A solid dispersion of acetoflavonoids, a solid dosage form and a preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a solid dispersion of acetosalis flavonoids, a solid dosage form, and a preparation method thereof. The raw materials for the solid dispersion include acetosalis flavonoids, a homopolymer of N-vinylpyrrolidone, and inulin, wherein the N-vinylpyrrolidone homopolymer is povidone K30. The acetosalis flavonoid solid dosage form of this invention achieves a cumulative dissolution rate of over 90% within 30 minutes; the preparation process is simple, does not use any organic solvents, and exhibits very rapid dissolution.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a solid dispersion of acetoflavonoids, a solid preparation, and a preparation method thereof. Background Technology

[0002] Sea buckthorn (Hippophagus rhamnoides L.), also known as vinegar willow, is a plant belonging to the genus Hippophae in the family Elaeagnaceae. It is rich in vitamins, various trace elements, various amino acids and fatty acids, as well as flavonoids, triterpenes and steroidal compounds. The flavonoid compounds that have been identified include: quercetin, isorhamnetin, kaempferol and its glycosides, myricetin, chlorogenic acid, succinic acid, catechin and astragaloside, etc.

[0003] Flavonoids extracted from the fruit of the vinegar willow possess a wide range of pharmacological effects, including anti-myocardial ischemia, anti-arrhythmia, improved hypoxia tolerance, reduced serum cholesterol, inhibition of platelet aggregation, anti-ulcer, anti-tumor, anti-inflammatory, anti-allergic, antioxidant, anti-aging, anti-radiation, antibacterial, antiviral, and immune-enhancing properties. Currently, commercially available dosage forms include ordinary tablets, capsules, and dispersible tablets. Clinically, the main formulation used is vinegar willow flavonoid tablets (Xindakang tablets), primarily used to increase hypoxia tolerance, increase coronary blood flow, and improve myocardial ischemia; reduce myocardial contractility, thereby reducing myocardial oxygen consumption; prevent ischemic myocardial damage induced by posterior pituitary extract; and have a significant antagonistic effect on the increased myocardial oxygen consumption caused by isoproterenol; reduce serum cholesterol and combat arteriosclerosis; and scavenge superoxide anion free radicals and hydroxyl free radicals, protecting the myocardium.

[0004] However, the flavonoids in acetaminophen are only slightly soluble in water (all less than 3.65 μg / mL), and their membrane permeability is also poor (all less than 0.1392 × 10⁻⁶). -6 The absorption rate is low (cm / s), and the absorption process is affected by intestinal mucosal efflux proteins (P-gp, MRPs). Therefore, the in vitro dissolution and oral bioavailability of the flavonoid preparation are not ideal, which greatly limits its efficacy. It is urgent to solve the problem of poor oral bioavailability of this preparation in order to reduce the dosage and improve the overall efficacy of the preparation.

[0005] Hot melt extrusion, also known as melt extrusion technology, refers to the technology of mixing drugs, polymers, and other extruders in a molten state and extruding them under certain pressure, speed, and shape to form a product. This technology can significantly improve drug solubility and increase bioavailability. Chinese invention patent application CN113384532A discloses a solid dispersion of a CYP17 inhibitor and its preparation method. The method involves melting and extruding abiraterone acetate, an antioxidant, and copovidone using a hot melt extruder at 115℃-125℃ to prepare a solid dispersion. The extrudate is then pulverized and mixed with fillers and disintegrants, followed by the addition of a lubricant and compression into tablets. These tablets exhibit rapid dissolution, good stability, and good process reproducibility, making them suitable for large-scale production. However, there are no reports of this technology being applied to the preparation of acetoflavonoid solid dosage forms.

[0006] Literature reports that the dissolution rate of acetoflavonoid tablets (in water) is 8% after 120 min (Weng Shuiwang, Fang Rong. Study on in vitro dissolution rate of acetoflavonoid tablets [J]. Chinese Traditional and Herbal Drugs, 2002, 24(12):918-920). The dissolution rate is too slow, which has a certain impact on the absorption rate and extent of the active ingredients in the body, as well as the therapeutic effect.

[0007] Chinese invention patent application CN101574380A discloses a solid dispersion of acetosine flavonoids and its preparation method. It uses acetosine flavonoids and a hydrophilic carrier to prepare a solid dispersion through a solvent method, thereby improving bioavailability. However, the preparation process uses a large amount of organic solvents such as ethanol, methanol, dichloromethane, chloroform or acetonitrile, and it is difficult to achieve large-scale production.

