Quick-absorption frovatriptan succinate tablet and preparation method thereof

Abstract

The invention discloses a quick-absorption frovatriptan succinate tablet and a preparation method thereof. In raw materials for preparing the quick-absorption frovatriptan succinate tablet, auxiliary materials comprise lactose and mannitol, and preferably, the weight ratio of the lactose to the mannitol is (3-5): 1. The frovatriptan succinate tablet capable of being rapidly absorbed is high in dissolution speed, stable in dissolution and capable of rapidly releasing drugs in vivo and accelerating drug absorption, so that the onset time of the drugs is shortened. And more medicines can be absorbed to enter blood circulation, so that the bioavailability of the medicines is increased, and the treatment effect is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of migraine drugs, and particularly relates to a fast-absorbing furotriptan succinate tablet and a preparation method thereof. Background Art

[0002] Migraine is a chronic neurological disease and the second most common disabling neurological disease in the world. The disease has a comorbid relationship with anxiety, depression, sleep disorders, etc. Related studies have found that it may also increase the risk of cognitive dysfunction and cardiovascular and cerebrovascular diseases. Migraine is characterized by high prevalence, high disability, and high disease burden. Frovatriptan Succinate is a 5-HT receptor agonist with high affinity for 5-HT1B and 5-HT1D receptors, no significant effect on GABAA-mediated channel activity, and no significant affinity for benzodiazepine binding sites.

[0003] In the early research of the inventors of this patent (Liu Xiaoxia, Wang Minggang, Chen Yangsheng, et al. Preparation and in vitro dissolution behavior of furotriptan succinate film-coated tablets [J]. Chinese Pharmacy, 2017, 28 (19): 2696-2699.), furotriptan succinate film-coated tablets were prepared and their in vitro dissolution behavior was investigated. Furotriptan succinate tablets were prepared with lactose monohydrate, microcrystalline cellulose, silicon dioxide, sodium carboxymethyl starch and magnesium stearate as excipients, and furotriptan succinate film-coated tablets were prepared by spray coating with opadryl premixed coating solution. A single factor experiment was used to screen the tablet formulation based on moisture, angle of repose, hardness, friability, disintegration time and dissolution, and the amount of coating material was screened based on dissolution. It was found that the dissolution of furotriptan succinate film-coated tablets needs to be further optimized. Summary of the invention

[0004] In view of the above problems, the present invention provides a fast-absorbing furotriptan succinate tablet and a preparation method thereof.

[0005] The first aspect of the present invention is to disclose a fast-absorbing furotriptan succinate tablet. Among the raw materials for preparation, the auxiliary materials include lactose and mannitol, and the weight ratio of the lactose to mannitol is preferably (3-5):1.

[0006] In some embodiments of the present invention, in the prepared raw materials, auxiliary materials further include microcrystalline cellulose and pregelatinized starch, and preferably the weight ratio of the microcrystalline cellulose to the pregelatinized starch is (1-6):1.

[0007] In some embodiments of the present invention, in the prepared raw materials, the weight ratio of lactose to mannitol, microcrystalline cellulose and pregelatinized starch is (75-85): (15-25): (15-20): (15-20).

[0008] In some embodiments of the present invention, in the prepared raw materials, the auxiliary materials also include a flow agent, and preferably the flow agent is silicon dioxide and stearic acid.

[0009] In some embodiments of the present invention, in the prepared raw materials, the weight percentage content of silicon dioxide and stearic acid in the tablet is 0.1-1%, preferably 0.3-0.8%.

[0010] In some embodiments of the present invention, the prepared raw materials include the following components in parts by weight: Furotriptan succinate 1-5 parts; Lactose monohydrate 75-85 parts; Mannitol 15-25 parts; Microcrystalline cellulose 15-20 parts; 15-20 parts of pregelatinized starch; Silicon dioxide 0.1-1 part; Stearic acid 0.1-1 part.

