A capsule of oseltamivir phosphate for antiviral and a preparation method thereof
By optimizing the stable prosolvent system and preparation process, the stability and dissolution rate issues of oseltamivir phosphate capsules were resolved, resulting in a capsule formulation with high stability and high bioavailability, suitable for the field of antiviral drugs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG LUKANG SANYE PHARM CO LTD
- Filing Date
- 2025-10-20
- Publication Date
- 2026-07-31
AI Technical Summary
Existing oseltamivir phosphate capsules suffer from poor stability and uneven dissolution rates. In particular, they are prone to oxidative degradation and drug particle aggregation under light conditions, which affects bioavailability.
A stable co-solvent system with a specific ratio and pretreatment process are used, including low-temperature dissolution and vacuum drying to prepare a complex of guar gum aqueous solution with inositol and disodium EDTA. The complex is then combined with fillers such as lactose and microcrystalline cellulose, uniformly mixed by a three-dimensional mixer, dried and granulated under specific conditions, and finally filled into capsules by a fully automatic capsule filling machine.
It significantly improves the stability and dissolution performance of oseltamivir phosphate capsules, with the total impurities controlled within 0.1%, a dissolution rate of over 98%, and an effective ingredient retention rate of 99%, ensuring rapid onset of action.
Smart Images
Figure CN121102163B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of antiviral drug formulation technology, specifically relating to an oseltamivir capsule for antiviral use and its preparation method. Background Technology
[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
[0003] Influenza, an acute respiratory infectious disease caused by influenza A and B viruses, is characterized by high infectivity, rapid spread, and wide impact. It is especially likely to induce serious complications such as pneumonia, respiratory failure, and myocarditis in infants, young children, the elderly, patients with chronic underlying diseases, and people with weakened immune systems, and can even lead to death.
[0004] Oseltamivir phosphate (chemical name: (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate) is the most widely used neuraminidase inhibitor antiviral drug in clinical practice. Its mechanism of action is as follows: after oral administration, it is rapidly converted into the active metabolite oseltamivir carboxylate in the body, specifically inhibiting the activity of neuraminidase on the surface of influenza viruses, preventing the release of newly synthesized viral particles from the host cell surface, thereby interrupting the viral replication and transmission chain in the body. It can shorten the duration of influenza symptoms by 1-2 days and reduce the incidence of complications by 30%-50%. It also exhibits highly effective inhibitory activity against influenza A (H1N1), H3N2, and influenza B viruses.
[0005] As the mainstream formulation of oseltamivir phosphate, oseltamivir phosphate capsules occupy a significant share of the global influenza treatment drug market due to their advantages such as convenient administration (adults and children over 6 years old can swallow directly), precise dosage (common strengths are 30mg, 45mg, and 75mg), and good storage and transportation stability. However, existing oseltamivir phosphate capsules still face the following technical bottlenecks that urgently need to be overcome in research and development, production, and clinical application: (1) Stability issues: Oseltamivir phosphate has poor chemical stability. The amino and phosphate groups in its molecular structure are prone to hydrolysis and oxidative degradation under light conditions, producing impurities.
[0006] (2) Issues with formulation dissolution and bioavailability: Existing formulations often use lactose, microcrystalline cellulose, etc., as fillers. Oseltamivir phosphate and lactose easily form hydrogen bonds, leading to drug particle aggregation and a slower dissolution rate. When mixed with microcrystalline cellulose, the density difference between the two can easily cause stratification, resulting in some capsules dissolving too quickly. However, this technical solution does not consider the issue of fluctuations in the content of the active ingredient.
[0007] Chinese Patent Publication No. CN111297823A discloses a method for preparing oseltamivir phosphate capsules. This invention effectively improves the uniformity of drug dissolution by controlling the addition method and amount of the glidant. Chinese Patent Publication No. CN119385967A discloses a capsule containing oseltamivir phosphate and its uses. The capsule is composed of oseltamivir phosphate, turmeric, microcrystalline cellulose, sorbitol, povidone, and a lubricant, exhibiting good dissolution and low levels of related substances. While the introduction of compound excipients such as turmeric improves dissolution and related substance indicators, the curcumin components in turmeric are easily degraded by light, potentially interacting with oseltamivir phosphate.
