ORAL SUSTAINED-RELEASE COMPOSITION FOR INSOLUBLE DRUG, AND PREPARATION METHOD THEREOF

Abstract

Disclosed is an oral sustained-release composition for an insoluble drug, which is especially suitable for a low-dose insoluble drug, the oral sustained-release composition comprises a sustained-release granule part and a gel skeleton part, the sustained-release granule part comprises the insoluble drug, an enteric material, and a strong liquid sorbent, and the gel skeleton part comprises a hydrophilic gel skeleton material; and the sustained-release granules are obtained by preparing the insoluble drug and the enteric material into a suspension and then spraying the suspension onto the strong liquid sorbent, the sustained-release granules are wrapped by the gel skeleton to form a multiple sustained-release system technology, which prolongs a release time, and has a simple preparation process, high efficiency, uniform drug mixing, and less content loss.

Claims

1. An oral sustained-release composition for an insoluble drug, wherein the oral sustained-release composition comprises a sustained-release granule part and a gel skeleton part, the sustained-release granule part comprises the insoluble drug, an enteric material and a strong liquid sorbent; the gel skeleton part comprises a hydrophilic gel skeleton material; and the sustained-release granules are obtained by preparing the insoluble drug and a liquid substance containing the enteric material into a suspension and then spraying the suspension onto the strong liquid sorbent, wherein the insoluble drug in the sustained-release granules accounts for 2%-15% of a weight of the sustained-release granules, a weight ratio of the insoluble drug to the enteric material is 1:2 to 1:4, and the strong liquid sorbent accounts for 35%-75% of the weight of the sustained-release granules; the sustained-release granules account for 40%-70% of a weight of the oral sustained-release composition; and a dose of the hydrophilic gel skeleton material account for 20%-50% of the weight of the oral sustained-release composition.

2. The oral sustained-release composition according to claim 1, wherein the insoluble drug is present in the oral sustained-release composition at a weight ratio of less than 10%.

3. The oral sustained-release composition according to claim 1, wherein d90 in particle size distribution of the insoluble drug is controlled to be less than 20 microns.

4. The oral sustained-release composition according to claim 1, wherein the enteric material is a polymer material soluble in a pH range of 6-8, and the drug coated by the enteric material is capable of being completely released in a position of colon.

5. The oral sustained-release composition according to claim 1, wherein the liquid substance containing the enteric material is in an aqueous dispersion form or an organic solvent solution form of the enteric material, wherein the aqueous dispersion form of the enteric material is obtained by adding water and/or water containing an alkaline substance to the enteric material, and the organic solvent solution of the enteric material is obtained by dissolving the enteric material with an organic solvent.

6. The oral sustained-release composition according to claim 4, wherein the enteric material is any one of a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate.

7. The oral sustained-release composition according to claim 1, wherein a solid content of the drug-containing suspension is 10-35%.

8. The oral sustained-release composition according to claim 1, wherein the strong liquid sorbent is any one of microcrystalline cellulose, croscarmellose sodium, croscarmellose, polyvinylpolypyrrolidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, starch and pregelatinized starch.

9. The oral sustained-release composition according to claim 1, wherein the sustained-release granules are capable of being added with an adhesive, the adhesive comprises any one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carrageenan, alginic acid, arabic gum, pectin, xanthan gum and tragacanth, and a dose of the adhesive is 0-5% of the weight of the sustained-release granules.

10. The oral sustained-release composition according to claim 1, wherein the liquid substance containing the enteric material is capable of being optionally added with any one or a combination of several of 0-8% of anti-sticking agent, 0-8% of plasticizer and 0-3% of surfactant by weight of the sustained-release granules before use, wherein the anti-sticking agent is selected from colloidal silicon dioxide, talcum powder, and glyceryl monostearate; the plasticizer is selected from glyceryl monostearate, triethyl citrate, and polyethylene glycol; and the surfactant is selected from sorbitan fatty acid, polysorbate, and sodium dodecyl sulfate.

11. The oral sustained-release composition according to claim 1, wherein the hydrophilic gel skeleton material is any one of arabic gum, tragacanth gum, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, shellac, hydroxypropyl cellulose, hydroxyethyl cellulose, alginate, methylated cellulose, carrageenin, carboxymethyl cellulose, and sodium carboxymethylcellulose, carbomer, and polyvinyl alcohol.

