A sucrose ferric oxyhydroxide tablet composition and method of preparation

Abstract

The present application aims to provide a sucrose hydroxyl ferric oxide tablet composition and a preparation method thereof. The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sucrose hydroxyl ferric oxide tablet composition and a preparation method thereof. The sucrose hydroxyl ferric oxide is a particle with a certain particle size distribution, and the pharmaceutical composition is prepared by adding pharmaceutically acceptable pharmaceutical adjuvants, the preparation method is simple, the product has small friability, is easy to package, and is more conducive to commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a sucrose ferric hydroxide tablet composition and its preparation method. Background Technology

[0002] Sucrose ferric hydroxide was developed by Vifor Fresenius and approved for marketing in the United States in December 2013 under the brand name Velphoro. It is available in chewable tablet form, with a strength of 500 mg. Velphoro is a non-calcium, iron-based, chewable phosphate binder. It is currently marketed in 32 countries worldwide. The original formulation of this product was approved for marketing in China in February 2023, with a strength of 500 mg.

[0003] Sucrose ferric hydroxide is an iron-based, calcium-free, chewable phosphate binder. Clinical trials have shown that it does not increase the body's iron load and is superior to calcium-containing phosphate binders in preventing vascular calcification. It can be used to treat hyperphosphatemia, hyperphosphatemia in adult chronic kidney disease (CDK) patients undergoing hemodialysis or peritoneal dialysis, and hyperphosphatemia in 12-year-old and older CKD stage 4-5 patients or pediatric CKD patients undergoing dialysis.

[0004] WO 20101015827 A2 discloses an iron ion composition that can be used clinically to treat hyperphosphatemia, wherein the iron ion composition is a solid ligand-modified polyoxy-hydroxy metal ion material represented by the formula (MxLy(OH)n), where M represents Fe 3+ One or more metal ions, where L represents one or more ligands including a carboxylic acid ligand or its ionized form, and OH represents an oxygen or hydroxyl group, wherein the material has a polymeric structure, wherein the ligand L can be substantially substituted by any oxygen or hydroxyl group, and wherein the solid ligand-modified polyoxy-hydroxy metal ion material has one or more renewable physicochemical properties. While this document mentions a certain particle size of the solid ligand-modified polyoxy-hydroxy metal ion material, it does not disclose any particle size distribution of a specific pharmaceutical composition, but only discloses the particle size distribution of a newly prepared phosphate binder material. Therefore, this document does not teach anything about the relevance of the particle size distribution used in pharmaceutical compositions. WO 20101015827 A2 does not contain any examples of specific pharmaceutical compositions.

[0005] CN 112022796 A discloses an orally administered pharmaceutical composition comprising a high loading of ferric hydroxyoxide, particularly administered via an oral delivery system that can be swallowed directly or disintegrated in the mouth. This document describes the excipient composition and preparation method, but does not specify the particle size of the active pharmaceutical ingredient.

[0006] CN115175670 A discloses granules of a mixture of ferric hydroxide, sucrose, and one or more starches with a specific particle size distribution. Preferably, the proportion of particles larger than 90 μm, as determined by sieve analysis, is 50% or more by weight, of which the proportion of particles larger than 125 μm is 35% or more by weight. Based on these granules, by adding magnesium stearate, talc, and optionally one or more flavoring agents, microtablets that are easily ejected during tableting can be prepared, preferably with a mass of 11.4 to about 13.6 mg, suitable for pediatric use or patients with dysphagia.

[0007] Patent 201480065206.0 protects a pharmaceutical composition comprising phosphate binder particles with a specific particle size distribution. The phosphate binder comprises particles with a particle size distribution, wherein at least 40% of the particles have a particle size range of 4-200 μm and a d50 range of 40 μm-100 μm. The phosphate binder particles are sucrose ferric hydroxide. The pharmaceutical composition is a chewable tablet prepared by direct compression of powder. The average particle size of the sucrose ferric hydroxide ranges from 40 μm to 100 μm. Particles larger than 100 μm have poor compressibility and low hardness, failing to meet production and transportation requirements. Particles smaller than 40 μm have poor material flowability and significant losses during tableting. Therefore, the special requirements for the particle size range restrict the manufacturing of the product. At the same time, the patented product with an average particle size of 40μm-100μm has a high degree of brittleness. According to the appearance of commercially available products, there are cases of missing corners and powder falling off, indicating that there are also certain challenges in the transportation process.

