Cilostazol controlled release preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a cilostazol controlled-release preparation and a preparation method thereof. The preparation is based on a composite carrier composed of mesoporous silica and low-substituted hydroxy propyl cellulose, the cilostazol is highly dispersed in the composite carrier in an amorphous state through combination of ball milling pretreatment and a high-temperature fluidized bed melt dispersion process, and a final tablet is obtained through tabletting by adopting a step-by-step design of internally and externally adding a disintegrating agent. The dissolution rate of the cilostazol preparation prepared by the invention is greater than or equal to 80% within 15 minutes and greater than or equal to 95% within 30 minutes, so that rapid and stable drug release is realized, and the risk of burst release of the drug and adverse reaction caused by fluctuation of blood concentration are effectively reduced; and the preparation shows excellent stability, and an acceleration test (6 months) result shows that the increase of related substances of the preparation is less than or equal to 0.5%, the change rate of the dissolution rate is less than or equal to 3%, and the consistency and reliability of the curative effect in the clinical medication process can be effectively guaranteed.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a controlled-release formulation of cilostazol and its preparation method. Background Technology

[0002] Cilostazol, a quinolinone derivative, belongs to the phosphodiesterase-III (PDE-III) inhibitor class. Its mechanism of action involves increasing platelet and intravascular cyclic adenosine monophosphate (cAMP) levels, thereby inhibiting platelet aggregation, dilating peripheral blood vessels, and suppressing vascular smooth muscle cell proliferation. Clinically, this drug is primarily used to treat intermittent claudication caused by chronic arterial occlusive disease, and it also has important applications in preventing recurrent cerebral infarction and restenosis after coronary stent implantation.

[0003] However, existing cilostazol formulations have significant pharmaceutical defects that seriously affect their clinical efficacy and patient compliance. Cilostazol has poor water solubility, belongs to BCS Class II drugs, and its oral bioavailability is significantly limited. The dissolution rate of ordinary tablets is low, making it difficult to fully exert its therapeutic effect. Its immediate-release formulation is prone to large fluctuations in blood drug concentration peaks and troughs, which can lead to adverse reactions such as headache and palpitations, affecting medication safety. At the same time, conventional formulations require twice-daily dosing (100 mg each time), which is a high dosing frequency and is not conducive to long-term patient compliance.

[0004] To address the above problems, several solutions have been disclosed in the existing technology. (1) Micronization technology: By controlling the particle size D90≤40μm, the drug dissolution rate can be improved. However, it requires high precision of the pulverizing equipment, and the drug particles are prone to aggregation during long-term storage, which leads to a decrease in the stability of the formulation. (2) Rapid disintegration technology: Micronized silica gel is used as a disintegrating agent. Combined with cross-linked PVP / CMC-Na internal and external disintegrating agent method, the disintegration time of the tablet is shortened to less than 3 minutes. However, this technology has the risk of drug burst release and does not solve the core problem of excessive fluctuation in blood drug concentration. (3) Solid dispersion technology: It can significantly improve the dissolution efficiency (dissolution rate ≥90% within 15 minutes), but it fails to solve the problem of peak and valley fluctuations in blood drug concentration caused by rapid release, and the risk of related adverse reactions still exists. (4) Bilayer sustained-release tablet technology: By combining the rapid-release layer containing hydrophilic amino acids with the shellac-ethyl cellulose sustained-release layer, 24-hour sustained release can be achieved. However, the process is complicated, requires special equipment, and the alkaline amino acid environment may accelerate drug degradation. (5) Matrix sustained-release tablet technology: Ethylene-vinyl acetate copolymer (EVA) and artemisinin are used to construct a sustained-release matrix. However, EVA often requires the use of organic solvents, which poses a risk of solvent residue and affects clinical safety.

[0005] In summary, developing a controlled-release formulation of cilostazol that can improve dissolution while achieving stable release, minimal side effects, simple processing, and high safety has become a pressing technical problem to be solved in this field. Summary of the Invention

[0006] To address the problems of poor dissolution, large fluctuations in blood drug concentration, significant side effects, and high dosing frequency in existing cilostazol formulations, this invention provides a controlled-release cilostazol formulation and its preparation method.

