Ziprasidone sustained-release granule, ziprasidone controlled-release tablet and preparation method

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to ziprasidone sustained-release granules, ziprasidone controlled-release tablets and a preparation method. The invention aims to solve the problem of incomplete filling during sustained-release particle tabletting. The first aspect of the invention is to provide a ziprasidone sustained-release particle, and in the ziprasidone sustained-release particle, the proportion of particles with the particle size greater than 250 [mu] m is less than 30% by weight. The second aspect of the invention is to provide a method for preparing the ziprasidone sustained-release granule. The third aspect is to provide a ziprasidone controlled release tablet comprising the ziprasidone sustained release particle. The fourth aspect is to provide a method for preparing the ziprasidone controlled release tablet.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more specifically, to ziprasidone sustained-release granules, ziprasidone controlled-release tablets and a preparation method thereof. Background Art

[0002] Ziprasidone is an atypical antipsychotic drug with good efficacy. It can be used as an intramuscular injection in emergency situations, and oral capsules are often used for long-term treatment. The specifications are 20mg, 40mg, 60mg and 80mg, generally taken twice a day with food. Ziprasidone is currently the only atypical antipsychotic drug that has an inhibitory effect on the reuptake of norepinephrine and 5-HT, and it has a good efficacy. At present, most ziprasidone preparations use a single release method, which results in a slow onset of effect after taking the drug and insufficient bioavailability. For example:

[0003] Chinese patent document CN107714669A discloses a ziprasidone sustained-release agent and a preparation method thereof, which is prepared by a solid dispersion process and has the problem of complex process.

[0004] Chinese patent document CN1874761A discloses a sustained-release dosage form of rasidone, and the sample is prepared using an organic solvent, which is costly and has certain safety risks during drying.

[0005] Chinese patent document CN108078934A discloses a ziprasidone hydrochloride solid dispersible tablet and a hot-melt extrusion method thereof, which also has only one drug release form, and the hot-melt extrusion process is complicated, which is not conducive to cost control and quality control.

[0006] It can be seen that the existing preparations of ziprasidone have a relatively single release mode, which is not conducive to improving bioavailability and is not conducive to patients' medication compliance. However, if ziprasidone preparations with multiple release modes are to be constructed, there are many challenges in the stability of the preparations and the preparation process. Summary of the invention

[0007] The present invention aims to overcome at least one defect of the above-mentioned prior art and provides a ziprasidone sustained-release granule, a ziprasidone controlled-release tablet and a preparation method thereof.

[0008] The first aspect of the present invention is to provide ziprasidone sustained-release particles, in which particles with a particle size greater than 250 μm account for less than 30% by weight.

[0009] Preferably, the particle size distribution of the ziprasidone sustained-release particles is as follows: by weight percentage, particles with a size of >250 μm account for less than 30%, particles with a size of 125-250 μm account for less than 30%, and particles with a size of <125 μm account for more than 50%.

[0010] More preferably, the particle size distribution of the ziprasidone sustained-release particles is as follows: by weight percentage, particles with a size of >250 μm account for 15-30%, particles with a size of 125-250 μm account for 20-30%, and particles with a size of <125 μm account for 50%-60%.

[0011] The present invention shows that when the ziprasidone sustained-release granules adopt the above-mentioned particle size, suitable fluidity can be obtained after granulation, and the tablets are completely filled, and the overall stability of the prepared preparation is good, which is helpful to obtain a ziprasidone preparation with good stability and drug release performance that meets the requirements of controlled release, so as to achieve the purpose of rapid onset and prolonged drug efficacy for patients, and improve patient compliance with medication.

[0012] In some embodiments, the ziprasidone sustained-release granules include a first ziprasidone, a first filler, a first glidant, a first lubricant, and a sustained-release polymer.

[0013] In some embodiments, the weight ratio of the sustained-release polymer in the ziprasidone sustained-release granules is 25-45%.

[0014] Studies have shown that the use of sustained-release polymers in this weight ratio can enable ziprasidone to be released continuously and smoothly for 24 hours, with a higher dissolution rate, significantly improving bioavailability.

[0015] In some embodiments, the sustained-release polymer is any one or more combinations of methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), and hydroxypropyl cellulose (HPC), and is particularly a combination of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC).

[0016] Studies have shown that the use of celluloses such as HPMC and HPC as sustained-release polymers can maintain stable and sustained release for 24 hours, prolong the treatment time for patients, and reduce the number of times patients take medicine. The research of the present invention also shows that when natural gums are used as sustained-release polymers, it will be difficult to release ziprasidone. Therefore, the sustained-release polymer of the present invention cannot contain natural gum components, such as sodium alginate, agar, xanthan gum, tragacanth gum, locust bean gum, etc.

