High-stability rosaxostat orally disintegrating tablet and moisture-proof composition thereof

Abstract

The invention discloses a high-stability rosaxostat orally disintegrating tablet and a moisture-proof composition thereof, and belongs to the technical field of pharmaceutical preparations. The rosaxostat orally disintegrating tablet comprises rosaxostat, a solubilizing stabilizer, a disintegrating agent, a filling agent and a lubricating agent. The drug degradation is inhibited through a wet grinding process, the dissolution efficiency is improved, and the stability of the preparation is remarkably improved in combination with damp-proof packaging of an aluminum-plastic blister composite film.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a highly stable roxadustat orally disintegrating tablet and its moisture-proof composition. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Roxadustat is a potent reversible hypoxia-inducible factor prolyl hydroxylase inhibitor. Roxadustat can transiently stabilize and activate the hypoxia-inducible factor transcription factor, initiate an adaptive transcriptional response, and thus, under normal oxygen content conditions, simulate the erythropoietic response that occurs only in the hypoxic environment of the human body, including the production of endogenous erythropoietin and iron mobilization by reducing hepcidin, ultimately inducing erythropoiesis and improving anemia. The roxadustat capsule was first successfully launched in China in December 2018 under the trade name Aeriduo, and is used to treat anemia caused by chronic kidney disease, including dialysis and non-dialysis patients.

[0004] Chinese Patent No. CN113855638A discloses a roxadustat pharmaceutical preparation, which specifically includes roxadustat, cyclodextrin derivative, potassium polacrylate, diluent and disintegrant. Although the hydrophobicity is improved by cyclodextrin inclusion, the problem of moisture absorption of the tablet in a high-humidity environment is not solved, and the dissolution rate still shows a downward trend in the accelerated test.

[0005] The patent with publication number WO2014197660A1 uses an effective amount of a light stabilizer to increase the stability of the roxadustat pharmaceutical preparation, so that the photodegradation products of the pharmaceutical preparation are less than about 0.2% w / w.

[0006] Currently, the oral solid preparations of roxadustat used in clinical practice are mostly ordinary tablets or capsules. However, due to the poor water solubility of the drug, the oral bioavailability is relatively low, and it is significantly affected by the gastrointestinal environment. In recent years, orally disintegrating tablets have become a research hotspot due to their characteristics of not requiring water for administration, rapid disintegration, and rapid onset of action. However, roxadustat itself is sensitive to humidity and is prone to moisture absorption during storage, resulting in the degradation of the active ingredient, which affects the stability and shelf life of the drug.

[0007] Existing technical solutions only optimize for a single performance (such as dissolution rate or light stability), lacking systematic integrated design of the functionality of the preparation. For example, the moisture-proof layer (such as film coating) usually requires sacrificing the disintegration speed, while the introduction of super disintegrants will exacerbate the risk of moisture absorption. This contradiction makes it impossible for the existing technology to simultaneously meet the multiple requirements of roxadustat orally disintegrating tablets for "rapid disintegration, high dissolution rate, and long-term stability", and there is an urgent need for an innovative solution based on multi-dimensional coordinated regulation. Summary of the Invention

[0008] Overcoming the deficiencies of the prior art, the present invention provides a roxadustat orally disintegrating tablet with rapid disintegration, high dissolution rate, and long-term stability.

[0009] The roxadustat orally disintegrating tablet of the present invention is calculated by weight as follows: 20 parts of roxadustat, 9 - 15 parts of solubilizing and stabilizing agent, 10 - 25 parts of disintegrant, 100 - 300 parts of filler, and 1 - 3 parts of lubricant. The roxadustat orally disintegrating tablet is prepared by wet grinding the roxadustat and solubilizing and stabilizing agent, and then directly tabletting with the disintegrant, filler, and lubricant.

[0010] The solubilizing and stabilizing agent is glycine and L-asparagine with a mass ratio of 1 - 3:1; the disintegrant is selected from at least one of potassium polacrilin, crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; the filler is selected from at least one of starch, mannitol, sucrose, and lactose; the lubricant is selected from at least one of colloidal silicon dioxide, talc, and magnesium stearate.

[0011] Further, the wet grinding step is: mixing roxadustat and solubilizing and stabilizing agent, adding ethanol, grinding, with a rotation speed of 2500 - 3500 rpm, a time of 30 - 50 min, and a temperature of 2 - 8°C.