[0007] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: In a first aspect, the present invention provides a cilostazol controlled-release formulation comprising the following components in parts by weight: a head comprising cilostazol-carrier complex particles, an external disintegrant, and a lubricant; The cilostazol-carrier complex particles include cilostazol, a composite porous carrier, an internally added disintegrant, and a binder, wherein the composite porous carrier includes mesoporous silica and low-substituted hydroxypropyl cellulose. The cilostazol is dispersed in the composite porous carrier in an amorphous form.

[0008] Compared to existing technologies, the cilostazol controlled-release formulation provided by this invention uses mesoporous silica (MSN) and low-substituted hydroxypropyl cellulose (L-HPC) as a composite carrier, achieving both improved dissolution rate and stable release. Mesoporous silica possesses a large specific surface area, a regular pore structure, and excellent adsorption properties, allowing cilostazol to be uniformly loaded into the pores, significantly increasing the contact area between the drug and the dissolution medium, thereby increasing the drug's water solubility and dissolution efficiency, fundamentally improving its poor water solubility. Low-substituted hydroxypropyl cellulose combines hydrophilicity, a certain degree of viscosity, and rapid swelling upon contact with water. Its hydrophilicity and rapid swelling properties facilitate water penetration into the depths of the MSN pores, promoting drug release. Its own viscosity and synergy with MSN enhance the system's adsorption and retention capacity for the drug, improving the formulation's physical stability. More importantly, the bonding network it forms provides a structural basis for controlling the drug release rate.

[0009] Internally added disintegrants are embedded within the drug-loaded composite particles, promoting moderate particle disintegration during the initial dissolution phase to ensure rapid drug release and avoid the slow onset of action common in conventional sustained-release formulations. Simultaneously, their release is constrained by the porous, binding framework structure formed by L-HPC, effectively slowing the overall drug diffusion rate and preventing the sudden release and drastic fluctuations in blood drug concentrations common in immediate-release formulations. Externally added disintegrants act on the entire formulation, ensuring uniform disintegration and allowing the internally loaded drug particles to remain continuously and stably exposed to the release medium, further maintaining stable blood drug concentrations.

[0010] As a specific embodiment of the present invention, the cilostazol controlled-release formulation comprises the following components in parts by weight: 50 parts of cilostazol, 30 to 60 parts of composite porous carrier, 2 to 9 parts of internal disintegrant, 3 to 6 parts of external disintegrant, 1 to 5 parts of binder, 0.5 to 2 parts of lubricant, and 20 to 40 parts of filler.

[0011] Furthermore, the mesoporous silica has a pore size of 2nm~10nm and a specific surface area of ​​800m². 2 / g~1200m 2 / g.

[0012] The optimized pore size range ensures efficient drug loading into the pores while also leveraging the nanoscale spatial confinement to stabilize the drug and improve its storage stability. A larger specific surface area provides more dispersion interfaces for the drug, which is beneficial for improving its water solubility and dissolution efficiency.

[0013] Furthermore, the degree of substitution of the low-substituted hydroxypropyl cellulose is 0.10~0.13, and the swelling volume is 5.5mL / g~8.5mL / g.

[0014] This degree of substitution gives it a moderate balance of hydrophilicity, viscosity, and water-induced swelling capacity: it can effectively bind drug-loaded mesoporous silica particles through viscosity to form a stable porous framework structure; and during dissolution, it can promote the penetration of the medium into the interior of the framework and deep into the mesopores through moderate and continuous swelling, assisting drug release, while avoiding premature disintegration of the framework or sudden drug release due to excessive swelling.

[0015] Furthermore, the mass ratio of the mesoporous silica to the low-substituted hydroxypropyl cellulose is 1:(2~4).

