Amlodipine besylate orally disintegrating tablet and preparation method thereof

Abstract

The invention provides an amlodipine besylate orally disintegrating tablet and a preparation method thereof, and the preparation method comprises the following steps: mixing a diluent, adding a binder aqueous solution for granulation, and then drying to obtain blank particles; adding an additional material into the blank particles, and uniformly mixing to obtain total mixed particles; and tabletting the total mixed particles to obtain the amlodipine besylate orally disintegrating tablet. Wherein the additional material is amlodipine besylate and one or more of a diluent, a disintegrating agent, an opacifying agent, a sweetening agent and a lubricant. According to the scheme, by preparing the blank particles and adopting the form of externally adding the raw material medicines, the raw material medicines are prevented from being subjected to heat-moisture treatment, and the blank particles and the externally added materials are mixed and then tableted, so that the stability of the product is improved, the impurity content is reduced, the flowability and bulk density of the particle mixed powder are superior to those of the mixed powder, and the next tableting procedure is facilitated; and the chip weight stability is ensured.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to an amlodipine besylate orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Amlodipine besylate is a dihydropyridine calcium antagonist that mainly inhibits the calcium storage capacity and calcium ion binding capacity of the myocardial and vascular smooth muscle cell membranes, and achieves the antihypertensive effect by dilating vascular arterioles and reducing peripheral resistance.

[0003] Huizhi Pharmaceutical launched amlodipine besylate orally disintegrating tablets in Japan in July 2008. Huizhi Pharmaceutical's amlodipine besylate orally disintegrating tablets are made using a powder coating process, which includes powder coating, total mixing, tableting, and packaging. The complex powder coating process increases production costs while also reducing product stability. The most direct manifestation is that the company's amlodipine film-coated tablets have a shelf life of 3 years, while the powder-coated amlodipine orally disintegrating tablets have a shelf life of 2 years.

[0004] Japanese generic drug companies have imitated the orodisintegrating tablets. Most companies have adopted the powder direct compression process to replace the original powder coating process, which can keep the shelf life consistent with that of film-coated tablets (3 years). However, most of the excipients used are water-insoluble excipients such as magnesium aluminum metasilicate and anhydrous calcium hydrogen phosphate, and they account for a large proportion, resulting in a poor tablet taste. Due to the poor fluidity and low bulk density of the powder, it is difficult to achieve low tablet weight tableting with the powder direct compression process; therefore, in order to ensure that the tablet weight of the 2.5mg specification tablet remains stable during the tableting process, the tablet weight is increased from 80mg to more than 90mg.

[0005] In summary, when producing amlodipine besylate orodisintegrating tablets, the use of powder coating technology will increase the cost and reduce the stability of the tablets; while the powder direct compression process will increase the weight of the tablets and make the tablets feel obviously gritty after disintegration. Summary of the invention

[0006] The main purpose of the present invention is to provide an amlodipine besylate orally disintegrating tablet and a preparation method thereof, aiming to solve the technical problems that the powder coating process of the existing amlodipine besylate orally disintegrating tablets will reduce the stability of the tablets; and the powder direct compression process will lead to a poor tablet taste.

[0007] To achieve the above object, the present invention provides a method for preparing an amlodipine besylate orally disintegrating tablet, which comprises the following steps: After the diluent is mixed, an aqueous binder solution is added to granulate, and then dried to obtain blank granules; Adding additional materials to the blank particles and mixing them evenly to obtain total mixed particles; Compressing the total mixed granules into tablets to obtain amlodipine besylate orally disintegrating tablets; Wherein, the added material is amlodipine besylate and one or more of a diluent, a disintegrant, a sunscreen, a sweetener and a lubricant.

[0008] Optionally, the diluent is microcrystalline cellulose or mannitol.

[0009] Optionally, in the diluent, the weight ratio of microcrystalline cellulose to mannitol is (0.2~1):1.

[0010] Optionally, in the diluent, the weight of the mannitol accounts for 50% to 100% of the prescribed amount.

[0011] Optionally, the aqueous binder solution is prepared from one or more of sodium alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone and water.

[0012] Optionally, the solid content of the binder aqueous solution is 5%.

[0013] Optionally, the disintegrant package is low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

[0014] Optionally, the sweetener is one or more of sucralose, aspartame, and menthol.

[0015] Optionally, the lubricant is one or more of silicon dioxide, magnesium stearate, and talc.

