Azithromycin fumarate sustained release tablet and preparation method thereof

Abstract

The invention discloses an azithromycin fumarate sustained-release tablet and a preparation method thereof, and particularly relates to the technical field of pharmaceutical preparations, and the sustained-release tablet comprises the following components based on 100% of the total mass of the sustained-release tablet: 30-50% of azithromycin fumarate, 5-20% of a wax retardant material, 20-40% of a high polymer material sustained-release matrix, 10-20% of a filler, 5-10% of a sweetener, 0.5-5% of a lubricating flow aid, and the balance of an adhesive. According to the invention, the dissolution and release degree of the medicine can be reduced, the peak concentration of the medicine is reduced, the peak valley fluctuation of the blood concentration is reduced, the adverse reaction of the medicine is slowed down, the effective blood concentration duration is prolonged, the clinical treatment effect of the medicine is improved, and the compliance, convenience and compliance of patient medication are also improved; the generation of drug resistance is reduced to the greatest extent.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a fumarate azithromycin sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] Fumarate azithromycin is a salt compound of fumaric acid and azithromycin. Azithromycin is slightly soluble in water. After being salted with fumaric acid to form fumarate azithromycin, the water solubility of azithromycin is improved. After oral administration of fumarate azithromycin, the dissolution and absorption degree of fumarate azithromycin in the body are also greatly improved, thereby improving the bioavailability and clinical treatment effect. In vitro tests show that the improved water solubility of fumarate azithromycin also improves its in vitro bactericidal effect.

[0003] Fumarate azithromycin and azithromycin have the same antibacterial mechanism and have antibacterial effects on a variety of common pathogenic bacteria in clinical practice, such as Staphylococcus aureus, Streptococcus pyogenes (group A hemolytic streptococcus), Streptococcus pneumoniae, hemolytic streptococcus (viridans streptococcus) and other streptococci, diphtheria (rod-shaped) bacillus, influenza (hemophilic) bacillus, parainfluenza (hemophilic) bacillus, catarrhal (mora) bacillus, acinetobacter, yersinia, legionella pneumophila, pertussis bacillus, parapertussis bacillus, shigella, pasteurella, vibrio cholera, parahemolytic bacillus, and shigella-like proteus.

[0004] Fumarate azithromycin is mainly used in clinical practice for the following infections caused by sensitive bacteria: middle ear infection, sinusitis, pharyngitis, tonsillitis, and other upper respiratory tract infections; bronchial pneumonia and other lower respiratory tract infections; skin and soft tissue infections; simple genital infections caused by chlamydia trachomatis; and simple genital infections caused by non-multidrug-resistant gonococci.

[0005] After administration of fumarate azithromycin, patients may experience a series of adverse reactions. The main adverse reactions are allergic reactions and gastrointestinal reactions, each accounting for 26.42% and 23.32%. The main manifestations are skin rash, skin itching, nausea, vomiting, abdominal pain, diarrhea, upper abdominal discomfort, and other adverse reactions such as dizziness, dyspnea, and anorexia. The incidence of adverse reactions caused by oral administration is 44.82%, and the incidence of adverse reactions caused by intravenous administration is 55.18%. The incidence of adverse reactions caused by intravenous administration is higher than that of oral administration, which is closely related to the dosage, usage, and other factors. These adverse reaction rates increase with the increase of the dosage level. SUMMARY

[0006] The purpose of this invention is to provide an azithromycin fumarate sustained-release tablet and its preparation method, which can reduce the degree of drug dissolution and release, reduce peak drug concentration, reduce fluctuations in blood drug concentration, alleviate adverse drug reactions, prolong the duration of effective blood drug concentration, improve the clinical therapeutic effect of the drug, and also improve patient compliance, convenience and adherence to medication, and minimize the development of drug resistance.

[0007] To achieve the above and other related objectives, the present invention provides an azithromycin fumarate sustained-release tablet, which, based on the total mass of the sustained-release tablet (100%), comprises the following components: 30-50% azithromycin fumarate, 5-20% waxy blocking material, 20-40% polymeric sustained-release matrix, 10-20% filler, 5-10% sweetener, 0.5-5% lubricating and flow aid, and the balance being a binder.

[0008] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the waxy blocking material includes one or more of cetyl alcohol, octadecanol, hydrogenated castor oil, and carnauba wax.

