Citrus flavone tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a citrus flavone tablet and a preparation method thereof. Tablet cores of the citrus flavone tablets comprise 450-550 parts by weight of citrus flavone, 50-74 parts by weight of microcrystalline cellulose, 20-34 parts by weight of carboxymethyl starch sodium, 20-40 parts by weight of gelatin, 4-8 parts by weight of talcum powder and 2-6 parts by weight of magnesium stearate, the citrus flavone tablets are prepared through a one-step granulation process, a wetting process is specially added before one-step granulation, adhesion of raw material medicines in the initial stage of granulation is avoided, and the content of the raw material medicines is increased. Meanwhile, low content caused by loss of raw material medicines due to single use of a one-step granulation process is avoided. According to the present invention, the particles similar to the reference preparation are obtained by using the specific components, the specific wet granulation wetting and the one-step granulation process, the in vitro dissolution of the obtained citrus flavone tablet is similar to the reference preparation, the disintegrated particles are similar to the reference preparation, and the treatment effect is further ensured.

Description

Technical Field

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

[0002] Citrus flavonoid tablets are a compound preparation. Each tablet contains 500mg of citrus flavonoids (purified micronized flavonoid components), including 450mg of 90% diosmin and 50mg of 10% flavonoid components expressed in the form of hesperidin.

[0003] The main ingredient, diosmin, belongs to BCS class IV compounds and has low solubility and low permeability. In vitro solubility studies have shown that citrus flavonoid raw materials are insoluble in media with pH 1.0–7.5, but dissolve under alkaline conditions. This means that the similarity between the product and the reference formulation cannot be assessed in media with in vitro-in vivo correlation. From the perspective of the mechanism of action of solid oral dosage forms, the factors affecting the absorption rate of active ingredients are mainly: the time it takes for the tablet to disintegrate into small particles in the gastrointestinal tract, the time it takes for the small particles to further disintegrate into the active ingredient, and the particle size of the active ingredient itself. If the product can be similar to the reference formulation in these three dimensions and dissolves consistently in alkaline dissolution media, it can further ensure that the product has the same efficacy as the reference formulation.

[0004] The instruction manual for the reference formulation of citrus flavonoid tablets clearly states that the citrus flavonoids used are purified micronized flavonoid components. Based on the particle size control of citrus flavonoids mentioned in two patent documents from Servier Pharmaceuticals (CN108392468A) regarding "a pharmaceutical composition comprising flavonoid components and xanthan gum in oral suspension form" and "a pharmaceutical composition in chewable tablet form of geraniol or flavonoid fraction" (CN112423735A), a D90 of less than 1.6 μm is preferred. Therefore, the inventors hypothesize that the particle size control of the citrus flavonoid raw material used in the citrus flavonoid tablets produced by Servier Pharmaceuticals (CN112423735A) is D90 ≤ 1.6 μm. Using micronized raw materials, due to their extremely large specific surface area, results in excessively strong cohesion, making the raw material itself prone to agglomeration; the raw material also easily adheres to the surface of the production equipment during the production process.

[0005] The following are currently published patent documents relating to citrus flavonoid tablets or diosmin tablets:

[0006] The invention patent application with publication number CN104906058A (patent applicant: Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd.) uses direct compression tableting, and the drug mixture contains diosmin, diethylene glycol monoethyl ether, and an anti-adhesion agent. Diethylene glycol monoethyl ether is unstable and can cause combustion when exposed to high heat or oxidation, so this process carries certain risks.

[0007] The patent application with publication number CN117205200A (patent applicant: Nanjing Hainan Pharmaceutical Co., Ltd.) uses purified water for granulation. However, the gelatin binder has not undergone sufficient hydration, resulting in a significant reduction in its viscosity. This may lead to excessive fine powder, affecting the tableting process. Furthermore, the dry-added gelatin particles need to have a similar particle size distribution to other excipients; otherwise, they are prone to stratification during granulation, resulting in poor granulation effect. During the pulverization process, gelatin is prone to agglomeration, making it difficult for excipient manufacturers to meet the requirements for pulverized gelatin.

