Compound oral preparation containing m-BPA and metronidazole as well as preparation method and application of compound oral preparation

Abstract

The invention relates to the technical field of medical medicines, in particular to a compound oral preparation containing m-BPA and metronidazole as well as a preparation method and application of the compound oral preparation. The compound oral preparation comprises a medicine core and a coating completely coating the medicine core, wherein the medicine core is prepared from the following raw materials in parts by weight: 600 parts of m-BPA, 150 to 300 parts of metronidazole, 135 to 150 parts of microcrystalline cellulose, 25 to 35 parts of hydroxypropyl methylcellulose, 15 to 20 parts of polyvinylpolypyrrolidone, 2.5 to 3.5 parts of vitamin C and 15 to 17 parts of magnesium stearate. The compound oral enteric-coated granule taking m-boron phenylalanine as a boron source and metronidazole as a hypoxic sensitizer is suitable for BNCT synergistic treatment of LAT1 high-expression hypoxic solid tumors (head and neck tumors, melanoma and pancreatic cancer), and can realize a simplified treatment process of'single oral administration + neutron irradiation '; the boron drug and the sensitizer are ensured to synchronously reach the peak, and the hypoxic tumor cells are synergistically killed.

Description

Technical Field

[0001] This invention relates to the field of medical pharmaceutical technology, and in particular to compound oral preparations containing m-BPA and metronidazole, their preparation methods and applications. Background Technology

[0002] BNCT involves injecting a non-toxic boron-10 drug with tumor-promoting properties into the patient's bloodstream. After the boron-10 drug automatically targets and accumulates in the nuclei of cancer cells, the tumor site is irradiated with a superthermal neutron beam. The body's own slowing process generates thermal neutrons in the treatment area. Due to the high nuclear reaction cross-section (3840 target) between thermal neutrons and boron-10, selective thermal neutron-boron-10 nuclear reactions release radiation with a range shorter than the cancer cells and a high linear energy transfer density (LET) (e.g., alpha particles). 7 Li heavy ions generate high-density ionization energy per unit distance, causing the DNA double strand to be broken simultaneously. Its function is the same as the ionization density caused by heavy ions, thereby achieving high relative biological effect (RBE) particles to kill cancer cells. The treatment process basically does not damage the normal cells around the cancer cells. It is a radiotherapy mode with automatic selection of boron-10 drugs by thermal neutrons, high LET energy transfer and biological targeting enhancement.

[0003] More than 50% of solid tumors contain hypoxic regions (oxygen partial pressure <10 mmHg). Cells in these regions have reduced sensitivity to neutron irradiation, resulting in a single BNCT killing rate of <60%. Hypoxia sensitizers can enhance radiation sensitivity by inhibiting DNA repair in hypoxic cells. Current BNCT treatments rely on single boron drugs or a combination of boron drugs and sensitizers, which have the following limitations:

[0004] (1) Defects of single boron drugs: m-boronophenylalanine (m-BPA, i.e. 3-Borono-L-Phenylalanine) has a water solubility of 125±12g / L, which is more than 100 times that of para-boronophenylalanine (4-BPA). It does not require solubilization and has excellent LAT1 targeting. However, when used alone, it cannot overcome the radiation resistance of hypoxic cells and has insufficient killing effect in hypoxic areas.

[0005] (2) Deficiencies of combined medication: The existing regimen requires separate oral / injection of boron drugs and sensitizers (such as metronidazole, misonitroazole, nicotinamide), which have problems such as difficulty in controlling the dosage ratio (patients are prone to deviation when administering the medication themselves), easy misalignment of the administration sequence (sensitizers need to be present in cells during irradiation, so sensitizers need to be synchronized with the tumor peak of boron drugs), and poor patient compliance (multiple administrations).

[0006] (3) Formulation gap: There is no compound formulation of "boron drug + hypoxia sensitizer" designed for BNCT, which cannot solve the three core problems of "dose synergy, release synchronization and administration convenience" in combination therapy, thus limiting the large-scale clinical application of BNCT. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide a compound oral preparation containing m-BPA and metronidazole, and its preparation method and application, so as to at least solve the problems of unstable synergy and complicated administration of existing BNCT treatments that rely on single boron drugs or "boron drugs + sensitizers".

[0008] 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 can be described in more detail in other parts of this disclosure.

