A freeze-dried indobufen orally disintegrating tablet and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and specifically provides a kind of indobufen freeze-dried oral disintegrating tablet and a preparation method thereof.The freeze-dried oral disintegrating tablet contains indobufen and xanthan gum, and the freeze-dried oral disintegrating tablet can be obtained by freeze-drying technology after the above components are prepared into a suspension.The freeze-dried oral disintegrating tablet provided by the application has the technical characteristics of good properties, complete demolding, high drug loading, good content uniformity, rapid disintegration and rapid dissolution, and can meet the needs of rapid anti-platelet therapy in acute thrombosis events.

Description

Technical Field

[0001] This invention relates to indobufen lyophilized orally disintegrating tablets and their preparation method, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Indobufen is a selective, reversible platelet cyclooxygenase (COX-1) inhibitor. Its core mechanism of action is the reversible inhibition of platelet cyclooxygenase-1 (COX-1) activity, reducing the production of thromboxane A2 (TXA2), thereby inhibiting platelet aggregation and adhesion and reducing the risk of thrombosis. Clinically, indobufen is widely used for the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases, including acute myocardial infarction, stroke, peripheral artery disease, and postoperative thromboembolism, and is especially suitable for patients who are intolerant to or have contraindications to aspirin.

[0003] Currently, only indobufen tablets are available on the market. This dosage form has the following drawbacks: 1) Indobufen tablets must be swallowed whole, which poses a drug administration challenge for elderly patients, those who are weak after surgery, or those with swallowing difficulties, easily leading to decreased compliance and even the risk of choking. 2) Indobufen tablets undergo disintegration, dissolution, and absorption processes sequentially in the gastrointestinal tract. The drug absorption rate is significantly affected by the disintegration and release rate of the formulation, making it difficult to meet the needs of rapid antiplatelet therapy in acute thrombotic events.

[0004] To overcome the shortcomings of the aforementioned clinical applications, lyophilized orally disintegrating tablets, which disintegrate rapidly in the oral cavity without the need for water or with only a small amount of saliva, better meet clinical needs. Despite the significant advantages of lyophilized orally disintegrating tablets, their development for use in indobufen faces a series of challenges that are difficult to overcome with existing technologies:

[0005] (1) Limitation on high drug loading: The drug loading of lyophilized orally disintegrating tablets is usually limited. Currently, the single-tablet dose of most marketed products is less than 10 mg. Indobufen is a poorly soluble drug. For indobufen with a single dose as high as 100 mg to 200 mg, if it is to be made into a single-tablet oral lyophilized orally disintegrating tablet, its high drug loading will require more structural stabilizers, and may destroy the original loose and porous structure of the lyophilized orally disintegrating tablet, resulting in dense tablets and reduced porosity, thus making it difficult for it to disintegrate rapidly.

[0006] (2) Content uniformity limitation: Indobufen is a poorly soluble drug. When preparing the drug solution for lyophilization, the drug particles settle rapidly without a suitable suspending agent, which makes it impossible to be uniformly dispensed into the mold of the blister pack. This results in significant differences in content between unit doses, which cannot meet the pharmacopoeia requirements for content uniformity and poses a serious safety hazard.

[0007] (3) The contradiction between mechanical strength and rapid disintegration: Lyophilized oral disintegrating tablets disintegrate rapidly, but they are usually loose in structure, have poor mechanical strength, and are fragile. Moreover, under the condition of high drug loading, how to ensure that the tablets have sufficient mechanical strength to withstand the physical pressure during packaging, transportation and use, while maintaining their rapid disintegration characteristics in the oral cavity, is also a core contradiction in the existing technology.

[0008] In summary, there are currently no publicly available patent or non-patent literature reports on the successful preparation of lyophilized orally disintegrating tablets of the poorly soluble drug indobufen, which has a large single-dose capacity, while maintaining its core advantages of rapid disintegration and dissolution, and ensuring high drug loading and good content uniformity. Therefore, developing a novel lyophilized orally disintegrating tablet of indobufen to overcome these challenges has significant clinical applicability and technological innovation. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a high-drug-load, suspension-type, rapidly disintegrating and dissolving indobufen lyophilized orally disintegrating tablet and its preparation method. This invention aims to solve the key technical challenges mentioned above in the development of high-dose, poorly soluble drugs in lyophilized orally disintegrating tablets, ensuring drug quality and improving patient medication adherence.