[0017] In some embodiments, the ziprasidone sustained-release granules include the following components in parts by weight:

[0018] 8-12 parts of first ziprasidone;

[0019] 40-60 parts of the first filler;

[0020] 0.5-5 parts of a first glidant;

[0021] 0.5-5 parts of the first lubricant;

[0022] 25-45 parts of sustained release polymer.

[0023] The second object of the present invention is to provide a method for preparing ziprasidone sustained-release particles. During the preparation process, the sustained-release polymer includes an internally added sustained-release polymer and an externally added sustained-release polymer. The preparation method comprises:

[0024] Weighing the first ziprasidone, the internally added sustained-release polymer, and the first filler together for wet granulation, and then drying them in sequence to obtain dry granules;

[0025] Weigh the externally added sustained-release polymer, the first glidant and the dry whole granules, sieve and mix together;

[0026] The first lubricant in a prescribed amount is weighed and sieved and mixed with a preset amount of premixed particles to obtain ziprasidone sustained-release particles.

[0027] In the present invention, the sustained-release polymer is partially added internally and partially added externally, so that the ziprasidone sustained-release granules can be completely filled after tableting. In addition, no organic solvent granulation is required during the preparation process, and only water is used as a granulating agent, thereby reducing the preparation cost and drying risk.

[0028] In some embodiments, the weight ratio of the internally added sustained-release polymer to the externally added sustained-release polymer is 1:15-1:1.

[0029] The present invention shows that when the weight ratio of the internally added sustained-release polymer to the externally added sustained-release polymer is less than 1:15, the difference in the proportion of ziprasidone sustained-release particles with a particle size of 125-250 μm exceeds 30%, and the proportion of ziprasidone sustained-release particles with a particle size of less than 125 μm is less than 50%, which leads to insufficient filling of the ziprasidone sustained-release particles during tableting, which causes the stability and dissolution performance of the preparation to fail to meet the requirements; when the weight ratio of the internally added sustained-release polymer to the externally added sustained-release polymer is greater than 1:1, the difference in the proportion of ziprasidone sustained-release particles with a particle size of more than 250 μm exceeds 30%, the difference in the proportion of ziprasidone sustained-release particles with a particle size of 125-250 μm also exceeds 30%, and the proportion of ziprasidone sustained-release particles with a particle size of less than 125 μm is less than 50%, thus causing the Hausner If the Ratio value is too large, the fluidity will increase, which will also lead to insufficient filling of the ziprasidone sustained-release granules during tableting, thereby causing the stability and dissolution performance of the preparation to fail to meet the requirements.

[0030] The third aspect of the present invention provides a ziprasidone controlled-release tablet, comprising a ziprasidone immediate-release layer and a ziprasidone sustained-release layer, wherein the ziprasidone immediate-release layer is made of ziprasidone immediate-release granules, and the ziprasidone sustained-release layer is made of the ziprasidone sustained-release granules according to any one of claims 1 to 6.

[0031] The ziprasidone controlled-release tablet of the present invention can provide a suitable drug release rate, thereby meeting the purpose of rapid onset of effect and long-term treatment for patients, and the preparation has good stability and a simple preparation process.

[0032] In some embodiments, the ziprasidone sustained-release granules include a first ziprasidone and a sustained-release excipient, the ziprasidone immediate-release granules include a second ziprasidone and an immediate-release excipient, and the weight ratio of the second ziprasidone to the first ziprasidone is (12.5-37.5):(62.5-87.5).

[0033] The present invention shows that the weight ratio of the second ziprasidone to the first ziprasidone can make the dissolution of the ziprasidone in the immediate release portion meet the needs of rapid effect on patients, and at the same time, the dissolution of the ziprasidone in the sustained release portion is sufficient to ensure continuous effect on patients within 24 hours.

[0034] In some embodiments, the particle size D90 of the second ziprasidone is 15 μm to 70 μm.

[0035] The research of the present invention shows that when the second ziprasidone adopts the particle size range, the ziprasidone immediate-release layer can obtain suitable fluidity after granulation, and the ziprasidone immediate-release layer is fully dissolved within 2 hours, thereby improving bioavailability. At the same time, the release rate is appropriate, which can meet the requirement of rapid onset of effect on patients without causing safety hazards due to excessive release.

[0036] In some embodiments, the immediate-release excipients include a second filler, a second glidant, a second lubricant, and a disintegrant.

[0037] In some embodiments, the ziprasidone immediate-release granules include the following components in parts by weight:

[0038] 5-15 parts of second ziprasidone;

[0039] 65-85 parts of a second filler;

[0040] 0.5-5 parts of a second glidant;

[0041] 0.5-5 parts of a second lubricant;

[0042] 2-10 parts of disintegrant.