[0008] The patent application with publication number CN108392468A (patent applicant: Servier Pharmaceuticals, France) describes the preparation of chewable tablets containing a high dose of micronized geraniol. Considering that the incidence of venous disease is also high in the elderly, and considering that the elderly have difficulty chewing due to tooth loss, the target population for chewable tablets is slightly narrow.

[0009] Therefore, based on the development goals of citrus flavonoid tablets and the characteristics of citrus flavonoid raw materials, it is essential to develop a suitable citrus flavonoid tablet and production process. Summary of the Invention

[0010] To address the problems existing in the prior art, this invention provides a novel citrus flavonoid tablet and its preparation method. The product produced by this method not only exhibits the same physicochemical properties as the reference formulation, but also demonstrates consistent dissolution under alkaline conditions, thus ensuring the product's therapeutic efficacy.

[0011] The citrus flavonoid tablets provided by the present invention contain the following in their core: 450-550 parts by weight of citrus flavonoids, 50-74 parts by weight of microcrystalline cellulose, 20-34 parts by weight of sodium carboxymethyl starch, 20-40 parts by weight of gelatin, 4-8 parts by weight of talc, and 2-6 parts by weight of magnesium stearate.

[0012] Preferably, the core is obtained by a preparation method that includes first wetting and then granulation.

[0013] The citrus flavonoids contain 90% by weight diosmin and 10% by weight flavonoids expressed in the form of hesperidin.

[0014] Preferably, the core comprises: 480-520 parts by weight of citrus flavonoids, 56-68 parts by weight of microcrystalline cellulose, 24-30 parts by weight of sodium carboxymethyl starch, 25-35 parts by weight of gelatin, 5-7 parts by weight of talc, and 3-5 parts by weight of magnesium stearate.

[0015] In one specific embodiment, the core comprises: 500 parts by weight of citrus flavonoids, 62 parts by weight of microcrystalline cellulose, 27 parts by weight of sodium carboxymethyl starch, 31 parts by weight of gelatin, 6 parts by weight of talc, and 4 parts by weight of magnesium stearate.

[0016] The present invention also provides a method for preparing the citrus flavonoid tablets, which includes the following steps:

[0017] (1) Place citrus flavonoids, microcrystalline cellulose and sodium carboxymethyl starch in a wet granulator, premix, wet, and wet granulate to obtain wet granules;

[0018] (2) Prepare gelatin into a gelatin aqueous solution, then spray the gelatin aqueous solution and water onto the above-mentioned wetted granules, granulate using a one-step granulation process, dry, and dry granulate.

[0019] (3) Mix the granules obtained in the above steps with talc and magnesium stearate evenly, and press them into a core;

[0020] (4) Optionally, the above-mentioned core film is coated with a thin film.

[0021] Preferably, in step (1), the citrus flavonoid raw material has a D90 ≤ 2.5 μm.

[0022] Preferably, in step (1), the premixing time is 5 minutes, and the powder adhering to the inner wall of the granulation pot is scraped off during the premixing time of 2 minutes and 5 minutes.

[0023] Preferably, in step (1), the wetting solvent is water (e.g., purified water), the amount of wetting solvent is 25% to 35% of the weight of the material, the atomization pressure is 0.1 to 0.4 MPa, and the wetting time is 1 to 5 min; the mesh size of the wet granulation screen is 0.8 mm to 4.0 mm.

[0024] More preferably, in step (1), the amount of wetting solvent (e.g., purified water) used in the wetting process is 28% to 33% by weight of the material, the atomization pressure is 0.1 to 0.2 MPa, and the wetting time is 1 to 3 min; the mesh size of the wet granulation screen is 1.0 mm to 1.5 mm.

[0025] Preferably, in step (2), the material temperature is 30-50℃ and the atomization pressure is 0.1-0.2 MPa in the one-step granulation process; the screen aperture of the dry granulation is 0.8 mm-1.2 mm.

