPA solution and freeze-drying it under a vacuum degree of 10 to 20 Pa to obtain the freeze-dried preparation.

[0008] In another preferred embodiment, during the liquid preparation process, the temperature of the solution is controlled to be no higher than 60°C, preferably 18-50°C, and more preferably 18-40°C.

[0009] In another preferred embodiment, the weight ratio of BPA to polyol is 1:1-1.3; preferably 1:1.1-1.25.

[0010] In another preferred embodiment, the vacuum degree of freeze-drying is 10-20Pa, preferably 10-11Pa.

[0011] In another preferred embodiment, the clear solution is adjusted to a pH value of 7.6 to 8.1 to obtain a BPA solution.

[0012] In another preferred embodiment, the base includes: lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.

[0013] In another preferred embodiment, during the liquid preparation process, BPA and polyol are dissolved in an aqueous solution by using an alkali to obtain a clear solution, and the pH value of the clear solution is 8.5-9.5.

[0014] In another preferred embodiment, the polyols include: fructose, lactose, sorbitol, maltose, mannitol, xylitol, ribose, glucose, and sucrose.

[0015] In another preferred embodiment, a filtration step is further included after the liquid preparation process and before the freeze-drying process.

[0016] In another preferred embodiment, the freeze-drying process takes 39-80 hours.

[0017] In another preferred embodiment, the vacuum degree during the freeze-drying process is 10-11 Pa.

[0018] In another preferred embodiment, the freeze-drying process further includes a pre-freezing process. Preferably, the temperature of the pre-freezing process is -20°C to -50°C. Preferably, the time of the pre-freezing process is 5-15 hours.

[0019] In another preferred embodiment, the freeze-drying process further includes a sublimation process. Preferably, the temperature of the sublimation process is -20°C to -35°C. Preferably, the vacuum degree of the sublimation process is 10 to 20 Pa. Preferably, the time of the sublimation process is 30-55 hours.

[0020] In another preferred embodiment, the freeze drying process also includes an analytical drying process. Preferably, the temperature of the analytical drying process is 20°C to 40°C. Preferably, the vacuum degree of the analytical drying process is 10 to 20 Pa. Preferably, the time of the analytical drying process is 4 to 10 hours.

[0021] The second aspect of the present invention provides a BPA freeze-dried preparation prepared by the method described in the first aspect of the present invention.

[0022] The third aspect of the present invention provides a composition, which comprises the BPA freeze-dried preparation as described in the second aspect.

[0023] In a fourth aspect, the present invention provides a kit, wherein the kit contains the BPA freeze-dried preparation as described in the second aspect.

[0024] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a preferred production process of the BPA freeze-dried preparation of the present invention.

[0026] the term

[0027] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and public materials cited in the entirety of this article are incorporated herein by reference in their entirety.

[0028] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that, unless otherwise clearly stated in the text, the singular form used in this specification and claims includes the plural form of the referred thing. It should also be noted that, unless otherwise stated, the "or" and "or" used represent "and / or". In addition, the terms "including" and other forms used, such as "including", "containing" and "containing" are not restrictive. The section titles used in this article are only used for the purpose of organizing the article and should not be interpreted as limiting the subject matter. All documents or parts of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference as a whole.

[0029] The "base" described in the invention is mainly an inorganic base, including but not limited to: lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide. The "acid" described in the present invention includes inorganic acids and organic acids. Inorganic acids, for example, include but are not limited to perchloric acid, hydroiodic acid, sulfuric acid, hydrobromic acid, hydrochloric acid, nitric acid, iodic acid, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, carbonic acid, citric acid, hydrofluoric acid, malic acid, gluconic acid, formic acid, lactic acid, benzoic acid, acrylic acid, acetic acid (acetic acid), propionic acid, stearic acid, hydrosulfuric acid, hypochlorous acid, boric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and the preferred acid is hydrochloric acid.

[0030] The "BPA" described in the present invention is 4-dihydroxyborylphenylalanine, and its chemical formula is Where B includes 10 B and 11 B. When B is 10 B, can be used as a drug for boron neutron capture therapy (BNCT), which has two isomers, namely L-type and D-type Both configurations should be included in the protection scope of the present invention. The BPA described in the present invention is preferably L-BPA (L-BPA).

[0031] Method for preparing BPA freeze-dried preparation

[0032] The present invention provides a method for preparing a BPA lyophilized preparation, comprising a liquid preparation process and a freeze drying process: wherein the liquid preparation process comprises: (1) dissolving BPA and a polyol in an aqueous solution by using an alkali to obtain a clear solution; (2) adjusting the clear solution to 7.5 < pH ≤ 8.5 by using an acid to obtain a BPA solution; and the freeze drying process comprises: (3) packaging the BPA solution, and freeze drying it under a vacuum degree of 10 to 20 Pa to obtain the lyophilized preparation. In order to ensure that the chemical properties of the components in the solution do not change, the temperature of the solution needs to be controlled to be no higher than 60°C during the liquid preparation process, and the "solution" referred to herein refers to any "solution" described in the liquid preparation process. Preferably, the temperature is 18 to 50°C, and more preferably 18 to 40°C.

