Enteric-coated granules containing m-boron phenylalanine as well as preparation method and application of enteric-coated granules

Abstract

The invention relates to the technical field of medical pharmaceutical preparations, in particular to enteric-coated granules containing m-boron phenylalanine as well as a preparation method and application of the enteric-coated granules. The enteric granule comprises a medicine core and a coating completely coating the medicine core, wherein the medicine core comprises the following raw materials in parts by weight: 500 parts of m-BPA, 280-320 parts of microcrystalline cellulose, 45-55 parts of HPMC K15M and 8-12 parts of lauryl sodium sulfate; the coating comprises the following raw materials in parts by weight: 70-90 parts of acrylic resin IV and 7-9 parts of glyceryl triacetate. According to the enteric-coated granules, solubilizers such as sorbitol / fructose do not need to be added, venipuncture is not needed during oral administration, the curative effect meets the BNCT requirement, the technical problems that an existing BNCT boron medicine vein preparation is poor in compliance and many in side effect are solved, and the preparation method is simple and easy to implement.

Description

Technical Field

[0001] This invention relates to the field of medical pharmaceutical formulation technology, and in particular to enteric-coated granules containing m-boron phenylalanine, their preparation methods and applications. Background Technology

[0002] BNCT is the most advanced cancer radiotherapy method to date. It involves injecting a non-toxic boron-10 drug with a tumor-adaptive effect into the patient's bloodstream. After the boron-10 drug automatically accumulates in the nuclei of cancer cells, a superthermal neutron beam irradiates the tumor site. The body's own slowing effect further 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] The key to BNCT lies in enriching boron-10-containing drugs in the nuclei of cancer cells. Currently, p-boron phenylalanine (4-BPA) is commonly used clinically, and its structure is as follows: Figure 2 As shown, 4-BPA is used as a boron drug in BNCT, but its water solubility at room temperature is only 0.72±0.13g / L, requiring the addition of sorbitol as a solubilizer. However, the addition of sorbitol can cause hypoglycemia and liver and kidney damage in patients with hereditary fructose intolerance. In addition, oral administration of 4-BPA may cause 4-BPA crystals in the urine, leading to hematuria. It can only be administered via intravenous drip, requiring patients to stay in bed for 2-4 hours, resulting in poor compliance.

[0004] m-Boronphenylalanine (m-BPA), as the meta-isomer of 4-BPA, has the following chemical structural formula: Figure 1As shown, its pKa1=2.26, pKa2=8.46, and pKa3=9.95, exhibiting good stability at neutral pH. In vivo, it accumulates in tumor cells via LAT1 transport. In melanoma-bearing hamster experiments, the peak tumor boron concentration of m-BPA reached 6.4±1.0 ppm, with no significant accumulation in normal tissues. Furthermore, its water solubility at approximately 25°C is 125±12 g / L, more than 100 times that of 4-BPA. m-BPA, as a boron drug for BNCT, can be prepared into a dosing solution without solubilization, and its tumor targeting is comparable to 4-BPA. However, currently, only intravenous administration of m-BPA has been reported. Intravenous administration is difficult for elderly patients and children with poor vascular conditions to tolerate, and it cannot be used for home treatment or rapid outpatient administration. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide enteric-coated granules containing m-boronylphenylalanine, their preparation method and application, so as to at least solve the problem that existing m-BPA relies solely on intravenous administration, which limits the target population. 10 The problem of achieving the required concentration of BCNT in tumor cells by boron atoms.

[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 enteric-coated granule containing m-boron phenylalanine, the enteric-coated granule comprising a core and a coating that completely encapsulates the core, the core comprising the following raw materials in parts by weight: 500 parts m-BPA, 280-320 parts microcrystalline cellulose, 45-55 parts HPMC K15M, and 8-12 parts sodium dodecyl sulfate.

[0008] In conjunction with the first aspect, in some embodiments, the purity of the m-BPA is ≥99.0%.

[0009] In conjunction with the first aspect, in some embodiments, the coating comprises the following raw materials in parts by weight: 70-90 parts of acrylic resin IV and 7-9 parts of triacetyl ester.

