Plasma concentration (µg/mL) of pure drug

Time in
Rabbit
hours
Animal 1 Animal 2 Animal 3 Animal 4 Animal 5 Animal 6 Mean±s.d.
0 0 0 0 0 0 0 0±0
0.5 50.64 61.78 60.85 56.94 72.89 64.89 61.33±7.48
1 102.45 210.32 182.67 130.16 125.01 165.84 152.74±40.47
1.5 238.21 274.42 286.27 268.04 315.24 207.1 264.88±37.8
2 390.65 420.97 453.57 522.16 550.54 460.12 466.3±60.32
2.5 655.12 799.64 720.57 755.2 854.61 741.4 754.4±68.20
3 1168.34 1242.87 1290.64 1224.57 1350.31 1225.97 1250.45±62.69
4 723.57 838.24 805.8 759.37 885.83 821.08 805.64±57.63
6 322.21 300.54 303.54 314.2 366.17 332.31 323.16±24.13
8 178.23 167.77 158.29 188.64 199.08 178.01 178.33±14.49
12 80.49 95.48 85.5 100.55 106.57 74.42 90.5±12.39
16 10.17 15.4 19.05 30.01 21.01 25.05 20.1±7.0
20 0.12 0.11 0.08 0.12 0.11 0.08 0.1±0.01
24 0 0 0 0 0 0 0
24 0 0 0 0 0 0 0

61.331667 7.4871661 7.4871661

152.74167 40.474102
264.88 37.800731
466.335 60.323605
754.42333 68.204583
1250.45 62.698978
805.64833 57.633346
323.16167 24.130377
178.33667 14.49197
90.501667 12.392048
20.115 7.0047805
0.1033333 0.018619
0 0
0 0
0 #DIV/0!

Time
in Animal 1Animal 2Animal 3 Animal 4
hours
0 0 0 0 0
0.5 458.26 462.62 538.18 444.61
1 1115.13 1146.04 1214.7 1063.615
1.5 2074.6 2167.9 2249.75 2036.84
2 3190.25 3705.43 3619.62 3540.77
2.5 2139.34 2208.79 2762.83 2586.39
 3 1179.45 1204.1 1390.39 1370.71
4 446.64 585.22 511.87 515.78
6 160.85 250.14 195.89 225.76
8 98.59 85.95 95.97 129.37
12 10.45 9.65 12.2 10.64
16 0.5 0.7 0.6 0.3
20 0.1 0.15 0.1 0.08
24 0 0 0 0

24 0 0 0 0

Iguratimod optimised nanosponges tablet

Plasma concentration

4000
3000
(µg/ml)

2000
1000
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time in hours
 Plasma concentration (µg/mL) of iguratimod marketed reference Plasma concentration (µg/m
Rabbit
Animal 1 Animal 2 Animal 3 Animal 4 Animal 5 Animal 6 Mean±s.d. Animal 1
0 0 0 0 0 0 0±0 0
758.26 712.62 828.43 744.61 810.35 704.415 759.78±50.58 23.55
1715.13 1746.26 1774.7 1663.615 1686.74 1705.455 1715.317±40.17 54.66
2774.6 2767.91 2849.59 2633.84 2903.452 2775.03 2784.07±90.15 129.53
3690.31 3705.49 3919.68 3556.97 3808.62 3660.59 3723.61±125.57 154.25
2713.6 2708.79 2962.83 2886.39 2866.87 2910.79 2841.545±105.97 842.18
1779.48 1804.29 1985.51 1880.84 1821.4 1853.73 1854.2±73.62 1832.23
935.49 925.396 1010.51 892.89 870.5 840.28 912.51±59.43 2809.36
408.94 380.94 461.78 424.92 314.17 353.16 390.65±52.75 2080.63
160.85 180.14 195.89 205.76 187.82 175.22 184.28±15.85 1159.74
44.95 45.21 68.94 59.57 51.72 60.2 55.1±9.48 363.6
9.45 8.65 11.2 10.64 9.89 10.8 10.1±0.955 66.49
0.1 0.15 0.1 0.08 0.09 0.08 0.1±0.026 24.49
0 0 0 0 0 0 0 0.09
0 0 0 0 0 0 0

