Gastro-protected meloxicam benzene sulfonic acid tablet and preparation method thereof

Abstract

The present application relates to a kind of stomach-protecting meloxicam benzene sulfonic acid tablets and preparation method, include by weight parts: meloxicam benzene sulfonic acid-Bis-Tris·BH3 Adduct 8.5~9.5 parts, mannitol 70~80 parts, microcrystalline cellulose PH 102 40~50 parts, sodium carboxymethyl starch 3.5~4.5 parts, DL-tartaric acid 2.0~3.0 parts, magnesium metasilicate aluminum 0.6~0.8 parts, magnesium stearate 1.0~1.5 parts.Adduct in meloxicam benzene sulfonic acid and Bis-Tris·BH3 Molar ratio is 10:1, and adduct is prepared by solvent-assisted ball milling method.The present application can significantly reduce the irritability of gastrointestinal tract by the hydrogen gas released by the hydrolysis of adduct in gastric juice and the formation of buffer pair, synergistic with the adsorption of magnesium metasilicate aluminum.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a gastric-protective melogabalin besylate tablet and its preparation method. Background Technology

[0002] Merogabalin besylate is a novel α2δ subunit ligand for calcium ion channels. It inhibits neuronal overexcitation by selectively blocking voltage-dependent calcium channels and reducing calcium ion influx. It is used to treat pain, numbness and other symptoms caused by diabetic peripheral neuropathy.

[0003] However, existing melogabalin besylate tablets have the drawback of strong gastrointestinal irritation: melogabalin besylate can stimulate gastric mucosal epithelial cells to produce reactive oxygen species (ROS), causing oxidative damage to cells. Some patients with sensitive gastrointestinal tracts may experience adverse gastrointestinal reactions such as nausea, vomiting, abdominal pain, and diarrhea after taking it, which limits the long-term use of the drug by diabetic patients with sensitive gastrointestinal tracts. Summary of the Invention

[0004] This invention provides a method for preparing mixed peptides to solve the above-mentioned technical problems.

[0005] This invention provides a gastroprotective melogabalin besylate tablet, comprising, by weight: 8.5-9.5 parts melogabalin besylate-Bis-Tris·BH3 adduct, 70-80 parts mannitol, 40-50 parts microcrystalline cellulose PH 102, 3.5-4.5 parts sodium carboxymethyl starch, 2.0-3.0 parts DL-tartaric acid, 0.6-0.8 parts magnesium aluminum metasilicate, and 1.0-1.5 parts magnesium stearate;

[0006] Merogabalin besylate and Bis-Tris·BH3, upon entering the gastric juice, undergo hydrolysis in an acidic aqueous environment, releasing hydrogen molecules and generating buffering Bis-Tris. The hydrogen molecules selectively scavenge hydroxyl radicals locally in the gastric mucosa, reducing oxidative stress damage. The generated Bis-Tris forms an acidic buffer system in situ with DL-tartaric acid in the formulation, maintaining the pH stability of the microenvironment surrounding the drug particles and preventing a decrease in drug solubility due to pH elevation. Magnesium aluminum metasilicate reduces the local concentration of free drug through physical adsorption. The three components work synergistically to reduce gastrointestinal irritation by both combating oxidative damage and controlling local drug concentration.

[0007] Among them, magnesium aluminum metasilicate has a specific surface area of ​​200~300 m². 2With an average pore size of 2~10nm, magnesium aluminum metasilicate has a strong adsorption capacity, which can adsorb free drug molecules in gastric juice. The particle size is 5~10μm, which allows it to be evenly dispersed around the drug particles. Its surface charge can generate physical adsorption with the gastric mucosa, prolonging the residence time in the stomach.

[0008] In the melogabalin benzyl sulfonate-Bis-Tris·BH3 adduct, the molar ratio of melogabalin benzyl sulfonate to Bis-Tris·BH3 is 10:1.