[0009] The present invention solves the above-mentioned technical problems through the following technical means:

[0010] A first aspect of the present invention provides a compound oral preparation containing m-BPA and metronidazole, wherein the compound oral preparation is an enteric-coated granule, the compound oral preparation comprising a core and a coating that completely encapsulates the core, the core comprising the following raw materials in parts by weight: 600 parts m-BPA, 150-300 parts metronidazole, 135-150 parts microcrystalline cellulose, 25-35 parts hydroxypropyl methylcellulose, 15-20 parts crospovidone, 2.5-3.5 parts vitamin C, and 15-17 parts magnesium stearate.

[0011] Furthermore, the mass ratio of m-BPA to metronidazole is (2-4):1.

[0012] Furthermore, the raw material for the coating is acrylic resin L100, and the weight gain of the coating is 8% to 10% of the core mass.

[0013] Furthermore, each gram of the compound oral preparation comprises the following ingredients: m-BPA 600mg, metronidazole 200mg, microcrystalline cellulose 145mg, hydroxypropyl methylcellulose 30mg, crospovidone 18mg, vitamin C 3mg, magnesium stearate 16mg, and acrylic resin L100 48mg.

[0014] A second aspect of the present invention provides a method for preparing a compound oral formulation containing m-BPA and metronidazole, comprising the following steps:

[0015] Weigh out m-BPA, metronidazole, microcrystalline cellulose, hydroxypropyl methylcellulose, crospovidone, vitamin C, magnesium stearate, and acrylic resin L100 respectively. Pass m-BPA and metronidazole through a 100-mesh sieve respectively.

[0016] m-BPA, half of the microcrystalline cellulose, and hydroxypropyl methylcellulose were mixed and then wet-granulated with water for the first time. The resulting granules were dried at 28-35℃ to obtain the first active granules.

[0017] Metronidazole, the remaining half of the microcrystalline cellulose, crospovidone, and vitamin C were mixed, and then wet granulated with water for the second time. After drying, the second active granules were obtained.

[0018] The first active granules and the second active granules are mixed, and the resulting core granules are placed in a fluidized bed coating machine to be coated with acrylic resin L100 coating liquid. The coating weight gain is controlled at 8% to 10%. The resulting enteric granules are packaged into aluminum-plastic composite bags, sealed, and stored away from light.

[0019] Furthermore, the compound oral preparation comprises the following raw materials in parts by weight: 600 parts m-BPA, 150-300 parts metronidazole, 135-150 parts microcrystalline cellulose, 25-35 parts hydroxypropyl methylcellulose, 15-20 parts crospovidone, 2.5-3.5 parts vitamin C, 15-17 parts magnesium stearate, and 45-50 parts acrylic resin L100.

[0020] Furthermore, the amount of water added in the first wet granulation is 28% to 32% of the total mass of the mixture of m-BPA, microcrystalline cellulose, and hydroxypropyl methylcellulose, and the amount of water added in the second wet granulation is 23% to 28% of the total mass of the mixture of metronidazole, microcrystalline cellulose, crospovidone, and vitamin C.

[0021] Furthermore, when the first active particles and the second active particles are mixed, the overall mixing uniformity RSD needs to be controlled to be ≤3%.

[0022] Furthermore, the mass concentration of acrylic resin L100 in the acrylic resin L100 coating solution is 13% to 16%, and the temperature of the coating operation is controlled at 32 to 36°C.

[0023] The third aspect of the present invention provides the use of the compound oral formulation containing m-BPA and metronidazole as described in the first aspect, or the compound oral formulation prepared by the preparation method described in the second aspect, in the preparation of a boron neutron capture therapy for tumors.

[0024] The present invention relates to a compound oral formulation containing m-BPA and metronidazole, which is a compound oral enteric-coated granule with m-boron phenylalanine as the boron source and metronidazole as the hypoxia sensitizer. It is suitable for BNCT synergistic treatment of hypoxic solid tumors (head and neck tumors, melanoma, pancreatic cancer) with high LAT1 expression. It can realize a simplified treatment process of "single oral administration + neutron irradiation" and ensure that the boron drug and the sensitizer reach their peak simultaneously and synergistically kill hypoxic tumor cells. Metronidazole enters the hypoxic region of the tumor via passive diffusion, is reduced to its active metabolites, inhibits DNA repair enzymes, and does not affect LAT1 transport. It does not interact with m-BPA, which is transported to tumor cells (including hypoxic regions) via LAT1. The concentration ratio of metronidazole to m-BPA at the tumor site is stable (1:0.29), with a stable synergistic index (CI) ≤0.65. α particles and Li nuclei precisely kill hypoxic cells while avoiding damage to normal tissues (m-BPA targeting + low toxicity of metronidazole, normal tissue damage rate ≤4.3%).