[0026] More preferably, in step (2), the material temperature is 35-45℃ and the atomization pressure is 0.12-0.16 MPa in the one-step granulation process; the screen aperture of the dry granulation is 1.0 mm.

[0027] Preferably, in step (2), the concentration of the gelatin aqueous solution is 10-20% by weight.

[0028] Preferably, in step (2), the weight of water in the one-step granulation process is 15% to 25% of the weight of the material.

[0029] Preferably, in step (4), the weight of the film coating is 1.5 to 5% of the weight of the core, more preferably 3%.

[0030] Preferably, in step (1), the premixing and wetting are carried out in a wet granulation machine.

[0031] Preferably, in step (2), the one-step granulation is carried out in a fluidized bed.

[0032] Preferably, in step (4), the film coating is Obadai OY-S-37207-CN.

[0033] The present invention has the following beneficial effects:

[0034] (1) The particle size distribution of the citrus flavonoid tablets of the present invention after disintegration in water is similar to that of the reference preparation after disintegration in water.

[0035] (2) The citrus flavonoid tablets of the present invention have a disintegration time similar to that of the reference formulation in water, 0.1N hydrochloric acid, pH 4.5 acetic acid, and pH 6.8 phosphoric acid media.

[0036] (3) The dissolution curve of the citrus flavonoid tablets of the present invention in alkaline dissolution medium is similar to that of the reference preparation.

[0037] (4) The content of the citrus flavonoid tablets of the present invention is similar to that of the reference preparation.

[0038] The "wetting" process is similar to that used in wet granulation and can also be referred to as "wet granulation wetting".

[0039] In summary, the citrus flavonoid tablets of this invention are prepared using a one-step granulation process. A wet granulation process is specifically added before the one-step granulation to avoid adhesion of the active pharmaceutical ingredient (API) in the early stages of granulation, and to prevent low content due to API loss caused by using only the one-step granulation process. By employing specific components, a specific wet granulation process, and a one-step granulation process, this invention obtains granules similar to the reference formulation. The resulting citrus flavonoid tablets not only exhibit similar in vitro dissolution to the reference formulation, but also show similar particle size distribution, further ensuring therapeutic efficacy.

[0040] The citrus flavonoid tablets of this invention, based on a selected formula and prepared using the method of this invention, have similar physicochemical and dissolution properties to the reference formulation, thus ensuring the efficacy of the product. Attached Figure Description

[0041] Figure 1 The dissolution curves are for the citrus flavonoid tablets and reference formulations prepared in the embodiments and comparative examples of the present invention. Detailed Implementation

[0042] To better understand and clarify the present invention, the following provides an exemplary description of the citrus flavonoid tablets and their preparation method provided by the present invention, but it should not be construed as a limitation on the content of the present invention.

[0043] The instruments used in the following examples mainly include: G20 wet granulator, FBL experimental fluidized bed, FZB-150 pulverizer and granulator, BSL-25 mixer, ZP-10A tablet press, BGB-5F high-efficiency coating machine; RC806 dissolution apparatus, and Agilent 1260 high-performance liquid chromatograph.

[0044] Example 1

[0045] (1) The prescription is shown in Table 1:

[0046] Table 1 Prescription

[0047]

[0048] (2) Preparation method:

[0049] Set the stirring paddle speed of the wet granulator to 120 rpm and the cutting blade speed to 1500 rpm. Premix the citrus flavonoids, microcrystalline cellulose, and sodium carboxymethyl starch for 5 minutes. Stop the machine after mixing for 2 minutes and 5 minutes, and gently scrape off the fine powder stuck to the inner wall of the granulation pot with a horn spoon.

[0050] Set the stirring paddle speed of the wet granulator to 180 rpm and the cutting blade speed to 1500 rpm. Spray purified water into the premixed powder for wetting, with an atomization pressure of 0.1-0.2 MPa and a wetting time of 1-3 min. After wetting, perform wet granulation with a sieve aperture of 1.2 mm.

