A minodronic acid tablet and a method for preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a minodronic acid tablet and a preparation method thereof.The tablet provided by the application contains minodronic acid with a specific particle size, hydroxypropyl cellulose and pharmaceutically acceptable excipients, and the synergistic adaptation of the raw materials and the excipients is realized by controlling the particle size of minodronic acid and the suitable weight ratio of minodronic acid and hydroxypropyl cellulose.The application effectively solves the problems of sticking and bumping in the production of minodronic acid tablets, poor dissolution and low bioavailability, and the quality of the preparation is stable and the content is uniform, the preparation process is simple and easy to implement, is suitable for large-scale production, and has biological equivalence with the original research drug, and has a good clinical application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a minodronic acid tablet and its preparation method. Background Technology

[0002] Osteoporosis (OP) is a systemic skeletal disease characterized by decreased bone mass and deterioration of bone microstructure. It can lead to decreased bone strength and fractures, and has become a prevalent chronic disease affecting the elderly. Patients with hyperthyroidism, rheumatoid arthritis, malabsorption syndrome, multiple myeloma, as well as those who use glucocorticoids, GnRH agonists, and antagonists long-term, are all high-risk groups for osteoporosis. Developing safe, effective, low-side-effect, and cost-effective treatments has significant clinical value and application prospects.

[0003] Bisphosphonates can inhibit osteoclast activity, reduce bone turnover, and increase bone mineral density, showing definite efficacy in treating osteoporosis and tumor-related bone diseases. Representative drugs include alendronate sodium, ibandronate sodium, pamidronate disodium, and minodronate. Minodronate is a third-generation nitrogen-containing aromatic heterocyclic bisphosphonate developed by Astellas Pharma Ltd. of Japan. It was approved for marketing by the Japanese Ministry of Health, Labour and Welfare in 2009 for the treatment of osteoporosis and hypercalcemia caused by osteoporosis and malignant tumors. Animal studies have shown that minodronate's bone resorption inhibitory activity is 30 to 100 times that of alendronate sodium and pamidronate disodium; clinical trials have demonstrated its significant advantage in reducing the incidence of vertebral fractures.

[0004] Minodronic acid faces two major formulation technology bottlenecks: First, the drug is almost insoluble in water, and its solubility increases with the increase of the medium pH. In human simulated gastric juice (pH 0.9~1.8), its solubility is extremely low, resulting in poor gastric dissolution and low bioavailability of conventional solid dosage forms. Second, the dosage form is only 1mg / tablet or smaller, and the raw material is a white crystal that is lightweight, has low bulk density, and strong adsorption. It is easy to adhere to the inner wall of pharmaceutical equipment, resulting in extremely poor uniformity of mixing with excipients. Conventional tablet processes can easily lead to unqualified content uniformity, and large-scale production can easily result in batch scrap.

[0005] To address the aforementioned problems, extensive research has been conducted in the existing technology field. Patent WO1994000462A1 discloses a formulation for minodronic acid, which includes lactose, corn starch, a 10% hydroxypropyl cellulose aqueous solution, and magnesium stearate to form tablets; however, its in vitro dissolution effect is unsatisfactory. Patent CN102144982A discloses minodronic acid tablets, in which the minodronic acid solid dispersion is prepared by heating polyethylene glycol to a molten state, then slowly adding excipients, stirring until dissolved, then adding minodronic acid, stirring until completely dissolved, cooling, and allowing it to stand for 18-24 hours. The resulting solid dispersion is then pulverized and sieved, and other excipients are added and mixed before finally compressing to obtain minodronic acid tablets. However, the preparation process is complex, time-consuming, energy-intensive, and demanding, making it prone to errors in workshop production and posing difficulties for industrial-scale production. Patent CN102114025A discloses a technology that micronizes minodronic acid raw materials to improve its dissolution rate (up to 99.7% within 60 minutes). However, micronized raw materials are more prone to aggregation, increasing the difficulty of mixing and easily causing uneven content. Patent CN102078323A discloses adding alkaline excipients such as sodium carbonate to minodronic acid formulations to improve dissolution rate. However, these excipients are highly alkaline and can disrupt the gastric acid environment, resulting in poor patient compliance. Patent CN104771379A discloses a minodronic acid tablet prepared by dissolving minodronic acid and hydroxypropyl methylcellulose in an aqueous sodium hydroxide solution and coating this solution onto blank tablets. Minodronic acid itself easily causes gastroesophageal irritation, and the strongly alkaline coating layer directly contacts gastric acid and the gastric mucosa, exacerbating gastrointestinal adverse reactions.