[0010] In conjunction with the first aspect, in some embodiments, the enteric-coated granules comprise the following raw materials in parts by weight: 500 parts m-BPA, 300 parts microcrystalline cellulose, 50 parts HPMC K15M, 10 parts sodium dodecyl sulfate, 80 parts acrylic resin IV, and 8 parts triacetyl ester.

[0011] Secondly, embodiments of the present invention provide a method for preparing enteric-coated granules containing m-boron phenylalanine, comprising the following steps:

[0012] m-BPA, microcrystalline cellulose and HPMC K15M were sieved through an 80-mesh sieve and set aside for later use.

[0013] The sieved m-BPA, microcrystalline cellulose and HPMC K15M were mixed and stirred at 150-200 rpm for 10-15 min. Then, sodium dodecyl sulfate aqueous solution was added, granulated by passing through a 20-mesh sieve, and dried by forced air to obtain 20-40 mesh core particles.

[0014] The drug-coated granules were placed in a fluidized bed coating machine. The operating parameters of the fluidized bed coating machine were set as follows: inlet air temperature 40-50℃, outlet air temperature 35-40℃, spray rate 3-5mL / min, and atomization pressure 0.15-0.25MPa. The coating solution was sprayed onto the surface of the drug-coated granules. The coating weight gain was controlled at 9.0%-10.0%. The resulting enteric granules were packaged into aluminum-plastic composite bags, sealed, and stored away from light.

[0015] In conjunction with the second aspect, in some embodiments, the core particles comprise the following raw materials in parts by weight: 500 parts m-BPA, 280-320 parts microcrystalline cellulose, 45-55 parts HPMC K15M, 8-12 parts sodium dodecyl sulfate, 75-85 parts acrylic resin IV, and 7-9 parts triacetyl ester.

[0016] In conjunction with the second aspect, in some embodiments, the mass concentration of the sodium dodecyl sulfate aqueous solution is 5%.

[0017] In conjunction with the second aspect, in some embodiments, the temperature of the forced-air drying is 55-65°C, the time is 1.5-2.5 hours, and the moisture content of the core particles is controlled at 3.0%-4.0%.

[0018] In conjunction with the second aspect, in some embodiments, the coating solution is an ethanol solution containing acrylic resin IV and triacetin, wherein the mass concentration of acrylic resin IV in the coating solution is 8%, and the mass ratio of acrylic resin IV to triacetin is 10:1.

[0019] Thirdly, the embodiments of the present invention also provide the application of the enteric-coated granules described in the first aspect above, or the enteric-coated granules prepared by the preparation method of the second aspect, in the preparation of boron neutron capture therapy drugs for tumor treatment.

[0020] One or more technical solutions provided in the embodiments of the present invention have at least the following technical effects or advantages:

[0021] (1) Significantly improved safety: The enteric granules containing m-boron phenylalanine of the present invention do not require the addition of solubilizers such as sorbitol / fructose. Long-term toxicity test in mice (350mg / kg, once a day for 14 consecutive days) showed that blood glucose fluctuation was ≤5% (compared to 15%-20% of 4-BPA intravenous preparation), no crystal deposition was found in kidney tissue sections, and liver function indicators (ALT, AST) were normal.

[0022] (2) Improved patient compliance: Oral administration does not require intravenous puncture. Clinical survey (n=50) showed that patient acceptance increased from 42% for intravenous preparations to 89%. The administration can also be completed at home without hospitalization. The treatment time per session was shortened from 6-8 hours for intravenous preparations to 2 hours (including oral administration and imaging), which solved the problem of complicated operation of intravenous preparations.

[0023] (3) The efficacy meets the requirements of BNCT: The experiment verified that the peak value was reached 2 hours after the first administration (Cmax=8.7±1.2μg / mL), and the half-life t 1 / 2 =3.5h; 8h after administration, tumor tissue was digested, and ICP-MS was used to detect boron concentration of 28.6±3.2μg / g, T / S=6.3±0.8, T / P (tumor / plasma)=3.3±0.5, which met the core treatment criteria of "tumor boron concentration ≥20μg / g, T / S≥5";

[0024] (4) The enteric-coated granules containing m-boron phenylalanine prepared in this invention are suitable for patients with LAT1-high expression tumors (such as head and neck squamous cell carcinoma and malignant melanoma), as well as elderly and pediatric patients who cannot tolerate intravenous administration. Attached Figure Description

[0025] Figure 1 It is the chemical structural formula of m-boronylphenylalanine;

[0026] Figure 2 This is the chemical structural formula of p-boronylphenylalanine. 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] The English abbreviations used in this application are defined as follows: HPMC K15M: Hydroxypropyl methylcellulose; SDS: Sodium dodecyl sulfate.

