RU2779056C2 - Compositions containing modulators of sphingosine-1-phosphate (s1p) receptor - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: in the invention, stable compositions are described, containing a modulator of a sphingosine-1-phosphate (hereinafter – S1P) receptor, which can be used as dosage forms. Modulators of S1P receptor are, as a rule, sphingosine analogues, such as 2-substituted 2-aminopropane-1,3-diol or 2-aminopropanol derivatives, for example FTY720. The introduction of pre-gelatinized starch into the composition provides for an increase in the stability.

EFFECT: obtaining compositions containing modulators of sphingosine-1-phosphate receptor.

8 cl, 11 tbl, 10 ex

Description

The present invention relates to a composition containing a sphingosine-1-phosphate (S1P) receptor modulator.

In particular, the present invention relates to stable compositions containing a sphingosine-1-phosphate (S1P) receptor modulator that can be used as dosage forms.

S1P receptor modulators are typically sphingosine analogs such as 2-substituted 2-aminopropane-1,3-diol or 2-aminopropanol derivatives, for example compounds containing a group of formula Y.

S1P receptor modulators

Sphingosine-1-phosphate (hereinafter referred to as "S1P") is a naturally occurring serum lipid. Eight S1P receptors are currently known, namely S1P1 to S1P8. S1P receptor modulators are typically sphingosine analogs such as 2-substituted 2-aminoropan-1,3-diol or 2-aminopropanol derivatives, for example compounds containing a group of formula Y

,

,

in which Z denotes H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, phenyl, phenyl substituted with OH, C ₁ -C ₆ alkyl substituted with 1-3 substituents selected from the group , including halogen, C ₃ -C ₈ cycloalkyl, phenyl and phenyl substituted with OH, or CH ₂ -R _4z where R _4z is OH, an acyloxy group or a residue of formula (a)

,

,

in which Z ₁ denotes a direct connection or O, preferably O;

R _5z and R _{6z are} each independently H or C ₁ -C ₄ alkyl optionally substituted with 1, 2 or 3 halogen atoms;

R _1z is OH, an acyloxy group or a residue of formula (a); and R _2z and R _{3z are} each independently H, C ₁ -C ₄ alkyl or acyl.

A group of formula Y is a functional group attached as an end group to a fragment, which may be hydrophilic or lipophilic and contains one or more aliphatic, alicyclic, aromatic and/or heterocyclic residues, whereby the resulting molecule, in which at least one of Z and R _1z is or contains a residue of formula (a), functions (signals) as an agonist when bound to one or more sphingosine-1-phosphate receptors.

S1P receptor modulators are compounds that function (signal) as an agonist when bound to one or more sphingosine-1-phosphate receptors, eg S1P1 to S1P8. Binding of an agonist to the S1P receptor can result, for example, in the dissociation of intracellular heterotrimeric G proteins to form Gα-GTP and Gβγ-GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signal transduction pathways/kinases.

Examples of suitable S1P receptor modulators containing a group of formula Y are, for example:

compounds described in EP 627406 A1, for example, a compound of formula I

,

,

in which R ₁ denotes a straight or branched (C ₁₂ -C ₂₂ )-chain,

- where the chain may contain a bond or a heteroatom selected from a double bond, triple bond, O, S, NR ₆ where R ₆ denotes H, C ₁ -C ₄ alkyl, aryl-C ₁ -C ₄ alkyl, acyl or (C ₁ -C ₄ alkoxy)carbonyl and carbonyl, and/or

- may contain as a substituent C ₁ -C ₄ alkoxy group, C ₂ -C ₄ alkenyloxy group, C ₂ -C ₄ alkynyloxy group, aryl-C ₁ -C ₄ alkyloxy group, acyl, C ₁ -C ₄ alkylamino group, C ₁ -C ₄ alkylthio, acylamino, (C ₁ -C ₄ alkoxy)carbonyl, (C ₁ -C ₄ alkoxy)carbonylamino, acyloxy, (C ₁ -C ₄ alkyl)carbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy, or carboxy; or

R ₁ means

- phenylalkyl, where alkyl represents a straight or branched carbon (C ₆ -C ₂₀ )-chain; or

- phenylalkyl, where alkyl is a straight or branched carbon (C ₁ -C ₃₀ ) chain, where phenylalkyl is substituted

- straight or branched carbon (C ₆ -C ₂₀ )-chain, optionally substituted with halogen,

- (C ₆ -C ₂₀ )straight or branched alkoxy group, optionally substituted with halogen,

- straight or branched (C ₆ -C ₂₀ ) alkenyloxy group,

- phenyl C ₁ -C ₁₄ alkoxy, halophenyl C ₁ -C ₄ alkoxy, phenyl C ₁ -C ₁₄ alkoxy C ₁ -C ₁₄ alkyl, phenoxy C ₁ -C ₄ alkoxy or phenoxy C _1-4 alkyl,

- cycloalkylalkyl substituted with C ₆ -C ₂₀ alkyl,

- heteroarylalkyl substituted with C ₆ -C ₂₀ alkyl,

- heterocyclic C ₆ -C ₂₀ alkyl or

- heterocyclic alkyl substituted with C ₂ -C ₂₀ alkyl,

and in which

the alkyl moiety can have

- in the carbon chain, a bond or heteroatom selected/selected from a double bond, triple bond, O, S, sulfinyl, sulfonyl or NR ₆ , where R ₆ is as defined above, and

- as a substituent C ₁ -C ₄ alkoxy group, C ₂ -C ₄ alkenyloxy group, C ₂ -C _-4 alkynyloxy group, aryl-C ₁ -C ₄ alkyloxy group, acyl, C ₁ -C ₄ alkylamino group, C ₁ -C ₄ alkylthio group , acylamino, (C ₁ -C ₄ alkoxy)carbonyl, (C ₁ -C ₄ alkoxy)carbonylamino, acyloxy, (C ₁ -C ₄ alkyl)carbamoyl, nitro, halogen, amino, hydroxy or carboxy, and