12. The oral sustained-release composition according to claim 1, wherein the gel skeleton part is capable of being optionally added with a filler, an adhesive, a lubricant, and a glidant.

13. A preparation method of the oral sustained-release composition according to claim 1, comprising the following steps: (i) dispersing the insoluble drug into a liquid solution containing an enteric material to obtain a suspension, and then spraying the obtained suspension onto a strong liquid sorbent for granulation to form sustained-release granules; and (ii) mixing the sustained-release granules obtained in step (i) with a material containing a hydrophilic gel skeleton material, and tableting, wherein the sustained-release granules are added into components of the gel skeleton part for granulation together, or the gel skeleton part is granulated separately, then mixed with the prepared sustained-release granules, and tableted.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG. 1 shows dissolution curves of Embodiment 10 to13;

[0053] FIG. 2 shows dissolution curves of Embodiment 14 to 17; and

[0054] FIG. 3 shows dissolution curves of Embodiments 18 to 20.

DETAILED DESCRIPTION

[0055] The present invention will be further described in detail below with reference to the embodiments.

Embodiments 1 to 4

[0056] The formula and dose ratio used in Embodiments 1 to 4 were shown in Table 1 below, and the total weight of materials in each batch was 500 g (excluding the weight of solvents).

TABLE-US-00001 TABLE 1 Embodiment 1 Embodiment 2 Parts Parts by Percent by Percent Material weight age weight age API Apremilast 30  9.84% 30  9.12% (d90: 3.3 microns) Enteric Eudragit S100 60 19.67% 75 22.80% material Anti-sticking Talcum powder — — 12  3.65% agent Plasticizer Triethyl citrate — — 12  3.65% Solvent Ethanol (95%)* 800 — 700 — Strong liquid Microcrystalline 215 70.49% 200 60.79% sorbent cellulose Total 305 329 Acid dissolution 79% 73% rate Embodiment 3 Embodiment 4 Parts Parts by Percent by Percent Material weight age weight age API Apremilast 30  8.50% 30  7.61% (d90: 3.3 microns) Enteric Eudragit S100 90 25.50% 120 30.46% material Anti-sticking Talcum powder 18  5.10% 24  6.09% agent Plasticizer Triethyl citrate 15  4.25% 20  5.08% Solvent Ethanol (95%)* 600 — 500 — Strong liquid Microcrystalline 200 56.66% 200 50.76% sorbent cellulose Total 353 394 Acid dissolution 55% 42% rate

[0057] The solvent was dried and removed during processing.

[0058] Preparation process steps of Embodiments 1 to 4: [0059] 1) dissolving Utech S100 in an appropriate amount of ethanol (95%); and adding apremilast, talcum powder and triethyl citrate into an appropriate amount of ethanol (95%), homogenizing the mixture for about 10 minutes by a homogenizer, then pouring the mixture into Utech S100 solution, and continuously stirring the suspension by a stirrer during granulation; [0060] 2) spraying the suspension in the step 1) into microcrystalline cellulose by WBF-2G fluidized bed top-spray granulation, and controlling an atomization pressure at 0.5-2.0 bar (increasing 0.5 bar every 10 minutes until the maximum value) and a spray rate at 5-15 g/min (increasing 5 g/min every 10 minutes until the maximum value), an air volume at 90 m.sup.3/h and air inlet temperature at 45° C. during the process; after spraying the suspension, drying at 50-60° C. for 20 minutes to remove the residual solvent and obtain dried granules; and [0061] 3) dry-grading the dried granules obtained in step 2) by a sieve with a pore diameter of 40 meshes to obtain sustained-release granules.

[0062] Samples were taken to detect acid dissolution rates of the sustained-release granules, and each sample contained about 60 mg of apremilast.

Embodiments 5 to 8

[0063] The formula and dose ratio used in Embodiments 5 to 8 were shown in Table 2 below, wherein d90 in particle size distribution of API apremilast was 7.4 microns, and the total weight of materials in each batch was 500 g (excluding the weight of solvents).

