Bempedoic acid pharmaceutical composition
Magnesium aluminometasilicate addresses the stickiness and fluidity issues of bempedoic acid, enhancing manufacturing efficiency and maintaining the solubility profile of bempedoic acid tablets, achieving a stable and bioequivalent formulation.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- SYNTHON BV
- Filing Date
- 2026-02-06
- Publication Date
- 2026-05-19
AI Technical Summary
Existing pharmaceutical compositions of bempedoic acid face challenges due to its high stickiness and low fluidity, which complicate manufacturing processes and affect the quality of the final product, necessitating a stable and bioequivalent formulation.
Incorporation of magnesium aluminometasilicate into the pharmaceutical composition to reduce stickiness and improve fluidity, allowing for efficient granulation and compression without prolonged mixing times, resulting in a stable and bioequivalent product.
The composition achieves reduced stickiness and improved manufacturing efficiency, maintaining the solubility profile of commercially available bempedoic acid tablets while ensuring stability and bioequivalence.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention relates to a pharmaceutical composition containing bempegic acid, which is a compound represented by formula (1), and a method for producing the same.
Background Art
[0002] This invention relates to
Chemical Formula
[0003] Bempegic acid, that is, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, has a dual function as an activator of AMP-activated protein kinase (AMPK) and an inhibitor of ATP citrate lyase (ACL). Bempegic acid has been approved as an oral therapeutic agent for hypercholesterolemia. In Europe, it is sold as tablets under the trade name NILEMDO (registered trademark) (Daiichi Sankyo Europe GmbH), and in the United States, it is sold under the trade name NEXLETOL (registered trademark) (Esperion Therapeutics, Inc.).
[0004] Bempegic acid was first described in International Publication No. 2004 / 067489. Pharmaceutical compositions containing bempegic acid are described in International Publication Nos. 2018 / 218147 and 2019 / 161307. Due to the high content of BPA in the pharmaceutical composition, the properties of BPA (low melting point, poor fluidity and adhesiveness) have a great impact on the manufacturing process and the properties of the final pharmaceutical product. In International Publication No. 2019 / 161307, a sustained-release composition containing bempegic acid was prepared to improve the bioavailability and pharmacokinetics of bempegic acid.
[0005] International Publication No. 2018 / 218147 addresses the low fluidity and stickiness of bempedoic acid by avoiding standard granulation processes and pre-mixing it with lubricants (e.g., colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate) for an extended period (at least 45 minutes). However, there is still a need for another improved formulation to mitigate the impact of inadequate active pharmaceutical ingredient properties, particularly stickiness, on the manufacturing process and pharmaceutical quality. Therefore, it is desirable to develop a simple and stable pharmaceutical composition of bempedoic acid that overcomes the problems of the prior art, is advantageously manufactured, and is bioequivalent to the commercially available bempedoic acid tablets NILEMDO® / NEXLETOL®. [Overview of the project]
[0006] The present invention relates to a pharmaceutical composition containing bempedoic acid and magnesium aluminometasilicate, which are compounds represented by formula (1), and a method for producing the same. [ka]
[0007] The pharmaceutical composition of the present invention is simple, stable, advantageously manufactured, and has a solubility profile similar to commercially available bempedoic acid tablets NILEMDO® / NEXLETOL®. [Brief explanation of the drawing]
[0008] [Figure 1] Figure 1 shows the dissolution profiles of the compositions of Examples 1, 2, and 3. [Figure 2] Figure 2 shows the steps of Example 1. [Figure 3] Figure 3 shows the steps of Example 2. [Figure 4] Figure 4 shows the steps of Example 3. [Modes for carrying out the invention]
[0009] Detailed description of the invention The present invention relates to a pharmaceutical composition comprising bempedoic acid and magnesium aluminometasilicate.
[0010] The magnesium aluminometasilicate of the present invention is synonymous with silodorate hydrate, simaldorate, and magnesium aluminum silicate oxide.
[0011] Bempedoic acid has low fluidity and exhibits sticky bulk properties, making it difficult to incorporate in processes such as granulation, mixing, and compression.
[0012] These problems negatively impact the pharmaceutical manufacturing process, preventing common operations such as granulation and compression from being performed.