[0008] Therefore, there is an urgent need for a technical solution that can effectively improve the stability and bioavailability of oseltamivir phosphate capsules. Summary of the Invention
[0009] The core objective of this invention is to overcome the technical defects of existing oseltamivir phosphate capsules, such as poor stability and uneven dissolution rate, and to provide a scientifically formulated and rationally processed oseltamivir phosphate capsule and its preparation method. By optimizing the combination of excipients and the preparation process, the stability and dissolution performance of the formulation are synergistically improved.
[0010] Specifically, the technical solution of the present invention is as follows: (I) Formulation Design of Oseltamivir Phosphate Capsules The oseltamivir phosphate capsules provided by this invention are composed of the following components by weight: Active ingredient: 30-75 parts of oseltamivir phosphate. Filler: 50-150 parts, selected from at least one of lactose, microcrystalline cellulose, mannitol, starch, sucrose, and dextrin, preferably a compound system of lactose, microcrystalline cellulose, and mannitol. Stabilizing solubilizer: 1.2-3.6 parts, composed of disodium EDTA, inositol, and guar gum in a mass ratio of 2:1:1. pH adjuster: 0.5-2 parts, selected from at least one of sodium citrate, sodium acetate, and sodium bicarbonate. Disintegrant: 5-15 parts, selected from at least one of crospovidone, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch. Lubricant: 0.5-2 parts, selected from at least one of magnesium stearate, micronized silica gel, and talc.
[0011] (II) Pretreatment process for stabilizing the solvent The stabilized solubilizer is prepared using a specific low-temperature dissolution-vacuum drying process: a guar gum aqueous solution with a mass fraction of 5%-10% (preferably 8%) is prepared at 5-15℃ (preferably 10℃), and inositol and disodium EDTA in a predetermined ratio are added. After stirring until completely dissolved, the solution is vacuum dried, pulverized, and sieved to obtain a uniformly dispersed composite stabilized solubilizer, which enhances the protection and solubilization effect of the drug.
[0012] (III) Preparation method of oseltamivir phosphate capsules Pretreatment: Oseltamivir phosphate is pulverized and passed through an 80-mesh sieve. The filler, pH adjuster, and disintegrant are passed through a 100-mesh sieve. Material Mixing: The pretreated oseltamivir phosphate, filler, pH adjuster, disintegrant, and stabilizing solvent are added to a three-dimensional mixer and mixed for 15-20 minutes to ensure uniform dispersion of all components. Granulation: Purified water is slowly added to the mixture, and a stirring speed of 200-300 rpm is controlled to prepare a soft mass. The mass is then passed through a 16-20 mesh sieve to form wet granules. Drying and Granulation: The wet granules are dried at 50-60℃ for 4-6 hours, controlling the moisture content to 1.0%-3.0%. After drying, the granules are passed through an 18-24 mesh sieve to remove any agglomerated particles. Final Mixing: The granulated granules and lubricant are added to a three-dimensional mixer and mixed at 150-200 rpm for 5-8 minutes. Capsule Filling: No. 0 or No. 1 empty capsules are used for filling using a fully automatic capsule filling machine.
[0013] Compared with the prior art, the technical advantages of the present invention are as follows: (1) Significantly improved stability: This invention can effectively inhibit the hydrolysis and oxidative degradation of oseltamivir phosphate by using a specific ratio of compound stabilizing solvent and pretreatment process. After 6 months of accelerated testing, the total impurity content is controlled within 0.1%, and the retention rate of effective ingredients is over 99%, which is significantly better than commercially available products and existing technologies.
[0014] (2) Optimized dissolution performance: The composite excipient system of the present invention works synergistically to avoid drug particle aggregation. The dissolution rate of the formulation can reach more than 98% within 30 minutes, and the dissolution rate is fast in the early stage, with a dissolution rate of more than 65% within 5 minutes, which effectively improves the bioavailability of the drug and ensures rapid onset of action. Attached Figure Description
[0015] Figure 1 Dissolution rate of oseltamivir phosphate capsules.
[0016] Figure 2 Accelerated test for the content of related substances in oseltamivir phosphate capsules.
[0017] Figure 3 Accelerated test of the active ingredient content of oseltamivir phosphate capsules. Detailed Implementation
[0018] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.
