A rimexolane sulfate orally disintegrating tablet and a method for preparing the same
Remegapan sulfate orally disintegrating tablets were prepared by direct powder compression. By using a combination of excipients such as microcrystalline cellulose, the problems of fragility and high cost of lyophilized remegapan sulfate tablets were solved, and orally disintegrating tablets with rapid disintegration and good stability were achieved, which are suitable for industrial production.
Patent Information
- Application Number
- CN202510111018.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-23
- Publication Date
- 2026-07-24
Smart Images
Figure BDA0005256641440000031 
Figure BDA0005256641440000032 
Figure BDA0005256641440000041
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a pan-disintegrating tablet of retamiprid sulfate and its preparation method. Background Technology
[0002] Migraine is a common neurological disorder characterized by recurrent, usually unilateral, moderate to severe throbbing headaches, often accompanied by nausea, vomiting, photophobia, and phonophobia. The WHO lists migraine as the third most common disease worldwide, and it ranks second in healthy years of life lost due to disability (YLD), making it the second leading cause of disability globally, especially among women under 50. Currently, there are approximately 1.3 billion migraine sufferers worldwide, with an annual prevalence of 15%. In my country, the annual prevalence is approximately 9.3%, affecting about 130 million people. The female-to-male ratio is approximately 3:1, meaning about 1 in 10 people suffer from migraines. Migraines typically begin in adolescence, with a significantly increased incidence after age 20, peaking between 35 and 39 years of age.
[0003] Remdesivir sulfate orally disintegrating tablets are currently the only CGRP receptor antagonist approved by the US FDA for both acute and preventative treatment of migraines, marking a milestone in the specific treatment of migraines. According to the 2022 revised edition of the "Chinese Guidelines for the Prevention and Treatment of Migraines," nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans are currently the main acute-phase treatments for migraines in China. However, frequent or prolonged use of these analgesics can lead to drug overuse headache (MOH), exacerbating migraine symptoms. Most traditional oral preventative treatments (such as beta-blockers, antiepileptic drugs, and tricyclic antidepressants) were not specifically developed for migraines, resulting in poor patient adherence. Therefore, the guidelines added detans and lemmas to the existing triptans for specific acute-phase treatment of migraines. Remdesivir, representing lemmas, is suitable for patients with contraindications to NSAIDs and triptans or those who have not responded to these treatments, providing a better and more comprehensive range of suitable options for patients.
[0004] Currently, the marketed dosage form of retemapam sulfate is orally disintegrating tablets, which are lyophilized suspension emulsion tablets with a high drug loading. These tablets are fragile and have poor folding resistance, posing significant challenges for packaging and transportation. Furthermore, lyophilized tablet production involves small batches, high energy consumption, and high production costs. As a novel CGRP receptor antagonist, the development of a direct compression method for retemapam sulfate orally disintegrating tablet powder can overcome some of the shortcomings of existing orally disintegrating tablets, enabling large-scale commercial production, reducing production costs, and improving production efficiency. Summary of the Invention
[0005] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a remdesivir sulfate orally disintegrating tablet and its preparation method. The preparation process provided by this invention is a direct powder compression method, including the following steps: mixing remdesivir sulfate, filler, disintegrant, lubricant, flavoring agent, and aromatic agent, followed by compression to obtain remdesivir sulfate orally disintegrating tablets; the remdesivir sulfate orally disintegrating tablets prepared by this invention, when tested using an orally disintegrating disintegration analyzer, can rapidly disintegrate within 60 seconds, with a fast dissolution rate. This invention does not require granulation, has a simple process, and solves the problem of high production costs associated with the original freeze-drying process, making it suitable for industrial production.
[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:
[0007] This invention proposes a method for preparing orally disintegrating tablets of Remegapan sulfate, which consists of the following raw and excipient materials in weight percentage: Remegapan 75mg / tablet, filler 30-60%, disintegrant 4.5-15%, lubricant 0.5-4%, flavoring agent 0.5-3%, and fragrance agent 0.5-3%, wherein the particle size distribution of Remegapan sulfate is D90 < 30μm.
[0008] Furthermore, the raw and excipient composition of the orally disintegrating tablets by weight percentage is as follows: Remegapan 75mg / tablet, filler 40-60%, disintegrant 6-13.5%, lubricant 1.0-3%, flavoring agent 1.0-2.0%, and fragrance 1-2%, and the particle size distribution of the Remegapan sulfate is D90 < 15μm.
[0009] The filler includes one or more of microcrystalline cellulose, microcrystalline cellulose colloidal silica co-treated material, and mannitol; preferably, the filler is microcrystalline cellulose colloidal silica co-treated material or microcrystalline cellulose.
[0010] The disintegrant includes one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose; preferably, the disintegrant is low-substituted hydroxypropyl cellulose.
[0011] The lubricant includes one or more of colloidal silica, sodium stearate fumarate, and magnesium stearate; preferably, the lubricant is colloidal silica and sodium stearate fumarate.