[0013] Surprisingly, the inventors found that magnesium aluminometasilicate in formulations containing bempedoic acid reduces the stickiness of bempedoic acid not only when pre-mixed with bempedoic acid, but also when added outside the granules and mixed with the bempedoic acid granules. Furthermore, long pre-mixing of magnesium aluminometasilicate and bempedoic acid is not required, reducing time and costs in commercial-scale manufacturing. Magnesium aluminometasilicate not only prevents stickiness but also prevents the melting of bempedoic acid during the compression process. Therefore, the use of this additive in tablet compositions prevents the formation of "flakes," which are molten material formed during compression and can jeopardize this process, thereby reducing or eliminating this problem. Normally, those skilled in the art adjust the compression speed to maintain tablet quality. Magnesium aluminometasilicate improves the tableting speed. The pharmaceutical composition of the present invention, comprising bempedoic acid and magnesium aluminometasilicate, is simple to manufacture, stable, and has a solubility profile similar to commercially available bempedoic acid tablets NILEMDO® / NEXLETOL®.
[0014] In a first aspect, the present invention relates to a pharmaceutical composition containing bendamustine and magnesium aluminometasilicate, wherein the weight ratio of magnesium aluminometasilicate to bendamustine is 1:2 to 1:120. A more preferred range is 1:20 to 1:80, an even more preferred range is 1:30 to 1:70, and the most preferred range is 1:40 to 1:60.
[0015] In particular, the pharmaceutical composition of the present invention contains a therapeutically effective amount of bendamustine with a particle size distribution D90 of 3 to 100 μm, preferably 3 to 50 μm, more preferably 3 to 40 μm.
[0016] The D90 value of the particle size distribution is defined as the particle diameter at which 90% by volume of the particles have a diameter smaller than the diameter corresponding to the D90 value measured by laser diffraction. Specifically, the particle size distribution was determined using a Malvern Instruments Mastersizer.
[0017] The present invention also provides a pharmaceutical composition in which the abundance of bendamustine is 20% to 80% by weight, preferably 30% to 70% by weight, more preferably 40% to 70% by weight, based on the total weight of the composition.
[0018] In a preferred embodiment of the present invention, the abundance of bendamustine is 60% by weight based on the total weight of the composition.
[0019] Furthermore, the present invention provides a pharmaceutical composition in which the abundance of magnesium aluminometasilicate is 0.5% to 25% by weight, preferably 0.5% to 15% by weight, more preferably 0.5% to 10% by weight, even more preferably 0.5% to 5% by weight, based on the total weight of the composition.
[0020] In the first aspect, the pharmaceutical composition described so far is produced by granulation and contains magnesium aluminometasilicate inside and / or outside the granules.
[0021] In addition to magnesium aluminum metasilicate, one or more pharmaceutically acceptable additives can be further used in the present invention. The additives can be used inside the granules, outside the granules, or both.
[0022] One or more pharmaceutically acceptable additives used in addition to magnesium aluminum metasilicate in the present invention can be selected from, for example, excipients, binders, disintegrants, lubricants, and fluidizing agents.
[0023] Excipients are used to increase the bulk volume of tablets or capsules. By combining the excipient with the active ingredient, the final product is given an appropriate weight and size to facilitate its manufacture and handling. The pharmaceutical composition of the present invention preferably contains at least one excipient.
[0024] Excipients are preferably used in an amount of 5% to 70% by weight, more preferably 10% to 50% by weight, even more preferably 10% to 40% by weight, and most preferably 10% to 30% by weight based on the total weight of the composition. Suitable examples of excipients used in the present invention include mannitol, sorbitol, crystalline cellulose, lactose, lactose monohydrate, phosphoric acid, cellulose, hydroxypropyl cellulose, starch, pregelatinized starch, modified starch, sucrose, glucose, dextrate, maltodextrin, xylitol, cyclodextrin, calcium phosphate, calcium sulfate, and talc.
[0025] In a preferred embodiment of the present invention, the excipient used is crystalline cellulose, lactose monohydrate, or a mixture thereof.
