NZ615023B2

NZ615023B2 - Formulations comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol

Info

Publication number: NZ615023B2
Application number: NZ615023A
Authority: NZ
Inventors: Supriya Rane
Original assignee: Novartis Ag
Priority date: 2011-04-01
Filing date: 2012-03-30
Publication date: 2016-11-01

Abstract

Provided is a solid pharmaceutical composition comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720 or fingolimod), a filler and a stabilizer comprising a cyclodextrin. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol is an immunomodulatory drug.

Description

Formulations com risin 2—amino—2- 2- 4—oct l hen | eth | ro ane—1 3-diol The present invention and the invention of NZ 714825, which was divided from the present application, relate to pharmaceutical compositions comprising a SP receptor modulator ed from 2—amino-2—[2-(4-octylphenyl) ethyl}propane-1,3-diol in free form, in a pharmaceutically acceptable salt form (fingolimod, FTY720) and a phosphate derivative thereof (FTY720—phosphate), as well as process for their production and use of the pharmaceutical compositions. 2—amino—2-[2-(4-octylphenyl)ethyl}propane-‘l,3-diol hloride became the first oral drug approved to reduce relapses and delay disability progression in patients with ing forms of multiple sclerosis (MS). Before, the MS drugs on the markets were all delivered by frequent injections, either intravenously or intra-muscularly, varying from er—day to once—per—week depending on the drug.

Fingolimod is believed to reduce the number of lymphocytes circulating in the blood stream by ibly trapping a proportion of them in the lymph nodes. Consequently, the number of activated lymphocytes reaching the brain is decreased, ing in reduced inflammatory destruction. Fingolimod efficacy in the treatment of multiple sclerosis has been shown in humans (e.g. as described in "FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis". Mehling M, et al., Neurology. 2008 Oct 14;71(16):1261-7; and "Oral imod (FTY720) for relapsing multiple sclerosis".Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW; FTY720 D2201 Study Group. N Engl J Med. 2006 Sep 14;355(11):1124-40.).

Pharmaceutical compositions sing 2-amino[2-(4—octylphenyl)ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (fingolimod) or as a phosphate derivative, in particular in form of oral formulations, are known in the art, e.g. as described in EP1613288A the content of which being incorporated herein by reference. EP1613288A describes a tablet comprising 1.4mg of the hydrochloride salt of o—2-[2-(4- octylphenyl)ethyl]propane-1,3-diol, and capsules comprising 0.56mg, 1.0mg or more of the hloride salt of 2-amino[2-(4-octylphenyl)ethyl]propane-1,3-diol.

Solid state forms of 2—amino[2-(4—octylphenyl) ethyl]propane-1,3-diol hydrochloride are described in the art. For example, 00204549D describes crystals of o—2—[2—(4— octylphenyl) ethyl]propane-1,3—diol hydrochloride prepared by mixing about 30wt% of 2— PCT/U52012/031340 amino—2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride with about 75wt% a- or {3- cyclodextrin in water and then evaporating water with ethanol to dryness, and drying the solid. There is no tion of using a low amount of 2-amino-2—[2-(4—octylphenyl) ethyl]propane-1,3—diol hydrochloride as in the present invention, even les preparing a composition comprising a low amount of 2-amino[2-(4-octylphenyl)ethyl]propane-1,3~diol hydrochloride which complies with all the ements of a pharmaceutical compositions, as now obtained with the itions of the present invention.

However there still exists a need for ing an improved pharmaceutical composition for oral administration containing 2—amino[2—(4-octylphenyl) ethyl]propane-1,3~diol, in free form, in a pharmaceutically acceptable salt form or as a phosphate tive. In particular there is a need for ing a pharmaceutical composition which can be used to administer on a safe and prolonged way a low amount of the compound, i.e. a composition which is stable, neous and shows appropriate content uniformity, while containing 0.5 mg or less of 2-amino-2—[2-(4-octylphenyl) ethyl]propane-‘l ,3-diol.

Obtaining a composition that is stable, homogeneous, e.g. which shows riate blend content uniformity and/or drug content uniformity is particularly critical for a composition ning a tow amount of the active substance since in such a case even minor modifications on the drug amount, e.g. due to degradation or lack of uniformity, may lead to be a significant impact on the total content of the drug that the patient es. With limited amount of drug in the composition, even a limited degradation thereof may result in administering to the patient a drug amount that is too low to provide the desired therapeutic t. 80 it may be paramount for the patient to receive the adequate drug dosage every time he (or she) is taking his (or her) medication in order to ensure long term efficacy of the drug. The lower the drug content is, the more these requirements are difficult to meet. For example, it can be shown that the stability of solid composition comprising fingolimod is dependent upon the concentration of the drug, and therefore the lower the concentration of the compound, the more it becomes sensitive to degradation.

Furthermore, when formulating an oral composition containing 2-amino[2—(4—octylphenyl) ethyl]propane-1,3-dio|, in free form, in a pharmaceutically acceptable salt form or as a phosphate derivative, the person skilled in the art is confronted with several difficulties due to the nature and characteristics of the compound. imod is instable in presence of many ents, especially at high temperatures or humidity conditions: many pharmaceutically acceptable ents are not compatible with fingolimod, i.e. when mixed thereto induce impurities or degradation products at a level above the acceptable level for a pharmaceutical ition, according to the Regulatory Health Authorities. Fingolimod, in particular when micronized, is also static in nature and has the cy to stick to metal surfaces, leading to non negligible drug segregation during the ation manufacture. This may pose problems when preparing large scales of fingolimod—containing compositions, in particular compositions comprising low dosage of the drug, for e 0.5mg or less. it has now been found that by using a stabilizer, for example a cyclodextrin, it s possible to prepare pharmaceutical compositions for oral administration comprising a low amount of 2-amino-2—[2—(4—octylphenyl)ethyl1propane-1,3-diol, in free form, in a pharmaceutically acceptable salt form or as a phosphate derivative, which show an appropriate content uniformity and are physically stable even during extended periods of time. In particular it has become possible to prepare stable compositions comprising less than 0.5mg of 2-amino-2—[2-(4-octylphenyl) propane-1,3-diol, eg. 0. 25mg or less.