[0030] The enteric-coated granules containing m-boronylphenylalanine of this application, using m-BPA as the active pharmaceutical ingredient, are used to provide... 10 Boolean atoms participate in the BNCT nuclear reaction; microcrystalline cellulose is used as a filler to improve particle flowability and ensure uniform m-BPA content; HPMC K15M is used as a binder to control the release rate and avoid blood drug fluctuations; sodium dodecyl sulfate is used as an absorption enhancer to improve intestinal permeability and increase bioavailability; acrylic resin IV is used as the main coating material for enteric protection to avoid gastric acid degradation; triacetin is used as a plasticizer to improve the flexibility of the coating film and prevent rupture. Specifically, the enteric-coated granules containing m-boronylphenylalanine of this application include a core and a coating that completely encapsulates the core. The core comprises the following raw materials in parts by weight: 500 parts m-BPA, 280-320 parts microcrystalline cellulose, 45-55 parts HPMC K15M, and 8-12 parts sodium dodecyl sulfate. The coating comprises the following raw materials in parts by weight: 70-90 parts acrylic resin IV and 7-9 parts triacetin. The weight gain of the coating is controlled at 9.0%-10.0%. The purity of m-BPA is ≥99.0%.

[0031] The following examples 1-3 will provide a detailed description of the enteric granules containing m-boron phenylalanine and their preparation method. The m-BPA used in the following examples has a purity of 99.2% and a water solubility of 123.5 g / L at 25°C. The microcrystalline cellulose is pharmaceutical grade and was purchased from Shandong Liaocheng Ahua Pharmaceutical Co., Ltd., HPMC K15M was purchased from Dow Chemical, sodium dodecyl sulfate is pharmaceutical grade and was purchased from Sigma-Aldrich, and acrylic resin IV was purchased from Shanghai Carvacrol.

[0032] Example 1

[0033] The preparation method of the enteric granules containing m-boron phenylalanine in this embodiment is as follows:

[0034] Weigh out 500g m-BPA, 300g microcrystalline cellulose, 50g HPMC K15M, and 10g sodium dodecyl sulfate respectively. Sieve m-BPA, microcrystalline cellulose, and HPMC K15M through an 80-mesh sieve for later use.

[0035] The sieved m-BPA, microcrystalline cellulose, and HPMC K15M were added to a three-dimensional mixer (model: SYH-10) and mixed. The mixture was stirred at 150 rpm for 10 min. Then, 200 mL of a 5% sodium dodecyl sulfate aqueous solution was added to prepare a soft mass. The mass was granulated by passing it through a 20-mesh sieve and dried at 60℃ for 2 h to obtain 20-40 mesh core particles. The moisture content of the core particles was controlled at 3.5%. The final mass of the core particles was 580 g, and the calculated yield was 96.7%.

[0036] 500g of drug-core granules were placed in a fluidized bed coating machine (GLATT GPCG 3). The operating parameters of the fluidized bed coating machine were set as follows: inlet air temperature 45℃, outlet air temperature 38℃, spray rate 5mL / min, and atomization pressure 0.2MPa. The coating solution was sprayed onto the surface of the drug-core granules. The coating solution was an ethanol solution containing 8wt% acrylic resin IV and 0.8wt% triacetylglycerol. The coating weight gain was controlled at 9.5%, and 547.5g of enteric-coated granules were obtained. The calculated yield was 98.5%. The enteric-coated granules were dispensed into aluminum-plastic composite bags at a specification of 5g / bag, sealed, and stored away from light.