759.78083 50.580501
1715.3167 40.176724
2784.0703 91.155398
3723.61 125.57689
2841.545 105.97279
1854.2083 73.623573
Iguratimod marketed
912.511 59.43919
4000
Plasma concentration (ng/ml)

390.65167 52.758712
3500
3000 184.28 15.854982 Animal 1
2500 55.098333 9.4846769 Animal 2
2000 10.105 0.9550445 Animal 3
1500 0.1 0.0260768 Animal 4
1000 0 0 Animal 5
500 0 0 Animal 6
0 #DIV/0!
0 2 4 6 8 10 12 14 16 18 20 22 24 26
501.48036
Time in hours

Animal 5
Animal Mean±s.d.
6
Iguratimo
0 0
1600
516.35 484.415
Plasma concentration (ng/ml)

1400
1096.74 1105.455
1200
2123.452 2196.73
3608.62 3660.59 1000

2366.87 2410.79 800

600
400
200
0
0 2 4 6 8 10 12
 Plasma concentration (ng
1200
1000
800

1351.4 1247.73 600

580.43 505.08 400

208.82 189.22 200

110.18 80.55 0
0 2 4 6 8 10 12
12.89 11.42
Time in ho
0.4 0.5
0.09 0.08
0 0
Time
0 0 in Animal 1 Animal 2 Animal 3
hours
0 0 0 0
0.5 35.99 43.84 48.27
1 100.1 120.01 82.05
1.5 195.83 209.22 142.09
nosponges tablet 2 254.25 300.15 344.58
2.5 1242.18 1255.65 1324.075
Animal 1
Animal 2
3 2280.63 2270.84 2279.705
Animal 3 4 3009.36 3645.38 3284.8
Animal 4 6 2135.78 2426.15 2679.39
Animal 5 8 1965.303 1838.411 1605.1
Animal 6
16 18 20 22 24 26 12 763.6 809.8 870.1
16 166.49 140.4 241.03
20 24.49 21.54 28.75
24 0.09 0.11 0.1
Plasma concentration (µg/mL) of iguratimod nanosponges optimised formulation
Rabbit
Animal 2 Animal 3 Animal 4 Animal 5 Animal 6 Mean±s.d.
0 0 0 0 0 0±0
18.32 22.44 20.65 19.86 22.48 21.216
48.49 56.28 52.86 49.72 52.98 52.5
108.54 132.95 119.57 116.5 124.62 121.95
200.15 244.58 211.27 228.05 220.38 209.78
855.65 924.075 817.605 832.28 860.15 855.32
1893.6 1965.303 1860.44 1872.51 1880.04 1884.02
3045.38 3284.8 3382.78 3193.647 3025.69 3123.61
2170.84 2079.705 2297.615 2145.26 2075.37 2141.57
1245.05 1318.19 1209.68 1300.62 1292.17 1254.24
409.8 470.1 430.2 420.5 380.81 412.5
40.4 141.03 110.28 70.2 115.4 90.63
21.54 28.75 25.65 22.94 21.66 24.17
0.11 0.1 0.15 0.05 0.1 0.1
0

21.22 1.9539362
52.50 2.9367493
121.95 8.9529915
209.78 31.098974
855.32 37.085335
1884.02 44.911565
3123.61 206.16392
2141.57 86.190246
1254.24 61.122322
412.50 37.677065
90.63 37.584605
24.17 2.7567765
0.10 0.032249
0.00 #DIV/0!
0 #DIV/0!
3.861767144 13.620807

Iguratimod pure drug

Animal 1
Animal 2
Animal 3
Animal 4
Animal 5
Animal 6

2 4 6 8 10 12 14 16 18 20 22 24 26
 Animal 1
Animal 2
Animal 3
Animal 4
Animal 5
Animal 6

2 4 6 8 10 12 14 16 18 20 22 24 26
Time in hours

Animal 4
Animal 5Animal 6Mean±s.d.