[0008] Therefore, it is urgent to invent a solid dosage form of acetoflavonoids that is free of organic solvents, has a simple preparation process, ensures a rapid dissolution rate, and can be mass-produced. Summary of the Invention

[0009] The technical problem this invention aims to solve is to overcome the difficulties in dissolution and absorption caused by the water insolubility of acetosaccharide. This invention proposes an acetosaccharide solid dispersion, a solid dosage form, and a method for preparing the same. By combining acetosaccharide with a specific polymer and using hot-melt extrusion technology, a acetosaccharide-containing solid dispersion composition is prepared. This composition is then pulverized and mixed with other excipients to obtain the desired oral dosage form. This preparation process is simple, does not use any organic solvents, dissolves very rapidly, and exhibits good stability.

[0010] To achieve the above-mentioned objectives of this invention, the specific technical solution adopted by this invention is as follows:

[0011] A solid dispersion of acetoflavonoids, wherein the raw materials of the solid dispersion include acetoflavonoids, a homopolymer of N-vinylpyrrolidone, and inulin, wherein the homopolymer of N-vinylpyrrolidone is polyvinylpyrrolidone K30.

[0012] Preferably, the weight ratio of the acetoflavonoids, povidone K30 and inulin is 1:6-10:1-6.

[0013] More preferably, the weight ratio of the acetoflavonoids, povidone K30 and inulin is 1:7-9:2-4, and more preferably 1:8:2-4.

[0014] This invention also relates to a method for preparing the above-mentioned acetylcholine flavonoid solid dispersion, comprising the following steps:

[0015] (1) Take the raw material of acetylcholine and pass it through a 70-90 mesh sieve;

[0016] (2) The sieved acetoflavonoids, povidone K30, and inulin were mixed evenly to obtain a mixture;

[0017] (3) Add the mixture to a hot melt extruder, extrude, cool, crush, and pass through a 55-65 mesh sieve to obtain the final product.

[0018] Preferably, the extruder in step (3) is selected from any one of a single-screw extruder, a twin-screw extruder, a meshing screw extruder, and a multi-screw extruder; preferably, it is a twin-screw extruder.

[0019] More preferably, the temperature settings of the twin-screw extruder are as follows: feed zone: 90-100℃, zone 1: 110-115℃, zone 2: 115-120℃, zone 3: 120-125℃, zone 4: 125-130℃, zone 5: 130-135℃, zone 6: 135-140℃, zone 7: 140-145℃, and die head: 130-135℃; the screw speed of the twin-screw extruder is 450-550 rpm.

[0020] The present invention also relates to a solid dosage form of acetic acid flavonoids, wherein the raw materials of the solid dosage form include the above-mentioned solid dispersion of acetic acid flavonoids, as well as fillers, disintegrants and lubricants.

[0021] Preferably, the raw materials of the acetosalis flavonoid solid dosage form, by weight, include: 30-100 parts of acetosalis flavonoid solid dispersion, 120-160 parts of filler and 5-15 parts of disintegrant.

[0022] More preferably, the raw materials of the acetosalis flavonoid solid dosage form, by weight, include: 50-80 parts of acetosalis flavonoid solid dispersion, 140-150 parts of filler and 8-12 parts of disintegrant.

[0023] Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin.

[0024] More preferably, the filler is a mixture of microcrystalline cellulose and mannitol.

[0025] Preferably, the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose and corn starch.

[0026] More preferably, the disintegrant is sodium carboxymethyl starch.

[0027] Preferably, the lubricant is selected from one or more of stearic acid, magnesium stearate, talc, and polyethylene glycol.

[0028] More preferably, the lubricant is magnesium stearate.

[0029] The present invention also relates to a method for preparing a solid dosage form of acetylcholine, comprising the following steps: mixing the above-mentioned solid dispersion of acetylcholine with a filler, a disintegrant and a lubricant evenly, and then filling the mixture into capsules to obtain the final product.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] (1) The solid preparation of flavonoids from the vinegar of the present invention has a cumulative dissolution rate of over 90% after 30 minutes;

[0032] (2) The preparation process of this formulation is simple, does not use any organic solvents, and dissolves very quickly. Detailed Implementation

[0033] The following detailed description of the acetoflavonoid composition of the present invention, with reference to specific embodiments, will be provided. It should be understood that the following embodiments are merely illustrative and explanatory of the invention and should not be construed as limiting the scope of protection of the invention. All technologies implemented based on the above description of the present invention are covered within the scope of protection intended by the present invention.