[0011] In some embodiments of the present invention, the prepared raw materials include the following components in parts by weight: Furotriptan succinate 3-4 parts; Lactose monohydrate 80 parts; Mannitol 20 parts; Microcrystalline cellulose 15-20 parts; 15-18 parts of pregelatinized starch; Silicon dioxide 0.5-1 part; Stearic acid 0.5-1 part.

[0012] In some embodiments of the present invention, the prepared raw materials include the following components in parts by weight: Furotriptan succinate 3-4 parts; Lactose monohydrate 80 parts; Mannitol 20 parts; Microcrystalline cellulose 18 parts; Pregelatinized starch 16.69 parts; Silicon dioxide 0.7 parts; Stearic acid 0.7 parts.

[0013] The second aspect of the present invention is to disclose a method for preparing the fast-absorbing furotriptan succinate tablets described in the first aspect, comprising the steps of raw material crushing, sieving, granulating, and tableting; Among them, the raw materials are passed through a 60-mesh sieve and the moisture content is controlled below 3% before granulation.

[0014] In some embodiments of the present invention, the step of film coating with Opadry is also included; Among them, the dosage of Opadry is 1-10%.

[0015] Beneficial effects: In the previous study, the inventor of this patent found that fillers and disintegrants are important factors affecting dissolution. In the subsequent study, it was unexpectedly found that the combination of lactose monohydrate and mannitol had a significant effect on dissolution, and the ratio of the two significantly affected the dissolution. Moreover, the influence of the two was also related to the ratio of microcrystalline cellulose to pregelatinized starch.

[0016] As excipients, the effect of their ratio on dissolution may be related to water channel formation and tablet microstructure. The ratio of the two will affect the dissolution rate and the formation of water channels, thereby affecting the dissolution rate. Microcrystalline cellulose and pregelatinized starch may provide the porosity and particle deformation to form a suitable overall microstructure and water channel microenvironment for lactose monohydrate and mannitol to play a role.

[0017] The fast-absorbing furotriptan succinate tablets of the present invention have a fast dissolution rate and a stable dissolution rate, can quickly release the drug in the body, accelerate the absorption of the drug, and thus accelerate the onset time of the drug. It can also enable more drugs to be absorbed into the blood circulation, increase the bioavailability of the drug, and improve the therapeutic effect. DETAILED DESCRIPTION

[0018] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0019] Unless otherwise specified, the examples and comparative examples are parallel tests with the same parameters such as components, component contents, preparation steps, preparation parameters, and dimensions.

[0020] Example 1 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 80.0 mg Mannitol 20 mg Microcrystalline cellulose 18.0 mg Pregelatinized starch 16.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0021] Example 2 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 75.0 mg Mannitol 25 mg Microcrystalline cellulose 18.0 mg Pregelatinized starch 16.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0022] Example 3 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 85.0 mg Mannitol 15 mg Microcrystalline cellulose 18.0 mg Pregelatinized starch 16.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0023] Example 4 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 80.0 mg Mannitol 20 mg Microcrystalline cellulose 15.0 mg Pregelatinized starch 19.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0024] Example 5 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 80.0 mg Mannitol 20 mg Microcrystalline cellulose 20.0 mg Pregelatinized starch 14.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0025] Based on Examples 1-5, when wetting particles with water, a wetting device is used to wet the mixture, and the wetting device includes: a monitoring and processing unit, a control and adjustment unit, and a uniform wetting unit. When the wetting device wets the mixture, the monitoring and processing unit performs a wetting pretreatment on the mixture so that the mixture is evenly dispersed in a target area, and identifies and obtains basic characteristic information of the mixture. Then, the control and adjustment unit performs a wetting humidity and wetting range analysis based on the basic characteristic information of the mixture, determines the wetting humidity control parameters and the effective wetting range, and obtains the wetting control information based on the wetting humidity control parameters and the effective wetting range, and then The uniform humidification unit regulates the humidification structure according to the humidification control information, and uses the humidification structure after regulation to perform humidification treatment on the mixture in the target through water atomization. At the same time, during the humidification treatment process, the monitoring and processing unit monitors the humidity of the mixture in the target area, obtains the humidification monitoring information of the mixture, and then the control and adjustment unit analyzes whether the mixture reaches the target humidity according to the humidification monitoring information, thereby generating humidification stop control information when the mixture reaches the target humidity, and then the humidification structure stops the humidification treatment of the mixture according to the humidification stop control information, wherein the mixture is a mixture of all raw materials except stearic acid. The basic characteristic information of the mixture includes: the effective range of the mixture in the target area, the dispersion thickness of the mixture in the target area, etc. The above technical scheme realizes uniform wetting of the mixture through the wetting device, ensures the wetting effect of the mixture, and avoids material loss or material agglomeration in the mixture during the wetting process. Moreover, through the monitoring and processing module, not only can the mixture be consistent during the wetting treatment, avoiding uneven wetting of the mixture affecting the subsequent use of the mixture, but also the control and adjustment unit can perform wetting according to the basic characteristic information of the mixture to adapt to the characteristics of the mixture, avoiding the incompatibility of the wetting treatment with the mixture and causing excessive loss of the mixture. In addition, the uniform wetting unit can enable the wetting structure to uniformly wet the effective range in the target area to ensure the wetting effect.