TABLE-US-00002 TABLE 2 Embodiment 5 Embodiment 6 Parts by Parts by Material weight Percentage Material weight Percentage API Apremilast 60 11.88% Apremilast 60 9.51% Enteric Eudragit 120 23.76% Eudragit 180 28.53% material FS 30D* FS 30D* Anti- Talcum 6 1.19% Talcum 10 1.58% sticking powder powder agent Plasticizer Triethyl 6 1.19% Polyethylene 18 2.85% citrate glycol 4000 Surfactant Tween 80 3 0.59% Tween 80 3 0.48% Solvent Purified Appropriate — Purified Appropriate — water ** water ** Adhesive Hydroxypropyl 10 1.98% Polyvidone 10 1.58% methylcellulose E3 k30 Strong Microcrystalline 300 59.41% Sodium 350 55.47% liquid cellulose carboxymethyl sorbent starch Total 505 Total 631 Acid 78% Acid 69% dissolution dissolution rate rate Embodiment 7 Embodiment 8 Parts by Percent Parts by Percent Material weight age Material weight age API Apremilast 60 8.88% Apremilast 60 9.38% Enteric Eudragit 224 33.14% Eudragit 286 44.69% material FS 30D* FS 30D* Anti- Talcum 16 2.37% Talcum 26 4.06% sticking powder powder agent Plasticizer Triethyl 16 2.37% — — — citrate Solvent Purified Appropriate — Purified Appropriate — water ** water ** Adhesive Sodium 10 1.48% Hydroxypropyl 18 2.81% carboxy- cellulose methylcellulose Strong Starch 350 51.78% Croscarmellose 250 39.06% liquid sorbent Total 676 Total 640 Acid 60% Acid 45% dissolution dissolution rate rate

[0064] Based on the weight of solid matters in Utrecht aqueous dispersion.

[0065] The dose of the purified water comprised the amount of water in Utrecht aqueous dispersion and the added amount of water. The purified water was dried and removed during processing. In the prescription, other components except the strong liquid sorbent and the adhesive were mixed with the solvent to prepare the suspension, and the dose of the solvent used was about 20%-25% of the solid contents in the suspension.

[0066] Preparation process steps of Embodiments 5 to 8: [0067] 1) adding an anti-sticking agent, a plasticizer, a surfactant and an API into a certain amount of solvent hot water (70° C. to 80° C.), homogenizing the mixture for 10 minutes with a high-shear homogenizer to obtain a suspension, and continuously stirring the suspension for later use; [0068] 2) spraying the suspension in step 1) into microcrystalline cellulose by WBF-2G fluidized bed top-spray granulation, and controlling an atomization pressure at 0.5-2.0 bar (increasing 0.5 bar every 10 minutes until the maximum value) and a spray rate at 5-15 g/min (increasing 5 g/min every 10 minutes until the maximum value), an air volume at 90 m.sup.3/h and air inlet temperature at 45° C. during the process; after spraying the suspension, drying at 50-60° C. for 20 minutes to remove the residual solvent and obtain dried granules; and [0069] 3) dry-grading the dried granules obtained in step 2) by a sieve with a pore diameter of 30 meshes to obtain sustained-release granules.

[0070] Samples were taken to detect acid dissolution rates of the sustained-release granules, and each sample contained about 60 mg of apremilast.

Embodiment 9

[0071] The formula and dose ratio used in Embodiment 9 were shown in Table 3 below, wherein d90 in particle size distribution of API apremilast was 15 microns, and the total weight of materials in each batch was 500 g (excluding the weight of solvents).

TABLE-US-00003 TABLE 3 Embodiment 9 Parts by Material weight Percentage API Apremilast 30 6.31% Enteric Eudragit L100 120 25.23% material Alkaline Sodium 1.6 0.34% substance hydroxide Anti-sticking Talcum powder 9 1.89% agent Plasticizer Triethyl citrate 10 2.10% Solvent Purified water* 500 — Adhesive Hydroxypropyl 5 1.05% methylcellulose E5 Strong liquid Low substituted 300 63.08% sorbent hydroxypropyl cellulose Total 475.6 Acid dissolution 68% rate

[0072] In the prescription, other components except the strong liquid sorbent and the adhesive were mixed with the solvent to prepare the suspension. A dose of the solvent used was 25.4% of the solid content in the suspension, and purified water was dried and removed during processing.