[0026] The pharmaceutical compositions of the present invention may also contain one or more binders. The binders ensure the formation of tablets and granules having the desired or required mechanical strength. Suitable binders for use in the present invention include povidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylpropylcellulose, sodium carboxymethylcellulose, pregelatinized starch, starch, PEG, and gelatin. The binder is used in an amount of preferably 0.5% to 8% by weight, more preferably 1% to 6% by weight, based on the total weight of the composition.
[0027] In a preferred embodiment of the present invention, the binder used includes hydroxypropyl cellulose.
[0028] The pharmaceutical compositions of the present invention may also contain one or more disintegrants. Disintegrants are added to tablet or capsule compositions to promote the breakdown of tablets / capsules into smaller fragments in an aqueous environment, thereby increasing the surface area and facilitating the rapid release of the active pharmaceutical ingredient. Suitable examples of disintegrants used in the present invention include crospovidone, sodium starch glycolate, sodium croscarmellose, natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, cross-linked carboxymethylcellulose sodium, cross-linked croscarmellose, cross-linked polyvinylpyrrolidone, sodium alginate, and rubbers. Disintegrants are used in an amount of preferably 1% to 15% by weight, more preferably 2% to 10% by weight, and even more preferably 5% to 10% by weight, based on the total weight of the composition.
[0029] In a preferred embodiment of the present invention, sodium starch glycolate is used as the disintegrant.
[0030] The pharmaceutical composition of the present invention may also contain one or more lubricants. Lubricants are generally used to reduce sliding friction, particularly to reduce interfacial friction in mixing and compression machines. Suitable lubricants for use in the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, talc, and sodium stearyl fumarate. The lubricant is used in an amount of preferably 0.5% to 10% by weight, more preferably 1% to 5% by weight, and even more preferably 1% to 2% by weight, based on the total weight of the composition. In a preferred embodiment of the present invention, the lubricant used is magnesium stearate.
[0031] The pharmaceutical composition of the present invention may optionally contain one or more fluidizing agents. Fluidizing agents enhance the fluidity of the product by reducing friction between particles. A preferred example according to the present invention is colloidal silicon dioxide. The fluidizing agent is used in an amount of preferably 0.2% to 10% by weight, more preferably 0.2% to 5% by weight, and even more preferably 0.2% to 2% by weight, based on the total weight of the composition.
[0032] In a first preferred embodiment, the pharmaceutical composition of the present invention comprises the following components relative to the total weight of the composition: a. Bempedoic acid in an amount of 20% to 80% by weight; b. Magnesium aluminometasilicate in an amount of 0.5% to 25% by weight; c. One or more excipients in an amount of 5% to 70% by weight; d. 0.5% to 8% by weight of one or more binders; e. One or more disintegrants in an amount of 1% to 15% by weight; f. A lubricant of 1 or higher in an amount of 0.5% to 10% by weight.
[0033] In certain embodiments, bempedoic acid, an excipient, a binder, and a disintegrant are used within the granules, while magnesium aluminometasilicate, another excipient, another disintegrant, and a lubricant are used outside the granules.
[0034] In a second preferred embodiment, the pharmaceutical composition of the present invention comprises the following components relative to the total weight of the composition: a. Bempedoic acid in an amount of 20% to 80% by weight; b. Magnesium aluminometasilicate in an amount of 0.5% to 25% by weight; c. One or more excipients in an amount of 5% to 70% by weight; d. 0.5% to 8% by weight of one or more binders; e. One or more disintegrants in an amount of 1% to 15% by weight; f. A lubricant of 1 or higher in an amount of 0.5% to 10% by weight; g. If necessary, add one or more fluidizing agents in a concentration of 0.2% to 10%.
[0035] In certain embodiments, bempedoic acid, magnesium aluminometasilicate, excipients, binders, and disintegrants are used within the granules, while other excipients, other disintegrants, lubricants, and optionally flow agents are used outside the granules.
[0036] The compositions of the present invention can be produced by granulating bempedoic acid, magnesium aluminometasilicate, and one or more acceptable additives using apparatus and methods widely known to those skilled in the art, and then encapsulating or compressing them as necessary.
[0037] In a preferred embodiment, the composition is manufactured by a granulation process and compressed into tablets. Granulation can be carried out by a wet or dry method, including wet granulation using water, an organic solvent, or a mixture thereof as the granulating liquid, and dry granulation known as the slug method and / or roll compression method.
