Oseltamivir phosphate freeze-dried tablet and preparation method thereof
By using water-soluble starch as a backbone material, oseltamivir phosphate lyophilized tablets were prepared, which solved the safety and high cost problems existing in the prior art, and achieved rapid disintegration and good taste, making them suitable for use by a variety of people.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- BEIJING XINGHAO YINGSHENG PHARM CO LTD
- Filing Date
- 2026-03-03
- Publication Date
- 2026-05-12
AI Technical Summary
The existing oseltamivir phosphate lyophilized tablets have problems such as the risk of animal-derived diseases, high cost, complex process and slow dissolution rate, which make it difficult to meet the needs of children, the elderly and patients with swallowing difficulties.
Oseltamivir phosphate lyophilized tablets were prepared by using water-soluble starch as a skeleton forming agent, combined with sweeteners and flavorings, and freeze-drying technology to form a porous and robust three-dimensional mesh skeleton, ensuring that the tablets disintegrate rapidly in the oral cavity.
Water-soluble starch materials are safe and low-cost, and the resulting freeze-dried tablets have high mechanical strength, good taste, and rapid disintegration, making them suitable for large-scale production. This reduces production costs, expands the international market, and improves patient medication adherence.
Smart Images
Figure CN122005471A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a lyophilized oseltamivir phosphate tablet and its preparation method. Background Technology
[0002] Currently, influenza virus (also known as flu virus) is an RNA virus that primarily infects the human respiratory tract and causes influenza. Elderly people, infants, pregnant women, or those with chronic underlying diseases or immunosuppression are more susceptible to developing severe illness after influenza virus infection, potentially leading to serious complications such as pneumonia, myocarditis, and respiratory failure, and even death.
[0003]
[0004] Oseltamivir is a neuraminidase inhibitor that treats influenza by inhibiting the neuraminidase activity of the influenza virus, preventing the release of newly formed viral particles from host cells, thus interrupting the viral infection cycle. Oseltamivir is a highly effective and selective antiviral drug successfully developed based on rational drug design using the three-dimensional structure of the influenza virus neuraminidase. Oseltamivir phosphate, as an important neuraminidase inhibitor, is a first-line drug for the treatment and prevention of influenza A and B. Currently, commercially available oseltamivir phosphate formulations are mainly in capsule and dry suspension (requiring on-site preparation). Swallowing capsules is difficult for children, the elderly, and patients with swallowing difficulties. While dry suspensions solve the swallowing problem, they require water to dissolve, which is inconvenient in situations lacking clean water or during travel, and dosage accuracy is easily affected by the preparation process. Oral lyophilized tablets are a dosage form that can rapidly disintegrate or dissolve in the mouth without water, perfectly solving the above problems.
[0005] Existing oral freeze-dried tablets often use gelatin, mannitol, pullulan, etc., as the backbone. However, these materials have some drawbacks: gelatin poses risks of animal-derived diseases, is restricted by vegetarianism, and is greatly affected by temperature and pH, and its structure is prone to shrinkage and deformation after freeze-drying; mannitol, when used alone, has a loose and fragile structure after freeze-drying and cannot form a stable backbone with sufficient strength; pullulan is produced by microbial fermentation, which is a complex process with high costs and potential supply fluctuations, and the resulting backbone is usually quite dense, dissolves relatively slowly, has a slightly viscous taste, and is prone to absorbing moisture.
[0006] Therefore, there is an urgent need in this field to develop a new technology for preparing oral lyophilized tablets of oseltamivir phosphate using safer, lower-cost, and more widely available framework materials. Summary of the Invention
[0007] The purpose of this invention is to provide a lyophilized oseltamivir phosphate tablet and its preparation method. The lyophilized tablet has the advantages of rapid disintegration, good taste, simple preparation process, high safety and low cost.
[0008] In a first aspect, the present invention provides a lyophilized tablet of oseltamivir phosphate, comprising an active ingredient and a matrix forming agent; wherein the active ingredient is a therapeutically effective amount of oseltamivir phosphate, and the matrix forming agent is water-soluble starch.
[0009] Preferably, the content of the skeleton forming agent is 10%-40%.
[0010] Preferably, the water-soluble starch is commercially available and can be obtained through public channels (Jia Ke Biotechnology, batch number 20250102), meets pharmaceutical grade standards, is completely soluble in cold water, and has a solubility of 60g / 100ml or more in water at room temperature.