[0016] This ratio ensures sufficient low-substituted hydroxypropyl cellulose as a binding matrix to form a stable, porous overall framework, while avoiding over-encapsulation that would block the active surface of the mesoporous silica.

[0017] Furthermore, both the internally added disintegrant and the externally added disintegrant are croscarmellose sodium.

[0018] The strong water absorption and swelling properties of cross-linked sodium carboxymethyl cellulose can effectively promote the rapid penetration of water into the porous framework formed by low-substituted hydroxypropyl cellulose, accelerating the dissolution of drugs from mesoporous silica. However, because it is insoluble in water and only swells, it does not cause premature disintegration of the framework structure. Thus, while promoting disintegration, it can still maintain the regulatory effect of the framework on drug release.

[0019] Furthermore, the adhesive is hydroxypropyl cellulose.

[0020] Hydroxypropyl cellulose has good compatibility with the low-substituted hydroxypropyl cellulose in the composite porous carrier, which allows the binder solution to uniformly wet and encapsulate the drug-carrier complex, forming wet particles with certain mechanical strength and ensuring the smooth progress of the granulation process.

[0021] Furthermore, the lubricant is sodium fumarate stearate.

[0022] The preferred lubricant can improve the flowability in tablet production, and in addition, it can improve the hardness and smoothness of the prepared tablets.

[0023] Furthermore, the filler is a microcrystalline cellulose-lactose complex.

[0024] Furthermore, the mass ratio of microcrystalline cellulose to lactose in the filler is 1:(0.8~1.2).

[0025] The selected filler can improve the flowability and compressibility of the material, making the tableting process smoother and reducing tablet weight variation.

[0026] Secondly, the present invention also provides a method for preparing a cilostazol controlled-release formulation, comprising the following steps: S1, Cilostazol and composite porous carrier are mixed and ball-milled, internal disintegrant and filler are added, mixed evenly, and binder aqueous solution is added to make soft material and granulated to obtain wet granules; S2, the wet particles are subjected to phase change treatment in a fluidized bed to melt cilostazol, and then dried to obtain cilostazol-carrier complex particles. S3, mix the cilostazol-carrier complex particles, external disintegrant and lubricant evenly, compress into tablets to obtain cilostazol controlled-release formulation.

[0027] Compared with the prior art, the preparation method of cilostazol controlled-release formulation provided by the present invention firstly mixes and grinds cilostazol and composite porous carrier to break the initial crystalline aggregate state of the drug. Then, it is mixed with an internally added disintegrant, filler and binder solution and granulated. After granulation, it is subjected to phase change treatment in a fluidized bed, so that cilostazol melts and rapidly penetrates into the MSN pores and adsorbs onto the surface. After cooling, a stable amorphous loading is formed. At the same time, low-substituted hydroxypropyl cellulose binds the drug-loaded MSN to form a porous network structure, forming cilostazol-carrier complex particles. Finally, it is mixed with an externally added disintegrant and lubricant and directly compressed into tablets to obtain the cilostazol controlled-release formulation.

[0028] The cilostazol controlled-release formulation prepared by the above process has the characteristics of high dissolution and stable release, which is conducive to fully exerting the efficacy of cilostazol and reducing adverse reactions such as headache and palpitations caused by sudden drug release and excessive fluctuations in blood drug concentration. It has high clinical application value and industrialization prospects.

[0029] Furthermore, in S1, the rotation speed of the mixing ball mill is 300 rpm to 500 rpm, and the milling time is 30 min to 40 min.

[0030] Furthermore, in S1, the ball milling is carried out at room temperature, the grinding media is zirconia balls, and the ball-to-material ratio is (4~6):1.

[0031] Furthermore, in S1, the mass concentration of the adhesive aqueous solution is 3% to 8%.

[0032] Furthermore, in S1, granulation is performed using an 18-mesh sieve.

[0033] Furthermore, in S2, the phase change treatment temperature is 160℃~165℃, and the treatment time is 10min~15min.

[0034] Furthermore, in S2, the drying is carried out using fluidized bed drying at a temperature of 40℃~50℃ until the moisture content is ≤3%.