Unexpectedly, despite the low amount of 2—amino[2-(4-octylphenyl)ethyl]propane—1,3-diol, the interaction of fingolimod with the other excipients that are needed for preparing a solid composition for oral stration are now minimized.

Furthermore, the segregation which otherwise occurs during the manufacturing process and leads to a partial loss of the drug substance, is reduced. Thus compositions comprising a low amount of o[2—(4—octylphenyl)ethyl]propane—1,3-diol, e.g. 0.5mg or less, can be prepared on large scales with limited variations in the drug content amongst the different batches" In particular, the use of a stabilizer, for example a cyclodextrin or derivative thereof, in the formulation process permits blending of the different ingredients (active substance and ents) in such a way that a mixture of uniform particle size is obtained and thus an even distribution of the drug content in the final composition is ensured.

The invention provides solid pharmaceutical compositions le for oral administration, and comprising a) a compound selected from 2—amino—2—[2-(4-octylphenyl)ethyl]propane-1,3-diol, a pharmaceutically able salt thereof, and a phosphate tive thereof, b) a filler, c) a stabilizer, and optionally d) a binder and/or a lubricant.

[FOLLOWED BY PAGE 3a] In a particular embodiment, the present invention provides a solid pharmaceutical composition formulated for oral administration, comprising a) a first compound selected from 2—amino[2-(4— octylphenyl)ethyl]propane-1,3-diol, a pharmaceutically acceptable salt thereof, and a phosphate derivative thereof, b) a , and c) a stabilizer against the inducement of degradation products sing a cyclodextrin or a derivative thereof.

[FOLLOWED BY PAGE 4] W0 2012/135561 PCT/U82012/031340 The compound of the invention is selected from 2-amino[2-(4-octylphenyl)ethyl]propane— 1,3-diol in free form, a pharmaceutically acceptable salt thereof, and a phosphate derivative f, e.g. is 2-amino-2—[2—(4—octylphenyl)ethyl]propane-1,3-diol in free form or a pharmaceutically able salt thereof.

The ure of 2—amino[2-(4-octylphenyl)ethyl1propane—1,3-diol (FTY720) is shown below: HO H The structure of phosphate derivative thereof is shown below: Ho—-—— PHz—OH HO H According to the present invention, the compound may be a salt selected from ascorbate, oxalate, phosphate, mandelate, adipate, ethanesulfonate, naphtalene-1,5-disulfonate, naphtalene-1—sulfonate, naphtalene-Z-sulfonate, aspartate, e.g. L-aspartate, benzoate, 4- acetamidobenzoate, (+) camphorate, (+)camphor—10-sulfonate, decanoate, hexanoate, octanoate, cinnamate, dodecylsulfate, ethane—1,2-disultonate, 2-hydroxyethanesulfonate, glutarate, lactate, e.g. DL—lactate, 1-hxdroxynaphthoate, laureate, salicylate, hydrochloride, tartrate, mesylate, citrate, benzoate, succinate, malonate, acetate, propionate salts and mixture thereof. The salt is optionally crystalline. in one c embodiment of the invention, the salt is hydrochloride.

The composition of the ion may contain 0.01 to 20% by weight of the compound of the invention, for example 0.1 to 10%, e.g. 0.05 to 10%, e.g. 0.05 to 5%, e.g. 0.05 to 2%, e.g. 0.1 to 5%, e.g. 0.1 to 2%, e.g. 0.1 to 5%, e.g. 0.1 to 2%, e.g. 0.5 to 5%, e.g. 0.5 to 2%, e.g. 0.8 to 1.3%, e.g. 0.9 to 1.2%, by weight, based on the total weight of the composition, or e.g. 0.1 to 0.5%, e.g. 0.15 to 0.5, e.g. 0.2 to 0.3% by weight, based on the total weight of the ition. For e, the composition of the ion comprises about 1% by weight of the 81 P or modulator, based on the total weight of the composition, for example 1% by weight plus or less 0.15% of the 81 P receptor modulator, based on the total weight of the composition. For example about 0.6% by weight, for example about 0.5% by weight, for example about 0.4% by weight, for example about 0.3% by weight, for example about 0.25% by weight, for example about 0.2% by weight, for e about 0.15% by weight, based on the total weight of the composition. in another example, the composition of the invention comprises less than 2% by weight, less than 1.5% by weight, less than 1% by weight of the 81 P receptor modulator, e.g. less than 0.5% by , e.g. less than 0.4% by weight e.g. less than 0.3% by weight, e.g. less than 0.2% by weight, based on the total weight of the composition According to the ion, the stabilizer may be selected from a cyclodextrin or a derivative thereof, glycine HCl, sodium bicarbonate, and e thereof. In one embodiment of the invention, the izer comprises a cyclodextrin or a derivative thereof, or consists of a cyclodextrin or a derivative f, eg as herein below defined.