[0011] Preferably, it also includes flavoring agents; the flavoring agents include one or two of sweeteners and flavorings.
[0012] Preferably, the sweetener includes one or more of sucralose, aspartame, acesulfame potassium, sodium saccharin, and steviol glycosides.
[0013] Preferably, the flavoring includes one or more of orange flavoring, grapefruit flavoring, chocolate flavoring, and coffee flavoring.
[0014] A second aspect of the present invention provides a method for preparing oseltamivir phosphate lyophilized tablets, comprising the following steps: S1. Dissolve or suspend oseltamivir phosphate, water-soluble starch and other excipients in purified water to form a homogeneous drug solution; S2. The liquid medicine obtained in step S1 is quantitatively injected into the mold plate; S3. Place the mold plate in an environment of -75℃ to -120℃ to rapidly freeze the liquid medicine; S4. Freeze-dry the quick-frozen drug solution to obtain oseltamivir phosphate freeze-dried tablets.
[0015] Preferably, in step S1, the solid content of the liquid medicine is controlled between 5% and 30%.
[0016] Preferably, in step S4, the freeze-drying step includes: S41. Pre-freezing: Keep at -20℃ to -30℃ for 2-4 hours; S42. Sublimation drying: Maintain at -10℃ to 10℃ and a vacuum of 20Pa to 50Pa for 4-8 hours; S43. Desorption and drying: Keep at 20℃ to 30℃ for 2-3 hours.
[0017] After three stages of pre-freezing, sublimation drying, and desorption drying, moisture is removed, forming a porous and loose sheet-like structure.
[0018] Preferably, the following steps are also included: S5. Lamination, cutting, and printing of batch numbers and production dates are carried out under strict humidity control conditions.
[0019] Compared with the prior art, the present invention has at least the following beneficial effects: (1) Innovative framework material: For the first time, water-soluble starch was used in the framework construction of oseltamivir phosphate oral lyophilized tablets. Water-soluble starch is derived from natural plants, is inexpensive, and has good biocompatibility and extremely high safety. Since it does not contain animal ingredients, it avoids the risk of carrying animal-specific zoonotic diseases (such as mad cow disease BSE, foot-and-mouth disease, etc.), significantly reducing biosafety hazards in the production and distribution of the drug. In addition, water-soluble starch does not involve animal ingredients, which also meets the needs of vegetarians and greatly expands the product's international market potential.
[0020] (2) Excellent performance: Water-soluble starch has moderate and good viscosity, which enables it to form a uniform and robust three-dimensional network skeleton during freeze-drying. This structure not only gives the oral freeze-dried tablets high mechanical strength and good taste, but also ensures that the tablets have sufficient hardness for easy patient use. At the same time, the tablets can rapidly disintegrate in oral saliva within 5 seconds, releasing the drug quickly and significantly improving patient medication compliance. Water-soluble starch also exhibits excellent heat resistance, is not prone to browning reaction, and has excellent emulsifying and thickening abilities. In addition, it has strong tolerance to humidity, is not prone to clumping or absorbing moisture, thus effectively maintaining the structural stability of the freeze-dried orally disintegrating tablets and the uniform distribution of the drug.
[0021] (3) Simplified process and cost advantage: Water-soluble starch has a strong hydration ability and can dissolve directly at room temperature. At least 60 grams of sample can be dissolved in 100 ml of water. Compared with materials such as gelatin and pullulan, water-soluble starch does not require heating during the production process and can be quickly dissolved in cold water, making the process simpler and more efficient. It is very suitable for large-scale production and can significantly reduce production costs.
[0022] (4) Masking potential: Water-soluble starch itself is tasteless and has a natural and mild taste. At the same time, the dense and porous structure formed in the formulation can encapsulate the drug to a certain extent, which helps to mask the bitter taste of oseltamivir phosphate, thereby effectively improving the taste. Attached Figure Description
[0023] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.
[0024] Figure 1 The image shows the microstructure of the oseltamivir phosphate lyophilized tablets provided by this invention. Detailed Implementation
[0025] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.
[0026] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments according to this application. As used herein, the singular form includes the plural form unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.