[0012] The particle size of roxadustat is detected by Mastersizer 3000, and D90 of roxadustat in the present invention is < 31.9 μm.

[0013] The present invention also provides a moisture-proof composition, which consists of the above-mentioned roxadustat orally disintegrating tablet and a moisture-proof protective package. The moisture-proof protective package is a polyvinyl chloride foil covered with aluminum foil, and the moisture-proof protective package is a cold-sealed blister.

[0014] Compared with the prior art, the technical effect of the present invention is as follows:

[0015] The present invention adopts a double - amino - acid synergistic wet - grinding process for solubilization and stabilization technology. Using a specific mass ratio of glycine and L - asparagine as solubilizing and stabilizing agents, at low temperature, an ethanol solvation grinding method is employed. Through their synergistic effect, roxadustat is encapsulated to inhibit drug degradation and improve dissolution efficiency. Additionally, in combination with a packaging material of polyvinyl chloride foil covered with cold - sealed aluminum foil, the stability of the roxadustat orally disintegrating tablets of the present invention can be further enhanced. Description of the Drawings

[0016] Figure 1 : Changes in the content of the active ingredient during the tests of Formulas 1 - 7.

[0017] Figure 2 : Changes in the total impurity content of the moisture - proof compositions 1 - 6 during the tests.

[0018] Figure 3 : Structural formulas of Impurities 1 - 5. Detailed Description of the Invention

[0019] In order to make the objectives and technical solutions of the present invention clearer, the following, in combination with embodiments, further describes the present invention. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Example 1 Roxadustat Orally Disintegrating Tablets

[0021] Formulation:

[0022]

[0023] Preparation method:

[0024] (1) Mix roxadustat and the solubilizing and stabilizing agent, add 10 ml of anhydrous ethanol, grind at a grinding speed of 3000 rpm for 40 min at a temperature of 4°C to obtain a roxadustat mixture.

[0025] (2) Mix the roxadustat mixture with the disintegrant, dry, then add the filler and lubricant, mix, and press tablets to obtain roxadustat orally disintegrating tablets.

[0026] Example 2 Roxadustat Orally Disintegrating Tablets

[0027] Formulation:

[0028]

[0029]

[0030] Preparation method:

[0031] (1) Mix roxadustat and solubilizing stabilizer, add 8 ml of absolute ethanol, and grind at a grinding speed of 2500 rpm for 30 min at a temperature of 2°C to obtain a roxadustat mixture.

[0032] (2) Mix the roxadustat mixture with a disintegrant, dry it, then add a filler and a lubricant, mix, and press into tablets to obtain roxadustat orally disintegrating tablets.

[0033] Example 3 Roxadustat Orally Disintegrating Tablets

[0034] Formulation:

[0035]

[0036] Preparation method:

[0037] (1) Mix roxadustat and solubilizing stabilizer, add 12 ml of absolute ethanol, and grind at a grinding speed of 3500 rpm for 50 min at a temperature of 8°C to obtain a roxadustat mixture.

[0038] (2) Mix the roxadustat mixture with a disintegrant, dry it, then add a filler and a lubricant, mix, and press into tablets to obtain roxadustat orally disintegrating tablets.

[0039] Stability and Dissolution of Roxadustat Orally Disintegrating Tablets

[0040] The following item detections are all carried out in accordance with the Chinese Pharmacopoeia. The impurities and the content of the active ingredient are detected by high performance liquid chromatography, and the dissolution is the paddle method.

[0041] Table 1 Stability and Dissolution of Roxadustat Orally Disintegrating Tablets in Examples 1 to 3

[0042]

[0043] Note: Test conditions: temperature 40±2°C, relative humidity 75%±5%, illuminance 4500 lx±500 lx.

[0044] The present invention uses two amino acids as solubilizing stabilizers, utilizes the wet grinding process, and improves the drug dispersibility and the stability of roxadustat through synergistic effects. The dissolution rates of Examples 1 to 3 on the 0th day and the 180th day both exceed 99%, indicating that the drug can be rapidly released in vivo and meet the treatment requirements. The contents of roxadustat orally disintegrating tablets (Al-PVDC cold-sealed blister packaging) in Examples 1 to 3 are always close to 100%, and the total impurity increase is extremely low, proving that the formulation of the present invention can effectively inhibit drug degradation and extend the shelf life.

