Title of Invention

A PROCESS FOR PRODUCING A PHARMACEUTICAL COMPOSITION

Abstract A solid pharmaceutical composition suitable for oral administration, comprising: (a) A S1P receptor agonist; and (b) A sugar alcohol.
Full Text

The present invention relates to pharmaceutical compositions comprising a sphingosine-1 phospliate receptor agonist. Sphingosine-1 phosphate (hereinafter "SIP") is a natural serum lipid. Presently there are 8 known S1P receptors, namely S1P1 to S1P8. SIP receptor agonists have accelerating lymphocyte homing properties.
SIP receptor agonists are immunomodulating compounds, which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, evoking a generalized immunosuppression. Naive cells are sequestered, CD4 and CD8 T-cells and B-ceils from the blood are stimulated to migrate into lymph nodes (LN) and Payer’s patches (PP), and thus infiltration of cells into transplanted organs is inhibited.
The various known S1P receptor agonists show structural similarities, which result in related problems in providing a suitable formulation. In particular, there is a need for an SIP receptor agonist containing formulation which is well-adapted for oral administration in a solid form, e.g. as a tablet or capsule.
Accordingly, the present invention provides a solid pharmaceutical composition suitable for oral administration, comprising a SIP receptor agonist and a sugar alcohol.
It has surprisingly been found that solid compositions comprising a sugar alcohol provide formulations which are particularly well suited to the oral administration of SIP receptor agonists. The compositions provide a convenient means of systemic administration of SIP receptor agonists, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage properties. In particular, the compositions of the present invention may show a high level of uniformity in the distribution of the S1P receptor agonist throughout the composition, as well as high stability. The compositions of the invention may be manufactured on high speed automated equipment, and thus do not require hand encapsulation.

SIP receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives. Examples of appropriate S1P receptor agonists are, for example:
- Compounds as disclosed in EP627406A1, e.g. a compound of formula I

wherein Ri is a straight- or branched (Ci2.22)carbon chain
- which may have in the chain a bond or a hetero atom selected from a double bond, a triple
bond, O, S, Nero, wherein Re is H, alkyl, aurally, acyl or alkoxycarbonyl, and carbonyl,
and/or
- which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy,
acyl, alkylamino, alkylthio, acyiamino, alkoxycarbonyl, alkoxycarbonylamino,
acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or
carboxy; or
Ri is
- a phenylalkyi wherein alkyl is a straight- or branched (C6.2o)carbon chain; or
- a phenylalkyi wherein alkyl is a straight- or branched (Ci.3o)carbon chain wherein said phenylalkyi is substituted by

- a straight- or branched (C6.2o)carbon chain optionally substituted by halogen, " a straight- or branched (C6.2o)alkoxy chain optionally substitued by halogen,
- a straight- or branched (C6-2o)alkenyloxy.
- phenylalkoxy, halophenylalkoxy. phenylalkoxyalkyl. Phenoxyalkoxy or phenoxyalkyi,
- cycloalkyialkyi substituted by C6-2oalkyl,
- heteroarylalkyi substituted by C6.2oalkyl,
- heterocyclic C6.2oalkyl or
- heterocyclic alkyl substituted by C2.2oalkyl, and wherein
the alkyl moiety may have

- in the carbon chain, a bond or a heteroatoms selected from a double bonk, a triple bond, 0,
S, slimly, sulfenyl, or Nero, wherein Re is as defined above, and
- as a substituent alkoxy, alkenyloxy, alkynyioxy, aralkyloxy, acyl, alkylamino, alkylthio,
acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen,
amino, hydroxy or carboxy, and
each of R2, R3. R4 and R5. independently, is H, alkyl or acyl or a pharmaceutically acceptable salt thereof;
- Compounds as disclosed in EP 1002792A1, e.g. a compound of formula 11

wherein W is H; alkyl, C2-6alkenyl or Ca-ealkynyl; unsubstituted or by OH substituted phenyl; R"40(CH2)n; or alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, cycloalkyI, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3 substitutents selected from the group consisting of G1-6 alkyl, OH, Ci,6alkoxy, acyloxy, amino, alkylamino, acylamino, 0x0, halo alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of alkyl, OH, alkoxy, acyl, acyloxy, amino, Cvealkylamino, acylamino, haloCvealkyi and halogen; Y is H, alkyl, OH, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, haloCialkyl or halogen, Z2 is a single bond or a straight chain alkylene having a number or carbon atoms of q.