Under cyclodextrin and derivative thereof it is meant eg. a l cyclodextrin, a branched cyclodextrin, an alkyl-cyclodextrin or a hydroxyalkyl-cyclodextrin. For example extrin or and derivative thereof may be oc-cyclodextrin; B—cyclodextrin, y—cyclodextrin; hydroxypropyl- cyclodextrin such as ypropyl-oc-cyclodextrin or hydroxypropyl-B—cyclodextrin ; sulfobutylether B-cyclodextrin; dodecakis-2,6,0—methyl~a—cyclodextrin; tetradecakis-2,6,0- methyl-B-cyclodextrin; hexadecakis-2,6,0-methyl-y—cyclodextrin; tetradecakis-Z,6,0—ethyl—B— cyclodextrin; (ac-cyclodextrin lly etherized with 2~hydroxypropyl; B—cyclodextrin partially etherized with 2-hydroxypropyl; branched oc-cyclodextrin and branched B-cyclodextrin where glucose or maltose has been bound via oc-1,6 glucoside bound. in a specific embodiment of the invention, cyclodextrin or derivative thereof is hydroxypropyl— a—cyclodextrin or hydroxypropyl~p~cyclodextrin, e.g. hydroxypropyl~B-cyclodextrin (also herein referred as HP-B CD).

In r embodiment of the invention, cyclodextrin and derivative thereof is not 0L- cyclodextrin nor B-cyclodextrin.

The composition of the invention, eg. the final t for oral administration or an intermediate form thereof.may contain 0.1 to 30%, eg. 0.2 to 15% by weight of the stabilizer, e.g. cyclodextrin or a derivative thereof, for example 0.4 to 10%, eg. 0.5 to 10%, 8.9. 0.6 to PCT/USZOI2/031340 %, e.g. 1.5 to 8% or 1.5 to 3.5%, e.g. 1.0 to 5% or 1.0 to 3%, e.g. 0.1 to 10%, e.g. 0.1 to 8%, e.g. 0.1 to 5%, e.g. 0.1 to 3%, e.g. 0.1 to 1%, e.g. 0.5 to 1%, by weight of the stabilizer, e.g. cyclodextrin, based on the total weight of the composition. For example the composition of the invention may contain about 5%, e.g. about 4%, e.g. about 3%, e.g. about 2.5%, e.g. about 2%, e.g. about 1.5%, e.g. about 1%, e.g. about 0.5% by weight of the stabilizer, e.g. cyclodextrin, based on the total weight of the composition, e.g. the final product for oral administration or an intermediate form thereof According to the invention, the stabilizer, e.g. the cyclodextrin, may be present in an amount about 7, e.g. about 6, e.g. about 5 times, e.g. about 4 times (weight ratios) r than the amount of the 81 P receptor tor of the invention, e.g. than the amount of 2—amino~2~[2- (4~octylphenyl)ethyl]propane-1,3—diol or a pharmaceutically acceptable salt thereof, in a weight to weight ratio. For example, the amount of the stabilizer, e.g. the cyclodextrin, may be about 5 time higher, e.g. four times higher, e.g. three times , than the amount of the S1P receptor modulator of the invention, e.g. than the amount of 2-amino-2—[2-(4- octylphenyl)ethyl]propane-1,3-diol in free form or as a pharmaceutically acceptable salt thereof, e.g. 2-amino-2—[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochtoride, in a weight to weight ratio.

According to the invention, the stabilizer, e.g. the cyclodextrin, may be present in an amount about 0 to 4 times, e.g. about 0.2 to 3 times, eg. about 0.4 to 3 times, e.g. about 0.4 times, e.g. about 1 time, e.g. about 1.5 times, e.g. about 2 times, e.g. about 2.5 times, e.g. about 3 times, e.g. about 3.5 times (molar ratios) r than the amount of the S1P receptor modulator of the invention, e.g. than the amount of 2-amino[2—(4 octylphenyl)ethyl]propane -1,3-diol or a pharmaceutically acceptable salt thereof, in a molar to molar ratio. For example, the amount of the stabilizer, e.g. the extrin, may be about 3 times or 2 times , than the amount of the 81 P receptor modulator of the invention, e.g. than the amount of 2— amino-2—[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically able salt thereof, in a molar to molar ratio. In one embodiment the molar ratio of the extrin to 2- amino[2-(4-octylphenyl)ethyl]propane-1,3-diol in free or as a pharmaceutically acceptable salt thereof, e.g. as hydrochloride, is of about 0.6 to 1.2, e.g. is about 0.7, e.g. about 0.8, e.g. about 0.9, e.g. about 1.0, e.g. about 1.1, e.g. about 1.2.

W0 135561 According to the invention, the filler may be ed from a sugar alcohol, microcrystalline cellulose (e.g. Avice|®), methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch (e.g. corn starch, pregelatinized starch), ium phosphate, and mixture thereof.

In a specific ment of the invention, the fiiier is selected from a sugar alcohol, microcrystalline cellulose (e.g. Avicel®) and mixture thereof, for example the filler ts of one or more sugar alcohol or a mixture of one sugar alcohol with microcrystalline cellulose, e.g. a mixture of mannitol with microcrystalline cellulose, e.g. mannitol with Avicel® .

According to the invention, the weight ratio sugar alcohol (e.g. mannitol or mixture of mannitoi with another sugar alcohol) to microcrystalline cellulose may be of about 5:95, e.g. about 10:90, e.g. about 15:85, e.g. about 20:80; e.g. about 25:75; e.g. about 30:70; e.g. about 35:65; e.g. about 40:60 ; e.g. about ; e.g. about 50:50; e.g. about 55:45; e.g. about 60:50; e.g. about 65:45; e.g. about 70:00. in a specific embodiment the weight ratio mannitol: Avicel is of about 10:90, e.g. about 15:85, e.g. about 20:80; e,g, about 25:75, e.g. about 30: 70, e.g. about 35:65.