[0043] The fourth aspect of the present invention is to provide a method for preparing the ziprasidone controlled-release tablet, comprising:

[0044] Weigh the prescribed amount of immediate-release layer ziprasidone and immediate-release excipients, and obtain ziprasidone immediate-release granules after premixing and final mixing;

[0045] Weigh the prescribed amount of sustained-release layer ziprasidone and sustained-release excipients, and obtain ziprasidone sustained-release granules after wet granulation, premixing, and final mixing;

[0046] Ziprasidone rapid-release granules and ziprasidone sustained-release granules are compressed into tablets to obtain ziprasidone controlled-release tablets.

[0047] Compared with the prior art, the beneficial effects of the present invention are as follows: by setting a specific mesh distribution mode for the ziprasidone sustained-release granules, the fluidity after granulation is good, the ziprasidone sustained-release granules are filled completely when tabletted, the preparation can stably and continuously release the drug, and has good stability; by using the sustained-release polymer in an inside-out manner, there is no need to use an organic solvent for granulation, and only water is used as a granulating agent, thereby reducing the preparation cost and drying risk. The ziprasidone controlled release provided by the present invention is fully filled during tableting, has good stability after tableting, and has a suitable drug release rate, which can take into account both rapid onset and long-lasting treatment for patients, thereby reducing the number of times patients take the drug and improving compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The dissolution curves of ziprasidone in Examples 1 and 2 and Comparative Examples 1 and 2 are shown.

[0049] Figure 2 The dissolution curves of ziprasidone in Examples 3 and 4 and Comparative Examples 3 and 4 are shown in FIG.

[0050] Figure 3 The dissolution curves of ziprasidone in Examples 5 and 6 and Comparative Examples 5 and 6 are shown.

[0051] Figure 4 The dissolution curves of ziprasidone in Examples 1 and 7 and Comparative Examples 7 and 8 are shown. DETAILED DESCRIPTION

[0052] Example 1

[0053] This embodiment provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 1:

[0054] Table 1. Prescription table of Example 1

[0055]

[0056] The preparation method of this embodiment is as follows:

[0057] S100. Preparation of Ziprasidone Immediate Release Granules:

[0058] S101. Weigh the prescribed amount of ziprasidone hydrochloride in the immediate-release layer and crush it with a grinder for later use;

[0059] S102. Premixing: weigh the raw materials and excipients in the prescription amount of the immediate release layer except magnesium stearate, sieve them together, transfer them to a mixer and mix them to obtain immediate release premixed granules;

[0060] S103. Final mixing: weigh the prescribed amount of magnesium stearate and an appropriate amount of the immediate-release premixed granules in step S102, sieve them, and then mix them in a pot to obtain the ziprasidone immediate-release granules.

[0061] S200. Preparation of Ziprasidone sustained-release granules:

[0062] S201. Weigh the sustained-release layer of ziprasidone hydrochloride, 4% HPC EF (with an added sustained-release polymer), microcrystalline cellulose PH101, and lactose G200, and wet-granulate them together, and then dry them in sequence to obtain dry granules;

[0063] S202. Premixing: weigh the remaining 6% HPC EF (externally added sustained-release polymer), HPMC K4M (externally added sustained-release polymer), colloidal silicon dioxide and the dry granules of step S201, sieve them together, transfer them to a mixer and mix them to obtain sustained-release premixed granules;

[0064] S203. Final mixing: Weigh the prescribed amount of magnesium stearate and an appropriate amount of the sustained-release premixed granules in step S202, sieve them, and then mix them in a pot to obtain the ziprasidone sustained-release granules.

[0065] S300. Tablet pressing

[0066] The prescribed amount of ziprasidone sustained-release granules is placed in the die of a tablet press and pre-compressed; then the prescribed amount of ziprasidone immediate-release granules is placed in the die of the tablet press and the appropriate main pressure is adjusted to press into tablets.

[0067] S400. Coating.

[0068] Among them, the sieve mesh number of this embodiment is 40 mesh, the particle size D90 of the immediate-release layer ziprasidone hydrochloride is 35 μm, and the particle size distribution of the ziprasidone sustained-release particles is shown in Table 2:

[0069] Table 2. Particle size distribution of Ziprasidone sustained-release granules in Example 1

[0070] Particle size Proportion >250μm 21.1％ 125-250μm 21.5％ <125μm 57.4％

[0071] Example 2

[0072] This embodiment provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 3:

[0073] Table 3. Prescription table of Example 2

[0074]

[0075] The preparation method of Example 2 is exactly the same as that of Example 1, and the particle size D90 of the ziprasidone hydrochloride in the immediate-release layer is 35 μm.

