Preparation comprising sevelamer or pharmaceutically acceptable salt thereof and method for preparing same

Abstract

The present invention relates to an oral preparation comprising sevelamer or a pharmaceutically acceptable salt thereof, and a method for preparing same. The oral preparation is prepared through fluidized bed granules so that the preparation is less damaged and less deviated due to abrasion, thereby maintaining excellent quality. In particular, the preparation of the present invention has an increased uniformity while having a small granule size, thereby improving medication convenience by reducing the size of the preparation.

Description

Preparation comprising sevelamer or a pharmaceutically acceptable salt thereof and method for preparing the same

[0001] The present invention relates to an oral formulation comprising Sevelamer or a pharmaceutically acceptable salt thereof and a method for producing the same, wherein the formulation is less damaged and less deviated due to wear through fluidized bed granulation, thereby maintaining excellent quality.

[0002] Patients with renal dysfunction experience reduced phosphate excretion through the kidneys, making dialysis difficult to remove. If phosphate is absorbed directly into the body, it can lead to hyperphosphatemia, while calcium binds to phosphate, resulting in hypocalcemia, a condition characterized by low blood calcium levels. Furthermore, calcium and phosphate can cause calcification, the formation of crystals within body tissues, including within blood vessel walls, which can lead to severe arteriosclerosis, stroke, heart attack, and circulatory failure.

[0003] Sevelamer is a non-calcium phosphate regulator that binds to dietary phosphate in the gastrointestinal tract, preventing its absorption into the bloodstream. Sevelamer carbonate is insoluble in water, but tends to swell and form sticky lumps upon contact with water. This swelling tendency can lead to variations in physical properties and the formation of lumps during wet granulation, depending on the conditions, resulting in problems with granule uniformity. Furthermore, the swelling and lump formation of granules increases the size of the tablet, making oral administration difficult and compromising ease of administration.

[0004] Accordingly, there is a continuous need for research and development of a formulation and a manufacturing method thereof that can improve the convenience of taking the medication while maintaining the quality of the Sevelamer formulation.

[0005] An object of the present invention is to provide a pharmaceutical composition comprising granules obtained through fluidized bed granulation, comprising Sevelamer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

[0006] Another object of the present invention is to provide a method for preparing an oral formulation, comprising the step of granulating sevelamer or a pharmaceutically acceptable salt thereof through a fluidized bed granulator.

[0007] One aspect of the present invention for achieving the above object relates to a pharmaceutical composition comprising granules obtained through fluidized bed granulation, comprising Sevelamer or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable additives selected from the group consisting of a binder, a disintegrant, and a lubricant.

[0008] Specifically, the pharmaceutically acceptable salt may be a carbonate, but is not limited thereto, and may be modified and applied as needed to a salt, hydrate, solvate, etc. prepared by a method conventional in the art.

[0009] Also specifically, the pharmaceutically acceptable additives may include, but are not limited to, microcrystalline cellulose; sodium chloride and zinc stearate.

[0010] In the present invention, "fluidized bed granulation" is a process of combining particles using a fluidized bed granulator, in which a powder sample is placed in a closed space (chamber), and a binding solution is sprayed while stirring and circulating the powder by blowing it with hot air, thereby granulating the sample.

[0011] Specifically, in the fluidized bed granules, the binder may be added in an amount of 0.1 to 5.0 parts by weight based on the total weight of the tablet, and more specifically, the binder may be added in an amount of 0.5 to 4.5 parts by weight, but is not limited thereto. The 'total weight of the tablet' includes all active ingredients and any additives including the binder used in the manufacture of the tablet.

[0012] In addition, specifically, the binder may be water, but is not limited thereto, and any aqueous solvent capable of exhibiting the effects of the present invention may be applied as needed.

[0013] Also, specifically, the average particle size of the granules obtained through the fluidized bed granulation may be 75 to 400 μm, and more specifically, 100 to 400 μm.

[0014] In one embodiment of the present invention, it was confirmed that when manufactured through fluidized bed granulation under the same composition, the tablets suffered less damage and had less variation due to tablet wear, thereby maintaining better quality (Table 2 and Fig. 1). Furthermore, it was confirmed that the granules had increased uniformity despite their smaller size (Table 3). Therefore, the pharmaceutical composition of the present invention can maintain uniform quality while minimizing damage to the formulation through fluidized bed granulation, thereby preventing loss of pharmacological effect due to quality damage to the formulation, while also improving convenience of taking the medication due to the smaller size.

[0015] The pharmaceutical composition of the present invention may be formulated as an oral preparation, such as a tablet, pellet, capsule, granule, or powder, but is not limited thereto. Specifically, the oral preparation may be in the form of a tablet.

[0016] Another aspect of the present invention relates to a method for preparing an oral formulation, comprising the step of granulating sevelamer or a pharmaceutically acceptable salt thereof through a fluidized bed granulator.