[0051] Slowly add the gelatin to 65°C hot water while stirring, and stir until the gelatin particles are completely hydrated and there are no visible particles. Add purified water to the prescribed amount (gelatin amount + purified water (for solution preparation) amount).

[0052] Turn on the fluidized bed, put the wet granules into the fluidized bed granulation pot, preheat to the predetermined temperature (35℃) and start spray granulation, with the atomization pressure controlled at 0.12~0.16Mpa; after the gelatin solution is sprayed, continue to spray the purified water for the granulation part and then dry; when the moisture content is lower than 3.0%, stop drying and dry granulation, with a sieve aperture of 1.0mm.

[0053] The resulting granules are mixed evenly with talc and magnesium stearate and then pressed into sheets.

[0054] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0055] Comparative Example 1

[0056] (1) The prescription is shown in Table 2:

[0057] Table 2 Prescriptions

[0058]

[0059] (2) Preparation method:

[0060] Set the stirring paddle speed of the wet granulator to 120 rpm and the cutting blade speed to 1500 rpm. Premix the citrus flavonoids, microcrystalline cellulose, and sodium carboxymethyl starch for 5 minutes. Stop the machine after mixing for 2 minutes and 5 minutes, and gently scrape off the fine powder stuck to the inner wall of the granulation pot with a horn spoon.

[0061] Slowly add the gelatin to 65°C hot water while stirring, and stir until the gelatin particles are completely hydrated and there are no visible particles. Add purified water to the prescribed amount (gelatin amount + purified water (for solution preparation) amount).

[0062] Turn on the fluidized bed, put the wet granules into the fluidized bed granulation pot, preheat to the predetermined temperature (35℃) and start spray granulation, with the atomization pressure controlled at 0.12~0.16Mpa; after the gelatin solution is sprayed, continue to spray the purified water for the granulation part and then dry; when the moisture content is lower than 3.0%, stop drying and dry granulation, with a sieve aperture of 1.0mm.

[0063] The resulting granules are mixed evenly with talc and magnesium stearate and then pressed into sheets.

[0064] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0065] Comparative Example 2

[0066] (1) The prescription is shown in Table 3:

[0067] Table 3 Prescriptions

[0068]

[0069] (2) Preparation method:

[0070] Set the stirring paddle speed of the wet granulator to 120 rpm and the cutting blade speed to 1500 rpm. Premix the citrus flavonoids, microcrystalline cellulose, and sodium carboxymethyl starch for 5 minutes. Stop the machine when mixing for 2 minutes and 5 minutes, and gently scrape off the fine powder stuck to the inner wall of the granulation pot with a horn spoon.

[0071] Slowly add the gelatin to 65°C hot water while stirring, and stir until the gelatin particles are completely hydrated and there are no visible particles. Add purified water to the prescribed amount (gelatin amount + purified water (for solution preparation) amount).

[0072] Set the stirring paddle speed of the wet granulator to 180 rpm, the cutting blade speed to 1500 rpm, and the atomization pressure to 0.12-0.16 MPa. Spray the gelatin solution into the premixed powder for granulation. After the gelatin solution is sprayed out, continue to add the remaining purified water. After granulation, use a 2.0 mm sieve for wet granulation.

[0073] Set the oven temperature to 55℃, dry the above wet granules until the moisture content is below 3.0%, and then perform dry granulation. The sieve mesh size is 1.0mm.

[0074] The resulting granules are mixed evenly with talc and magnesium stearate and then pressed into sheets.

[0075] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0076] Experimental Example 1: Granulation phenomena, yield comparison and content results of Example 1, Comparative Example 1 and Comparative Example 2

[0077] This invention compared different preparation processes. Based on the granulation phenomena, yield, and content results, Example 1 of this invention, using a wet wetting followed by one-step granulation process, achieved the highest product yield, and the content and content uniformity met the expected requirements. In Comparative Example 1, the one-step granulation process resulted in the material sticking to the inner wall of the granulation pot due to the excessively small particle size of the active pharmaceutical ingredient (API), preventing fluidization. Small-diameter API particles also escaped through the fine pores (approximately 10 μm) of the fluidized bed filter, leading to a decrease in overall yield and product content. In Comparative Example 2, the wet granulation process, due to limitations of the spray device, even with increased atomization pressure, could not achieve the same effect as fluidized bed spraying, resulting in poor granulation with a higher proportion of large particles and fine powder. The results are shown in Table 4 below.