[0006] Therefore, a minodronic acid tablet and its preparation method that can overcome the aforementioned defects are needed. On the one hand, this method can solve the problems of adhesion and punching during tablet compression, reduce drug irritation, improve patient compliance, and increase absorption rate, allowing the drug to better serve patients. On the other hand, this formulation and process have greater production tolerance, and product quality can be guaranteed using ordinary machinery and equipment. This enables minodronic acid tablets to meet the requirements of safety, efficacy, and controllable quality, with a simple and efficient preparation process and high product yield. Summary of the Invention

[0007] Minodronic acid has extremely low bioavailability, mainly due to the following factors: the drug is a low-permeability drug, and its absorption site is limited to the duodenum, resulting in a narrow absorption window. These factors work together to lead to low drug absorption efficiency, which limits its clinical efficacy.

[0008] To address the aforementioned issues, formulation researchers initially considered increasing the drug's hydrophilicity by reducing its particle size, thereby ensuring complete dissolution in the stomach and improving absorption efficiency. Based on this, the inventors referenced the minodronic acid particle size range (1μm < D50 < 20μm) described in Japanese Patent JP5874545B2, pulverizing minodronic acid to a D50 of 15μm. Using 4mg of hydroxypropyl cellulose as an excipient, tablets were prepared using a wet granulation process, and a bioequivalence (BE) test was conducted. The results showed that the relative bioavailability of this formulation was lower than that of the original formulation, failing to achieve the expected results.

[0009] After further reflection, the inventors concluded that even if the drug can dissolve sufficiently, if the dissolved solution passes through the duodenal absorption window rapidly without making sufficient contact with the intestinal mucosa, it will lead to inadequate absorption and thus affect bioavailability. The viscosity of the drug solution directly determines its residence rate in the duodenum: if the viscosity is too low, the solution will pass through the duodenum quickly, preventing sufficient absorption; if the viscosity is too high, dissolution may be slowed, which is also detrimental to absorption.

[0010] Based on this hypothesis, the inventors optimized the formulation and process. On the one hand, they further reduced the particle size of minodronic acid to a D50 of 6 μm; on the other hand, they increased the amount of hydroxypropyl cellulose to 20 mg, while still using a wet granulation process to prepare tablets. BE (bioavailability) studies showed that the relative bioavailability of this formulation was equivalent to that of the original formulation, verifying the inventors' hypothesis that "drug solution viscosity affects drug absorption." However, significant process defects emerged during the formulation production process, with the issue of punch sticking being particularly prominent. Specifically, the prepared granules were too large and uneven in size, resulting in poor granule flowability. During tableting, the drug granules easily adhered to the surface and edges of the tableting machine punch, causing powder to adhere to the punch surface, resulting in obvious scratches, and even powder clumping. The compressed tablets were rough and uneven, with issues such as dents, pits, and rough edges. Some tablets even suffered from corner defects or cracks due to punch sticking, severely affecting the appearance quality and product uniformity. At the same time, punch sticking led to a significant increase in the frequency of punch cleaning, reducing production efficiency. It could even cause tablet content deviations due to the powder adhering to the punch falling off, failing to meet the quality requirements of large-scale production.