[0073] Preparation process steps of Embodiment 9: [0074] 1) slowly pouring an enteric material Utrecht L100 into water and stirring for 5-10 minutes; after the enteric material was completely wetted, slowly adding sodium hydroxide powder or solution and keep stirring, and finally keep stirring for 30 minutes; and then, adding a bulk drug, a plasticizer and an anti-sticking agent, continuously stirring the mixture uniformly, filtering with a 40-mesh sieve to obtain a suspension, and keeping stirring the suspension for later use; [0075] 2) spraying the suspension in step 1) into microcrystalline cellulose by WBF-2G fluidized bed top-spray granulation, and controlling an atomization pressure at 0.5-2.0 bar (increasing 0.5 bar every 10 minutes until the maximum value) and a spray rate at 5-15 g/min (increasing 5 g/min every 10 minutes until the maximum value), an air volume at 90 m3/h and air inlet temperature at 45° C. during the process; after spraying the suspension, drying at 50-60° C. for 20 minutes to remove the residual solvent and obtain dried granules; and [0076] 3) dry-grading the dried granules obtained in step 2) by a sieve with a pore diameter of 20 meshes to obtain sustained-release granules.

[0077] Samples were taken to detect acid dissolution rates of the sustained-release granules, and each sample contained about 60 mg of apremilast.

Embodiments 10 to 13

[0078] The formula and dose ratio used in Embodiments 10 to 13 were shown in Table 4 below, and the total weight of blended granules in each batch was 400 g.

TABLE-US-00004 TABLE 4 Embodiment 10 Embodiment 11 Parts by Parts by Material weight Percentage weight Percentage Source of Embodiment — Embodiment — sustained- 1 2 release granules Sustained- 305 69.32% 329 67.98% release granules Hydrophilic Hydroxypropyl 130 29.55% 150 30.99% gel material methylcellulose K15M PH DC Lubricant Magnesium 5 1.14% 5 1.03% stearate Tablet weight 440 484 mg Specification 60 60 mg Content 7.2 8.6 uniformity A + 2.2 S Embodiment 12 Embodiment 13 Parts by Parts by Material weight Percentage weight Percentage Source of Embodiment — Embodiment — sustained- 3 4 release granules Sustained- 353 67.88% 394 67.81% release granules Hydrophilic Hydroxypropyl 160 30.77% 180 30.98% gel material methylcellulose K15M PH DC Lubricant Magnesium 7 1.35% 7 1.20% stearate Tablet weight 520 581 mg Specification 60 60 mg Content 6.2 5.1 uniformity A + 2.2 S

[0079] Preparation process steps of Embodiments 10 to 13: [0080] 1) mixing sustained-release granules with a hydrophilic gel material and a lubricant for 10 minutes to obtain blended granules; and [0081] 2) pouring the blended granules into a tablet press, selecting a round die with a diameter of Φ11 mm, and pressing according to a target tablet weight to obtain sustained-release tablets.

[0082] Dissolution situations of the tablets prepared in Embodiments 10 to 13 were shown in

[0083] Table 5 below, and the dissolution curves were shown in FIG. 1.

TABLE-US-00005 TABLE 5 Dissolution rate (%) Time/hour 0 1 2 3 6 9 12 16 20 24 Embodiment 10 0 14 30 45 69 75 80 89 95 99 Embodiment 10 0 12 24 35 62 68 70 85 92 97 11 Embodiment 10 0 10 19 30 45 51 56 72 90 99 12 Embodiment 10 0 7 14 23 34 42 51 71 85 95 13

Embodiments 14 to 17

[0084] The formula and dose ratio used in Embodiments 14 to17 were shown in Table 5 below, and the total weight of blended granules in each batch was 400 g.

