Sucrose iron hydroxide-containing granules and pharmaceutical composition

Abstract

The present invention aims to provide a novel formulation containing sucrose iron hydroxide, in particular a novel formulation that can be taken without chewing. [Solution] The present invention relates to a novel formulation containing sucrose iron hydroxide, discovered through diligent research to provide a novel formulation containing sucrose iron hydroxide. This discovery is based on the finding that granules containing sucrose iron hydroxide having a specific size and shape, as well as specific physicochemical properties, are easy to take without chewing and possess suitable formulation characteristics for industrial production.

Description

[Technical Field]

[0001] This invention relates to granules and pharmaceutical compositions containing sucrose iron hydroxide. [Background technology]

[0002] To date, the following pharmaceuticals containing sucrose iron hydroxide have been sold: "Pitol® Chewable Tablets 250mg" and "Pitol® Chewable Tablets 500mg." Both are donut-shaped chewable tablets with outer diameters of 16.5mm and 20.5mm, respectively, and are intended to be chewed in the mouth for the improvement of hyperphosphatemia in chronic kidney disease patients undergoing dialysis.

[0003] Chewable tablets, which are taken by disintegrating them in the mouth through chewing, are convenient to carry and easy to take as they can be taken without water. However, chewable tablets are generally large and difficult to swallow as is, and may not be easy for the elderly or patients with reduced chewing ability to take them. In addition, many patients are concerned about the taste of the drug and the staining of the mouth that occurs when chewing (Patent Document 1 or Non-Patent Document 1). Although tablets are sometimes changed to powdered granules, it has been reported that many elderly people complain of discomfort due to the granules spreading in the mouth, sticking to the throat, and getting stuck between dentures, so this has not always been satisfactory (Non-Patent Document 1).

[0004] To date, the only granular form available for treating hypercholesterolemia is Colestimine (registered trademark) Mini, which contains colestimide as its active ingredient and has a diameter of approximately 3 mm (Non-Patent Literature 2).

[0005] Until now, the only known formulations containing sucrose iron hydroxide were chewable tablets, and there was a need for a novel formulation that could be taken without chewing. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2017-178829 [Non-Patent Document 1] Oshima, Taishi, "Pharm Stage," 2007, Vol. 7, No. 6, pp. 16-20. [Non-Patent Document 2] Yamanouchi Pharmaceutical, "News Release: Yamanouchi Pharmaceutical Launches New Hypercholesterolemia Treatment Drug 'Collevine Mini 83%'", [online], October 7, 2002, [Retrieved July 30, 2018], Internet<https: / / www.astellas.com / jp / corporate / news / yamanouchi / 021007.html> [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present invention aims to provide a novel formulation containing sucrose iron hydroxide, in particular a formulation that can be taken without chewing. [Means for solving the problem]

[0008] The present inventors diligently studied to provide a novel formulation containing sucrose iron hydroxide and, as a result, discovered that granules having a specific size and shape, as well as specific physicochemical properties, are easy to take without chewing and possess suitable formulation characteristics for industrial production, thus completing the present invention. That is, the present invention relates to the following [1] to [7], etc. [1] Contains sucrose iron hydroxide, has a roughly spherical shape with a maximum length of 1.0 to 4.0 mm, and has a tensile strength of 1.0 to 5.5 N / mm². 2 Granules characterized by the following: [2] The granules described in [1] above, wherein the roughly spherical shape consists of a cylinder and a cap portion formed by convex bulges from its upper and lower surfaces, and the diameter of the cylinder is 1.0 to 4.0 mm. [3] The granules according to [1] or [2] above, having a roughly spherical shape, wherein the ratio of diameter to thickness is 0.7 to 1.2 and the ratio of thickness to height of the cylinder is 1.05 to 3.0. 〔4〕The granules according to any one of 〔1〕to 〔3〕, characterized in that the disintegration time is within 30 minutes and the wear rate is 1.0% or less. 〔5〕The granules according to any one of 〔1〕to 〔4〕, wherein the granules are in the form of a compression molded body. 〔6〕A pharmaceutical composition comprising the granules according to any one of 〔1〕to 〔5〕. 〔7〕The pharmaceutical composition according to 〔6〕, containing 200 mg to 600 mg of iron per package container.