R ₂ , R ₃ , R ₄ and R ₅ are each independently H, C ₁ -C ₄ alkyl or acyl,

or a pharmaceutically acceptable salt or hydrate thereof;

- compounds described in EP 1002792 A1, for example, a compound of formula II

,

,

in which m denotes 1-9 and R' ₂ , R' ₃ , R' ₄ and R' ₅ each independently of the other denotes H, C ₁ -C ₆ alkyl or acyl,

or a pharmaceutically acceptable salt or hydrate thereof;

- compounds described in EP 0778263 A1, for example, a compound of formula III

,

,

in which W denotes H; C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; unsubstituted or OH-substituted phenyl; R'' ₄ O(CH ₂ ) _n ; or C ₁ -C ₆ alkyl substituted with 1-3 substituents selected from the group consisting of halogen, C ₃ -C ₈ cycloalkyl, phenyl and phenyl substituted with OH;

X is H or an unsubstituted or substituted straight chain alkyl having p carbon atoms, or an unsubstituted or substituted straight chain alkoxy group having (p-1) carbon atoms, e.g. substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, OH, C ₁ -C ₆ alkoxy, acyloxy, amino, C ₁ -C ₆ alkylamino, acylamino, oxo, halo-C ₁ -C ₆ alkyl, halogen, unsubstituted phenyl and phenyl substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, OH, C ₁ -C ₆ alkoxy, acyl, acyloxy, amino, C ₁ -C ₆ alkylamino, acylamino, halo-C ₁ -C ₆ alkyl, and halogen; Y is H, C ₁ -C ₆ alkyl, OH, C ₁ -C ₆ alkoxy, acyl, acyloxy, amino, C ₁ -C ₆ alkylamino, acylamino, halo-C ₁ -C ₆ alkyl or halogen, Z ₂ is straight a bond or a straight chain alkylene having q carbon atoms,

where each of the symbols p and q independently of each other denotes an integer from 1 to 20, provided that 6<p+q<23, m' denotes 1, 2 or 3, n denotes 2 or 3,

R'' ₁ , R'' ₂ , R'' ₃ and R'' ₄ are each independently H, C ₁ -C ₄ alkyl or acyl,

or a pharmaceutically acceptable salt or hydrate thereof;

compounds described in WO 02/18395, for example a compound of formula IVa or IVb

,

,

in which X _a denotes O, S, NR _1s or a group -(CH ₂ ) _na -, where the group is unsubstituted or substituted by 1-4 halogen atoms; n _a is 1 or 2, R _1s is H or C ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted with halogen; R _1a denotes H, OH, C ₁ -C ₄ alkyl or OC ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted by 1-3 halogen atoms; R _1b denotes H, OH or C ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted by halogen; R _2a is each independently selected from H or C ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted with halogen; R _3a is H, OH, halogen or OC ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted with halogen; and R _3b is H, OH, halogen, C ₁ -C ₄ alkyl where alkyl is unsubstituted or substituted with hydroxy, or OC ₁ -C ₄ alkyl where alkyl is unsubstituted or substituted with halogen; Y _a is -CH ₂ -, C(O)-, -CH(OH)-, -C(=NOH)-, O or S, and R _4a is

C ₄ -C ₁₄ alkyl or C ₄ -C ₁₄ alkenyl;

or a pharmaceutically acceptable salt or hydrate thereof;

amino alcohol derivatives of formula V

,

,

in which X denotes O, S, SO or SO _2;

R ₁ is halogen, trihalomethyl, OH, C ₁ -C ₇ alkyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy, cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH ₂ -OH, CH ₂ -CH ₂ -OH, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, benzylthio, acetyl, nitro or cyano, or phenyl, phenylC ₁ -C ₄ alkyl or phenyl C ₁ -C ₄ alkoxy, where each phenyl group optionally substituted with halogen, CF ₃ , C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₂ is H, halogen, trihalomethyl, C ₁ -C ₄ alkoxy, C ₁ -C ₇ alkyl, phenethyl or benzyloxy;

R ₃ is H, halogen, CF ₃ , OH, C ₁ -C ₇ alkyl, C ₁ -C ₄ alkoxy, benzyloxy, phenyl, or C ₁ -C ₄ alkoxymethyl;

R ₄ and R ₅ are each independently H or a residue of formula (a)

(a),

(a)

in which R ₈ and R ₉ are each independently H or C ₁ -C ₄ alkyl optionally substituted with halogen; and

n is an integer from 1 to 4;

or their pharmaceutically acceptable salts;

or a compound of formula VI

,

,

wherein

R _1a is halogen, trihalomethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, aralkyl optionally substituted with phenoxy or aralkyloxy;

R _2a is H, halogen, trihalomethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, aralkyl or aralkyloxy;

R _3a is H, halogen, CF ₃ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio or benzyloxy;

R _4a is H, C ₁ -C ₄ alkyl, phenyl, optionally substituted benzyl or benzoyl, or lower aliphatic C ₁ -C ₅ acyl;

R _5a is H, monohalomethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxymethyl, C ₁ -C ₄ alkylthiomethyl, hydroxyethyl, hydroxypropyl, phenyl, aralkyl, C ₂ -C ₄ alkenyl or alkynyl;

R _6a is H or C ₁ -C ₄ alkyl;