[0034] Povidone K30 was purchased from BASF (China) Co., Ltd.

[0035] Acetyl flavonoids were purchased from Xi'an Youbohui Biotechnology Co., Ltd.

[0036] Unless otherwise specified, all reagents are industrial products and are commercially available.

[0037] Example 1

[0038] The raw materials and their proportions for the solid preparation of acetic acid flavonoids in Example 1 are shown in Table 1.

[0039] Table 1 Raw materials and proportions for Example 1

[0040]

[0041]

[0042] A method for preparing a solid dispersion of acetylcholine flavonoids:

[0043] The flavonoid raw material was passed through an 80-mesh sieve. The sieved flavonoid was then mixed evenly with povidone K30 and inulin. The temperature of the twin-screw hot melt extruder was set as follows: feed zone: 90℃, zone 1: 110℃, zone 2: 115℃, zone 3: 120℃, zone 4: 125℃, zone 5: 130℃, zone 6: 135℃, zone 7: 140℃, die head: 130℃; screw speed: 500 rpm. The mixture was placed in the twin-screw hot melt extruder and, through mixing, melting, and extrusion, a strip-shaped transparent extrudate was obtained. The extrudate was placed in a pan and allowed to cool and solidify naturally at room temperature. Then, it was transferred to a pulverizer for pulverization and passed through a 60-mesh sieve to obtain a solid dispersion composition.

[0044] Preparation method of acetic acid flavonoid solid dosage form: Take the above solid dispersion composition and mix it with the excipients microcrystalline cellulose, mannitol, sodium carboxymethyl starch and magnesium stearate in a certain proportion, and fill it into capsules.

[0045] Example 2

[0046] The raw materials and their proportions for the solid preparation of acetic acid flavonoids in Example 2 are shown in Table 2.

[0047] Table 2 Raw materials and proportions for Example 2

[0048]

[0049] A method for preparing a solid dispersion of acetylcholine flavonoids:

[0050] The flavonoid raw material was passed through a 70-mesh sieve. The sieved flavonoid was then mixed evenly with povidone K30 and inulin. The temperature settings of the twin-screw hot-melt extruder were as follows: feed zone: 100℃, zone 1: 110℃, zone 2: 120℃, zone 3: 125℃, zone 4: 130℃, zone 5: 135℃, zone 6: 140℃, zone 7: 145℃, die head: 135℃; screw speed: 550 rpm. The mixture was placed in the twin-screw hot-melt extruder, and through mixing, melting, and extrusion, a strip-shaped transparent extrudate was obtained. The extrudate was placed in a pan and allowed to cool and solidify naturally at room temperature. It was then transferred to a pulverizer and pulverized, passing through a 55-mesh sieve to obtain a solid dispersion composition.

[0051] Preparation method of acetic acid flavonoid solid dosage form: Take the above solid dispersion composition and mix it with the excipients microcrystalline cellulose, mannitol, sodium carboxymethyl starch and magnesium stearate in a certain proportion, and fill it into capsules.

[0052] Example 3

[0053] The raw materials and their proportions for the solid preparation of acetic acid flavonoids in Example 3 are shown in Table 3.

[0054] Table 3. Raw materials and proportions for Example 3

[0055]

[0056] A method for preparing a solid dispersion of acetylcholine flavonoids:

[0057] The flavonoid raw material was passed through a 90-mesh sieve. The sieved flavonoid was then mixed evenly with povidone K30 and inulin. The temperature settings of the twin-screw hot melt extruder were as follows: feed zone 95℃, zone 1: 110℃, zone 2: 118℃, zone 3: 123℃, zone 4: 130℃, zone 5: 130℃, zone 6: 135℃, zone 7: 140℃, and die head: 130℃; the screw speed of the twin-screw extruder was 450 rpm. The mixture was placed in the twin-screw hot melt extruder, and through mixing, melting, and extrusion, a strip-shaped transparent extrudate was obtained. The extrudate was placed in a pan and allowed to cool and solidify naturally at room temperature. Then, it was transferred to a pulverizer for pulverization and passed through a 65-mesh sieve to obtain a solid dispersion composition.

[0058] Preparation method of acetic acid flavonoid solid dosage form: Take the above solid dispersion composition and mix it with the excipients microcrystalline cellulose, mannitol, sodium carboxymethyl starch and magnesium stearate in a certain proportion, and fill it into capsules.