[0009] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the polymeric sustained-release matrix includes one or more of chitosan, carbomer, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, povidone, and polyoxyethylene.

[0010] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the filler includes one or more of microcrystalline cellulose, lactose, sucrose, starch, dextrin, pregelatinized starch, calcium sulfate, and calcium phosphate.

[0011] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the sweetener includes one or more of glucose, xylitol, mannitol, glycyrrhizate, stevioside, sodium saccharin, and aspartame.

[0012] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the lubricating and flow aid includes one or more of magnesium stearate, silica, talc, and micronized silica gel.

[0013] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the adhesive comprises one or more of methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, povidone, highly substituted hydroxypropylcellulose, and polyoxyethylene.

[0014] This invention also provides a method for preparing azithromycin fumarate sustained-release tablets, the steps of which include: (1) Pulverization: Pulverize azithromycin fumarate, polymer slow-release matrix, filler and sweetener separately and pass them through a 60-100 mesh sieve; (2) Preparation of wax dispersion: The wax barrier material is heated and melted, then pulverized azithromycin fumarate is added and stirred and dispersed evenly. After cooling to room temperature, it is pulverized to obtain the wax dispersion. Alternatively, the waxy blocking material can be heated and melted, then a diluent can be added and stirred evenly. Then, pulverized azithromycin fumarate can be added and stirred to disperse evenly. The diluent can be heated and evaporated to near dryness, cooled to room temperature, and then pulverized to obtain a waxy dispersion. (3) Preparation of mixture: The wax dispersion is mixed evenly with the pulverized polymer slow-release matrix, filler and sweetener to obtain the mixture; (4) Add the adhesive to the solvent and stir to mix evenly to obtain a solution or suspension of the adhesive; (5) Particle preparation: The mixture and the solution or suspension of the binder are stirred and mixed evenly to obtain a soft material. The soft material is prepared into particles using a sieve. The obtained particles are dried at 40-70°C. The dried particles are stirred and mixed evenly with a lubricating flow aid. (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0015] In one example of the preparation method of the azithromycin fumarate sustained-release tablets of the present invention, in step (2), the diluent includes one or more of ethanol, propanol, and isopropanol.

[0016] In one example of the preparation method of azithromycin fumarate sustained-release tablets of the present invention, in step (4), the solvent is one or more of water, ethanol, acetone, and isopropanol.

[0017] In one example of the preparation method of the azithromycin fumarate sustained-release tablets of the present invention, the concentration of the adhesive solution or suspension is 5-15%.

[0018] This invention relates to azithromycin fumarate sustained-release tablets and their preparation method. By dispersing azithromycin fumarate in a waxy blocking material, its water solubility is reduced, making it easier to control drug release through formulation, especially showing a significant control effect on the initial drug release, achieving the release standard requirements. The polymeric sustained-release matrix is ​​mainly composed of hydrophilic materials. After oral administration, the polymeric sustained-release matrix absorbs water and swells, simultaneously binding into a colloidal state to encapsulate the drug. Under the peristalsis of the gastrointestinal tract and the erosion of body fluids, the adhesive layer gradually peels off, and the drug is gradually released, thereby achieving the purpose of slow drug release. An appropriate amount of sweetener is added to the formulation to mask the bitterness of the drug and improve patient comfort. The above formulation is then wet-granulated and compressed to obtain the corresponding sustained-release tablets, achieving the goal of slowing down the drug release rate. The excipients of this invention are readily available, the preparation process is simple, the sustained-release effect is significant, and it is environmentally friendly and safe, making it suitable for large-scale industrial production. Attached Figure Description

[0019] Figure 1 This is a dissolution curve of the azithromycin fumarate sustained-release tablets produced in Example 1 of the present invention; Figure 2 This is a dissolution curve of the azithromycin fumarate sustained-release tablets produced in Example 2 of the present invention; Figure 3 This is a dissolution curve of the azithromycin fumarate sustained-release tablets produced in Example 3 of the present invention. Detailed Implementation

[0020] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that, unless otherwise specified, the following embodiments and features can be combined with each other. It should also be understood that the terminology used in the embodiments of the present invention is for describing specific implementation schemes and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or according to the conditions recommended by the respective manufacturers.