[0008] This invention controls the average particle size of sucrose ferric hydroxide to below 40 μm. At the same time, through a certain preparation process, the brittleness of the produced product meets the pharmacopoeia requirements. Furthermore, the low-hardness sample does not exhibit chipping or powdering during storage and transportation, ensuring the accuracy of the patient's dosage. In addition, the prescription and process are conducive to commercial production. Summary of the Invention

[0009] The purpose of this invention is to provide a sucrose ferric hydroxide composition and its preparation method, wherein the average particle size of the sucrose ferric hydroxide is less than 40 μm. The product prepared by dry granulation process has stable quality and is consistent with the key quality attributes of commercially available products. At the same time, the product prepared by this method has less brittleness and is superior to commercially available products, which greatly benefits commercial production, transportation and product stability.

[0010] This invention provides a sucrose hydroxyferric oxide composition, which is a chewable tablet. The chewable tablet composition provided by this invention comprises sucrose ferric hydroxide, a flow aid, a lubricant, and a flavoring agent, wherein the selected composition is chosen from: (1) Contains 90-98% by weight of sucrose hydroxy iron oxide; its average particle size is less than 40 μm; (2) 0.5~5% by weight of gliding agent; (3) 0.5~5% by weight of lubricant; (4) 0.5~5% by weight of flavoring agent The flow aid described in this invention can improve material uniformity and ensure that multiple materials are mixed into a uniform state. It is characterized by being selected from one or more combinations of talc powder or colloidal silica.

[0011] The lubricant of the present invention can improve the flowability of the mixture and the appearance of the tablets during the tableting process, and is characterized by being selected from one or more combinations of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, sodium stearate fumarate, sodium lauryl sulfate, and glyceryl behenate.

[0012] The flavoring agent described in this invention can improve the taste and smell when taken by the user, thereby increasing patient compliance. It may include flavorings and sweeteners. The flavorings may be selected from one of the following: raspberry flavoring, sweet orange flavoring, mango flavoring, lychee flavoring, grass jelly flavoring, etc. The sweeteners may be selected from one of the following: neohesperidin dihydrochalcone, cyclamate, acesulfame potassium, aspartame, etc.

[0013] The preparation method of the present invention is characterized in that sucrose hydroxyl iron oxide and lubricant are granulated into particles of a certain size by dry granulation, and then mixed with a certain amount of glidant, lubricant and flavoring agent for tableting.

[0014] One object of the present invention is to provide a technology for the commercial production of sucrose ferric hydroxide with an average particle size of less than 40 μm.

[0015] Another object of the present invention is to provide the stability of chewable tablets prepared by the new process during transportation, thereby improving the safety of patient medication.

[0016] The above and other objectives can be achieved by means of the present invention, which provides chewable tablets that have the same key quality attributes as commercially available products and better ensure product integrity during transportation.

[0017] Beneficial effects of the present invention The sucrose ferric hydroxide chewable tablets of the present invention are prepared into stable tablets by means of a suitable preparation process, which produces sucrose ferric hydroxide with an average particle size of less than 40 μm, thus realizing the commercial production, transportation and storage of sucrose ferric hydroxide with an average particle size of less than 40 μm. Detailed Implementation

[0018] This disclosure is further described in detail through the following embodiments and experimental examples. These embodiments and experimental examples are for illustrative purposes only and are not intended to limit the scope of this disclosure. Example 1

[0019] Each piece: 2500mg of sucrose hydroxyferric oxide Magnesium stearate 37.5mg 12.5 mg of colloidal silica Raspberry flavoring 40mg Neohesperidin dihydrochalcone 0.01mg Preparation process of Example 1: (1) Premixing: sucrose hydroxy ferric oxide with an average particle size of 15 μm is mixed evenly with a portion of magnesium stearate; (2) Dry granulation: The above materials are pressed into thin sheets of a certain density by a dry granulator under appropriate pressure, and then crushed into fine particles by a granulation screen. (3) Mixing: Mix the granulated material with the remaining magnesium stearate, colloidal silica, raspberry flavor, and neohesperidin dihydrochalcone to form a homogeneous material; (4) Tableting: Use a 20mm round flat slant die to control the hardness of tablets to 80~230N. Example 2

[0020] Each piece: 2500mg of sucrose hydroxyferric oxide Hydrogenated vegetable oil 25mg 50mg talc Sweet orange flavoring 30mg Sweetener 0.05mg Preparation process of Example 2: (1) Premixing: Mix sucrose ferric hydroxide with an average particle size of 35 μm with partially hydrogenated vegetable oil until homogeneous; (2) Dry granulation: The above materials are pressed into thin sheets of a certain density by a dry granulator with appropriate pressing, and then crushed into fine particles by passing through a granulation screen. (3) Mixing: Mix the granulated material with the remaining hydrogenated vegetable oil, talc, sweet orange flavoring and sweet syrup to form a homogeneous material; (4) Tableting: Use a 20mm round flat slant die to control the hardness of tablets to 80~230N; Comparative Example 1