R _7a is H, C ₁ -C ₄ alkyl or a residue having the above formula (a),

X _a is O, S, SO or SO ₂ ; and

n _a is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In relation to the compounds of formulas (I) and (II), the term "halogen" means fluorine, chlorine, bromine and iodine. The term "trihalomethyl group" means trifluoromethyl and trichloromethyl. "C ₁ -C ₇ alkyl" means straight or branched alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, t -butyl, pentyl, hexyl or heptyl. The term "substituted or unsubstituted phenoxy group" refers to phenoxy groups which carry a halogen atom at any position on their benzene ring, such as fluorine, chlorine, bromine and iodine, trifluoromethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. The term "aralkyl group" in the case of "aralkyl group" or "aralkyloxy group" means benzyl, diphenylmethyl, phenethyl and phenylpropyl. Any alkyl moiety present in "C ₁ -C ₄ alkoxy", "C ₁ -C ₄ alkylthio", "C ₁ -C ₄ alkylsulfinyl", or "C ₁ -C ₄ alkylsulfonyl" is C ₁ -C ₄ alkyl straight or branched chain, such as methyl, ethyl, propyl, isopropyl or butyl. The term "substituted or unsubstituted aralkyl group" means aralkyl groups which carry at any position on their benzene ring a halogen atom, such as fluorine, chlorine, bromine and iodine, trifluoromethyl, (lower) alkyl having 1-4 carbon atoms, or ( lower) alkoxy group having 1-4 carbon atoms.

Other compounds of formula V include compounds of formula Va

,

,

wherein

R ₂ , R ₃ , R ₄ , R ₅ and n are as defined above; and Y is O or S and

R ₆ is hydrogen, halogen, C ₁ -C ₇ alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl.

The compounds of formulas V and Va are known, they are described in, for example, WO 03/029205, WO 03/029184 and WO 04/026817, and phosphorylated derivatives are described in, for example, WO 04/074297, respectively, the contents of these documents are fully incorporated herein. description as reference. These compounds can be obtained according to the methods described in the cited references.

Phosphorylated derivatives of the compounds mentioned herein can be prepared using procedures for the synthesis of said phosphorylated compounds known in the art, such as those described in WO 2005/021503 (see, for example, pp. 11-12).

Optically active compounds and their phosphorylated derivatives can be obtained in high purity using art-known procedures described, for example, in Hinterding et al., Synthesis, vol. 11, 2003, ss. 1667-1670.

The following examples of modulators are

- compounds described in WO 02/06268 A1, for example a compound of formula VI

,

,

in which R _1d and R _2d each independently of the other represents H or an amino protecting group;

R _3d is hydrogen, a hydroxy protecting group, or a residue having the formula

R _4d is C ₁ -C ₄ alkyl;

n _d is an integer from 1 to 6;

X _d is ethylene, vinylene, ethynylene, a group of formula -D-CH ₂ - (in which D is carbonyl, -CH(OH)-, O, S or N), aryl or aryl having up to three substituents selected from group a below;

Y _d denotes a single bond, C ₁ -C ₁₀ alkylene, C ₁ -C ₁₀ alkylene having up to three substituents selected from groups a and b, C ₁ -C ₁₀ alkylene bearing O or S in the middle or at the end of the carbon chain, or C ₁ -C ₁₀ alkylene bearing O or S in the middle or at the end of the carbon chain, which has up to three substituents selected from groups a and b;

R _5d is hydrogen, C ₃ -C ₆ cycloalkyl, aryl, heterocyclic, C ₃ -C ₆ cycloalkyl with up to three substituents selected from groups a and b, aryl with up to three substituents selected from groups a and b, or a heterocyclic group having up to three substituents selected from groups a and b;

R _6d and R _7d are each independently H or substituents selected from group a;

R _8d and R _{9d are} each independently H or C ₁ -C ₄ alkyl optionally substituted with halogen;

<group a> includes halogen, (lower) alkyl, halo(lower) alkyl, (lower) alkoxy, (lower) alkylthio, carboxyl, (lower) alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono- (lower) alkylamino, di-C ₁ -C ₄ alkylamino, acylamino, cyano or nitro; and

<group b> includes C ₃ -C ₆ cycloalkyl, aryl or heterocyclic group, each/each of which optionally has up to three substituents selected from group a;

with the proviso that when R _5d is hydrogen, Y _d is either a single bond or linear C ₁ -C ₁₀ alkylene,

or its pharmacologically acceptable salt, ester or hydrate;

- compounds described in JP-14316985 (JP 2002316985), for example a compound of formula VII

,

,

in which R _1e ,R _2e ,R _3e ,R _4e ,R _5e ,R _6e ,R _7e , n _e , X _e and Y _e have the meanings specified in JP-14316985;

or its pharmacologically acceptable salt, ester or hydrate;

- compounds described in WO 03/062252 A1, for example a compound of formula VIII

VIII,

VIII,

wherein

Ar is phenyl or naphthyl; each of the symbols m _g and n _g independently from each other denotes 0 or 1; A is selected from COOH, PO ₃ H ₂ , PO ₂ H, SO ₃ H, PO-C ₁ -C ₃ alkyl-OH and 1H-tetrazol-5-yl; R _1g and R _2g are each independently H, halogen, OH, COOH or C ₁ -C ₄ alkyl optionally substituted with halogen; R _3g is H or C ₁ -C ₄ alkyl optionally substituted with halogen or OH; R _4g each independently of the other represents a halogen or optionally substituted/halogen-substituted C ₁ -C ₄ alkyl or C ₁ -C ₃ alkoxy group; and R _g and M each have one of the values specified in WO 03/062252 A1 for B and C, respectively;

or a pharmacologically acceptable salt, solvate or hydrate thereof;