[0010] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0011] This invention provides an indobufen lyophilized orally disintegrating tablet comprising an active ingredient and a suspending agent, wherein the suspending agent is xanthan gum; the active ingredient comprises an indobufen racemic configuration, an S-indobufen configuration, or any of its pharmaceutically acceptable salts.

[0012] Further, preferably, the content of the active ingredient is 20-65% by weight, and the content of xanthan gum is 0.5-3.5%.

[0013] Further, preferably, the particle size D of the active ingredient 90 No larger than 126μm, and further, D is preferred. 90 Preferably, the size is no larger than 100 μm.

[0014] Furthermore, preferably, the indobufen lyophilized orally disintegrating tablets of the present invention further contain a structure stabilizer, wherein the content of the structure stabilizer is 30-75% by weight.

[0015] Furthermore, preferably, the structural stabilizer of the present invention is selected from one or more of mannitol, maltitol, dextran, pullulan, trehalose, sucrose, glycine, arginine, alanine, and aspartic acid.

[0016] Furthermore, preferably, the indobufen lyophilized orally disintegrating tablets of the present invention further contain a surfactant; the content of the surfactant is 0.5~2.5% by weight percentage.

[0017] Further, preferably, the surfactant of the present invention includes anionic surfactants and electrically neutral surfactants, wherein the surfactants are selected from one or more of sodium dodecyl sulfate, cholates, sodium docusate, polysorbate, poloxamer, sucrose laurate, and vitamin E polyethylene glycol succinate.

[0018] Furthermore, preferably, the indobufen lyophilized orally disintegrating tablets of the present invention further contain a flavoring agent, the content of which is 0.2-3.5%.

[0019] Furthermore, preferably, the flavoring agent of the present invention is selected from one or more of acesulfame potassium, aspartame, neomethyl hesperidin, strawberry flavoring, orange flavoring, and banana flavoring.

[0020] Further, preferably, the indobufen lyophilized orally disintegrating tablets of the present invention release no less than 85% within 15 minutes in a pH 6.8 buffer solution, and even further, no less than 90%.

[0021] Furthermore, preferably, the preparation method of the indobufen lyophilized orally disintegrating tablets of the present invention includes the following steps:

[0022] 1) Add surfactants, structure stabilizers and / or flavoring agents to purified water as needed, and stir until completely dissolved;

[0023] 2) Add the suspending agent to the liquid obtained in step 1), stir until the material is dissolved, then add the active ingredient and stir evenly;

[0024] 3) Transfer the drug solution obtained in step 2) to the filling machine, fill the drug solution into the mold, transfer the filled sample and freeze-dry it to obtain the freeze-dried ortho-disintegrating tablets.

[0025] Compared with existing technologies and products, the indobufen lyophilized orally disintegrating tablets provided by this invention have the following beneficial effects:

[0026] (1) This invention has discovered that xanthan gum, a specific suspending agent, has an ideal suspending effect. Within the scope of the claims of this application, indobufen lyophilized orally disintegrating tablets with high drug loading, uniform suspension, good mechanical strength and disintegration properties, and rapid dissolution can be obtained. Other common suspending agents, however, cannot simultaneously balance the drug's suspension properties, mechanical properties, and disintegration behavior.

[0027] (2) The indobufen raw material used in this invention is preferably racemic or S-configuration, and its particle size distribution (D) is... 90The micrometer size should be controlled to be no greater than 126 μm, preferably no greater than 100 μm, to achieve faster dissolution than indobufen tablets (Ibustrin®).

[0028] (3) Through optimized formulation, this invention successfully increases the drug loading of a single indobufen tablet to 50-200 mg. Theoretically, 1-2 tablets can meet the single-dose needs of some patients, solving the problem that existing lyophilized orally disintegrating tablet technology cannot be applied to high-dose drugs. Furthermore, the tablets are of suitable size, easy to take orally, do not require a large amount of liquid, and can disintegrate rapidly in the oral cavity. After disintegration, they are easy to swallow, which can improve medication compliance in weak or dysphagia patients and meet the needs of rapid antiplatelet therapy in acute thrombotic events (such as pre-hospital emergency care). Detailed Implementation

[0029] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0030] In this document, the terms “comprising” and “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0031] As used herein, the terms "and / or," "or / and," and "and / or" encompass any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR."