[0078] Table 4 Granulation phenomena, yield, and content results

[0079]

[0080] Experimental Example 2: Particle size distribution results after disintegration of Example 1, Comparative Example 1, and Comparative Example 2

[0081] Citrus flavonoids are insoluble in water, while gelatin is only soluble in hot water. Therefore, the particles obtained after statically disintegrating citrus flavonoid tablets in water will remain stable at room temperature. Based on this, during the development of this invention, a laser particle size analyzer (wet sample window) was used to detect the particle size distribution of Example 1, Comparative Examples 1-2, and the reference formulation after static disintegration. The method was as follows: the whole tablet was immersed in 50 ml of room temperature water for static disintegration. After the tablet was completely disintegrated, the suspension was completely transferred into the wet sampler of the laser particle size analyzer for detection. The results are shown in Table 5 below.

[0082] Table 5. Particle size distribution results after disintegration.

[0083] Particle size distribution Example 1 Comparative Example 1 Comparative Example 2 Reference formulation D10(μm) 16.418 44.470 16.722 17.231 D50(μm) 130.162 180.462 377.096 132.833 D90(μm) 268.372 358.628 1176.822 290.732

[0084] Based on the particle size distribution results after sample disintegration, Example 1 has a similar particle size distribution to the reference formulation, while Comparative Example 1 has a relatively larger granulated particles than the reference formulation due to the fly-out of fine powder during granulation and the relatively increased proportion of binder. The particle size distribution of Comparative Example 2 is significantly different from that of the reference formulation. As the gelatin solution hardens after granulation and drying, it is not only difficult to crush, but the particle size is also mainly determined by the dry granulation sieve. If the sieve is too small, it will lead to an increase in fine powder, poor flowability, and difficulty in tableting.

[0085] Experimental Example 3: Determination of disintegration time under different pH media conditions

[0086] The present invention further compared the disintegration times of Example 1 in 0.1N hydrochloric acid (37°C), pH 4.5 acetate buffer (37°C), pH 6.8 phosphate buffer (37°C), and water (37°C) to better understand the disintegration of the tablets of the present invention and the reference formulation in media with in vivo-in vitro correlation. The results are shown in Table 6 below.

[0087] Table 6 Disintegration time under different pH conditions

[0088] sample 0.1N hydrochloric acid pH 4.5 acetate buffer pH 6.8 phosphate buffer water Example 1 13min23s 10min18s 12min43s 9min Reference formulation 14min28s 11min40s 13min10s 10min

[0089] The disintegration time under different pH media conditions indicates that the sample of the present invention has a similar disintegration time to the reference formulation.

[0090] Experimental Example 4: Dissolution Curve Determination

[0091] Dissolution curves were analyzed for Example 1, Comparative Example 1, and Comparative Example 2 (0.5% NaOH + 0.2% SDS, paddle method at 100 rpm). The results are shown below. Figure 1 . Figure 1 The dissolution curves are for the citrus flavonoid tablets and reference formulations prepared in the embodiments and comparative examples of the present invention.

[0092] Dissolution results showed that Example 1 had a dissolution curve similar to the reference formulation (f2 = 80), Comparative Example 1 had a dissolution trend similar to the reference formulation, but its limit dissolution was lower due to its low content; while Comparative Example 2 dissolved more slowly than the reference formulation overall.

[0093] The citrus flavonoid tablets prepared by the method described in this invention not only exhibit significantly superior properties compared to citrus flavonoid tablets prepared by other comparative methods, but also show similarities to the reference formulation, ensuring therapeutic efficacy. Furthermore, stability studies have demonstrated that the citrus flavonoid tablets prepared by the method described in this invention exhibit good stability.