- compounds described in WO 03/062248 A2, for example a compound of formula IX

,

,

in which Ar denotes phenyl or naphthyl; n is 2, 3 or 4; A is COOH, 1H-tetrazol-5-yl, PO ₃ H ₂ , PO ₂ H ₂ , -SO ₃ H or PO(R _5h )OH, where R _5h is selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, phenyl, -CO-C ₁ -C ₃ alkoxy and -CH(OH)-phenyl, where the phenyl or phenyl moiety is optionally substituted; R _1h and R _2h are each independently H, halogen, OH, COOH or optionally halo-substituted C ₁ -C ₆ alkyl or phenyl; R _3h is H or C ₁ -C ₄ alkyl optionally substituted with halogen and/or OH; R _4h are each independently halogen, OH, COOH, C ₁ -C ₄ alkyl, S(O) _{0.1 or 2} -C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkoxy, aryl or aralkoxy, where the alkyl moieties may optionally be substituted with 1-3 halogen atoms; and R _h and M each have one of the values specified in WO 03/062248 A2 for B and C, respectively,

or a pharmacologically acceptable salt, solvate or hydrate thereof.

- Compounds described in WO 04/103306A, WO 05/000833, WO 05/103309 or WO 05/113330, for example compounds of formula Xa or Xb

,

,

wherein

A _k is COOR _5k , OPO(OR _5k ) ₂ , PO(OR _5k ) _{2 ,} SO ₂ OR _5k , POR _5k OR _5k or 1H-tetrazol-5-yl, R _5k is H or C _1-6 alkyl;

W _k is a bond, C ₁ -C ₃ alkylene or C ₂ -C ₃ alkenylene;

Y _k is C ₆ -C ₁₀ aryl or C ₃ -C ₉ heteroaryl optionally substituted with 1-3 radicals selected from halo, OH, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; halogen-substituted C ₁ -C ₆ alkyl and halogen-substituted C ₁ -C ₆ alkoxy;

Z _k is a heterocyclic group as defined in WO 04/103306A, eg azetidine;

R _1k is C ₆ -C ₁₀ aryl or C ₃ -C ₉ heteroaryl optionally substituted with C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₄ alkyl, C ₃ - C ₉ heteroaryl, C ₃ -C ₉ heteroaryl-C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₄ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ heterocycloalkyl-C ₁ -C ₄ alkyl; where any aryl, heteroaryl, cycloalkyl or heterocycloalkyl, denoted R _1k , may be substituted by 1-5 groups selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and substituted/halogen-substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy groups;

R _2k is H, C ₁ -C ₆ alkyl, halo-substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl: and

R _3k or R _4k are each independently H, halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen-substituted/substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

and their N-oxide derivatives or prodrugs,

or their pharmacologically acceptable salts, solvates or hydrates.

The compounds of formulas I-Xb may exist in free form or in salt form. Examples of pharmaceutically acceptable salts of compounds of formulas III to VIII are salts with inorganic acids such as hydrochloride, hydrobromide and sulfate, salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate, or when suitably, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines such as triethylamine, and salts with dibasic amino acids such as lysine. Compounds and salts included in the combination proposed in the present invention may be in the form of hydrates and solvates.

Acyl, as indicated above, may represent the residue R _y -CO-, in which R _y denotes C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or phenyl-C ₁ -C ₄ alkyl. Unless otherwise indicated, alkyl, alkoxy, alkenyl, or alkynyl may be straight or branched chain.

Aryl may be phenyl or naphthyl, preferably phenyl.

When in compounds of formula I a carbon chain such as R ₁ is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted with halogen, nitro, amino, methoxy, hydroxy or carboxy.

Preferred compounds of formula I are those wherein R ₁ is C ₁₃ -C ₂₀ alkyl optionally substituted with nitro, halogen, amino, hydroxy or carboxy, and more preferably those wherein R ₁ is phenylalkyl substituted with C ₆ -C ₁₄ alkyl a chain optionally substituted with halogen, and the alkyl moiety is C ₁ -C ₆ alkyl optionally substituted with hydroxy. More preferably R ₁ is phenylC ₁ -C ₆ alkyl substituted on the phenyl moiety with a straight or branched, preferably straight, C ₆ -C ₁₄ alkyl chain. The C ₆ -C ₁₄ alkyl chain may be in the ortho , meta or para position, preferably in the para position.

Preferably R ₂ - R ₅ are each H.

In the above formula VII, a "heterocyclic group" is a 5-7 membered heterocyclic group having 1 to 3 heteroatoms selected from S, O and N. Examples of such heterocyclic groups are the above heteroaryl groups and heterocyclic compounds corresponding partially or fully hydrogenated heteroaryl groups, e.g. , tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl or pyrazolidinyl. Preferred heterocyclic groups are 5- or 6-membered heteroaryl groups, and the most preferred heterocyclic group is a morpholinyl, thiomorpholinyl, or piperidinyl group.

A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. The most preferred S1P receptor agonist of formula III is FTY720, ie. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in the form of a pharmaceutically acceptable salt (hereinafter referred to as Compound A), for example, in the form of a hydrochloride, represented by the following formula:

A preferred compound of formula II is one in which R' ₂ - R' ₅ are each H and m is 4, i.e. 2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol, in free form or in pharmaceutically acceptable salt form (hereinafter referred to as Compound B), for example, in the form of hydrochloride.

A preferred compound of formula III is one in which W is CH ₃ , R'' ₁ - R'' ₃ each is H, Z ₂ is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol, in free form or in the form of a pharmaceutically acceptable salt (hereinafter referred to as Compound B), for example, in the form of a hydrochloride. Most preferred is the R-enantiomer.

