Organic Compounds

Abstract

A solid pharmaceutical composition suitable for oral administration, comprising: (a) S 1 P receptor agonist; and (b) a sugar alcohol.

Claims

1. A solid pharmaceutical composition suitable for oral administration, comprising: (a) a therapeutically effective amount of a S1P receptor agonist, which is 2-amino-2-{2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl}-1,3-propanediol or a pharmaceutically acceptable salt thereof, and (b) a sugar alcohol.

2. A composition according to claim 1, wherein the sugar alcohol comprises mannitol.

3. A composition according to claim 1, further comprising a lubricant.

4. A composition according to claim 3, wherein the lubricant comprises magnesium stearate.

5. A composition according to claim 1, comprising 0.5 to 5% by weight of the S1P receptor agonist.

6. A composition according to claim 1, comprising 90 to 99.5% by weight of the sugar alcohol.

7. A composition according to claim 3, comprising 1.5 to 2.5% by weight of the lubricant.

8. A composition according to claim 1, in the form of a tablet.

9. A composition according to claim 1, in the form of a capsule.

10. A composition according to claim 3, comprising 0.01 to 5% by weight of the lubricant.

11. A composition according to claim 2, wherein the S1P receptor agonist is micronized.

12. A composition according to claim 2, wherein the S1P receptor agonist is pre-screened with a 400 to 500 μm mesh screen.

13. A method of treating multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim 2.

14. A method of treating multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim 1.

15. A composition according to claim 2, wherein the mannitol has a mean particle size of 100 to 300 μm.

16. A composition according to claim 2, wherein the mannitol has a mean particle size of 150 to 250 μm.

17. A composition according to claim 2, wherein the mannitol has a bulk density of 0.4 to 0.6 g/mL.

18. A composition according to claim 2, wherein the mannitol has a bulk density of 0.45 to 0.55 g/mL.

19. A composition according to claim 2, wherein the mannitol has a single point surface area of 1 m.sup.2/g to 7 m.sup.2/g.

20. A composition according to claim 2, wherein the S1P receptor agonist is 2-amino-2-{2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl}-1,3-propanediol hydrochloride.

Description

EXAMPLE 1

[0139] Micronized Compound A, e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride salt (FTY720), is screened and 116.7 g of the screened compound is mixed with 9683.3 g mannitol (Parteck M200 from E. Merck). The mixture is then milled in a Frewitt MGI device (Key International Inc. USA) using a 30 mesh screen. Magnesium stearate is screened using a 20 mesh screen and 200 g of the screened compound blended with the FTY720/mannitol mixture to produce a product composition.

[0140] The product composition is then compacted on a tablet press using a 7 mm die to form 120 mg tablets, each containing:

TABLE-US-00001 Compound A, e.g. FTY720 * 1.4 mg Mannitol M200 116.2 mg  Magnesium stearate 2.4 mg Total 120 mg  * 1 mg of Compound A in free form is equivalent to 1.12 mg of FTY720.

EXAMPLE 2

[0141] In a further example, the process of example 1 is repeated except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).

EXAMPLE 3

[0142] Compound A, e.g. FTY720, and mannitol (Parteck M200 from E. Merck) are each screened separately using an 18 mesh screen. 1.9 g screened FTY720 is mixed with 40 g screened mannitol for 120 revolutions in a blender at 32 rpm. The FTY720/mannitol mixture is then screened through a 35 mesh screen.

[0143] The screened FTY720/mannitol mixture is added to a granulator along with a further 340.1 g mannitol and 12 g hydroxypropylcellulose. The mixture is mixed for 3 minutes. Water is then added at a rate of 100 ml/minute and the mixture granulated for 2 minutes. The granulation is transferred into a tray dryer and dried at 50° C. for 150 minutes.

[0144] The mixture is then milled in a Frewitt MGI device using a 35 mesh screen. Magnesium stearate is screened and 6 g of the screened compound is blended for 90 revolutions at 32 rpm with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the SIP receptor agonist throughout the mannitol in the blend.

[0145] The product composition is then filled into size 3 hard gelatin shells on an Hoflinger & Karg 400 encapsulation device. 120 mg of the product composition is added to each capsule. Therefore each capsule contains:

TABLE-US-00002 FTY720 * 0.56 mg  Mannitol M200 114.04 mg   Hydroxypropylcellulose 3.6 mg Magnesium stearate 1.8 mg Total 120 mg 

EXAMPLE 4

[0146] In a further example, the process of example 3 is repeated except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).

EXAMPLE 5

[0147] In a further example, the process of example 3 is repeated except that the hydroxypropyl cellulose is replaced by hydroxypropylmethyl cellulose.

EXAMPLE 6a

[0148] Micronized Compound A, e.g. FTY720, is screened using a 400 μm (40 mesh) screen. 58.35 g of the screened compound is mixed with 4841.65 g mannitol (Parteck M200 from E. Merck) in a 25 L Bohie bin blender for 240 blending revolutions. The mixture is then milled in a Frewitt MGI device using a 400 μm mesh screen, and the milled mixture is blended once more. Magnesium stearate is screened and 100 g of the screened compound is blended with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the blend.

