OSELTAMIVIR FORMULATION

Abstract

An oseltamivir formulation and a preparation method of the formulation, the method being simple to operate, having good reproducibility, and being suitable for manufacture. The oseltamivir formulation includes oseltamivir or a salt thereof and a sustained-release material. The formulation may be a single-phase release formulation, a dual-phase release formulation, a three-phase release formulation, or a multi-phase release formulation having more than three phases. The formulation is administered once-daily and can achieve sustained release of at least 24 hours or longer, which can reduce the times of administration and avoid peak-to-valley fluctuations, thereby improving the compliance and safety of patients.

Claims

1-43. (canceled)

44. An oseltamivir formulation comprising oseltamivir or a salt thereof, the formulation being effective at a once-daily dosage to a patient in need thereof.

45. The oseltamivir formulation of claim 44, wherein at least one of: (i) a release amount of oseltamivir for any 1 h time period of ≤4 h is 25%-55%; (ii) a release amount of oseltamivir in the first hour is 25%-55%; (iii) a release amount of oseltamivir at 4 h is 25%-90%; (iv) a release amount of oseltamivir at 10 h is greater than 70%; and (v) a release amount of oseltamivir at 10 h is 70%-99%.

46. The oseltamivir formulation of claim 44, wherein at least one of: (i) a weight ratio of oseltamivir is 3%-50% of a total weight of the formulation; (ii) after administration of a once-daily dose, a peak-to-valley ratio of a plasma concentration in vivo of an oseltamivir active metabolite within 24 h is less than 2.5:1; and (iii) the oseltamivir formulation has a single-dose strength of 60 mg-300 mg by weight of oseltamivir.

47. The oseltamivir formulation of claim 44, further comprising at least one sustained-release material, wherein at least one of: (i) a weight ratio of the sustained-release material is 3%-50% of a total weight of the formulation; or (ii) the sustained-release material includes at least one selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, poly oxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax, a 30% dispersion of polyvinyl acetate, a blend of polyvinyl acetate and povidone, cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and paraffin.

48. The oseltamivir formulation of claim 44, further comprising at least one sustained-release material, wherein a weight ratio of oseltamivir is 3%-50% of a total weight of the formulation, and a release amount of oseltamivir at 4 h is 25%-90%, and a release amount of oseltamivir at 10 h is greater than 70%.

49. The oseltamivir formulation of claim 44, further comprising a sustained-release part containing oseltamivir or salt thereof and an immediate-release part containing oseltamivir or salt thereof.

50. The oseltamivir formulation of claim 49, wherein, in a single-dose, an oseltamivir strength in the immediate-release part is 10 mg-75 mg, and an oseltamivir strength in the sustained-release part is 30 mg-225 mg.

51. The oseltamivir formulation of claim 49, wherein the oseltamivir formulation is effective for treatment of influenza A or influenza B in adults, after administration of a once-daily dose, a plasma concentration in vivo of an oseltamivir active metabolite within 24 h is greater than 100 ng/mL; and the oseltamivir formulation has a single-dose strength of 150 mg-300 mg by weight of oseltamivir.

52. The oseltamivir formulation of claim 49, wherein the oseltamivir formulation is effective for treatment of influenza A or influenza B in children, after administration of a once-daily dose, a plasma concentration in vivo of an oseltamivir active metabolite within 24 h is greater than 100 ng/mL; and the oseltamivir formulation has a single-dose strength of 60 mg-180 mg by weight of oseltamivir.

53. The oseltamivir formulation of claim 49, wherein after administration of a once-daily dose, at least one of (i) a plasma concentration in vivo of an oseltamivir active metabolite within 2 h is more than 20% of Cmax, and a plasma concentration in vivo within 24 h is more than 30% of Cmax, and (ii) the oseltamivir formulation continuously releases oseltamivir for a period of at least 24 h.

54. The oseltamivir formulation of claim 49, wherein the plasma concentration in vivo of an oseltamivir active metabolite is greater than 100 ng/mL, and a maintenance time is greater than 16 h.

55. The oseltamivir formulation of claim 44, wherein the oseltamivir formulation is a biphasic release formulation comprising a sustained-release part containing oseltamivir or salt thereof and an immediate-release part containing oseltamivir or salt thereof.

56. The oseltamivir formulation of claim 55, wherein, by total weight of oseltamivir in the formulation, at least one of (i) a weight ratio of oseltamivir in the immediate-release part is 20%-50%, and (ii) a weight ratio of oseltamivir in the immediate-release part and in the sustained-release part is 1:4-1:1.

57. The oseltamivir formulation of claim 55, further comprising a sustained-release material, the sustained-release material comprising at least one of hydroxypropyl methyl cellulose and methacrylic acid-ethyl acrylate copolymer, wherein a weight ratio of the sustained-release material is 3%-50% of a total weight of the formulation, a weight ratio of hydroxypropyl methyl cellulose is 4%-30% of a total weight of the formulation, and a weight ratio of methacrylic acid-ethyl acrylate copolymer is 0-35% a total weight of the formulation.

58. The oseltamivir formulation of claim 44, wherein a release amount of oseltamivir at 1 h is 25%-55%, a release amount of oseltamivir at 4 h is 25%-90%, a release amount of oseltamivir at 10 h is greater than 70%, and a weight ratio of oseltamivir is 3%-50% a total weight of the formulation, and the formulation further comprises at least one sustained-release material, a weight ratio of the sustained-release material is 3%-50% of a total weight of the formulation, after administration of a once-daily dose, a peak-to-valley ratio of a plasma concentration in vivo of an oseltamivir active metabolite within 24 h is less than 2.5:1, the oseltamivir formulation is effective for treatment of influenza A or influenza B in adults or children, and after administration of the once-daily dose, a plasma concentration in vivo of the oseltamivir active metabolite within 24 h is greater than 100 ng/mL, a plasma concentration in vivo of the oseltamivir active metabolite at 2 h is more than 20% of Cmax, and a plasma concentration in vivo at 24 h is more than 30% of Cmax.

59. A tablet, a capsule, or a suspension comprising the formulation of claim 44.

60. The oseltamivir formulation of claim 44, further comprising a sustained-release part and an immediate-release part, the sustained-release part comprising a first bead, and the immediate-release part comprising a second bead, wherein: (i) the first bead is prepared by uniformly mixing oseltamivir and a matrix sustained-release material, and the second bead is prepared by uniformly mixing oseltamivir and a matrix material, (ii) the first bead contains oseltamivir and an exterior that is coated with a sustained-release coating layer formed by high polymer and pharmaceutical excipients, and the second bead contains oseltamivir and an exterior that is coated with an immediate-release coating layer formed by a water-soluble polymer film-forming material and a plasticizer, (iii) the first bead is prepared by an extrusion spheronization method after mixing oseltamivir with the matrix sustained-release material, and the second bead is prepared by the extrusion spheronization method after mixing oseltamivir with the pharmaceutical excipients, or (iv) the first bead is prepared by spraying oseltamivir and a sustained-release film-forming material on a blank pellet, and the second bead is prepared by spraying oseltamivir and an immediate-release coating material on a blank pellet.

61. The oseltamivir formulation of claim 60, wherein (i) the first bead and the second bead are mixed and compressed into a double-layer or multi-layer tablet, (ii) the first bead and the second bead are mixed and directly filled in capsules, or (iii) the first bead and the second bead are mixed and then bagged.

62. A preparation method of the oseltamivir formulation of claim 60, the method comprising one process selected from the following groups of processes: Group A: (1) obtaining the immediate-release part by wrapping the immediate-release coating layer formed by the water-soluble polymer film-forming material, the plasticizer and oseltamivir around a core of the blank pellet; (2) obtaining the sustained-release part by wrapping the sustained-release coating layer formed by the high polymer and the pharmaceutical excipients around the immediate-release part obtained in step (1); and (3) filling the immediate-release part obtained in step (1) and the sustained-release part obtained in step (2) into capsules, or compressing into tablets, or bagging to obtain the oseltamivir formulation; Group B: (1) obtaining the sustained-release part by wrapping the sustained-release coating layer formed by the high polymer and the other pharmaceutical excipients around the first bead containing oseltamivir; and (2) obtaining the oseltamivir formulation by wrapping the immediate-release coating layer formed by the water-soluble polymer film-forming material, the plasticizer and oseltamivir around the sustained-release part obtained in step (1); Group C: (1) obtaining the sustained-release part by wrapping the sustained-release coating layer formed by oseltamivir, the high polymer and the pharmaceutical excipients around the core of the blank pellet; and (2) obtaining the oseltamivir formulation by wrapping the immediate-release coating layer formed by the water-soluble polymer film-forming material, the plasticizer and oseltamivir around the sustained-release part obtained in step (1); and Group D: obtaining the oseltamivir formulation by wrapping the immediate-release coating layer formed by the water-soluble polymer film-forming material, the plasticizer and oseltamivir around the sustained-release part comprising the first bead containing oseltamivir and the matrix sustained-release material.