In r embodiment, the filler comprises a mixture of one or more sugar alcohoi with another filler as ned above. For e the fiiler is a mixture of one or more sugar alcohol with a second component selected from cellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose; e.g. the filler is a mixture of one or more sugar alcohol with hydroxypropylcellulose. In one specific example, the filler comprises a mixture of mannitol and hydroxypropylcellulose. in another embodiment of the invention, the filler is or comprises starch, e.g. corn starch or pregelatinized starch or a mixture thereof. For example, the weight ratio sugar alcohol (e.g, mannitol or mixture of mannitol with another sugar aicohol) to starch (e.g. corn starch or pregelatinized starch or a mixture thereof) is of about 50:50; e.g. of about 55:45; e.g. of about 60:40; e.g. of about 65:35; e.g. of about 70:30; e.g. of about 75:25; e.g. of about 80:20; e.g. of about 85:15; e.g. of about 90:10. in a specific embodiment the weight ratio mannitol: starch, e.g. ol: corn starch or pregelatinized starch is of about 55:45; e.g. of about 60:40; e.g. of about 65:35; e.g. of about 70:30; e.g. of about 75:25; e.g. of about 80:20; e.g. of about 85:15.

The filler may be present in an amount of from about 0.1 to about 90 % by weight, e.g. about 1 to about 30%, e.g. about 10 to about 30% by weight; e.g. about 15 to about 30% by weight; e.g. about 20 to about 30% by weight, e.g. about 10%, e.g. about 15%, e.g. about 20%, e.g.

PCT/U82012/03l340 about 25%, e.g. about 30%, e.g. about 35%, e.g. about 40%, e.g. about 45%, e.g. about 50%, e.g. about 55%, e.g. about 60%, e.g. about 65%, by weight, based on the total weight of the ition, e.g. in the final product or an intermediate form thereof.

According to the invention, the disintegrants may be selected from crosspovidone, strach (e.g. corn , atanised starch or mixture thereof), crosscarmellose sodium and mixture thereof. In one example, the disintegrant may comprise about 1 to 6 weight %, e.g. 2 to 5 weight %, e.g. 3 to 4 weight % of crosspovidone. it may comprise about 4 to 12 weight %, e.g. about 5to10 weight %, e.g. about 6 to 8 weight % of starch (e.g. corn starch, pregelatanised starch or mixture f).The desintegrant may comprise in one ment, the disintegrant may comprise a mixture of crosspovidone, pregelatanised starch and crossoarmellose sodium. For example, it may comprise about 5 to weight %, e.g. about 10 to 25 weight %, e.g. about 15 to 20 weight % of crosscarmellose sodium).

According to the invention, the sugar alcohol may be selected from mannitol, maltitol, inositol, xylitol, lactitol, and mixture thereof. For example, the sugar alcohol is a substantially non- hygroscopic sugar alcohol, e.g. ol, e.g. D—mannitol.

A single sugar alcohol may be used, or a mixture of two or more sugar ls, e.g. a mixture of mannitol and xylitol, e.g. in a ratio of 1:1 to 4:1.

In a particular embodiment, the sugar alcohol is prepared from a dried composition, e.g. mannitol composition, having a high specific surface area. The use of this type of mannitol composition may assist in promoting uniform distribution of the S1P receptor modulator throughout the mannitol in the composition. A higher e area may be achieved by providing a sugar alcohol, e.g. mannitol, preparation consisting of particles having a smaller mean size and/or a rougher surface on each particle. The use of a spray- dried sugar alcohol, e.g. mannitol, eg. with a mean particle size of 300 pm or less, has also been found to improve ssibility and hardness of tablets formed from the composition.

In one embodiment of the invention, the single point surface area of the sugar alcohol preparation, e.g. mannitol, is 1 to 7 mzlg, e.g. 2 to 6 mzlg or 3 to 5 m2/g. The mannitol preparation may suitably have a mean particle size of 10 to 400 um, e.g. 10 to 300 um, e.g. 150 to 250 pm. For e, the mannitol of the invention may have a mean particle size of 60 pM, 120 pM, 180 pM, 200 pM, 300 uM or 400uM.

PCT/U52012/031340 For example, the mannitol may have particle of 60um in e, or the mannitol may be Parteck M200. In a ic embodiment, a mixture of mannitol can be used, e.g. a mixture of mannitol (60um) and mannitol (180um), or mannitol (60um) and mannitol (120um). For example, the mannitol can be a mixture of mannitol (200um) with another mannitol, e.g. with mannitol (180um), mannitol (60um), mannitol (120um) or a mixture thereof.

The ratios Mannitol (60um): Mannitol (180um) may vary from e.g. 1:0 to 2:0, e.g. from 1:2 to 1:5. For example, it may be about 20% of Mannitol (60um): 70% of Mannitol (180um); e.g. about 30% of Mannitol (60um): 60% of ol (180um).; e.g. about 40% of Mannitol (60um): 50% of Mannitol (180um).

The ratios Mannitol ): other mannitol (e.g. Mannitol 180um) may vary from e.g. 1:0 to 2:0. For example, it may be about 20% of Mannitol (200um): 80% of the other forms of mannitol; e.g. about 30% of Mannitol (200um): 70% of the other forms of mannitol; e.g. about 40% of Mannitol (60um): 60% of the other forms of mannitol.

The mannitol may have a bulk density of 0.4 to 0.6 g/mL, e.g. 0.45 to 0.55 g/mL.

