Indobufen freeze-dried orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly provides an indobufen freeze-dried orally disintegrating tablet and a preparation method thereof. The freeze-dried orally disintegrating tablet contains indobufen and xanthan gum, and after the components are prepared into a suspension, the freeze-dried orally disintegrating tablet can be obtained through a freeze-drying technology. The freeze-dried orally disintegrating tablet provided by the invention has the technical characteristics of good character, complete demolding, high drug loading capacity, good content uniformity, rapid disintegration and rapid dissolution, and can meet the requirements of rapid antiplatelet therapy in acute thrombosis events.

Description

TECHNICAL FIELD

[0001] The present application relates to a lyophilized orally disintegrating tablet preparation of indobufen and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. BACKGROUND

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

[0003] Currently, only indobufen tablets are on the market. This dosage form has the following defects: 1) Indobufen tablets need to be swallowed whole, which poses a dosing barrier for elderly patients, postoperative weak or dysphagia patients, and can lead to decreased compliance and even asphyxiation risk. 2) Indobufen tablets need to go through the processes of disintegration, dissolution, and absorption in the gastrointestinal tract in sequence. The drug absorption rate is significantly affected by the disintegration and release rate of the preparation, making it difficult to meet the needs of rapid anti-platelet therapy in acute thrombotic events.

[0004] To overcome the above-mentioned clinical application shortcomings, lyophilized orally disintegrating tablets that can rapidly disintegrate in the oral cavity without the need for water or only a small amount of saliva can better meet clinical needs. Although lyophilized orally disintegrating tablets have significant advantages, their development for indobufen faces a series of challenges that existing technologies cannot solve: (1) High drug loading limit: The drug loading of lyophilized orally disintegrating tablets is usually limited, and the single tablet dose of currently marketed products is mostly less than 10 mg. Indobufen is a poorly soluble drug. For indobufen with a single dose of up to 100 mg to 200 mg, a high drug loading of lyophilized orally disintegrating tablets would require more structure stabilizers, which could destroy the original porous structure of the lyophilized orally disintegrating tablet, making the tablet dense and reducing the porosity, thereby making it difficult to rapidly disintegrate.

[0005] (2) Content uniformity limit: Indobufen is a poorly soluble drug. When preparing the drug solution for lyophilization, the drug particles quickly settle without a suitable suspending agent, making it impossible to be evenly distributed to the molds of the blister plate, resulting in significant differences in content between unit doses, which cannot meet the requirements of the pharmacopoeia on content uniformity, and poses a serious safety hazard.

[0006] (3) The contradiction between mechanical strength and rapid disintegration: freeze-dried orally disintegrating tablets disintegrate rapidly, but are usually loose in structure and poor in mechanical strength, and are easy to break. Moreover, in the case of high drug loading, how to ensure that the tablet has sufficient mechanical strength to withstand the physical pressure in the process of packaging, transportation and taking, and at the same time maintain its rapid disintegration characteristics in the oral cavity, is also a core contradiction in the prior art.

[0007] In summary, there is no published patent or non-patent literature reporting that a single dose of a large amount of poorly soluble drug indobufen can be successfully prepared into a freeze-dried orally disintegrating tablet which can maintain the core advantages of rapid disintegration and dissolution, and ensure high drug loading and good content uniformity of the preparation. Therefore, it is of great clinical practicality and technical creativity to develop a new type of indobufen freeze-dried orally disintegrating tablet to overcome the above challenges. SUMMARY

[0008] The purpose of the present application is to overcome the shortcomings of the prior art, and to provide a high drug loading, suspension type, rapid disintegration and dissolution freeze-dried orally disintegrating tablet of indobufen and a preparation method thereof. The present application aims to solve the key technical problems faced in the development of high-dose poorly soluble drugs in freeze-dried orally disintegrating tablets, ensure drug quality, and improve patient medication compliance.

[0009] The technical solution of the present application to solve the above technical problems is as follows: The present application provides a freeze-dried orally disintegrating tablet of indobufen, comprising an active ingredient and a suspending agent, wherein the suspending agent is xanthan gum; and the active ingredient comprises a racemic form of indobufen, an S-indobufen form or any pharmaceutically acceptable salt thereof.

[0010] Further, preferably, the content of the active ingredient is 20-65% by weight, and the content of the xanthan gum is 0.5-3.5% by weight.

[0011] Further, preferably, the particle size D 90 of the active ingredient is not more than 126 μm, and further preferably, D 90 is not more than 100 μm.

[0012] Further, preferably, the freeze-dried orally disintegrating tablet of indobufen according to the present application further comprises a structure stabilizer, and the content of the structure stabilizer is 30-75% by weight.