[0076] Comparative Example 1

[0077] This comparative example provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 4:

[0078] Table 4. Prescription table of comparative example 1

[0079]

[0080]

[0081] Comparative Example 1 Preparation method: completely the same as Example 1, the particle size of ziprasidone hydrochloride in the immediate release layer is D90=35 μm.

[0082] Comparative Example 2

[0083] This comparative example provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 5:

[0084] Table 5. Comparative Example 2 Prescription Table

[0085]

[0086] Comparative Example 2 Preparation method: Exactly the same as Example 1, the particle size of the ziprasidone hydrochloride in the immediate release layer is D90=35 μm.

[0087] Test Example 1

[0088] Dissolution Test 1

[0089] 1.1 Dissolution method

[0090] Dissolution method: basket method, rotation speed: 50 rpm, dissolution medium: pH 7.2 + 2.0% SDS, medium volume: 900 ml.

[0091] 1.2 Eligibility criteria

[0092] Time (h) Dissolution 0.5 10～40％ 12 ＜80％ 24 ＞85％

[0093] 1.3 Summary of Ziprasidone Dissolution

[0094] Table 6. Summary of Ziprasidone Release in Examples 1, 2 and Comparative Examples 1, 2

[0095] Time point (h) Example 1 Example 2 Comparative Example 1 Comparative Example 2 0 0 0 0 0 0.5 28 32 54 10 1 34 37 56 21 2 42 44 60 33 4 50 51 65 47 6 58 60 71 60 8 64 66 76 71 12 72 74 81 85 16 81 80 84 92 20 90 89 86 98 24 98 95 89 99

[0096] Refer to Table 6 and Figure 1 It can be seen that compared with Examples 1 and 2, in Comparative Example 1, the weight ratio of ziprasidone in the immediate-release layer to ziprasidone in the sustained-release layer was only adjusted up to 50:50, resulting in excessively rapid dissolution of ziprasidone, a decrease in the overall dissolution rate, and insufficient bioavailability; in Comparative Example 2, the weight ratio of ziprasidone in the immediate-release layer to ziprasidone in the sustained-release layer was adjusted down to 5:95, resulting in excessively slow dissolution of ziprasidone, and the active drug in the immediate-release portion could not meet the purpose of rapid onset of effect on patients.

[0097] Example 3

[0098] This embodiment provides a ziprasidone immediate-release granule, the formulation of which is exactly the same as that of the immediate-release layer in Example 1, and the method for preparing the ziprasidone immediate-release granule in this embodiment is exactly the same as the step of preparing the ziprasidone immediate-release granule in S100 in the embodiment. The only difference from Example 1 is that the particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of this embodiment is 40 μm.

[0099] Example 4

[0100] This embodiment provides a ziprasidone immediate-release granule, the formulation of which is exactly the same as the immediate-release layer in Example 1, and the method for preparing the ziprasidone immediate-release granule in this embodiment is exactly the same as the step S100. of preparing the ziprasidone immediate-release granule in the embodiment. The only difference from Example 1 is that the particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of this embodiment is 60 μm.

[0101] Comparative Example 3

[0102] This comparative example provides a ziprasidone immediate-release granule. The prescription and preparation method of this comparative example are exactly the same as those of Example 3, except that the particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of this comparative example is 10 μm.

[0103] Comparative Example 4

[0104] This comparative example provides a ziprasidone immediate-release granule. The prescription and preparation method of this comparative example are exactly the same as those of Example 3, except that the particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of this example is 80 μm.

[0105] Test Example 2

[0106] Dissolution Test 2

[0107] 2.1 Dissolution method

[0108] Refer to 1.1.

[0109] 2.2 Eligibility criteria

[0110] Release no less than 75% within 45 minutes

[0111] 2.3. Ziprasidone dissolution

[0112] Table 7. Summary of Ziprasidone Release in Examples 3, 4 and Comparative Examples 3, 4

[0113] Time point (min) Example 3 Example 4 Comparative Example 3 Comparative Example 4 0.0 0 0 0 0 5 64 44 72 36 10 81 62 86 45 15 88 69 91 48 20 91 73 94 51 30 95 79 97 55 45 97 85 98 61 60 98 88 98 66 120 98 91 99 73

[0114] Angle of repose detection 1

[0115] 3.1 Detection method

[0116] The injection method is used for testing: the particulate material flows out of the funnel and falls on the plane to form a cone, and the bottom angle of the cone is the angle of repose.