[0011] To address the aforementioned viscosity issue, the inventors further increased the dosage of hydroxypropyl cellulose to 30 mg and conducted another bioequivalence (BE) test. The results showed that the relative bioavailability of the formulation actually decreased. The reason for this is speculated to be that the excessive dosage of hydroxypropyl cellulose significantly slowed the drug dissolution rate and increased the viscosity of the drug solution in vivo, prolonging the drug's residence time at the absorption site but reducing absorption efficiency, ultimately leading to decreased bioavailability.

[0012] To address the bioavailability and production process compatibility issues encountered in the aforementioned experiments, this invention, through extensive experimental trials, has finally found a technical solution that balances bioequivalence and production feasibility by precisely controlling the matching relationship between drug particle size and hydroxypropyl cellulose dosage. The details are as follows:

[0013] The present invention relates to minodronic acid tablets, comprising minodronic acid of a specific particle size, hydroxypropyl cellulose, and pharmaceutical excipients, wherein the weight ratio of minodronic acid to hydroxypropyl cellulose is 1:0.06-0.6.

[0014] The particle size of minodronic acid and the weight ratio of minodronic acid to hydroxypropyl cellulose (HPC) must meet the following matching relationship: when the particle size D50 of minodronic acid is ≤6μm and >4μm, the weight ratio of minodronic acid to hydroxypropyl cellulose (HPC) is 1:0.4-0.6; when the particle size D50 of minodronic acid is ≤4μm and >2μm, the weight ratio of minodronic acid to HPC is 1:0.2-0.4; when the particle size D50 of minodronic acid is ≤2μm and >1μm, the weight ratio of minodronic acid to HPC is 1:0.06-0.2.

[0015] Preferably, the particle size of minodromic acid is D50 ≤ 2 μm and > 1 μm, and the weight ratio of minodromic acid to hydroxypropyl cellulose is 1:0.06-0.2; more preferably, the weight ratio of minodromic acid to hydroxypropyl cellulose is 1:0.08.

[0016] The hydroxypropyl cellulose is selected from one or more of the following: viscosity range of 2.0 mPa·s to 400.0 mPa·s.

[0017] The pharmaceutical excipients include fillers, disintegrants, and lubricants.

[0018] The filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, dextrin, pregelatinized starch, and starch-lactose complex.

[0019] The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose.

[0020] The lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and zinc stearate.

[0021] The present invention also provides a method for preparing the above-mentioned minodronic acid tablets, specifically including the following steps: mixing minodronic acid with a pharmaceutically acceptable filler evenly, granulating with an aqueous binder solution, drying, mixing evenly with a pharmaceutically acceptable disintegrant and lubricant, and finally compressing into tablets to obtain minodronic acid tablets. Film coating can be selectively performed, and the film coating material is not limited. A film coating premix (gastric-soluble type) can be selected, with components including hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc, and red iron oxide. The coating weight gain is 2% to 5%.

[0022] Compared with existing technologies, this invention precisely controls the particle size D50 of minodronic acid to 1~6μm and matches it with hydroxypropyl cellulose at a weight ratio of 1:0.06~0.6 according to particle size grades. This synergistically solves the core problems of minodronic acid tablets, such as stickiness, poor dissolution, low bioavailability, and difficulty in industrial production, achieving the following key technical effects:

[0023] 1. Production Feasibility: Precise matching of particle size and ratio completely eliminates the problem of tablet sticking during compression, resulting in tablets with regular appearance and uniform content, suitable for large-scale production.

[0024] 2. Excellent dissolution: Dissolution rate ≥85% at 15 min, far exceeding the pharmacopoeia requirements; no significant decrease in dissolution after accelerated stability test, indicating good formulation stability.

[0025] 3. Bioequivalence: The AUC confidence interval of the original drug is within the equivalent range, the bioavailability meets the standard, and it conforms to the narrow absorption window characteristics of the drug.