0 0 0
41.2 37.28 40.81
94.6 110.7 107.55
233.5 150.65 220.415
311.27 328.05 320.38
1217.605 1232.28 1260.15
2297.615 2300.26 2275.37
3482.78 3193.647 3325.69
2951.4 2230.85 2825.73
1755.15 2050.5 1910.74
830.2 820.5 780.81
210.28 170.2 215.4
25.65 22.94 21.66
0.15 0.05 0.1
 Iguratimod Pure Iguratimod marketed product
Time (h) drug (µg/ml) (µg/ml)

0 0 0
0.5 61.33 759.78
1 152.74 1715.317
1.5 264.88 2784.07
2 466.3 3723.61
2.5 754.4 2841.545
3 1250.45 1854.2
4 805.64 912.5
6 323.16 390.63
8 178.33 184.17
12 90.5 55.1
16 20.1 10.1
0+'[4 20 0.1 0.1
24 0.1 0
24 0 0

15.3325 189.945
53.5175 618.77425
104.405 1124.84675
182.795 1626.92
305.175 1641.28875
501.2125 1173.93625
1028.045 1383.35
1128.8 1303.13
501.49 574.8
537.66 478.54
221.2 130.4
40.4 20.4
0.4 0.2
0 0
 Iguratimod nanosponges
optimised formulation (µg/ml) 4000
Iguratimod
3500
0 Iguratimod
3000

Concentration (ng/ml)
21.23 (µg/ml)
52.5 2500
121.95 2000
209.78
855.317 1500

1884.07 1000
3123.61
500
2141.545
1254.2 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
412.5
90.63 Time (hours)
24.17
0.1
0

Auc 0-infinity
5.3075 4626.7193081761
18.4325 10517.8203225806
43.6125 18797.5763636364
82.9325
266.27425
684.84675
2503.84
5265.155
3395.745
3333.4
1006.26
229.6
48.54
0
 Iguratimod Pure drug (µg/ml)

Iguratimod marketed product

(µg/ml)

6 8 10 12 14 16 18 20 22 24 26

Time (hours)

auc k T-HALF
4620.43 0.0636 4.36
10516.53 0.155 1.79
16958.94 0.0264 10.51
 Plasma concentration (ng/mL) of pure drug Plasma concentr
Time in
Rabbit
hours
Animal 1 Animal 2 Animal 3 Animal 4 Animal 5 Animal 6 Mean±SD. Animal 1
0 0 0 0 0 0 0 0±0 0
0.5 519.68 509.93 550.65 445.71 454.9 558.45 506±0.83 1547.49
1 1108.94 1140.94 1161.96 1184.92 1194.17 1123.16 1152.3±1.25 3284.73
1.5 612.02 650.5 662.69 633.17 694.5 605.61 643.08±1.09 1902.61
2 432.16 405.74 390.6 462.91 387.6 391.57 411.76±1.26 1274.32
2.5 242.02 280.6 312.53 326.08 336.01 278.94 296.03±1.58 910.49
3 204.49 185.94 181.65 227.48 190.78 205.28 199.27±0.39 598.8
4 94.46 86.75 96.16 84.47 92.73 102.65 92.87±1.56 245.49
6 44.95 45.21 38.94 39.57 41.72 40.12 41.75±1.93 118.31
8 12.44 13.15 9.26 13.78 14.03 14.01 12.77±0.37 33.51
12 2.32 3.31 3.15 2.1 2.69 2.27 2.64±1.04 8.95
16 0.1 0.13 0.12 0.07 0.09 0.09 0.1±0 0.54
20 0 0 0 0 0 0 0±0 0
24 0 0 0 0 0 0 0±0 0
24 0 0 0 0 0 0 0 0

Time
in Animal 1Animal 2 Animal 3 Animal 4 Animal 5
hours
0 0 0 0 0 0
0.5 1547.49 1500.396 1490.21 1630.59 1590.7
1 3284.73 2993.26 2852.6 3868.83 3825.72
1.5 1902.61 1933.05 2000.18 2018.68 1980.59
2 1274.32 1177.85 1236.66 1332.29 1285.03
2.5 910.49 814.66 822.02 982.31 910.71
3 598.8 564.49 601.75 657.27 630.19
4 245.49 302.05 260.6 330.81 283.78
6 118.31 109.14 133.27 140.52 121.38
8 33.51 41.37 32.47 40.65 36.88
12 8.95 8.77 8.26 9.63 8.64