[0117] 3.2 Angle of repose results

[0118] Table 8. Summary of the angles of repose of ziprasidone immediate-release granules of Examples 3, 4 and Comparative Examples 3, 4

[0119] Example 2 Example 2 Comparative Example 3 Comparative Example 4 Repose angle (<40°) 37 38 44 35

[0120] Refer to Table 7, Table 8 and Figure 2 Compared with Examples 3 and 4, Comparative Example 3 uses small-sized ziprasidone with a particle size of D90=10 μm, which results in a too fast dissolution rate of the ziprasidone immediate-release granules, an increased angle of repose, poor fluidity, and may cause incomplete filling during tableting; Comparative Example 4 uses large-sized ziprasidone with a particle size of D90=80 μm, which results in a too slow dissolution rate of the ziprasidone immediate-release granules, a significant decrease in the overall dissolution rate, and poor bioavailability.

[0121] Example 5

[0122] This embodiment provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 6:

[0123] Table 9. Prescription table of Example 5

[0124]

[0125] Preparation method of Example 5: The difference from Example 1 is that the slow-release polymer added internally in step S201 is 3% HPMC K15M, the slow-release polymer added externally in step S202 is 37% HPMC K15M, and the other steps are the same.

[0126] The particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of Example 5 is 35 μm.

[0127] The particle size distribution of the ziprasidone sustained-release granules of Example 5 is shown in Table 9:

[0128] Table 9. Particle size distribution of Ziprasidone sustained-release granules in Example 5

[0129] Particle size Proportion >250μm 24.6％ 125-250μm 20％ <125μm 55.4％

[0130] Example 6

[0131] This embodiment provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 10:

[0132] Table 10. Prescription table of Example 6

[0133]

[0134]

[0135] Preparation method of Example 6: The difference from Example 1 is that the slow-release polymer added internally in step S201 is 3% HPMC K4M, the slow-release polymer added externally in step S202 is (17% HPMC K4M+20% HPMC K100LV), and the other steps are the same.

[0136] The particle size of the ziprasidone hydrochloride in the immediate-release layer of Example 6 is D90=35 μm.

[0137] The particle size distribution of the ziprasidone sustained-release granules of Example 6 is shown in Table 11:

[0138] Table 11. Particle size distribution of Ziprasidone sustained-release granules in Example 6

[0139] Particle size Proportion >250μm 18.4％ 125-250μm 25.6％ <125μm 56.0％

[0140] Comparative Example 5

[0141] This comparative example provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 12:

[0142] Table 12. Comparative Example 5 Prescription Table

[0143]

[0144]

[0145] Preparation method of Comparative Example 5: The difference from Example 1 is that the slow-release polymer added internally in step S201 is 10% xanthan gum, the slow-release polymer added externally in step S202 is 30% xanthan gum, and the other steps are the same.

[0146] The particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of Comparative Example 5 was 35 μm.

[0147] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 5 is shown in Table 13:

[0148] Table 13. Particle size distribution of ziprasidone sustained-release granules in comparative example 5

[0149] Particle size Proportion ≥60 mesh 47.1％ 60 mesh-120 mesh 28.6％ ≤120 mesh 24.3％

[0150] Comparative Example 6

[0151] This comparative example provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 14:

[0152] Table 14. Comparative Example 6 Prescription Table

[0153]

[0154] Preparation method of Comparative Example 6: The difference from Example 1 is that the slow-release polymer added internally in step S201 is 10% locust bean gum, the slow-release polymer added externally in step S202 is (20% HECG+10% locust bean gum), and the other steps are the same.

[0155] The particle size of the ziprasidone hydrochloride in the immediate-release layer of Comparative Example 6 was D90=35 μm.

[0156] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 6 is shown in Table 15:

[0157] Table 15. Particle size distribution of ziprasidone sustained-release granules in comparative example 6

[0158] Particle size Proportion >250μm 43.6％ 125-250μm 31.2％ <125μm 25.2％

[0159] Test Example 3

[0160] Dissolution Test 3

[0161] 4.1 Dissolution method

[0162] Refer to 1.1.

[0163] 4.2 Eligibility criteria

[0164] Refer to 1.2.