Advantages of the Invention

[0009] The present invention provides a novel preparation containing scor-oxy iron hydroxide. The granules and pharmaceutical composition of the present invention can provide a novel preparation excellent in the ingestibility and manufacturability for patients with difficulty in chewing.

Brief Description of the Drawings

[0010] [Figure 1] It is a schematic view showing an example of the shortest dimension and the longest dimension of the granules. [Figure 2] It is a view showing an example of an embodiment as the granules of the present invention. [Figure 3] It is a view showing an example of another embodiment as the granules of the present invention. [Figure 4] It is a schematic view for measuring the hardness of the granules.

Explanation of Reference Numerals

[0011] Lmin Shortest dimension Lmax Longest dimension (A) Plan view (B) Side view (1) Diameter (2) Thickness (3) Height of the cylinder (4) Cap part (5) Direction of applying force when measuring hardness F Force when measuring hardness

Modes for Carrying Out the Invention

[0012] Hereinafter, embodiments of the present invention will be described in more detail.

[0013] In the present invention, each term has the following meaning unless otherwise specified.

[0014] The term "granule" means granulated matter and includes compressed mini-tablets or micro-tablets.

[0015] The term "substantially spherical shape" refers to a shape such as a spherical shape, an oval shape, a shape composed of a cylinder and convex cap portions bulging from its upper and lower surfaces, etc., whose outer shape is approximately spherical and shapes similar thereto, and means that the ratio of the longest dimension to the shortest dimension (longest dimension / shortest dimension) when projected onto a horizontal plane is 1.0 to 1.5. The granules of the present invention refer to those having a longest dimension of 1.0 to 4.0 mm, preferably 1.5 to 3.0 mm, and more preferably 2.1 to 2.5 mm. The ratio of the longest dimension to the shortest dimension is preferably 1.0 to 1.2, and more preferably 1.0. Regarding the method for determining the longest dimension and the shortest dimension, when the granule is projected onto a horizontal plane, the shortest dimension is set as the shortest dimension, and the longest dimension among the straight lines orthogonal thereto is measured as the longest dimension. For example, in the case of a cylindrical granule having a cap portion shown in FIG. 1, among the diameter and the thickness, the diameter of the shortest dimension is set as the shortest dimension, and the thickness orthogonal thereto is set as the longest dimension.

[0016] As the substantially spherical granules, for example, based on FIG. 2 or FIG. 3 showing an example of an embodiment of the present invention, it has a predetermined diameter (1), thickness (2), and height of the cylinder (3), and both surfaces of the cylinder are composed of convexly bulging cap portions (4). The cap portion (4) may be in the shape of a frustum of a cone with a flat top surface, in the shape of a dome with a curved top surface, or in the shape of a dome with a predetermined radius of curvature. Here, the ratio of the diameter to the thickness is "(value of (1)) / (value of (2))", and the ratio of the height of the cylinder to the thickness is "(value of (2)) / (value of (3))", which are calculated respectively.

[0017] As one embodiment of the spherical granules, for example, the diameter (1) is 1.0 to 4.0 mm, preferably 1.5 to 3.0 mm, more preferably 2.0 to 2.5 mm, and the cap portion (4) is a convex surface in the shape of a frustum of a cone with a planar top, preferably having convex curved surfaces with a radius of curvature of 0.5 to 5.0 mm, more preferably a radius of curvature of 1 to 4 mm on both sides of the cap portion (4). The ratio of the diameter (1) to the thickness (2) is 0.7 to 1.2, preferably 0.9 to 1.1, more preferably 0.95 to 1.05. The ratio of the thickness (2) to the height (3) of the cylinder is 1.05 to 3.0, preferably 1.4 to 2.5, more preferably 1.6 to 1.9, and the specific gravity is 1.0 to 2.0 mg / mm 3 , preferably 1.4 to 1.8 mg / mm 3 , more preferably 1.5 to 1.7 mg / mm 3 , and the tensile strength is 1.0 to 5.5 N / mm 2 , preferably 1.0 to 4.7 N / mm 2 , more preferably 1.0 to 3.9 N / mm 2 . At this time, when the ratio of the diameter (1) to the thickness (2) is 0.7 to 1.2, it is preferable in terms of productivity and ease of taking. Also, when the ratio of the thickness (2) to the height (3) of the cylinder is 1.05 to 3.0, it is preferable because chipping and wear are less likely to occur. When the tensile strength is 1.0 N / mm 2 or more, it is preferable in terms of disintegration time and durability of the granules. For example, when filling into a packaging container, the number of granules that are worn is less likely to increase. On the other hand, when the tensile strength is 5.5 N / mm 2 or less, it is preferable in terms of disintegration property. For example, it is likely to disintegrate within 30 minutes in the general test method "Disintegration Test Method" of the Japanese Pharmacopoeia.