[0045] It should be noted that only partial data are listed in the application documents of the present invention. For example, the inventors have recorded relevant experiments such as impurities 1-5, active ingredient content, disintegration time limit, dissolution rate, etc. on the 30th day and 90th day during the experiment. Since some experimental data can clearly express and compare the technical effects, they are not shown here. If needed during the examination process, they can be provided. Additionally, the solubilizing stabilizers are 9g, 10g, 11g, 12g, 13g, 14g, 15g, and the weight ratio of glycine to L-asparagine is 2:1; the solubilizing stabilizers are 9g, 10g, 11g, 12g, 13g, 14g, 15g, and the weight ratio of glycine to L-asparagine is 1:1; the solubilizing stabilizers are 9g, 10g, 11g, 12g, 13g, 14g, 15g, and the weight ratio of glycine to L-asparagine is 3:1. The active ingredient content, impurity content, disintegration time limit, and dissolution rate data of the roxadustat orally disintegrating tablets prepared are similar to those in Examples 1-3 of Table 1, and the data difference is less than 0.5%.

[0046] Screening of solubilizing stabilizers

[0047] Based on the basic formula and preparation process of Example 1, the effects of solubilizing stabilizers were screened.

[0048] Table 2 Formulations for screening solubilizing stabilizers

[0049]

[0050]

[0051] Note: Other conditions are the same as in Example 1.

[0052] Table 3 Effect of solubilizing stabilizers on the content of roxadustat

[0053]

[0054] Note: Test conditions: temperature 40±2°C, relative humidity 75%±5%, illuminance 4500lx±500lx.

[0055] Table 4 Effect of solubilizing stabilizers on impurity content

[0056]

[0057]

[0058] Note: Test conditions: temperature 40±2°C, relative humidity 75%±5%, illuminance 4500lx±500lx.

[0059] Examples 1, Formulations 1-7 all use Al-PVDC cold-sealed blister packaging. Tables 2-4 Figure 1Analysis shows that the present invention uses a certain proportion of glycine + L-asparagine as the solubilizing and stabilizing agent combination for roxadustat orally disintegrating tablets, showing optimal stability and quality control effects. In the test (40°C / 75% RH / 4500 lx), the content of the active ingredient in the roxadustat orally disintegrating tablets of Example 1 only decreased by 0.06% in 180 days, and the total impurity content was low, significantly better than other formulations (such as glycine or L-asparagine alone, where the content of the active ingredient decreased by nearly 2%). The synergistic effect of glycine and L-asparagine effectively delays drug degradation, inhibits impurity generation, and has better cost-effectiveness than polymer materials (such as Formulation 6). The formulation without a stabilizer (Formulation 7) has the worst stability, with a total impurity of up to 0.67%. Considering the factors of stability, impurity control, and cost, the amino acid composite stabilizer scheme of the present invention provides a reliable technical path for industrial production.

[0060] Table 5 Effects of solubilizing and stabilizing agents on dissolution and disintegration

[0061]

[0062] Note: Test conditions: temperature 40 ± 2°C, relative humidity 75% ± 5%, illuminance 4500 lx ± 500 lx.

[0063] As can be seen from Table 5, the best solubilizing and stabilizing agent combination is glycine + L-asparagine, which can not only maintain the disintegration time but also ensure the dissolution rate. Using a single stabilizer alone (such as glycine or L-asparagine) or using a traditional solubilizing system (such as Formulation 6) generally has average performance effects. The formulation without a solubilizing and stabilizing agent (Formulation 7) has the worst stability.

[0064] Addition method of solubilizing and stabilizing agents

[0065] Based on the basic formulation and preparation process of Example 1, the effects of solubilizing and stabilizing agents were screened.

[0066] Table 6 Screening of the addition method of solubilizing and stabilizing agents

[0067]

[0068] Note: Other conditions are the same as those in Example 1 (Al-PVDC cold-sealed blister packaging)

[0069] Table 7 Effects of the addition method of solubilizing and stabilizing agents on stability and dissolution

[0070]

[0071] Note: Test conditions: temperature 40 ± 2°C, relative humidity 75% ± 5%, illuminance 4500 lx ± 500 lx.