[0026] The key to this invention is the precise matching of minodronic acid particle size and the weight ratio of hydroxypropyl cellulose. Simply adjusting the particle size or the amount of binder cannot simultaneously achieve production, dissolution, and bioequivalence. Only by synergistic matching of the two can the industrial production of minodronic acid tablets and clinical efficacy be unified. Detailed Implementation

[0027] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0028] Example 1: Minodronic acid tablets

[0029] prescription: Minodronic acid 5.0g; Mannitol 15.0g; Lactose 5.0g; Hydroxypropyl cellulose SL 2.8g; 3.0g of croscarmellose sodium cellulose; Magnesium stearate 0.6g; 0.8g of film coating premix.

[0030] Preparation process:

[0031] Minophosphonic acid was micronized to a particle size D50 of 5.5 μm. Mannitol, minophosphonic acid, and lactose were added to a fluidized bed for premixing. Hydroxypropyl cellulose was used to prepare an 8% aqueous solution. The premixed powder was granulated. The dry granules were then mixed with the prescribed amounts of cross-linked carboxymethyl cellulose sodium and magnesium stearate. The mixture was then compressed into tablets and coated to obtain the final product.

[0032] Example 2: Minodronic acid tablets

[0033] prescription: Minodronic acid 5.0g; Lactose 10.0g; 10.0g of microcrystalline cellulose; Hydroxypropyl cellulose SL 1.4g; 3.0g of croscarmellose sodium cellulose; Magnesium stearate 0.5g; 0.9g of film coating premix.

[0034] Preparation process:

[0035] Minophosphonic acid was micronized to a particle size D50 of 3.6 μm. Minophosphonic acid and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 6% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of cross-linked carboxymethyl cellulose sodium and magnesium stearate, compressed into tablets, and coated to obtain the final product.

[0036] Example 3: Minodronic acid tablets

[0037] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 0.4g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0038] Preparation process

[0039] Minophosphonic acid was micronized to a particle size D50 of 1.9 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0040] Example 4: Minodronic acid tablets

[0041] prescription: Minodronic acid 5.0g; 6.0g of starch; Lactose 14.0g; Hydroxypropyl cellulose SL 2.0g; 3.8g of croscarmellose sodium cellulose; Sodium stearate 0.6g; Magnesium stearate 0.3g; 0.6g of film coating premix.

[0042] Preparation process:

[0043] Minophosphonic acid was micronized to a particle size D50 of 2.6 μm. Starch, minophosphonic acid, and lactose were added to a fluidized bed for premixing. The premixed powder was granulated using an 8% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0044] Example 5: Minodrotic acid tablets

[0045] prescription: Minodronic acid 5.0g; Mannitol 18.0g; Microcrystalline cellulose 1.0g; Hydroxypropyl cellulose SL 2.1g; 5.0g of croscarmellose sodium cellulose; Magnesium stearate 0.6g; 1.2g of film coating premix.

[0046] Preparation process:

[0047] Minophosphonic acid was micronized to a particle size D50 of 4.3 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 9% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of cross-linked carboxymethyl cellulose sodium and magnesium stearate, compressed into tablets, and coated to obtain the final product.

[0048] Example 6: Minodronic acid tablets

[0049] prescription: Minodronic acid 5.0g; 12.0g of pregelatinized starch; Starch-lactose complex 8.0g; Hydroxypropyl cellulose (SSL) 2.5g; Sodium carboxymethyl starch 3.2g; Zinc stearate 0.7g; 0.8g of film coating premix.

[0050] Preparation process:

[0051] Minophosphonic acid was micronized to a particle size D50 of 5.8 μm. Pregelatinized starch, starch-lactose complex, and minophosphonic acid were added to a fluidized bed and premixed. The premixed powder was granulated using a 10% hydroxypropyl cellulose SSL aqueous solution. The dry granules were then mixed with the prescribed amount of sodium carboxymethyl starch and zinc stearate, compressed into tablets, and coated to obtain the final product.