TABLE-US-00006 TABLE 6 Embodiment 14 Embodiment 15 Parts by Percen- Parts by Percen- Material weight tage weight tage Source of Embodi- Embodi- sustained- ment 5 ment 6 release granules Sustained- 505 49.61% 631 58.64% release granules Hydro- Hydroxypropyl 500 49.12% — — philic gel methylcellulose material K4M PH DC Hydro- Hydroxypropyl — — 400 37.17% philic gel methylcellulose material K15M PH DC Filler Lactose 10 0.98% 40 3.72% Lubricant Magnesium 3 0.29% 5 0.46% stearate Tablet weight 1018 1076 mg Specification 60 60 mg Content 7.8 5.6 uniformity A + 2.2 S Embodiment 16 Embodiment 17 Parts by Percen- Parts by Percen- weight tage weight tage Source of Embodi- Embodi- sustained- ment 7 ment 8 release granules Sustained- 676 66.08% 640 69.04% release granules Hydro- Hydroxypropyl 300 29.33% — — philic gel methylcellulose material K100M PH DC Hydro- Hydroxypropyl — — 240 25.89% philic gel cellulose MXF material Filler Lactose 40 3.91% 40 4.31% Lubricant Magnesium 7 0.68% 7 0.76% stearate Tablet weight 1023 927 mg Specification 60 60 mg Content 6.6 5.3 uniformity A + 2.2 S

[0085] Preparation process steps of Embodiments 14 to 17: [0086] 1) mixing sustained-release granules with a hydrophilic gel material and a lubricant for 10 minutes to obtain blended granules; and [0087] 2) pouring the blended granules into a tablet press, selecting a capsule type die to perform tableting according to a target tablet weight to obtain sustained-release tablets.

[0088] Dissolution situations of the tablets prepared in Embodiments 14 to17 were shown in Table 7 below, and the dissolution curves were shown in FIG. 2.

TABLE-US-00007 TABLE 7 Dissolution rate (%) Time/hour 0 1 2 3 6 9 12 16 20 24 Embodiment 14 0 15 29 45 65 73 78 89 95 99 Embodiment 15 0 13 27 38 55 68 70 84 94 99 Embodiment 16 0 10 23 32 49 55 59 79 91 98 Embodiment 17 0 8 21 29 43 47 51 73 85 95

Embodiment 18

[0089] The formula and dose ratio used in Embodiment 18 were shown in Table 8 below, wherein d90 in particle size distribution of apixaban was 4.3 microns, and the total weight of blended granules was 500 g.

TABLE-US-00008 TABLE 8 Embodiment 18 Percen- tage of total Parts by tablet Material weight weight Sustained- API Apixaban 10 2.73% release Enteric Eudragit FS 30 D* 32 8.74% granule material part Anti-sticking Talcum powder 6 1.64% agent Surfactant Sodium dodecyl 6 1.64% sulfate Plasticizer Triethyl citrate 2 0.55% Solvent Purified water ** Appro- — priate Strong liquid Microcrystalline 100 27.32% sorbent cellulose Gel skeleton Hydrophilic gel Hydroxypropyl 40 10.93% part material methylcellulose K4M Hydrophilic gel Polyvinyl alcohol 40 10.93% material 17-88 Filler Pregelatinized 120 32.79% starch Solvent Purified water Appro- — priate Glidant Aerosil 5 1.37% Lubricant Magnesium stearate 5 1.37% Tablet weight mg 366 Content uniformity 6.8 A + 2.2 S Based on the weight of solid matters in Utrecht aqueous dispersion. ** The dose of the purified water comprised the amount of water in Utrecht aqueous dispersion and the added amount of water. The purified water was dried and removed during processing. In the prescription, other components except the strong liquid sorbent and the adhesive were mixed with the solvent to prepare the suspension, and the dose of the solvent used was about 30 of the solid contents in the suspension.