[0009] A molar ratio of 10:1 allows melogabalin benzyl sulfonic acid molecules to form a stable three-dimensional crystal lattice structure, encapsulating Bis-Tris·BH3 molecules within the lattice. This structure remains stable under dry storage conditions, preventing premature reaction between Bis-Tris·BH3 and acidic excipients. Upon entering gastric juice, the adduct gradually dissolves, and the Bis-Tris released by the hydrolysis of Bis-Tris·BH3 forms a buffer pair with DL-tartaric acid.

[0010] The adduct is prepared through the following steps:

[0011] S1. Weigh out melogabalin benzyl sulfonate and Bis-Tris·BH3 adduct by molar ratio;

[0012] S2. Add 4-6% of the total weight of melogabalin benzyl sulfonate and Bis-Tris·BH3 in anhydrous ethanol as a cosolvent.

[0013] S3. Place in a ball mill and grind for 30-35 minutes at a speed of 300-320 rpm;

[0014] S4, vacuum dry at 38~42℃ for 2~2.5 hours, pass through a 100~110 mesh sieve to obtain adduct powder;

[0015] Prepared via steps S1 to S4, this adduct allows for the ordered rearrangement of two solid molecules to form a supramolecular adduct. Compared to simple physical mixing, this adduct stably encapsulates Bis-Tris·BH3 within the melogabalin benzenesulfonic acid lattice, achieving physical isolation from acidic excipients and effectively suppressing premature hydrolysis and gas generation during storage. Simultaneously, it synchronizes the release rates of the drug and the borane complex within the adduct, prolonging the stable hydrogen production time.

[0016] The Bis-Tris·BH3 adduct was prepared by the following steps:

[0017] S11. Dissolve Bis-Tris in anhydrous ethanol and cool it to 0~5℃ in an ice bath; Bis-Tris is bis(2-hydroxyethyl)amino(tris(hydroxymethyl)methane.

[0018] S12. Under the protection of an inert gas, slowly add borane-tetrahydrofuran complex or borane-dimethyl sulfide complex to make the molar ratio of Bis-Tris to BH3 1:1, and control the dropping rate to keep the reaction temperature below 10℃.

[0019] S13. After the addition is complete, continue stirring in an ice bath for 1 to 1.5 hours, then raise to room temperature and stir for 2 to 2.5 hours.

[0020] S14. Remove the solvent by vacuum distillation to obtain a white solid;

[0021] S15. Wash 2-3 times with anhydrous diethyl ether, and dry under vacuum at 38-42°C for 3.5-4.5 hours to obtain a white powder of Bis-Tris·BH3 adduct;

[0022] In the above reaction, the tertiary amine nitrogen atom in the Bis-Tris molecule provides a lone pair of electrons, which form a stable N→B coordinate bond with the empty orbital of the boron atom in BH3, generating the Bis-Tris·BH3 adduct.

[0023] A method for preparing a gastroprotective merogalaline besylate tablet includes the following steps:

[0024] S1a. Weigh the adduct powder, mannitol, microcrystalline cellulose PH 102, DL-tartaric acid and magnesium aluminum metasilicate according to the full weight parts, pass them through a 40-mesh sieve, and then place the material in a low-frequency alternating electric field with an electric field strength of 230~250V / m, a frequency of 12~15Hz, and a treatment time of 18~20 minutes, accompanied by hot air circulation at 45~50℃, and then premix for 10~12 minutes.

[0025] A low-frequency alternating electric field can induce a redistribution of surface charges in powder particles, breaking up particle agglomeration; simultaneous 45-50℃ hot air circulation can remove trace amounts of moisture from the material. This pretreatment can improve the uniformity of adduct distribution in excipients, reduce the impact of moisture on adduct stability, and provide uniform and dry material for subsequent tableting.

[0026] S2a. Weigh out the full weight proportions and add sodium carboxymethyl starch, mix for 5-6 minutes; sodium carboxymethyl starch, as a super disintegrant, is evenly dispersed in the powder. After absorbing water, its volume expands significantly, which promotes the rapid and uniform disintegration of the tablets in the gastric juice, so that the drug dissolution rate matches the adduct hydrolysis rate, and avoids excessively high local drug concentration.