The composition may comprise 20 to 99.99% by weight ; e.g. 30 to 99.99% by weight ; e.g. 40 to 99.99% by weight ; e.g. 50 to 99.99% by weight ; e.g. 60 to 99.99% by weight ; e.g. 70 to 99.99% by weight ; e.g.75 to 99.99% by weight ; e.g. 20 to 60% by weight ; e.g. 25 to 55% by weight 30 to 50% by weight; e.g. about 20 % by ; e.g. 85 to 99.9%, e.g. 90 to 99.5%, e.g. 92 to 97%, e.g. 93 to 96% by weight; of the sugar alcohol, e.g. of the mannitol, based on the total weight of the ition, e.g. of the final product suitable for oral administration or an intermediate form thereof. For example, it may se about e.g. about 25 % by weight; e.g. about 30 % by weight; e.g. about 35 % by weight; e.g. about 40 % by weight; e.g. about 45 % by ; e.g. about 50 % by weight; e.g. about 55 % by weight; e.g. about 60 % by weight, e.g. about 70% by weight, e.g. about 80% by weight e.g. about 90 % by weight, e.g. about 92% by weight, e.g. about 94% by weight, e.g. about 95% by weight, e.g. about 96% by , of the sugar alcohol, e.g. of the mannitol.

The composition preferably further comprises a lubricant. Suitable ants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryi ostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g.

W0 2012/135561 PCT/U82012/031340 Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon e, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer, or a mixture of any of the above. For example the lubricant comprises magnesium stearate, hydrogenated castor oil, mineral oil, colloidal silicon dioxide, polyethylene glycol or a mixture thereof, e.g. ium stearate, hydrogenated castor oil, mineral oil or a mixture thereof. In a specific embodiment the lubricant consists of magnesium stearate, hydrogenated castor oil, mineral oil or a mixture thereof, e.g. consists of magnesium stearate or a mixture of magnesium te with another lubricant. ' The composition preferably comprises 0.01 to 5% by weight of the lubricant, e.g. of magnesium stearate, for example 0.5 to 3% by , 1 to 2% by weight, e.g. about 3% by weight, e.g. about 2% by , about 1% by weight, about 0.5% by weight about 0.05% by weight, based on the total weight of the composition.

The composition may comprise one or more further excipients such as a binder. The binder may be selected from polyvinyl pyrrolidone, methylcelluiose, hydroxypropyl cellulose, hydroxypropylmethyl ose, and e thereof. When used, the binder may be included in an amount of 1 to 8 %, e.g. 3 to 6% by weight, based on the total weight of the composition.

The use of a binder increases the granule strength of the formulation, which is ularly ant for fine granulations. Microcrystalline cellulose and celluiose are particularly preferred where a high tablet hardness and/or longer egration time is required.

Hydroxypropyl cellulose may be preferred where faster distintegration is required. Where appropriate, xylitol may also be added as an additional binder, for example in addition to microcrystalline cellulose, e.g. in an amount up to 30% by weight , e.g. up to 20% by weight; e.g. up to 10% by weight of the sugar alcohol, e.g. mannitol or xylitol or mixture thereof.

The composition of the invention refers to a solid composition suitable for oral administration, or to an intermediate form thereof, e.g. a formulation can be used to prepare a solid composition suitable for oral administration The composition may be in the form of a soft gel, powder, granule or pellets or a unit dosage form, for e as a tablet or capsule, e.g. a friezed dried tablet. The compositions of the present invention are well—adapted for encapsulation into an orally administrable capsule shell, ularly a hard gelatin shell or a HPMC (hypromellose) capsule . For e, it can be compositions that are filled using the WO 35561 liquid dispensing technology for hard gelatin capsule. The solution ning the compound of the invention, may be dispensed in a capsule which is prefilled with the sugar alcohol as herein above defined, e.g. mannitol.

Alternatively the itions may be compacted into tablets. The tablets may optionally be coated, for instance with talc or a poiysaccharide (e.g. cellulose) or hydroxypropylmethylcellulose coating.

The composition of the invention does not refer to an injection or another parenteral composition.

Where the pharmaceutical composition is in unit dosage form, each unit dosage may contain 0.01 mg to 5 mg of the S1 P receptor modulator, e.g. 0.01 mg to 1 mg, e.g. 0.01 mg to 0.7 mg, e.g. 0.03 to 0.50 mg, e.g. 0.05 mg to 0.50 mg, e.g. 0.06 mg to 0.50 mg, e.g. 0.10 mg to 0.50 mg, e.g. 0.12 to 0.50 mg, e.g. 0.13 mg to 0.50 mg, e.g. 0.14 mg to 0.50 mg, e.g. 0.15 mg to 0.50 mg, e.g. 0.16 mg to 0.50 mg, e.g. 0.17 mg to 0.50 mg, e.g. 0.18 mg to 0.50 mg, e.g. 0.19 mg to 0.50 mg, e.g. 0.20 mg to 0.50 mg, e.g. 0.21 mg to 0.50 mg, e.g. to 0.22 mg to 0.50 mg, e.g. to 0.23 mg to 0.50 mg e.g. to 0.24 mg to 0.50 mg e.g. to 0.25 mg to 0.50 mg, e.g. to 0.26 mg to 0.50 mg, e.g. to 0.27 mg to 0.50 mg e.g. to 0.28 mg to 0.50 mg, e.g. to 0.29 mg to 0.50 mg, e.g. to 0.30 mg to 0.50 mg, , e.g. to 0.32 mg to 0.50 mg, e.g. to 0.34 mg to 0.50 mg. in another embodiment, each unit dosage may contain 0.01 mg to 0.40 mg, e.g. 0.02 mg to 0.40 mg, e.g. 0.03 mg to 0.40 mg, e.g. 0.06 mg to 0.40 mg, e.g. 0.10 mg to 0.40 mg, e.g. 0.12 mg to 0.40 mg, e.g. 0.13 mg to 0.40 mg, e.g. 0.14 mg to 0.40 mg, e.g. 0.15 mg to 0.40 mg, e.g. 0.16 mg to 0.40 mg, e.g. 0.17 mg to 0.40 mg, e.g. 0.18 mg to 0.40 mg, e.g. 0.20 mg to 0.40 mg, e.g. 0.22 mg to 0.40 mg, e.g. 0.25 mg to 0.40 mg, e.g. 0.30 mg to 0.40 mg, e.g. 0.35 mg to 0.40 mg.