16 0.54 0.46 0.48 0.51 0.52

Actarit op
20 0 0 0 0 0
24 0 0 0 03500 0
24 0 0 0 03000 0

Plasma concentration (ng/ml)

2500

2000

1500

1000

500

0
0 2 4 6 8 10
T
Plasma concentration (ng/mL) of actarit marketed product Plasma concentration (ng/mL) of actarit nanospon
Rabbit Rabbit
Animal 2 Animal 3 Animal 4 Animal 5 Animal 6 Mean±SD Animal 1 Animal 2 Animal 3
0 0 0 0 0 0±0 0 0 0
1500.396 1490.21 1630.59 1590.7 1610.28 1561.61 78.36 79.28 83.47
2993.26 2852.6 3868.83 3825.72 3805.63 3438.46 100.6 110.49 170.53
1933.05 2000.18 2018.68 1980.59 1962.14 1966.2 185.37 208.8 262.11
1177.85 1236.66 1332.29 1285.03 1307.25 1268.9 352.85 422.53 380.8
814.66 822.02 982.31 910.71 945.47 897.6 2201.74 2235.05 2300.19
564.49 601.75 657.27 630.19 610.5 610.5 3078.71 3073.84 3079.65
302.05 260.6 330.81 283.78 292.91 285.94 2387.19 2583.95 2554.17
109.14 133.27 140.52 121.38 130.02 125.44 1410.19 1417.43 1400.62
41.37 32.47 40.65 36.88 45.58 38.41 695.49 607.37 690.6
8.77 8.26 9.63 8.64 8.495 8.79 223.55 225.32 212.44
0.46 0.48 0.51 0.52 0.49 0.5 58.85 58.75 57.46
0 0 0 0 0 0±0 0.84 0.86 0.98
0 0 0 0 0 0±0 0 0 0
0 0 0 0 0 0 0 0 0

Actarit pure drug

1400
Plasma concentration (ng/ml)

1200
1000 An
An
800
An
600 An
400 An
An
200

Animal Mean±s.d.
6 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time in hours
0
Actarit marketed
1610.28 4500
Plasma concentration (ng/ml)

3805.63 4000
3500 Anim
1962.14
3000 Anim
1307.25 2500 Anim
945.47 2000 Anim
1500 Anim
1000 Anim
500
0
 Plasma concentration (ng
3500 Anim
3000 Anim
2500 Anim
2000 Anim
610.5 1500 Anim
292.91 1000 Anim
500
130.02
0
45.58 0 2 4 6 8 10 12 14 16 18 20 22 24 26
8.495 Time in hours
Time
0.49 in Animal 1Animal 2Animal 3 Animal 4 Animal 5
hours
Actarit optimised nanosponges tablet
0 0 0 0 0 0 0
0 0.5 78.36 79.28 83.47 90.55 91.46
0 1 100.6 110.49 170.53 117.4 128.85
1.5 185.37 208.8 262.11 238.74 205.88
Animal 1
2 352.85 422.53Animal380.8
2
434.61 450.45
2.5 1501.74 1535.05 1600.19
Animal 3 1615.68 1580.62
3 2878.71 2873.84 2879.65
Animal 4 2887.615 2900.26
4 1787.19 1983.95 1954.17
Animal 5 2195.85 1911.85
6 910.19 917.43Animal900.62
6 982.36 950.72
8 395.49 307.37 390.6 435.84 383.79
12 123.55 125.32 112.44 140.65 114.86
2 4 6 8 10 12 14 16 18 20 22 24 26
16 8.85 8.75 7.46 9.63 8.64
Time in hours 20 0.84 0.86 0.98 0.91 0.99
24 0 0 0 0 0
24 0 0 0 0 0
ng/mL) of actarit nanosponges optimised formulation
Rabbit
Animal 4 Animal 5 Animal 6 Mean±SD
0 0 0 0±0
90.55 91.46 71.88 82.5±0.61
117.4 128.85 137.74 127.6
238.74 205.88 215.56 219.4
434.61 450.45 374.415 402.6
2315.68 2280.62 2192.17 2254.24
3087.615 3100.26 2905.37 3054.24
2795.85 2511.85 2414.114 2541.185
1482.36 1450.72 1435.66 1432.88
735.84 683.79 710.49 687.26
240.65 214.86 223.73 223.425
59.63 58.64 58.45 58.63
0.91 0.99 0.89 0.91
0 0 0 0±0
0 0 0 0