[0027] S3a. Weigh and add magnesium stearate according to the full weight proportions, then apply an axial pulsed magnetic field: magnetic field strength 0.5~0.6T, pulse frequency 2~3Hz, duration 3~4 minutes; finally mix for 4~5 minutes. The axial pulsed magnetic field can induce magnesium stearate flake crystals to align oriented along the magnetic field direction, forming a uniform lubricating layer on the particle surface. This technology can avoid localized accumulation of lubricant, reduce sticking during tableting, improve the uniformity of tablet hardness, and thus improve the consistency of product quality within a batch.

[0028] S4a. The mixed granules are statically immersed in supercritical carbon dioxide for 15-30 minutes, then rapidly depressurized to atmospheric pressure; the supercritical carbon dioxide pressure is 8-10 MPa, and the temperature is 35-40℃; then tableting is performed, controlling the tablet hardness to 6-7 kg. Supercritical CO2 has high diffusivity and low viscosity, allowing it to penetrate into the granules; during rapid depressurization, the CO2 volume expands rapidly, forming a uniform microporous structure on the surface and inside the granules. This pore-forming technology can optimize the pore structure of the granules, improve the uniformity of drug dissolution, and eliminate the need for additional pore-forming agents.

[0029] S5a. The uncoated tablets are placed in a low-temperature plasma treatment chamber for 50-60 seconds. The working gas for the low-temperature plasma treatment is argon, the pressure is 25-30 Pa, and the discharge power is 70-80 W. Then, a gastric-soluble film coating is performed, resulting in a coating weight gain of 3.0 ± 0.2%. Finally, the coated tablets are placed in a microwave vacuum drying apparatus for 8-10 minutes and then naturally cooled to room temperature. The microwave power for microwave vacuum drying is 460-500 W, the vacuum degree is -0.06 to -0.08 MPa, and the temperature is 35-40℃. The argon low-temperature plasma can etch the surface of the uncoated tablets, introducing polar groups, improving the surface energy and wettability of the tablets, thereby enhancing the adhesion between the coating film and the tablet core. Microwave vacuum drying can achieve rapid dehydration at low temperatures, avoiding damage to the active ingredients from high temperatures, and can also eliminate internal stress in the coating film, preventing coating cracking. The combined use of these two methods can significantly improve coating quality, shorten the drying cycle, and is suitable for continuous industrial production.

[0030] Compared with the prior art, the beneficial effects of the present invention are:

[0031] 1. The adduct formed by merogabarine besylate and Bis-Tris·BH3 enters the gastric juice and undergoes gradual hydrolysis, simultaneously releasing hydrogen molecules and Bis-Tris. The hydrogen molecules selectively scavenge excess hydroxyl radicals in the gastric mucosa, blocking the oxidative stress damage pathway induced by merogabarine besylate. The generated Bis-Tris forms an acidic, stable buffer system in situ with DL-tartaric acid in the formulation, which can better maintain the constant pH of the microenvironment around the drug particles, avoiding uneven dissolution and excessively high local concentrations due to pH fluctuations. Magnesium aluminum metasilicate reduces the concentration of free drug through physical adsorption and prolongs the local protective time through physical adsorption with the gastric mucosa via its surface charge. These three components work synergistically from three dimensions: anti-oxidative damage, control of local drug exposure, and prolongation of action time, significantly reducing the degree of gastric mucosal damage and the occurrence of gastrointestinal adverse reactions.

[0032] 2. By employing a suitable molar ratio of melogabalin besylate to Bis-Tris·BH3, and utilizing solvent-assisted ball milling, the two solid molecules can be ordered to rearrange to form a supramolecular adduct. Compared to simple physical mixing, this adduct can stably encapsulate Bis-Tris·BH3 within the melogabalin besylate lattice, achieving physical isolation from acidic excipients and effectively suppressing premature hydrolysis and gas generation during storage. Simultaneously, it can synchronize the release rates of the drug and the borane complex in the adduct, prolonging the stable hydrogen production time. Detailed Implementation

[0033] To better understand the technical content of this invention, specific embodiments are provided below, and the invention will be further explained.