[0027] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0028] Test case The preparation steps of the oseltamivir phosphate lyophilized tablets in this experimental example are as follows: (1) Solution preparation: According to the four sets of test raw material ratios in Table 1, add oseltamivir phosphate and water-soluble starch to an appropriate amount of purified water, stir to dissolve evenly, and obtain a drug solution with a solid content of about 26%.
[0029] (2) Filling: The above-mentioned liquid medicine is filled into the mold plate with a volume of 0.25 mL per hole through the filling machine.
[0030] (3) Quick-freezing: The liquid medicine is quickly frozen into a solid at -85℃.
[0031] (4) Freeze-drying: Quickly transfer the quick-frozen mold plate into the freeze dryer. Perform freeze-drying according to the following procedure: keep at -30℃ for 2 hours; keep at 0℃ and 20Pa for 6 hours; keep at 20℃ and 20Pa for 2 hours.
[0032] (5) Packaging: Under strict humidity control, the product is laminated, cut, and the batch number and production date are printed.
[0033] Table 1
[0034] The appearance and disintegration time of oseltamivir phosphate lyophilized tablets prepared under four different raw material ratios were tested, and the results are shown in Table 2. The preferred content of water-soluble starch is 10%-40%.
[0035] Table 2
[0036] Example 1 This embodiment provides a lyophilized oseltamivir phosphate tablet, the composition and content of which are shown in Table 3.
[0037] Table 3
[0038] The preparation steps of the oseltamivir phosphate lyophilized tablets in this embodiment are as follows: (1) Solution preparation: Add oseltamivir phosphate, water-soluble starch, sucralose and chocolate flavoring to an appropriate amount of purified water, stir to dissolve evenly, and obtain a drug solution with a solid content of about 15%.
[0039] (2) Filling: The above-mentioned liquid medicine is filled into the mold plate with a volume of 0.4 mL per hole through the filling machine.
[0040] (3) Quick-freezing: The liquid medicine is quickly frozen into a solid at -100℃.
[0041] (4) Freeze-drying: Quickly transfer the quick-frozen mold plate into the freeze dryer. Perform freeze-drying according to the following procedure: keep at -30℃ for 3 hours; keep at 0℃ and 50Pa for 6 hours; keep at 25℃ and 20Pa for 3 hours.
[0042] (5) Packaging: Under strict humidity control, the product is laminated, cut, and the batch number and production date are printed.
[0043] The microstructure of the oseltamivir phosphate lyophilized tablets prepared in this embodiment is as follows: Figure 1 As shown, a uniform and robust three-dimensional mesh framework is formed during the freeze-drying process. This structure not only gives the oral freeze-dried tablets high mechanical strength and good taste, but also ensures that the tablets have sufficient hardness for easy use by patients.
[0044] Example 2 This embodiment provides a lyophilized oseltamivir phosphate tablet, the composition and content of which are shown in Table 4.
[0045] Table 4
[0046] The preparation steps of the oseltamivir phosphate lyophilized tablets in this embodiment are as follows: (1) Solution preparation: Add oseltamivir phosphate, water-soluble starch, sucralose and coffee flavoring to an appropriate amount of purified water, stir to dissolve evenly, and obtain a drug solution with a solid content of about 18%.
[0047] (2) Filling: The above-mentioned liquid medicine is filled into the mold plate with a volume of 0.5 mL per hole through the filling machine.
[0048] (3) Quick-freezing: The liquid medicine is quickly frozen into a solid at -120℃.
[0049] (4) Freeze-drying: Quickly transfer the quick-frozen mold plate into the freeze dryer. Perform freeze-drying according to the following procedure: keep at -30℃ for 4 hours; keep at -5℃ and 50Pa for 8 hours; keep at 25℃ and 20Pa for 3 hours.
[0050] (5) Packaging: Under strict humidity control, the product is laminated, cut, and the batch number and production date are printed.
[0051] Example 3 This embodiment provides a lyophilized oseltamivir phosphate tablet, the composition and content of which are shown in Table 5.
[0052] Table 5
[0053] The preparation steps of the oseltamivir phosphate lyophilized tablets in this embodiment are as follows: (1) Solution preparation: Add oseltamivir phosphate, water-soluble starch, sucralose and grapefruit flavoring to an appropriate amount of purified water, stir to dissolve evenly, and obtain a drug solution with a solid content of about 10%.