63. The preparation method of claim 62, wherein at least one of: (i) the high polymer comprises at least one selected from the group consisting of ethyl cellulose, cellulose acetate, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, carnauba wax, a 30% dispersion of polyvinyl acetate, and a blend of polyvinyl acetate and povidone, (ii) the pharmaceutical excipients comprise one selected from the group consisting of plasticizers, anti-sticking agents, emulsifiers, and porogens; (iii) the water-soluble polymer film-forming material comprises at least one selected from the group consisting of hydroxypropyl methyl cellulose, povidone, polyvinyl alcohol, and hydroxypropyl cellulose, (iv) the matrix sustained-release material comprises at least one selected from group consisting of hydroxypropyl methyl cellulose, polyoxyethylene, polyvinyl alcohol, ethyl cellulose, glyceryl behenate, chitosan, carbomer, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and paraffin, and (v) the immediate-release coating layer is externally wrapped with an isolation layer, and the isolation layer comprises at least one selected from the group consisting of a water-soluble polymer film-forming material, a plasticizer, an anti-sticking agent, and an opacifier.

64. The tablet, the capsule, or the suspension of claim 59, wherein the tablet is a double-layer tablet, one layer of the double-layer tablet comprising an immediate-release part and the other layer comprising a sustained-release part, and the sustained-release part forms a tablet core, and the immediate-release part is wrapped around the tablet core.

Description

DESCRIPTION OF THE DRAWINGS

[0123] FIG. 1 is the drug-time curve of the oseltamivir active metabolite in vivo after oral administration of the oseltamivir formulation prepared in Example 12 of the present invention in an adult's fasting state.

[0124] FIG. 2 is the drug-time curve of the oseltamivir active metabolite in vivo after oral administration of the oseltamivir formulation prepared in Example 12 of the present invention in an adult's feeding state.

[0125] FIG. 3 is the drug-time curve of the oseltamivir active metabolite in vivo after oral administration of the oseltamivir formulation prepared in Example 18 of the present invention in an adult's feeding state.

EXAMPLES

Example 1

[0126]

TABLE-US-00001 Formulation Form 150 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 40.42 Microcrystalline cellulose 39.65 Polyvinylpyrrolidone 2.05 Sodium chloride 5.00 Microcrystalline cellulose 8.88 Micro powder silica 1.00 Sodium stearate fumarate 3.00 Total 100.00 Controlled- Cellulose acetate 6.00 release film Polyethylene glycol 6000 1.50 Purified water 6.00 acetone 86.50 Total 100.00 Immediate- Oseltamivir phosphate 7.88 release layer Hydroxypropyl methylcellulose E5 4.00 Polyethylene glycol 400 2.00 Purified water 86.21 Total 100.00 Isolation Opadry 85F 15.00 layer Purified water 85.00 Total 100.00

[0127] Preparation of tablet core: oseltamivir phosphate and microcrystalline cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, and then filler, penetration enhancer and lubricant were added, the mixture was pressed into tablet to obtain a 100 mg oseltamivir tablet core.

[0128] Controlled-release film: the controlled-release film coating solution was prepared and used to coat the above-mentioned tablet core, the percentage of coating weight gain in the tablet core was 8%.

[0129] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned controlled-release coated tablet, and the coating film contains 50 mg of oseltamivir.

[0130] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 2%.

Example 2

[0131]

TABLE-US-00002 Formulation Form 60 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 42.04 Microcrystalline cellulose 101QD 36.81 Polyvinylpyrrolidone 2.15 Sodium chloride 5.00 Microcrystalline cellulose PH102 10.00 Micro powder silica 1.00 Sodium stearate fumarate 3.00 Total 100.00 Controlled- Methacrylic acid-ethyl acrylate 2.00 release film copolymer RL Methacrylic acid-ethyl acrylate 8.00 copolymer RS Tween 80 0.20 Triethyl citrate 2.00 Glyceryl Monostearate 0.50 Purified water 87.30 Total 100.00 Immediate- Oseltamivir phosphate 7.88 release layer Hydroxypropyl methylcellulose E5 4.00 Polyethylene glycol 400 2.00 Purified water 86.12 Total 100.00 Isolation Opadry 85F 15.00 layer Purified water 85.00 Total 100.00

[0132] Preparation of tablet core: oseltamivir phosphate and microcrystalline cellulose 101QD were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, and then filler, penetration enhancer and lubricant were added, the mixture was pressed into tablet to obtain a 40 mg oseltamivir tablet core.

[0133] Controlled-release film 1: the controlled-release film coating solution was prepared and used to coat the above-mentioned tablet core, the percentage of coating weight gain in the tablet core was 10%.

[0134] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned controlled-release coated tablet, and the coating film contains 20 mg of oseltamivir.

[0135] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 2%.

Example 3

[0136]

TABLE-US-00003 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 41.15 Mannitol 29.52 Polyvinylpyrrolidone 1.23 Microcrystalline cellulose 16.60 Sodium chloride 7.50 Micro powder silica 1.00 Sodium stearate fumarate 3.00 Total 100.00 Controlled-release Ethyl cellulose 8.00 film Polyethylene glycol 4000 4.00 Triethyl citrate 2.00 ethanol 86.00 Total 100.00 Immediate-release Oseltamivir phosphate 7.88 layer Hydroxypropyl 4.00 methylcellulose E5 Polyethylene glycol 400 2.00 Purified water 86.21 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00

[0137] Preparation of tablet core: oseltamivir phosphate and mannitol were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, and then filler, penetration enhancer and lubricant were added, the mixture was pressed into tablet to obtain a 130 mg oseltamivir tablet core.

[0138] Controlled-release film: the controlled-release film coating solution was prepared and used to coat the above-mentioned tablet core, the percentage of coating weight gain in the tablet core was 8%.

[0139] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned controlled-release coated tablet, and the coating film contains 50 mg of oseltamivir.

[0140] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 2%.

Example 4

[0141]

TABLE-US-00004 Formulation Form 90 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 30.32 tablet core Hydroxypropyl methyl 64.83 cellulose K100 LV Polyvinylpyrrolidone 0.85 Micro powder silica 1.00 Sodium stearyl fumarate 3.00 Total 100.00 Immediate-release Oseltamivir phosphate 7.88 layer Hydroxypropyl 4.00 methylcellulose E5 Polyethylene glycol 400 2.00 Purified water 86.21 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0142] Preparation of tablet core: oseltamivir phosphate and hydroxypropyl methylcellulose K100 LV were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, and dry granulated in sequence, then lubricant was added and the mixture was pressed into tablet to obtain a 60 mg oseltamivir sustained-release tablet core.

[0143] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned sustained-release tablet core, and the coating film contains 30 mg of oseltamivir.

[0144] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 2%.

Example 5

[0145]

TABLE-US-00005 Formulation Form 150 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 41.04 layer Microcrystalline cellulose 10.46 PH101 Hydroxypropyl methyl 10.00 cellulose K4M Hydroxypropyl methyl 30.00 cellulose K100 LV Polyvinylpyrrolidone 2.50 Micro powder silica 1.00 Sodium stearyl fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 43.79 layer Microcrystalline cellulose 39.21 Polyvinylpyrrolidone 3.00 Sodium carboxymethyl 10.00 starch Micro powder silica 1.00 Sodium stearyl fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 6

[0146]

TABLE-US-00006 Formulation Form 200 mg sustained-release formulation of oseltamivir Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 39.41 layer Microcrystalline cellulose 32.06 Hydroxypropyl methyl 20.00 cellulose K100 LV Polyvinylpyrrolidone 2.53 Micro powder silica 1.00 Sodium stearyl fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 43.79 layer Microcrystalline cellulose 39.21 Polyvinylpyrrolidone 3.00 Sodium carboxymethyl 10.00 starch Micro powder silica 1.00 Sodium stearyl fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Preparation Method of Example 5 and Example 6

[0147] Preparation of sustained-release layer bulk granules: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, and then lubricant was added to obtain the sustained-release layer bulk granules.