[0025] The oral compound preparation of the present invention containing m-BPA and metronidazole can be administered in outpatient settings without the need for medical personnel to guide the dosing sequence; it also exhibits good stability (content decay ≤3%) after 6 months of storage at 4°C, making it suitable for clinical stockpiling; the damage rate to normal tissues (skin, kidneys) is 4.1±0.5% (no statistical difference compared to the combined drug group of 4.3±0.6%, p>0.05); after screening for gastrointestinal irritation, the enteric coating reduces the irritation of metronidazole to the gastric mucosa, with no new side effects (such as gastrointestinal irritation or neurotoxicity), which meets the low toxicity characteristics of metronidazole. Detailed Implementation

[0026] 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.

[0027] 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.

[0028] To address the shortcomings of existing combination therapies, such as unstable synergy, complex administration, and unsystematic formulation screening, this application proposes a compound oral formulation containing m-BPA and metronidazole, and its preparation method, based on the pharmacokinetic characteristics of m-BPA and metronidazole (m-BPA reaches peak concentration 2 hours after oral administration, metronidazole reaches peak concentration 1-2 hours after oral administration) and screening data of synergistic treatment regimens. Based on the principles of "fixed dose, synchronized release, convenient administration, and controllable quality," this application uses enteric-coated granules (avoiding gastric acid destruction and reducing gastrointestinal irritation). Through "systematic screening of active ingredients + optimized screening of excipients + verification of process parameters," it ensures that m-BPA and metronidazole dissolve and are transported to the tumor site simultaneously in vivo, with precise dosage ratios (optimal dose based on synergistic treatment regimen optimization: 300 mg / kg m-BPA corresponds to 500 mg / m² metronidazole).

[0029] Specifically, the compound oral preparation containing m-BPA and metronidazole of this application includes a drug core and a coating that completely encapsulates the drug core. The drug core comprises the following raw materials in parts by weight: 600 parts m-BPA, 150-300 parts metronidazole, 135-150 parts microcrystalline cellulose, 25-35 parts hydroxypropyl methylcellulose, 15-20 parts crospovidone, 2.5-3.5 parts vitamin C, and 15-17 parts magnesium stearate. The mass ratio of m-BPA to metronidazole is (2-4):1. The raw material for the coating is acrylic resin L100, and the coating weight gain is 8%-10% of the drug core mass.

[0030] In the compound oral formulation of this application, m-BPA serves as the active ingredient, providing 10B atoms to target tumor cells; metronidazole acts as a hypoxia sensitizer, enhancing hypoxia sensitivity and inhibiting DNA repair; microcrystalline cellulose acts as a filler, improving flowability without affecting dissolution; hydroxypropyl methylcellulose acts as a binder, ensuring particle formation without dissolution interference; L100 acrylic resin acts as an enteric coating for targeted release into the intestine; crospovidone acts as a disintegrant, promoting simultaneous dissolution; vitamin C acts as a stabilizer, preventing oxidative degradation of m-BPA without affecting the activity of metronidazole; and magnesium stearate acts as a lubricant, preventing tablet / bag adhesion and ensuring no interference with content uniformity.

[0031] The following examples 1-3 provide a detailed description of the compound oral preparations containing m-BPA and metronidazole of this application, their preparation methods, and applications:

[0032] Example 1

[0033] The preparation method of the compound oral preparation containing m-BPA and metronidazole in this embodiment is as follows:

[0034] (1) Weigh out 600 g of m-BPA, 200 g of metronidazole, 145 g of microcrystalline cellulose, 30 g of hydroxypropyl methylcellulose, 18 g of crospovidone, 3 g of vitamin C, 16 g of magnesium stearate and 48 g of acrylic resin L100. Pass m-BPA and metronidazole through a 100-mesh sieve.

[0035] (2) Mix m-BPA, 72.5g microcrystalline cellulose and hydroxypropyl methylcellulose, add 30% pure water (211g) of the total mass of the mixture of m-BPA, microcrystalline cellulose and hydroxypropyl methylcellulose, wet granulate, and dry the resulting granules at 30℃ to obtain the first active granules.

[0036] (3) Mix metronidazole, 72.5g microcrystalline cellulose, crospovidone and vitamin C, add 25% of the total mass of the mixture of metronidazole, microcrystalline cellulose, crospovidone and vitamin C in pure water (78g), wet granulation, and dry the resulting granules at 30℃ to obtain the second active granules.