[0019] Example 1 Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare an 8% (w / w) guar gum aqueous solution at 10℃; add inositol and disodium EDTA, stir until completely dissolved, transfer to a vacuum drying oven, and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid, pulverize, and pass through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0020] (2) Pretreatment of other auxiliary materials After pulverizing oseltamivir phosphate, pass it through an 80-mesh sieve. Take the filler, pH adjuster, lubricant, and disintegrant and pass them through a 100-mesh sieve for later use.
[0021] (3) Material mixing The pretreated oseltamivir phosphate, along with the filler, pH adjuster, disintegrant, and stabilizer, was added to a three-dimensional mixer and mixed for 15-20 minutes.
[0022] (4) Granulation Slowly add purified water to the mixed material, stir (stirring speed 250r / min), form soft material, granulate, pass through an 18-mesh sieve, and form wet granules.
[0023] (5) Drying and granulation Spread the wet granules evenly on a stainless steel tray and transfer them into a hot air circulating drying oven. Dry them at 50-60℃ for 4-6 hours, turning the granules over every hour during the drying process. Control the moisture content of the dried granules to 1.0%-3.0%. Then, feed the dried granules into a swing granulator and granulate them through a 22-mesh sieve.
[0024] (6) Total Mix The granulated particles and lubricant are fed into a three-dimensional mixer and mixed for 5-8 minutes at a speed of 180 r / min.
[0025] (7) Capsule filling Select either No. 0 or No. 1 hollow capsules and fill them using a fully automatic capsule filling machine.
[0026] Example 2 Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare a 5% (w / w) guar gum aqueous solution at 5℃; add inositol and disodium EDTA, stir until completely dissolved, transfer to a vacuum drying oven, and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid, pulverize, and pass through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0027] (2) Pretreatment of other auxiliary materials After pulverizing oseltamivir phosphate, pass it through an 80-mesh sieve. Take the filler, pH adjuster, lubricant, and disintegrant and pass them through a 100-mesh sieve for later use.
[0028] (3) Material mixing The pretreated oseltamivir phosphate, along with the filler, pH adjuster, disintegrant, and stabilizer, was added to a three-dimensional mixer and mixed for 15-20 minutes.
[0029] (4) Granulation Slowly add purified water to the mixed material, stir (stirring speed 200r / min), form soft material, granulate, pass through a 16-mesh sieve, and form wet granules.
[0030] (5) Drying and granulation Spread the wet granules evenly on a stainless steel tray and transfer them into a hot air circulating drying oven. Dry them at 50-60℃ for 4-6 hours, turning the granules over every hour during the drying process to control the moisture content of the dried granules to 1.0%-3.0%. Then, feed the dried granules into a swing granulator and granulate them through an 18-mesh sieve.
[0031] (6) Total Mix The granulated particles and lubricant are fed into a three-dimensional mixer and mixed for 5-8 minutes at a speed of 150 r / min.
[0032] (7) Capsule filling Select either No. 0 or No. 1 hollow capsules and fill them using a fully automatic capsule filling machine.
[0033] Example 3 Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment A 10% guar gum aqueous solution was prepared at 15℃; inositol and disodium EDTA were added and stirred until completely dissolved. The solution was then transferred to a vacuum drying oven and dried at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid. The solid was then pulverized and passed through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0034] (2) Pretreatment of other auxiliary materials After pulverizing oseltamivir phosphate, pass it through an 80-mesh sieve. Take the filler, pH adjuster, lubricant, and disintegrant and pass them through a 100-mesh sieve for later use.
[0035] (3) Material mixing The pretreated oseltamivir phosphate, along with the filler, pH adjuster, disintegrant, and stabilizer, was added to a three-dimensional mixer and mixed for 15-20 minutes.
[0036] (4) Granulation Slowly add purified water to the mixed material, stir (stirring speed 300r / min), form soft material, granulate, pass through a 20-mesh sieve, and form wet granules.
[0037] (5) Drying and granulation Spread the wet granules evenly on a stainless steel tray and transfer them into a hot air circulating drying oven. Dry them at 50-60℃ for 4-6 hours, turning the granules over every hour during the drying process. Control the moisture content of the dried granules to 1.0%-3.0%. Then, feed the dried granules into a swing granulator and granulate them through a 24-mesh sieve.
[0038] (6) Total Mix The granulated particles and lubricant are fed into a three-dimensional mixer and mixed for 5-8 minutes at a speed of 200 r / min.
[0039] (7) Capsule filling Select either No. 0 or No. 1 hollow capsules and fill them using a fully automatic capsule filling machine.