[0012] The present invention also provides a method for preparing the orally disintegrating tablets of retemapam sulfate, comprising the following steps: mixing retemapam sulfate with excipients evenly, compressing into tablets to obtain orally disintegrating tablets of retemapam sulfate with a hardness of 30-90N; preferably, the hardness of the orally disintegrating tablets of retemapam sulfate is 50-70N.
[0013] The present invention has the following technical effects:
[0014] 1. Due to its high drug loading and low solubility, Remegapan sulfate makes it difficult for orally disintegrating tablets prepared by ordinary solid dosage form preparation techniques to achieve rapid disintegration. This invention solves the technical difficulties of direct compression process of Remegapan sulfate orally disintegrating tablet powder by utilizing the combination of different excipients, enabling rapid disintegration in an orally disintegrating disintegrator with a disintegration time of less than 60 seconds.
[0015] 2. This invention does not require granulation, has a simple process, produces tablets with high hardness and good stability, and is convenient for transportation and storage. It solves the problem of high production cost of the original research process using freeze-drying, and is suitable for industrial production. Detailed Implementation
[0016] The following embodiments are for better illustration of the present invention and are not intended to limit the scope of protection of the present invention.
[0017] Example 1: The prescription (dosage per 1000 tablets) for the aforementioned Remdesivir sulfate orally disintegrating tablets is as follows:
[0018]
[0019] The specific preparation method is as follows:
[0020] The prescribed amounts of retemapam sulfate, microcrystalline cellulose colloidal silica co-treated product, colloidal silica, sucralose, and peppermint flavoring were added to a hopper mixer and premixed to obtain premix 1. Premix 1 was then fed into a granulator, sieved, and mixed. Low-substituted hydroxypropyl cellulose was added and mixing continued. After mixing was complete, sodium stearate fumarate was added and the mixture was thoroughly mixed before compression into tablets to obtain retemapam sulfate orally disintegrating tablets.
[0021] The prepared Remdesivir sulfate pan-disintegrating tablets have a smooth and clean appearance, qualified brittleness, a disintegration time of less than 1 minute as measured by the disintegration test, and a dissolution rate of more than 85% as measured by the dissolution test, which meet the requirements.
[0022] Example 2: The prescription (dosage for 1000 tablets) for the aforementioned Remdesivir sulfate orally disintegrating tablets is as follows:
[0023]
[0024]
[0025] The specific preparation method is as follows:
[0026] The prescribed amounts of retemapam sulfate, microcrystalline cellulose, colloidal silica, sucralose, and peppermint flavoring were added to a hopper mixer and premixed to obtain premix 1. Premix 1 was then fed into a granulator, sieved, and mixed. Low-substituted hydroxypropyl cellulose was added and mixing continued. After mixing was complete, sodium stearate fumarate was added and the mixture was thoroughly mixed before compression into tablets to obtain retemapam sulfate orally disintegrating tablets.
[0027] The prepared Remdesivir sulfate pan-disintegrating tablets have a smooth and clean appearance, qualified brittleness, a disintegration time of less than 1 minute as measured by the disintegration test, and a dissolution rate of more than 85% as measured by the dissolution test, which meet the requirements.
[0028] Example 3: The prescription (dosage for 1000 tablets) for the aforementioned Remdesivir sulfate orally disintegrating tablets is as follows:
[0029] name Feed quantity (g, 1000 tablets) Percentage / % effect Remdesivir sulfate 85.67 (75 in Remyquid) 30.6 Active ingredients microcrystalline cellulose 143.93 51.4 filler Low-substituted hydroxypropyl cellulose 35 12.5 Disintegrant colloidal silica 2.8 1 Flow aid Sodium stearate 5.6 2 lubricant Sucralose 2.8 1 Flavoring agents Peppermint flavoring 4.2 1.5 Fragrance total 280 100 /
[0030] The specific preparation method is as follows:
[0031] The prescribed amounts of retemapam sulfate, microcrystalline cellulose, colloidal silica, sucralose, and peppermint flavoring were added to a hopper mixer and premixed to obtain premix 1. Premix 1 was then fed into a granulator, sieved, and mixed. Low-substituted hydroxypropyl cellulose was added and mixing continued. After mixing was complete, sodium stearate fumarate was added and the mixture was thoroughly mixed before compression into tablets to obtain retemapam sulfate orally disintegrating tablets.
[0032] The prepared Remdesivir sulfate pan-disintegrating tablets have a smooth and clean appearance, qualified brittleness, a disintegration time of less than 1 minute as measured by the disintegration test, and a dissolution rate of more than 85% as measured by the dissolution test, which meet the requirements.
[0033] Example 4: The prescription (dosage for 1000 tablets) for the aforementioned Remdesivir sulfate orally disintegrating tablets is as follows:
[0034]
[0035]
[0036] The specific preparation method is as follows:
[0037] The prescribed amounts of retemapam sulfate, microcrystalline cellulose, colloidal silica, sucralose, and peppermint flavoring were added to a hopper mixer and premixed to obtain premix 1. Premix 1 was then fed into a granulator, sieved, and mixed. Low-substituted hydroxypropyl cellulose was added and mixing continued. After mixing was complete, sodium stearate fumarate was added and the mixture was thoroughly mixed before compression into tablets to obtain retemapam sulfate orally disintegrating tablets.