[0018] Sucroferric oxyhydroxide (generic name) is a compound known as an iron(III) hydroxide / sucrose / starch mixture and can be produced according to the methods described in the literature. For example, it can also be produced according to the methods described in International Publication No. 97 / 22266 or International Publication No. 2015 / 078900, etc.

[0019] In sucrose iron(III) oxyhydroxide, a particularly preferred mixture of iron(III) oxyhydroxide, sucrose, and starch contains about 25-40% by weight of iron(III) oxyhydroxide, about 25-40% by weight of sucrose, and about 25-40% by weight of starch, based on the total dry weight (i.e., 100% by weight) of the sucrose iron(III) oxyhydroxide. A particularly preferred mixture of iron(III) oxyhydroxide, sucrose, and starch contains about 30-35% by weight of iron(III) oxyhydroxide, about 30-35% by weight of sucrose, and about 30-35% by weight of starch, based on the total dry weight (i.e., 100% by weight) of the sucrose iron(III) oxyhydroxide based on the above mixture, wherein the iron(III) oxyhydroxide preferably contains β-iron(III) oxyhydroxide.

[0020] The starch contained in sucrose iron hydroxide may be one, two, or more types of starch, for example, only natural starch, only pregelatinized starch, or a mixture of natural starch and pregelatinized starch. Sucrose iron hydroxide containing a mixture of natural starch and pregelatinized starch is preferred.

[0021] The granules of the present invention can be produced by adding one or more pharmaceutically acceptable additives, such as excipients, disintegrants, binders, lubricants, etc., to sucrose iron hydroxide. In preferred embodiments, the lubricant is included, and examples include colloidal silica, light anhydrous silicic acid, magnesium trisilicate, talc, tricalcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, and glycerol behenate, and one or more of these can be used. More preferably, magnesium stearate, light anhydrous silicic acid, and talc are used individually or in combination in a ratio of 0.1-2% by weight:0-4% by weight:0-4% by weight, respectively. Preferably, the additive is present in the granules at a concentration of 0.1-10% by weight, more preferably 1-6% by weight.

[0022] In further embodiments, the granules of the present invention contain one or more pharmaceutically acceptable flavorings or colorings for oral formulations. Examples of flavorings include apple flavor, orange flavor, caramel flavor, black tea flavor, cocoa flavor, sesame flavor, strawberry flavor, banana flavor, vanilla flavor, matcha flavor, menthol, yogurt flavor, lemon flavor, chocolate flavor, etc. Examples of colorings include ferric oxide, yellow ferric oxide, black iron oxide, caramel, etc.

[0023] The method for producing the granules of the present invention is not particularly limited and can be produced by known methods. For example, they can be produced using a conventional tablet press such as a single-stroke tablet press, a rotary tablet press, or an external smooth tablet press, and using a punch suitable for producing the substantially spherical granules of the present invention (e.g., a single-tip punch, a multi-tip punch, etc.). One method is to mold them with pressure that exhibits the substantially spherical shape and formulation characteristics (flowability, abrasion resistance, disintegration, manufacturability, ease of administration, etc.) of the present invention.

[0024] One embodiment of the pharmaceutical composition of the present invention is a granular formulation.

[0025] The pharmaceutical composition of the present invention is administered orally. For example, when used to improve hyperphosphatemia in patients with chronic kidney disease undergoing dialysis, it is administered as a pharmaceutical composition in which multiple granules of the present invention are filled into a packaging container so that the dose per administration is 200 mg to 600 mg of iron.

[0026] The aforementioned packaging container is not particularly limited and can include pillow packaging, stick packaging, and other types commonly used as pharmaceutical packaging. Stick packaging containers with an opening width of approximately 20 mm and a length of approximately 70 mm to 120 mm are preferred as they are considered easy for patients to take.