[0149] The product composition is then filled into size 3 hard gelatin shells on an Hoflinger & Karg 400 encapsulation device. 120 mg of the product composition is added to each capsule. Therefore each capsule contains:

TABLE-US-00003 FTY720 * 1.4 mg Mannitol M200 116.2 mg  Magnesium stearate 2.4 mg Total 120 mg 

EXAMPLE 6b

[0150] In an alternative embodiment, capsules are manufactured using the components and in the amounts as described in Example 6a, but the FTY720 is first mixed with 14 mg mannitol (before screening). This mixture is then screened as described above. The screened mixture is then blended with the remaining mannitol and the magnesium stearate is added, followed by additional blending and filling into capsules.

EXAMPLES 7 AND 8

[0151] In further examples, capsules are prepared as described in example 6, except that each capsule contains each component in the following amounts:

TABLE-US-00004 Example 7 Example 8 FTY720 * 2.8 mg  5.6 mg Mannitol M200 114.8 mg  112 mg Magnesium stearate 2.4 mg  2.4 mg Total 120 mg  120 mg

EXAMPLES 9 TO 11

[0152] In further examples, capsules are prepared as described in examples 6 to 8, except that the magnesium stearate is replaced in each case by Cutina® (hydrogenated castor oil).

EXAMPLES 12 TO 22

[0153] In further examples, capsules or tablets are prepared as described in examples 1 to 11, except that FTY720 is replaced in each case by 2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol hydrochloride.

EXAMPLES 23 AND 24

[0154] Capsules containing the following ingredients are prepared, by weighing each component and mixing in a mortar, then filling into capsules:

TABLE-US-00005 Example 23 Example 24 FTY720 5 mg 1 mg D-mannitol 83.7 mg   117 mg  Corn starch 24 mg  — Avicel ® PH101 12 mg  — Hydroxypropylcellulose 0.3 mg.sup.  7 mg Talc 3 mg 3 mg Lubri wax ®101 2 mg 2 mg Total 130 mg  130 mg 

EXAMPLES 25 TO 27

[0155] Pharmaceutical compositions containing the following ingredients are produced:

TABLE-US-00006 Example 25 Example 26 Example 27 FTY720 5 g  10 g 100 g D-mannitol 991 g   986 g 897 g Methylcellulose SM-25 4 g   4 g  3 g Total 1000 g   1000 g 1000 g 

[0156] The FTY720 and a proportion of the D-mannitol equal to twice the weight of the FTY720 are mixed in a Microspeed Mixer MS-5 type (Palmer, USA) for 2 minutes at 1200 rpm. The remaining D-mannitol is added to the mixture and mixed for another 2 minutes. 80 or 60 milliliters of 5% methylcellulose SM-25 solution is supplied from a hopper and granulated under the same conditions. The mixture is extruded through a screen with 0.4 mm apertures using an extruder RG-5 type. The extruded material is dried at 65° C. by a fluidized-bed granulator STREA I Type (Patheon, Canada) and then sieved through a 24 mesh sieve. Fine particles which pass through a 60 mesh sieve are removed. The obtained fine granules are filled into capsules by a Zuma capsule-filling machine (100 mg per capsule).

EXAMPLES 28 TO 31

[0157] Tablets containing the following ingredients (in mg) are produced:

TABLE-US-00007 Example Example Example Example 28 29 30 31 FTY720 1 1 1 1 D-mannitol 62.3 62.3 62.0 62.0 Xylitol* 26.7(5.4) 26.7(5.4) 26.6 26.6 Methylcellulose — — 0.4 0.4 Microcrystalline 24.0 — 24.0 — cellulose Low-substituted — 24.0 — 24.0 Hydroxypropyl- cellulose Hydrogenated oil 6.0 6.0 6.0 6.0 Total 120.0 120.0 120.0 120.0 *The amount of xylitol indicated in brackets was used as a binder.

[0158] FTY720, D-mannitol and xylitol are placed in a fluid-bed granulator (MP-01 model, Powrex), mixed for five minutes, and granulated under spray of binder solution, followed by drying till the exhaust temperature reaches 40° C. The granulation conditions are as shown below. Dried powder is passed through a 24-mesh sieve, added to the specified amount of filler and lubricant, and mixed in a mixer (Tubular Mixer, WAB) for three minutes to make the powder for compression.

[0159] The resulting powder is compressed by a tabletting machine (Cleanpress correct 12 HUK, Kikushui Seisakusho) with a punch of 7 mm i.d.×7.5 mm R at a compression force of 9800 N.

[0160] Granulation Conditions:

TABLE-US-00008 Item Setting Charge-in amount 1170 g Volume of intake-air 50 m.sup.3/min Temperature of intake-air 75° C. Flow rate of spray solution 15 mL/min Spray air pressure 15 N/cm.sup.2 Spray air volume 30 L/min Volume of binder solution 351 mL

EXAMPLES 32 TO 39

[0161] Tablets containing the following ingredients (in mg) are produced:

TABLE-US-00009 Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 FTY720 1 1 1 1 1 1 1 1 D-mannitol 116.6 114.2 104.6 114.2 104.6 116.6 115.4 113 magnesium 2.4 2.4 2.4 2.4 2.4 — — — stearate glycine HCl — 2.4 12 — — — — — sodium — — — 2.4 12 — — — bicarbonate zinc — — — — — 2.4 — — stearate silicone fluid — — — — — — 3.6 — mineral oil — — — — — — — 6 Total 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0