[0033] The weight ratio of BPA to polyol affects the dissolution of BPA, and there is no particular limitation on the weight ratio. Preferably, the weight ratio of BPA to polyol is 1:1 to 1.3; more preferably 1:1.1 to 1.25. The polyol includes: fructose, lactose, sorbitol, maltose, mannitol, xylitol, ribose, glucose, and sucrose.

[0034] In the preparation process, BPA and polyol are dissolved in an aqueous solution by alkali to obtain a clear solution, wherein the pH value of the clear solution is 8.5 to 9.5. Furthermore, the clear solution needs to be adjusted to a pH value of 7.6 to 8.1 by acid to obtain a BPA solution.

[0035] During the freeze-drying process, the vacuum degree of the freeze-drying is 10-20Pa, preferably 10-11Pa. The freeze-drying process time is 39-80 hours. In actual operation, it can be determined according to the actual parameters in the liquid preparation process, without special restrictions. The freeze-drying process includes: pre-freezing process, sublimation process and analytical drying process, and the temperature, time, vacuum degree and other parameters in the three processes can be independently selected according to actual needs. As a preferred solution, the BPA solution is freeze-dried under the following conditions to obtain a BPA freeze-dried preparation: Pre-freezing process: cool the sample to -20℃~-60℃ for 5-15 hours to completely freeze the sample. Sublimation process: heat to -15℃~-35℃, maintain vacuum 10-11pa, and continue for 30-55 hours. Analytical drying process: heat the partition, heat to 0℃~40℃, maintain for 4-10 hours, and maintain vacuum 10-11pa throughout the analytical drying process. As a preferred solution, during the pre-freezing process, the temperature can be adjusted multiple times according to actual needs, such as first cooling to -60°C for a period of time, and then heating to -20 to -50°C. As a preferred solution, during the analytical drying process, the temperature can be first raised to a lower temperature, and then gradually raised to a higher temperature, such as first raising the temperature to 0°C for a period of time, and then raising the temperature to 30±10°C.

[0036] The main advantages of the present invention include:

[0037] 1. During the freeze-drying process, optimized process parameters are used to avoid the adverse effects of incomplete water removal and poor temperature control on product morphology to a great extent, and the moisture content of the product is controlled at the lowest level; at the same time, the temperature is evenly transmitted, the product is loose and full, the particles are uniform, and there will be no collapse, bubbles, looseness, shrinkage and other phenomena.

[0038] 2. The product has good solubility, dissolves quickly in water, has high purity and good stability.

[0039] 3. The product has no visible foreign matter, low content of related substances, and good impurity control effect. DETAILED DESCRIPTION

[0040] After extensive and in-depth research, the inventors have developed a BPA freeze-dried preparation and preparation method, including a liquid preparation process and a freeze-drying process. In the freeze-drying process, optimized process parameters are used to avoid the adverse effects of incomplete water removal and poor temperature control on the product form during the freeze-drying process to a great extent. The preparation has good stability and low impurity content. On this basis, the present invention was completed.

[0041] The present invention is further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. On the basis of a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0042] Example 1

[0043] Preparation of BPA solution:

[0044] (1) Add 1.0 kg BPA, 1.1-1.3 kg fructose and an appropriate amount of water for injection into the preparation tank, rinse the containers containing BPA and fructose with water three times, transfer the rinsed water to the preparation tank, and stir for 10 minutes;

[0045] (2) adding sodium hydroxide solution to the liquid preparation tank to dissolve BPA and stirring until the solution is clear;

[0046] (3) Add hydrochloric acid solution to adjust the pH value of the solution to 7.6.

[0047] To investigate whether the solution is stable after being adjusted with hydrochloric acid, the added hydrochloric acid is adjusted to different pH values ​​close to the physiological pH value, and the experimental results of observing whether the solution has precipitation after 48 hours under the condition of pH = 7.3-8.5 are shown in Table 1. In addition, the pH values ​​under the conditions of pH = 7.6, 8.0, and 8.5, as shown in Table 2, did not change significantly within 24 hours.

[0048] Table 1 48-hour precipitation of solutions under different pH conditions

[0049]

[0050]

[0051] Table 2 Changes in pH value of solutions under different pH conditions within 24 hours

[0052]

[0053] Example 2

[0054] The BPA solution was freeze-dried under the following conditions to obtain a BPA freeze-dried preparation:

[0055] (1) Pre-freezing process: cool the sample to -20℃~-60℃ for 5-15 hours to completely freeze the sample.

[0056] (2) Sublimation process: Heat to -15℃~-35℃, maintain vacuum 10-11Pa, and continue for 30-55 hours.

[0057] (3) Drying process: Heat the partition to 0℃~40℃ and maintain it for 4-10 hours. The vacuum is maintained at 10-11Pa during the whole drying process.