[0040] Comparative Example 1: Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare an 8% (w / w) guar gum aqueous solution at 10℃; add disodium ethylenediaminetetraacetate and stir until completely dissolved. Transfer to a vacuum drying oven and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid. Crush the solid and pass it through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0041] Steps (2)-(7) are the same as in Example 1.
[0042] Comparative Example 2: Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare an 8% (w / w) guar gum aqueous solution at 10℃; add inositol and stir until completely dissolved, transfer to a vacuum drying oven, and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid. Crush the solid and pass it through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0043] Steps (2)-(7) are the same as in Example 1.
[0044] Comparative Example 3: Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare an 8% (w / w) guar gum aqueous solution at 10℃; add inositol and disodium EDTA, stir until completely dissolved, transfer to a vacuum drying oven, and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid, pulverize, and pass through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0045] Steps (2)-(7) are the same as in Example 1.
[0046] Comparative Example 4: Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare an 8% (w / w) gelatin aqueous solution at 10℃; add inositol and disodium EDTA, stir until completely dissolved, transfer to a vacuum drying oven, and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid, pulverize, and pass through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0047] Steps (2)-(7) are the same as in Example 1.
[0048] Comparative Example 5: Oseltamivir Phosphate Capsules formula: Preparation method: (1) Stabilizing solvent pretreatment Prepare an 8% (w / w) guar gum aqueous solution at 25℃; add inositol and disodium EDTA, stir until completely dissolved, transfer to a vacuum drying oven, and dry at 45-55℃ and a vacuum of -0.08 to -0.06 MPa to obtain a dry solid, pulverize, and pass through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0049] Steps (2)-(7) are the same as in Example 1.
[0050] Comparative Example 6: Oseltamivir Phosphate Capsules formula: Same as Example 1.
[0051] Preparation method: (1) Stabilizing solvent pretreatment Guar gum, inositol, and disodium EDTA are physically mixed, pulverized, and passed through an 80-mesh sieve to obtain a pretreated stable solvent for later use.
[0052] (2) Pretreatment of other auxiliary materials After pulverizing oseltamivir phosphate, pass it through an 80-mesh sieve. Take the filler, pH adjuster, lubricant, and disintegrant and pass them through a 100-mesh sieve for later use.
[0053] (3) Material mixing The pretreated oseltamivir phosphate, along with the filler, pH adjuster, disintegrant, and stabilizer, was added to a three-dimensional mixer and mixed for 15-20 minutes.
[0054] (4) Granulation Slowly add purified water to the mixed material, stir (stirring speed 250r / min), form soft material, granulate, pass through an 18-mesh sieve, and form wet granules.
[0055] (5) Drying and granulation Spread the wet granules evenly on a stainless steel tray and transfer them into a hot air circulating drying oven. Dry them at 50-60℃ for 4-6 hours, turning the granules over every hour during the drying process. Control the moisture content of the dried granules to 1.0%-3.0%. Then, feed the dried granules into a swing granulator and granulate them through a 22-mesh sieve.
[0056] (6) Total Mix The granulated particles and lubricant are fed into a three-dimensional mixer and mixed for 5-8 minutes at a speed of 180 r / min.
[0057] (7) Capsule filling Select either No. 0 or No. 1 hollow capsules and fill them using a fully automatic capsule filling machine.
[0058] Comparative Example 7: Oseltamivir Phosphate Capsules formula: Same as Example 1.
[0059] Preparation method: (1) Pretreatment of raw and auxiliary materials After pulverizing oseltamivir phosphate, pass it through an 80-mesh sieve. Take the filler, guar gum, inositol, disodium EDTA, pH adjuster, lubricant, and disintegrant and pass them through a 100-mesh sieve for later use.
[0060] (2) Material mixing The pretreated oseltamivir phosphate, along with filler, guar gum, inositol, disodium EDTA, pH adjuster, disintegrant, and stabilizing agent, were added to a three-dimensional mixer and mixed for 15-20 minutes.
[0061] (3) Granulation Slowly add purified water to the mixed material, stir (stirring speed 250r / min), form soft material, granulate, pass through an 18-mesh sieve, and form wet granules.