[0032] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0033] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0034] To facilitate understanding of the invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0035] In this application, terms such as "further" and "preferred" are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0036] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions. Unless otherwise specified, all technical features and optional technical features of this application can be combined to form new technical solutions.

[0037] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0038] All embodiments and comparative examples provided in this application were prepared according to the following process steps.

[0039] 1) Add the surfactant, structure stabilizer, and flavoring agent to the purified water and stir until completely dissolved.

[0040] 2) Add a suspending agent to the liquid obtained in step 1), stir until the material is dissolved, then add indobufen raw material and stir evenly.

[0041] 3) Transfer the drug solution obtained in step 2) to the filling machine, and fill the drug solution into the mold according to the active ingredient specifications. Transfer the filled sample to the freeze dryer.

[0042] 4) Run the freeze-drying process, remove from the box, seal, and package to obtain the freeze-dried tablets.

[0043] The prescriptions for Examples 1-10 and Comparative Example 1 are shown in Table 1.

[0044] Table 1. Prescription composition (Examples 1-10, Comparative Example 1)

[0045]

[0046] The prescriptions for Examples 11-12 and Comparative Examples 2-7 are shown in Table 2.

[0047] Table 2. Prescription composition (Example 3, Examples 11-12, Comparative Examples 2-7)

[0048]

[0049] Example 13

[0050] Visually inspect and record the appearance and demolding effect of the product after freeze-drying (characterizing mechanical strength).

[0051] The disintegration time test method for orally disintegrating tablets (General Chapter 0921 of the Chinese Pharmacopoeia 2020 Edition) was used to check whether the sample met the pharmacopoeia requirements.

[0052] By using the content method, check the mixing uniformity of the upper / middle / lower layer liquids after the suspension has been left to stand for a certain period of time after the solution preparation and before freeze-drying. The content should be 90~110% and the RSD should not exceed 5%.

[0053] The dissolution and release determination method (General Chapter 0931, Method II, Chinese Pharmacopoeia 2020 Edition) was used. 1000 mL of phosphate buffer (pH 6.8) was used as the dissolution medium, and the rotation speed was 50 rpm. After the sample was wrapped with a thin iron wire to increase its weight, the procedure was carried out according to the method. After a certain time (e.g., 15 min), an appropriate amount of solution was taken, filtered, and the filtrate was collected and tested according to the content method.

[0054] The test results of Examples 1-10, Comparative Example 1, and Ibustrin® tablets are shown in Table 3.

[0055] Table 3. Results 1 (Examples 1-10, Comparative Example 1, Indobufen Tablets (Ibustrin®))

[0056]

[0057] Note Indobufen tablets (Ibustrin®) are available in 200mg tablets.

[0058] Experimental conclusion:

[0059] In Examples 3-10, the dissolution rate of samples within 15 minutes was no less than 90%, indicating that the samples were basically completely dissolved. This rapid dissolution demonstrates the advantage of lyophilized orally disintegrating tablets in rapidly disintegrating and dissolving.

[0060] Both Example 3 and Ibustrin® tablets are 200mg in strength. However, the Example 3 sample dissolved 96% within 15 minutes, essentially completely, while the Ibustrin® sample dissolved only 80% within 15 minutes. This means that Example 3 dissolved significantly faster than Ibustrin®. This indicates that the lyophilized orally disintegrating tablets described in this invention dissolve significantly faster than Ibustrin® tablets, better meeting the clinical need for urgent drug efficacy.

[0061] Both Example 9 and Comparative Example 1 were 50mg tablets. However, the sample in Example 9 dissolved 90% within 15 minutes, essentially completely, while the sample in Comparative Example 1 dissolved only 56% within 15 minutes. This means that the dissolution of Comparative Example 1 was significantly slower than that of Example 9, and even slower than that of indobufen tablets (Ibustrin®). This further illustrates that when the particle size D90 of the active pharmaceutical ingredient exceeds 126μm, the dissolution of lyophilized orally disintegrating tablets is significantly slower.

[0062] Results of tests for Examples 3, 11-12, and 2-7.

