Pharmaceutical composition containing prostaglandins, and preparation method therefor

Abstract

A pharmaceutical composition containing prostaglandins, and a preparation method therefor. The composition comprises a limaprost α-cyclodextrin inclusion compound and β-cyclodextrin, wherein the content of the limaprost α-cyclodextrin inclusion compound is 0.2%, and the content of β-cyclodextrin is 10.1-25.5%. The composition significantly improves the stability, dissolution robustness, reproducibility and safety of the product, and tableting can be completed by means of direct powder compression using a conventional rotary tablet machine without the need for dry granulation, which simplifies the production process.

Description

Pharmaceutical compositions containing prostaglandins and their preparation methods Technical Field

[0001] This invention relates to the field of pharmaceutical biology, specifically to a pharmaceutical composition containing prostaglandins and its preparation method. Background Technology

[0002] Lima prostol formulations are micro-volume preparations, with a specification of 5 μg. Existing data indicate that lima prostol is extremely unstable and highly sensitive to moisture and heat. Current technologies address the challenges of drug instability and poor uniformity in micro-volume preparations by encapsulating lima prostol with α-cyclodextrin, employing specific formulations, and utilizing various techniques such as freeze-drying dispersion of the active ingredient, granulation and tableting, vacuum drying of tablets, and complex packaging processes.

[0003] Besides specific composition formulations and special processes, the stability of original research products also largely depends on their packaging systems. If the original research product and the original patent 201280027255.6 formulation product Example 4 are removed from their packaging (bare tablets) or packaged with ordinary materials, the stability will significantly deteriorate, even if the packaging form remains the same.

[0004] The original product exhibited poor parallelism in its dissolution curves, with significant fluctuations in the early dissolution phase. In aqueous media at pH 6.8, pH 1.2, pH 4.5, and 5 min, the dissolution rate differed considerably between the 5 min and 10 min time points, with the 5 min RSD% reaching as high as 50.2%–57.0% and the 10 min RSD% reaching as high as 17.6%–25.2%.

[0005] Patent application 201280027255.6 describes a process that has high equipment requirements, necessitating an external lubrication device for the rotary tablet press. During the tableting process, magnesium stearate lubricant needs to be sprayed into the tablet press, and this device is not a standard, general-purpose rotary tablet press.

[0006] Patent application 201280027255.6 describes a complex process that requires dry granulation before tableting. The formulation contains a large amount of β-cyclodextrin excipients, which have poor flowability, resulting in poor feeding during tableting, severe sticking and sluggish feeding, and blurred lettering on the product surface.

[0007] Patent application 201010194734 involves a complex process that requires dry granulation before tableting, which has varying degrees of impact on the product's dissolution and stability.

[0008] Original research paper Improved Stability of Tablets under Humid Conditions IV:Effect of Polysaccharides and Disintegrants on the Stability and Dissolution Property of Tablets describe how adding β-cyclodextrin to the lyophilized solution can further improve the stability of the limaprost α-cyclodextrin inclusion complex. The principle is to reduce the formation of the impurity 11-deoxy-limaprost by decreasing water migration. Increased β-cyclodextrin content can lead to poor formulation flowability, uneven feeding during tableting, severe sticking and chafing, and blurred lettering on the product surface.

[0009] Therefore, it is necessary to develop improved formulations containing prostaglandins. Summary of the Invention

[0010] In view of the above-mentioned technical status, the present invention aims to provide a pharmaceutical composition containing prostaglandins, the composition comprising lima prostol α-cyclodextrin inclusion complex and β-cyclodextrin, wherein, based on the mass of the composition, the content of the lima prostol α-cyclodextrin inclusion complex is 0.2%;

[0011] The content of the β-cyclodextrin is 10.1% to 25.5%, preferably 10.1% to 20%, and by way of example, it can be 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% or 19%.

[0012] In this invention, as one embodiment, the composition further includes a lyophilized support agent, wherein the content of the lyophilized support agent is 0.25% to 2.0% by weight of the composition, preferably 0.3% to 1.7%. As an example, the content can be 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, or 1.6%.

[0013] In this invention, as one embodiment, the freeze-drying support agent includes dextran, sucrose, trehalose, lactose, mannitol or sorbitol, or a combination of two or more of them; preferably dextran.

[0014] In this invention, as one embodiment, the composition further includes a disintegrant. The content of the disintegrant, based on the mass of the composition, is 5-30%, preferably 10-30%, more preferably 20%. As an example, it can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%.