[0026] Furthermore, when each raw material is crushed separately, it includes: determining crushing parameters for the raw material to be crushed; crushing the raw material to be crushed according to the crushing parameters, and using the first collection method to collect the first crushed raw material during the crushing process to obtain the first crushing result, and at the same time using the second collection method to obtain the crushed raw material, transferring the crushed raw material to the diversion device for export, and using the fine diversion net to separate the crushed raw material during the export process to obtain the second crushing result and the third crushing result respectively, and then merging the first crushing result and the second crushing result to obtain the fourth crushing result, and then when passing through a 60-mesh sieve, the fourth crushing result is preferentially passed through a 60-mesh sieve, and then the third crushing result is passed through a 60-mesh sieve. Among them, the first collection method refers to the first crushed raw material that is produced in the crushing process by gasping, and the fine diversion net is set in the diversion device, which can divert relatively fine raw materials during the diversion process. The above technical scheme collects the crushed raw materials generated in the crushing process through the first collection method, thereby avoiding the powder raw materials in the crushing process from being dispersed in the air to cause raw material waste and air pollution, and in the export process, the crushed raw materials are separated by using a fine diversion net so that the crushed raw materials are divided into two parts according to different states, thereby achieving fine separation of the crushing results and providing convenience for subsequent mesh screening, and when passing through a 60-mesh sieve, the fourth crushing result is preferentially passed through a 60-mesh sieve so that relatively fine raw materials are preferentially screened, thereby avoiding larger and finer raw materials blocking the aperture and affecting the efficiency of passing through the 60-mesh sieve.

[0027] Comparative Example 1 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 100.0 mg Microcrystalline cellulose 18.0 mg Pregelatinized starch 16.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0028] Comparative Example 2 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Mannitol 100 mg Microcrystalline cellulose 18.0 mg Pregelatinized starch 16.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0029] Comparative Example 3 A preparation method of fast-absorbing furotriptan succinate tablets (1) Formula (per tablet) Furotriptan succinate 3.91 mg Lactose monohydrate 80.0 mg Mannitol 20 mg Microcrystalline cellulose 28.0 mg Pregelatinized starch 6.69 mg Silicon dioxide 0.7 mg Stearic acid 0.7 mg (2) Grind each raw material separately and pass through a 60-mesh sieve; Take all the raw materials except stearic acid, mix them, make wet granules with water, dry them until the moisture content is less than 3%, and granulate them; The obtained granules are mixed with stearic acid and compressed into tablets to obtain plain tablets; The obtained plain tablets were film-coated with Opadry at a weight ratio of 100:5 to obtain coated tablets.

[0030] Performance Testing The samples obtained in the examples and comparative examples were taken and the dissolution was determined according to the method of the previous study (Liu Xiaoxia, Wang Minggang, Chen Yangsheng, et al. Preparation and in vitro dissolution behavior of furotriptan succinate film-coated tablets [J]. Chinese Pharmacy, 2017, 28(19): 2696-2699.), that is, the 2015 edition of the "Chinese Pharmacopoeia" (Volume 4) General Chapter 0931 "Dissolution Determination Method", and the cumulative dissolution after 10 minutes and 15 minutes was calculated.