[0021] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention, as well as the prior art known to those skilled in the art and the description of the invention, may be implemented using any prior art methods, devices, and materials similar to or equivalent to the methods, devices, and materials in the embodiments of the present invention.

[0022] This invention provides an azithromycin fumarate sustained-release tablet, which, based on the total mass of the sustained-release tablet (100%), comprises the following components: 30-50% azithromycin fumarate, 5-20% waxy blocking material, 20-40% polymeric sustained-release matrix, 10-20% filler, 5-10% sweetener, 0.5-5% lubricating and flow aid, with the remainder being a binder.

[0023] In one example of the azithromycin fumarate sustained-release tablets of the present invention, the waxy blocking material includes one or more of cetyl alcohol, octadecanol, hydrogenated castor oil, and carnauba wax. The polymeric sustained-release matrix includes one or more of chitosan, carbomer, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, povidone, and polyoxyethylene.

[0024] The filler includes one or more of microcrystalline cellulose, lactose, sucrose, starch, dextrin, pregelatinized starch, calcium sulfate, and calcium phosphate. The sweetener includes one or more of glucose, xylitol, mannitol, glycyrrhizate, stevioside, sodium saccharin, and aspartame. The lubricating and flow-aiding agent includes one or more of magnesium stearate, silica, talc, and micronized silica gel. The binder includes one or more of methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, povidone, highly substituted hydroxypropyl cellulose, and polyethylene oxide.

[0025] This invention also provides a method for preparing azithromycin fumarate sustained-release tablets, the steps of which include: (1) Pulverization: Pulverize azithromycin fumarate, polymer slow-release matrix, filler and sweetener separately and pass them through a 60-100 mesh sieve; (2) Preparation of wax dispersion: The wax barrier material is heated and melted, then pulverized azithromycin fumarate is added and stirred and dispersed evenly. After cooling to room temperature, it is pulverized to obtain the wax dispersion. Alternatively, the waxy blocking material can be heated and melted, then a diluent can be added and stirred evenly. Then, pulverized azithromycin fumarate can be added and stirred to disperse evenly. The diluent can be heated and evaporated to near dryness, cooled to room temperature, and then pulverized to obtain a waxy dispersion. (3) Preparation of mixture: The wax dispersion is mixed evenly with the pulverized polymer slow-release matrix, filler and sweetener to obtain the mixture; (4) Add the adhesive to the solvent and stir to mix evenly to obtain a solution or suspension of the adhesive; (5) Particle preparation: The mixture and the solution or suspension of the binder are stirred and mixed evenly to obtain a soft material. The soft material is prepared into particles using a sieve. The obtained particles are dried at 40-70°C. The dried particles are stirred and mixed evenly with a lubricating flow aid. (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0026] In one example of the preparation method of the azithromycin fumarate sustained-release tablets of the present invention, in step (2), the diluent includes one or more of ethanol, propanol, and isopropanol. In step (4), the solvent is one or more of water, ethanol, acetone, and isopropanol. The concentration of the adhesive solution or suspension is 5-15%.

[0027] The present invention will be further described below through several embodiments. It should be noted that, unless otherwise specified, the materials, reagents and equipment used in the embodiments can all be purchased through commercial means.

[0028] Example 1: 1. Formulation quantity (per 1000 tablets) Azithromycin fumarate 500g 80g of stearyl alcohol 150g of hydroxypropyl methylcellulose Sodium carboxymethyl cellulose 50g 100g lactose 50g xylitol Povidone 30g 5g of silicon dioxide 5g magnesium stearate 2. Preparation method (1) Grinding: Grind azithromycin fumarate, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, lactose and xylitol into powder and pass them through a 100-mesh sieve.

[0029] (2) Preparation of wax dispersion: After heating and melting octadecyl alcohol, add 150g of ethanol and stir evenly. Then add pulverized azithromycin fumarate and stir to disperse evenly. Heat and evaporate ethanol to near dryness, cool to room temperature and then pulverize to obtain wax dispersion.

[0030] (3) Preparation of mixture: The wax dispersion is mixed evenly with pulverized hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, lactose and xylitol to obtain the mixture.

[0031] (4) Add povidone to water and stir to mix evenly to prepare an aqueous solution with a concentration of 15%.