[0013] Further, preferably, the structure stabilizer according to the present application is selected from one or more of mannitol, maltitol, dextran, pullulan, trehalose, sucrose, glycine, arginine, alanine and aspartic acid.

[0014] Further, preferably, the lyophilized orally disintegrating tablet of indobufen of the present application further comprises a surfactant, and the content of the surfactant is 0.5-2.5% by weight.

[0015] Further, preferably, the surfactant of the present application comprises anionic surfactant and electrically neutral surfactant, and the surfactant is selected from one or more of sodium dodecyl sulfate, cholate, sodium docusate, polysorbate, poloxamer, sucrose laurate, vitamin E polyethylene glycol succinate.

[0016] Further, preferably, the lyophilized orally disintegrating tablet of indobufen of the present application further comprises a flavoring agent, and the content of the flavoring agent is 0.2-3.5%.

[0017] Further, preferably, the flavoring agent of the present application is selected from one or more of aspartame, aspartame-acesulfame, neomethyl orange, strawberry flavor, orange flavor, banana flavor.

[0018] Further, preferably, the lyophilized orally disintegrating tablet of indobufen of the present application releases not less than 85% in 15 minutes in pH 6.8 buffer solution, and further, not less than 90%.

[0019] Further, preferably, the preparation method of the lyophilized orally disintegrating tablet of indobufen of the present application comprises the following steps: 1) According to the need, the surfactant, the structure stabilizer and / or the flavoring agent are added to purified water, and stirred until completely dissolved; 2) The suspending agent is added to the solution prepared in step 1), and stirred until the material is dissolved, and then the active ingredient is added and stirred uniformly; 3) The drug solution prepared in step 2) is transferred to a filling machine, and the drug solution is filled into a mold, and then the sample after filling and transferring is freeze-dried to obtain the finished product of the lyophilized orally disintegrating tablet.

[0020] Compared with the prior art and products, the lyophilized orally disintegrating tablet of indobufen provided by the present application has the following beneficial effects: (1) The present application finds that the use of a specific suspending agent xanthan gum has an ideal suspending effect. According to the range described in the claims of the present application, a lyophilized orally disintegrating tablet of indobufen with high drug loading, uniform suspension, good mechanical strength and disintegration performance, and fast dissolution can be obtained. Other common suspending agents cannot balance the suspension performance, mechanical performance and disintegration behavior of the drug at the same time.

[0021] (2) The raw material drug of indobufen used in the present application is preferably in the racemic configuration or S-configuration, and the particle size distribution (D 90 ) of the raw material drug is controlled to be not more than 126 μm, preferably not more than 100 μm, so that a faster dissolution effect than Ibustrin® tablet can be obtained.

[0022] (3) The present application successfully increases the drug loading of single indobufen tablet to 50-200 mg by optimized prescription, and theoretically 1-2 tablets can meet the single-dose needs of some patients, solving the problem that the existing freeze-dried oral disintegrating tablet technology cannot be applied to high-dose drugs. Moreover, the size is appropriate, convenient to enter the mouth, does not need a large amount of liquid to serve, can be rapidly disintegrated in the oral cavity, easy to swallow after disintegration, can improve the medication compliance of the weak or dysphagia population, and can meet the needs of rapid anti-platelet therapy in acute thrombotic events (such as pre-hospital emergency). DETAILED DESCRIPTION

[0023] The present application will be further described in detail below in conjunction with specific embodiments, but the present application is not limited to the following embodiments.

[0024] In this document, the terms "comprising" and "including" are open-ended, i.e., including the indicated content but not excluding other aspects.

[0025] The terms "and / or", "or / and", "and / or" used in this document are selected from two or more related listed items, and also include any and all combinations of related listed items, including any two related listed items, any more related listed items, or all related listed items. It should be noted that when at least two conjunctions selected from "and / or", "or / and", "and / or" are combined to connect at least three items, it should be understood that in this application, the technical solution undoubtedly includes the technical solution connected by "logical and", and also undoubtedly includes the technical solution connected by "logical or".

[0026] In this application, the technical features described in an open-ended manner include a closed technical solution consisting of listed features, and also include an open technical solution containing listed features.

[0027] In this document, the endpoints of the ranges and any values disclosed are not limited to the precise range or value, and should be understood to include values approximately around the range or value. For numerical ranges, the endpoints of each range, the endpoints of each range 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.

[0028] In order to more easily understand the present application, some technical and scientific terms are specifically defined as follows. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which the present application belongs.

[0029] In the present application, "further", "preferably" and the like are used to describe purposes and indicate differences in content, but should not be understood as limiting the scope of protection of the present application.