[0035] Furthermore, in S3, the tablet hardness is controlled to be 4kg~6kg.

[0036] It should be noted that the present invention can use any type of tablet press to directly compress the mixed materials to obtain tablets, and the specific parameters of the compression process can be conventionally adjusted by those skilled in the art.

[0037] In summary, this invention provides a controlled-release formulation of cilostazol and its preparation method. The formulation is based on a composite carrier composed of mesoporous silica and low-substituted hydroxypropyl cellulose. Through ball milling pretreatment combined with a high-temperature fluidized bed melt dispersion process, cilostazol is highly dispersed in an amorphous form within the composite carrier. A stepwise design involving the addition of internal and external disintegrants is employed, followed by tableting to obtain the final tablets. The cilostazol formulation prepared by this invention exhibits a dissolution rate ≥80% within 15 minutes and ≥95% within 30 minutes, achieving rapid and stable drug release, effectively reducing the risk of drug burst release and adverse reactions caused by fluctuations in blood drug concentration. Furthermore, the formulation demonstrates excellent stability; accelerated testing (6 months) results show that the increase in related substances is ≤0.5%, and the dissolution rate change is ≤3%. This invention provides a novel oral controlled-release dosage form of cilostazol with controllable dissolution rate and stable quality, showing promising application prospects in improving clinical efficacy and medication safety. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0039] To better illustrate the present invention, further examples are provided below.

[0040] The mesoporous silica used in the following examples and comparative examples has a pore size of 2nm~10nm and a specific surface area of ​​800m². 2 / g~1200m 2 / g; the degree of substitution of the low-substituted hydroxypropyl cellulose used is 0.10~0.13, and the swelling volume is 5.5mL / g~8.5mL / g.

[0041] Example 1 This embodiment provides a cilostazol controlled-release formulation, with the following prescription dosage: Cilostazol 500g, composite porous carrier (MSN:L-HPC=1:3) 450g, cross-linked sodium carboxymethyl cellulose 100 parts, hydroxypropyl methylcellulose 30 parts, sodium stearate fumarate 10 parts, microcrystalline cellulose-lactose complex (1:1) 300 parts.

[0042] The preparation method of the above-mentioned cilostazol controlled-release formulation is as follows: S1, weigh out the prescribed amount of cilostazol and the composite porous carrier, mix them, place them in a planetary ball mill, use zirconia balls as the ball milling medium, the ball-to-material ratio is 5:1, ball mill at 400 rpm for 35 min, the grinding temperature is ≤25℃, and the grinding complex is obtained. S2, the grinding complex is mixed with 50% of the total amount of cross-linked carboxymethyl cellulose sodium and the prescribed amount of microcrystalline cellulose-lactose complex, and then 5% of the mass concentration of hydroxypropyl methylcellulose aqueous solution is added to make a soft material, which is granulated through an 18-mesh sieve to obtain wet granules. S3. Place the above wet granules in a fluidized bed and heat-treat at 160℃ for 10 min, controlling the inlet air humidity to ≤50%. Then dry them in a fluidized bed at 45℃ until the moisture content is ≤3%. Add the remaining cross-linked sodium carboxymethyl cellulose and sodium stearate fumarate, mix for 8 min, compress into tablets, and control the tablet hardness to 4 kg~6 kg to obtain the cilostazol controlled-release formulation.

[0043] Example 2 This embodiment provides a cilostazol controlled-release formulation, with the following prescription dosage: Cilostazol 500g, composite porous carrier (MSN:L-HPC=1:2) 300g, cross-linked sodium carboxymethyl cellulose 50 parts, hydroxypropyl methylcellulose 10 parts, sodium stearate fumarate 5 parts, microcrystalline cellulose-lactose complex (1:1) 200 parts.