[0034] Example 1

[0035] A gastroprotective melogabalin besylate tablet comprises, by weight: 8.5 parts melogabalin besylate-Bis-Tris·BH3 adduct, 70 parts mannitol, 40 parts microcrystalline cellulose PH 102, 3.5 parts sodium carboxymethyl starch, 2.0 parts DL-tartaric acid, 0.6 parts magnesium aluminum metasilicate, and 1.0 part magnesium stearate;

[0036] Among them, magnesium aluminum metasilicate has a specific surface area of ​​200~300m² / g, an average pore size of 2~10nm, and a particle size of 5~10μm;

[0037] In the melogabalin benzyl sulfonate-Bis-Tris·BH3 adduct, the molar ratio of melogabalin benzyl sulfonate to Bis-Tris·BH3 is 10:1.

[0038] The adduct is prepared through the following steps:

[0039] S1. Weigh out melogabalin benzyl sulfonate and Bis-Tris·BH3 raw materials by molar ratio;

[0040] S2. Add 4% by weight of anhydrous ethanol as a cosolvent, which is the total weight of melogabalin benzenesulfonic acid and Bis-Tris·BH3.

[0041] S3. Place in a ball mill and grind at 300 rpm for 30 minutes;

[0042] S4, vacuum dried at 38℃ for 2 hours, then passed through a 100-mesh sieve to obtain adduct powder.

[0043] The Bis-Tris·BH3 adduct was prepared by the following steps:

[0044] S11. Dissolve Bis-Tris in anhydrous ethanol and cool it to 0°C in an ice bath.

[0045] S12. Under the protection of an inert gas, slowly add the borane-tetrahydrofuran complex to make the molar ratio of Bis-Tris to BH3 1:1, and control the dropping rate to keep the reaction temperature below 10℃.

[0046] S13. After the addition is complete, continue stirring in an ice bath for 1 hour, then raise to room temperature and stir for 2 hours.

[0047] S14. Remove the solvent by vacuum distillation to obtain a white solid;

[0048] S15. Wash twice with anhydrous diethyl ether, and dry under vacuum at 38°C for 3.5 hours to obtain a white powder of Bis-Tris·BH3 adduct.

[0049] A method for preparing a gastroprotective merogalaline besylate tablet includes the following steps:

[0050] S1a. Weigh the adduct powder, mannitol, microcrystalline cellulose PH 102, DL-tartaric acid and magnesium aluminum metasilicate by weight, pass them through a 40-mesh sieve, and then place the material in a low-frequency alternating electric field with an electric field strength of 230V / m, a frequency of 12Hz, and a treatment time of 18 minutes, while simultaneously circulating hot air at 45℃, and then premix for 10 minutes.

[0051] S2a. Weigh out the sodium carboxymethyl starch according to the weight parts and add it, then mix for 5 minutes.

[0052] S3a. Weigh out the magnesium stearate according to the weight ratio and add it, then apply an axial pulsed magnetic field: magnetic field strength 0.5T, pulse frequency 2Hz, duration 3 minutes; finally mix for 4 minutes.

[0053] S4a. Place the mixed granules in supercritical carbon dioxide and statically soak for 15 minutes, then quickly depressurize to atmospheric pressure; the pressure of supercritical carbon dioxide is 8 MPa and the temperature is 35℃; then compress the tablets and control the tablet hardness to 6 kg.

[0054] S5a. Place the raw film in a low-temperature plasma treatment chamber for 50 seconds. The working gas for the low-temperature plasma treatment is argon, the pressure is 25 Pa, and the discharge power is 70 W. Then perform gastric-soluble film coating, and the coating weight gain is 3.0 ± 0.2%.

[0055] Example 2

[0056] A gastroprotective melogabalin besylate tablet comprises, by weight: 9.5 parts melogabalin besylate-Bis-Tris·BH3 adduct, 80 parts mannitol, 50 parts microcrystalline cellulose PH 102, 4.5 parts sodium carboxymethyl starch, 3.0 parts DL-tartaric acid, 0.8 parts magnesium aluminum metasilicate, and 1.5 parts magnesium stearate;

[0057] Among them, magnesium aluminum metasilicate has a specific surface area of ​​200~300m² / g, an average pore size of 2~10nm, and a particle size of 5~10μm;

[0058] In the melogabalin benzyl sulfonate-Bis-Tris·BH3 adduct, the molar ratio of melogabalin benzyl sulfonate to Bis-Tris·BH3 is 10:1.