[0030] All embodiments and optional embodiments of the present application can be combined to form new technical solutions if not specifically stated. All technical features and optional technical features of the present application can be combined to form new technical solutions if not specifically stated.

[0031] The solutions of the present application will be explained below in combination with examples. Those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be regarded as limiting the scope of the present application. If no specific technology or condition is indicated in the examples, the technology or condition described in the literature in the art or according to the product instruction is used. If no manufacturer of the reagent or instrument is indicated, it is a conventional product that can be obtained by market purchase.

[0032] All examples and comparative examples provided in the present application are prepared according to the following process steps.

[0033] 1) Add surfactant, structure stabilizer, and flavoring agent to purified water, and stir until completely dissolved.

[0034] 2) Add suspending agent to the solution prepared in step 1), stir until the material is dissolved, and then add indobufen drug substance, and stir until uniform.

[0035] 3) Transfer the solution prepared in step 2) to a filling machine, and fill the solution into molds according to the active ingredient specification, and transfer the filled samples to a freeze-drying machine box.

[0036] 4) Run the freeze-vacuum drying program, take out the box, seal, and package to obtain the freeze-dried oral disintegrating tablet product.

[0037] The formulations of examples 1-10 and comparative example 1 are shown in Table 1.

[0038] Table 1 Formulation composition (examples 1-10, comparative example 1) The formulations of examples 11-12 and comparative examples 2-7 are shown in Table 2.

[0039] Table 2 Formulation composition (example 3, examples 11-12, comparative examples 2-7) Example 13 The appearance and morphology of the product after freeze-drying, and the demolding effect (characterizing mechanical strength) are visually inspected and recorded.

[0040] The sample is checked by the disintegration time limit test method of oral disintegrating tablets (Chinese Pharmacopoeia 2020 Edition General 0921) to see if it meets the requirements of the pharmacopoeia.

[0041] The uniformity of the mixture of the upper layer liquid / middle layer liquid / lower layer liquid after the suspension is left for a certain period of time after the end of the solution preparation before freeze-drying is checked by the content method. The content of each layer should be 90-110%, and the RSD should not exceed 5%.

[0042] The dissolution and release test method (Chinese Pharmacopoeia 2020 Edition General 0931 Method 2) is used to check the sample. Phosphate buffer (pH 6.8) 1000 mL is used as the dissolution medium, the rotation speed is 50 rpm, the sample is wound with fine iron wire to increase the weight, and then the operation is carried out according to the method. After a certain period of time (such as 15 min), an appropriate amount of solution is taken, filtered, and the filtrate is taken for content testing.

[0043] The test results of Examples 1-10, Comparative Example 1, and Ibustrin® tablets are shown in Table 3.

[0044] Table 3 Research Results 1 (Examples 1-10, Comparative Example 1, and Ibustrin® tablets) Note : Ibustrin® tablets are 200 mg in size.

[0045] Test Conclusion: The samples of Examples 3-10 all have a 15 min dissolution of not less than 90%, which is basically complete dissolution, and can be quickly dissolved, which reflects the advantage of the freeze-dried oral disintegrating tablets in quickly disintegrating and dissolving.

[0046] Examples 3 and Ibustrin® tablets are both 200 mg in size, but the sample of Example 3 has a 15 min dissolution of 96%, which is basically complete dissolution, while the sample of Ibustrin® tablets has a 15 min dissolution of 80%. That is, the dissolution of Example 3 is significantly faster than that of Ibustrin® tablets. This shows that the freeze-dried oral disintegrating tablets of the present application can dissolve significantly faster than Ibustrin® tablets, and better meet the clinical needs of urgent drug use.

[0047] Examples 9 and Comparative Example 1 are both 50 mg in size, but the sample of Example 9 has a 15 min dissolution of 90%, which is basically complete dissolution, while the sample of Comparative Example 1 has a 15 min dissolution of 56%. That is, the dissolution of Comparative Example 1 is significantly slower than that of Example 9, and even slower than that of Ibustrin® tablets. This further shows that when the particle size D90 of the raw material is more than 126 μm, the dissolution of the freeze-dried oral disintegrating tablets is significantly slower.

[0048] Example 3, Example 11~12, Comparative Example 2~7

[0049] Table 4 Research results 2 (Example 3, Example 11~12, Comparative Example 2~7) Note : Example 3, Example 11~12, Comparative Example 2, after the end of the preparation of the liquid suspension, the upper liquid / middle liquid / lower liquid was taken respectively, and the content was detected.

[0050] Note : Comparative Example 3~7, after the end of the preparation of the liquid suspension, the upper liquid / middle liquid / lower liquid was taken respectively, and the content was detected.