[0054] (2) Filling: The above-mentioned liquid medicine is filled into the mold plate with a volume of 0.3 mL per hole through the filling machine.
[0055] (3) Quick-freezing: The liquid medicine is quickly frozen into a solid at -85℃.
[0056] (4) Freeze-drying: Quickly transfer the quick-frozen mold plate into the freeze dryer. Perform freeze-drying according to the following procedure: keep at -30℃ for 2 hours; keep at 0℃ and 50Pa for 4 hours; keep at 25℃ and 20Pa for 2 hours.
[0057] (5) Packaging: Under strict humidity control, the product is laminated, cut, and the batch number and production date are printed.
[0058] Comparative Example 1 This comparative example provides a lyophilized oseltamivir phosphate tablet, the composition and content of which are shown in Table 6.
[0059] Table 6
[0060] The preparation steps of the oseltamivir phosphate lyophilized tablets in this comparative example are as follows: (1) Solution preparation: Add an appropriate amount of water to the gelatin and heat to above 60°C, stir to dissolve, and then cool to 20°C~30°C. Add oseltamivir phosphate, mannitol, and sucralose to the gelatin solution, stir to dissolve evenly, and obtain a drug solution with a solid content of about 15%.
[0061] (2) Filling: The above-mentioned liquid medicine is filled into the mold plate with a volume of 0.4 mL per hole through the filling machine.
[0062] (3) Quick-freezing: The liquid medicine is quickly frozen into a solid at -100℃.
[0063] (4) Freeze-drying: Quickly transfer the quick-frozen mold plate into the freeze dryer. Perform freeze-drying according to the following procedure: keep at -30℃ for 3 hours; keep at 0℃ and 50Pa for 6 hours; keep at 25℃ and 20Pa for 3 hours.
[0064] (5) Packaging: Under strict humidity control, the product is laminated, cut, and the batch number and production date are printed.
[0065] Comparative Example 2 This comparative example provides a lyophilized oseltamivir phosphate tablet, the composition and content of which are shown in Table 7.
[0066] Table 7
[0067] The preparation steps of the oseltamivir phosphate lyophilized tablets in this comparative example are as follows: (1) Solution preparation: Add an appropriate amount of water to pullulan and heat to 80℃~100℃, stir to dissolve, and cool to 20℃~30℃. Add oseltamivir phosphate, mannitol, and sucralose to the pullulan solution, stir to dissolve evenly, and obtain a drug solution with a solid content of about 18%.
[0068] (2) Filling: The above-mentioned liquid medicine is filled into the mold plate with a volume of 0.4 mL per hole through the filling machine.
[0069] (3) Quick-freezing: The liquid medicine is quickly frozen into a solid at -100℃.
[0070] (4) Freeze-drying: Quickly transfer the quick-frozen mold plate into the freeze dryer. Perform freeze-drying according to the following procedure: keep at -30℃ for 3 hours; keep at 0℃ and 50Pa for 6 hours; keep at 25℃ and 20Pa for 3 hours.
[0071] (5) Packaging: Under strict humidity control, the product is laminated, cut, and the batch number and production date are printed.
[0072] The appearance, taste, gritty texture, and disintegration time of the oseltamivir phosphate lyophilized tablets of Examples 1-3 and Comparative Examples 1-2 were tested, and the results are shown in Table 8.
[0073] Table 8
[0074] As shown in Table 8, compared to Comparative Examples 1-2, the oseltamivir phosphate lyophilized tablets prepared in Examples 1-3 of this invention have a smooth surface, high taste score, no gritty feel, and an oral disintegration time of less than 5 seconds, indicating rapid disintegration. Furthermore, compared to Comparative Examples 1-2, Examples 1-3 of this invention eliminate the heating, heat preservation, and cooling steps during the solution preparation process, thus eliminating the temperature control step. The production process is shorter and simpler. This not only saves the time required for heating and cooling, shortening the production cycle, but also improves overall production efficiency. Simultaneously, by avoiding the impact of temperature control fluctuations on the process, batch-to-batch quality consistency is better, and process robustness is significantly improved. In addition, in terms of equipment, there is no need for heating jackets, heat exchangers, precision temperature control systems, etc., reducing the special requirements for solution preparation equipment, thereby reducing equipment investment and maintenance costs, and also reducing energy consumption (steam, electricity) in production.