[0037] The following quality tests were performed on the enteric-coated granules of this embodiment: (1) Dissolution rate: 3.8% dissolved in 2 hours at pH=1.2 and 92.5% dissolved in 45 minutes at pH=6.8; (2) Content: each bag contains 501.2 mg of m-BPA, RSD=1.2%, which meets the content uniformity requirements; (3) Stability: after 6 months of storage at 40℃ / 75% RH, the m-BPA content degraded by 2.2%, the granules did not stick together, and the coating film did not break; (4) Heavy metal residue: Pd≤0.001%, Cu≤0.0005%.

[0038] The microcrystalline cellulose in Example 1 was replaced with lactose and mannitol, respectively, while other raw materials and conditions remained the same. The performance test results of the enteric granules containing m-boron phenylalanine were shown in Table 1.

[0039] Table 1

[0040] filler Particle flowability (angle of repose) Dissolution (pH 6.8 buffer, 45 min) m-BPA content uniformity (RSD) in conclusion microcrystalline cellulose 32.5° 92.3±1.5% 1.2% The optimal choice (non-reducible, avoids reaction with m-BPA, and improves liquidity) lactose 35.8° 88.6±2.1% 1.8% Slightly low dissolution rate, excluded Mannitol 38.2° 85.7±2.4% 2.1% Poor liquidity, excluded

[0041] The data in Table 1 show that microcrystalline cellulose is non-reducing, can avoid reacting with m-BPA, and can improve flowability. Therefore, microcrystalline cellulose is a preferred filler.

[0042] In Example 1, HPMC K15M was replaced with PVP K30 and sodium carboxymethyl starch, respectively. All other raw materials and conditions were the same. The performance test results of the prepared enteric granules containing m-boron phenylalanine are shown in Table 2.

[0043] Table 2

[0044] Adhesive Particle hardness (N) Release rate (t50, pH 6.8) Bioavailability (absolute) in conclusion HPMC K15M 1.8±0.2 22.5±1.3min 46.8±2.9% The optimal choice (slow-release formulation, controlling the slow release of m-BPA to match the LAT1 transport rate) PVP K30 2.5±0.3 15.8±1.1min 41.2±2.5% Too rapid release causes fluctuations in blood drug levels, which should be ruled out. Sodium carboxymethyl starch 1.2±0.1 35.6±1.5min 37.5±2.3% Release is too slow, bioavailability is low, and exclusion is necessary.

[0045] The SDS in Example 1 was replaced with Tween 80 (1%) and sodium cholate (1%), respectively. All other raw materials and conditions were the same. The performance test results of the enteric granules containing m-boron phenylalanine were shown in Table 3.

[0046] Table 3

[0047] Absorption enhancer <![CDATA[Intestinal permeability (Papp, ×10⁻ 6 cm / s)]]> Bioavailability (absolute) Mucosal irritation (rat small intestine) in conclusion SDS (1%) 8.9±0.5 46.8±2.9% No obvious redness or swelling The optimal choice (reducing intestinal mucosal surface tension, increasing transmembrane permeability, and minimizing intestinal irritation). Tween 80 (1%) 6.2±0.3 39.5±2.4% slight redness and swelling Insufficient permeability, exclude Sodium cholate (1%) 7.5±0.4 42.1±2.6% Moderate redness and swelling Highly irritating, excluded

[0048] Example 2

[0049] The preparation method of the enteric granules containing m-boron phenylalanine in this embodiment is as follows:

[0050] Weigh out 500g m-BPA, 280g microcrystalline cellulose, 45g HPMC K15M, and 8g sodium dodecyl sulfate respectively. Separately sieve m-BPA, microcrystalline cellulose, and HPMC K15M through an 80-mesh sieve and set aside.

[0051] The sieved m-BPA, microcrystalline cellulose, and HPMC K15M were added to a three-dimensional mixer (model: SYH-10) and mixed. The mixture was stirred at 180 rpm for 12 min. Then, 160 mL of a 5% sodium dodecyl sulfate aqueous solution was added to prepare a soft mass. The mass was granulated by passing it through a 20-mesh sieve and dried at 55°C for 2.5 h to obtain 20-40 mesh core particles. The moisture content of the core particles was controlled at 3.0%. Finally, the core particles were obtained.