[0051] The experimental results show that: the disintegration time of the freeze-dried orally disintegrating tablets prepared in Example 3, Example 11~12 meets the requirements, the properties, demolding effect and mixing uniformity during the preparation of the liquid are good.

[0052] Example 3, Example 11~12, Comparative Example 2~3 all contain xanthan gum in the prescription. Among them, the freeze-dried orally disintegrating tablets prepared in Example 3, Example 11~12 all disintegrate completely within 60s, which shows that the samples can meet the requirements of rapid disintegration; the disintegration time of the freeze-dried orally disintegrating tablets prepared in Comparative Example 2 is 97s, which shows that the sample does not meet the requirements of rapid disintegration, further indicating that the proportion of xanthan gum in the prescription of indomethacin orally disintegrating tablets should not exceed 3.5%. The suspension of Example 3, Example 11~12 is placed for 18h after the end of the preparation of the liquid, the content under the mixing uniformity is 90~110%, and the RSD is not more than 5%, which shows that the liquid suspension is uniform and stable, and the risk of content unevenness of the finished product after filling is low; the suspension of Comparative Example 3 is placed for 10min after the end of the preparation of the liquid, the content under the mixing uniformity exceeds 90~110%, and the RSD exceeds 5%, which shows that the liquid has settled, and the risk of content unevenness of the finished product after filling is high, further indicating that the proportion of xanthan gum in the prescription of indomethacin orally disintegrating tablets should not be less than 0.5%.

[0053] The prescription of example 3 and example 11~12 all contain xanthan gum, and the prescription of comparative example 4~7 all do not contain xanthan gum but contain other types of suspending agents. Among them, the suspension liquid of example 3, example 11~12 is placed for 18h after preparation, and the sample mixing uniformity meets the requirements, indicating that the sample is uniformly suspended and stable; the suspension liquid of comparative example 4~7 is placed for 10min after preparation, and the sample mixing uniformity does not meet the requirements, indicating that the sample has sedimentation. It is proved that the sample prepared by the present application can balance the problems of high drug loading limit, mixing uniformity limit, mechanical strength and rapid disintegration of the product at the same time when a certain proportion of xanthan gum (0.5~3.5%) is contained in the prescription of the sample, and a good quality freeze-dried oral disintegration tablet is prepared.

[0054] The technical features of the above-described embodiments can be combined in any manner. To make the description concise, all possible combinations of the technical features in the above-described embodiments are not described, but as long as the combinations of the technical features do not contradict, they should be considered as falling within the scope of the present disclosure.

[0055] The above-described embodiments of the present application are only preferred embodiments, not to limit the scope of the present application, and various changes can be made to the above-described embodiments of the present application. Any simple, equivalent changes or modifications made to the content of the claims and the description of the present application are within the scope of the claims of the present patent. The present application does not describe all the conventional technical contents.

Claims

1. A lyophilized orally disintegrating tablet of indobufen, characterized in that, The lyophilized orally disintegrating tablets contain an active ingredient and a suspending agent, wherein the suspending agent is xanthan gum; the active ingredient contains an indobufen racemic configuration, an S-indobufen configuration, or any of its pharmaceutically acceptable salts.

2. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The active ingredient comprises 20-65% by weight, and the xanthan gum comprises 0.5-3.5%.

3. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The particle size D of the active ingredient 90 No larger than 126 μm.

4. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The lyophilized orthotic tablets also contain a structure stabilizer, the content of which is 30-75% by weight.

5. The indobufen lyophilized orally disintegrating tablets as described in claim 4, characterized in that, The structural stabilizer is selected from one or more of mannitol, maltitol, dextran, pullulan, trehalose, sucrose, glycine, arginine, alanine, and aspartic acid.

6. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The lyophilized orally disintegrating tablets also contain a surfactant; the surfactant content is 0.5-2.5% by weight.

7. The indobufen lyophilized orally disintegrating tablets as described in claim 6, characterized in that, The surfactants include anionic surfactants and electrically neutral surfactants, and the surfactants are selected from one or more of sodium dodecyl sulfate, cholate, sodium docusate, polysorbate, poloxamer, sucrose laurate, and vitamin E polyethylene glycol succinate.

8. The indobufen lyophilized orally disintegrating tablets as described in claim 1, characterized in that, The freeze-dried orally disintegrating tablets also contain a flavoring agent, the content of which is 0.2-3.5% by weight.

9. The indobufen lyophilized orally disintegrating tablets as described in claim 8, 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.

10. 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.

11. The method for preparing indobufen lyophilized orally disintegrating tablets according to any one of claims 1-10, characterized in that, Includes the following steps: 1) Add surfactants, structure stabilizers and / or 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, transfer the filled sample and freeze-dry it to obtain the freeze-dried ortho-disintegrating tablets.

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