[0032] (5) Particle preparation: The mixture and the aqueous solution of polyvinyl ketone are stirred and mixed evenly to obtain a soft material. The soft material is then prepared into particles using a sieve. The obtained particles are dried at 50°C. The dried particles are then stirred and mixed evenly with silica and magnesium stearate.

[0033] (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0034] 3. Testing According to the Chinese Pharmacopoeia (General Chapter 0931, Method II, 2025 Edition), the dissolution medium was determined using 900 ml of phosphate buffer (pH 6.0) (600 ml of 0.1 mol / L disodium hydrogen phosphate solution, with approximately 40 ml of hydrochloric acid added to adjust the pH to 6.0 ± 0.05). The dissolution was performed at 100 rpm. Samples of 10 ml were taken at 2, 4, 6, 8, and 12 hours, with the same volume and temperature of dissolution medium added simultaneously. Dissolution was then determined using high-performance liquid chromatography (HPLC). The dissolution limits at 2, 4, and 8 hours were 15–40%, 40–60%, and above 80%, respectively. The dissolution curves are shown below. Figure 1 .

[0035] Table 1 shows the dissolution test results of the azithromycin fumarate sustained-release tablets prepared in Example 1.

[0036] Example 2: 1. Formulation quantity (per 1000 tablets) Azithromycin fumarate 500g Cetyl alcohol 120g 130g of sodium alginate Carbomer 80g Calcium sulfate 120g Stevia 60g 10g of hydroxypropyl methylcellulose 5g of silicon dioxide 5g magnesium stearate 2. Preparation method (1) Grinding: Grind azithromycin fumarate, sodium alginate, carbomer, calcium sulfate and stevioside into powder and pass them through a 100-mesh sieve.

[0037] (2) Preparation of wax dispersion: Hexadecyl alcohol is heated and melted, then pulverized azithromycin fumarate is added and stirred and dispersed evenly. After cooling to room temperature, it is pulverized to obtain wax dispersion.

[0038] (3) Preparation of mixture: The wax dispersion is mixed evenly with pulverized sodium alginate, carbomer, calcium sulfate and stevioside to obtain the mixture.

[0039] (4) Add hydroxypropyl methylcellulose to water and stir to mix evenly to prepare an aqueous solution with a concentration of 5%.

[0040] (5) Particle preparation: The mixture and the aqueous solution of hydroxypropyl methylcellulose are stirred and mixed evenly to obtain a soft material. The soft material is then prepared into particles using a sieve. The obtained particles are dried at 50°C. The dried particles are then stirred and mixed evenly with silica and magnesium stearate.

[0041] (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0042] 3. Testing According to the Chinese Pharmacopoeia (General Chapter 0931, Method II, 2025 Edition), the dissolution medium was determined using 900 ml of phosphate buffer (pH 6.0) (600 ml of 0.1 mol / L disodium hydrogen phosphate solution, with approximately 40 ml of hydrochloric acid added to adjust the pH to 6.0 ± 0.05). The dissolution was performed at 100 rpm. Samples of 10 ml were taken at 2, 4, 6, 8, and 12 hours, with the same volume and temperature of dissolution medium added simultaneously. Dissolution was then determined using high-performance liquid chromatography (HPLC). The dissolution limits at 2, 4, and 8 hours were 15–40%, 40–60%, and above 80%, respectively. The dissolution curves are shown below. Figure 2 .

[0043] Table 2 shows the dissolution test results of the azithromycin fumarate sustained-release tablets prepared in Example 2.

[0044] Example 3: 1. Formulation quantity (per 1000 tablets) Azithromycin fumarate 300g 50g of hydrogenated castor oil 150g of chitosan Sodium carboxymethyl cellulose 150g 100g of hydroxypropyl cellulose 150g of microcrystalline cellulose 50g of glucose 45g of methylcellulose 5g of talcum powder 2. Preparation method (1) Pulverization: Azithromycin fumarate, chitosan, sodium carboxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and glucose are pulverized and passed through a 100-mesh sieve.

[0045] (2) Preparation of wax dispersion: After heating and melting hydrogenated castor oil, add 100g of propanol and stir evenly. Then add pulverized azithromycin fumarate and stir to disperse evenly. Heat and evaporate propanol to near dryness, cool to room temperature and then pulverize to obtain wax dispersion.

[0046] (3) Preparation of mixture: The wax dispersion is mixed evenly with pulverized chitosan, sodium carboxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and glucose to obtain a mixture.