A preferred compound of formula IVa is FTY720-phosphate (R _2a is H, R _3a is OH, X _a is O, R _1a and R _1b are OH). A preferred compound of formula IVb is the phosphate of Compound B (R _2a is H, R _3b is OH, X _a is O, R _1a and R _1b are OH, Y _a is O and R _4a is heptyl). A preferred compound of formula V is Compound B-phosphate.

A preferred compound of formula VII is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)benzo[b]thien-6-yl]-2-methylbutan-1-ol.

A preferred compound of formula Xa is, for example, 1-{4-[1-(4-cyclohexyl-3-trifluoromethylbenzyloxyimino)ethyl]-2-ethylbenzyl}azetidine-3-carboxylic acid or a prodrug thereof.

It should be understood that the compounds provided herein may directly represent active substances or may represent prodrugs. For example, the compounds may be in phosphorylated forms.

Oral formulations

Dosage form of the composition proposed in the present invention, for example, the final dosage form, may be a solid dosage form, for example, a tablet. In another embodiment of the present invention, the dosage form is granular, for example, may be in the form of a powder, and may be an integral part of a suspension or gel. Other dosage forms may be small multiparticulate pellets/granules. Other dosage forms may contain a solid or granular composition that can be dissolved in a liquid prior to administration to form a liquid formulation. Examples of such formulations are dissolvable tablets, capsules and sachets. The final liquid formulation may be ingested as a beverage.

The oral route of administration is often the most suitable route of drug administration. It may be in the form of a standard tablet, a conventional orally disintegrating tablet, a lyophilized tablet, or a thin film.

In the course of the invention, it has been found that compounds containing a group of formula Y, eg aminopropane-1,3-diols, eg S1P agonists, are difficult to formulate. In particular, they are difficult to incorporate into a solid oral formulation.

As such, it has surprisingly been found in the course of the present invention that only a limited number of excipients can be used in combination with such aminodiols.

Maillard reaction

The Maillard reaction is a chemical reaction between an amino acid and a reducing sugar (sugars containing aldehyde groups that oxidize to carboxylic acids are classified as reducing sugars; reducing sugars include glucose, glyceraldehyde, lactose, arabinose, and maltose), usually requiring the addition of heat . Like caramelization, it is a form of non-enzymatic browning reaction. The reactive carbonyl group of the sugar interacts with the nucleophilic amino group of the amino acid, resulting in the formation of interesting but poorly characterized "smell and taste molecules". This process is accelerated in an alkaline environment, since there is no neutralization of the amino groups. This reaction is the basis for the production of flavorings (flavourings), since the type of amino acid determines the final taste.

Potentially useful excipients are classified into, for example, fillers, binders, disintegrators, lubricants, flow regulators, plasticizers and matrix forming agents. Some excipients can be assigned to more than one class.

Typical ranges for the content of excipients in the final composition containing the connection presented in the present description are the following ranges:

fillers: 10-97%

binders: 1-15%

leavening agents: 1-15%

lubricants: 0.5-2%

flow regulators: 0.5-3%

matrix forming agents: 3-50%

plasticizers: 5-30%

corrigents: 1-20%

sweeteners: 1-20%.

Thus, the present invention relates to stable mixtures containing a compound that has a group of formula Y, and at least one excipient other than it.

In one embodiment, a compound having a group of formula Y may be mixed with one or more of the following excipients:

(a) excipients selected from lactose monohydrate, lactose anhydrous, cornstarch, mannitol, xylitol, sorbitol, sucrose, microcrystalline cellulose, eg Avicel PH101, dicalcium phosphate, maltodextrin, gelatin, eg DE 12;

and/or

(b) binders selected from HPMC, eg 3 cps, L-HPC, eg HP-cellulose LH-22, povidone;

and/or

(c) disintegrants selected from corn starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, eg Primojel, pregelatinized starch, eg starch 1500 (Sta RX), calcium silicate;

and/or

(d) lubricants selected from hydrogenated, e.g. ricinic acid-containing castor oil, e.g. Cutina, magnesium stearate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, sodium stearyl fumarate,

and/or

(e) flow regulators selected from colloidal silicon dioxide, eg Aerosil 200, talc;

and/or

(e) matrix-forming agents selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, pullulan, starch, eg Pure Cote type, povidone;

and/or

(g) plasticizers selected from PEG 400, dibutyl sebacate, sorbitol;

and/or

(h) flavors selected from menthol, tutti fruti;

and/or

(i) sweeteners selected from sucralose, sodium saccharin.

The fillers are preferably selected from the group of fillers including lactose monohydrate, lactose anhydrous, corn starch, xylitol, sorbitol, sucrose, microcrystalline cellulose such as Avicel PH101, dicalcium phosphate, maltodextrin and gelatin.

According to one embodiment of the invention, preferred lubricants are selected from magnesium stearate and calcium stearate.

Another embodiment of the present invention relates to a binary mixture containing a compound having a group of formula Y and one excipient selected from:

sorbitol, xylitol, dicalcium phosphate, lactose, microcrystalline cellulose, HPMC, HPC, crospovidone, croscarmellose sodium, starch, preferably anhydrous, calcium silicate, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate.

Preferably, there is no moisture in the mixture.

In particular, excipients are selected from:

secondary calcium phosphate, HPC, crospovidone, calcium silicate, magnesium stearate.

In particular, the formulation or mixture of the present invention does not contain reducing sugars such as glucose, glyceraldehyde, lactose, arabinose and maltose.

More preferably, the formulation or mixture of the present invention does not contain PEG, stearic acid.

Stabilizers can be added as needed to raise or lower the pH value. By modifying the pH value, the composition can be adapted to reduce the likelihood of a Maillard reaction or other side reactions that may occur. An example of a stabilizer is citric acid.