[0052] Example 7: Minodrotic acid tablets

[0053] prescription: Minodronic acid 5.0g; 9.0g of dextrin; Microcrystalline cellulose 11.0g; Hydroxypropyl cellulose L 1.5g; Cross-linked polyvinylpyrrolidone 2.8g; Sodium stearate 0.6g; 0.7g of film coating premix.

[0054] Preparation process:

[0055] Minophosphonic acid was micronized to a particle size D50 of 3.2 μm. Dextrin, microcrystalline cellulose, and minophosphonic acid were premixed in a fluidized bed. The premixed powder was granulated using a 7% hydroxypropyl cellulose L aqueous solution. The dry granules were then mixed with the prescribed amount of crospovidone and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0056] Example 8: Minodronic acid tablets

[0057] prescription: Minodronic acid 5.0g; 7.0g of starch; Lactose 13.0g; Hydroxypropyl cellulose ELF 0.5g; Low-substituted hydroxypropyl cellulose 3.0g; Magnesium stearate 0.4g; Zinc stearate 0.3g; 0.9g of film coating premix.

[0058] Preparation process:

[0059] Minophosphonic acid was micronized to a particle size D50 of 1.5 μm. Starch, lactose, and minophosphonic acid were premixed in a fluidized bed. The premixed powder was granulated using a 6% hydroxypropyl cellulose ELF aqueous solution. The dry granules were then mixed with the prescribed amount of low-substituted hydroxypropyl cellulose, magnesium stearate, and zinc stearate, compressed into tablets, and coated to obtain the final product.

[0060] Example 9: Minodronic acid tablets

[0061] prescription: Minodronic acid 5.0g; Mannitol 14.0g; 6.0g of pregelatinized starch; Hydroxypropyl cellulose SL 1.2g; Hydroxypropyl cellulose (SSL) 1.05g; Crosslinked sodium carboxymethyl cellulose 2.5g; Sodium carboxymethyl starch 1.5g; Sodium stearate 0.8g; 1.0g of film coating premix.

[0062] Preparation process:

[0063] Minophosphonic acid was micronized to a particle size D50 of 4.8 μm. Mannitol, pregelatinized starch, and minophosphonic acid were added to a fluidized bed for premixing. The premixed powder was granulated using a 9% hydroxypropyl cellulose aqueous solution. The dry granules were mixed with the prescribed amount of disintegrant and lubricant, compressed into tablets, and coated to obtain the final product.

[0064] Example 10: Minodronic acid tablets

[0065] prescription: Minodronic acid 5.0g; 10.0g of microcrystalline cellulose; 10.0g of dextrin; Hydroxypropyl cellulose ELF 1.25g; Low-substituted hydroxypropyl cellulose 2.0g; Cross-linked polyvinylpyrrolidone 1.8g; Magnesium stearate 0.6g; 0.8g of film coating premix.

[0066] Preparation process:

[0067] Minophosphonic acid was micronized to a particle size D50 of 2.2 μm. Microcrystalline cellulose, dextrin, and minophosphonic acid were added to a fluidized bed for premixing. The premixed powder was granulated using an 8% hydroxypropyl cellulose ELF aqueous solution. The dry granules were mixed with the prescribed amount of disintegrant and lubricant, compressed into tablets, and coated to obtain the final product.