[0047] (4) Add methylcellulose to ethanol and stir to mix evenly to prepare a 10% solution.

[0048] (5) Particle preparation: The mixture and the methylcellulose solution are stirred and mixed evenly to obtain a soft material. The soft material is then granulated using a sieve. The granules are dried at 40°C. The dried granules are then stirred and mixed evenly with talc powder.

[0049] (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0050] Example 4: 1. Formulation quantity (per 1000 tablets) Azithromycin fumarate 500g 100g of stearyl alcohol 100g xanthan gum 100g of hydroxyethyl cellulose 100g of dextrin 50g of mannitol 30g of ethyl cellulose 10g of talcum powder 10g of micronized silica 2. Preparation method (1) Grinding: Grind azithromycin fumarate, xanthan gum, hydroxyethyl cellulose, dextrin and mannitol into powder and pass them through a 60-mesh sieve.

[0051] (2) Preparation of wax dispersion: Stearyl alcohol is heated and melted, then pulverized azithromycin fumarate is added and stirred and dispersed evenly. After cooling to room temperature, it is pulverized to obtain wax dispersion.

[0052] (3) Preparation of mixture: The wax dispersion is mixed evenly with pulverized xanthan gum, hydroxyethyl cellulose, dextrin and mannitol to obtain the mixture.

[0053] (4) Add ethyl cellulose to propanol and stir to mix evenly to prepare a 10% solution.

[0054] (5) Particle preparation: The mixture and the ethyl cellulose solution are stirred and mixed evenly to obtain a soft material. The soft material is then granulated using a sieve. The granules are dried at 55°C. The dried granules are then stirred and mixed evenly with talc powder and micronized silica gel.

[0055] (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0056] Example 5: 1. Formulation quantity (per 1000 tablets) Azithromycin fumarate 300g 100g of cetyl alcohol 100g of stearyl alcohol 100g of polyvinylpyrrolidone 100g of polyoxyethylene 100g lactose 100g of starch 50g of sodium saccharin Povidone 30g 10g of silicon dioxide 10g magnesium stearate 2. Preparation method (1) Grinding: Grind azithromycin fumarate, polyvinylpyrrolidone, polyoxyethylene, lactose, starch and sodium saccharin into powder and pass them through a 60-mesh sieve.

[0057] (2) Preparation of wax dispersion: Hexadecyl alcohol and octadecyl alcohol are heated and melted, then pulverized azithromycin fumarate is added and stirred and dispersed evenly. After cooling to room temperature, it is pulverized to obtain wax dispersion.

[0058] (3) Preparation of mixture: The wax dispersion is mixed evenly with pulverized polyvinylpyrrolidone, polyoxyethylene, lactose, starch and sodium saccharin to obtain the mixture.

[0059] (4) Add povidone to water and stir to mix evenly to prepare a 10% solution.

[0060] (5) Particle preparation: The mixture and the solution of polyvinyl ketone are stirred and mixed evenly to obtain a soft material. The soft material is then prepared into particles using a sieve. The obtained particles are dried at 70°C. The dried particles are then stirred and mixed evenly with silica and magnesium stearate.

[0061] (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0062] Example 6: 1. Formulation quantity (per 1000 tablets) Azithromycin fumarate 300g 150g of carnauba wax 100g of sodium carboxymethyl cellulose 100g of hydroxypropyl cellulose 100g of starch Calcium phosphate 70g 50g of glucose 50g xylitol Povidone 30g 15g of talcum powder 15g of silicon dioxide 20g magnesium stearate 2. Preparation method (1) Grinding: Grind azithromycin fumarate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, starch, calcium phosphate, glucose and xylitol into powder and pass them through a 100-mesh sieve.

[0063] (2) Preparation of wax dispersion: After heating and melting carnauba wax, add 200g of ethanol and stir evenly. Then add pulverized azithromycin fumarate and stir to disperse evenly. Heat and evaporate the ethanol to near dryness, cool to room temperature and then pulverize to obtain wax dispersion.

[0064] (3) Preparation of mixture: The wax dispersion is mixed evenly with pulverized sodium carboxymethyl cellulose, hydroxypropyl cellulose, starch, calcium phosphate, glucose and xylitol to obtain a mixture.

[0065] (4) Add povidone to water and stir to mix evenly to prepare a 10% solution.