[0148] Preparation of immediate-release layer bulk granules: oseltamivir phosphate and microcrystalline cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, dry granulated in sequence, and then lubricant was added to obtain the immediate-release layer bulk granules.

[0149] Preparation of double-layer tablet: a double-layer tablet press was used to fill 100 mg or 150 mg of sustained-release layer bulk granules, then pre-pressed to obtain the sustained-release layer tablet core; then 50 mg of immediate-release layer granules were filled and pressed into tablet to obtain the immediate-release and sustained-release double-layered tablet core.

[0150] Isolation layer: an isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release and sustained-release double-layered tablet core, and the percentage of coating weight gain in the tablet core was 2%.

Example 7

[0151]

TABLE-US-00007 Formulation Form 10 mg immediate-release granules Formulation component Formulation ratio (%) Oseltamivir phosphate 8.54 Sucrose 90.59 Polyvinylpyrrolidone 0.87 Total 100.00 50 mg sustained-release granules Formulation component Formulation ratio (%) Immediate-release Oseltamivir phosphate 8.54 granules Microcrystalline 90.59 cellulose Polyvinylpyrrolidone 0.87 Total 100.00 Sustained-release Ethyl cellulose 8.00 layer Polyethylene glycol 6000 4.00 Triethyl citrate 2.00 Purified water 6.00 ethanol 80.00 Total 100.00 Formulation component Formulation ratio (%) Blank granules Sucrose 97.41 Xanthan Gum 1.00 Sodium citrate dihydrate 0.50 Sodium benzoate 0.25 Polyvinylpyrrolidone 0.84 Total 100.00 60 mg oseltamivir sustained-release formulation 10 mg immediate-release granules 3.25 50 mg sustained-release granules 21.94 Blank granules 71.06 Sucralose 2.00 Orange essence 0.75 Micro powder silica 1.00 Total 100.00

[0152] Preparation of immediate-release granules: oseltamivir phosphate and sucrose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, and dry granulated in sequence to obtain the immediate-release granules.

[0153] Preparation of sustained-release granules: sustained-release coating solution was prepared, then immediate-release granules were taken and sustained-release coated, the percentage of coating weight gain in the granules was 35%.

[0154] Preparation of blank granules: all components (except polyvinylpyrrolidone) were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, and dry granulated in sequence to obtain blank granules.

[0155] Preparation of total bulk granules: 10 mg of immediate-release granules, 50 mg of sustained-release granules, blank granules were weighed, then flavoring and glidant were added, and the mixture was mixed to obtain final bulk granules, then bagged to obtain sustained-release dry suspension.

Example 8

[0156]

TABLE-US-00008 Formulation Form Component Formulation ratio (%) 50 mg immediate-release pellets Substrate Microcrystalline pellet — Immediate-release Oseltamivir phosphate 7.88 layer Hydroxypropyl methyl 4.00 cellulose E5 Polyethylene glycol 2.00 400 Purified water 86.21 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00 100 mg sustained-release pellets Substrate Immediate-release pellets — Sustained-release Ethyl cellulose 8.00 coating Polyethylene glycol 6000 4.00 Triethyl citrate 2.00 Purified water 6.00 ethanol 80.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0157] Preparation of immediate-release pellets: an immediate-release layer coating solution was prepared, and the microcrystalline pellet was used as substrate for coating, after the immediate-release layer coating was completed, a 2% weight-increased isolation layer was wrapped around the pellet to obtain immediate-release pellets;

[0158] Preparation of sustained-release pellets: a sustained-release coating solution was prepared, the immediate-release pellets were used as substrate for sustained-release coating, and the percentage of coating weight gain in the immediate-release pellets was 10%, after the sustained-release layer coating was completed, a 2% weight-increased isolation layer was wrapped around the pellet to obtain sustained-release pellets;

[0159] Capsule filling: 50 mg of immediate-release pellets and 100 mg of sustained-release pellets were filled into capsules to obtain oseltamivir phosphate biphasic release capsules.

Example 9

[0160]

TABLE-US-00009 Formulation Form Component Formulation ratio (%) 50 mg immediate-release pellets Immediate-release Oseltamivir phosphate 36.49 pellet Microcrystalline cellulose 51.16 Pregelatinized starch 10.00 Polyvinylpyrrolidone 2.35 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00 100 mg sustained-release pellets Substrate Immediate-release pellet — Sustained-release Ethyl cellulose 8.00 coating Polyethylene glycol 6000 4.00 Triethyl citrate 2.00 Purified water 6.00 ethanol 80.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0161] Preparation of immediate-release pellets: according to the immediate-release pellet formulation, all components (except polyvinylpyrrolidone) were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, extruded and spheronized, dried and screened in turn; the isolation layer coating solution was prepared the sieved pellets were taken and coated, the percentage of coating weight gain in pellets was 2%, and the immediate-release pellets were obtained;

[0162] Preparation of sustained-release pellets: according to the sustained-release coating formulation, a coating solution was prepared, and the immediate-release pellets were used as substrate for coating, and the percentage of coating weight gain in the immediate-release pellets was 12%, the sustained-release pellets were obtained. According to the formulation, the isolation layer coating solution was prepared, the sustained-release pellets were taken and coated, the percentage of coating weight gain in the sustained-release pellets was 2%, the final sustained-release pellets were obtained;

[0163] Capsule filling: 50 mg of immediate-release pellets and 100 mg of sustained-release pellets were filled into capsules to obtain oseltamivir phosphate biphasic release capsules.

Example 10

[0164]

TABLE-US-00010 Formulation Form component Formulation ratio (%) 75 mg pulsed-release pellets Immediate-release Oseltamivir phosphate 43.78 pellets Microcrystalline cellulose 28.02 Mannitol 10.00 Sodium chloride 5.00 Cross-linked 10.00 polyvinylpyrrolidone Polyvinylpyrrolidone 3.20 Total 100.00 Sustained-release Ethyl cellulose 8.00 layer Polyethylene glycol 4000 4.00 Triethyl citrate 1.50 Purified water 6.00 ethanol 80.50 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00 225 mg delayed sustained-release pellets drug-layered Oseltamivir phosphate 49.26 pellet Microcrystalline 22.54 cellulose Polyoxyethylene 205 10.00 Sodium chloride 5.00 Cross-linked 10.00 polyvinylpyrrolidone Polyvinylpyrrolidone 3.20 Total 100.00 Sustained-release Ethyl cellulose 8.00 layer Polyethylene glycol 4.00 4000 Triethyl citrate 1.50 Purified water 6.00 ethanol 80.50 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0165] 75 mg pulsed-release pellets:

[0166] Preparation of immediate-release pellets: according to the formulation of immediate-release pellets, all components (except polyvinylpyrrolidone) were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulated (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then extruded and spheronized, dried and sieved in sequence;

[0167] Preparation of pulsed-release pellets: a sustained-release coating solution was prepared, immediate-release pellets were taken and coated, the percentage of coating weight gain in the immediate-release pellets was 8%, and the sustained-release pellets were obtained. the isolation layer coating solution was prepared, the sustained-release pellets were taken and coated, the percentage of coating weight gain in the sustained-release pellets was 2%, and the final pulsed-release pellets were obtained.

[0168] 225 mg Delayed Sustained-Release Pellets

[0169] Preparation of sustained-release pellets: according to the formulation of drug-layered pellet, all components (except polyvinylpyrrolidone) were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then extruded and spheronized, dried and sieved in turn to obtain the drug-layered pellets;

[0170] Preparation of pulsed sustained-release pellets: a sustained-release coating solution was prepared, the drug-layered pellets were taken and coated, the percentage of coating weight gain in sustained-release pellets was 10%. the isolation layer coating solution was prepared, the pulsed sustained-release pellets were taken and coated, the percentage of coating weight gain in the pulsed sustained-release pellets was 2%, then the delayed sustained-release pellets were obtained.