In a preferred embodiment of the invention, the compositions of the present invention are binary mixtures, i.e. a mixture of a compound having a group of formula Y and one of the excipients listed herein.

An important advantage of the stable binary mixtures presented in the present description is that they can be transported and stored until the preparation of the final formulation without the formation of cleavage products. Thus, the use of mixtures of the present invention, such as binary mixtures, provides a commercially viable opportunity to store the S1P modulator described herein under stable conditions.

Before the aforementioned unexpected results having the Y group of compounds were obtained in the present invention, due to their instability, they could not be safely stored without the possible formation of impurities. With the knowledge obtained during the creation of the present invention, the person skilled in the art can determine which excipients can be used in combination with S1P modulators for storage, and, more importantly, which excipients can be used to reduce the risk of contamination of the final drug product with impurities that form in if the Maillard reaction takes place.

Permissible impurity levels:

The compositions of the present invention, such as binary mixtures and/or final dosage forms, preferably do not contain impurities. It should be understood that the acceptable level of impurities should be determined based on accepted pharmaceutical standards.

However, it should also be understood that pharmaceutical standards can only be applied to the final dosage form, i.e. to the final product. A preferred embodiment of the present invention relates to binary mixtures containing the S1P receptor modulator as described herein, i.e. a compound having a group of formula Y, which have a low content of impurities, for example, do not contain impurities. Preferably, the binary mixtures of the present invention satisfy the following criteria in terms of impurity level:

- they contain no more than 4.5 wt.% impurities and/or no more than 2 wt.% impurities of the same type;

- preferably, the amount of impurities is 2 wt.% or less, while the amount of impurities of the same type is not more than 0.5 wt.%.

Expressed in "wt.%" the above values are an indication of the allowable amount of impurities. The designation "wt.%" means weight, expressed as a percentage relative to the weight of the entire formulation, for example, 4 wt.% means that a tablet weighing 100 mg contains 4 mg.

Example of acceptable impurity levels for reference compound FTY720

It has been established that three cleavage products characterized are present in the dosage form: acetylamide, palmitamide and stearatamide.

It has been established that the mechanism of formation of these cleavage products is that the nucleophilic group of the primary amine of the FTY720 molecule acts on the carbonyl carbon atom of acetic, palmitic, or stearic acid.

Based on a toxicological study, it was found that the allowable levels of the three main cleavage products, namely, acetylamide, palmitatamide and stearatamide, should not exceed 4.6%, 4.5% and 4.8%, respectively.

For the purposes of appropriate quality control and potency of the final dosage form product, it was assumed that the content of each characterized cleavage product should be equal to or not exceed 2.0% of the labeled content of the active substance.

The content of cleavage products determined must be 1.0% or less than the content of the active substance indicated on the label.

Novartis' policy to ensure the purity of medicinal products requires that unspecified cleavage products be present at or below 0.5% of the labeled content of active ingredient.

It is assumed that the total content of all cleavage products present in quantities above the limit of quantitative detection (0.1% in relation to the content of the active substance indicated on the label) should in total amount to or not exceed 4.5%.

FTY720: An example of a compound having a group of formula Y:

The program for evaluating the chemical stability of binary mixtures of FTY720 and excipients (1% drug substance was stored in closed vials for 1 month at 50°C) was carried out using FTY720 drug substance.

In general, the method for obtaining binary mixtures was as follows:

1. 10 mg drug substance and 1000 mg excipient were added to a glass vial (= binary mixture).

2. Closed vials were stored for 1 month at 50°C.

Analytical characterization was performed by gradient HPLC with UV detection. For analysis, the samples after storage were dissolved in 40 ml of 0.0005 N. hydrochloric acid solution in isopropanol and stirred with a magnetic stirrer for 30 minutes. The resulting solution was centrifuged and an aliquot of the clear supernatant was used as a test solution.

The limit of quantitative detection (loq) of the method was 0.1%. The relative standard deviation s _rel of the measurement results was ≤2%.

device HPLC system with gradient capability, autosampler and UV detector Column Waters Xterra ^™ MS C ₈ length 50 mm, inner diameter 4.6 mm, particle size 2.5 µm, batch number 186000603. Chromatography conditions Mobile phase A buffer 100mM NaClO ₄ , pH 2.8:methanol=93:7 (v/v) Mobile phase B acetonitrile Gradient (linear) program time [min.] phase A [%] phase B [%] 0 70 thirty 1.0 70 thirty 15.0 58 42 28.0 5 95 30.0 5 95 30.1 70 thirty 35.0 70 thirty Flow rate 1.5 ml/min Detection UV detection at 215 nm Column temperature 30°C Autosampler temperature Ambient temperature Injectable volume 10 µl Chase time 35 min

The tables below provide a list of potentially useful excipients, as well as the results obtained from the stability evaluation program.

Example 1: Stability Analysis of FTY720 Using Selected Excipients

Excipient Analysis results in % Σ impurity content in % Anhydrous lactose
Corn starch
Mannitol
Mannitol granular (SD 200)
Avicel
Citric acid + mannitol (10 + 90)
Sodium bicarbonate + mannitol (10 + 90) 101.4
102.2
102.3
99.5
97.9
102.4
102.7 0.0
0.0
0.0
0.3
0.2
0.0
0.0

Example 2 Stability Analysis of FTY720 Using Selected Binders

Excipient Analysis results in % Σ impurity content in % HPMC 3 sp
HP-cellulose LH-22 97.8
99.8 0.0
0.4

Example 3: Stability analysis of FTY720 using selected disintegrators:

Excipient Analysis results in % Σ impurity content in % Corn starch
sodium crosscarmellose
sodium carboxymethic starch (Primojel)
starch 1500 (Sta RX) 102.2
102.4
103.2
101.3 0.0
0.0
0.0
0.0