[0059] The adduct is prepared through the following steps:

[0060] S1. Weigh out melogabalin benzyl sulfonate and Bis-Tris·BH3 raw materials by molar ratio;

[0061] S2. Add 6% by weight of anhydrous ethanol as a cosolvent, which is the total weight of melogabalin benzyl sulfonate and Bis-Tris·BH3.

[0062] S3. Place in a ball mill and grind at 320 rpm for 35 minutes;

[0063] S4, vacuum dried at 42℃ for 2.5 hours, then passed through a 110-mesh sieve to obtain adduct powder.

[0064] The Bis-Tris·BH3 adduct was prepared by the following steps:

[0065] S11. Dissolve Bis-Tris in anhydrous ethanol and cool it to 5°C in an ice bath.

[0066] S12. Under the protection of an inert gas, slowly add the borane-dimethyl sulfide complex to make the molar ratio of Bis-Tris to BH3 1:1, and control the dropping rate to keep the reaction temperature below 10℃.

[0067] S13. After the addition is complete, continue stirring in an ice bath for 1.5 hours, then raise to room temperature and stir for 2.5 hours.

[0068] S14. Remove the solvent by vacuum distillation to obtain a white solid;

[0069] S15. Wash three times with anhydrous diethyl ether and dry under vacuum at 42°C for 4.5 hours to obtain a white powder of Bis-Tris·BH3 adduct.

[0070] A method for preparing a gastroprotective merogalaline besylate tablet includes the following steps:

[0071] S1a. Weigh the adduct powder, mannitol, microcrystalline cellulose PH 102, DL-tartaric acid and magnesium aluminum metasilicate by weight, pass them through a 40-mesh sieve, and then place the material in a low-frequency alternating electric field with an electric field strength of 250V / m and a frequency of 15Hz for 20 minutes, while simultaneously circulating hot air at 50℃, and then premix for 12 minutes.

[0072] S2a. Weigh out the sodium carboxymethyl starch according to the weight parts and add it, then mix for 6 minutes.

[0073] S3a. Weigh out and add magnesium stearate according to the weight proportions, then apply an axial pulsed magnetic field: magnetic field strength 0.6T, pulse frequency 3Hz, duration 4 minutes; finally mix for 5 minutes.

[0074] S4a. Place the mixed granules in supercritical carbon dioxide and statically soak for 30 minutes, then quickly depressurize to atmospheric pressure; the pressure of supercritical carbon dioxide is 10 MPa and the temperature is 40℃; then compress into tablets, controlling the tablet hardness to 7 kg.

[0075] S5a. Place the raw film in a low-temperature plasma treatment chamber for 60 seconds. The working gas for the low-temperature plasma treatment is argon, the pressure is 30 Pa, and the discharge power is 80 W. Then perform gastric-soluble film coating, and the coating weight gain is 3.0 ± 0.2%.

[0076] Example 3

[0077] A gastroprotective melogabalin besylate tablet comprises, by weight: 9.0 parts melogabalin besylate-Bis-Tris·BH3 adduct, 75 parts mannitol, 45 parts microcrystalline cellulose PH 102, 4.0 parts sodium carboxymethyl starch, 2.5 parts DL-tartaric acid, 0.7 parts magnesium aluminum metasilicate, and 1.3 parts magnesium stearate;

[0078] Among them, magnesium aluminum metasilicate has a specific surface area of ​​200~300m² / g, an average pore size of 2~10nm, and a particle size of 5~10μm;

[0079] In the melogabalin benzyl sulfonate-Bis-Tris·BH3 adduct, the molar ratio of melogabalin benzyl sulfonate to Bis-Tris·BH3 is 10:1.