In a r embodiment, each unit dosage may contain 0.050 mg to 0.350 mg, e.g. 0.050 mg to 0.325 mg, e.g. 0.060 mg to 0.350 mg, e.g. 0.060 mg to 0.325 mg, e.g. 0.125 mg to 0.350mg, e.g. 0.125 mg to 0.325 mg.

In a specific ment, each unit dosage contains about 0,125mg, about 0.250mg or about 0.500mg.

W0 2012/135561 In another specific embodiment, each unit dosage contains either about 0.03mg, about 0,06mg, about 0.125mg, about 0.250mg, about 0.325mg or about 0.500mg.

For example, when is in unit dosage form, each unit dosage of the composition of the invention may contain about 0.50 mg, e.g. about 0.40 mg, e.g. about 0.30 mg, e.g. about 0.25 mg, e.g. about 0.20 mg, e.g. about 0.15 mg, e.g. about 0.14 mg, e.g. about 0.13 mg, e.g. about 0.12 mg, e.g. about 0.11 mg, e.g. about 0.10 mg, , e.g. about 0.06mg, e.g. about 0.05mg, e.g. about 0.04mg, e.g. about , e.g. about 0.02mg, e.g. about 0.01mg, e.g. about 0.375mg, e.g. 0.325mg, e.g. 0.175mg, e.g. about 0.135mg, e.g. about 0.125mg, e.g. about 0.115mg, e.g. about g.

For example, the pharmaceutical composition of the ion is in unit dosage for, e.g. is a capsule or tablet, and comprises about 0.06mg, or about 0.125mg, or about g, or about 0.325mg or about 0.375mg of the 81 P or modulator of the invention, e.g. 2- amino—2~[2—(4-octylpheny|) ethyl]propane—1,3~diol hydrochloride.

The compositions of the invention may show good ity characteristics as indicated by standard ity trials, for example having a shelf life stability of up to one, two or three years, and even longer. As herein defined, stable pharmaceutical compositions refer to pharmaceutical compositions containing no impurities or impurities that are present in an amount acceptable, e.g. on storage at room temperature, in particular in View of the Regulatory Health Authorities tions and ements. Stability characteristics may be determined, e.g. by measuring decomposition products by HPLC analysis after e for particular times, at particular temperatures, e.g. 20°, 40° or 60°C, and/or under high humidity conditions.

The pharmaceutical compositions of the present invention may be produced by standard processes, for instance by conventional mixing, granulating, sugar~coating, dissolving or lyophilizing processes. Procedures which may be used are known in the art, e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuch der zeutischen Praxis, 4th Ed. (Springer , 1971) and Remington’s Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions.

PCT/U82012/031340 In one aspect, the present invention relates to a process for producing a pharmaceutical composition, comprising: (a) mixing the stabilizer, e.g. a cyclodextrin, with SfP receptor tor; and optionally milling and/or ating the mixture obtained (b) mixing the filler, e.g. the sugar alcohol, e.g. mannitol; optionally milling and/or granulating the e obtained; (0) optionally milling and/or granulating the mixture obtained in (b); and (d) mixing the milled and/or granulated mixture obtained in (b) or (c) with a lubricant. in step (b), the filler, e.g. the sugar alcohol, e.g. the mannitol, may optionally be milling and/or granulated before been mixed to the mixture obtained in step (a).

In another embodiment of the invention, the composition of the invention may be produced by a process, sing: (a) mixing the stabilizer, e.g. a eytrin, with 81 P receptor modulator; and optionally milling and/or granulating the mixture obtained (a1) mixing the binder (e.g. hydroxypropyl cellulose) of the invention with a sugar alcohol, e.g. mannitol; and optionally milling and/or granulating the‘mixture obtained; (b) mixing the mixtures obtained in step (a) and (at); (c) optionally milling and/or ating the mixture obtained in (b); and (d) mixing the milled and/or granulated e obtained in (b) or (c) with a lubricant.

By using this process, a ation having a good level of content and blend uniformity (i.e. a substantially uniform distribution of the 81 P receptor modulator throughout the composition), dissolution time and stability is obtained.

The 81 P receptor modulator, e.g. 2-amin0[2-(4-octylphenyl)ethyl]propane-1,3-diol, hloride, may ally be micronized, and/or pre—screened, e.g. with a 400 to 500 pm mesh screen, before step (a) in order to remove lumps. The mixing step (a) may suitably comprise blending the S1P or modulator and the filler, e.g. sugar alcohol, e.g. mannitol in any suitable r or mixer for e.g. 100 to 400 revolutions.

The process may be carried out by dry mixing the components. in this embodiment the milling step (a), (a1), or (c) may suitably comprise passing the mixture obtained in (a) or (at) PCT/U82012/031340 through a screen, which preferably has a mesh size of 400 to 500 um. Process step (a) may comprise the step of mixing the total amount of SiP receptor tor at first with a cyclodextrin in order to form a pre-mix. Subsequently the ed amount of sugar alcohol is added to the pre-mix.

Step (a), (at) or (c) may also comprise the step of adding a binder solution, e.g. methylcellulose and/or l, eg. an aqueous solution, to the e. Alternatively the binder is added to the mix dry and water is added in the ation step.

The milled mixture obtained in (a) or (a1) may optionally be blended once more before mixing with the lubricant. The lubricant, e.g. ium stearate, is preferably pre-screened, eg with a 800 to 900 um screen, before mixing.