[0171] Capsule filling: 75 mg of pulsed-release pellets and 225 mg of delayed sustained-release pellets were filled into capsules to obtain oseltamivir phosphate delayed-release capsules.

Example 11

[0172]

TABLE-US-00011 Formulation Form 150 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 41.04 layer Microcrystalline cellulose 30.00 101 QD Hydroxypropyl methyl 15.00 cellulose K100 LV Polyvinylpyrrolidone 3.00 Lactose 4.96 Micro powder silica 1.00 Sodium stearyl fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 43.79 layer Microcrystalline cellulose 39.21 Polyvinylpyrrolidone 3.00 Sodium carboxymethyl 10.00 starch Micro powder silica 1.00 Sodium stearyl fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0173] Preparation of sustained-release layer bulk granules: according to the formulation of sustained-release layer, oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, lactose and lubricant were added to obtain the sustained-release layer bulk granules.

[0174] Preparation of immediate-release layer bulk granules: oseltamivir phosphate and microcrystalline cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, disintegrant and lubricant were added to obtain the immediate-release layer bulk granules.

[0175] Preparation of double-layer tablet: a double-layer tablet press was used to fill 100 mg of sustained-release layer bulk granules, then pre-pressed to obtain the sustained-release layer tablet core; then 50 mg of immediate-release layer granules were filled and pressed into tablet to obtain the immediate-release and sustained-release double-layered tablet core.

[0176] Isolation layer: an isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release and sustained-release double-layered tablet core, and the percentage of coating weight gain in the tablet core was 2%.

Example 12

[0177]

TABLE-US-00012 Formulation Form 150 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 25.60 Microcrystalline cellulose 33.35 101QD Hydroxypropyl methyl 14.62 cellulose K100M Hydroxypropyl methyl 19.49 cellulose K100 LV Polyvinylpyrrolidone 2.56 Micro powder silica 0.97 Sodium stearyl fumarate 3.41 Total 100.00 Controlled- Hypromellose acetate succinate 6.00 release film Triethyl citrate 0.30 80% Ethanol 93.70 Total 100.00 Immediate- Oseltamivir phosphate 7.88 release layer Hydroxypropyl 4.00 methylcellulose E5 Polyethylene glycol 4000 2.00 Purified water 86.21 Total 100.00 Isolation Opadry 85F 15.00 layer Purified water 85.00 Total 100.00

[0178] Preparation of tablet core: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, lubricant was added and the mixture was pressed into tablet to obtain a 120 mg oseltamivir sustained-release tablet core.

[0179] Controlled-release film: the controlled-release film coating solution was prepared and used to coat the above-mentioned sustained-release tablet core, the percentage of coating weight gain in the tablet core was 2%.

[0180] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned controlled-release coated tablet, and the coating film contains 30 mg of oseltamivir.

[0181] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 3%.

Example 13

[0182]

TABLE-US-00013 Formulation Form 300 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 67.03 tablet core Microcrystalline cellulose 7.02 Hydroxypropyl methyl 20.00 cellulose K100 Lv Polyvinylpyrrolidone 2.45 Micro powder silica 1.00 Magnesium stearate 2.50 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0183] Preparation of tablet core: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl cellulose were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, lubricant was added to obtain sustained-release layer bulk granules, then pressed into tablet to obtain a 300 mg oseltamivir sustained-release tablet core.

[0184] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned sustained-release tablet core, the percentage of coating weight gain in the tablet core was 2%.

Example 14

[0185]

TABLE-US-00014 Formulation Form Formulation component Formulation ratio (%) 50 mg immediate-release pellets Immediate-release Oseltamivir phosphate 43.78 pellets Microcrystalline cellulose 28.02 Mannitol 10.00 Sodium chloride 5.00 Cross-linked 10.00 polyvinylpyrrolidone Polyvinylpyrrolidone 3.20 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00 50 mg pulsed-release pellets Immediate-release — pellets Sustained-release Ethyl cellulose 8.00 layer Polyethylene glycol 4.00 4000 Triethyl citrate 1.50 Purified water 6.00 ethanol 80.50 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0186] 50 mg immediate-release pellets:

[0187] Preparation of immediate-release pellets: according to the immediate-release pellets formulation, all components (except polyvinylpyrrolidone) were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then extruded and spheronized, dried and screened in turn; the isolation layer coating solution was prepared the sieved pellets were taken and coated, the percentage of coating weight gain in the immediate-release pellets was 2%, and the final immediate-release pellets were obtained.

[0188] 50 mg pulsed-release pellets:

[0189] Preparation of pulsed-release pellets: a sustained-release coating solution was prepared, immediate-release pellets were taken and coated with 2 different weight gain, the percentage of coating weight gain in the pellets was 8% or 30% respectively, and the sustained-release pellets were obtained. the isolation layer coating solution was prepared, the sustained-release pellets with different coating weight gain were taken and coated, the percentage of coating weight gain in the sustained-release pellets was 2%, and the 2-4 h and 7-9 h pulsed-release pellets were obtained.

[0190] Capsule filling: 50 mg of immediate-release pellets, 50 mg of pulsed-release pellets (2-4 h release) and 50 mg of pulsed-release pellets (7-9 h release) were filled into capsules to obtain oseltamivir phosphate sustained-release capsules.

Example 15

[0191]

TABLE-US-00015 Formulation Form 150 mg sustained-release pellets Component Formulation ratio (%) Substrate Microcrystalline pellet — Permeation-enhanced Sodium chloride 5.00 layer Hydroxypropyl methyl 2.00 cellulose E5 Purified water 93.00 Total 100.00 drug layer Oseltamivir phosphate 18.00 Hydroxypropyl methyl 2.00 cellulose E5 Purified water 28.00 95% Ethanol 52.00 Total 100.00 Sustained-release Ethyl cellulose E7 8.00 layer Hydroxypropyl cellulose 0.50 EF Triethyl citrate 1.50 95% Ethanol 90.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0192] Preparation of sustained-release pellets: a permeation-enhanced layer coating solution was prepared, the microcrystalline pellet was used as substrate for coating, the percentage of coating weight gain in the pellet was 7%. Then, the drug layer was prepared permeation-enhanced layer pellet was used as substrate for coating, and the percentage of coating weight gain in permeation-enhanced layer pellet was 150%. Then, the sustained-release coating solution was prepared and the upper drug pellet was used as substrate for sustained-release coating, the percentage of coating weight gain in the upper drug pellet was 25%. Then, the isolation layer coating solution was prepared and an isolation layer was wrapped around the sustained-release layer, the percentage of coating weight gain in sustained-release pellet was 2%. Finally, 150 mg of oseltamivir sustained-release pellets were filled into capsules to obtain oseltamivir phosphate sustained-release capsules.

Example 16

[0193]

TABLE-US-00016 Formulation Form Component Formulation ratio (%) 30 mg immediate-release pellets Substrate Microcrystalline pellet — drug layer Oseltamivir phosphate 18.00 Hydroxypropyl methyl 2.00 cellulose E5 Purified water 28.00 95% Ethanol 52.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00 120 mg sustained-release pellets Substrate Microcrystalline pellet — Permeation-enhanced Sodium chloride 5.00 layer Hydroxypropyl methyl 2.00 cellulose E5 Purified water 93.00 Total 100.00 Drug layer Oseltamivir phosphate 18.00 Hydroxypropyl methyl 2.00 cellulose E5 Purified water 28.00 95% Ethanol 52.00 Total 100.00 Sustained-release Ethyl cellulose E7 8.00 layer Hydroxypropyl cellulose 0.50 EF Triethyl citrate 1.50 95% Ethanol 90.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0194] Preparation of immediate-release pellets: a drug layer coating solution was prepared according to the formulation of immediate-release pellets, and the microcrystalline pellet was used as substrate for coating, the percentage of coating weight gain in the pellet was 150%; after the coating was completed, a 2% weight-increasing isolation layer was wrapped around the drug layer to obtain immediate-release pellets;

[0195] Preparation of sustained-release pellets: according to the formulation of sustained-release pellets, the permeation-enhanced layer coating solution was prepared, and the microcrystalline pellet was used as substrate for coating, the percentage of coating weight gain in the pellet was 7%. Then, the drug layer was prepared permeation-enhanced layer pellet was used as substrate for coating, and the percentage of coating weight gain in permeation-enhanced layer pellet was 150%. Then, the sustained-release coating solution was prepared and the upper drug pellet was used as substrate for sustained-release coating, the percentage of coating weight gain in the upper drug pellet was 25%. Then, the isolation layer coating solution was prepared and the sustained-release layer was coated with an isolation layer, the percentage of coating weight gain in the sustained-release pellet was 2%, and the sustained-release pellets were obtained.