[0017] Specifically, the sevelamer or a pharmaceutically acceptable salt thereof may further include one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants and lubricants.

[0018] In addition, specifically, the binder may be added in an amount of 0.5 to 4.5 parts by weight based on the total weight of the composition, and more specifically, the binder may be added in an amount of 0.5 to 4.5 parts by weight, but is not limited thereto.

[0019] Specifically, the method for manufacturing the oral formulation may include a) a step of mixing sevelamer or a pharmaceutically acceptable salt thereof and an excipient; b) a step of placing the mixture prepared in step a) into a fluidized bed granulator and injecting a binding solution to granulate; and c) a step of post-mixing sodium chloride and zinc stearate.

[0020] The oral preparation manufactured by the above manufacturing method may be in the form of a tablet, pellet, capsule, granule, or powder, and more specifically, may be in the form of a tablet.

[0021] The present invention relates to the manufacture of a formulation containing sevelamer through fluidized bed granulation. The resulting formulation exhibits minimal damage and wear-related variations, thereby maintaining excellent quality. In particular, the formulation of the present invention exhibits increased uniformity despite its small granule size, thereby enabling a reduction in the size of the formulation, thereby improving the convenience of administration.

[0022] Figure 1 shows the results of checking the wear and thickness of tablets manufactured according to Comparative Example 3 and Example 1.

[0023] Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are only illustrative of the present invention, and the present invention is not limited to the following examples.

[0024] Manufacturing example. Manufacturing of Sevelamer carbonate

[0025] 1-1. Manufacturing of Comparative Examples 1 to 5

[0026] According to the composition shown in Table 1 below, sevelamer carbonate and microcrystalline cellulose were mixed and placed in the chamber of a high-speed mixer (PTK, PM-C003), and operated at a speed of 200 rpm with an agitator and 3,000 rpm with a chopper. Purified water was injected as a binding solution, pre-mixed and sieved, and then dried. Afterwards, sodium chloride and zinc stearate were post-mixed and sieved, and then tableted with a rotary tablet press to a hardness of 25 kN and then coated to manufacture.

[0027] 1-2. Preparation of Examples 1 to 5 by Fluidized Bed Granulation

[0028] According to the composition shown in Table 1 below, sevelamer carbonate and microcrystalline cellulose were mixed and placed in the chamber of a fluidized bed granulator (Bosch, Huttlin Solidlab2.) and sprayed at a rate of 10 to 15 g / min under the conditions of an exhaust temperature of 60°C and a spray pressure of 1.0 bar, while injecting purified water as a binder, granulation was performed and drying was performed. Afterwards, sodium chloride and zinc stearate were post-mixed and sieved, and tablets were pressed into tablets with a hardness of 25 kN using a rotary tablet press and then coated to manufacture the composition.

[0029] Manufacturing method Sevelamer carbonate (mg) Microcrystalline cellulose (mg) Sodium chloride (mg) Zinc stearate (mg) Purified water (mg) Total (uncoated tablets) (mg) Comparative example 1 High shear granulation (HSM) 800 107.73.22.12 00 913.0 Comparative example 2800 107.73.22.13 00 913.0 Comparative example 3800 107.73.22.15 00 913.0 Comparative example 4800 107.73.22.11, 00 913.0 Comparative example 5800 107.73.22.11, 500 913.0 Example 1 Fluidized bed granulation 800 107.73.22.15 00 913.0 Example 2800107.73.22.11,000913.0 Example 3800107.73.22.12,000913.0 Example 4800107.73.22.13,000913.0 Example 5800107.73.22.14,000913.0

[0030] Experimental Example 1. Evaluation of the physical properties of purified water

[0031] In order to confirm the physical properties of Comparative Examples 1 to 5 and Examples 1 to 5 manufactured in the above manufacturing examples, the hardness, wear rate, and surface appearance of the tablets were confirmed.

[0032] The hardness of the tablets was measured using a hardness tester, and the friability and surface appearance of the tablets were evaluated using a friability tester.

[0033] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Hardness (kp) (25kN pressing pressure) 10~13 12~15 10~13 10~13 15~20 Wear rate (%) 0.20% 0.15% 0.22% 0.19% 0.14% Surface properties Easily broken Easily broken Easily broken Easily broken Easily broken Example 1 Example 2 Example 3 Example 4 Example 5 Hardness (kp) (25kN pressing pressure) 10~13 15~20 15~20 20~26 30~35 Wear rate (%) 0.09 0.09 0.06 0.07 0.01 or less Surface properties Fine breaking Fine breaking Fine breaking Almost no breaking No breaking at all

[0034] As shown in Table 2 above, it was confirmed that Examples 1 to 5 using fluidized bed granulation had higher hardness and significantly less wear compared to Comparative Examples 1 to 5. In addition, it was confirmed that Examples 1 to 5 had fine or almost no wear compared to Comparative Examples 1 to 5, which had surfaces that were easily worn away.