[0062] (4) Drying and granulation Spread the wet granules evenly on a stainless steel tray and transfer them into a hot air circulating drying oven. Dry them at 50-60℃ for 4-6 hours, turning the granules over every hour during the drying process. Control the moisture content of the dried granules to 1.0%-3.0%. Then, feed the dried granules into a swing granulator and granulate them through a 22-mesh sieve.
[0063] (5) Total Mixing The granulated particles and lubricant are fed into a three-dimensional mixer and mixed for 5-8 minutes at a speed of 180 r / min.
[0064] (6) Capsule filling Select either No. 0 or No. 1 hollow capsules and fill them using a fully automatic capsule filling machine.
[0065] Commercially available oseltamivir phosphate capsules: National Drug Approval Number H20223074.
[0066] Oseltamivir phosphate capsule dissolution Dissolution and release determination shall be performed according to the Chinese Pharmacopoeia (General Chapter 0931, Method II). Dissolution conditions: Use 900 ml of hydrochloric acid solution (9→1000) as the dissolution medium, rotate at 50 rpm, and operate according to the procedure. Take a sample after 20 minutes. Test solution: Take an appropriate amount of the dissolution solution, filter, and collect the filtrate. Reference solution: Accurately weigh an appropriate amount of oseltamivir phosphate reference standard, dissolve it in the dissolution medium, and quantitatively dilute it to prepare a solution containing approximately 110 μg per ml. Chromatographic conditions and system suitability requirements are detailed under the Assay section. Determination method: See the Assay section. Calculate the amount dissolved per tablet.
[0067] Table 1 Dissolution of Oseltamivir Phosphate Capsules Table 1 shows that the oseltamivir phosphate capsules in Examples 1-3 of this invention exhibit a faster dissolution rate, achieving a higher dissolution volume in a shorter time, and a more complete dissolution process. The comparative examples, due to the absence of a stabilizing solubilizing agent, improper proportions, substitution with other components, unsuitable processing temperatures, or lack of specific pretreatment methods, all showed inferior dissolution performance compared to the examples. The dissolution rate and completeness of commercially available products are also lower than those of the examples of this invention, demonstrating the advantages of the formulation and preparation process of this invention in improving drug dissolution performance.
[0068] Stability of oseltamivir phosphate capsules Accelerated test: Placed in commercial packaging at a temperature of 40±2℃ and a relative humidity of 75%±5% for 6 months.
[0069] 1. Related substances The determination was performed according to the High Performance Liquid Chromatography (HPLC) method (General Chapter 0512) of the Chinese Pharmacopoeia. Test solution: Take the contents from the volume variation section, mix thoroughly, accurately weigh an appropriate amount (approximately equivalent to 38 mg of oseltamivir), place in a 50 ml volumetric flask, dissolve and dilute to the mark with solvent, shake well, filter, and collect the filtrate. Reference solution: Accurately measure 2 ml of the test solution, place in a 100 ml volumetric flask, dilute to the mark with solvent, shake well, accurately measure 5 ml, place in a 50 ml volumetric flask, dilute to the mark with solvent, and shake well. Reference standard solution: Take appropriate amounts of impurity I reference standard, impurity II reference standard, and impurity III reference standard, accurately weigh them separately, dissolve in solvent, and quantitatively dilute to prepare a solution containing approximately 2.2 μg of impurity I, 1.5 μg of impurity II, and 3.5 μg of impurity III per ml. Chromatographic conditions: Octylsilane-bonded silica gel was used as the stationary phase; the mobile phase was 0.05 mol / L potassium dihydrogen phosphate solution (adjusted to pH 5.6 with 1 mol / L potassium hydroxide solution)-methanol-acetonitrile (700:245:135); the flow rate was 1.0 mL / min; the detection wavelength was 207 nm; the column temperature was 50 °C; and the injection volume was 15 μL. Solvent: 0.003 mol / L phosphoric acid solution-methanol-acetonitrile (620:245:135). System suitability requirements: In the chromatogram of the reference solution, the resolution between the peaks of impurity I, impurity II, and impurity III should meet the requirements. Assay: Accurately measure the test solution, reference solution, and reference standard solution, and inject them separately into the liquid chromatograph. Record the chromatograms up to twice the retention time of the main component peak. Limits: If impurity peaks are present in the chromatogram of the test solution, the peak areas of impurity I, impurity II, and impurity III, calculated by external standard method, shall not exceed 0.1%, 0.1%, and 0.2%, respectively. The area of any other single impurity peak shall not exceed the area of the main peak of the control solution (0.1%). The total amount of impurities shall not exceed 0.5%.