Alternatively, a wet granulation process may be ed. ln this embodiment, the SIP receptor tor is preferably solubilized in a solvent with the stabilizer, e.g. cyclodextrin and sprayed on the dry-mix of the desired filler, e,g. sugar alcohol, e.g. mannitol. The obtained filler/81P or tor mixture, e.g. sugar alcohol/81P receptor modulator e, e.g. mannitol/SiP receptor mOdulator mixture, may then be dry-mixed with another binder such as eg, hydroxypropyl cellulose or hydroxypropylmethyl cellulose. The solvent is then added and the mixture granulated, eg. using an automated granulator. The granulation is then dried and milled. The solvent may be water.

Alternatively, a spray g process may be employed. in this embodiment the DS is solution (D3 + CD) is sprayed on sugar beads or mannitol beads, the solvent is evaporate and the dried beads are than encapsulated in hard gelatin or HPMC capsules. Solvents used to prepare the DS solution could be water (aqueous) or Ethanol (non-aqueous). lf desirable, an additional amount of binder may be added in step (d) to the mixture obtained in (b).

The process may comprise a further step of tabietting or encapsulating the mixture obtained in (d), e.g. into a hard gelatin capsule using an automated encapsulation device. The capsules may be coloured or marked so as to impart an individual appearance and to make them instantly recognizable. The use of dyes can serve to enhance the appearance as well as to identify the capsules. Dyes suitable for use in pharmacy typically e carotinoids, iron oxides, and chlorophyll. Preferably, the capsules of the invention are marked using a code.

PCT/U52012/031340 According to the invention, there is provided a process for producing a solid composition for oral administration of 2-amino—2-[2—(4-octylphenyl) ethyl]propane-1,3~diol in free form, in a pharmaceutically acceptable salt form or in a phosphate derivative form, comprising the steps of (i) mixing a compound selected from 2—amino—2-[2-(4-octylphenyl)ethyl]propane-1 ,3- diol, a pharmaceutically acceptable salt thereof, and a phosphate derivative f, with a stabilizer, eg. a extrin, in a solvent; (ii) mixing a filler, e,g. sugar alcohol, to the mixture obtained in step (i); (iii) adding the solvent ; (iv) granulating, (v) drying, milling, blending, and (vi) optionally tabletting or encapsulating.

Optionally a binder may be mixed, e.g. dry mixed, to the mixture obtained in step (ii) and/or step (iii). In a specific embodiment, in step (ii) the used filler, eg. the sugar alcohol, e.g. mannitol, is spray—dried.

By using this process, a preparation having a good level of content and blend uniformity (is. a substantially m distribution of the drug throughout the composition), and stability is obtained.

The pharmaceutical compositions of the present invention are useful, either alone or in ation with other active , for the treatment and prevention of conditions eg. as disclosed in US 5,604,229, WO 97/24112, WO 01/01978, US 6,004,565, US 629 and 16985, the contents of which are incorporated herein by reference. in particular, the pharmaceutical compositions are useful for: a) treatment and prevention of organ or tissue transplant rejection, for example for the treatment of the recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants, and the prevention of graft—versus-host e, such as sometimes occurs ing bone marrow transplantation; particularly in the treatment of acute or chronic allo— and xenograft rejection or in the transplantation of insulin producing cells, e.g. pancreatic islet cells; b) treatment and prevention of mune disease or of inflammatory conditions, eg. chronic long term diseases, eg. multiple sclerosis, arthritis (for example rheumatoid arthritis), matory bowel e, hepatitis, etc.; Multiple sclerosis takes l forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). As herein W0 2012f135561 PCT/U82012/031340 defined, multiple sclerosis refers, but is not limited to, relapsing ing multiple sclerosis (RRMS) or primary progressive multiple sis (PPMS), e.g. RRMS.

According to the present invention the terms "treatment" or "treat" refer to both prophylactic or tive treatment as well as curative or disease—modifying treatment, including treatment of patients at risk of contracting the disease or disorder, or suspected to have contracted the disease or er, as well as patients who are ill or have been diagnosed as suffering from the disease or disorder.

As herein defined, treating le sclerosis refers to, but is not limited to, reducing the frequency of clinical exacerbations, delaying the ssion of symptoms or disorders associated with multiple sclerosis or delaying the accumulation of physical disability induced by multiple sclerosis.

Symptoms or ers associated with multiple sclerosis encompass ogical symptoms, physical and cognitive disability and sychiatric disorders.

Accordingly, in further aspects the present invention provides: 1. A composition as defined above, for use in ng or ting a disease or condition as defined above. 2. A method of treating a subject in need of immunomodulation, comprising administering to the subject an effective amount of a composition as defined above. 3. A method of treating or preventing a disease or condition as d above, comprising administering to the subject a composition as defined above. 4. Use of a pharmaceutical composition as defined above for the preparation of a medicament for the prevention or treatment of a disease or condition as defined above.

The ion will now be described with reference to the following specific embodiments.

Example 1 FTY720 is dissolved in water to form approximately 20 percent (solution A). HP—B CD is dissolved in water to form approximately 15 percent (solution B). Mannitol is added in a low shear granulator and sprayed solutions A and B. The granulated material thus PCT/U82012/031340 obtained is dried in a tray dryer set at 60°C. The dried granules are then milled h a Frewitt mill attached with a 18 mesh screen. The milled granules are blended with magnesium stearate in a bin r.