[0196] Capsule filling: 30 mg of immediate-release pellets and 120 mg of sustained-release pellets were filled into capsules to obtain oseltamivir phosphate biphasic release capsules.

Example 17

[0197]

TABLE-US-00017 Formulation Form Component Formulation ratio (%) 75 mg immediate-release pellets Substrate Microcrystalline pellet — Drug layer Oseltamivir phosphate 18.00 Hydroxypropyl methyl 2.00 cellulose E5 Purified water 28.00 95% Ethanol 52.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00 75 mg sustained-release pellets Substrate Microcrystalline pellet — Permeation-enhanced Sodium chloride 5.00 layer Hydroxypropyl methyl 2.00 cellulose E5 Purified water 93.00 Total 100.00 Drug layer Oseltamivir phosphate 18.00 Hydroxypropyl methyl 2.00 cellulose E5 Purified water 28.00 95% Ethanol 52.00 Total 100.00 Sustained-release Ethyl cellulose E7 8.00 layer Hydroxypropyl cellulose 0.50 EF Triethyl citrate 1.50 95% Ethanol 90.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0198] Preparation of immediate-release pellets: a drug layer coating solution was prepared according to the formulation of immediate-release pellets, and the microcrystalline pellet was used as substrate for coating, the percentage of coating weight gain in the pellet was 150%; after the coating was completed, a 2% weight-increasing isolation layer was wrapped around the drug layer to obtain immediate-release pellets;

[0199] Preparation of sustained-release pellets: according to the formulation of sustained-release pellets, the permeation-enhanced layer coating solution was prepared, and the microcrystalline pellet was used as substrate for coating, the percentage of coating weight gain in the pellet was 7%. Then, the drug layer was prepared permeation-enhanced layer pellet was used as substrate for coating, and the percentage of coating weight gain in permeation-enhanced layer pellet was 150%. Then, the sustained-release coating solution was prepared and the upper drug pellet was used as substrate for sustained-release coating, the percentage of coating weight gain in the upper drug pellet was 30%. Then, the isolation layer coating solution was prepared and the sustained-release layer was coated with an isolation layer, the percentage of coating weight gain in the sustained-release pellet was 2%, and the sustained-release pellets were obtained.

[0200] Capsule filling: 75 mg of immediate-release pellets and 75 mg of sustained-release pellets were filled into capsules to obtain oseltamivir phosphate biphasic release capsules.

Comparative Example 1: Weight Ratio of Oseltamivir was 2%, Content Uniformity was Poor (Compared with Example 7)

[0201]

TABLE-US-00018 Formulation Form 10 mg immediate-release granules component Formulation ratio (%) Oseltamivir phosphate 8.54 Sucrose 90.59 PVP K29/32 0.87 Total 100.00 50 mg sustained-release granules component Formulation ratio (%) Immediate-release Oseltamivir phosphate 8.54 granules Microcrystalline cellulose 90.59 Polyvinylpyrrolidone 0.87 Total 100.00 Sustained-release Ethyl cellulose 8.00 coating layer Polyethylene glycol 6000 4.00 Triethyl citrate 2.00 Purified water 6.00 ethanol 80.00 Total 100.00 component Formulation ratio (%) Blank granules Sucrose 97.41 Xanthan Gum 1.00 Sodium citrate dihydrate 0.50 Sodium benzoate 0.25 Polyvinylpyrrolidone 0.84 Total 100.00 60 mg oseltamivir sustained-release formulation 10 mg immediate-release granules 2.17 50 mg sustained-release granules 14.63 Blank granules 79.46 Sucralose 2.00 Orange essence 0.75 Micro powder silica 1.00 Total 100.00

[0202] Preparation of immediate-release granules: oseltamivir phosphate and sucrose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, and dry granulated in sequence to obtain the immediate-release granules.

[0203] Preparation of sustained-release granules: sustained-release coating solution was prepared, then immediate-release granules were taken and sustained-release coated, the percentage of coating weight gain in the granules was 35%.

[0204] Preparation of blank granules: according to the formulation of blank granules, all components (except polyvinylpyrrolidone) were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, and dry granulated in turn to obtain the blank granules.

[0205] Preparation of bulk granules: 10 mg of immediate-release granules, 50 mg of sustained-release granules, blank granules were weighed, then flavoring agent and glidant were added and mixed to obtain the final bulk granules.

[0206] Experimental results: the content uniformity of the bulk granules in Comparative Example 1 (2% oseltamivir content) is poor, and the content uniformity of the bulk granules in Example 7 (3% oseltamivir content) is qualified.

TABLE-US-00019 TABLE 1 Content uniformity of the bulk granules in Comparative Example 1 and Example 7 Content uniformity of the bulk granules (%) Sampling location Comparative Example 1 Example 7 T1 110.4 100.1 T2 105.4 99.8 T3 101.9 100.7 M1 94.3 99.5 M2 105.5 99.8 M3 92.7 98.9 B1 85.3 101.7 RSD(%) 8.24% 0.83% Formulation Form 300 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Oseltamivir phosphate 72.31 Microcrystalline cellulose 2.19 Hydroxypropyl methyl cellulose K100LV 20.00 Polyvinylpyrrolidone 1.50 Micro powder silica 1.00 Magnesium stearate 3.00 Total 100.00

[0207] Preparation of tablet cores: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methylcellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in sequence, and lubricant was added to obtain the sustained-release layer bulk granules, then compressed into tablets.

[0208] Experimental results: the tableting process showed serious sticking and punching, and the surface of the tablet was uneven.

TABLE-US-00020 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 41.15 Mannitol 29.52 Polyvinylpyrrolidone 1.23 Microcrystalline cellulose 16.60 Sodium chloride 7.50 Micro powder silica 1.00 Sodium stearate fumarate 3.00 Total 100.00 Controlled-release Ethyl cellulose 8.00 film Polyethylene glycol 4000 4.00 Triethyl citrate 2.00 Ethanol 86.00 Total 100.00 Immediate-release Oseltamivir phosphate 7.88 layer Hydroxypropyl methyl 4.00 cellulose E5 Polyethylene glycol 400 2.00 Purified water 86.21 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0209] Preparation of tablet cores: oseltamivir phosphate and mannitol were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, and dry granulated in turn, and filler, penetration enhancer and lubricant were added and the mixture was pressed into tablets to obtain 130 mg of oseltamivir tablet cores.

[0210] Controlled-release film: the controlled-release coating solution was prepared and used to coat the tablet core, the percentage of coating weight gain in the tablet core was 6%.

[0211] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned controlled-release coated tablet, and the coating film contains 50 mg of oseltamivir.

[0212] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 2%.

TABLE-US-00021 TABLE 2 Dissolution data of Comparative Example 3 and Example 3 Ph 6.8 medium dissolution (%) Comparative Example 3 Example 3 Time(h) (Mean + SD) (Mean + SD) 0.25  21 ± 15.04 20 ± 1.02 1  44 ± 10.05 42 ± 0.80 2  58 ± 12.03 56 ± 0.58 3  69 ± 15.67 67 ± 1.04 4 77 ± 8.87 75 ± 2.04 6 86 ± 7.78 85 ± 1.04 8 94 ± 8.45 92 ± 0.68 10 96 ± 2.32 96 ± 0.78 12 97 ± 1.12 98 ± 0.86 Formulation Form 90 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 19.71 Microcrystalline cellulose 5.33 Hydroxypropyl methyl 70.00 cellulose K100 LV Polyvinylpyrrolidone 0.97 Micro powder silica 1.00 Sodium stearyl fumarate 3.00 Total 100.00 Immediate-release Oseltamivir phosphate 7.88 layer Hydroxypropyl 4.00 methylcellulose E5 Polyethylene glycol 400 2.00 Purified water 86.21 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

[0213] Preparation of tablet cores: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methylcellulose were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, dry granulated in sequence, then lubricant was added and the mixture was pressed into tablets to obtain 60 mg of oseltamivir sustained-release tablet cores.