[0070] Table 2. Related substances from the accelerated test of oseltamivir phosphate capsules at 6 months. Table 2 shows that after 6 months of accelerated testing, the content of all impurities in the oseltamivir phosphate capsules of Examples 1-3 of this invention was at extremely low levels, demonstrating significant impurity control. In contrast, the comparative examples showed a significant increase in impurity content due to improper matching of the stabilizing prosolvent and inappropriate processing methods, with some impurities even approaching or exceeding the limits. The impurity content of commercially available products was also higher than that of the examples of this invention, indicating that the stabilizing prosolvent system and preparation process of this invention can effectively inhibit drug degradation during storage and improve the stability of the formulation.
[0071] Oseltamivir phosphate content The content of oseltamivir phosphate capsules was determined according to the high-performance liquid chromatography (HPLC) method (General Chapter 0512) in the Chinese Pharmacopoeia. Reference solution: Accurately weigh an appropriate amount of oseltamivir phosphate reference standard, dissolve it in solvent, and quantitatively dilute it to prepare a solution containing approximately 1 mg per ml. Solvent, test solution, chromatographic conditions, and system suitability requirements: See the section on oseltamivir phosphate content determination. Assay: Accurately measure the test solution and reference solution, inject them separately into the HPLC instrument, and record the chromatograms. Calculate the content using the external standard method based on peak area, and multiply the result by 0.761.
[0072] Table 3. Oseltamivir Phosphate Content in Accelerated Tests Table 3 shows that the content of the active ingredient in the oseltamivir phosphate capsules of Examples 1-3 of this invention remained stable throughout the accelerated testing period, with minimal decrease even after 6 months of accelerated storage. The comparative examples, due to defects in the use of a stabilizing solubilizer, experienced a more significant decrease in the content of the active ingredient, indicating poorer stability. The content decrease in commercially available products was also greater than that in the examples of this invention, demonstrating that the formulation design and preparation method of this invention can better protect the active ingredient, reduce its loss during storage, and ensure the efficacy stability of the formulation.
Claims
1. A capsule of oseltamivir phosphate for antiviral use, characterized in that, The oseltamivir phosphate capsules are composed of the following components in parts by weight: Oseltamivir phosphate 30-75 parts, filler 50-150 parts, stabilizing solubilizer 1.2-3.6 parts, pH adjuster 0.5-2 parts, disintegrant 5-15 parts, lubricant 0.5-2 parts; The stabilizing solvent is disodium ethylenediaminetetraacetate, inositol, and guar gum in a mass ratio of 2:1:
1. The method for treating the stabilized solvent is as follows: prepare a 5%-10% guar gum aqueous solution at a temperature of 5-15℃, add inositol and disodium EDTA, stir to dissolve, vacuum dry, pulverize, and sieve.
2. The oseltamivir phosphate capsule according to claim 1, wherein The filler is selected from at least one of lactose, microcrystalline cellulose, mannitol, starch, sucrose, and dextrin.
3. The oseltamivir phosphate capsule according to claim 1, wherein The pH adjuster is selected from at least one of sodium citrate, sodium acetate, and sodium bicarbonate.
4. The oseltamivir phosphate capsule according to claim 1, wherein The disintegrant is selected from at least one of crospovidone, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch.
5. The oseltamivir phosphate capsule according to claim 1, wherein The lubricant is selected from at least one of magnesium stearate, micronized silica gel, and talc.
6. The oseltamivir phosphate capsule according to claim 1, characterized in that, The temperature is 10°C.
7. The oseltamivir phosphate capsule according to claim 1, characterized in that, The mass fraction of the guar gum aqueous solution is 8%.
8. A method for preparing oseltamivir phosphate capsules according to any one of claims 1-7, characterized in that, The preparation method includes the following steps: (1) Pretreatment: Oseltamivir phosphate is crushed and sieved, and the filler, pH adjuster and lubricant are sieved separately; (2) Material mixing: Oseltamivir phosphate is mixed with filler, pH adjuster, disintegrant, and stabilizing solvent. (3) Granulation: Add purified water to the mixed material, stir, form soft material, granulate, and sieve; (4) Drying and granulation; (5) Mixing: Mix the granulated particles with the lubricant; (6) Capsule filling.