[0165] 4.3 Dissolution

[0166] Table 16. Summary of dissolution of Examples 5, 6 and Comparative Examples 5, 6

[0167] Time point (h) Example 5 Example 6 Comparative Example 5 Comparative Example 6 0 0 0 0 0 0.5 27 29 2 3 1 33 35 2 3 2 41 44 3 4 4 49 53 3 4 6 57 59 5 6 8 63 66 5 6 12 71 74 8 7 16 80 84 8 9 20 89 92 9 10 24 97 99 9 10

[0168] Refer to Table 16 and Figure 3 In Examples 5 and 6, celluloses such as HPMC K15M, HPMC K4M, and HPMC K100LV are used as sustained-release polymers, and the dissolution curves of the obtained ziprasidone controlled-release tablets meet the requirements of the qualified standards, and can achieve the purpose of rapid onset and long-term treatment for patients. However, in Comparative Example 5, xanthan gum is used as a sustained-release polymer, and in Comparative Example 6, a combination of HEC G and locust bean gum is used as a sustained-release polymer. That is, the two comparative examples use natural gums alone or in combination as sustained-release polymers, which results in that ziprasidone is difficult to release and cannot achieve the purpose of treatment.

[0169] Example 7

[0170] This embodiment provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 17:

[0171] Table 17. Prescription table of Example 8

[0172]

[0173] Preparation method of Example 7: The only difference from Example 1 is that the slow-release polymer added internally in step S201 is, and the slow-release polymer added externally in step S202 is (25% HPMC K4M and 11% HPC EF), and the other steps are the same.

[0174] The particle size of the ziprasidone hydrochloride in the immediate-release layer of Example 7 is D90=35 μm.

[0175] Comparative Example 7

[0176] This comparative example provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 18:

[0177] Table 18. Comparative Example 7 Prescription Table

[0178]

[0179]

[0180] Preparation method of Comparative Example 7: The only difference from Example 1 is that the slow-release polymer added internally in step S201 is, and the slow-release polymer added externally in step S202 is (15% HPC EF), and the other steps are the same.

[0181] The particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of Comparative Example 7 was 35 μm.

[0182] Comparative Example 8

[0183] This comparative example provides a ziprasidone controlled-release tablet, the prescription of which is shown in Table 19:

[0184] Table 19. Prescription table of comparative example 8

[0185]

[0186] Comparative Example 8 Preparation method: The only difference from Example 1 is that the slow-release polymer added internally in step S201 is, and the slow-release polymer added externally in step S202 is (25% HPMC K4M and 20% HPC EF), and the other steps are the same.

[0187] The particle size D90 of the ziprasidone hydrochloride in the immediate-release layer of Comparative Example 8 was 35 μm.

[0188] Test Example 4

[0189] Dissolution Test 4

[0190] 5.1 Dissolution method

[0191] Refer to 1.1.

[0192] 5.2 Eligibility criteria

[0193] Refer to 1.2.

[0194] 5.3 Dissolution

[0195] Table 20. Summary of Ziprasidone Dissolution in Examples 1, 7 and Comparative Examples 7, 8

[0196] Time point (h) Example 1 Example 8 Comparative Example 7 Comparative Example 8 0 0 0 0.0 0.0 0.5 28 27 26 4 1 34 31 39 6 2 42 38 56 10 4 50 47 82 17 6 58 56 99 24 8 64 61 100 32 12 72 70 103 46 16 81 79 101 59 20 90 88 101 71 24 98 96 101 82

[0197] Refer to Table 20 and Figure 4 Compared with Examples 1 and 7, in Comparative Example 7, the weight proportion of the sustained-release polymer was lowered to 20%, resulting in an excessively fast dissolution rate of ziprasidone, which was completely dissolved in 6 hours and could not provide long-term treatment for the patient; in Comparative Example 8, the weight proportion of the sustained-release polymer was increased to 50%, resulting in an excessively slow dissolution rate of ziprasidone, the dissolution rate of the immediate-release part could not meet the rapid therapeutic effect, and the dissolution rate decreased significantly within 24 hours, resulting in poor bioavailability of ziprasidone.

[0198] Example 8

[0199] This embodiment provides a ziprasidone sustained-release granule. The prescription of this embodiment is completely the same as the sustained-release layer of Example 1. The preparation method of this embodiment is completely the same as S200 in Example 1 for preparing ziprasidone sustained-release granules.

[0200] The particle size distribution of the ziprasidone sustained-release granules of Example 8 is shown in Table 21:

[0201] Table 21. Particle size distribution of ziprasidone sustained-release granules of Example 8

[0202] Particle size Proportion >250μm 21.1％ 125-250μm 21.5％ <125μm 57.4％

[0203] Example 9

[0204] This embodiment provides a ziprasidone sustained-release granule. The prescription of this embodiment is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this embodiment is different from S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is (5% HPMC K4M + 2% HPC EF), the externally added sustained-release polymer in step S202 is (20% HPMC K4M + 8% HPC EF), and the other steps are the same.