[0015] In this invention, as one embodiment, the disintegrant is selected from croscarmellose sodium, croscarmellose, calcium carboxymethyl cellulose or carboxymethyl cellulose, or a combination of two or more of them, preferably carboxymethyl cellulose.

[0016] In this invention, as one embodiment, the composition further includes a filler, the content of which is 52.2% to 67.2% by weight of the composition. For example, it can be 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, or 67%.

[0017] In this invention, as one embodiment, the filler is selected from microcrystalline cellulose, mannitol, starch, pregelatinized starch or lactose, or a combination of two or more of them, preferably pregelatinized starch, lactose or a combination of both.

[0018] In this invention, as one embodiment, the pharmaceutical composition further includes a gliding agent, wherein the content of the gliding agent is 0.1-5.0% by weight of the composition, preferably 0.2-1.0%. As an example, it can be 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.

[0019] In this invention, as one embodiment, the flow aid is selected from colloidal silica or talc or a combination thereof, preferably silica.

[0020] In this invention, as one embodiment, the pharmaceutical composition further includes a lubricant, wherein the lubricant content is 0.5-2.0% by weight of the composition, preferably 1.0-1.7%. As an example, it can be 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, or 1.6%.

[0021] In this invention, as one embodiment, the lubricant is selected from magnesium stearate or sodium dodecyl sulfate or a combination thereof, preferably magnesium stearate.

[0022] In this invention, as one embodiment, the β-cyclodextrin is added in batches. The amount of β-cyclodextrin added to the lyophilized powder is 0.1% to 0.5% of the tablet weight (as an example, it can be any natural value in the range of 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.1% to 0.5%). The remaining amount of β-cyclodextrin is added during the mixing process of the lyophilized powder obtained after freeze-drying with the remaining excipients.

[0023] As an example, if the total amount of β-cyclodextrin added is 20% of the tablet weight, and the amount of β-cyclodextrin added to the lyophilized powder is 0.1% of the tablet weight, then the amount of β-cyclodextrin added in the process of mixing the lyophilized powder obtained after freeze-drying with the remaining excipients is 19.9% ​​of the tablet weight; if the total amount of β-cyclodextrin added is 25.5% of the tablet weight, and the amount of β-cyclodextrin added to the lyophilized powder is 0.5% of the tablet weight, then the amount of β-cyclodextrin added in the process of mixing the lyophilized powder obtained after freeze-drying with the remaining excipients is 25% of the tablet weight; if the total amount of β-cyclodextrin added is 10.1% of the tablet weight, and the amount of β-cyclodextrin added to the lyophilized powder is 0.1% of the tablet weight, then the amount of β-cyclodextrin added in the process of mixing the lyophilized powder obtained after freeze-drying with the remaining excipients is 10% of the tablet weight.

[0024] In this invention, as one embodiment, the lima prost α-cyclodextrin inclusion complex is a lima prost α-cyclodextrin inclusion complex known in the art, for example, the content of lima prost is 3% and the content of α-cyclodextrin is 97% based on the mass of the inclusion complex.

[0025] In this invention, as one embodiment, the composition comprises:

[0026] or

[0027] In this invention, as one embodiment, the composition is a tablet.

[0028] In this invention, as one embodiment, the method includes the following steps:

[0029] (1) Freeze-drying process to prepare freeze-dried mixture: Mix purified water and β-cyclodextrin, dissolve them, add limaprost α-cyclodextrin inclusion complex and freeze-drying support, stir to dissolve, freeze-dry the solution, after freeze-drying, pulverize the freeze-dried material, sieve through 60-100 mesh, and collect the freeze-dried powder.

[0030] (2) Mixing, tableting and vacuum drying: Mix the freeze-dried powder with silica, then mix the mixture with β-cyclodextrin, filler and disintegrant, and finally add magnesium stearate lubricant and mix. Then compress the mixture into tablets and vacuum dry to obtain the final product.

[0031] In this invention, as one of the embodiments, the β-cyclodextrin is added in two parts. One part is added in the freeze-drying process in the pre-process of step (1), accounting for 0.1 to 0.5% of the tablet weight, and the remaining part is added in the mixing process in the post-process of step (2).

[0032] In this invention, as one embodiment, the dextran is added only in the previous freeze-drying process, accounting for 0.25 to 2.0% of the tablet weight.