[0037] (4) Mix the first active granules with the second active granules, control the total mixing uniformity RSD≤3%, put the obtained core granules into a fluidized bed coating machine, spray 15wt% acrylic resin L100 coating solution at a coating temperature of 35℃ for coating, control the coating weight gain to 8%, and the obtained enteric granules are packaged into aluminum-plastic composite bags according to the specification of 2.4g / bag, each bag contains 1.8g m-BPA and 0.6g metronidazole, suitable for a single dose for 60kg adults, and stored at 4℃ after sealing.

[0038] Example 2

[0039] The preparation method of the compound oral preparation containing m-BPA and metronidazole in this embodiment is as follows:

[0040] (1) Weigh out 600 g of m-BPA, 300 g of metronidazole, 150 g of microcrystalline cellulose, 35 g of hydroxypropyl methylcellulose, 20 g of crospovidone, 3.5 g of vitamin C, 17 g of magnesium stearate, and 50 g of acrylic resin L100. Pass m-BPA and metronidazole through a 100-mesh sieve.

[0041] (2) Mix m-BPA, 150g microcrystalline cellulose and hydroxypropyl methylcellulose, add 32% pure water (252g) of the total mass of the mixture of m-BPA, microcrystalline cellulose and hydroxypropyl methylcellulose, wet granulate, and dry the resulting granules at 35℃ to obtain the first active granules.

[0042] (3) Mix metronidazole, 150g microcrystalline cellulose, crospovidone and vitamin C, add 28% of the total mass of the mixture of metronidazole, microcrystalline cellulose, crospovidone and vitamin C in pure water (138g), wet granulation, and dry the resulting granules at 35℃ to obtain the second active granules.

[0043] (4) Mix the first active granules with the second active granules, control the total mixing uniformity RSD≤3%, put the obtained core granules into a fluidized bed coating machine, spray 16wt% acrylic resin L100 coating solution at a coating temperature of 36℃ for coating, control the coating weight gain to 10%, and the obtained enteric granules are packaged into aluminum-plastic composite bags according to the specification of 2.4g / bag, each bag contains 1.8g m-BPA and 0.6g metronidazole, suitable for a single dose for 60kg adults, and stored at 4℃ after sealing.

[0044] Example 3

[0045] The preparation method of the compound oral preparation containing m-BPA and metronidazole in this embodiment is as follows:

[0046] (1) Weigh out 600 g of m-BPA, 150 g of metronidazole, 135 g of microcrystalline cellulose, 25 g of hydroxypropyl methylcellulose, 15 g of crospovidone, 2.5 g of vitamin C, 15 g of magnesium stearate, and 45 g of acrylic resin L100. Pass m-BPA and metronidazole through a 100-mesh sieve.

[0047] (2) Mix m-BPA, 67.5g microcrystalline cellulose and hydroxypropyl methylcellulose, add 28% pure water (194g) of the total mass of the mixture of m-BPA, microcrystalline cellulose and hydroxypropyl methylcellulose, wet granulate, and dry the resulting particles at 28℃ to obtain the first active particles.

[0048] (3) Mix metronidazole, 67.5g microcrystalline cellulose, crospovidone, and vitamin C. Add 23% of the total mass of the mixture of metronidazole, microcrystalline cellulose, crospovidone, and vitamin C in pure water (68g). Perform wet granulation and dry the resulting granules at 28°C to obtain the second active granules.

[0049] (4) Mix the first active granules with the second active granules, control the total mixing uniformity RSD≤3%, put the obtained core granules into a fluidized bed coating machine, spray 13wt% acrylic resin L100 coating liquid at a coating temperature of 32℃ for coating, control the coating weight gain to 9%, and the obtained enteric granules are packaged into aluminum-plastic composite bags according to the specification of 2.4g / bag, each bag contains 1.8g m-BPA and 0.6g metronidazole, suitable for a single dose for 60kg adults, and stored at 4℃ after sealing.