[0066] (5) Particle preparation: The mixture and the solution of polyvinyl ketone are stirred and mixed evenly to obtain a soft material. The soft material is prepared into particles using a sieve. The obtained particles are dried at 60°C. The dried particles are stirred and mixed evenly with talc, silicon dioxide and magnesium stearate.

[0067] (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0068] Comparative Example 1 To compare the effect of wax-based blocking materials in the formulation on controlling the initial release of the drug, Comparative Example 1 did not add wax-based blocking materials to the formulation, but instead added an equal amount of polymeric sustained-release matrix. After sample preparation, dissolution was tested and compared with the dissolution of the sample in Example 1.

[0069] 1. Dosage per 1000 tablets Azithromycin fumarate 500g 230g of hydroxypropyl methylcellulose Sodium carboxymethyl cellulose 50g 100g lactose 50g xylitol Povidone 30g 5g of silicon dioxide 5g magnesium stearate 2. Preparation method (1) Grinding: Grind azithromycin fumarate, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, lactose and xylitol into powder and pass them through a 100-mesh sieve.

[0070] (2) Preparation of mixture: The pulverized azithromycin fumarate, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, lactose and xylitol are stirred and mixed evenly to obtain the mixture.

[0071] (3) Add povidone to water and stir to mix evenly to prepare an aqueous solution with a concentration of 15%.

[0072] (4) Particle preparation: The mixture and the aqueous solution of polyvinyl ketone are stirred and mixed evenly to obtain a soft material. The soft material is then prepared into particles using a sieve. The obtained particles are dried at 50°C. The dried particles are then stirred and mixed evenly with silica and magnesium stearate.

[0073] (5) Tableting: Add the uniformly mixed material from step (4) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

[0074] 3. Testing According to the Chinese Pharmacopoeia (General Chapter 0931, Method II, 2025 Edition), the dissolution medium was determined using 900 ml of phosphate buffer (pH 6.0) (600 ml of 0.1 mol / L disodium hydrogen phosphate solution, with approximately 40 ml of hydrochloric acid added to adjust the pH to 6.0 ± 0.05). The dissolution was performed at 100 rpm. Samples of 10 ml were taken at 2, 4, 6, 8, and 12 hours, with the same volume and temperature of dissolution medium added simultaneously. Dissolution was then determined using high-performance liquid chromatography (HPLC). The dissolution limits at 2, 4, and 8 hours were 15–40%, 40–60%, and above 80%, respectively. The dissolution curves are shown below. Figure 3 .

[0075] Table 3 shows the dissolution test results of the azithromycin fumarate extended-release tablets prepared in Comparative Example 1.

[0076] The dissolution rate of Comparative Example 1 sample at 2, 4 and 6 hours was significantly higher than that of Example 1 sample. After using wax-based blocking materials to prepare azithromycin fumarate dispersion, its dissolution rate was significantly slowed down, allowing the drug release to be controlled, and the product quality met the quality standard requirements.

[0077] According to the above dissolution test method and the following related material analysis method, the azithromycin fumarate sustained-release tablets prepared in Examples 1 and 2 were subjected to an accelerated test (humidity 75±5%, temperature 40±2℃) for 6 months and a long-term stability test (humidity 60±5%, temperature 25±2℃) for 6 months. The test results are shown in Tables 4 to 7.

[0078] Related material analysis methods Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; phosphate buffer-acetonitrile (45:55) was used as mobile phase A, methanol was used as mobile phase B, and the column temperature was 30℃; linear gradient elution was performed; the flow rate was 1.0 ml per minute, the detection wavelength was 210 nm, and the injection volume was 50 µl.

[0079] System suitability requirements: In the system suitability solution chromatogram, the resolution between each peak should be greater than 1.2, and in the sensitivity solution chromatogram, the signal-to-noise ratio of the peak height of the main component should be greater than 10.

[0080] If there are impurity peaks in the chromatogram of the test solution, impurity B shall not exceed 2.0%, impurities R, Q, J, I, S, A, and H shall not exceed 1.0%, other single impurities shall not exceed 1.0%, and the total impurities shall not exceed 4.0%.

[0081] Table 4 shows the accelerated test results of the 6-month test of the azithromycin fumarate extended-release tablets prepared in Example 1.