[0033] In this invention, as one embodiment, the β-cyclodextrin, filler, and disintegrant are mixed in equal increments or gradually. As an example, the specific process of equal increments or gradual mixing is as follows: When the ratio of raw materials and excipients differs significantly, for example, 1:500, equal increments are used. Specifically, the following steps are referenced: (1) Initial mixing: a small amount of the active pharmaceutical ingredient is mixed with an equal amount of excipients; (2) Gradual increments: the above mixture is then mixed with an equal amount of excipients; (3) Repeated process: this "equal increments" process continues until all excipients are added.

[0034] In this invention, as one of the implementation schemes, the ratio of purified water to β-cyclodextrin in step (1) of the method is not limited to 60:1, or it can be other appropriate ratios to effectively dissolve β-cyclodextrin.

[0035] In this invention, as one of the embodiments, the ratio of limaprost α-cyclodextrin inclusion complex to lyophilized support in step (1) of the method is 1:1 to 10, preferably 1:1.5 to 8.

[0036] In this invention, as one of the implementation schemes, the ratio of freeze-dried powder to silicon dioxide in step (2) of the method is 1:0.1 to 3.

[0037] In this invention, as one embodiment, the method further includes:

[0038] (1) Freeze-drying process to prepare freeze-dried mixture: Dissolve purified water and β-cyclodextrin in a ratio of 60:1. After dissolving, add limaprost α-cyclodextrin inclusion complex and freeze-drying support agent in a ratio of 1:1.5 to 8. Stir to dissolve, put the solution into a freeze dryer for freeze-drying, after freeze-drying, pulverize the freeze-dried material, pass it through a 60-100 mesh sieve, and collect the freeze-dried powder;

[0039] (2) Mixing, tableting and vacuum drying: Mix the freeze-dried powder with silica at a ratio of 1:0.1 to 2, then mix the mixture with β-cyclodextrin, filler and disintegrant in equal increments or by gradual mixing, and finally add lubricant and mix. Use a tablet press to compress the tablets, and then use a negative pressure dryer for vacuum drying.

[0040] In this invention, as one of the implementation schemes, the freeze-drying support agent in method step (1) is dextran 40.

[0041] In this invention, as one of the embodiments, the filler in step (2) of the method includes α-cyclodextrin, β-cyclodextrin, dextrin, lactose or pregelatinized starch, or a combination of two or more of them.

[0042] In this invention, as one of the embodiments, the disintegrant in step (2) of the method includes croscarmellose sodium, croscarmellose polyvinyl ketone, or carboxymethyl cellulose, or a combination of two or more of them.

[0043] In this invention, as one of the implementation schemes, the lubricant in step (2) of the method is magnesium stearate. Beneficial effects

[0044] 1. Improved product stability: The product prepared by the composition ratio of the present invention can achieve better stability of unpackaged (naked tablets) products at 30°C / 75%RH than Control Example 1 (Patent Application 201280027255.6 Example 4). Under the same packaging conditions (same packaging form and materials), the accelerated stability at 40°C / 75%RH is better than Control Example 1 and Control Example 2 (name: Limaprost Alfacyclodextrin Tablets, manufacturer: Ono Pharmaceutical Co., Ltd., Japan), that is, the product stability is improved.

[0045] 2. Improved product dissolution robustness and reproducibility: The dissolution curves of existing products show large fluctuations in the early dissolution rate (5 min and 10 min). The products prepared by the composition ratio of this invention significantly reduce the RSD of dissolution at 5 min and 10 min, resulting in better dissolution stability and improved product quality and safety.

[0046] 3. Simplified Production Process: Existing technical compositions contain a large amount of β-cyclodextrin, necessitating granulation to ensure material flowability and improve viscosity, thus solving problems related to uniformity and tableting continuity, resulting in a complex process. The composition formulation of this invention eliminates the need for dry granulation, enabling direct powder compression and simplifying the product manufacturing process.

[0047] 4. Reduced equipment requirements: Existing technology products have high equipment requirements in their manufacturing processes, requiring specialized rotary tablet presses for tableting. The composition formulation process of this invention can be completed using a conventional rotary tablet press. Detailed Implementation

[0048] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0049] Example 1 Sample Preparation

[0050] ① Preparation of the freeze-dried mixture using freeze-drying process: Weigh purified water and β-cyclodextrin at a ratio of 60:1, dissolve them, and then add the prescribed proportions of limaprost α-cyclodextrin inclusion complex and dextran 40, stirring to dissolve. Place the solution in a freeze dryer for freeze-drying. After freeze-drying, pulverize the freeze-dried material, sieve it (60-100 mesh), and collect the freeze-dried powder.