The lubricated granules are compressed to form s of the desired dose of 0.04mg, and then encapsulated to achieve the desired dose of 0.125mg, containing: Table 1 ingredients Quantity per Quantity per 0.040mg mini- 0.125mg tablet (mg) capsule (mg) FTY720 HCI 0.0448 0.140 Mannitol USP 3.755 11.735 Hydroxy propyl beta cyciodextrin 0.120 0.375 (HP-i3 cm Magnesium Stearate 0.040 0.125 1 1.0 part of FTY720 is equivalent to 1.119 part of FTY720 HCI salt Example 2 The composition with Hydroxy—beta-cyciodextrin in Example 1 is used to s the bulk powder for mini tablets and capsules.

Table 2: Blend uniformity assay results with total degradation products %FTY720 Mass Range / Assay Total ation Balance Average "—-93,8 — 99.2 %RS D: 2.3 Tabie 2 shows blend uniformity results for the final blend with an RSD of 2.3% indicating no segregation issues after final blending. The ﬁnal blend is then compressed in mini tablets and encapsulated.

PCT/U52012/031340 The compressed tablets are of 4mg in weight delivering a dose of 40micrograms of drug.

Table 3: stability under diﬁ‘erent conditions including stress condition of 50°C/75%RH.

Stability Condition /Time Points Mass Balance 5013 ~ 75% mm week 50D ~ 75% RH/ 12 wk 106.7 107.2 25D/60%RH/4week SOD-Dry/4week---E—_- 50D - 75%RM week CD = cyclodextrin The data below shows a total degradation product of 1.4% at 50°C/75% RH for 4 weeks in the formulation with HP-B CD.

The capsules are encapsulated with a ﬁll weight of 14mg to deliver a dose of 125 micrograms each. The table 4 summarizes the data for stability at ent ions including the stress ions of 50°C/75% RH (Relative Humidity) Table 4 Stability Condition %FTY720 Assay rrime Points % Total Deg Mass Balance ----nn- --————m --110.47-106.29-0.4-1‘2-11o.9_107.4 500 - 75% RH / 12 wk The data shows a total degradation t of 2.5% in the formulation with HP—B CD.

PCT/U82012/031340 Stability results in both tablets and capsules are indicative of increased ity of FTY720 in the drug product.

Example 3 Hard gelatin capsules containing FTY720 are prepared as follow: HP-CD and FTY720 are dissolved in water to form approximately 20 percent (solution A). HPC is dissolved in water to form approximately 7 percent (solution B). ol is added to a fluid bed drier and sprayed with solutions A and B. The granulated material is than dried at a set inlet ature of 65°C in the fluid bed drier. The dried granules are then milled through a Frewitt mill attached with a 18 mesh screen. The milled granules are blended with ium stearate in a bin blender. The lubricated es are encapsulated to obtain the desired dose of 0.03mg.

The same process is used to prepare the other capsules whose ents are listed below: Table 5: Composition of FTY720 0.03, 0.06 mg, 0.125 mg and 0.25mg capsules Ingredient 0.03 mg 0.06 mg 0.125 mg 0.25 mg capsule (mg) capsule (mg) capsule (mg) capsule (mg) FTY720 HCI 1 0.0336 0.0671 0.140 0.280 Hydroxypropylcellulose 0.438 0.875 0.875 1.750 Hydroxypropyl-beta~ cyclodextrin 0.145 0.289 0.301 0.603 Mannitol 11.759 23.5189 23.434 46.868 ium Stearate 2 0.125 0.2500 0.250 0.500 Water, puriﬁed 3 --- ~-- --— --- Capsule fill weight 12.50 25.00 25.00 50.00 (theoretical weight) Empty capsule shell Weight of capsule shell 48.00 48.00 48.00 48.00 Total weight 60.50 73.00 73.00 98.00 The molecular weight ratio of FTY720 HCl to FTY720 base is approximately 1.12 to 1.0 2 Vegetable origin Used as a granulating aid and removed during processing.

Claims

What is claimed

1.A solid pharmaceutical composition formulated for oral administration, comprising a) a first compound selected from 2-amino[2—(4— octylphenyl)ethyl]propane-1,3-diol, a pharmaceutically acceptable salt thereof, and a phosphate derivative thereof, b) a filler, and c) a stabilizer against the inducement of degradation products comprising a cyclodextrin or a derivative thereof.

2.A composition ing to claim 1, sing less than 1.5% by weight of the first compound, based on the total weight of the composition.

3.A composition according to claim 1, comprising 0.5mg or less of the first compound.

4.A composition ing to any one of the ing claims, wherein the filler comprises a sugar alcohol.

5.A composition according to claim 4, wherein the filler comprises mannitol.

6.A composition according to any one of the preceding claims, further comprising a binder.

7.A composition ing to claim 6, wherein the binder comprises hydroxypropylcellulose.

8.A composition according to any one of the preceding claims, further comprising a lubricant.

9.A composition according to claim 8, wherein the lubricant comprises ium stearate.

10. A composition according to any one of the preceding claims, wherein the izer comprises hyd roxypropyI-beta-cyclodextrin.

11. A composition according to any one of the preceding claims, wherein the first compound is 2—amino[2—(4—octylphenyl)ethyl]propane—1,3-diol or a ceutically acceptable salt thereof.

12. A composition according to any one of the preceding claims for treating an autoimmune disease.

13. Use of a therapeutically effective amount of a compound ed from 2-amino- 2—[2-(4—octylphenyl)ethyl]propane—1,3—diol, a pharmaceutically acceptable salt thereof, and a phosphate derivative thereof, with a pharmaceutical ition as defined in any one of claims 1 to 11 in the manufacture of a medicament for treating an autoimmune disease.

14. A composition according to claim 1, substantially as herein described with reference to any one of the Examples thereof.

15. A composition according to any one of claims 1 to 12, substantially as herein described.

16. A use according to claim 13, ntially as herein described.