Animal 1
Animal 2
Animal 3
Animal 4
Animal 5
Animal 6

20 22 24 26

ed

Animal 1
Animal 2
Animal 3
Animal 4
Animal 5
Animal 6
 Animal 1
Animal 2
Animal 3
Animal 4
Animal 5
Animal 6

18 20 22 24 26

Animal Mean±s.d.
6

0
71.88
137.74
215.56
374.415
1492.17
2705.37
1814.114
935.66
410.49
123.73
8.45
0.89
0
0
 Actarit Pure Actarit marketed product
Time (h) drug (ng/ml) (ng/ml)

0 0 0
0.5 506 1561.61
1 1152.3 3238.46
1.5 643.08 1966.2
2 411.76 1268.9
2.5 296.03 897.6
3 199.27 610.5
4 92.87 285.94
6 41.75 125.44
8 12.77 38.41
12 2.64 8.79
16 0.1 0.5
20 0 0
24 0 0
24 0 0

126.5 390.4025
414.575 1200.0175
448.845 1301.165
263.71 808.775
176.9475 541.625
123.825 377.025
146.07 448.22
134.62 411.38
54.52 163.85
30.82 94.4
5.48 18.58
0.2 1
0 0
0 0
0 0
0 0
0
Actarit nanosponges optimised
formulation (ng/ml)
3500

0 3000
38.1
82.5

Concentration (ng/ml)
2500
127.6
219.4 2000
1254.24
2754.24 1500
1641.185
652.88 1000
357.26
223.425 500
108.63
50.91 0
0 2 4 6 8 10 12 14
1.1
0 Time (hour

9.525
30.15
52.525
86.75
368.41
1002.12
2197.7125
2294.065
1010.14
1161.37
664.11
319.08
104.02
0
 3500
Actarit Pure drug (ng/ml)

3000 Actarit marketed product

(ng/ml)
Concentration (ng/ml)

2500 Actarit nanosponges optimised

formulation (ng/ml)
2000

1500

1000

500

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (hours)

actarit thalf
1926.1125 pure drug 1.22
5756.44 marketed 1.23
9299.97 NS tablet 3.57
Time conc logC logC extra antilog Cextra C residual log C residual
0 0 Err:502 3.2957 1975.604469433 1975.604469433 3.2957
0.5 1561.61 3.1935725814 3.3727 2358.848235629 797.238235629 2.9015881193
1 3438.46 3.53636397651 3.4497 2816.436733578 -622.023266422 Err:502
1.5 1966.2 3.29362769177 3.5267 3362.791956868 1396.591956868 3.1450695366
2 1268.9 3.10342739738 3.6037 4015.133594288 2746.233594288 3.4387374755
2.5 897.6 2.95308284391 3.6807 4794.021749415 3896.421749415 3.5906659589
3 610.5 2.78568566828 3.7577 5724.004941345 5113.504941345 3.70871868
4 285.94 2.45627491284 3.9117 8160.184910197 7874.244910197 3.8962089184
6 125.44 2.09843604534
8 38.41 1.58444430717
12 8.79 0.94398887507
16 0.5 -0.3010299957
20 0.91 -0.0409586077
24 0.1 -1
24 0.1
k=
t1/2=
 logC
time logC 4

0 0 3.5
0.5 3.193573 3
1 3.536364 f(x) = 0.0340841331437578 x + 2.40345483222371
2.5
1.5 3.293628 R² = 0.0427496816615968

2 3.103427 2

2.5 2.953083 1.5

3 2.785686 1
4 2.456275
0.5
6 2.098436
0
8 1.584444 0 2 4 6 8 10
12 0.943989
16 1.76812
20 1.383277
24 0.041393
0.517024 24
1.235921
 logC

x + 2.40345483222371

6 8 10 12 14