[0075] In summary, this invention is the first to apply water-soluble starch to the matrix construction of oseltamivir phosphate oral lyophilized tablets. Water-soluble starch is derived from natural plants, is inexpensive, and possesses excellent biocompatibility and extremely high safety. Because it contains no animal components, it avoids the risk of carrying zoonotic diseases specific to animals (such as BSE and foot-and-mouth disease), significantly reducing biosafety hazards during drug production and distribution. Furthermore, water-soluble starch does not involve animal components, meeting the needs of vegetarians and greatly expanding the product's international market potential. Water-soluble starch has moderate and good viscosity, enabling the formation of a uniform and robust three-dimensional network matrix during lyophilization. This structure not only gives the oral lyophilized tablets high mechanical strength and a good taste but also ensures sufficient tablet hardness for easy patient dispensing. Simultaneously, the tablets rapidly disintegrate within 5 seconds in oral saliva, quickly releasing the drug and significantly improving patient adherence. Water-soluble starch also exhibits excellent heat resistance, is not prone to browning, and possesses excellent emulsifying and thickening abilities. Furthermore, it exhibits strong tolerance to humidity, resisting clumping or moisture absorption, thus effectively maintaining the structural stability of lyophilized orally disintegrating tablets and the uniform distribution of the drug. Water-soluble starch possesses strong hydration capabilities, dissolving directly at room temperature; at least 60 grams of sample can dissolve in 100 ml of water. Compared to materials like gelatin and pullulan, water-soluble starch requires no heating during production, dissolving rapidly in cold water alone, simplifying and maximizing the efficiency of the process. This makes it ideal for large-scale production and significantly reduces production costs. Water-soluble starch itself is tasteless, with a naturally mild flavor. Simultaneously, the dense and porous structure it forms in formulations can encapsulate the drug to some extent, helping to mask the bitterness of oseltamivir phosphate and effectively improving the palatability.
[0076] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A lyophilized tablet of oseltamivir phosphate, characterized in that, It includes an active ingredient and a matrix forming agent; the active ingredient is oseltamivir phosphate, and the matrix forming agent is water-soluble starch.
2. The oseltamivir phosphate lyophilized tablets according to claim 1, characterized in that, The content of the skeleton forming agent is 10%-40%.
3. The oseltamivir phosphate lyophilized tablets according to claim 1, characterized in that, The solubility of the water-soluble starch is not less than 60g / 100ml.
4. The oseltamivir phosphate lyophilized tablets according to claim 1, characterized in that, It also includes flavoring agents; the flavoring agents include one or two of sweeteners and flavorings.
5. The oseltamivir phosphate lyophilized tablets according to claim 4, characterized in that, The sweeteners include one or more of sucralose, aspartame, acesulfame potassium, sodium saccharin, and steviol glycosides.
6. The oseltamivir phosphate lyophilized tablets according to claim 4, characterized in that, The flavorings include one or more of the following: orange flavoring, grapefruit flavoring, chocolate flavoring, and coffee flavoring.
7. The method for preparing oseltamivir phosphate lyophilized tablets according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Dissolve or suspend oseltamivir phosphate, water-soluble starch and other excipients in purified water to form a homogeneous drug solution; S2. The liquid medicine obtained in step S1 is quantitatively injected into the mold plate; S3. Place the mold plate in an environment of -75℃ to -120℃ to rapidly freeze the liquid medicine; S4. Freeze-dry the quick-frozen drug solution to obtain oseltamivir phosphate freeze-dried tablets.
8. The method for preparing oseltamivir phosphate lyophilized tablets according to claim 7, characterized in that, In step S1, the solid content of the liquid medicine is controlled between 5% and 30%.
9. The method for preparing oseltamivir phosphate lyophilized tablets according to claim 7, characterized in that, In step S4, the freeze-drying step includes: S41. Pre-freezing: Keep at -20℃ to -30℃ for 2-4 hours; S42. Sublimation drying: Maintain at -10℃ to 10℃ and a vacuum of 20Pa to 50Pa for 4-8 hours; S43. Desorption and drying: Keep at 20℃ to 30℃ for 2-3 hours.
10. The method for preparing oseltamivir phosphate lyophilized tablets according to claim 7, characterized in that, It also includes the following steps: S5. Lamination, cutting, printing batch number and production date.