[0027] The "tensile strength" of the granules of this invention can be calculated as the value obtained by dividing the hardness of the granules by the fracture area. This tensile strength, calculated by dividing the hardness by the fracture area, eliminates the influence of the size, thickness, shape, etc. of the granules and can be used for direct comparison and evaluation of strength. Further details will be described later.

[0028] The "abrasion rate" of the granules of the present invention refers to a value indicating the wear resistance and brittleness of the formulation against impact. Specifically, it refers to a value obtained by referring to the abrasion rate test method for tablets listed in the 17th edition of the Japanese Pharmacopoeia, placing multiple 6.5g granules into a transparent, smooth-surfaced plastic drum-type tester with an inner diameter of approximately 287mm and a depth of approximately 38mm, rotating it 100 or 500 times at a rotation speed of 24 to 26 revolutions per minute, then precisely weighing the total mass of the granules, and calculating the mass percentage of the mass reduction relative to the initial mass. In a preferred embodiment, the abrasion rate of the granules of the present invention when tested at 100 revolutions is 1.0% or less. More preferably, the abrasion rate of the granules of the present invention is 0.8% or less, even more preferably 0.7% or less, and particularly preferably 0.5% or less.

[0029] Due to the shape and physicochemical properties of the granules of this invention, they possess durability and appropriate fluidity, resulting in a low rate of wear, chipping, and breakage during manufacturing, thus improving filling accuracy. In particular, because the granules are less likely to crack or chip due to collisions with each other when filling them into packaging containers, clogging of machinery by the generated fine powder is less likely. Their excellent fluidity allows for accurate measurement of the required quantity of granules, preventing spillage from the filling device, and minimizing damage to the granules themselves, enabling filling even into narrow, elongated stick packaging containers, thus improving the efficiency of packaging container filling. Furthermore, because the generation of fine powder due to cracking or chipping is suppressed during transport from the packaging container to the patient, issues such as oral discoloration, throat adhesion, and clogging of dentures by fine powder are less likely to occur during administration, and the granules come out smoothly from the packaging container, improving ease of administration.

[0030] Furthermore, the shape of the granules and their physicochemical properties in this invention exhibit excellent characteristics for continuous granule production. In addition, even with continuous production over long periods, the variation in the mass of the produced granules is small, the impact on disintegration time is minimal, and the rate of cracking and chipping does not increase. As a result, less cleaning of the molding equipment is required, making it possible to produce granules with extremely small deviations in mass and content homogeneity, making it suitable for the continuous, i.e., industrial production of high-quality formulations.

[0031] The granules of the present invention exhibit excellent disintegration properties; for example, in the general test method "Disintegration Test Method" of the Japanese Pharmacopoeia, they preferably disintegrate within 30 minutes, and more preferably within 20 minutes. [Examples]

[0032] The contents of the present invention will be described in more detail based on the following test examples, embodiments, and reference examples, but the contents of the present invention are not limited thereto. Example 1: Production of granules The following amounts of sucrose iron hydroxide, excipients (light anhydrous silicic acid, talc, magnesium stearate), and fragrance were mixed together. After sieving the resulting mixture, it was compressed and molded to a thickness of 2.3 mm using a tablet press with a rounded punch and die with a diameter of 2.3 mm and a radius of curvature of 1.5 mm, yielding cylindrical granules with a diameter of 2.3 mm, a radius of curvature of 1.5 mm at the convex part, a thickness of 2.3 mm, and a cap portion with a height of 1.3 mm at the cylindrical part.

[0033] [Table 1]

[0034] Examples 2-14, Reference Examples 1-2: Granule production Using the same method as in Example 1, a mixture of sucrose iron hydroxide, light anhydrous silicic acid, talc, magnesium stearate, and fragrance shown in Table 1 was compressed into tablets while adjusting the thickness using a tablet press with punches and dies of different diameters and radii of curvature of the depressions, thereby producing granules in the shapes of Examples 2-14 and Reference Examples 1-2. Manufacturing of pharmaceutical compositions Multiple portions of the granules obtained in Examples 1 to 14 were weighed out so that each packaged container contained 250 mg of iron, thereby obtaining a pharmaceutical composition containing 250 mg of iron per packaged container. Test Example 1: Hardness Measurement The hardness of the granules in Examples 1-14 and Reference Examples 1-2 was measured using a hardness tester (Okada Seikou Co., Ltd., PC-30) by applying force in the direction shown in Figure 4, and the pressure (N: Newtons) was measured when the granules were crushed and fractured at a constant speed. The measurement results are shown in Table 2. Test Example 2: Calculation of Tensile Strength The tensile strength of the granules in Examples 1-14 and Reference Examples 1-2 was calculated using the following formula (Equation 1), which divides the hardness of each granule measured in Test Example 1 by its fracture area. The calculation results are shown in Table 2.