[0080] The adduct is prepared through the following steps:

[0081] S1. Weigh out melogabalin benzyl sulfonate and Bis-Tris·BH3 raw materials by molar ratio;

[0082] S2. Add 5% by weight of anhydrous ethanol as a cosolvent, which is the total weight of melogabalin benzyl sulfonate and Bis-Tris·BH3.

[0083] S3. Place in a ball mill and grind at 310 rpm for 33 minutes;

[0084] S4, vacuum dried at 40℃ for 2.5 hours, then passed through a 110-mesh sieve to obtain adduct powder.

[0085] The Bis-Tris·BH3 adduct was prepared by the following steps:

[0086] S11. Dissolve Bis-Tris in anhydrous ethanol and cool it to 3°C in an ice bath.

[0087] S12. Under the protection of an inert gas, slowly add the borane-tetrahydrofuran complex to make the molar ratio of Bis-Tris to BH3 1:1, and control the dropping rate to keep the reaction temperature below 10℃.

[0088] S13. After the addition is complete, continue stirring in an ice bath for 1.25 hours, then raise to room temperature and stir for 2 hours.

[0089] S14. Remove the solvent by vacuum distillation to obtain a white solid;

[0090] S15. Wash three times with anhydrous diethyl ether and dry under vacuum at 40°C for 4 hours to obtain a white powder of Bis-Tris·BH3 adduct.

[0091] A method for preparing a gastroprotective merogalaline besylate tablet includes the following steps:

[0092] S1a. Weigh the adduct powder, mannitol, microcrystalline cellulose PH 102, DL-tartaric acid and magnesium aluminum metasilicate by weight, pass them through a 40-mesh sieve, and then place the material in a low-frequency alternating electric field with an electric field strength of 240V / m and a frequency of 13Hz for 19 minutes. At the same time, 47℃ hot air is circulated, and then premixed for 11 minutes.

[0093] S2a. Weigh out the sodium carboxymethyl starch according to the weight parts and add it, then mix for 5 minutes.

[0094] S3a. Weigh out and add magnesium stearate according to the weight proportions, then apply an axial pulsed magnetic field: magnetic field strength 0.5T, pulse frequency 3Hz, duration 3 minutes; finally mix for 4 minutes.

[0095] S4a. The mixed granules are statically immersed in supercritical carbon dioxide for 22 minutes, and then the pressure is rapidly released to atmospheric pressure. The pressure of the supercritical carbon dioxide is 9 MPa and the temperature is 37°C. Then the tablets are compressed to control the tablet hardness at 6 kg.

[0096] S5a. Place the raw film in a low-temperature plasma treatment chamber for 55 seconds. The working gas for the low-temperature plasma treatment is argon, the pressure is 27 Pa, and the discharge power is 75 W. Then perform gastric-soluble film coating, and the coating weight gain is 3.0 ± 0.2%.

[0097] Comparative Example 1

[0098] Compared to Example 3, the Bis-Tris·BH3 adduct was removed, and the corresponding preparation process steps for the adduct were also removed; otherwise, it was the same as Example 3.

[0099] Comparative Example 2

[0100] Compared to Example 3, the Bis-Tris·BH3 adduct and melogabalin benzenesulfonic acid are not prepared into an adduct through steps S1 to S4, but are mixed in step S1a, otherwise the same as in Example 3.

[0101] Effect verification

[0102] I. Gastric mucosal protection test

[0103] 1. Experimental Methods

[0104] Seventy SD rats were randomly divided into seven groups (blank control group, comparative example group 1, comparative example group 2, example group 1, example group 2, and example group 3), with ten rats in each group. Each group was administered 10 mg / kg (calculated as merogabarine besylate) via gavage. All tablets used in the examples and comparative examples were freshly prepared (within 24 hours of production). Specifically, the tablets were ground and dispersed in physiological saline and administered within 3 minutes. The blank control group received an equal volume of physiological saline. Thirty minutes after administration, anhydrous ethanol (1 ml / 100 g body weight) was administered via gavage to induce gastric mucosal injury. Rats were sacrificed one hour later, and their stomachs were harvested, cut along the greater curvature, rinsed with physiological saline, and the extent of gastric mucosal injury was observed. The Guth method was used to calculate the gastric mucosal injury index, and the injury inhibition rate was calculated.