Example 4: Stability Analysis of FTY720 Using Selected Lubricants:

Excipient Analysis results in % Σ impurity content in % Hydrogenated ricinoleic oil (Cutina)
Magnesium stearate+mannitol (1+99) 103.6
103.5 0.0
0.5

Example 5: Stability Analysis of FTY720 Using Selected Flow Regulators:

Excipient Analysis results in % Σ impurity content in % Aerosil 200 101.5 0.6

Example 6: Stability Analysis of FTY720 Using Selected Matrix Forming Substances:

Excipient Analysis results in % Σ impurity content in % Hydroxypropyl methylcellulose
Hydroxypropylcellulose
Methylcellulose
Ethylcellulose
Pullulan
Starch, e.g. Pure Cote
Povidone 97.8
99.8
-
-
-
102.2
95.4 0.0
0.4
-
-
-
0.0
0.5

Polymers of different molecular weights can be used in the same formulation, eg low molecular weight and high molecular weight, i.e. a mixture of, for example, low and high MW cellulose type polymers can be used to provide different properties.

Example 7: Stability Analysis of FTY720 Using Selected Plasticizers:

Excipient Analysis results in % Σ impurity content in % PEG 400
Dibutylsebacate
Sorbitol -
-
- -
-
-

Example 8: Stability Analysis of FTY720 Using Selected Flavors:

Excipient Analysis results in % Σ impurity content in % Menthol - - Tutti fruity

Example 9: Stability Analysis of FTY720 Using Selected Sweeteners:

Excipient Analysis results in % Σ impurity content in % Sucralose
Saccharin sodium -
- -
-

Example 10 Unsuitable Excipients

An example of an unsuitable excipient is shown below. In this case, the same binary mixture preparation and analytical characterization methods as described above were used.

Excipient Analysis results in % Σ impurity content in % Glyceryl behenate (compritol) 96.2 > 2

Example 10: S1P Analysis

The binding affinity of S1P receptor modulators to individual human S1P receptors can be assessed using the following assay:

The activities of the compounds as modulators of the S1P receptor were assayed using the human S1P receptors S1P ₁ , S1P ₂ , S1P ₃ , S1P ₄ and S1P ₅ . Functional receptor activation is determined by quantifying compound-induced binding of GTP [γ- ³⁵ S] to a membrane protein derived from transfected CHO or RH7777 cells stably expressing the corresponding human S1P receptor. As an analysis method, SPA (scintillation analysis using molecularly imprinted polymers (MIPs)) is used. In general, the method is as follows. Serial dilutions of the compounds dissolved in DMSO are prepared and added to the S1P receptor expressing membrane protein immobilized on a SPA-bead (Amersham-Pharmacia) (10-20 μg/well) in the presence of 50 mM Hepes, 100 mM NaCl, 10 mM MgCl ₂ , 10 μM GTP , 0.1% defatted BSA and 0.2nM GTP [γ- ³⁵ S] (1200 Ci/mmol). After incubation in 96-well microtiter plates at RT for 120 minutes, unbound GTP [γ - ³⁵ S] is removed by centrifugation. The luminescence of SPA beads initiated by membrane-bound GTP [γ- ³⁵ S] was quantified using a TOPcount type plate reader (Packard). EC ₅₀ values are calculated using software based on a standard curve fit. S1P receptor modulators preferably have an S1P receptor binding affinity of <50nM as measured by this assay.

Preferred S1P receptor modulators are, for example, compounds which, in addition to their ability to bind to S1P, also have the ability to accelerate lymphocyte homing, for example, compounds that cause lymphopenia due to a redistribution, preferably reversible, of lymphocytes from the circulation to the secondary lymphatic tissue without causing generalized immunosuppression. Unsensitized cells are removed; stimulate CD4 and CD8 T cells and B cells to migrate from the circulation to the lymph nodes (LN) and Peyer's patches (PP).

The ability of compounds to induce lymphocyte homing can be assessed using the following blood lymphocyte depletion assay:

The S1P receptor modulator or vehicle is administered to rats orally via gavage. For monitoring hematological parameters, blood samples are taken from the tail vein on day -1, obtaining individual baseline parameter values, and at 2, 6, 24, 48 and 72 hours after administration. In this assay, an S1P receptor agonist or modulator causes a depletion of, for example, 50% peripheral blood lymphocytes when administered at a dose of, for example, <20 mg/kg.

Preparation of the final product:

The preparation of final pharmaceutical products can be carried out using conventional methods. Examples of such methods are described below for the purpose of illustration.

Compressed tablets

Compressed tablets are obtained by subjecting the material to high pressure to compact it. If a sufficiently homogeneous mixture cannot be obtained by conventional mixing, then the ingredients should be subjected to granulation prior to compression to ensure uniform distribution of the active ingredient in the final tablet. To obtain powders intended for granulation for the manufacture of tablets, two main methods are used: the wet granulation method and the dry granulation method.

Powders that mix well and therefore do not need to be granulated can be compressed into tablets by a method known as "direct compression".

Lyophilized tablets

Such tablets can be prepared by forming a suspension containing the active substance and other excipients, for example, gelatin, in an amount of about 3 wt.%, structure-forming substances, such as mannitol or sorbitol, for example, in an amount of about 1 .5 wt.%, sweeteners and flavorings.

The following is an example of a lyophilized tablet formulation:

The gelatin/mannitol solution is cooled to 23°C and mixed with the active ingredient. The total solids content is preferably less than 50%. Then the suspension is cooled to 15°C to prevent sedimentation of the suspension, after which the lyophilization is started.