[0050] The synergistic effect verification test of the compound oral formulation containing m-BPA and metronidazole in this application is as follows:

[0051] (I) Using B16F10 hypoxic melanoma-bearing mice (n=6) as the experimental model, with the hypoxic region accounting for 35%, a single oral administration of the compound oral preparation of Example 1 was administered. The dosage, converted according to body weight, was: m-BPA 300mg / kg and metronidazole 100mg / kg. Six hours later, neutron irradiation (20Gy) was performed, and the tumor boron concentration and metronidazole concentration were detected. The detection results are as follows:

[0052] ① Tumor boron concentration: 28.5±2.3μg / g during irradiation (meeting the threshold of ≥20μg / g);

[0053] ②Metronidazole concentration for tumors: 8.2±0.6μg / g (concentration ratio 1:0.29, matching in vivo synergistic requirements);

[0054] ③ Kill rate in hypoxic areas: 83.2±2.1%;

[0055] ④ Synergy Index (CI): 0.62 (stable);

[0056] ⑤ Tumor inhibition rate at 14 days: 90.1±3.8% (89.5±4.1% in the combination therapy group).

[0057] (II) The compound oral preparation of Example 1 was compared with the combination therapy of "boron drug + sensitizer" in accordance with the method in (I). The comparison results are shown in Table 1:

[0058] Table 1

[0059] index Compound preparation group (n=10) Combination therapy group (n=10) Difference (p-value) Tumor m-BPA concentration (μg / g) 28.5±2.3 27.8±3.1 ＞0.05 Tumor metronidazole concentration (μg / g) 8.2±0.6 7.5±1.2 ＜0.05 Concentration fluctuation (%) 3.2±1.1 12.5±3.8 ＜0.01 Synergy Index (CI) 0.62±0.03 0.71±0.08 ＜0.01

[0060] (III) The amount of metronidazole in Example 1 was replaced with 300g (corresponding to a mass ratio of m-BPA to metronidazole of 2:1) and 150g (corresponding to a mass ratio of m-BPA to metronidazole of 4:1), while the other raw materials and conditions remained unchanged. The synergistic effect of different m-BPA and metronidazole ratios was studied in accordance with the method in (I). The final test results are shown in Table 2.

[0061] Table 2

[0062] Ratio (m-BPA: metronidazole) Tumor boron concentration (μg / g) Kill rate in hypoxic areas (%) Synergy Index (CI) Normal tissue damage rate (%) 2:1 25.3±2.1 76.5±3.2 0.78 4.0±0.4 3:1 (optimal) 28.6±3.2 83.2±3.5 0.62 4.3±0.6 4:1 31.2±2.8 84.1±3.1 0.68 8.7±1.2

[0063] The data in Table 2 show that a mass ratio of m-BPA to metronidazole of 3:1 can ensure a high kill rate while minimizing damage to normal tissues.

[0064] (iv) The coating material L100 acrylic resin in Example 1 was replaced with acrylic resin S100 and shellac, while the other raw materials and conditions remained unchanged. The dissolution synchronicity of different enteric coating materials was studied in accordance with the method in (i). The final test results are shown in Table 3:

[0065] Table 3

[0066] Coating material pH 1.2 Dissolution rate (%) pH 6.8 Dissolution (m-BPA / metronidazole) Dissolution synchronicity (difference %) Stability (content decay % over 6 months) Acrylic resin L100 ≤5 85.2% / 82.0% 3.2 2.8 Acrylic resin S100 ≤5 83.5% / 76.0% 7.5 3.1 shellac ≤8 80.3% / 71.1% 9.2 4.5

[0067] The data in Table 3 show that when acrylic resin L100 is used as a coating material, it exhibits the best dissolution synchronization and low gastric dissolution, which meets the requirements for targeted release into the intestine.

[0068] (v) The vitamin C in Example 1 was replaced with sodium bisulfite and propyl gallate, respectively, while the other raw materials and conditions remained unchanged. The effects of different stabilizers were studied, and the final test results are shown in Table 4:

[0069] Table 4

[0070] stabilizer type Dosage (percentage) 40℃ / 75% RH accelerated 3 months m-BPA oxidation product limit (%) Effect on the stability of metronidazole in conclusion Vitamin C 0.5% Content decrease of 2.1% ≤0.5 No impact Optimal Sodium bisulfite 0.5% Content decreased by 2.3%. ≤0.6 Slight degradation (1.2%) Affecting the stability of metronidazole propyl gallate 0.5% Content decreases by 3.5%. ≤0.8 No impact Poor stability

[0071] The data in Table 4 indicate that vitamin C is the preferred stabilizer for the compound oral formulation of this application.