[0105] 2. Experimental Results

[0106]

[0107] 3. Conclusion

[0108] The gastric mucosal damage inhibition rates of Examples 1 to 3 of the present invention all reached over 89%, which is significantly better than Comparative Example 1 (49.3%) and Comparative Example 2 (57.3%), indicating that the gastric protective tablets of the present invention can effectively reduce gastric mucosal damage.

[0109] II. In vitro dissolution test

[0110] 1. Experimental Methods

[0111] The dissolution was determined according to the Chinese Pharmacopoeia paddle method. The dissolution medium was pH 6.8 phosphate buffer, 900 ml, at 50 rpm and 37°C. Six tablets from each example and comparative example were taken and sampled at 15 minutes. The cumulative dissolution rate was determined by HPLC. All tablets from each example and comparative example were freshly prepared (within 24 hours after production).

[0112] 2. Experimental Results

[0113]

[0114] 3. Conclusion

[0115] The dissolution rates of the embodiments of the present invention all exceed 96%, while those of the comparative examples are only about 72%, indicating that the present invention solves the problem of unstable dissolution and easy burst release of drugs in different acid and alkaline environments.

[0116] III. Hydrogen Generation Verification Test

[0117] 1. Experimental Methods

[0118] Tablets from each example and comparative example were sealed in pharmaceutical-grade aluminum-plastic blister packs and placed in a 40°C / 75%RH constant temperature and humidity chamber for accelerated testing to obtain tablets produced within 24 hours, 6 months, and 12 months. One tablet from each of the above time points was placed in 50 ml of simulated gastric fluid at pH 1.2 and incubated at 37°C.

[0119] 1) Observe the bubble generation continuously using the water displacement gas collection method, and record the duration (in minutes) from the start of gas production to the point where the bubbles basically stop; this is the hydrogen production time. Take 3 tablets from each group for testing and take the average value. Observe the appearance of the tablets at the same time.

[0120] 2) Collect the gases generated in Examples 1 to 3 and inject them into a gas chromatograph to detect the gas type. Use hydrogen standard for qualitative confirmation and calculate the hydrogen purity (hydrogen percentage).

[0121] 2. Experimental Results

[0122]

[0123] 3. Conclusion

[0124] Comparative Example 1: No bubbles were ever produced, and the hydrogen production time was 0.

[0125] Comparative Example 2: Initial hydrogen production time was approximately 8 minutes, with hydrogen being released rapidly; after 6 months of accelerated production, almost no hydrogen was produced, and the tablets were severely deformed. This indicates that simple physical mixing not only results in short hydrogen production time and an inability to release hydrogen continuously, but also exhibits extremely poor storage stability.

[0126] Embodiments of the present invention: The gas produced in the embodiments of the present invention contains >99% hydrogen, and no toxic or harmful gases such as borane and diborane were detected within the detection limit, indicating that the hydrogen production process of the tablets of the present invention in simulated gastric juice has good safety; the initial hydrogen production time is over 30 minutes, and the hydrogen is released steadily and slowly; after 12 months of accelerated production, the hydrogen production time still remains above 30 minutes, and the tablets remain intact. This demonstrates that the adduct of the present invention can achieve slow and continuous release of hydrogen, and the release behavior remains unchanged after long-term storage.