Thin films

The compositions of the present invention may be further mixed with other excipients to form final products. End products can be prepared from binary compositions using one of the following standard methods:

Products can be prepared using casting, drawing, extrusion or coating/lamination processes:

Casting is a manufacturing process in which a drug/excipient mixture is introduced into a mold, allowed to solidify in the mold, and then removed or broken out of the mold to form an individual thin film.

The drawing process makes it possible to obtain a roll by drawing the molten drug/excipient mixture until its length is increased. This is usually accompanied by thinning of the material. Segments containing a single dose are then cut or die-cut from these rolls and packaged, for example, in pouches.

The extrusion process makes it possible to obtain rolls by pushing and/or pulling material through a die having the desired profile shape. The extrusion can be carried out continuously (getting an infinitely long product) or semi-continuously (getting many short rolls). Segments containing a single dose are then cut or die-cut from these rolls and packaged, for example, in pouches.

The coating/lamination process can be described as the production of a laminate (laminate) primarily by coating and laminating. After that, the resulting roll is divided into small rolls. Segments containing a single dose are then cut or die-cut from these rolls and packaged, for example, in pouches.

According to the invention, the compositions of the present invention, for example in the form of final dosage forms, can be used to:

a) treatment and prevention of organ or tissue transplant rejection, for example, to treat transplant recipients of the heart, lung, heart-lung complex, liver, kidney, pancreas, skin or cornea, and to prevent graft-versus-host disease, which sometimes occurs after bone marrow transplantation; especially for the treatment of acute or chronic allo- and xenograft rejection, or in the case of transplantation of insulin-producing cells, for example pancreatic islet cells;

b) treating and preventing autoimmune disease or inflammatory conditions, eg, multiple sclerosis, arthritis (eg, rheumatoid arthritis), inflammatory bowel disease, hepatitis, etc.;

c) treatment and prevention of viral myocarditis and viral diseases such as hepatitis and AIDS associated with viral myocarditis;

d) treating and preventing cancer, eg solid tumors, carcinomas, eg preventing the spread of tumor metastases or preventing or inhibiting the growth of micrometastases.

By "solid tumors" is meant tumors and/or metastases (regardless of location) other than lymphatic cancer, e.g., tumors of the brain and other parts of the central nervous system (e.g., tumors of the meninges, brain, spinal cord, cranial nerves and other parts of the central nervous system, such as glioblastoma or medulloblastoma); head and/or neck cancer; breast tumors; tumors of the circulatory system (eg, heart, mediastinum and pleura, and other organs located in the chest, vascular tumors and tumor-associated vascular tissue); tumors of the excretory system (eg, kidney, renal pelvis, ureter, bladder, other and non-specific organs of the urinary system); tumors of the gastrointestinal tract (eg, esophagus, stomach, small intestine, colon, colon and rectum (colorectal tumors), rectosigmoid junction, rectum, anus, and anal canal), tumors affecting the liver and intrahepatic bile ducts, tumors of the bile bladder, other and non-specific sections of the biliary tract, pancreas, other organs and organs of the digestive system); oral cavity (lips, tongue, gums, floor of the mouth, palate and other parts of the mouth, parotid salivary gland and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform pocket, hypopharynx and other areas on the lips, in the oral cavity and pharynx) ; tumors of the reproductive system (eg, vulva, vagina, cervix, body of the uterus, uterus, ovary and other areas associated with the female genital organs, placenta, penis, prostate, testicles and other areas associated with the male genital organs); tumors of the respiratory tract (eg, nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi, and lung, eg, small cell lung cancer and non-small cell lung cancer); tumors of the skeletal system (for example, bone and articular cartilage of the extremities, osteoarticular cartilage and other areas); skin tumors (eg, malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, mesothelioma, Kaposi's sarcoma); and tumors affecting other tissues, including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and its appendages, thyroid, adrenal and other endocrine glands, and related structures, secondary and non-specific malignant neoplasm of the lymph nodes , secondary malignant neoplasm of the respiratory and digestive systems, and secondary malignant neoplasm of other areas.

When a tumor, neoplastic disease, carcinoma or cancer is mentioned above or below in the present description, then, as an alternative or additionally, metastases to the primary organ or tissue and / or to any other area are also meant, regardless of the location of the tumor and / or metastases.

Thus, the following objects of the present invention are:

1. The composition presented in the present description, which is intended for the treatment or prevention of the above disease or condition.

2. A method of treating an individual in need of immunomodulation, comprising administering to the individual an effective amount of the above composition.

3. A method for treating or preventing the above disease or condition, comprising administering the above composition to the subject.

4. The use of the above pharmaceutical composition for the preparation of a medicament for the treatment or prevention of the above disease or condition.

Claims (9)

1. Pharmaceutical composition for the treatment of multiple sclerosis, containing a stable mixture consisting of: Free form 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol (FTY720) or a pharmaceutically acceptable salt thereof and pregelatinized starch. 2. The pharmaceutical composition of claim 1 further comprising a lubricant selected from hydrogenated castor oil, glyceryl behenate, magnesium stearate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, and sodium stearyl fumarate. 3. Dosage form for the treatment of multiple sclerosis, containing the pharmaceutical composition according to claim 1. 4. Dosage form according to claim 3, in the form of a tablet or capsule. 5. A stable pharmaceutical mixture consisting of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) in free form or a pharmaceutically acceptable salt thereof and pre-gelled starch for use in preparation of a drug for the treatment of multiple sclerosis. 6. Dosage form for the treatment of multiple sclerosis, containing a stable pharmaceutical mixture according to claim 5. 7. Dosage form according to claim 6, in the form of a tablet or capsule. 8. Use of a stable mixture consisting of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) in free form or a pharmaceutically acceptable salt thereof and pre-gelled starch for the manufacture of a drug agents for the treatment of multiple sclerosis.