[0059] Examples 4-5

[0060] The solid dosage forms of acetic acid flavonoids in Examples 4-5, by weight, are shown in Table 4 below. The preparation process of the solid dispersion and solid dosage forms of acetic acid flavonoids is the same as that in Example 1.

[0061] Table 4. Raw materials and proportions for Examples 4-5

[0062]

[0063] Comparative Example 1

[0064] The raw materials and formulation of the solid dosage form of acetic acid flavonoids in Comparative Example 1 are shown in Table 5.

[0065] Table 5. Raw materials and proportions for Comparative Example 1

[0066] Raw material names effect Weight (mg) Acetyl flavonoids raw materials 5 Povidone K30 filler 40 Inulin filler 10 microcrystalline cellulose filler 75 Mannitol filler 70 Sodium carboxymethyl starch Disintegrant 10 magnesium stearate lubricant 1

[0067] Preparation method of flavonoid solid dosage form:

[0068] The flavonoid raw material was pulverized and passed through a 120-mesh sieve. The components were weighed according to the above prescription, and wet granulation was performed using water as a wetting agent. The granules were then dried in a fluidized bed and filled into gelatin empty capsules.

[0069] Comparative Examples 2-5

[0070] The raw materials and formulations of the solid dosage forms of acetosaccharin in Comparative Examples 2-5 are shown in Table 6.

[0071] Table 6 Raw materials and proportions for Comparative Examples 2-5

[0072]

[0073] The preparation methods of the solid dispersions of acetylcholine flavonoids in Comparative Examples 2-4 are as follows:

[0074] According to the raw materials and proportions in Table 6, take the acetoflavonoid raw material and pass it through an 80-mesh sieve. Mix the sieved acetoflavonoid with povidone K30 evenly. Set the temperature of the twin-screw hot melt extruder as follows: feed zone: 90℃, zone 1: 110℃, zone 2: 115℃, zone 3: 120℃, zone 4: 125℃, zone 5: 130℃, zone 6: 135℃, zone 7: 140℃, die head: 130℃; screw speed: 500 rpm. Place the mixture in the twin-screw hot melt extruder, and obtain a strip-shaped transparent extrudate through mixing, melting, and extrusion. Place the extrudate in a pan and allow it to cool and solidify naturally at room temperature. Then transfer it to a pulverizer for pulverization and pass it through a 60-mesh sieve to obtain a solid dispersion composition.

[0075] Preparation method of solid dosage form of acetosaccharide in comparative examples 2-4: Take the above solid dispersion composition and mix it with the excipients microcrystalline cellulose, mannitol, sodium carboxymethyl starch and magnesium stearate in proportion, and fill it into capsules.

[0076] The preparation method of the solid dispersion of acetylcholine in Comparative Example 5 is as follows:

[0077] According to the raw materials and proportions in Table 6, take the acetoflavonoid raw material and pass it through an 80-mesh sieve. Mix the sieved acetoflavonoid with inulin evenly. Set the temperature of the twin-screw hot melt extruder as follows: feed zone: 90℃, zone 1: 110℃, zone 2: 115℃, zone 3: 120℃, zone 4: 125℃, zone 5: 130℃, zone 6: 135℃, zone 7: 140℃, die head: 130℃; screw speed: 500 rpm. Place the mixture in the twin-screw hot melt extruder, and obtain a strip-shaped transparent extrudate through mixing, melting, and extrusion. Place the extrudate in a pan and allow it to cool and solidify naturally at room temperature. Then transfer it to a pulverizer for pulverization and pass it through a 60-mesh sieve to obtain a solid dispersion composition.

[0078] Comparative Example 5: Preparation method of solid dosage form of acetylcholine flavonoids: Take the above solid dispersion composition and mix it with the excipients microcrystalline cellulose, mannitol, sodium carboxymethyl starch and magnesium stearate in proportion, and fill it into capsules.

[0079] Effect test

[0080] Test Example 1: In vitro dissolution test

[0081] The in vitro dissolution curves were determined according to the Chinese Pharmacopoeia, using the following method: a paddle method was employed at a rotation speed of 100 rpm, using 900 ml of dissolution medium. Dissolution curves of the products obtained in Examples 1-5 and Comparative Examples 1-5 were measured in purified water + 1.0% SDS. Appropriate amounts of the dissolution solution were taken at 5 min, 10 min, 20 min, 30 min, 45 min, and 60 min, filtered, and the filtrate was used as the test solution. The absorbance was measured at 374 nm under ultraviolet light, and the cumulative dissolution percentage was calculated by substituting the results into the standard curve. The results are shown in Table 7.