[0031] Table 1 Cumulative dissolution

[0032] The data show that the 10 min cumulative dissolution of Examples 1-5 is significantly higher than that of Comparative Examples 1 and 2, indicating the synergistic effect of lactose monohydrate and mannitol on dissolution in the present invention. Among them, among Examples 1-3, Example 1 has a significant advantage. In addition, the 10 min cumulative dissolution of Examples 1-3 is significantly higher than that of Examples 4 and 5, and Examples 1-5 is also significantly higher than Comparative Example 3, indicating the effect of microcrystalline cellulose and pregelatinized starch in the present invention.

[0033] The preferred specific implementation modes and embodiments of the present invention are described in detail above, but the present invention is not limited to the above implementation modes and embodiments, and various changes can be made within the knowledge scope of those skilled in the art without departing from the concept of the present invention.

Claims

1. A fast-absorbing furotriptan succinate tablet, characterized in that: Among the prepared raw materials, the auxiliary materials include lactose and mannitol, and the weight ratio of lactose to mannitol is preferably (3-5):

1.

2. The fast-absorbing furotriptan succinate tablet according to claim 1, characterized in that: In the prepared raw materials, auxiliary materials also include microcrystalline cellulose and pregelatinized starch, and preferably the weight ratio of the microcrystalline cellulose to the pregelatinized starch is (1-6):

1.

3. The fast-absorbing furotriptan succinate tablet according to claim 1 or 2, characterized in that: In the prepared raw materials, the weight ratio of lactose to mannitol, microcrystalline cellulose and pregelatinized starch is (75-85): (15-25): (15-20): (15-20).

4. The fast-absorbing furotriptan succinate tablets according to any one of claims 1 to 3, characterized in that: In the prepared raw materials, auxiliary materials also include flow agents, and preferably the flow agents are silicon dioxide and stearic acid.

5. The fast-absorbing furotriptan succinate tablet according to any one of claims 1 to 4, characterized in that: In the prepared raw materials, the weight percentage content of silicon dioxide and stearic acid in the tablet is 0.1-1%, preferably 0.3-0.8%.

6. The fast-absorbing furotriptan succinate tablets according to any one of claims 1 to 5, wherein the raw materials for preparation include the following components in parts by weight: Furotriptan succinate 1-5 parts; Lactose monohydrate 75-85 parts; Mannitol 15-25 parts; Microcrystalline cellulose 15-20 parts; 15-20 parts of pregelatinized starch; Silicon dioxide 0.1-1 part; Stearic acid 0.1-1 part.

7. The fast-absorbing furotriptan succinate tablets according to any one of claims 1 to 6, wherein the raw materials for preparation include the following components in parts by weight: Furotriptan succinate 3-4 parts; Lactose monohydrate 80 parts; Mannitol 20 parts; Microcrystalline cellulose 15-20 parts; 15-18 parts of pregelatinized starch; Silicon dioxide 0.5-1 part; Stearic acid 0.5-1 part.

8. The fast-absorbing furotriptan succinate tablets according to any one of claims 1 to 9, wherein the raw materials for preparation include the following components in parts by weight: Furotriptan succinate 3-4 parts; Lactose monohydrate 80 parts; Mannitol 20 parts; Microcrystalline cellulose 18 parts; Pregelatinized starch 16.69 parts; Silicon dioxide 0.7 parts; Stearic acid 0.7 parts.

9. A method for preparing the fast-absorbing furotriptan succinate tablets according to any one of claims 1 to 8, characterized in that: It includes the steps of raw material crushing, screening, granulation and tableting; Among them, the raw materials are passed through a 60-mesh sieve and the moisture content is controlled below 3% before granulation.

10. A method for preparing the fast-absorbing furotriptan succinate tablets according to any one of claims 1 to 8, characterized in that: Also included is the step of film coating with Opadry; Among them, the dosage of Opadry is 1-10%.

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