[0058] As shown in Table 3, after the freeze-dried sample was reconstituted with water to prepare a solution and placed at room temperature for 24 hours, the pH, clarity, transmittance, and content determination results did not change significantly. The solution of this product had good stability after being placed at room temperature for 24 hours after preparation.

[0059] Table 3 Stability of solution after reconstitution of freeze-dried samples

[0060]

[0061]

[0062] Example 3

[0063] like Figure 1 As shown in the figure, the production process of BPA freeze-dried preparations includes: ① preparation process; ② filling process; ③ freeze-drying process; ④ unpacking and capping process; ⑤ packaging process. The detailed process description is as follows:

[0064] ① Preparation process

[0065] Add water for injection into the liquid tank, add the prescribed amount of BPA and auxiliary materials, add sodium hydroxide solution, rinse the containers containing auxiliary materials and sodium hydroxide solution with water for injection respectively and transfer them to the liquid preparation tank. Stir until the solution is clear. Adjust the pH, add the remaining water for injection, stir well, detect the intermediate, and filter. The auxiliary material is the polyol described in the present invention.

[0066] ②Filling process

[0067] Adjust the filling volume according to the intermediate content, fill, half-stopper, and put into the freeze-drying box.

[0068] ③ Freeze drying process

[0069] It includes: pre-freezing stage, sublimation stage and analytical drying stage.

[0070] ④ Unpacking and capping process

[0071] Unpacking: Semi-finished products are placed under the protection of Class 100 laminar flow, and defective products such as missing plugs, displacement of plugs, and broken bottles are picked out and scrapped. Capping: Samples are taken before, during, and after production to test their appearance.

[0072] ⑤Packing process

[0073] Labeling, boxing, packing and warehousing.

[0074] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a lyophilized 4-boric acid-phenylalanine preparation, characterized in that: It includes a liquid preparation process and a freeze-drying process; wherein, The preparation process includes: (1) dissolving BPA and fructose in an aqueous solution by using an alkali to obtain a clear solution; (2) adjusting the clear solution to pH 7.5 < pH ≤ 8.5 by using an acid to obtain a BPA solution; the weight ratio of BPA to fructose is 1:1 to 1.3; The freeze-drying process includes: (3) packaging the BPA solution and freeze-drying it under a vacuum degree of 10 to 20 Pa to obtain the freeze-dried preparation; Wherein, the freeze-drying process further comprises: Pre-freezing process, the temperature of the pre-freezing process is -20°C to -60°C; the time of the pre-freezing process is 5-15 hours; Sublimation process, the temperature of the sublimation process is -15°C to -35°C; the time of the sublimation process is 30-55 hours; The drying process is carried out at a temperature of 0°C to 40°C and lasts for 4 to 10 hours.

2. The method according to claim 1, characterized in that The temperature of any solution during the solution preparation process is controlled to be no higher than 60°C.

3. The method according to claim 2, characterized in that The temperature is 18~50℃.

4. The method according to claim 2, characterized in that The temperature is 18~40°C.

5. The method according to claim 1, characterized in that The weight ratio of BPA to fructose is 1:1.1-1.

25.

6. The method according to claim 1, characterized in that In the solution preparation process, BPA and fructose are dissolved in the aqueous solution by alkali to obtain a clear solution, and the pH value of the clear solution is 8.5-9.

5.

7. The method according to claim 1, characterized in that The alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide.

8. The method according to claim 1, characterized in that The base is sodium hydroxide.

9. The method according to claim 1, characterized in that During the solution preparation process, the clear solution is adjusted to a pH value of 7.6-8.1 by acid adjustment.

10. The method according to claim 1, characterized in that The acid is hydrochloric acid.

11. The method according to claim 1, characterized in that The freeze-drying process takes 39-80 hours.

12. The method according to claim 1, characterized in that The vacuum degree of the freeze drying is 10~11Pa.

13. The method according to claim 1, characterized in that It includes a liquid preparation process and a freeze-drying process; wherein, The liquid preparation process includes: (1) dissolving BPA and fructose in an aqueous solution by a sodium hydroxide solution to obtain a clear solution, wherein the weight ratio of BPA to fructose is 1:1-1.3; (2) adjusting the clear solution to 7.5 < pH ≤ 8.5 by a hydrochloric acid solution to obtain a BPA solution; The BPA solution was freeze-dried under the following conditions to obtain a BPA freeze-dried preparation: Pre-freezing process: The temperature of the pre-freezing process is -20°C~-60°C and lasts for 5-15 hours; Sublimation process: The temperature of the sublimation process is -15°C~-35°C, the vacuum is maintained at 10-11Pa, and it lasts for 30-55 hours; Desorption and drying process: The temperature of the desorption and drying process is 0°C~40°C, and the vacuum is maintained at 10-11Pa for 4-10 hours.

14. A lyophilized 4-boric acid-phenylalanine preparation prepared by the method of any one of claims 1 to 13.

15. A composition, characterized in that The composition comprises the lyophilized 4-boronic acid-phenylalanine preparation according to claim 14.

16. A kit, characterized in that: The kit contains the lyophilized 4-boronic acid-phenylalanine preparation according to claim 14.

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