[0052] Take 500g of drug core granules and put them into a fluidized bed coating machine (GLATT GPCG 3). Set the working parameters of the fluidized bed coating machine as follows: inlet air temperature 40℃, outlet air temperature 35℃, spray rate 3mL / min, and atomization pressure 0.15MPa. Spray the coating solution onto the surface of the drug core granules. The coating solution is an ethanol solution containing 8wt% acrylic resin IV and 0.8wt% triacetylglycerol. The coating weight gain is controlled at 9.0% to obtain enteric granules. Dispense the enteric granules into aluminum-plastic composite bags at a specification of 5g / bag, seal them, and store them away from light.

[0053] The following quality tests were performed on the enteric-coated granules of this embodiment: (1) Dissolution rate: 4.2% dissolved in 2 hours at pH=1.2 and 93.4% dissolved in 45 minutes at pH=6.8; (2) Content: each bag contains 500.3 mg of m-BPA, RSD=1.5%, which meets the content uniformity requirements; (3) Stability: after 6 months of storage at 40℃ / 75% RH, the m-BPA content degraded by 2.5%, the granules did not stick together, and the coating film did not break; (4) Heavy metal residue: Pd≤0.001%, Cu≤0.0005%.

[0054] Example 3

[0055] The preparation method of the enteric granules containing m-boron phenylalanine in this embodiment is as follows:

[0056] Weigh out 500g m-BPA, 320g microcrystalline cellulose, 55g HPMC K15M, and 12g sodium dodecyl sulfate respectively. Sieve m-BPA, microcrystalline cellulose, and HPMC K15M through an 80-mesh sieve for later use.

[0057] The sieved m-BPA, microcrystalline cellulose, and HPMC K15M were added to a three-dimensional mixer (model: SYH-10) and mixed. The mixture was stirred at 200 rpm for 15 min. Then, 240 mL of a 5% sodium dodecyl sulfate aqueous solution was added to prepare a soft mass. The mass was granulated by passing it through a 20-mesh sieve and dried at 65°C for 1.5 h to obtain 20-40 mesh core particles. The moisture content of the core particles was controlled at 4.0%. Finally, the core particles were obtained.

[0058] Take 500g of drug core granules and put them into a fluidized bed coating machine (GLATT GPCG 3). Set the working parameters of the fluidized bed coating machine as follows: inlet air temperature 50℃, outlet air temperature 40℃, spray rate 5mL / min, and atomization pressure 0.25MPa. Spray the coating solution onto the surface of the drug core granules. The coating solution is an ethanol solution containing 8wt% acrylic resin IV and 0.8wt% triacetylglycerol. The coating weight gain is controlled at 9.5% to obtain enteric granules. Dispense the enteric granules into aluminum-plastic composite bags at a specification of 5g / bag, seal them, and store them away from light.

[0059] The following quality tests were performed on the enteric-coated granules of this embodiment: (1) Dissolution rate: 3.5% dissolved in 2 hours at pH=1.2 and 89.7% dissolved in 45 minutes at pH=6.8; (2) Content: each bag contains 500.1 mg of m-BPA, RSD=1.3%, which meets the content uniformity requirements; (3) Stability: after 6 months of storage at 40℃ / 75% RH, the m-BPA content degraded by 2.1%, the granules did not stick together, and the coating film did not break; (4) Heavy metal residue: Pd≤0.001%, Cu≤0.0005%.

[0060] The enteric-coated granules containing m-boron phenylalanine prepared in Example 1 were used as samples for efficacy verification tests, as follows:

[0061] B16F10 melanoma-bearing mice (n=6, tumor diameter approximately 10 mm) were selected as experimental animals. The mice were orally administered the enteric-coated granules containing m-boron phenylalanine prepared in Example 1 at a dose of 350 mg / kg. A second oral administration was administered 4 hours later. The boron concentration within the tumor cells of the tumor-bearing mice was measured. The results are as follows: HPLC-UV detection showed that the peak concentration was reached 2 hours after the first administration (Cmax = 8.7 ± 1.2 μg / mL), and the half-life was t... 1 / 2 =3.5h; 8h after administration, tumor tissue was digested, and ICP-MS analysis showed a boron concentration of 28.6±3.2μg / g, T / S=6.3±0.8, and T / P=3.3±0.5. Therefore, the enteric-coated granules containing m-boronylphenylalanine of this application meet the requirements for BNCT treatment in terms of targeting and aggregation concentration in tumor cells.