each of p and q, independently, is an integer of 1 to 20, with the proviso of 6 1, 2or3, n is 2 or 3,
each of R'S, R"2, Rs and R"4, independently, is H, alkyl or acyl.
or a pharmaceutically acceptable salt thereof,
- Compounds as disclosed in WO02/18395, e.g. a compound of formula Ivan or IVc

wherein Ax is O, S, Nis or a group -(CH2)an-, which group is unsubstituted or substituted by 1 to 4 halogen; an is 1 or 2, Rips is H or alkyi, which alkyl is unsubstituted or substituted by halogen; Ria is H, OH, (CM)alkyl or 0 alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; Rib is H, OH or alkyl. wherein alkyl is unsubstituted or substituted by halogen; each R2s is independently selected from H or alkyl, which alkyl is unsubstituted or substitued by halogen; Rsa is H, OH, halogen or 0 alkyl wherein alkyl is unsubstituted or substituted by halogen; and Rs is H, OH, halogen alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or 0 alkyl wherein alkyl is unsubstituted or substituted by halogen; Yaw is -Char. -0(0)-. -CH(OH)-, -C(=NOH)-, O or S, and R4a is (C4. i4)alkyl or (C4.i4)alkenyl; or a pharmaceutically acceptable salt or hydrate thereof;
- Compounds as disclosed in WO 02/076995, e.g. a compound of formula V


Rica is H; alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-perylene; C2-6alkenyl; C2-6alkynyi; or phenyl optionally substituted by OH; R2C is

wherein Rs is H or alkyl optionally substituted by 1, 2 or 3 halogen atoms, and Reek
is H or alkyl optionally substituted by halogen; each of Rs and R4C. independently, is H, Dialkyl optionally substituted by halogen, or acyl, and Re is Ci3.2oalkyl which may optionally have in the chain an oxygen atom and which may
optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of
formula (a)

wherein is H, alkyl or Ciwlkoxy, and Rac is substituted Ci.2oalkanoyl, phenylCvalkyl wherein the Ci.i4alkyl is optionally substituted by halogen or OH, cycloalkylCi.ualkoxy or phenylCvualkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, alkyl and/or Ci-4alkoxy, phenylCi.i4alkoxy-Ci-i4alkyl, peroxy alkoxy or phenoxyCi.i4alkyl,
Re being also a residue of formula (a) wherein Rs is alkoxy when Rica is Dialkyl alkenyl or C2-6alkynyl,
or a compound of formula VI

wherein
is 2, 3 or 4
is H; Creaky optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-perylene; C2-6alkenyl; C2^alkynyl; or phenyl optionally substituted by OH;

R2x is H, Chalky oracle
each of and R4X, independently is H, alkyl optionally substituted by halogen oracle,
Rs is H alkyl or alkoxy, and
Rex is Cv2oalkanoyl substituted by cycloalkyl; cyloalkylCvi4alkoxy wherein the cyclo alkyi ring is optionally substituted by halogen, Dialkyl and/or alkoxy; phenyl alkoxy wherein the phenyl ring is optionally substituted by halogen, Dialkyl and/or alkoxy,
Rex being also C4-i4alkoxy when RxR is C2-4alkyl substituted by OH, or benzyloxy or hexyl when Ri is alkyl,
provided that Rex is other than phenyl-butylenoxy when either Rs is H or RxR is methyl,
or a pharmaceutically acceptable salt thereof;
- Compounds as disclosed in WO02/06268A1, e.g. a compound of formula VII

R4d is lower alky!;
nod is an integer of 1 to 6;
Dd is ethylene, inline, ethynylene, a group having a formula - D-CH2- (wherein D is
carbonyl, - CH(OH)-, O, S or N), aryl or aryl substituted by up to three substitutents selected
from group a as defined hereinafter;
Yd is single bond. Cvioalkylene, Ci.ioalkylene which is substituted by up to three substitutents
selected from groups a and b, Ci.ioalkylene having 0 or S in the middle or end of the carbon
chain, or Ci.ioalkylene having O or S in the middle or end of the carbon chain which is
substituted by up to three substituents selected from groups a and b;
Rs is hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl substituted by up to three
substituents selected from groups a and b, aryl substituted by up to three substituents
selected from groups a and b, or heterocycle substituted by up to three substituents selected
from groups a and b;

each of Red and Rid, independently, is H or a substituent selected from group a;
each of Red and Red, independently, is H or Dialkyl optionally substituted by halogen;
is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy. lower alkylthlo,
carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-lower alkylamino,
di-lower alkylamino, lower aliphatic acylamino, cyano or nitro; and
is cycloaikyi, aryl, heterocycle, each being optionally substituted by up to three
substituents selected from group a;
with the proviso that when Rest is hydrogen, Yd is a group exclusive of single bond and linear
COMA alkylene, or a pharmacologically acceptable salt or ester thereof;
-Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a compound of formula VIII:

wherein each of Rs and Rga, independently, is H or Dialkyl optionally substituted by halogen; e.g. 2-amino-2-[4-(3-ben2yloxyphenoxy)"2-chlorophenyl]propyl-1,3-propane-diol or 2-amino-2-[4-(benzyloxyphenylthio)-2- cholorophenyl]propyl-1,3-propane-diol, or a pharmacological salt thereof.
-Compounds as disclosed in WO03/062252A1, e.g. a compound of formula X