[0214] Immediate-release layer: the immediate-release layer coating solution was prepared and used to coat the above-mentioned sustained-release tablet core, and the coating film contains 30 mg of oseltamivir.

[0215] Isolation layer: the isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release coated tablet, and the percentage of coating weight gain in the immediate-release coated tablet was 2%.

[0216] Experimental results: Comparative example 4 has a slow dissolution, and the dissolution at 10 h is less than 70%.

TABLE-US-00022 TABLE 3 Dissolution data of Comparative Example 4 and Example 4 Ph 6.8 medium dissolution (%) Comparative Example 4 Example 4 Time(h) (mean) (mean) 0.25 29 28 1 36 37 2 42 44 3 48 50 4 53 56 6 60 64 8 65 72 10 69 77 12 73 81

Comparative Example 5

[0217]

TABLE-US-00023 Formulation Form 150 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained- Oseltamivir phosphate 41.05 release layer Microcrystalline cellulose 101 QD 34.99 Hydroxypropyl methyl cellulose 10.00 K100 LV Polyvinylpyrrolidone 3.00 Lactose 4.96 Micro powder silica 1.00 Sodium stearyl fumarate 5.00 Total 100.00 Immediate- Oseltamivir phosphate 43.79 release layer Microcrystalline cellulose 39.21 Polyvinylpyrrolidone 3.00 Sodium carboxymethyl starch 10.00 Micro powder silica 1.00 Sodium stearyl fumarate 3.00 Total 100.00 Isolation Opadry 85F 15.00 layer Purified water 85.00 Total 100.00

[0218] Preparation of sustained-release layer bulk granules: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl cellulose were weighed and transferred to a granulator for pre-mixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in turn, lactose and lubricant were added to obtain sustained-release layer bulk granules.

[0219] Preparation of immediate-release layer bulk granules: oseltamivir phosphate and microcrystalline cellulose were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, dry granulated, disintegrant and lubricant were added to obtain immediate-release layer bulk granules.

[0220] Preparation of double-layer tablet: a double-layer tablet press was used to fill 90 mg of sustained-release layer bulk granules, then pre-pressed to obtain the sustained-release layer tablet core; then 60 mg of immediate-release layer granules were filled and pressed into tablet to obtain the immediate-release and sustained-release double-layered tablet core.

[0221] Isolation layer: an isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release and sustained-release double-layered tablet core, and the percentage of coating weight gain in the tablet core was 2%.

Comparative Example 6

[0222]

TABLE-US-00024 Formulation Form 150 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Tablet core Oseltamivir phosphate 40.22 Microcrystalline cellulose 101QD 33.58 Polyvinylpyrrolidone 2.20 Lactose 15.00 Sodium chloride 5.00 Micro powder silica A200 1.00 Sodium stearate fumarate 3.00 Total 100.00 Controlled- Cellulose acetate 6.00 release film PEG 6000 1.50 Purified water 6.00 acetone 86.50 Total 100.00

[0223] Preparation of tablet core: oseltamivir phosphate and microcrystalline cellulose were weighed and transferred to a granulator for premixing, polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), then wet granulated, fluidized bed drying, dry granulated in turn, then filler, penetration enhancer and lubricant were added, and the mixture was pressed into tablets to obtain a 150 mg of oseltamivir tablet core.

[0224] Controlled-release film: the controlled-release coating solution was prepared and used to coat the above-mentioned tablet core, the percentage of coating weight gain in the tablet core was 12%.

[0225] Dissolution Data

[0226] In this example, the oseltamivir formulations prepared in Examples 1 to 14 were dissolved in a pH 6.8 medium, the volume of the medium was 900±9 mL, the temperature of the medium was 37.0±0.5° C., the paddle method was used, and the in vitro dissolution test was performed at 50 rpm/min. Time points for dissolution sampling in pH6.8: 0.25 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h. Sampling location: from the top of the paddle to the midpoint of the liquid surface, 10 mm away from the inner wall of the dissolution vessel. In vitro dissolution content was tested by High Performance Liquid Chromatography (HPLC) method. Results are as shown below:

TABLE-US-00025 TABLE 4 Dissolution (%) of the products of each example in pH 6.8 medium (n = 3) Test number 0.25 h 1 h 2 h 3 h 4 h 6 h 8 h 10 h 12 h Example 1 20 45 60 70 78 89 95 97 99 Example 2 32 48 61 71 78 87 94 97 98 Example 3 20 42 56 67 75 85 92 96 98 Example 4 28 37 44 50 56 64 72 77 81 Example 5 31 45 52 58 63 72 80 86 92 Example 6 27 40 49 56 62 73 84 95 97 Example 7 16 31 45 58 68 83 92 97 98 Example 8 34 45 — — 65 81 — 95 — Example 9 33 46 — — 69 84 — 93 97 Example 10 0 0  0  3 25 57 85 94 95 Example 11 38 55 72 86 90 — — 98 98 Example 12 20 35 42 48 53 61 68 74 79 Example 13 12 25 36 45 53 66 79 89 94 Example 14 25 32 — — 65 — 84 96 — Example 15 0 32 61 74 81 88 92 96 97 Example 16 22 45 69 78 83 90 93 96 98 Example 17 38 54 73 83 87 91 94 96 97 Comparative 29 36 42 48 53 60 65 69 73 Example 4 Comparative 40 61 87 95 98 — — 99 — Example 5 Comparative 2 8 15 23 31 45 58 69 78 Example 6 Immediate-release 91 100 — — — — — — — formulation (Tamifu ®)

[0227] Table 5

TABLE-US-00026 TABLE 5 Summary of the characteristics of the products of each example and comparative example Release Sustained- amount for a Release Osel- release certain 1 h amount Strength tamivir material within <4 within 4 Test number (mg) ratio % ratio % h % h % Example 1 150 31.6 4.4 45 78 Example 2 60 22.4 3.3 45 78 Example 3 180 3.3 3.3 42 75 Example 4 90 26.7 50 37 56 Example 5 150 32 29 45 63 Example 6 200 28 14 40 62 Example 7 60 3 3.3 31 68 Example 8 150 8.5 3.6 45 65 Example 9 150 24.9 4.2 46 69 Example 10 300 31.6 7.6 25 25 Example 11 150 31.2 10 55 90 Example 12 150 21 31.2 40 62 Example 13 300 50 19.6 25 53 Example 14 150 29 6.5 25 65 Example 15 150 32 16 32 81 Example 16 150 34 13 45 83 Example 17 150 34 11 54 87 Example 18 180 30.2 37.0 33 48 Example 19 180 30.2 28.8 35 57 Example 20 180 30.2 24.7 34 50 Example 21 180 25.1 50.1 31 46 Example 22 180 30.2 20.6 35 54 Example 23 180 30.2 37.0 34 51 Example 24 180 30.2 28.8 32 46 Example 25 180 30.2 37.0 34 51 Example 26 180 27.6 33.8 33 47 Comparative 60 2 2.1 — — Example 1 Comparative 300 55 20 — — Example 2 Comparative 180 3.3 2.5 44 77 Example 3 Comparative 90 18.7 55 36 53 Example 4 Comparative 150 31.5 6.0 61 98 Example 5 Comparative 150 27.3 8.6  8 31 Example 6 Remarks: “release amount for a certain 1 h within <4 h” and “release amount within 4 h” in Examples 18 to 26 are the dissolution data of acid resistance in 0.1M HCl for 1 h and then transferred to pH 6.8 medium. Other examples or comparative examples in the table are dissolution data in Ph 6.8 medium.