[0035] In addition, the properties were evaluated based on the same amount of binding liquid (500 mg / T), and as shown in Fig. 1, when comparing Comparative Example 3 and Example 1, it was confirmed that Example 1, which is a fluidized bed granule, had a smaller thickness than Comparative Example 3, but showed less wear in both the uncoated and coated tablets. These results indicate that in the case of tablets using the fluidized bed granules of the present invention, the damage to the tablets is less, and the deviation due to tablet wear is less, so that the quality can be maintained better.

[0036] Experimental Example 2. Evaluation of tablet weight and size

[0037] The weight and size of the tablet were measured and compared with those of existing commercial products.

[0038] As a result, the average weight of the tablets of Examples 1 to 5 using the fluidized bed granules of the present invention was about 946 mg, whereas the existing commercially available sevelamer carbonate tablets showed a weight of about 1,000 to 1,150 mg, confirming that the tablets of Examples 1 to 5 using the fluidized bed granules of the present invention showed a weight that was 5 to 10% (w / w) smaller than the existing commercially available products.

[0039] In addition, it was confirmed that the tablets of Examples 1 to 5 using the fluidized bed granules of the present invention were formed with a long axis average of about 17.4 mm, which is about 15% smaller in diameter than the long axis of existing commercial products, which is about 20 mm.

[0040] Experimental Example 3. Evaluation of Granule Size Distribution in Tablets

[0041] The granule size distribution of the tablets of Comparative Example 3 and Example 1 manufactured from the same amount of binding liquid (500 mg / T) was analyzed. Specifically, the particle size distribution was measured using a particle size analyzer (Bettersizer, PowerProA1).

[0042] Granule size distribution (μm) Comparative example 3 (%) Example 1 (%) 0~457.6 0.145~75 14.6 0.875~150 15.8 8.41 50~250 4.76 4.42 50~35 53.22 3.23 55~425 1.41 34 25~1,000 27.5 1.8 > 1,000 25.20 Sum 100 100

[0043] As a result, in the case of Example 1 manufactured through the fluidized bed granulation as shown in Table 3 above, it was confirmed that the uniformity of the granule size was high, as 87.6% was distributed in the particle size range of 150 to 355 μm. In addition, in the case of Example 1, only 3.1% of the granules had a size exceeding 355 μm, and no granules had a size exceeding 1,000 μm, whereas in the case of Comparative Example 3, the granules had a size exceeding 355 μm at 54.1%, which was more than half of the total granules, and in particular, the granules had a size exceeding 1,000 μm at 25.2%.

[0044] This indicates that the particle size and uniformity of the granules produced differ depending on the granulation method even when manufactured from the same amount of binding liquid and combination of components. In the present invention, it was confirmed that the size of the granules was reduced while the uniformity was increased through fluidized bed granulation.

[0045] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0046] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. Sevelamer or a pharmaceutically acceptable salt thereof; and Containing one or more pharmaceutically acceptable additives selected from the group consisting of binders, disintegrants and glidants, A pharmaceutical composition comprising granules obtained through fluidized bed granulation.

2. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is a carbonate.

3. In paragraph 1, A pharmaceutical composition comprising microcrystalline cellulose as the pharmaceutically acceptable additives; sodium chloride and zinc stearate.

4. In paragraph 1, A pharmaceutical composition, wherein in the fluidized bed granules, the binder is added in an amount of 0.1 to 5.0 parts by weight based on the total weight of the tablet.

5. In paragraph 3, A pharmaceutical composition wherein the binder is water.

6. In paragraph 1, A pharmaceutical composition, wherein the average particle size of the above granules is 75 to 400 μm.

7. In paragraph 1, The pharmaceutical composition above is in the form of a tablet.

8. A method for preparing an oral formulation, comprising the step of granulating sevelamer or a pharmaceutically acceptable salt thereof using a fluidized bed granulator.

9. In paragraph 8, A method for producing an oral formulation, further comprising at least one pharmaceutically acceptable additive selected from the group consisting of excipients, binders, disintegrants and lubricants, to the above sevelamer or a pharmaceutically acceptable salt thereof.

10. A method for manufacturing an oral formulation, wherein in clause 9, the binder is added in an amount of 0.5 to 4.5 parts by weight based on the total weight of the composition.

11. In paragraph 8, a) a step of mixing sevelamer or a pharmaceutically acceptable salt thereof and excipients; b) a step of placing the mixture prepared in step a) into a fluidized bed granulator and injecting a binding solution to granulate; and c) A method for producing an oral formulation, comprising the step of post-mixing sodium chloride and zinc stearate.

12. A manufacturing method according to any one of claims 8 to 11, wherein the oral preparation is in the form of a tablet.

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