[0063] Table 4. Results of Study 2 (Examples 3, Examples 11-12, Comparative Examples 2-7)

[0064]

[0065] Note Examples 3, 11-12, and Comparative Example 2: After the solution preparation was completed, the suspension was allowed to stand for 18 hours, and then the upper layer, middle layer, and lower layer were taken respectively to detect the content.

[0066] Note Comparative Examples 3-7: After the solution preparation is completed, the suspension is allowed to stand for 10 minutes. The upper layer, middle layer, and lower layer are taken separately and the content is detected.

[0067] Experimental results show that the disintegration time of the lyophilized disintegrating tablets prepared in Examples 3 and 11-12 all meet the requirements, and the properties and demolding effects are good. In addition, the mixing uniformity during the preparation of the solution is good.

[0068] Xanthan gum was present in the formulations of Examples 3, 11-12, and Comparative Examples 2-3. The lyophilized orally disintegrating tablets prepared in Examples 3 and 11-12 completely disintegrated within 60 seconds, indicating that the samples met the requirements for rapid disintegration. The lyophilized orally disintegrating tablets prepared in Comparative Example 2 disintegrated in 97 seconds, indicating that the sample did not meet the requirements for rapid disintegration. This further demonstrates that the proportion of xanthan gum in the indobufen orally disintegrating tablet formulation should not exceed 3.5%. In Examples 3 and 11-12, after the preparation of the solution, the suspension was allowed to stand for 18 hours. The content of the mixture was 90-110% and the RSD was no more than 5%, indicating that the drug solution was uniformly and stably suspended, and the risk of uneven content in the finished product after filling was low. In Comparative Example 3, after the preparation of the solution, the suspension was allowed to stand for 10 minutes. The content of the mixture exceeded 90-110% and the RSD exceeded 5%, indicating that the drug solution had settled, and the risk of uneven content in the finished product after filling was high. This further illustrates that the proportion of xanthan gum in the formulation of indobufen orally disintegrating tablets should not be less than 0.5%.

[0069] Examples 3 and 11-12 all contain xanthan gum, while Comparative Examples 4-7 do not contain xanthan gum but contain other types of suspending agents. In Examples 3 and 11-12, after the suspension was prepared and allowed to stand for 18 hours, the sample mixing uniformity met the requirements, indicating that the sample suspension was uniform and stable. In Comparative Examples 4-7, after the suspension was prepared and allowed to stand for 10 minutes, the sample mixing uniformity did not meet the requirements, indicating that the sample had sedimentation. This demonstrates that the samples prepared by this invention, when containing a certain proportion of xanthan gum (0.5-3.5%), can simultaneously balance the limitations of high drug loading, mixing uniformity, mechanical strength, and rapid disintegration, thus producing high-quality lyophilized orally disintegrating tablets.

[0070] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the invention. Various variations can be made to the above embodiments of the present invention. Any simple or equivalent changes or modifications made to the content of the claims and description of this application fall within the protection scope of the claims of this patent. All aspects not described in detail in this invention are conventional technical content.

Claims

1. A lyophilized orally disintegrating tablet of indobufen, characterized in that, By weight percentage, the lyophilized orally disintegrating tablets contain 20-65% of the active ingredient, 0.5-3.5% of the suspending agent xanthan gum, 30-75% of the structure stabilizer mannitol or sucrose, 0.5-2.5% of the surfactant sodium dodecyl sulfate, and 0.2-3.5% of the flavoring agent. The active ingredient is indobufen racemic, S-indobufen, or any pharmaceutically acceptable salt thereof, and the particle size D90 of the active ingredient is not greater than 126 μm.

2. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The flavoring agent is selected from one or more of acesulfame potassium, aspartame, neomethyl hesperidin, strawberry flavoring, orange flavoring, and banana flavoring.

3. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The orally disintegrating tablets release at least 85% of their contents within 15 minutes in a pH 6.8 buffer solution.

4. The method for preparing indobufen lyophilized orally disintegrating tablets according to any one of claims 1-3, characterized in that, Includes the following steps: 1) Add surfactants, structure stabilizers, and flavoring agents to purified water as needed, and stir until completely dissolved; 2) Add the suspending agent to the liquid obtained in step 1), stir until the material is dissolved, then add the active ingredient and stir evenly; 3) Transfer the drug solution obtained in step 2) to the filling machine, fill the drug solution into the mold, and freeze-dry the filled sample to obtain the freeze-dried ortho-disintegrating tablets.

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