[0082] Table 7. Cumulative dissolution rate data (%)

[0083] Sample Name 5min 10min 20min 30min Example 1 65.4 92.5 93.2 95.8 Example 2 69.7 91.0 93.8 98.1 Example 3 55.6 90.5 92.8 97.7 Example 4 41.7 90.5 93.2 96.3 Example 5 48.1 90.9 94.7 95.9 Comparative Example 1 23.5 31.9 48.7 55.6 Comparative Example 2 33.2 56.5 71.0 85.4 Comparative Example 3 30.6 61.8 73.4 82.7 Comparative Example 4 35.7 59.7 75.8 84.3 Comparative Example 5 39.1 62.8 71.5 81.6

[0084] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A solid dispersion of acetoflavonoids, characterized in that, The raw materials for the solid dispersion are acetoflavonoids, homopolymers of N-vinylpyrrolidone and inulin, wherein the homopolymer of N-vinylpyrrolidone is polyvinylpyrrolidone K30; The weight ratio of the acetoflavonoids, povidone K30 and inulin is 1:6-10:1-6; The preparation method of the acetylcholine flavonoid solid dispersion includes the following steps: (1) Take the raw material of acetoflavonoids and pass it through a 70-90 mesh sieve; (2) Mix the sieved acetoflavonoids with povidone K30 and inulin evenly to obtain a mixture; (3) Add the mixture to a hot melt extruder, extrude, cool, crush, and pass through a 55-65 mesh sieve to obtain the final product.

2. The flavonoid solid dispersion of acetaminophen according to claim 1, characterized in that, The weight ratio of the acetoflavonoids, povidone K30 and inulin is 1:7-9:2-4.

3. A method for preparing the acetoflavonoid solid dispersion according to any one of claims 1-2, characterized in that, Includes the following steps: (1) Take the raw material of acetoflavonoids and pass it through a 70-90 mesh sieve; (2) Mix the sieved acetoflavonoids with povidone K30 and inulin evenly to obtain a mixture; (3) Add the mixture to a hot melt extruder, extrude, cool, crush, and pass through a 55-65 mesh sieve to obtain the final product.

4. The preparation method according to claim 3, characterized in that, The extruder mentioned in step (3) is selected from any one of a single-screw extruder, a twin-screw extruder, a meshing screw extruder, and a multi-screw extruder.

5. The preparation method according to claim 4, characterized in that, The temperature settings of the twin-screw extruder are as follows: feed zone: 90-100℃, zone 1: 110-115℃, zone 2: 115-120℃, zone 3: 120-125℃, zone 4: 125-130℃, zone 5: 130-135℃, zone 6: 135-140℃, zone 7: 140-145℃, die head: 130-135℃; the screw speed of the twin-screw extruder is 450-550 rpm.

6. A solid dosage form of acetoflavonoids, characterized in that, The raw materials for the flavonoid solid dosage form of the vinegar willow include the flavonoid solid dispersion as described in any one of claims 1-2, as well as fillers, disintegrants and lubricants.

7. The flavonoid solid dosage form according to claim 6, characterized in that, The raw materials of the acetosaccharin solid dosage form, by weight, include: 30-100 parts of acetosaccharin solid dispersion, 120-160 parts of filler, 5-15 parts of disintegrant, and 0.1-2 parts of lubricant; the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin; the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, and corn starch; the lubricant is selected from one or more of stearic acid, magnesium stearate, talc, and polyethylene glycol.

8. The flavonoid solid dosage form according to claim 7, characterized in that, The raw materials of the acetosaccharin solid dosage form, by weight, include: 50-80 parts of acetosaccharin solid dispersion, 140-150 parts of filler, 8-12 parts of disintegrant and 0.5-1.5 parts of lubricant; the filler is a mixture of microcrystalline cellulose and mannitol; the disintegrant is sodium carboxymethyl starch; and the lubricant is magnesium stearate.

9. A method for preparing a solid dosage form of acetosaccharin, characterized in that, The process includes the following steps: mixing the acetoflavonoid solid dispersion according to any one of claims 1-2 with a filler, a disintegrant and a lubricant, and then filling the mixture into capsules to obtain the final product.

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