[0205] The particle size distribution of the ziprasidone sustained-release granules of Example 9 is shown in Table 22:

[0206] Table 22. Particle size distribution of Ziprasidone sustained-release granules of Example 9

[0207] Particle size Proportion >250μm 25.2％ 125-250μm 23.4％ <125μm 51.4％

[0208] Example 10

[0209] This embodiment provides a ziprasidone sustained-release granule. The prescription of this embodiment is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this embodiment is different from S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is (8% HPMC K4M + 3% HPC EF), the externally added sustained-release polymer in step S202 is (17% HPMC K4M + 7% HPC EF), and the other steps are the same.

[0210] The particle size distribution of the ziprasidone sustained-release granules of Example 10 is shown in Table 23:

[0211] Table 23. Particle size distribution of Ziprasidone sustained-release granules of Example 10

[0212] Particle size Proportion >250μm 20.4％ 125-250μm 34.4％ <125μm 45.2％

[0213] Comparative Example 9

[0214] This comparative example provides a ziprasidone sustained-release granule. The prescription of this comparative example is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this comparative example is different from that of S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is (25% HPMC K4M + 10% HPC EF), and no externally added polymer is added in step S202, that is, all the sustained-release polymers are added internally, and the other steps are the same.

[0215] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 9 is shown in Table 24:

[0216] Table 24. Particle size distribution of ziprasidone sustained-release granules of Comparative Example 9

[0217] Particle size Proportion >250μm 48.6％ 125-250μm 30.3％ <125μm 21.1％

[0218] Comparative Example 10

[0219] This comparative example provides a ziprasidone sustained-release granule. The prescription of this comparative example is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this comparative example is different from that of S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is 25% HPMC K4M, the externally added polymer in step S202 is 10% HPC EF, and the other steps are the same.

[0220] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 10 is shown in Table 25:

[0221] Table 25. Particle size distribution of ziprasidone sustained-release granules of Comparative Example 10

[0222]

[0223] Comparative Example 11

[0224] This comparative example provides a ziprasidone sustained-release granule. The prescription of this comparative example is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this comparative example is different from that of S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is 2% HPC EF, the externally added polymer in step S202 is (25% HPMC K4M + 8% HPC EF), and the other steps are the same.

[0225] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 11 is shown in Table 26:

[0226] Table 26. Particle size distribution of ziprasidone sustained-release granules of Comparative Example 11

[0227] Particle size Proportion >250μm 28.4％ 125-250μm 20.4％ <125μm 51.2％

[0228] Comparative Example 12

[0229] This comparative example provides a ziprasidone sustained-release granule. The prescription of this comparative example is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this comparative example is different from that of S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is (8% HPMC K4M + 10% HPC EF), the externally added polymer in step S202 is 17% HPMC K4M, and the other steps are the same.

[0230] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 12 is shown in Table 27:

[0231] Table 27. Particle size distribution of ziprasidone sustained-release granules of Comparative Example 12

[0232] Particle size Proportion >250μm 36.1％ 125-250μm 34.3％ <125μm 29.6％

[0233] Comparative Example 13

[0234] This comparative example provides a ziprasidone sustained-release granule. The prescription of this comparative example is exactly the same as that of the sustained-release layer in Example 1. The preparation method of this comparative example is different from that of S200 in Example 1 only in that the internally added sustained-release polymer in step S201 is (15% HPMC K4M + 4% HPC EF), the externally added polymer in step S202 is (10% HPMC K4M + 6% HPCEF), and the other steps are the same.

[0235] The particle size distribution of the ziprasidone sustained-release granules of Comparative Example 13 is shown in Table 28:

[0236] Table 28. Particle size distribution of ziprasidone sustained-release granules of Comparative Example 13

[0237]

[0238]

[0239] Test Example 5

[0240] Repose angle detection 2

[0241] 6.1 Detection Method

[0242] Refer to 3.1

[0243] Hausner Ratio Test

[0244] 7.1 Detection Method

[0245] The bulk density and tap density were determined according to the method for determining bulk density and tap density in General Rule 0993 of Part IV of the Chinese Pharmacopoeia.

[0246] Hausner Ratio = tap density / bulk density

[0247] Testing situation

[0248] Table 29. Summary of angle of repose and Hausner Ratio tests of Examples 8, 9 and Comparative Examples 9, 10

[0249]

[0250] Filling integrity testing

[0251] 8.1 Detection methods

[0252] Visual inspection during tableting.