[0068] Comparative Example 1: Minodronic acid tablets

[0069] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 0.4g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0070] Preparation process:

[0071] Minophosphonic acid was micronized to a particle size D50 of 6 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0072] Comparative Example 2: Minodronic acid tablets

[0073] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 0.4g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0074] Preparation process:

[0075] Minophosphonic acid was micronized to a particle size D50 of 2.1 μm. Mannitol, minophosphonic acid, microcrystalline cellulose, and hydroxypropyl cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using purified water. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0076] Comparative Example 3: Minodronic acid tablets

[0077] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 0.2g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0078] Preparation process:

[0079] Minophosphonic acid was micronized to a particle size D50 of 1.0 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0080] Comparative Example 4: Minodronic acid tablets

[0081] prescription: Minodronic acid 5.0g; Mannitol 15.8g; Microcrystalline cellulose 4.5g; Hydroxypropyl cellulose SL 1.2g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0082] Preparation process:

[0083] Minophosphonic acid was micronized to a particle size D50 of 0.6 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0084] Comparative Example 5: Minodrotic Acid Tablets

[0085] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 0.5g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0086] Preparation process

[0087] Minophosphonic acid was micronized to a particle size D50 of 3.5 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0088] Comparative Example 6: Minodronic acid tablets

[0089] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 1.5g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0090] Preparation process

[0091] Minophosphonic acid was micronized to a particle size D50 of 5.5 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0092] Comparative Example 7: Minodrotic Acid Tablets

[0093] prescription: Minodronic acid 5.0g; Mannitol 15.8g; 4.5g of microcrystalline cellulose; Hydroxypropyl cellulose SL 1.5g; Crosslinked sodium carboxymethyl cellulose 2.9g; Magnesium stearate 0.6g; Sodium stearate 0.9g; 0.9g of film coating premix.

[0094] Preparation process

[0095] Minophosphonic acid was micronized to a particle size D50 of 1.9 μm. Mannitol, minophosphonic acid, and microcrystalline cellulose were added to a fluidized bed for premixing. The premixed powder was granulated using a 7% hydroxypropyl cellulose aqueous solution. The dry granules were then mixed with the prescribed amounts of croscarmellose sodium, magnesium stearate, and sodium stearate fumarate, compressed into tablets, and coated to obtain the final product.

[0096] Determination of adhesion and impact

[0097] The adhering weight method was used to measure the weight of material adhering to the punch surface after 1000 tablet compressions, reflecting the severity of punch adhesion. Before tablet compression, the weight of the cleaned punch was accurately measured (denoted as W0). With fixed compression parameters (pressure, speed, material batch), 1000 tablets were continuously compressed. After stopping compression, the material adhering to the punch surface was wiped with lint-free paper, and the total weight of the lint-free paper and adhering material after wiping was accurately measured (denoted as W1). Simultaneously, the weight of the blank lint-free paper was measured (denoted as W2). The adhering weight per compression was calculated as follows: Adhering weight (mg / compression) = (W1 - W2) / 1000.

[0098] Judgment criteria: Adhesion weight < 0.01 mg / stroke is acceptable; 0.01~0.1 mg / stroke is slight adhesion; > 0.1 mg / stroke is moderate / severe adhesion.

[0099] Table 1. Weight and Appearance of Sub-adhesion

[0100] Dissolution test

[0101] The dissolution rate of minodronic acid tablets was determined by high-performance liquid chromatography (HPLC) using an octadecylsilane-bonded silica column; the mobile phase was 0.1% phosphoric acid solution-methanol (80:20); the flow rate was 1.0 mL / min; and the detection wavelength was 223 nm. Separately, an appropriate amount of minodronic acid reference standard was accurately weighed, dissolved in methanol, and diluted to prepare a solution containing approximately 56 μg per mL, which served as the reference solution. 10 µL of each of the two solutions was accurately injected into the HPLC system, and the chromatograms were recorded. The dissolution rate of minodronic acid in the test solution was calculated using the external standard method based on the peak area. The dissolution rate of this product within 15 min should not be less than 85% of the labeled amount (Q).

[0102] Dissolution medium: water, medium volume: 900 ml, stirring speed: 50 rpm. The dissolution rate determination method was based on Method II of Dissolution and Release Determination, Part IV, Chinese Pharmacopoeia 2025 Edition, Volume IV. The results are shown in Table 2.