[0038] In a preferred embodiment, the composition is manufactured by a wet granulation method.
[0039] In one embodiment of the present invention, the composition is prepared by a standard granulation method in which bempedoic acid and one or more pharmaceutically acceptable additives are granulated for 7 to 20 minutes, preferably about 15 minutes. The resulting granules are crushed, and magnesium aluminometasilicate and one or more pharmaceutically acceptable additives are added outside the granules and mixed. Finally, the mixture is compressed.
[0040] In another aspect of the present invention, the composition is first prepared by a standard granulation method in which bempedoic acid is granulated with magnesium aluminometasilicate for 15 to 30 minutes, preferably about 15 minutes; and one or more pharmaceutically acceptable additives are further added. The resulting granules are crushed, one or more pharmaceutically acceptable additives are added outside the granules and mixed. Finally, the mixture is compressed.
[0041] The present invention also relates to a pharmaceutical composition of a tablet containing granules as described above.
[0042] The pharmaceutical compositions described in this specification can be manufactured using conventional methods and apparatus widely known in the art.
[0043] The pharmaceutical composition of the present invention exhibits an in vitro dissolution profile in which at least 75% of bempedoic acid is released within 15 minutes when the composition is dissolved in 900 ml of 0.1 N hydrochloric acid (pH 6.6) using a USP instrument II at 50 rpm and 37°C. Preferably, at least 80% of bempedoic acid is released from the pharmaceutical composition within 15 minutes. The pharmaceutical composition of the present invention is bioequivalent to commercially available bempedoic acid tablets (NILEMDO® / NEXLETOL®).
[0044] The present invention will be explained by the following examples. [Examples]
[0045] Example 1 [Table 1]
[0046] 20 g of povidone K30 was dissolved in water. 600 g of bempedoic acid, 40 g of hydroxypropyl cellulose, 93.33 g of lactose monohydrate, and 52.5 g of sodium starch glycolate were sieved through a 1.5 mm mesh and mixed in a bottle blender at 20 rpm for 5 minutes. The sieved powder was transferred to a high-shear mixer, povidone K30 solution was added, and granulation was performed. The moist granules were sieved through a 5 mm mesh as needed and dried in a fluidized bed at approximately 60°C. The same procedure was repeated twice to obtain three batches of granules. These three batches were sieved through a 1.1 mm mesh and transferred to a suitable bottle blender. 35 g of magnesium aluminometasilicate was sieved through a 0.8 mm mesh and mixed with the sieved granules at 20 rpm for 30 minutes. 450 g of crystalline cellulose and 52.5 g of sodium starch glycolate were crushed and placed in a blender, where they were mixed at 20 rpm for 10 minutes. 45 g of magnesium stearate was sieved and mixed with the resulting mixture in a bottle blender at 20 rpm for 3 minutes.
[0047] A homogeneous mixture was compressed using a tablet press under controlled humidity. The tablets were coated with Opadry® II until their weight increased by 3%.
[0048] Example 2 [Table 2]
[0049] 20 g of povidone K30 was dissolved in water. 600 g of bempedoic acid and 11.67 g of magnesium aluminometasilicate were sieved through a 1.5 mm mesh and mixed in a bottle blender at 20 rpm for 30 minutes. 40 g of hydroxypropyl cellulose, 93.33 g of lactose monohydrate, and 52.5 g of sodium starch glycolate were sieved through a 1.5 mm mesh and mixed with the above mixture in a bottle blender at 20 rpm for 5 minutes. The sieved mixture was transferred to a high-shear mixer, povidone K30 solution was added, and granulation was performed. The moist granules were sieved through a 5 mm mesh as needed and dried in a fluidized bed at approximately 60°C. The same procedure was repeated twice to obtain three batches of granules. These three batches were sieved through a 1.1 mm mesh and transferred to a suitable bottle blender. 450 g of crystalline cellulose and 52.5 g of sodium starch glycolate were crushed and placed in a blender, where they were mixed at 20 rpm for 10 minutes. 45 g of magnesium stearate was sieved and mixed with the resulting mixture in a bottle blender at 20 rpm for 3 minutes.