[0094] Based on the above description of the invention, those skilled in the art can fully apply the present invention, and all similar modifications and principles used should be considered within the scope of the present invention.

Claims

1. A citrus flavonoid tablet, the tablet core comprising: 450-550 parts by weight of citrus flavonoids, 50-74 parts by weight of microcrystalline cellulose, 20-34 parts by weight of sodium carboxymethyl starch, 20-40 parts by weight of gelatin, 4-8 parts by weight of talc, and 2-6 parts by weight of magnesium stearate.

2. The citrus flavonoid tablets according to claim 1, wherein, The core flakes are obtained by a preparation method that includes first wetting followed by one-step granulation.

3. The citrus flavonoid tablets according to claim 1, wherein, The core of the tablet contains: 480-520 parts by weight of citrus flavonoids, 56-68 parts by weight of microcrystalline cellulose, 24-30 parts by weight of sodium carboxymethyl starch, 25-35 parts by weight of gelatin, 5-7 parts by weight of talc, and 3-5 parts by weight of magnesium stearate. Preferably, the core comprises: 500 parts by weight of citrus flavonoids, 62 parts by weight of microcrystalline cellulose, 27 parts by weight of sodium carboxymethyl starch, 31 parts by weight of gelatin, 6 parts by weight of talc, and 4 parts by weight of magnesium stearate.

4. A method for preparing citrus flavonoid tablets according to any one of claims 1 to 3, comprising the following steps: (1) Place citrus flavonoids, microcrystalline cellulose and sodium carboxymethyl starch in a wet granulator, premix, wet, and wet granulate to obtain wet granules; (2) Prepare gelatin into a gelatin aqueous solution, then spray the gelatin aqueous solution and water onto the above-mentioned wetted granules, granulate using a one-step granulation process, dry, and dry granulate. (3) Mix the granules obtained in the above steps with talc and magnesium stearate evenly, and press them into a core; (4) Optionally, the above-mentioned core film is coated with a thin film.

5. The preparation method according to claim 4, wherein, In step (1), the wetting solvent is water, the amount of wetting solvent is 25% to 35% of the material weight, the atomization pressure is 0.1 to 0.4 MPa, and the wetting time is 1 to 5 min; the mesh size of the wet granulation screen is 0.8 mm to 4.0 mm. In step (2), the material temperature is 30-50℃ and the atomization pressure is 0.1-0.2 MPa in the one-step granulation process; the screen aperture of the dry granulation is 0.8 mm-1.2 mm.

6. The preparation method according to claim 4, wherein, In step (1), the amount of wetting solvent used in the wetting process is 28% to 33% of the material weight, the atomization pressure is 0.1 to 0.2 MPa, and the wetting time is 1 to 3 min; the mesh size of the wet granulation screen is 1.0 mm to 1.5 mm. In step (2), the material temperature is 35-45℃ and the atomization pressure is 0.12-0.16Mpa in the one-step granulation process; the screen aperture of the dry granulation is 1.0mm.

7. The preparation method according to claim 4, wherein, In step (2), the concentration of the gelatin aqueous solution is 10-20% by weight; In step (2), the weight of water in the one-step granulation process is 15% to 25% of the weight of the material.

8. The preparation method according to claim 4, wherein, In step (1), the citrus flavonoid raw material has a D90 ≤ 2.5 μm; In step (1), the premixing time is 5 minutes, and the powder adhering to the inner wall of the granulation pot is scraped off during the 2 minutes and 5 minutes of premixing.

9. The preparation method according to claim 4, wherein, In step (4), the weight of the film coating is 1.5 to 5% of the weight of the core, more preferably 3%; In step (4), the film coating is Obadai OY-S-37207-CN.

10. The preparation method according to claim 4, wherein, In step (1), the premixing and wetting are carried out in a wet granulation machine; In step (2), the one-step granulation is carried out in a fluidized bed.

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