[0090] Preparation process steps of Embodiment 18: [0091] 1) adding an anti-sticking agent, a plasticizer, a surfactant and an API into a certain amount of solvent hot water (70° C. to 80° C.), homogenizing the mixture for 10 minutes with a high-shear homogenizer to obtain a suspension with a solid content about 30%, and continuously stirring the suspension for later use; [0092] 2) slowly pouring the suspension in the step 1) into an enteric material Utrecht FS 30D, stirring with a common stirrer at a medium speed at the same time, and then filtering the suspension with a 40-mesh sieve for later use; [0093] 3) adding an adhesive and a strong liquid sorbent into an EMG2-6 high-shear granulator for pre-mixing for 5 minutes, after uniformly mixing the mixture, spraying the suspension obtained in step 2) into the granulator within 1-3 minutes, and continuing stirring for 2 minutes to obtain a soft material with an appropriate wetting degree; [0094] 4) wet-grading the soft material in step 3) with a 40-mesh swing granulator; [0095] 5) drying the material obtained in the step 4), and dry-grading the obtained dried granules by using a sieve with a pore diameter of 15 meshes to obtain sustained-release granules; [0096] 6) preparing a gel skeleton part by a high-shear granulating process; adding a hydrophilic gel material and a filler into the high-shear granulator and uniformly mixing, spraying solvent purified water into the material in the granulator, and continuously stirring the mixture to obtain a soft material with an appropriate wetting degree; [0097] 7) wet-grading the soft material in step 2) with a rotary Comil pulverizer under an 8*8 mm square hole sieve; [0098] 8) drying the material obtained in the step 3), and dry-grading the obtained dried granules by using a sieve with a pore diameter of 20 meshes to obtain gel skeleton granules; [0099] 9) mixing the sustained-release granules, the gel skeleton granules and a lubricant in a mixing barrel for 20 minutes to obtain blended granules; and [0100] 10) tableting the blended granules with a high-speed rotary tablet press, and selecting a Φ10 mm round die, each tablet containing 10 mg of apixaban, to obtain apixaban sustained-release tablets.

[0101] In Embodiment 18, an acid dissolution rate of a certain amount of the sustained-release granules (containing about 10 mg of apixaban) was 60%. A dissolution situation of the prepared tablets was shown in Table 11 below, and a dissolution curve was shown in FIG. 3.

Embodiment 19

[0102] The formula and dose ratio used in Embodiment 19 were shown in Table 9 below, wherein d90 in particle size distribution of lenalidomide was 7.5 microns, and the total weight of blended granules was 500 g.

TABLE-US-00009 TABLE 9 Embodiment 19 Percentage of total Parts by tablet Material weight weight Sustained- API Lenalidomide 20 3.45% release Enteric Eudragit S100 60 10.34% granule material part Anti-sticking Talcum powder 5 0.86% agent Plasticizer Triethyl citrate 10 1.72% Solvent Ethanol* 500 — Strong liquid Microcrystalline 200 34.48% sorbent cellulose Gel Hydrophilic gel Sodium alginate 130 22.41% skeleton material part Filler Pregelatinized 150 25.86% starch Solvent Purified water* Appro- — priate Lubricant Magnesium 5 0.86% stearate Tablet core weight 580 mg Gastric Coating Opadry 85F18422 weight increment of coating material 3% of tablet core weight Content uniformity 7.2 A + 2.2 S

[0103] The solvent was dried and removed during processing.

[0104] Preparation process steps of Embodiment 19: [0105] 1) referring to Embodiment 1 for the preparation process of sustained-release granule part; [0106] 2 preparing a gel skeleton part by a fluidized bed granulating process: adding a hydrophilic gel material and a filler into a granulating fluidized bed, mixing for 10 minutes, spraying solvent purified water into the materials in a granulator, controlling a temperature of the materials at about 40° C. and an air volume at 1,103 m/h for granulation, and drying for 30 minutes after spraying to obtain dried granules; [0107] 3) dry-grading the dried granules obtained in step 2) by a sieve with a pore diameter of 20 meshes to obtain gel skeleton granules. [0108] 4) mixing the sustained-release granules, the gel skeleton granules and a lubricant in a mixing barrel for 20 minutes to obtain blended granules; and [0109] 5) tableting the blended granules by a high-speed rotary tablet press, selecting a Φ12 mm round die, and tableting according to the target tablet weight to obtain lenalidomide sustained-release tablets; and [0110] 6) dispersing a gastric coating material in purified water to obtain a suspension with a solid content of 10%, placing uncoated tablets in a high-efficiency porous coating machine, spraying a suspension for coating, and coating according to a weight increase of 3% of a tablet core weight to obtain lenalidomide sustained-release tablets.