[0044] The preparation method of the above-mentioned cilostazol controlled-release formulation is as follows: S1, weigh out the prescribed amount of cilostazol and the composite porous carrier, mix them, place them in a planetary ball mill, use zirconia balls as the ball milling medium, the ball-to-material ratio is 5:1, ball mill at 300 rpm for 40 min, the grinding temperature is ≤25℃, and the grinding complex is obtained. S2, the grinding complex is mixed with 40% of the total amount of crosslinked carboxymethyl cellulose sodium and the prescribed amount of microcrystalline cellulose-lactose complex, and then 3% of the mass concentration of hydroxypropyl methylcellulose aqueous solution is added to make a soft material, which is granulated through an 18-mesh sieve to obtain wet granules. S3. Place the above wet granules in a fluidized bed and heat-treat at 165℃ for 10 min, controlling the inlet air humidity to ≤50%. Then dry them in a fluidized bed at 50℃ until the moisture content is ≤3%. Add the remaining cross-linked sodium carboxymethyl cellulose and sodium stearate fumarate, mix for 5 min, and compress into tablets. Control the tablet hardness to 4 kg~6 kg to obtain the cilostazol controlled-release formulation.

[0045] Example 3 This embodiment provides a cilostazol controlled-release formulation, with the following prescription dosage: Cilostazol 500g, composite porous carrier (MSN:L-HPC=1:4) 600g, cross-linked sodium carboxymethyl cellulose 150 parts, hydroxypropyl methylcellulose 50 parts, sodium stearate fumarate 20 parts, microcrystalline cellulose-lactose complex (1:1) 400 parts.

[0046] The preparation method of the above-mentioned cilostazol controlled-release formulation is as follows: S1, weigh out the prescribed amount of cilostazol and the composite porous carrier, mix them, place them in a planetary ball mill, use zirconia balls as the ball milling medium, the ball-to-material ratio is 5:1, and ball mill at 500 rpm for 30 min, with a grinding temperature ≤25℃, to obtain the grinding composite. S2, the grinding complex is mixed with 60% of the total amount of crosslinked carboxymethyl cellulose sodium and the prescribed amount of microcrystalline cellulose-lactose complex, and then 8% of the mass concentration of hydroxypropyl methylcellulose aqueous solution is added to make a soft material, which is granulated through an 18-mesh sieve to obtain wet granules. S3. Place the above wet granules in a fluidized bed and heat-treat at 162℃ for 12 minutes, controlling the inlet air humidity to ≤50%. Then dry them in a fluidized bed at 40℃ until the moisture content is ≤3%. Add the remaining cross-linked sodium carboxymethyl cellulose and sodium stearate fumarate, mix for 10 minutes, and compress into tablets. Control the tablet hardness at 4kg~6kg to obtain the cilostazol controlled-release formulation.

[0047] Comparative Example 1 Cilostazol tablets were prepared according to Example 1 in CN113768889B.

[0048] Comparative Example 2 Cilostazol bilayer sustained-release tablets were prepared according to Example 1 in CN114533690B.

[0049] Comparative Example 3 Cilostazol tablets were prepared according to Example 1 in CN1241566C.

[0050] Comparative Example 4 This comparative example provides a cilostazol tablet, which differs from Example 1 only in that the composite porous carrier is replaced with an equal amount of colloidal silica; otherwise, the contents are identical. The specific formulation and dosage are as follows: Cilostazol 500g, colloidal silica 450g, croscarmellose sodium 100 parts, hydroxypropyl methylcellulose 30 parts, sodium stearate fumarate 10 parts, microcrystalline cellulose-lactose complex (1:1) 300 parts.

[0051] Cilostazol tablets were prepared using the same method as in Example 1, which will not be repeated here.

[0052] Comparative Example 5 This comparative example provides a cilostazol tablet, which differs from Example 1 only in that the composite porous carrier is replaced with an equal amount of β-cyclodextrin; otherwise, the contents are identical. The specific formulation and dosage are as follows: Cilostazol 500g, β-cyclodextrin 450g, croscarmellose sodium 100 parts, hydroxypropyl methylcellulose 30 parts, sodium stearate fumarate 10 parts, microcrystalline cellulose-lactose complex (1:1) 300 parts.

