WO2025143585A1 - Preparation comprising sevelamer or pharmaceutically acceptable salt thereof and method for preparing same - Google Patents

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

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.

Patients with renal dysfunction have a reduced amount of phosphorus excreted from the body through the kidneys, which is difficult to remove even through dialysis. If phosphate is absorbed directly into the body, it will develop into hyperphosphatemia, and calcium will bind to phosphate, leading to hypocalcemia, which is a low calcium level in the blood. In addition, calcium and phosphate can cause calcification, which forms crystals in body tissues, including the inside of blood vessel walls, which can cause severe arteriosclerosis, stroke, heart attack, and circulatory failure.

Sevelamer is a non-calcium phosphate regulator that binds to phosphate ingested through food in the gastrointestinal tract, preventing phosphorus from being absorbed into the bloodstream. Sevelamer carbonate is insoluble in water, but tends to swell and form sticky lumps when in contact with water. Due to this swelling tendency, the granules swell and form lumps depending on the conditions during wet granulation, resulting in differences in physical properties and problems with granule uniformity. In addition, the swelling and lump formation of the granules increases the size of the tablet, making oral administration difficult, and there were also problems with the convenience of taking the medication.

Accordingly, there is a continuous demand 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.

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.

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 granulation.

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 glidant.

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

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

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.

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 of the active ingredients and any additives including the binder solution used in the manufacture of the tablet.

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.

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.

In one embodiment of the present invention, it was confirmed that when manufactured through fluidized bed granulation under the same composition, the damage to the tablets was less, the deviation due to tablet wear was less, and the quality could be maintained better (Table 2 and Fig. 1). Furthermore, it was confirmed that the size of the granules was small but the uniformity was increased (Table 3). Therefore, the pharmaceutical composition of the present invention can maintain the quality uniformly so that the damage to the formulation is minimized through fluidized bed granulation, thereby preventing the loss of the pharmacological effect due to the quality damage of the formulation and improving the convenience of taking the medication due to the reduced size.

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

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 using a fluidized bed granulator.

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.

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.

Specifically, the method for manufacturing the oral formulation may include 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 binder solution to granulate; and c) a step of post-mixing sodium chloride and zinc stearate.

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.

The present invention relates to a preparation comprising sevelamer by means of fluidized bed granulation, and the preparation thus prepared has less damage and less variation due to wear and tear, thereby maintaining excellent quality. In particular, the preparation of the present invention has a small granule size but increased uniformity, thereby improving convenience of administration by reducing the size of the preparation.

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

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only intended to illustrate the present invention, and the present invention is not limited to the following examples.

Manufacturing example. Manufacturing of Sevelamer carbonate

1-1. Manufacturing of Comparative Examples 1 to 5

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 for the agitator and 3,000 rpm for the chopper, purified water was injected as a binding solution, pre-mixed and sieved, and then dried. After that, sodium chloride and zinc stearate were post-mixed and sieved, and then pressed into tablets with a hardness of 25 kN using a rotary tablet press, and then coated to manufacture.

1-2. Manufacturing of Examples 1 to 5 by Fluidized Bed Granulation

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, granulate, and then dry. Afterwards, sodium chloride and zinc stearate were post-mixed, granulated, and then pressed into tablets with a hardness of 25 kN using a rotary tablet press, followed by coating to manufacture.

manufacturing
method Sevelamer carbonate (mg) Microcrystalline Cellulose (mg) Sodium chloride
(mg) Zinc stearate (mg) Purified water
(mg) total
(Na Jeong) (mg) Comparative Example 1 High shear granulation(HSM) 800 107.7 3.2 2.1 200 913.0 Comparative Example 2 800 107.7 3.2 2.1 300 913.0 Comparative Example 3 800 107.7 3.2 2.1 500 913.0 Comparative Example 4 800 107.7 3.2 2.1 1,000 913.0 Comparative Example 5 800 107.7 3.2 2.1 1,500 913.0 Example 1 Fluidized bed granulation 800 107.7 3.2 2.1 500 913.0 Example 2 800 107.7 3.2 2.1 1,000 913.0 Example 3 800 107.7 3.2 2.1 2,000 913.0 Example 4 800 107.7 3.2 2.1 3,000 913.0 Example 5 800 107.7 3.2 2.1 4,000 913.0

Experimental Example 1. Evaluation of the physical properties of purified water

In order to confirm the 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.

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.

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 and tear (%) 0.20% 0.15% 0.22% 0.19% 0.14% Surface appearance Easy to split Easy to split Easy to split Easy to split Easy to split 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 and tear (%) 0.09 0.09 0.06 0.07 0.01 or less Surface appearance Fineness of the split Fineness of the split Fineness of the split Almost no split No split at all

As shown in Table 2 above, it was confirmed that Examples 1 to 5 using fluidized bed granulation had higher hardness and significantly lower wear compared to Comparative Examples 1 to 5. In addition, it was confirmed that Examples 1 to 5 had very little or no wear compared to Comparative Examples 1 to 5, which were easily worn on the surface of the manufactured tablets.

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.

Experimental Example 2. Evaluation of tablet weight and size

The weight and size of the purified product were measured and compared with the weight and size of existing commercial products.

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) less than the existing commercial products.

In addition, it was confirmed that the tablets of Examples 1 to 5 using the fluidized bed granules of the present invention formed tablets having an average long axis 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.

Experimental Example 3. Evaluation of granule size distribution within the tablet

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 measuring device (Bettersizer, PowerProA1).

Granular particle size distribution (μm) Comparative Example 3 (%) Example 1 (%) 0~45 7.6 0.1 45~75 14.6 0.8 75~150 15.8 8.4 150~250 4.7 64.4 250~355 3.2 23.2 355~425 1.4 1.3 425~1,000 27.5 1.8 >1,000 25.2 0 bout 100 100

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 since 87.6% was distributed in the particle size of 150 to 355 μm. In addition, in the case of Example 1, the granules with a size exceeding 355 μm were only 3.1% and no granules with a size exceeding 1,000 μm appeared, whereas in the case of Comparative Example 3, the granules with a size exceeding 355 μm were 54.1%, which was more than half of the total granules, and in particular, the granules with a size exceeding 1,000 μm also appeared at 25.2%.

This shows 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.

The above description of the present invention is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential characteristics of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single component may be implemented in a distributed manner, and likewise, components described as distributed may be implemented in a combined form.

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 (12)

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. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is a carbonate. In the first paragraph, A pharmaceutical composition comprising microcrystalline cellulose as the pharmaceutically acceptable additives; sodium chloride and zinc stearate. In the first paragraph, 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. In the third paragraph, A pharmaceutical composition wherein the binder is water. In the first paragraph, A pharmaceutical composition, wherein the average particle size of the above granules is 75 to 400 μm. In the first paragraph, The pharmaceutical composition above is in the form of a tablet. A method for preparing an oral formulation, comprising the step of granulating sevelamer or a pharmaceutically acceptable salt thereof using a fluidized bed granulator. In Article 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. A method for manufacturing an oral formulation, wherein in claim 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. In Article 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. 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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