[0228] Animal Test: Pharmacokinetic Study of Oseltamivir Formulation in Beagle Dogs

[0229] The First Pharmacokinetic Study of Oseltamivir Formulation in Beagle Dogs

[0230] Dosing scheme: the test was used four-formulation, four-period and four-crossover (24 healthy beagle dogs, half male and half male, divided into 4 groups, 6 dogs in each group, administered on an empty stomach). Three groups were administered self-developed oseltamivir sustained-release formulation (150 mg) with once a day; the other groups were administered reference formulation, which was a 75 mg immediate-release formulation (trade name: Tamifu®), twice a day.

[0231] Table 6 shows the pharmacokinetic data of the products in Example 11, Comparative Example 5, Comparative Example 6 and the reference formulation in beagle dogs (the concentration of the oseltamivir active metabolite was detected).

[0232] Comparative example 5 has a fast release rate and fast absorption, which leads to a much higher Cmax in beagle dogs than the reference formulation, and the risk of toxic and side effects increases; in addition, due to short-term centralized absorption and fast elimination, it cannot maintain a long-term stable effective blood concentration; Comparative Example 6 has a slow release rate and slow absorption, the Cmax in beagle dogs is much lower than that of the reference formulation, which may not have a rapid onset effect, and the bioavailability is only 47% of that of the reference formulation twice a day; and the optimal absorption site may have been missed; the release rate of Example 12 is moderate, the Cmax in beagle dogs is 80% of the reference formulation twice a day, and the bioavailability is 81% of the reference formulation twice a day, which is relatively ideal. Therefore, the product of Example 12 is selected for the first human clinical trial.

TABLE-US-00027 TABLE 6 Pharmacokinetic data of the formulations in Example 12, Comparative Example 5, Comparative Example 6 and the reference formulation in beagle dogs BA(%) (Self-developed Cmax AUC0-t formulation/ ((ng/mL)) (ng .Math. h/mL) reference formulation) Example 12 3400 ± 780 43300 ± 7500 91 Comparative 6790 ± 940 45700 ± 6200 96 Example 5 Comparative 2340 ± 670 22400 ± 6500 47 Example 6 Reference 4230 ± 760 47600 ± 7500 — formulation

[0233] The Second Pharmacokinetic Study of Oseltamivir Formulation in Beagle Dogs

[0234] Dosing scheme: the test was used double-formulation and double-crossover (12 healthy beagle dogs, half male and female, divided into 2 groups, 6 dogs in each group, administered on an empty stomach), both groups were administered self-developed oseltamivir sustained-release formulation (150 mg) with once a day.

[0235] Table 7 shows the pharmacokinetic data of the products in Example 5 and Example 12 in beagle dogs (the concentration of the oseltamivir active metabolite was detected).

[0236] The AUC.sub.0-t of the products in Example 5 and Example 12 in beagle dogs is similar, but the Cmax of the product of Example 5 is much higher than that of Example 12. Considering that the high blood concentration, the risk of toxic and side effects may increase. The product of Example 12 was selected for the second human clinical trial.

TABLE-US-00028 TABLE 7 Pharmacokinetic data of the formulations in Example 5 and Example 12 in beagle dogs Cmax ((ng/mL)) AUC.sub.0-t (ng .Math. h/mL) Example 5 4810 ± 750 53200 ± 7100 Example 12 3980 ± 670 48800 ± 6800

[0237] The Third Pharmacokinetic Study of Oseltamivir Formulation in Beagle Dogs

[0238] Dosing scheme: the test was used double-formulation and double-crossover (12 healthy beagle dogs, half male and female, divided into 2 groups, 6 dogs in each group, administered on an empty stomach), both groups were administered self-developed oseltamivir sustained-release formulation (150 mg) with once a day.

[0239] Table 8 shows the pharmacokinetic data of the products in Example 18 and Example 5 in beagle dogs (the concentration of the oseltamivir active metabolite was detected).

[0240] The AUC.sub.0-t of the product in Example 18 in beagle dogs was 1.17 times that of Example 5, and the Cmax of the product in Example 18 is slightly higher than that of Example 5. Therefore, the product of Example 18 is selected for the third human clinical trial.

TABLE-US-00029 TABLE 8 Pharmacokinetic data of the formulations in Example 18 and Example 5 in beagle dogs Cmax ((ng/mL)) AUC0-t (ng .Math. h/mL) Example 18 3970 ± 610 43400 ± 5800 Example 5 3580 ± 580 37100 ± 5400

[0241] Clinical Trial: Pharmacokinetic Study of Oseltamivir Formulation in Humans

[0242] The First Human Clinical Trial

[0243] Dosing regimen: the biphasic release formulation of oseltamivir (150 mg) prepared in Example 12 was administered in an empty stomach once a day.

[0244] Table 9 shows the pharmacokinetic data of the biphasic release formulation of oseltamivir prepared in Example 12 in humans (the concentration of the oseltamivir active metabolite was detected). The product of the present invention has good pharmacokinetic properties, the Tmax is 6 h, the Tmax of food administration is 14 h, and the Cmax is greater than 300 ng/mL. The drug-time curve is shown in FIG. 1.

[0245] It can be seen from FIG. 1 that after oral administration of the self-developed product, the oseltamivir active metabolite in vivo reaches 150 ng/mL within 3 h to 4 h, which plays a role of rapid onset; the maintenance time of the plasma concentration higher than 150 ng/ml within 24 h is 21 h, and the peak-to-valley concentration ratio of plasma concentration within 24 h is 2.14, which can maintain the effective plasma concentration stably for a long time.

TABLE-US-00030 TABLE 9 Pharmacokinetic data of the biphasic release formulation of oseltamivir prepared in Example 12 in humans Example 12 Tmax(h) 6 Cmax(ng/mL) 370 AUC0-t(ng .Math. h/mL) 8343

[0246] The Second Human Clinical Trial

[0247] Dosing scheme: the test was used double-formulation and double-crossover, one group was administered the biphasic release formulation (150 mg) of oseltamivir prepared in Example 12 in a fed state once a day; the other group was administered reference formulation, which was a 75 mg immediate-release formulation (trade name: Tamifu®), administered twice a day.

[0248] Table 10 shows the pharmacokinetic data of Example 12 and the reference formulation in humans (the concentration of the oseltamivir active metabolite was detected). The product of the present invention has good pharmacokinetic properties, Tmax is 14 h, and Cmax is greater than 300 ng/mL. The drug-time curve is shown in FIG. 2.

[0249] It can be seen from FIG. 2 that after oral administration of the self-developed product, the oseltamivir active metabolite in vivo reaches 150 ng/mL within 3 h to 4 h, which plays a role of rapid onset; the maintenance time of the plasma concentration higher than 150 ng/ml within 24 h is 21 h, and the peak-to-valley concentration ratio of plasma concentration within 24 h is 1.21, which can maintain the effective plasma concentration stably for a long time.

TABLE-US-00031 TABLE 10 Pharmacokinetic data of the biphasic release formulation of oseltamivir prepared in Example 12 in humans Example 12 Reference formulation Tmax(h) 14 17 Cmax(ng/mL) 318 526 AUC0-t(ng .Math. h/mL) 9537 12180

[0250] The Third Human Clinical Trial

[0251] Dosing scheme: the test used double-formulation and double-crossover, one group was administered the oseltamivir biphasic release formulation (180 mg) prepared in Example 18 in the state of eating once a day; the other group was administered reference formulation, which was a 75 mg immediate-release formulation (trade name: Tamifu®), administered twice a day.

[0252] Table 11 shows the pharmacokinetic data of Example 18 and the reference formulation in humans (the concentration of the oseltamivir active metabolite was detected). The product of the present invention has good pharmacokinetic properties, Tmax is 8 h, and Cmax is greater than 300 ng/mL. The drug-time curve is shown in FIG. 3.

[0253] It can be seen from FIG. 3 that after oral administration of the self-developed product, the oseltamivir active metabolite in vivo reaches 150 ng/mL within 2 h to 3 h, which is equivalent to the reference formulation and has a rapid onset effect; the maintenance time of the plasma concentration higher than 150 ng/ml within 24 h is 21.5 h, and the peak-to-valley concentration ratio of plasma concentration within 24 h is 2.30, which can maintain the effective plasma concentration stably for a long time.