[0016] Optionally, the sunscreen is yellow iron oxide.

[0017] The present invention also provides an amlodipine besylate orally disintegrating tablet, which comprises the following components in parts by mass: 343 parts of amlodipine besylate, 7 to 20 parts of a binder, 60 to 100 parts of a disintegrant, 5 to 20 parts of a sweetener, 10 to 30 parts of a lubricant, and 1 to 20 parts of a sunscreen.

[0018] In the technical solution of the present invention, blank particles are prepared and the raw material is added externally, thereby avoiding the wet heat treatment of the raw material, and the blank particles are mixed with the added material and then tableted. This not only improves the stability of the product and reduces the impurity content, but also the fluidity and bulk density of the granular mixed powder are better than those of the mixed powder, which is convenient for the next tableting process and ensures the stability of the tablet weight. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

[0020] Figure 1 The present invention is a schematic flow chart of an embodiment of a method for preparing a taste-masked pitavastatin calcium orally disintegrating tablet.

[0021] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0022] To make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them.

[0023] It should be noted that, in the embodiments, those without specifying specific conditions are carried out according to normal conditions or conditions recommended by the manufacturer. Those without specifying the manufacturer of reagents or instruments used are conventional products that can be purchased commercially. In addition, the meaning of "and / or" appearing in the full text includes three parallel schemes, and "A and / or B" is taken as an example, including schemes A, B, or A and B that meet the same time. In addition, the technical schemes between the various embodiments can be combined with each other, but must be based on the ability of ordinary technicians in the field to achieve. When the combination of the technical schemes is contradictory or cannot be achieved, it should be considered that the combination of such technical schemes does not exist, and is not within the scope of protection required by the present invention. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work, all belong to the scope of protection of the present invention.

[0024] When producing amlodipine besylate orodisintegrating tablets, the use of powder coating technology will increase the cost and reduce the stability of the tablets; while the powder direct compression process will increase the weight of the tablets and make the tablets feel gritty after disintegration.

[0025] In view of this, the present invention provides a method for preparing amlodipine besylate orally disintegrating tablets, Figure 1 A schematic flow chart of an embodiment of a method for preparing an amlodipine besylate orally disintegrating tablet is provided, which comprises the following steps: Step S10: After the diluent is mixed, an aqueous binder solution is added to perform granulation, and then dried to obtain blank particles.

[0026] In this embodiment, the diluent is microcrystalline cellulose and mannitol, and the weight ratio of microcrystalline cellulose to mannitol in the diluent is (0.2~1):1; the weight of mannitol in the diluent accounts for 50%~100% of the prescription amount. The binder aqueous solution is prepared by one or more of sodium alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyvinyl pyrrolidone and water. The solid content of the binder aqueous solution is 5%. The disintegrant package is low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone. The sweetener is one or more of sucralose, aspartame, and menthol. The lubricant is one or more of silicon dioxide, magnesium stearate, and talc. The sunscreen is yellow iron oxide.

[0027] Step S20, adding additional materials to the blank particles, and mixing them evenly to obtain total mixed particles.

[0028] In this embodiment, the added material is amlodipine besylate and one or more of a diluent, a disintegrant, a sunscreen, a sweetener, and a lubricant.

[0029] Step S30, compressing the total mixed granules into tablets to obtain amlodipine besylate orally disintegrating tablets.

[0030] In this embodiment, the tablet hardness is controlled to be 4 kg.

[0031] The present invention also provides an amlodipine besylate orally disintegrating tablet, which comprises the following components in parts by mass: 343 parts of amlodipine besylate, 7 to 20 parts of a binder, 60 to 100 parts of a disintegrant, 5 to 20 parts of a sweetener, 10 to 30 parts of a lubricant, and 1 to 20 parts of a sunscreen.