[0050] A homogeneous mixture was compressed using a tablet press under controlled humidity. The tablets were coated with Opadry® II until their weight increased by 3%.
[0051] Example 3 [Table 3]
[0052] 600 g of bempedoic acid and 11.67 g of magnesium aluminometasilicate were sieved through a 1.5 mm mesh and mixed in a bottle blender at 20 rpm for 30 minutes. 40 g of hydroxypropyl cellulose, 93.33 g of lactose monohydrate, and 52.5 g of sodium starch glycolate were sieved through a 1.5 mm mesh and mixed with the above mixture in a bottle blender at 20 rpm for 5 minutes. The sieved mixture was transferred to a high-shear mixer, aqueous solution was added, and granulation was performed. The moist granules were sieved through a 5 mm mesh as needed and dried in a fluidized bed at approximately 60°C. The same procedure was repeated twice to obtain three batches of granules. These three batches were sieved through a 1.1 mm mesh and transferred to a suitable bottle blender. 495g of crystalline cellulose, 15g of colloidal silicon dioxide, and 52.5g of sodium starch glycolate were crushed and placed in a blender, where they were mixed at 20 rpm for 10 minutes. 45g of magnesium stearate was sieved, and the resulting mixture was mixed with it in a bottle blender at 20 rpm for 3 minutes.
[0053] A homogeneous mixture was compressed using a tablet press under controlled humidity. The tablets were coated with Opadry® II until their weight increased by 3%.
Claims
1. A pharmaceutical composition containing bempedoic acid and magnesium aluminometasilicate.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of magnesium aluminometasilicate to bempedoic acid is 1:2 to 1:
120.
3. The pharmaceutical composition according to claim 1 or 2, wherein the amount of bempedo acid present is 20% to 80% by weight relative to the total weight of the composition.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the magnesium aluminometasilicate is present in an amount of 0.5% to 25% by weight relative to the total weight of the composition.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is manufactured by granulation and the granules contain bempedoic acid.
6. The pharmaceutical composition according to claim 5, wherein the magnesium aluminometasilicate is present outside and / or inside the granules.
7. In relation to the total weight of the composition, a. Bempedoic acid in an amount of 20% to 80% by weight; b. Magnesium aluminometasilicate in an amount of 0.5% to 25% by weight; c. One or more excipients in an amount of 5% to 70% by weight; d. One or more binders in an amount of 0.5% to 8% by weight; e. One or more disintegrants in an amount of 1% to 15% by weight; f. A lubricant of 1 or more units in an amount of 0.5% to 10% by weight; A pharmaceutical composition containing any one of claims 1 to 6.
8. In relation to the total weight of the composition, a. Bempedoic acid in an amount of 20% to 80% by weight; b. Magnesium aluminometasilicate in an amount of 0.5% to 25% by weight; c. One or more excipients in an amount of 5% to 70% by weight; d. One or more binders in an amount of 0.5% to 8% by weight; e. One or more disintegrants in an amount of 1% to 15% by weight; f. A lubricant of 1 or more units in an amount of 0.5% to 10% by weight; g. If necessary, add one or more fluidizing agents in an amount of 0.2% to 10%; A pharmaceutical composition containing any one of claims 1 to 6.
9. The pharmaceutical composition according to claim 7 or 8, wherein the excipient is selected from the group consisting of mannitol, sorbitol, crystalline cellulose, lactose, lactose monohydrate, phosphoric acid, cellulose, hydroxypropylcellulose, starch, pregelatinized starch, modified starch, sucrose, glucose, dextrate, maltodextrin, xylitol, cyclodextrin, calcium phosphate, calcium sulfate, and talc.
10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the binder is selected from the group consisting of povidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylpropylcellulose, sodium carboxymethylcellulose, pregelatinized starch, starch, PEG, and gelatin.
11. The pharmaceutical composition according to any one of claims 7 to 10, wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, sodium croscarmellose, natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, cross-linked sodium carboxymethylcellulose, cross-linked croscarmellose, cross-linked polyvinylpyrrolidone, sodium alginate, and rubbers.
12. The pharmaceutical composition according to any one of claims 7 to 11, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, talc, and sodium stearyl fumarate.