[0062] Similarly, B16F10 melanoma-bearing mice (n=6, tumor diameter approximately 10 mm) were selected as experimental animals. The mice were orally administered the enteric-coated granules containing m-boronylphenylalanine prepared in Example 1 at a dose of 350 mg / kg, once daily for 14 days. Blood glucose fluctuations were measured to be ≤5% (compared to 15%-20% for intravenous 4-BPA), no crystal deposition was observed in kidney tissue sections, and liver function indicators (ALT, AST) were normal. Gastric mucosal irritation tests showed no redness, swelling, or ulceration after oral administration of the enteric-coated granules, indicating that the enteric-coated granules containing m-boronylphenylalanine of this application are non-toxic and safe.

[0063] Therefore, the enteric-coated granules containing m-boron phenylalanine of this application can be used as a boron neutron capture therapy for tumors.

[0064] 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.

[0065] 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. Enteric granules containing m-boron phenylalanine, characterized in that, The enteric granules comprise a drug core and a coating completely covering the drug core, and the drug core comprises the following raw materials in parts by weight: m-BPA 500 parts, microcrystalline cellulose 280-320 parts, HPMC K15M 45-55 parts, and sodium dodecyl sulfate 8-12 parts.

2. The m-boron-phenylalanine-containing enteric granules according to claim 1, wherein, The purity of the m-BPA is ≥99.0%.

3. The m-boron-phenylalanine-containing enteric granules according to claim 2, wherein, The coating comprises the following raw materials in parts by weight: acrylic resin No. IV 70-90 parts and glyceryl triacetate 7-9 parts.

4. The m-boron phenylalanine-containing enteric granules according to claim 3, wherein, The enteric granules comprise the following raw materials in parts by weight: m-BPA 500 parts, microcrystalline cellulose 300 parts, HPMC K15M 50 parts, sodium dodecyl sulfate 10 parts, acrylic resin No. IV 80 parts, and glyceryl triacetate 8 parts.

5. Process for the preparation of enteric granules containing meta- boron phenylalanine, characterized in that, The method comprises the following steps: The m-BPA, microcrystalline cellulose, and HPMC K15M are sieved through an 80-mesh sieve, respectively, and are prepared for use; The sieved m-BPA, microcrystalline cellulose, and HPMC K15M are mixed and stirred at 150-200 rpm for 10-15 min, and then an aqueous sodium dodecyl sulfate solution is added, the mixture is granulated through a 20-mesh sieve, and air blowing drying is performed to obtain drug core granules with a particle size of 20-40 μm; The drug core granules are placed in a fluidized bed coating machine, and the working parameters of the fluidized bed coating machine are set as follows: air inlet temperature 40-50℃, air outlet temperature 35-40℃, spraying rate 3-5 mL / min, and atomization pressure 0.15-0.25 MPa; the coating solution is sprayed onto the surface of the drug core granules, and the coating weight gain is controlled at 9.0%-10.0%, and the obtained enteric granules are divided into aluminum-plastic composite bags, sealed, and stored in the dark.

6. The production method according to claim 5, wherein The drug core granules comprise the following raw materials in parts by weight: m-BPA 500 parts, microcrystalline cellulose 280-320 parts, HPMC K15M 45-55 parts, sodium dodecyl sulfate 8-12 parts, acrylic resin No. IV 75-85 parts, and glyceryl triacetate 7-9 parts.

7. The production method according to claim 5, wherein The mass concentration of the aqueous sodium dodecyl sulfate solution is 5%.

8. The production method according to claim 5, wherein The air blowing drying is performed at a temperature of 55-65℃ for 1.5-2.5 h, and the moisture content of the drug core granules is controlled at 3.0%-4.0%.

9. The production method according to claim 5, wherein The coating solution is an ethanol solution containing acrylic resin No. IV and glyceryl triacetate, the mass concentration of the acrylic resin No. IV in the coating solution is 8%, and the mass ratio of the acrylic resin No. IV to the glyceryl triacetate is 10:

1.

10. Use of the enteric granules according to claims 1-4 or prepared by the preparation method according to claims 5-9 in the preparation of a boron neutron capture tumor treatment drug.

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