[0051] ② Mixing, tableting, and vacuum drying: The lyophilized powder is mixed with silica according to the formulation ratio. The mixture is then added in equal increments or gradually with fillers including α-cyclodextrin, β-cyclodextrin, dextrin, lactose, and pregelatinized starch, and disintegrants including croscarmellose sodium, croscarmellose, and carboxymethyl cellulose. Finally, magnesium stearate is added as a lubricant and mixed. Tableting is performed using a tableting machine (tablet weight 85mg–100mg; diameter 6.0mm). After tableting, vacuum drying is performed using a negative pressure dryer.

[0052] Example 2: Investigation of disintegrants

[0053] 2.1 Investigation of disintegrants in prescriptions 1-6

[0054] Table 1

[0055] 2.2 Results of stability study of formulations 1-6 samples at -30℃ / 75%RH - bare tablets

[0056] Table 2

[0057] Formulas 1-6 are products prepared using different types and proportions of disintegrants. The conventional formulation proportions of croscarmellose sodium, croscarmellose XL-10, and carboxymethyl cellulose as disintegrants are 2-5%, 1-5%, and 8-15%, respectively. To investigate the impact of different disintegrants at the same proportion on product quality, the effect of each disintegrant at an 8% proportion was uniformly examined. Unpackaged (naked tablets) products of Formulas 1-6 were placed at 30℃ / 75%RH for 7 and 15 days to examine the level of degradation impurity 11-deoxy-limaprost.

[0058] As shown in Table 2, the stability of products containing carboxymethyl cellulose disintegrants is significantly better than that of the other two disintegrants and the formulation without disintegrants. Other disintegrants will cause the product stability to deteriorate due to the capillary water absorption principle.

[0059] Example 3: Investigation of the filler

[0060] 3.1 Filler Evaluation (Comparative Example 1 and Formulations 7-16)

[0061] Table 3

[0062] As shown in Table 3, Comparative Example 1 is Example 4 of Patent Application 201280027255.6. Due to the high content of β-cyclodextrin, the material had poor flowability, making direct powder compression impossible during tableting. Furthermore, as tableting progressed, unclear lettering and sticking occurred. Dry granulation followed by tableting improved flowability, but the problem of unclear lettering persisted. The original patented technology used a special rotary tablet press equipped with an external lubrication device, spraying magnesium stearate lubricant into the press during the tableting process. The β-cyclodextrin content in the formulation was reduced to 10.1–25.5%, resulting in formulations 7–16. Formulations 7–8 were for dry granulation and tableting, while formulations 9–16 were for direct powder compression. The pregelatinized starch content was 7.2–67.2%, and the lactose content was 7.2–67.2%. During tableting, the material flowed well without sticking. Further stability studies were conducted on each formulation sample.

[0063] 3.2 Results of the filler stability study (Comparative Example 1 and Formulations 7-16)

[0064] Table 4

[0065] The stability study results of unpackaged (naked tablets) showed that, compared with control example 1, formulations 7 and 8 demonstrated that α-cyclodextrin and dextrin did not have the same effect as β-cyclodextrin in reducing the growth of 11-deoxy-limaprost impurities. Through formulation ratio adjustments, formulations 9–16 were optimized. Formulations 9–13 showed little difference in naked tablet stability compared to control example 1 at 30℃ / 75% RH (Formulation 9–13: 2.39–3.74; Control example 1: 2.80). Formulations 14, 15, and 16, using 52.2–67.2% pregelatinized starch as the main filler and combined with 10–25% β-cyclodextrin as an excipient, showed lower growth of 11-deoxy-limaprost impurities than control example 1 (Formulation 14: 1.83; Formulation 15: 1.89; Formulation 16: 1.86; Control example 1: 2.80).

[0066] In addition, Comparative Example 1 and Formulas 9, 10, 14, 15, and 16 were packaged in the same packaging form and materials and placed in an accelerated incubator at 40℃ / 75%RH to examine their accelerated stability.