[0032] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments and drawings. It should be understood that the following embodiments are only used to explain the present invention, and are not used to limit the present invention. Example 1

[0033] The prescription is as follows:

[0034] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol are added to a wet granulator, mixed at a main stirring speed of 60RPM for 10min, and then an aqueous solution of sodium alginate with a solid content of 5% is added for granulation, and wet granulation is performed through a 0.8mm sieve. The wet material is transferred to a fluidized bed and dried until the moisture content is less than 2%. The granules are granulated through a 1.0mm sieve to obtain blank granules; 43.4g of amlodipine besylate, 125.0g of microcrystalline cellulose, 343.1g of mannitol, 80.0g of cross-linked polyvinylpyrrolidone, 5.0g of aspartame, 10.0g of silicon dioxide, 1.0g of yellow iron oxide, and 5.0g of menthol are added to the obtained blank granules, mixed at a speed of 20RPM for 10min, 5.0g of magnesium stearate is added, and mixed for 3min; a total mixed material is obtained; the obtained total mixed material is tableted, and the tablet hardness is controlled to be 4kg. Example 2

[0035] The prescription is as follows:

[0036] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol are added to a wet granulator, mixed at a main stirring speed of 60RPM for 10min, and then an aqueous solution of 5% hydroxypropyl cellulose is added for granulation, and wet granulation is performed through a 0.8mm sieve. The wet material is transferred to a fluidized bed and dried until the moisture content is less than 2%. The granules are granulated through a 1.0mm sieve to obtain blank granules; 43.4g of amlodipine besylate, 125.0g of microcrystalline cellulose, 343.1g of mannitol, 80.0g of cross-linked polyvinylpyrrolidone, 5.0g of aspartame, 10.0g of silicon dioxide, 1.0g of yellow iron oxide, and 5.0g of menthol are added to the obtained blank granules, mixed at a speed of 20RPM for 10min, 5.0g of magnesium stearate is added, and mixed for 3min; a total mixed material is obtained; the obtained total mixed material is tableted, and the tablet hardness is controlled to be 4kg. Example 3

[0037] The prescription is as follows:

[0038] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol are added to a wet granulator, mixed at a main stirring speed of 60RPM for 10min, and then an aqueous solution of 5% hydroxypropyl methylcellulose is added for granulation, and wet granulation is performed through a 0.8mm sieve. The wet material is transferred to a fluidized bed and dried until the moisture content is less than 2%. The granules are granulated through a 1.0mm sieve to obtain blank granules; 43.4g of amlodipine besylate, 125.0g of microcrystalline cellulose, 335.7g of mannitol, 80.0g of cross-linked polyvinylpyrrolidone, 5.0g of aspartame, 10.0g of silicon dioxide, 1.0g of yellow iron oxide, and 5.0g of menthol are added to the obtained blank granules, mixed at a speed of 20RPM for 10min, 5.0g of magnesium stearate is added, and mixed for 3min; a total mixed material is obtained; the obtained total mixed material is tableted, and the tablet hardness is controlled to be 4kg. Example 4

[0039] The prescription is as follows:

[0040] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol are added to a wet granulator, mixed at a main stirring speed of 60RPM for 10min, and then an aqueous solution of polyvinyl pyrrolidone with a solid content of 5% is added for granulation, and wet granulation is performed through a 0.8mm sieve. The wet material is transferred to a fluidized bed and dried until the moisture content is less than 2%. The granules are granulated through a 1.0mm sieve to obtain blank granules; 43.4g of amlodipine besylate, 125.0g of microcrystalline cellulose, 343.1g of mannitol, 80.0g of cross-linked polyvinylpyrrolidone, 5.0g of aspartame, 10.0g of silicon dioxide, 1.0g of yellow iron oxide, and 5.0g of menthol are added to the obtained blank granules, mixed at a speed of 20RPM for 10min, 5.0g of magnesium stearate is added, and mixed for 3min; a total mixed material is obtained; the obtained total mixed material is tableted, and the tablet hardness is controlled to be 4kg. Comparative Example 1

[0041] The prescription is as follows:

[0042] Wet granulation process: 93.8g microcrystalline cellulose, 281.3g mannitol, and 43.4g amlodipine besylate are added to the wet granulator, mixed at a main stirring speed of 60RPM for 10min, and then an aqueous solution of 5% hydroxypropyl cellulose is added for granulation, and wet granulation is performed through a 0.8mm sieve; the wet material is transferred to a fluidized bed and dried to a moisture content of less than 2%. 125.0g microcrystalline cellulose, 80.00g cross-linked polyvinylpyrrolidone, 5.0g aspartame, 10.0g silicon dioxide, 1.0g yellow iron oxide, and 5.0g menthol are added to the obtained granules, mixed at a speed of 20RPM for 10min, 5.0g magnesium stearate is added, and mixed for 3min; a total mixed material is obtained; the obtained total mixed material is tableted, and the tablet hardness is controlled to be 4kg. Comparative Example 2