[0072] (vi) The effects of different disintegrants were studied by replacing crospovidone in Example 1 with sodium carboxymethyl starch and sodium crospovidone carboxymethyl cellulose, respectively, while keeping the other raw materials and conditions unchanged. The final test results are shown in Table 5:

[0073] Table 5

[0074] Disintegrant type Dosage (percentage) Dissolution rate at 30 min (m-BPA / metronidazole) Dissolution synchronicity (difference %) Particle flowability (angle of repose) in conclusion Cross-linked polyvinylpyrrolidone 3% 85.2% / 82.0% 3.2 ≤30° Optimal Sodium carboxymethyl starch 3% 81.5% / 78.3% 3.2 ≤32° Poor liquidity Cross-linked carboxymethyl cellulose sodium 3% 83.1% / 79.5% 3.6 ≤31° Slightly poor synchronization

[0075] The data in Table 5 indicate that crospovidone is the most preferred disintegrant for the compound oral formulation of this application.

[0076] In summary, the oral compound formulation containing m-BPA and metronidazole of this application can be used as a boron neutron capture therapy drug for tumor treatment.

[0077] 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.

[0078] 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. A compound oral preparation containing m-BPA and metronidazole, characterized in that, The compound oral preparation is an enteric-coated granule, comprising a core and a coating that completely encapsulates the core. The core comprises the following raw materials in parts by weight: m-BPA 600 parts, metronidazole 150-300 parts, microcrystalline cellulose 135-150 parts, hydroxypropyl methylcellulose 25-35 parts, crospovidone 15-20 parts, vitamin C 2.5-3.5 parts, magnesium stearate 15-17 parts.

2. The compound oral preparation containing m-BPA and metronidazole according to claim 1, characterized in that, The mass ratio of m-BPA to metronidazole is (2-4):

1.

3. The compound oral preparation containing m-BPA and metronidazole according to claim 1, characterized in that, The raw material for the coating is acrylic resin L100, and the weight gain of the coating is 8% to 10% of the core mass.

4. The compound oral preparation containing m-BPA and metronidazole according to claim 3, characterized in that, Each gram of the compound oral preparation comprises the following ingredients: m-BPA 600mg, metronidazole 200mg, microcrystalline cellulose 145mg, hydroxypropyl methylcellulose 30mg, crospovidone 18mg, vitamin C 3mg, magnesium stearate 16mg, acrylic resin L100 48mg.

5. A method for preparing a compound oral preparation containing m-BPA and metronidazole, characterized in that, Includes the following steps: Weigh out m-BPA, metronidazole, microcrystalline cellulose, hydroxypropyl methylcellulose, crospovidone, vitamin C, magnesium stearate, and acrylic resin L100 respectively. Pass m-BPA and metronidazole through a 100-mesh sieve respectively. m-BPA, half of the microcrystalline cellulose, and hydroxypropyl methylcellulose were mixed and then wet-granulated with water for the first time. The resulting granules were dried at 28-35℃ to obtain the first active granules. Metronidazole, the remaining half of the microcrystalline cellulose, crospovidone, and vitamin C were mixed, and then wet granulated with water for the second time. After drying, the second active granules were obtained. The first active granules and the second active granules are mixed, and the resulting core granules are placed in a fluidized bed coating machine to be coated with acrylic resin L100 coating liquid. The coating weight gain is controlled at 8% to 10%. The resulting enteric granules are packaged into aluminum-plastic composite bags, sealed, and stored away from light.

6. The preparation method according to claim 5, characterized in that, The compound oral preparation comprises the following raw materials in parts by weight: m-BPA 600 parts, metronidazole 150-300 parts, microcrystalline cellulose 135-150 parts, hydroxypropyl methylcellulose 25-35 parts, crospovidone 15-20 parts, vitamin C 2.5-3.5 parts, magnesium stearate 15-17 parts, and acrylic resin L100 45-50 parts.

7. The preparation method according to claim 5, characterized in that, The amount of water added in the first wet granulation process is 28% to 32% of the total mass of the mixture of m-BPA, microcrystalline cellulose, and hydroxypropyl methylcellulose. The amount of water added in the second wet granulation process is 23% to 28% of the total mass of the mixture of metronidazole, microcrystalline cellulose, crospovidone, and vitamin C.

8. The preparation method according to claim 5, characterized in that, When the first active particles and the second active particles are mixed, the overall mixing uniformity RSD must be controlled to be ≤3%.

9. The preparation method according to claim 5, characterized in that, The mass concentration of acrylic resin L100 in the coating solution is 13% to 16%, and the temperature of the coating operation is controlled at 32 to 36°C.

10. The use of the compound oral preparation containing m-BPA and metronidazole according to any one of claims 1-4, or the compound oral preparation prepared by the preparation method according to any one of claims 5-9, in the preparation of a boron neutron capture therapy for tumors.