[0038] The prepared Remdesivir sulfate pan-disintegrating tablets have a smooth and clean appearance, qualified brittleness, a disintegration time of less than 1 minute as measured by the disintegration test, and a dissolution rate of more than 85% as measured by the dissolution test, which meet the requirements.
[0039] Example 5: The prescription (dosage for 1000 tablets) for the aforementioned Remdesivir sulfate orally disintegrating tablets is as follows:
[0040] name Feed quantity (g, 1000 tablets) Percentage / % effect Remdesivir sulfate 85.67 (75 in Remyquid) 30.6 Active ingredients microcrystalline cellulose 153.93 55 filler Low-substituted hydroxypropyl cellulose 25 8.9 Disintegrant colloidal silica 2.8 1 Flow aid Sodium stearate 5.6 2 lubricant Sucralose 2.8 1 Flavoring agents Peppermint flavoring 4.2 1.5 Fragrance total 280 100 /
[0041] The specific preparation method is as follows:
[0042] The prescribed amounts of retemapam sulfate, microcrystalline cellulose, colloidal silica, sucralose, and peppermint flavoring were added to a hopper mixer and premixed to obtain premix 1. Premix 1 was then fed into a granulator, sieved, and mixed. Low-substituted hydroxypropyl cellulose was added and mixing continued. After mixing was complete, sodium stearate fumarate was added and the mixture was thoroughly mixed before compression into tablets to obtain retemapam sulfate orally disintegrating tablets.
[0043] The prepared Remdesivir sulfate pan-disintegrating tablets have a smooth and clean appearance, qualified brittleness, a disintegration time of less than 1 minute as measured by the disintegration test, and a dissolution rate of more than 85% as measured by the dissolution test, which meet the requirements.
[0044] Example 6: The prescription (dosage for 1000 tablets) for the aforementioned Remdesivir sulfate orally disintegrating tablets is as follows:
[0045]
[0046]
[0047] The specific preparation method is as follows:
[0048] The prescribed amounts of retemapam sulfate, microcrystalline cellulose, colloidal silica, sucralose, and peppermint flavoring were added to a hopper mixer and premixed to obtain premix 1. Premix 1 was then fed into a granulator, sieved, and mixed. Low-substituted hydroxypropyl cellulose was added and mixing continued. After mixing was complete, sodium stearate fumarate was added and the mixture was thoroughly mixed before compression into tablets to obtain retemapam sulfate orally disintegrating tablets.
[0049] The prepared Remdesivir sulfate pan-disintegrating tablets have a smooth and clean appearance, qualified brittleness, a disintegration time of less than 1 minute as measured by the disintegration test, and a dissolution rate of more than 85% as measured by the dissolution test, which meet the requirements.
[0050] Example 7: All of the above examples meet the quality standards. Finally, the sample produced in Example 2 was selected and packaged. Stability tests were conducted in accordance with the stability requirements of the Chinese Pharmacopoeia.
[0051] Comparison of results for different examples of disintegration time testing of orally disintegrating tablets according to the disintegration time test method in the Chinese Pharmacopoeia:
[0052]
[0053] Stability test results:
[0054]
[0055]
[0056] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A method for preparing remdesivir sulfate orally disintegrating tablets, characterized in that, It is composed of the following raw and auxiliary materials in weight percentage: Remegapan 75mg / tablet, filler 30-60%, disintegrant 4.5-15%, lubricant 0.5-4%, flavoring agent 0.5-3%, and fragrance agent 0.5-3%. The particle size distribution of the Remegapan sulfate is D90 < 30μm.
2. The pan-disintegrating tablets of retamiprid sulfate according to claim 1, characterized in that: The filler is one or more of microcrystalline cellulose, microcrystalline cellulose colloidal silica co-treated material, and mannitol.
3. The pan-disintegrating tablets of retamiprid sulfate according to claim 1, characterized in that: The disintegrant is one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose.
4. The pan-disintegrating tablets of retamiprid sulfate according to claim 1, characterized in that: The lubricant is one or more of colloidal silica, sodium stearate fumarate, and magnesium stearate.
5. The pan-disintegrating tablets of retamiprid sulfate according to claim 1, characterized in that: The flavoring agent is one or more of sucralose, aspartame, neotame, and stevioside.
6. The pan-disintegrating tablets of retamiprid sulfate according to claim 1, characterized in that: The fragrance is one or more of the following: peppermint flavoring, apple flavoring, raspberry flavoring, lemon flavoring, and strawberry flavoring.
7. A method for preparing the orally disintegrating tablets of remdesivir sulfate according to any one of claims 1-6, characterized in that, The process includes the following steps: mixing retemapam sulfate with excipients until homogeneous, compressing into tablets to obtain retemapam sulfate orally disintegrating tablets with a hardness of 30–90 N.