[0067] As shown in Table 4, the accelerated stability of formulations 14, 15, and 16 under packaging conditions is superior to that of control example 1. (Formulation 14: 2.02; Formulation 15: 2.12; Formulation 16: 2.08; Control example 1: 2.23). Based on the above results, the accelerated stability of formulations 14, 15, and 16 of the present invention, both as bare tablets and in packaging, is superior to that of control example 1. 3.3 Accelerated stability study of formulation 14 and control example 2 under 40℃ / 75%RH conditions.

[0068] The growth of 11-deoxy-limaprost impurities was investigated under controlled ambient humidity (<10% RH, comparing control example 2 and formulation 14) at 40°C / 75% RH accelerated conditions. The results are shown in Table 5.

[0069] Table 5

[0070] The results showed that, under the same packaging conditions, the level of 11-deoxy-limaprost impurities in Formulation 14 was lower than that in Control Example 2 at all time points under accelerated conditions of 40℃ / 75%RH, indicating that the stability of Formulation 14 of the present invention was superior to that of Control Example 2.

[0071] Example 4: Dissolution Curve Study

[0072] (1) Dissolution studies were conducted in accordance with the second method (paddle method) of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia. The dissolution curves of Control Example 2 and Formula 14 were determined under pH 6.8 medium, pH 4.5 medium, pH 1.2 medium and water medium conditions, respectively. The paddle method was used with a medium volume of 500 ml, a medium temperature of 37 ± 0.5 ℃, and a sample size of 12 tablets. Samples were taken at 5, 10, 15, 30 and 45 minutes to test their dissolution and calculate the dissolution rate and RSD% value at each time point.

[0073] The results showed that this product is a rapid-release formulation, with a release rate of 85% at 15 min in all media. The study found that the dissolution data of Control Example 2 fluctuated greatly in the early stages in all media, with RSDs at 5 min and 10 min reaching 50.2–57.0% and 17.6–25.2%, respectively. In contrast, the dissolution data of Formulation 14 of this invention showed less fluctuation, with the RSD% at 5 min and 10 min decreasing to 11.9–15.9% and 3.6–6.1% under various media conditions, significantly lower than that of Control Example 2. This improved the large dissolution fluctuations, resulting in better dissolution stability and improved product quality and safety.

[0074] The specific dissolution RSD data results are shown in Table 6:

[0075] Table 6

[0076] Taking the main medium of this product at pH 6.8 as an example, the specific dissolution data are listed in Tables 7 and 8:

[0077] Table 7

[0078] Table 8

Claims

1. A pharmaceutical composition containing prostaglandins, characterized in that, The composition comprises limaprost α-cyclodextrin inclusion complex and β-cyclodextrin, wherein, based on the mass of the composition, The content of the lima prost α-cyclodextrin inclusion complex is 0.2%. The content of β-cyclodextrin is 10.1-25.5%, preferably 10.1-20%.

2. The pharmaceutical composition according to claim 1, characterized in that, The composition further includes a lyophilized support agent, wherein the content of the lyophilized support agent is 0.25-2.0% by weight of the composition, preferably 0.3-1.7%.

3. The pharmaceutical composition according to claim 1, characterized in that, The freeze-drying support includes dextran, sucrose, trehalose, lactose, mannitol or sorbitol, or a combination of two or more of them; preferably dextran.

4. The pharmaceutical composition according to claim 1, characterized in that, The composition further includes a disintegrant, wherein the content of the disintegrant is 5-30% by weight of the composition, preferably 10-30%, and more preferably 20%.

5. The pharmaceutical composition according to claim 4, characterized in that, The disintegrant is selected from croscarmellose sodium, croscarmellose, calcium carboxymethyl cellulose or carboxymethyl cellulose, or a combination of two or more of them, preferably carboxymethyl cellulose.

6. The pharmaceutical composition according to claim 1, characterized in that, The composition further includes a filler, wherein the filler content is 52.2% to 67.2% by weight of the composition.

7. The pharmaceutical composition according to claim 6, characterized in that, The filler is selected from microcrystalline cellulose, mannitol, starch, pregelatinized starch or lactose, or a combination of two or more of them, preferably pregelatinized starch, lactose or a combination of both.

8. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further includes a gliding agent, wherein the gliding agent content is 0.1-5.0% by weight of the composition, preferably 0.2-1.0%.

9. The pharmaceutical composition according to claim 8, characterized in that, The flow aid is selected from colloidal silica or talc or a combination thereof, preferably silica.

10. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further includes a lubricant, wherein the lubricant content is 0.5-2.0%, preferably 1.0-1.7%, based on the mass of the composition.

11. The pharmaceutical composition according to claim 10, characterized in that, The lubricant is selected from magnesium stearate or sodium dodecyl sulfate or a combination thereof, preferably magnesium stearate.

12. The pharmaceutical composition according to claim 1, characterized in that, The β-cyclodextrin is added in batches. The amount of β-cyclodextrin added to the freeze-dried powder is 0.1 to 0.5% of the tablet weight. The remaining β-cyclodextrin is added during the mixing process of the freeze-dried powder and the remaining excipients.

13. The pharmaceutical composition according to claim 1, characterized in that, The lima prostol α-cyclodextrin inclusion complex contains 3% lima prostol and 97% α-cyclodextrin by mass of the inclusion complex.

14. The pharmaceutical composition according to claim 1, characterized in that, The composition comprises: or 15. The pharmaceutical composition according to claims 1 to 14, characterized in that, The composition is a tablet.

16. A method for preparing the pharmaceutical composition of claim 15, characterized in that, The preparation of the tablet includes the following steps: (1) Freeze-drying process to prepare freeze-dried mixture: Mix purified water and β-cyclodextrin, dissolve them, add limaprost α-cyclodextrin inclusion complex and freeze-drying support, stir to dissolve, freeze-dry the solution, after freeze-drying, pulverize the freeze-dried material, sieve through 60-100 mesh, and collect the freeze-dried powder. (2) Mixing, tableting and vacuum drying: Mix the freeze-dried powder with silica, then mix the mixture with β-cyclodextrin, filler and disintegrant, and finally add magnesium stearate lubricant and mix. Then compress the mixture into tablets and vacuum dry to obtain the final product.

17. The preparation method according to claim 16, characterized in that, The β-cyclodextrin is added in two parts. One part is added in the freeze-drying process in the pre-process of step (1), accounting for 0.1 to 0.5% of the tablet weight. The remaining part is added in the mixing process in the post-process of step (2).

18. The preparation method according to claim 16, characterized in that, The dextran is added only during the preceding freeze-drying process, accounting for 0.25 to 2.0% of the tablet weight.

19. The preparation method according to claim 16, characterized in that, The β-cyclodextrin, filler, and disintegrant are mixed in equal increments or gradually.

20. The method according to claim 16, characterized in that, In step (1) of the method, the ratio of purified water to β-cyclodextrin is 60:

1.

21. The method according to claim 16, characterized in that, In step (1) of the method, the ratio of limaprost α-cyclodextrin inclusion complex to lyophilized support is 1:1 to 10, preferably 1:1.5 to 8.

22. The method according to claim 16, characterized in that, In step (2) of the method, the ratio of freeze-dried powder to silicon dioxide is 1:0.1 to 3, preferably 1:0.1 to 2.

23. The method according to claim 16, characterized in that, The method further includes: (1) Freeze-drying process to prepare freeze-dried mixture: Dissolve purified water and β-cyclodextrin in a ratio of 60:

1. After dissolving, add limaprost α-cyclodextrin inclusion complex and freeze-drying support agent in a ratio of 1:1.5 to 8. Stir to dissolve, put the solution into a freeze dryer for freeze-drying, after freeze-drying, pulverize the freeze-dried material, pass it through a 60-100 mesh sieve, and collect the freeze-dried powder; (2) Mixing, tableting and vacuum drying: Mix the freeze-dried powder with silica at a ratio of 1:0.1 to 2, then mix the mixture with β-cyclodextrin, filler and disintegrant in equal increments or by gradual mixing, and finally add lubricant and mix. Use a tablet press to compress the tablets, and then use a negative pressure dryer for vacuum drying.

24. The method according to claim 23, characterized in that, The freeze-drying support agent in step (1) of the method is dextran 40.

25. The method according to claim 23, characterized in that, The filler in step (2) of the method includes α-cyclodextrin, β-cyclodextrin, dextrin, lactose or pregelatinized starch, or a combination of two or more of them.

26. The method according to claim 23, characterized in that, The disintegrant in step (2) of the method includes croscarmellose sodium, croscarmellose polyvinyl ketone, or carboxymethyl cellulose, or a combination of two or more of them.

27. The method according to claim 23, characterized in that, In step (2) of the method, the lubricant is magnesium stearate.

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