[0053] Cilostazol tablets were prepared using the same method as in Example 1, which will not be repeated here.

[0054] Comparative Example 6 This comparative example provides a cilostazol tablet, which differs from Example 1 only in that the mesoporous silica composite carrier is replaced with an equal amount of micronized silica gel; otherwise, the contents are identical. The specific formulation and dosage are as follows: Cilostazol 500g, composite porous carrier (micronized silica gel: L-HPC=1:3) 450g, cross-linked sodium carboxymethyl cellulose 100 parts, hydroxypropyl methylcellulose 30 parts, sodium stearate fumarate 10 parts, microcrystalline cellulose-lactose complex (1:1) 300 parts.

[0055] Cilostazol tablets were prepared using the same method as in Example 1, which will not be repeated here.

[0056] Comparative Example 7 This comparative example provides a cilostazol tablet, which differs from Example 1 only in that the low-substituted hydroxypropyl cellulose in the composite porous carrier is replaced with an equal amount of croscarmellose sodium; otherwise, the contents are identical. The specific formulation and dosage are as follows: Cilostazol 500g, composite porous carrier (MSN: cross-linked sodium carboxymethyl cellulose = 1:3) 450g, cross-linked sodium carboxymethyl cellulose 100 parts, hydroxypropyl methylcellulose 30 parts, sodium stearate fumarate 10 parts, microcrystalline cellulose-lactose complex (1:1) 300 parts.

[0057] Cilostazol tablets were prepared using the same method as in Example 1, which will not be repeated here.

[0058] Comparative Example 8 This comparative example provides a cilostazol tablet with the exact same formulation as Example 1. The only difference between the two examples is the absence of phase change heat treatment; the rest is identical. The specific steps are as follows: S1, weigh out the prescribed amount of cilostazol and the composite porous carrier, mix them, place them in a planetary ball mill, use zirconia balls as the ball milling medium, the ball-to-material ratio is 5:1, ball mill at 400 rpm for 35 min, the grinding temperature is ≤25℃, and the grinding complex is obtained. S2, the grinding complex is mixed with 50% of the total amount of cross-linked carboxymethyl cellulose sodium and the prescribed amount of microcrystalline cellulose-lactose complex, and then 5% of the mass concentration of hydroxypropyl methylcellulose aqueous solution is added to make a soft material, which is granulated through an 18-mesh sieve to obtain wet granules. S3, the above wet granules are dried in a fluidized bed at 45°C until the moisture content is ≤3%, the remaining cross-linked sodium carboxymethyl cellulose and sodium stearate fumarate are added, mixed for 8 minutes, and tableted. The tablet hardness is controlled at 4kg~6kg to obtain cilostazol tablets.

[0059] Dissolution curve determination Take 12 tablets of cilostazol tablets prepared in Examples 1-3 and Comparative Examples 1-8, as well as commercially available cilostazol tablets (Zhejiang Otsuka Pharmaceutical Co., Ltd. 221203P), and dissolve them according to the method (Chinese Pharmacopoeia 2020 Edition Appendix XC Method II), using 500 mL of 0.3 wt% sodium dodecyl sulfate solution as solvent and rotating at 50 rpm. Take samples at 5 min, 10 min, 15 min and 30 min respectively, filter them, and take the filtrate as the test solution.

[0060] Take approximately 25 mg of cilostazol reference standard that has been dried at 105℃ for 2 h, place it in a 250 mL volumetric flask, add 10 mL of methanol, sonicate for 15 min to dissolve, dilute to the mark with 0.3 wt% sodium dodecyl sulfate solution, shake well, filter, and take the filtrate as the reference solution.

[0061] Accurately measure 3 mL of each of the above solutions and place them in separate 25 mL volumetric flasks. Dilute with water to the mark, shake well, and measure the absorbance at a wavelength of 257 nm using spectrophotometry (Appendix IV, Part II of the Chinese Pharmacopoeia 2000). Calculate the dissolution rate of each tablet and take the average value. The results are shown in Table 1.