[0021] Each piece: 2500mg of sucrose hydroxyferric oxide Magnesium stearate 37.5mg 12.5 mg of colloidal silica Raspberry flavoring 40mg Neohesperidin dihydrochalcone 0.01mg Preparation process of Comparative Example 1: (1) Mixing: Sucrose ferric hydroxide with an average particle size of less than 40 μm is mixed with magnesium stearate, colloidal silica, raspberry flavor and neohesperidin dihydrochalcone to form a homogeneous material; (2) Tableting: Use a 20mm round flat slant die to control the hardness of tablets to 80~220N; Comparative Example 2

[0022] Each piece: 2500mg of sucrose hydroxyferric oxide Magnesium stearate 37.5mg 12.5 mg of colloidal silica Raspberry flavoring 40mg Neohesperidin dihydrochalcone 0.01mg Comparative Example 2 Preparation Process: (3) Mixing: Sucrose ferric hydroxide with an average particle size of 40μm~100μm is mixed with magnesium stearate, colloidal silica, raspberry flavor and neohesperidin dihydrochalcone to form a homogeneous material; (4) Tableting: Use a 20mm round flat slant die to control the hardness of tablets to 80~230N.

[0023] Velphoro, a commercially available product ® (Viverri) ® The manufacturer is Vifor Fresenius Medical. The sucrose ferric hydroxide chewable tablets prepared in Examples 1-2 and Comparative Examples 1-2 were tested for hardness, disintegration time, and friability according to the 2020 edition of the Chinese Pharmacopoeia. Phosphate adsorption capacity and iron release were tested according to product quality standards. The results are shown in Table 1. Table 1 sample Example 1 Example 2 Comparative Example 1 Comparative Example 2 <![CDATA[Commercially available product Velphoro ® > Hardness N 90 120 140 135 140 Disintegration time limit min 9.25 10.25 3.15 8.69 9.21 Friability % 0.9 0.6 5.0 4.5 5.0 Phosphate adsorption capacity (mgP / mgFe) 0.30 0.31 0.25 0.28 0.29 Iron release (iron dissolved per 100 mg of iron) 0.28 0.28 0.38 0.27 0.29 .

[0024] Take this product and perform the dissolution and release assay according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). The apparatus uses a paddle method with 0.1N hydrochloric acid solution as the release medium and a rotation speed of 50 rpm. Take 20 ml of solution at 5, 10, 15, 20, 30, 45, and 60 min respectively, and immediately replenish with the same volume and temperature of dissolution medium. Use the dissolution solutions obtained within the above time periods as the test solution and determine the dissolution rate by titration. The results are shown in Table 2.

[0025] Table 2 time Example 1 Example 2 Comparative Example 1 Comparative Example 2 <![CDATA[Commercially available product Velphoro ® > 5min 27.0 24.6 43.8 28.0 26.5 10min 51.3 47.6 65.0 53.2 49.8 15min 70.2 65.4 80.6 71.5 67.3 20min 82.3 78.3 89.8 83.1 80.2 30min 91.2 87.6 95.6 93.2 89.8 45min 98.0 95.3 98.7 96.9 97.1 60min 99.3 96.3 98.9 97.3 97.7 Compared to commercially available F2 84 82 42 74 / .

[0026] As can be seen from the results of F2 in Table 2, Examples 1, 2, and Comparative Example 2 are all similar to the commercially available product Velphoro. ® The similarity indicates that their in vitro release behavior is consistent. Attached Figure Description

[0027] Figure 1 Examples 1 and 2, and the commercially available product Velphoro. ® Comparison of samples tested for friability.

[0028] Depend on Figure 1 It can be seen that Examples 1 and 2 have good appearance, indicating that they are more stable during production, transportation and storage.

Claims

1. An oral tablet composition comprising sucrose ferric hydroxide, wherein the sucrose ferric hydroxide is a particle with a certain particle size distribution, the particle d50 being in the range of 4~40 μm, wherein the above-mentioned sucrose ferric hydroxide particles are prepared into tablets with at least one lubricant and a flow aid according to a certain preparation method, wherein the preparation method employs a dry granulation process.

2. The sucrose ferric hydroxide tablet composition according to claim 1, characterized in that... Easy-to-chew tablets.

3. The sucrose ferric hydroxide tablet composition according to claim 1, characterized in that... Sucrose ferric hydroxide is a particle with a certain particle size distribution, with a d50 range of 4~40μm.

4. The sucrose ferric hydroxide tablet composition according to claim 1, characterized in that... The lubricant is one or more of magnesium stearate, stearic acid, calcium stearate, sodium dodecyl sulfate, and sodium stearate fumarate, and the flow aid is one or more of colloidal silica and talc.

5. The preparation method according to claim 1, characterized in that... A method that uses a dry granulation process to compress a drug composition into thin sheets of a certain density, and then uses crushing and granulation processes to produce a certain particle weight ratio.

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