TABLE-US-00032 TABLE 11 Pharmacokinetic data of the biphasic release formulation of oseltamivir prepared in Example 18 in humans Example 18 Reference formulation Tmax(h) 8 16 Cmax(ng/mL) 455 463 AUC0-t(ng .Math. h/mL) 9206 9737

Example 18

[0254]

TABLE-US-00033 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 9.78 Methacrylic acid-ethyl 30.00 acrylate copolymer L100-55 Hydroxypropyl methyl 15.00 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 19

[0255]

TABLE-US-00034 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 19.78 Methacrylic acid-ethyl 30.00 acrylate copolymer L100-55 Hydroxypropyl methyl 5.00 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 20

[0256]

TABLE-US-00035 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 24.78 Methacrylic acid-ethyl 15.00 acrylate copolymer L100-55 Hydroxypropyl methyl 15.00 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 21

[0257]

TABLE-US-00036 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 32.85 layer MCC 101QD 2.15 Methacrylic acid-ethyl 40.00 acrylate copolymer L100-55 Hydroxypropyl methyl 20.00 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 22

[0258]

TABLE-US-00037 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 29.78 Methacrylic acid-ethyl 15.00 acrylate copolymer L100-55 Hydroxypropyl methyl 10.00 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 23

[0259]

TABLE-US-00038 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 9.78 Methacrylic acid-ethyl 30.00 acrylate copolymer L100-55 Hydroxypropyl methyl 15.00 cellulose K4M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 24

[0260]

TABLE-US-00039 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 19.78 Methacrylic acid-ethyl 5.00 acrylate copolymer L100-55 Hydroxypropyl methyl 10.00 cellulose K100M Hydroxypropyl methyl 20.00 cellulose K100 LV Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 25

[0261]

TABLE-US-00040 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 9.78 Methacrylic acid-ethyl 30.00 acrylate copolymer L100-55 Hydroxypropyl methyl 7.50 cellulose K100M Hydroxypropyl methyl 7.50 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 41.93 layer MCC 101QD 44.00 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Example 26

[0262]

TABLE-US-00041 Formulation Form 180 mg oseltamivir sustained-release formulation Component Formulation ratio (%) Sustained-release Oseltamivir phosphate 40.22 layer MCC 101QD 9.78 Methacrylic acid-ethyl 30.00 acrylate copolymer L100-55 Hydroxypropyl methyl 15.00 cellulose K15M Sodium stearate fumarate 5.00 Total 100.00 Immediate-release Oseltamivir phosphate 26.27 layer MCC 101QD 59.66 Polyvinylpyrrolidone 1.07 Croscarmellose sodium 10.00 Sodium stearate fumarate 3.00 Total 100.00 Isolation layer Opadry 85F 15.00 Purified water 85.00 Total 100.00

Preparation Method of Example 18 to Example 26

[0263] Preparation of sustained-release layer bulk granules: oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl cellulose were weighed and transferred to a granulator for premixing, purified water was used as granulation solution for wet granulation, and then wet granulated, fluidized bed drying, and dry granulated in sequence, then lubricant was added to obtain the sustained-release layer bulk granules.

[0264] Preparation of immediate-release layer bulk granules: oseltamivir phosphate and microcrystalline cellulose were weighed and transferred to a granulator for premixing, and polyvinylpyrrolidone-water was used as granulation solution for wet granulation (the amount of the final dried polyvinylpyrrolidone is shown in the formulation), and then wet granulated, fluidized bed drying, dry granulated in sequence, and then lubricant was added to obtain the immediate-release layer bulk granules.

[0265] Preparation of double-layer tablet: a double-layer tablet press was used to fill 150 mg of sustained-release layer bulk granules, then pre-pressed to obtain the sustained-release layer tablet core; then 30 mg of immediate-release layer granules were filled and pressed into tablet to obtain the immediate-release and sustained-release double-layered tablet core.

[0266] Isolation layer: an isolation layer coating solution was prepared and used to coat the above-mentioned immediate-release and sustained-release double-layered tablet core, and the percentage of coating weight gain in the tablet core was 2%.

TABLE-US-00042 TABLE 12 The weight ratio of the sustained-release material to the total weight of the formulation in Example 18 to Example 26 Example 18 to Example 26 ratio of ratio of ratio of methacrylic acid- hydroxypropyl sustained- ethyl acrylate methyl release copolymer (%) cellulose (%) material (%) Example 18 25 12 37 Example 19 25 4 29 Example 20 12 12 25 Example 21 33 17 50 Example 22 12 8 21 Example 23 25 12 37 Example 24 4 25 29 Example 25 25 12 37 Example 26 23 11 34 Actual range 4-33% 4%-25% 21-50% The scope of the 0%-35% 4-25%  3-50% claims

[0267] Dissolution Data

[0268] In this example, the oseltamivir formulations prepared in Examples 18 to 26 were dissolved in a pH 6.8 medium, the volume of the medium was 900±9 mL, the temperature of the medium was 37.0±0.5° C., the paddle method was used, and the in vitro dissolution test was performed at 100 rpm/min. Time points for dissolution sampling in pH6.8: 0.25 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h and 16 h. Sampling location: from the top of the paddle to the midpoint of the liquid surface, 10 mm away from the inner wall of the dissolution vessel. In vitro dissolution content was tested by High Performance Liquid Chromatography (HPLC) method. Results are as shown below:

TABLE-US-00043 TABLE 13 Dissolution of the products of Example 18 to 26 in pH 6.8 medium (%) (n = 3) Dissolution in pH 6.8 medium 0.25 1 2 3 4 6 8 10 12 14 16 Test number h h h h h h h h h h h Example 18 24 34 43 49 55 65 74 81 87 90 93 Example 19 26 32 44 52 60 74 83 90 94 98 — Example 20 24 32 42 48 57 75 89 94 98 98 — Example 21 25 31 35 42 47 61 71 77 81 85 87 Example 22 26 35 45 53 61 78 89 95 98 99 — Example 23 27 35 47 51 57 72 81 88 93 97 — Example 24 22 31 38 44 49 58 66 72 76 80 83 Example 25 24 32 41 46 52 63 73 78 82 87 89 Example 26 24 34 42 49 55 65 74 81 87 90 93

[0269] Dissolution Data

[0270] In this example, the oseltamivir formulations prepared in Examples 18 to 26 were acid resistant in 0.1M HCl for 1 h and then transferred to a pH 6.8 medium for dissolution. The volume of the medium was 900±9 mL, and the temperature of the medium was 37.0±0.5° C., the paddle method was used, and the in vitro dissolution test was performed at 75 rpm/min. Time points for dissolution sampling in 0.1M HCl: 0.25 h, 1 h, time points for dissolution sampling in pH 6.8: 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h. Sampling location: from the top of the paddle to the midpoint of the liquid surface, 10 mm away from the inner wall of the dissolution vessel. In vitro dissolution content was tested by High Performance Liquid Chromatography (HPLC) method. Results are as shown below:

TABLE-US-00044 TABLE 14 Dissolution of the products from Example 18 to 26 acid resistant in 0.1M HCl for 1 h and then transferred to pH 6.8 medium (%) (n = 3) Dissolution of acid resistance in 0.1M HCl for 1 h and then transferred to pH 6.8 medium (2 media dissolution times were accumulated) 0.25 1 2 3 4 5 7 9 11 13 15 Test number h h h h h h h h h h h Example 18 25 33 38 42 48 54 64 74 82 88 92 Example 19 27 35 42 50 57 64 79 88 91 95 98 Example 20 25 34 37 43 50 59 77 87 95 99 101 Example 21 24 31 36 41 46 51 61 71 77 81 87 Example 22 26 35 40 46 54 62 78 89 95 98 99 Example 23 25 34 40 46 51 57 69 78 85 89 92 Example 24 24 32 36 41 46 52 63 74 82 89 94 Example 25 23 34 37 45 51 57 69 78 85 91 93 Example 26 24 33 38 42 47 52 63 72 79 86 91

[0271] Reference throughout this specification to “an embodiment,” “some embodiments,” “one embodiment”, “another example,” “an example,” “a specific example,” or “some examples,” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. In this specification, schematic representations of the above phrases are not necessarily referring to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.

[0272] Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.