[0253] Table 30. Summary of filling conditions of Examples 8, 10 and Comparative Examples 11, 12, and 13

[0254]

[0255] Referring to Tables 29 and 30, it can be seen that the weight ratio of the internally added sustained-release polymer to the externally added sustained-release polymer in Examples 8-10 is in the range of 1:15-1:2, so that the particle size distribution of the obtained ziprasidone sustained-release particles can meet the following requirements: by weight percentage, the particle size > 250 μm accounts for less than 30%, the particle size 125-250 μm accounts for less than <30%, and the particle size <125 μm accounts for more than 50%. In this way, the particle size repose angle of the obtained ziprasidone sustained-release particles is <40°, and the Hausner Ratio<1.35, having suitable fluidity, and being able to be completely filled during tableting; compared with the examples, the weight ratio of the internally added sustained-release polymer to the externally added sustained-release polymer in comparative examples 9-13 is not within the range of 1:15-1:2, resulting in that the particle size distribution of the obtained ziprasidone sustained-release particles cannot meet at least one of the particle size index requirements (particle size>250μm accounts for less than 30%, particle size 125-250μm accounts for less than 30%, and particle size<125μm accounts for more than 50%), resulting in fluidity not meeting the standard requirements, and ultimately causing insufficient filling during tableting.

[0256] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the technical solution of the present invention, and are not intended to limit the specific implementation methods of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the claims of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A ziprasidone sustained-release granule, characterized in that: In the ziprasidone sustained-release granules, the granules with a particle size greater than 250 μm account for less than 30% by weight.

2. The ziprasidone sustained-release granules according to claim 1, characterized in that: The particle size distribution of the ziprasidone sustained-release particles is as follows: by weight percentage, particles with a size of >250 μm account for less than 30%, particles with a size of 125-250 μm account for less than 30%, and particles with a size of <125 μm account for more than 50%.

3. The ziprasidone sustained-release granules according to claim 1 or 2, characterized in that: The ziprasidone sustained-release granules include a first ziprasidone, a first filler, a first glidant, a first lubricant and a sustained-release polymer.

4. The ziprasidone sustained-release granules according to claim 3, characterized in that: The weight proportion of the sustained-release polymer in the ziprasidone sustained-release granules is 25-45%; and / or, The sustained-release polymer is any one or more combinations of methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), and hydroxypropyl cellulose (HPC); and / or, Ziprasidone sustained-release granules include the following components in parts by weight: 8-12 parts of first ziprasidone; 40-60 parts of the first filler; 0.5-5 parts of a first glidant; 0.5-5 parts of the first lubricant; 25-45 parts of sustained release polymer.

5. A method for preparing the ziprasidone sustained-release granules according to claim 3 or 4, characterized in that: The sustained-release polymer includes an internally added sustained-release polymer and an externally added sustained-release polymer; Weighing the first ziprasidone, the internally added sustained-release polymer, and the first filler together for wet granulation, and then drying them in sequence to obtain dry granules; Weigh the externally added sustained-release polymer, the first glidant and the dry whole granules, sieve and mix together; The first lubricant in a prescribed amount is weighed and sieved and mixed with a preset amount of premixed particles to obtain ziprasidone sustained-release particles.

6. The method according to claim 5, characterized in that The weight ratio of the internally added sustained-release polymer to the externally added sustained-release polymer is 1:15-1:

1.

7. A ziprasidone controlled-release tablet, characterized in that: The invention comprises a ziprasidone immediate-release layer and a ziprasidone sustained-release layer, wherein the ziprasidone immediate-release layer is made of ziprasidone immediate-release particles, and the ziprasidone sustained-release layer is made of the ziprasidone sustained-release particles according to any one of claims 1 to 6.

8. The ziprasidone controlled-release tablet according to claim 7, characterized in that: The ziprasidone sustained-release granules include a first ziprasidone and a sustained-release excipient, and the ziprasidone immediate-release granules include a second ziprasidone and an immediate-release excipient. The weight ratio of the second ziprasidone to the first ziprasidone is (12.5-37.5):(62.5-87.5).

9. The ziprasidone controlled-release tablet according to claim 8, characterized in that: The particle size D90 of the second ziprasidone is 15 μm-70 μm; and / or, The rapid-release excipients include a second filler, a second glidant, a second lubricant and a disintegrant; and / or, Ziprasidone immediate-release granules include the following components in parts by weight: 5-15 parts of second ziprasidone; 65-85 parts of a second filler; 0.5-5 parts of a second glidant; 0.5-5 parts of a second lubricant; 2-10 parts of disintegrant.

10. A method for preparing the ziprasidone controlled-release tablet according to claim 8 or 9, characterized in that: include: Weigh the prescribed amount of the second ziprasidone and the immediate-release excipients, and obtain the ziprasidone immediate-release granules after premixing and final mixing; Weighing the first amount of ziprasidone and sustained-release excipients in the prescription, and obtaining ziprasidone sustained-release granules after wet granulation, premixing, and final mixing; Ziprasidone rapid-release granules and ziprasidone sustained-release granules are compressed into tablets to obtain ziprasidone controlled-release tablets.

Images