[0035] "Tensile strength" = 2F / (π × (1) × (2))········(Equation 1) In the formula, F represents the hardness of the granule (N: Newton), (1) represents the diameter of the granule (mm), and (2) represents the thickness of the granule (mm). Test Example 3: Collapse Test Disintegration tests were conducted according to the "Disintegration Test Method" of the 17th Revised Japanese Pharmacopoeia. Specifically, water was used as the test solution, and approximately 1.3 g of granules from Examples 1-3, 6-14, and Reference Examples 1-2 were weighed out and tested according to the same test method as for immediate-release formulations (tablets). The test results are shown in Table 2. Test Example 4: Abrasion Test The test was conducted according to the "Tablet Abrasion Test Method" of the 17th Revised Japanese Pharmacopoeia. Multiple granules totaling 6.5g each from Examples 1-5, 7, 9-10, 12-13, and Reference Examples 1-2 were weighed into a cylinder rotating at a constant speed (25 revolutions / minute), and the granules were repeatedly dropped using a central plate. After rotating for 4 minutes, the granules were removed from the cylinder. Broken and separated powder and small particles were sieved off, and the total mass of the granules was measured. The mass loss was calculated as a percentage of the initial mass. The test results are shown in Table 2.

[0036] [Table 2]

[0037] Test Example 5: Continuous production capability of granules The granules of Example 4 or Example 5 were continuously manufactured using a rotary tablet press, and the content, hardness, and abrasion rate were measured at each continuous manufacturing time. The abrasion rate was measured in the same manner as in Test Example 4. The measurements were taken, and the results are shown in Table 3. The granules of Example 4 or Example 5 were shown to not exhibit any significant changes in content, hardness, or abrasion even when manufactured continuously.

[0038] [Table 3]

[0039] Test Example 6: Fillability of granules into packaging materials The granules of Example 4 or Example 5 were continuously filled into packaging containers measuring 20 mm in width and 90 mm in length, so that each container contained 250 mg of iron. The average filling mass and the coefficient of variation of the average filling mass were measured after each filling, and the results are shown in Table 4. The granules of Example 4 or Example 5 exhibited excellent fluidity, allowing for accurate measurement of the required quantity of granules, preventing spillage from the filling device, and enabling consistent filling of a narrow-mouthed packaging container while minimizing the number of broken or chipped granules. The coefficient of variation of the average filling amount represents the variation in filling mass and was calculated as the percentage obtained by dividing the standard deviation of the change in average filling mass by the average filling mass.

[0040] [Table 4] [Industrial applicability]

[0041] The present invention is useful as a novel formulation containing sucrose iron hydroxide that does not require chewing.

Claims

1. It contains sucrose iron hydroxide, has a roughly spherical shape with a maximum length of 1.0 to 4.0 mm, and a tensile strength of 1.0 to 5.5 N / mm². ２ Granules characterized by the following:

2. The granules according to claim 1, wherein the roughly spherical shape consists of a cylinder and cap portions formed by convex bulges from its upper and lower surfaces, and the diameter of the cylinder is 1.0 to 4.0 mm.

3. The granules according to claim 1 or 2, wherein, in a roughly spherical shape, the ratio of diameter to thickness is 0.7 to 1.2, and the ratio of thickness to height of the cylinder is 1.05 to 3.

0.

4. The granules according to any one of claims 1 to 3, characterized in that the disintegration time is within 30 minutes and the degree of abrasion is 1.0% or less.

5. A pharmaceutical composition containing granules according to any one of claims 1 to 4.

6. The pharmaceutical composition according to claim 5, which contains 200 mg to 600 mg of iron per package.

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