[0127] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A gastroprotective merogabarine besylate tablet, characterized in that, By weight, it includes: 8.5-9.5 parts melogabalin-Bis-Tris·BH3 adduct of benzenesulfonic acid, 70-80 parts mannitol, 40-50 parts microcrystalline cellulose PH 102, 3.5-4.5 parts sodium carboxymethyl starch, 2.0-3.0 parts DL-tartaric acid, 0.6-0.8 parts magnesium aluminum metasilicate, and 1.0-1.5 parts magnesium stearate; In the melogabalin benzenesulfonic acid-Bis-Tris·BH3 adduct, the molar ratio of melogabalin benzenesulfonic acid to Bis-Tris·BH3 is 10:1; The adduct is prepared by the following steps: S1. Weigh out melogabalin benzyl sulfonate and Bis-Tris·BH3 adduct by molar ratio; S2. Add 4-6% of the total weight of melogabalin benzyl sulfonate and Bis-Tris·BH3 in anhydrous ethanol as a cosolvent. S3. Place in a ball mill and grind for 30-35 minutes at a speed of 300-320 rpm; S4. Vacuum dry at 38~42℃ for 2~2.5 hours, then pass through a 100~110 mesh sieve to obtain adduct powder.

2. The gastroprotective merogabarine besylate tablet according to claim 1, characterized in that, The Bis-Tris·BH3 adduct was prepared by the following steps: S11. Dissolve Bis-Tris in anhydrous ethanol and cool it to 0~5℃ in an ice bath; S12. Under the protection of an inert gas, slowly add borane-tetrahydrofuran complex or borane-dimethyl sulfide complex to make the molar ratio of Bis-Tris to BH3 1:1, and control the dropping rate to keep the reaction temperature below 10℃. S13. After the addition is complete, continue stirring in an ice bath for 1 to 1.5 hours, then raise to room temperature and stir for 2 to 2.5 hours. S14. Remove the solvent by vacuum distillation to obtain a white solid; S15. Wash 2-3 times with anhydrous diethyl ether, and vacuum dry at 38-42℃ for 3.5-4.5 hours to obtain a white powder of Bis-Tris·BH3 adduct.

3. The gastroprotective merogabarine besylate tablet according to claim 1, characterized in that, The aluminum magnesium metasilicate has a specific surface area of ​​200~300m² / g, an average pore size of 2~10nm, and a particle size of 5~10μm.

4. A method for preparing a gastroprotective merogabarine besylate tablet according to any one of claims 1 to 3, characterized in that, Includes the following steps: S1a. Weigh the adduct powder, mannitol, microcrystalline cellulose PH 102, DL-tartaric acid and magnesium aluminum metasilicate according to the full weight parts, pass through a 40-mesh sieve, and premix for 10-12 minutes. S2a. Weigh out the full weight proportions and add sodium carboxymethyl starch, mix for 5-6 minutes; S3a. Weigh out the full weight percentage and add magnesium stearate, mix for 4-5 minutes; S4a, tableting, controlling tablet hardness to 6~7kg; S5a. Gastric-soluble film coating was performed, and the coating weight gain was 3.0 ± 0.2%.

5. The preparation method according to claim 4, characterized in that, After sieving as described in step S1a, the material is placed in a low-frequency alternating electric field for treatment: electric field strength 230~250V / m, frequency 12~15Hz, treatment time 18~20 minutes, accompanied by hot air circulation at 45~50℃.

6. The preparation method according to claim 4, characterized in that, After adding magnesium stearate in step S3a, an axial pulsed magnetic field is applied: magnetic field strength 0.5~0.6T, pulse frequency 2~3Hz, duration 3~4 minutes.

7. The preparation method according to claim 4, characterized in that, Before tableting in step S4a, the mixed particles are statically immersed in supercritical carbon dioxide for 15-30 minutes, and then the pressure is rapidly released to atmospheric pressure; the pressure of the supercritical carbon dioxide is 8-10 MPa and the temperature is 35-40℃.

8. The preparation method according to claim 4, characterized in that, Before coating in step S5a, the uncoated film is placed in a low-temperature plasma treatment chamber for 50-60 seconds. The working gas for the low-temperature plasma treatment is argon, the pressure is 25-30 Pa, and the discharge power is 70-80 W.

9. The preparation method according to claim 4, characterized in that, After the coating process in step S5a is completed, the coated sheets are placed in a microwave vacuum drying apparatus and dried for 8-10 minutes, and then allowed to cool naturally to room temperature. The microwave power of the microwave vacuum drying apparatus is 460-500W, the vacuum degree is -0.06 to -0.08MPa, and the temperature is 35-40℃.

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