[0082] Table 5 shows the results of a 6-month long-term test of the azithromycin fumarate extended-release tablets prepared in Example 1.

[0083] Table 6 shows the accelerated test results of the 6-month test of the azithromycin fumarate extended-release tablets prepared in Example 2.

[0084] Table 7 shows the results of a 6-month long-term test of the azithromycin fumarate extended-release tablets prepared in Example 2.

[0085] Accelerated and long-term tests were conducted on the commercially available packaging. The results showed that under these packaging conditions, the related substances and release rates did not change significantly, meeting the requirements for drug storage and transportation. The azithromycin fumarate sustained-release tablets and their preparation method of this invention result in stable product quality, low impurity content, simple formulation, and a smooth process, ensuring product quality and clinical therapeutic effects, and achieving significant social and economic benefits.

[0086] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. An azithromycin fumarate sustained-release tablet, characterized in that, Based on the total mass of the sustained-release tablets (100%), the sustained-release tablets contain the following components: 30-50% azithromycin fumarate, 5-20% waxy blocking material, 20-40% polymeric sustained-release matrix, 10-20% filler, 5-10% sweetener, 0.5-5% lubricating and flow aid, and the remainder is a binder.

2. The azithromycin fumarate sustained-release tablet as described in claim 1, characterized in that, The waxy blocking material includes one or more of cetyl alcohol, octadecanol, hydrogenated castor oil, and carnauba wax.

3. The azithromycin fumarate sustained-release tablet as described in claim 1, characterized in that, The sustained-release polymer matrix includes one or more of chitosan, carbomer, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, povidone, and polyoxyethylene.

4. The azithromycin fumarate sustained-release tablet as described in claim 1, characterized in that, The filler includes one or more of microcrystalline cellulose, lactose, sucrose, starch, dextrin, pregelatinized starch, calcium sulfate, and calcium phosphate.

5. The azithromycin fumarate sustained-release tablet as described in claim 1, characterized in that, The sweeteners include one or more of glucose, xylitol, mannitol, glycyrrhizate, stevioside, sodium saccharin, and aspartame.

6. The azithromycin fumarate sustained-release tablet as described in claim 1, characterized in that, The lubricating and flow aid includes one or more of magnesium stearate, silica, talc, and micronized silica.

7. The azithromycin fumarate sustained-release tablet as described in claim 1, characterized in that, The adhesive includes one or more of methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, povidone, highly substituted hydroxypropylcellulose, and polyoxyethylene.

8. A method for preparing azithromycin fumarate sustained-release tablets according to any one of claims 1 to 7, comprising the steps of: (1) Pulverization: Pulverize azithromycin fumarate, polymer slow-release matrix, filler and sweetener separately and pass them through a 60-100 mesh sieve; (2) Preparation of wax dispersion: The wax barrier material is heated and melted, then pulverized azithromycin fumarate is added and stirred and dispersed evenly. After cooling to room temperature, it is pulverized to obtain the wax dispersion. Alternatively, the waxy blocking material can be heated and melted, then a diluent can be added and stirred evenly. Then, pulverized azithromycin fumarate can be added and stirred to disperse evenly. The diluent can be heated and evaporated to near dryness, cooled to room temperature, and then pulverized to obtain a waxy dispersion. (3) Preparation of mixture: The wax dispersion is mixed evenly with the pulverized polymer slow-release matrix, filler and sweetener to obtain the mixture; (4) Add the adhesive to the solvent and stir to mix evenly to obtain a solution or suspension of the adhesive; (5) Particle preparation: The mixture and the solution or suspension of the binder are stirred and mixed evenly to obtain a soft material. The soft material is prepared into particles using a sieve. The obtained particles are dried at 40-70°C. The dried particles are stirred and mixed evenly with a lubricating flow aid. (6) Tableting: Add the uniformly mixed material from step (5) to a tablet press for tableting to obtain azithromycin fumarate sustained-release tablets.

9. The method for preparing azithromycin fumarate sustained-release tablets as described in claim 8, characterized in that, In step (2), the diluent includes one or more of ethanol, propanol, and isopropanol, and in step (4), the solvent is one or more of water, ethanol, acetone, and isopropanol.

10. The method for preparing azithromycin fumarate sustained-release tablets as described in claim 8, characterized in that, The concentration of the adhesive solution or suspension is 5-15%.

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