[0111] An acid dissolution rate of the sustained-release granules in Embodiment 19 was 68%, a dissolution rate of the prepared tablets was shown in Table 11 below, and a dissolution curve was shown in FIG. 3.

Embodiment 20

[0112] The formula and dose ratio used in Embodiment 20 were shown in Table 10 below, wherein d90 in particle size distribution of lenalidomide was 10 microns, and the total weight of blended granules was 500 g.

TABLE-US-00010 TABLE 10 Embodiment 20 Percentage of total Parts by tablet Material weight weight Sustained- API Tofacitinib 22 4.07% release granule Enteric Eudragit FS 30 D* 44 8.15% part material Anti-sticking Talcum powder 10 1.85% agent Plasticizer Triethyl citrate 4 0.74% Solvent Purified water ** Appro- — priate Strong liquid Microcrystalline 100 18.52% sorbent cellulose Gel skeleton Hydrophilic gel Carbomer 980 80 14.81% part material Hydrophilic gel Hydroxypropyl 80 14.81% material cellulose HF Filler Pregelatinized 150 27.78% starch Solvent Purified water Appro- — priate Lubricant Magnesium stearate 5 0.93% Tablet weight mg 565 Content uniformity 6.1 A + 2.2 S *Based on the weight of solid matters in Utrecht aqueous dispersion. ** The dose of the purified water comprised the amount of water in Utrecht aqueous dispersion and the added amount of water. The purified water was dried and removed during processing. In the prescription, other components except the strong liquid sorbent and the adhesive were mixed with the solvent to prepare the suspension, and the dose of the solvent used was about 20%-25% of the solid contents in the suspension.

[0113] Preparation process steps of Embodiment 20: [0114] 1) referring to Embodiment 1 for the preparation process of sustained-release granule part; [0115] 2) preparing a gel skeleton part by a high-shear granulating process; adding sustained-release granules, a hydrophilic gel material and a filler into a high-shear granulator, after uniformly mixing, spraying solvent purify water into the material in the granulator, granulating, spraying solvent purified water into the materials in the granulator, and continuously stirring the mixture to obtain a soft material with an appropriate wetting degree; [0116] 3) wet-grading the soft material in step 2) with a rotary Comil pulverizer under an 8*8 mm square hole sieve; [0117] 4) drying the material obtained in the step 3), and dry-grading the obtained dried granules by using a sieve with a pore diameter of 20 meshes to obtain graded granules; [0118] 5) mixing the graded granules obtained in the step 4) and a lubricant in a mixing barrel for 20 minutes to obtain blended granules; and [0119] 6) tableting the blended granules by a high-speed rotary tablet press, selecting a Φ11mm round die, and tableting according to the target tablet weight to obtain tofacitinib sustained-release tablets.

[0120] In Embodiment 20, an acid dissolution rate of a certain amount of the sustained-release granules (containing about 22 mg of tofacitinib) was 66%. A dissolution situation of the prepared tablets was shown in Table 11 below, and a dissolution curve was shown in FIG. 3.

TABLE-US-00011 TABLE 11 Dissolution rate (%) Time/hour 0 1 2 3 6 9 12 16 20 24 Embodiment 18 0 7 12 21 40 55 72 89 95 99 Embodiment 19 0 8 16 32 55 65 70 82 91 99 Embodiment 20 0 10 21 29 46 52 59 82 93 98

COMPARATIVE EXAMPLE 1

[0121] To distinguish the difference between the present invention and the disclosed technology, the inventor referred to the preparation process of a solid dispersion disclosed in CN1204895, and adopted the similar prescription of sustained-release granules in Embodiment 1 of the present invention to prepare samples for comparison. [0122] (1) A solid dispersion of apremilast was prepared with reference to the method in CN1204895, wherein 10 g of apremilast and 20 g of Eudragit S100 powder were dissolved in ethanol needing to be more than 15 L first; according to the prescription of Embodiment 1 in the present invention, the ethanol used to prepare the same 10 g of apremilast sample was less than 1 L, which significantly reduced the dose of the organic solvent. [0123] (2) Because a preparation method of a skeleton tablet solid dispersion in CN1204895 was not fully disclosed, it was found that the solid substance was not completely dried by evaporating the solvent in an oven at 60° C. for 48 hours in a beaker containing 200 ml of solution A by the common drying method, and it would take a lot of time to continue drying. In Embodiment 1 of the present invention, the common fluidized bed granulator was used to spray the suspension onto the strong liquid sorbent quickly to complete the granulation operation, which could control the time within 60 minutes, and had a good drying effect.