[0103] Table 2 Dissolution test results

[0104] Pharmacokinetic studies

[0105] The formulations prepared according to the embodiments and comparative embodiments of the present invention, and commercially available minodronate tablets (trade name: Bonoteo) ® A fasting pharmacokinetic study was conducted in 12 healthy adults per group. Each adult was given a 50 mg dose of minodronate orally once 12 hours prior to administration, along with 250 ml of warm water. Blood samples were collected from subcutaneous veins at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration. The blood concentrations were measured in heparinized test tubes, similar to those of commercially available minodronate tablets (brand name: Bonoteo). ® By comparison, the confidence interval of AUC was calculated, and the results are shown in Table 2.

[0106] Table 3 Pharmacokinetic Test Results

[0107] Systematic verification through three experiments—adhesion degree, dissolution and stability, and pharmacokinetics—demonstrates that the technical solution of this invention, which controls the D50 of minodronic acid to 1-6 μm and precisely mixes it with hydroxypropyl cellulose at a ratio of 1:0.06-0.6, can simultaneously achieve triple optimization of formulation feasibility, in vitro dissolution stability, and in vivo bioequivalence. Experimental data show that in the embodiment of this invention with precise particle size-binder ratio, the adhesion weight of the tableting punch is <0.01 mg / punch, with no adhesion and a smooth and flat tablet appearance, meeting the requirements for large-scale production; the dissolution rate at 15 min is ≥85%, far exceeding the pharmacopoeia standard, and the dissolution rate does not decrease significantly after 6 months of accelerated dissolution at 40℃ and 75%RH, indicating excellent formulation stability; at the same time, the AUC confidence interval of the original drug Bonoteo® is within the equivalent range, achieving bioequivalence. Comparative samples deviating from the D50 range of 1~6μm or the hydroxypropyl cellulose ratio of this invention cannot simultaneously achieve the above effects: they may exhibit mild / moderate / severe sticking and tablet appearance defects, making industrial production impossible; they may have substandard dissolution and poor stability, making it difficult to guarantee clinical dissolution requirements; or they may be bioequivalent to the original drug, failing to achieve therapeutic equivalence. These results fully demonstrate that simple micronization or adjusting the amount of hydroxypropyl cellulose alone cannot solve the combined problems of sticking, insufficient dissolution, and low bioavailability in minodronic acid tablets. Only by precisely controlling the D50 of minodronic acid within the range of 1~6μm and synergistically matching it with hydroxypropyl cellulose in a specific ratio can the excellent effect of unifying production, dissolution, and bioequivalence be achieved.

Claims

1. A minodronic acid tablet, characterized in that, The minodronic acid tablets contain minodronic acid, hydroxypropyl cellulose, and pharmaceutically acceptable excipients; when the minodronic acid particle size D50 is less than or equal to 2 μm and greater than 1 μm, the weight ratio of minodronic acid to HPC is 1:0.06 to 0.

2.

2. The minodronic acid tablets according to claim 1, characterized in that, The hydroxypropyl cellulose is selected from one or more of the following: viscosity range of 2.0 mPa·s to 400.0 mPa·s.

3. A minodronic acid tablet according to claim 1, characterized in that, The pharmaceutical excipients mentioned are fillers, disintegrants, and lubricants.

4. A minodronic acid tablet according to claim 3, characterized in that, The filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, dextrin, pregelatinized starch, and starch-lactose complex.

5. A minodronic acid tablet according to claim 3, characterized in that, The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose.

6. A minodronic acid tablet according to claim 3, characterized in that, The lubricant is one or more of magnesium stearate, sodium stearate fumarate, and zinc stearate.

7. A method for preparing minodronic acid tablets according to claim 1, characterized in that, Includes the following steps: Minophosphonic acid is micronized, mixed with a filler to obtain a premixed powder, granulated using an aqueous solution of hydroxypropyl cellulose, and then a disintegrant and a lubricant are added, mixed, compressed into tablets, and optionally coated.

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