[0043] The prescription is as follows:

[0044] Powder direct compression process: weigh 4.34g of amlodipine besylate, 40.46g of microcrystalline cellulose, and 44.61g of mannitol, add them into a mixing barrel, mix at a speed of 20RPM for 5min, and sieve through a 1.5mm mesh to granulate; transfer the granulated material to a mixing barrel, add 8.00g of cross-linked polyvinylpyrrolidone, 0.50g of aspartame, 1.00g of silicon dioxide, 0.10g of yellow iron oxide and 0.50g of menthol, mix at a speed of 20RPM for 15min, add 0.50g of magnesium stearate, mix for 3min, and obtain a total mixed material; tablet the obtained total mixed material, and control the tablet hardness to 4kg.

[0045] The finished products prepared in the above examples were experimentally verified: 1. Disintegration test According to the orodisintegrating tablet test method in the general disintegration time test method of Part IV of the Chinese Pharmacopoeia 2020 edition, the disintegration time of the tablets was tested, see Table 1.

[0046] Table 1 Disintegration time test results of each example

[0047] Compared with Examples 1 to 4 using the granulation process, the disintegration time of Comparative Example 2 using the powder direct compression process was significantly increased.

[0048] 2. Palatability evaluation Six volunteers were arranged to taste the tablets of the examples and evaluate the tablets' mouthfeel, dissolution / disintegration time, and grittiness in the oral cavity, and the results were summarized.

[0049]

[0050] Insoluble microcrystalline cellulose is the main excipient that causes the grittiness, and the grittiness becomes more obvious as the amount of microcrystalline cellulose increases. Menthol and mannitol both bring a refreshing taste. Increasing the proportion of mannitol and reducing the proportion of microcrystalline cellulose in the prescription can reduce the grittiness and improve palatability. The proportion of mannitol in Examples 1 to 4 is more than 50%, and the taste is good.

[0051] 3. Tablet content uniformity inspection The content uniformity of the tablets of each example was tested.

[0052]

[0053] 4. Stability inspection: The tablets were packaged in PVC / PVDC medicinal composite hard tablets and medicinal aluminum foil and placed at 40°C / 75%RH for 3 months to observe the changes in related substances. The results are shown in Table 3.

[0054] Table 3 Stability test results of various examples

[0055] Comparative Example 1 is a granulation process using the internal humidification method of amlodipine besylate. After the accelerated test, the total impurities increased significantly. Examples 1 to 4, in which the drugs were not subjected to wet heat treatment, have relatively better stability.

[0056] In summary, the orodisintegrating tablets of amlodipine besylate obtained by the preparation method of the present application with the addition of the raw material drug not only have better chemical stability and content uniformity, but also disintegrate rapidly in the mouth and have a good taste.

[0057] The present application also investigates the effect of different binders on the flowability of the sheet. Example 5

[0058] The prescription is as follows:

[0059] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol were added to a wet granulator, mixed at a main stirring speed of 60RPM for 10 minutes, and then an aqueous solution containing 5% solid content of sodium alginate and 7.5g of hydroxypropyl cellulose (weight ratio 1:1.5) was added for granulation, and wet granulation was performed through a 0.8mm sieve. The wet material was transferred to a fluidized bed and dried until the moisture content was less than 2%. The granules were sieved through a 1.0 mm sieve to obtain blank granules; 43.4 g of amlodipine besylate, 125.0 g of microcrystalline cellulose, 343.1 g of mannitol, 80.0 g of cross-linked polyvinylpyrrolidone, 5.0 g of aspartame, 10.0 g of silicon dioxide, 1.0 g of yellow iron oxide, and 5.0 g of menthol were added to the obtained blank granules, and mixed at a speed of 20 RPM for 10 min, 5.0 g of magnesium stearate was added, and mixed for 3 min; a total mixed material was obtained; the obtained total mixed material was tableted to control the tablet hardness to 4 kg. Example 6

[0060] The prescription is as follows:

[0061] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol were added to a wet granulator, mixed at a main stirring speed of 60RPM for 10 minutes, and then an aqueous solution containing 5% sodium alginate and 7.5g of hydroxypropyl methylcellulose (weight ratio 1:1.5) was added for granulation, and wet granulation was performed through a 0.8mm sieve. The wet material was transferred to a fluidized bed and dried until the moisture content was less than 2%. The granules were sieved through a 1.0 mm sieve to obtain blank granules; 43.4 g of amlodipine besylate, 125.0 g of microcrystalline cellulose, 343.1 g of mannitol, 80.0 g of cross-linked polyvinylpyrrolidone, 5.0 g of aspartame, 10.0 g of silicon dioxide, 1.0 g of yellow iron oxide, and 5.0 g of menthol were added to the obtained blank granules, and mixed at a speed of 20 RPM for 10 min, 5.0 g of magnesium stearate was added, and mixed for 3 min; a total mixed material was obtained; the obtained total mixed material was tableted to control the tablet hardness to 4 kg. Example 7

[0062] The prescription is as follows:

[0063] Preparation process: 93.8g of microcrystalline cellulose and 281.3g of mannitol were added to a wet granulator, mixed at a main stirring speed of 60RPM for 10 minutes, and then an aqueous solution containing 5% sodium alginate and 7.5g polyvinyl pyrrolidone (weight ratio 1:1.5) was added for granulation, and wet granulation was performed through a 0.8mm sieve. The wet material was transferred to a fluidized bed and dried until the moisture content was less than 2%. The granules were sieved through a 1.0 mm sieve to obtain blank granules; 43.4 g of amlodipine besylate, 125.0 g of microcrystalline cellulose, 343.1 g of mannitol, 80.0 g of cross-linked polyvinylpyrrolidone, 5.0 g of aspartame, 10.0 g of silicon dioxide, 1.0 g of yellow iron oxide, and 5.0 g of menthol were added to the obtained blank granules, and mixed at a speed of 20 RPM for 10 min, 5.0 g of magnesium stearate was added, and mixed for 3 min; a total mixed material was obtained; the obtained total mixed material was tableted to control the tablet hardness to 4 kg.

[0064] Tablet content uniformity test 1. Test the content uniformity of the tablets in each example.

[0065]

[0066] 2. Stability inspection: The tablets were packaged in PVC / PVDC medicinal composite hard tablets and medicinal aluminum foil and placed at 40°C / 75%RH for 3 months to observe the changes in related substances. The results are shown in Table 3.

[0067] Table 4 Stability test results

[0068] According to the experimental results of Examples 1, 5, 6, and 7, it is found that the mixture of sodium alginate and hydroxypropyl cellulose as a binder has a better effect on the fluidity of the tablets, and the tablets have relatively better stability and better content uniformity.

[0069] The technical features of the above embodiments may be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0070] The above embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims.

Claims

1. A method for preparing an amlodipine besylate orally disintegrating tablet, characterized in that: The steps include: After the diluent is mixed, an aqueous binder solution is added to granulate, and then dried to obtain blank granules; Adding additional materials to the blank particles and mixing them evenly to obtain total mixed particles; Compressing the total mixed granules into tablets to obtain amlodipine besylate orally disintegrating tablets; Wherein, the added material is amlodipine besylate and one or more of a diluent, a disintegrant, a sunscreen, a sweetener and a lubricant.

2. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 1, characterized in that: The adhesive aqueous solution is prepared from one or more of sodium alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone and water.

3. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 2, characterized in that: The solid content of the binder aqueous solution is 5%.

4. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 1, characterized in that: The diluents are microcrystalline cellulose and mannitol, and the weight ratio of microcrystalline cellulose to mannitol is (0.2~1):

1.

5. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 4, characterized in that: In the diluent, the weight of the mannitol accounts for 50% to 100% of the prescription amount.

6. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 1, characterized in that: The disintegrant package is low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

7. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 1, characterized in that: The sweetener is one or more of sucralose, aspartame and menthol.

8. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 1, characterized in that: The lubricant is one or more of silicon dioxide, magnesium stearate and talc.

9. The method for preparing the amlodipine besylate orally disintegrating tablets according to claim 1, characterized in that: The sunscreen is yellow iron oxide.

10. A product obtained by the method for preparing the amlodipine besylate orally disintegrating tablets according to any one of claims 1 to 9, characterized in that: The invention comprises the following components in parts by weight: 343 parts of amlodipine besylate, 7 to 20 parts of a binder, 60 to 100 parts of a disintegrant, 5 to 20 parts of a sweetener, 10 to 30 parts of a lubricant, and 1 to 20 parts of a sunscreen.

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