[0124] Therefore, compared with the method recorded in CN1204895, the present invention can significantly reduce the dose of the organic solvent, shorten the drying time, save energy, protect the environment and have high efficiency.

COMPARATIVE EXAMPLE 2

[0125] In Comparative Example 2, samples were prepared with reference to the similar prescription of the sustained-release granules in Embodiment 5 of the present invention, except that lactose with poor liquid adsorption capacity was used to replace the strong liquid sorbent microcrystalline cellulose, and the obtained sustained-release granules were prepared into tablets by the prescription process in Embodiment 14.

[0126] During the experiment, it was found that particle sizes of the sustained-release granules were different, and stratification was easy to occur. The samples were tested, and an acid dissolution rate of the sustained-release granules of Comparative Example 2 was 91%, which exceeded the upper limit of the control target by 80%. Content uniformity (A+2.2S) of the tablets was 16.2, exceeding a qualified limit of 15; and the dissolution rate of the tablets was obviously too fast, as shown in Table 12 below.

TABLE-US-00012 TABLE 12 Dissolution rate (%) Time/hour 0 1 2 3 6 9 12 16 20 24 Comparative 0 21 35 49 67 82 92 95 97 97 Example 2

COMPARATIVE EXAMPLES 3 TO 4

[0127] In Comparative Example 3 and Comparative Example 4, tablets were prepared with reference to the sustained-release granule prescription in Embodiment 6 and the prescription in Embodiment 15 of the present invention, wherein in the sustained-release granule prescription in Comparative Example 3, the tablets of Comparative Example 3 were obtained by mixing the sustained-release granule powder with hydroxypropyl methylcellulose K15M PH DC, lactose and magnesium stearate without separate granulation. When granulating the sustained-release granules according to the prescription of Comparative Example 4, bulk drugs were mixed with polyvidone K30 and sodium carboxymethyl starch, and an enteric-coated material, an anti-sticking agent, a plasticizer and a surfactant were separately prepared into a suspension. The subsequent spray-granulation and tableting process was carried out according to Embodiment 15 to obtain tablets of Comparative Example 4.

[0128] The samples were detected, and content uniformity (A+2.2S) 2S of the tablets of

[0129] Comparative Example 3 and Comparative Example 4 were 17.2 and 18.3 respectively, exceeding the qualified limit of 15; a dissolution rate of the tablets of Comparative Example 3 was also obviously too fast, and final dissolution of Comparative Example 4 was incomplete. A specific dissolution rate was shown in Table 13 below.

TABLE-US-00013 TABLE 13 Dissolution rate (%) Time/hour 0 1 2 3 6 9 12 16 20 24 Comparative 0 22 35 45 64 76 85 91 92 95 Example 3 Comparative 0 19 32 41 55 64 68 74 76 79 Example 4

[0130] Compared with Comparative Example 3 and Comparative Example 4, Embodiment 15 adopting the content of the present invention effectively ensures that the content uniformity of the tablets is within an acceptable range, and the tablet dissolution is slow and lasting, and the final dissolution is complete (the dissolution rate is more than 80% in 20 hours).

[0131] In conclusion, according to the oral sustained-release composition of the insoluble drug disclosed by the present invention, the suspension of bulk drugs was prepared into the sustained-release granules with quick release, sustained release and controlled release by spraying the suspension with the enteric material having high pH sensitivity, and then further sustained-released by the hydrophilic gel material to form multiple sustained-release to the drug; meanwhile, the full dissolution of the insoluble drug can be effectively ensured, and the phenomenon of incomplete dissolution in the insoluble drug can be avoided through the dispersion and controlled release of the enteric material. The samples prepared according to the present invention have good content uniformity, long dissolution and release time, simple process and strong practicability.