[0062] Table 1 Dissolution rate (%) at different time points

[0063] 2. Stability Test The cilostazol tablets prepared in Example 1 of this invention were placed at 40°C and 75%RH for 6 months, and samples were taken at 0, 1, 3, and 6 months respectively. The content and dissolution curves of related substances in each sample were determined. The results are shown in Table 2.

[0064] Table 2 Stability Test Results

[0065] The results of the accelerated test (6 months) showed that the growth of formulation-related substances was ≤0.5% and the dissolution rate was ≤3%, indicating that the cilostazol tablets prepared in the embodiments of the present invention have good long-term stability and can effectively ensure the consistency and reliability of efficacy in clinical use.

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A controlled-release formulation of cilostazol, characterized in that, Includes cilostazol-carrier complex particles, external disintegrants, and lubricants; The cilostazol-carrier complex particles include cilostazol, a composite porous carrier, an internally added disintegrant, and a binder, wherein the composite porous carrier includes mesoporous silica and low-substituted hydroxypropyl cellulose. The cilostazol is dispersed in the composite porous carrier in an amorphous form.

2. The cilostazol controlled-release formulation as described in claim 1, comprising the following components in parts by weight: 50 parts cilostazol, 30 to 60 parts composite porous carrier, 2 to 9 parts internal disintegrant, 3 to 6 parts external disintegrant, 1 to 5 parts binder, 0.5 to 2 parts lubricant, and 20 to 40 parts filler.

3. The cilostazol controlled-release formulation as described in claim 1 or 2, characterized in that, The mesoporous silica has a pore size of 2nm~10nm and a specific surface area of ​​800m². 2 / g~1200m 2 / g; and / or The degree of substitution of the low-substituted hydroxypropyl cellulose is 0.10~0.13, and the swelling volume is 5.5mL / g~8.5mL / g; and / or The mass ratio of mesoporous silica to low-substituted hydroxypropyl cellulose is 1:(2~4).

4. The cilostazol controlled-release formulation as described in claim 1 or 2, characterized in that, Both the internally added disintegrant and the externally added disintegrant are croscarmellose sodium cellulose; and / or The adhesive is hydroxypropyl cellulose.

5. The cilostazol controlled-release formulation as described in claim 1 or 2, characterized in that, The lubricant is sodium fumarate stearate.

6. The cilostazol controlled-release formulation as described in claim 1 or 2, characterized in that, The filler is a microcrystalline cellulose-lactose complex.

7. The cilostazol controlled-release formulation as described in claim 6, characterized in that, The mass ratio of microcrystalline cellulose to lactose in the filler is 1:(0.8~1.2).

8. The method for preparing the cilostazol controlled-release formulation according to any one of claims 1 to 7, characterized in that, Includes the following steps: S1, Cilostazol and composite porous carrier are mixed and ball-milled, internal disintegrant and filler are added, mixed evenly, and binder aqueous solution is added to make soft material and granulated to obtain wet granules; S2, the wet particles are subjected to phase change treatment in a fluidized bed to melt cilostazol, and then dried to obtain cilostazol-carrier complex particles. S3, mix the cilostazol-carrier complex particles, external disintegrant and lubricant evenly, compress into tablets to obtain cilostazol controlled-release formulation.

9. The method for preparing the cilostazol controlled-release formulation as described in claim 8, characterized in that, In S1, the mixing ball mill rotates at a speed of 300 rpm to 500 rpm, and the milling time is 30 min to 40 min; and / or In S1, the mass concentration of the adhesive aqueous solution is 3% to 8%.

10. The method for preparing the cilostazol controlled-release formulation as described in claim 8, characterized in that, In S2, the phase change treatment temperature is 160℃~165℃, and the treatment time is 10min~15min; In S2, the drying process employs fluidized bed drying at a temperature of 40℃~50℃ until the moisture content is ≤3%; and / or In S3, the tablet hardness is controlled at 4kg~6kg.

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