[0072] Analysis of Table 7 shows that considering comprehensive stability (total impurity control and active ingredient content), dissolution rate, and disintegration speed, Method 3 (wet grinding addition) is the optimal process, which can significantly improve the preparation quality of roxadustat orally disintegrating tablets. The wet grinding process of the present invention effectively reduces drug particle aggregation through the solvation of ethanol, and at the same time enhances the encapsulation of the surface of roxadustat by solubilizing stabilizers (glycine, asparagine), improving the system stability; grinding further promotes the interaction between the stabilizer and the drug molecules, forming a more uniform dispersion system, thus significantly improving the dissolution efficiency; in addition, the loose and porous structure formed after drying the wet granules accelerates water penetration and shortens the disintegration time, ultimately achieving the synergistic optimization of preparation stability, dissolution performance, and disintegration rate.

[0073] Moisture-proof protection packaging and packaging method

[0074] Table 8 Moisture-proof compositions 1 - 6

[0075]

[0076]

[0077] Place moisture-proof compositions 1 - 6 in an environment with test conditions of temperature 40 ± 2°C, relative humidity 75% ± 5%, and illuminance 4500 lx ± 500 lx. Sampling is carried out on the 0th day, 30th day, 90th day, and 180th day to detect the contents of impurities 1 - 5, and calculate the total impurity content and the content of the active ingredient roxadustat. The content of the active ingredient roxadustat in moisture-proof compositions 1 - 3 is 99.98% ± 0.01 on the 180th day of the test. Figure 2 For the change in the total impurity content of moisture-proof compositions 1 - 6 during the test, compared with the total impurity content of roxadustat orally disintegrating tablets in Examples 1 - 3 in Table 1 during the test period, the impurity content of the compositions after moisture-proof packaging is lower and the stability is higher. However, it is also crucial to select appropriate packaging materials and blister sealing methods.

[0078] It should be noted that only partial data are listed in the application documents of the present invention because the applicant believes that the data can clearly express and compare the technical effects.

Claims

1. A roxadustat orally disintegrating tablet, characterized in that, The roxadustat orally disintegrating tablets are calculated by weight as follows: roxadustat 20 parts, solubilizing stabilizer 9 - 15 parts, disintegrant 10 - 25 parts, filler 100 - 300 parts, lubricant 1 - 3 parts. The roxadustat orally disintegrating tablets are prepared by wet grinding to mix roxadustat and solubilizing stabilizer, and then directly tabletting with disintegrant, filler and lubricant.

2. The roxadustat orally disintegrating tablet according to claim 1, wherein The solubilizing stabilizer is glycine and L - asparagine with a mass ratio of 1 - 3:1; preferably, the solubilizing stabilizer is glycine and L - asparagine with a mass ratio of 2:

1.

3. The roxadustat orally disintegrating tablet according to claim 1, wherein The disintegrant is selected from at least one of potassium polacrilate, crospovidone, sodium carboxymethyl starch, low - substituted hydroxypropyl cellulose; preferably, the disintegrant is potassium polacrilate.

4. The roxadustat orally disintegrating tablet according to claim 1, wherein The filler is selected from at least one of starch, mannitol, sucrose, lactose; preferably, the filler is starch and mannitol.

5. The roxadustat orally disintegrating tablet according to claim 1, wherein The lubricant is selected from at least one of colloidal silicon dioxide, talc, magnesium stearate; preferably, the lubricant is colloidal silicon dioxide.

6. The roxadustat orally disintegrating tablet according to claim 1, wherein The wet grinding step is: mixing roxadustat and solubilizing stabilizer, adding ethanol, grinding, with a rotation speed of 2500 - 3500 rpm, a time of 30 - 50 min, and a temperature of 2 - 8°C.

7. The roxadustat orally disintegrating tablet according to claim 1, wherein The D90 of the roxadustat is < 30 μm.

8. A moisture-proof composition, characterized in that, The moisture - proof composition consists of the roxadustat orally disintegrating tablets as described in claim 1 and a moisture - proof protective package.

9. The moisture-proof composition according to claim 8, wherein The moisture - proof protective package is a polyvinyl chloride foil covered with aluminum foil.

10. The moisture-proof composition according to claim 8, wherein The moisture - proof protective package is a cold - seal blister.

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