wherein
Ar is phenyl or naphthyl; each of mg and nag independently is 0 or 1; A is selected from COOH, P03H2, P02H, S03H, P0(C1"3alkyi)0H and 1H-tetra20l-5-yl; each of Rig and R2g independently is H, halogen, OH, COOH or C1-4alkyl optionally substituted by halogen; R3g is H or C1-4alkyl optionally substituted by halogen or OH; each R4g independently is halogen, or optionally halogen substituted C1-4alkyl or C1-3alkoxy; and each of Rg and M has one of the significances as indicated for B and C, respectively, in WO03/062252A1;
-Compounds as disclosed in WO 03/062248A2, e.g. a compound of formula XI

wherein Ar is phenyl or naphthyl; n is 2,3 or 4; A is COOH, 1 H-tetrazol-5-yI, P03H2, P02H2, -S03H or P0(R5h)0H wherein R5h is selected from C1-4alkyl, hydroxyC1-4a!kyl, phenyl, -CO-C1-3alkoxy and -CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionally substituted; each of Rah and R2h independently is H. halogen, OH, COOH, or optionally halogeno substituted C1-6alkyl or phenyl; R3h is H or C1-4alkyl optionally substituted by halogen and/ OH; each R4h independently is halogeno, OH, COOH, C1-4alkyl, S(O)0,1 or2G1-3aIkyl, C1-3alkoxy, C3-6cycloalkoxy, aryl or araloxy, wherein the alkyl portions may optionally be substituted by 1-3 halogens; and each of Rg and M has one of the significances as indicated for B and C, respectively, in WO03/062248A2.
According to a further embodiment of the invention, a SIP receptor agonist for use in a combination of the invention may also be a selective S1P1 receptor, e.g. a compound which possesses a selectivity for the SI PI receptor over the S1P3 receptor of at least 20 fold, e.g. 100, 500, 1000 or 2000 fold, as measured by the ratio of EC50 for the S1P1 receptor to the EC50 for the S1P3 receptor as evaluated in a 35S-GTPyS binding assay, said compound having an EC50 for binding to the SI PI receptor of 100 nM or less as evaluated by the 35S-GTPyS binding assay. Representative SI PI receptor agonists are e.g. the compounds listed

in WO 03/061567, the contents of which being incorporated herein by reference, for instance a compound of formula

In each case where citations of patent applications are given, the subject matter relating to the compounds is hereby incorporated into the present application by reference.
Acyl may be a residue Ry-CO- wherein Ri is cycloalkyI, phenyl or phenyl-Ic. 4alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.
When in the compounds of fonn I the carbon chain as Ri 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 by halogen, nitro, amino, methoxy, hydroxy or carboxy.
Preferred compounds of formula I are those wherein Ri is Ci3.2oalkyl. optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein Ri is phenylalkyi substituted by -alkyl chain optionally substituted by halogen and the alkyl moiety is a Cveaikyl optionally substituted by hydroxy. More preferably, R-i is phenyl-Ci.6alkyl substituted on the phenyl by a straight or branched, preferably straight, C6-i4alkyl chain. The C6.i4alkyl chain may be in ortho, meta or para, preferably in para.
Preferably each of R2 to R5 is H.
A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred S1P receptor agonist of formula I is FTY720, Le^ 2-amino-2-[2-(4-octylphenyl)

ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:

A preferred compound of formula II is the one wherein each of R'2 to R'5 is H and m is 4, i.e. 2"amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyI]ethyl}propane-1,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound B), e.g the hydrochloride.
A preferred compound of formula III is the one wherein W is CH3, each of R'S to R**3 is H, Z2 is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanoI, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride. The R-Enantiomers is particularly preferred.
A preferred compound of formula Via is the FTY720-phosphate (R2a is H, Rsa is OH, Xa is 0, Ria and Rib are OH). A preferred compound of formula IVb is the Compound C-phosphate (Raa is H, Rsb is OH, Xa is O, Ria and Rib are OH, Yaw is 0 and R48 is hefty). A preferred compound of formula V is Compound B-phosphate.
A preferred compound of formula V is phosphoric acid mono-[(R)-2-amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]ester.
A preferred compound of formula VIII is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbutan-1-oL
When the compounds of fondle I to Lila have one or more asymmetric centers in the molecule, the various optical isomers, as well as racemates, di stereoisomers and mixtures thereof are embraced.
Examples of pharmaceutically acceptable salts of the compounds of formulae I to Xvl include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumigate, male ate. benzoate, citrate, malice, methanesulfonate and benzenesulfonate salts, or, when appropriate, 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. The compounds and salts of the present invention encompass hydrate and solvate forms.
Binding to SIP receptors can be determined according to the following assays.
A. Binding affinity of S1P receptor agonists to individual human S1P receptors
Transient trisection of human S1P receptors into HEK293 cells
SIP receptors and Go proteins are cloned, and equal amounts of 4 cDNA for the EDG receptor, GpO, Grp and Gly are mixed and used to transect minelayers of HEK293 cells using the calcium phosphate precipitate method (M. Wagered al., Cell. 1977;11;223 and DS. Im et al., Mol. Pharmacology. 2000;57;753), Briefly, a DNA mixture containing 25 pg of DNA and 0.25 M Cacti is added to HEPES-buffered 2 mM Na2HP04. Sub confluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and riffed media (90% 1:1 Dubach’s modified essential media (DMEM):F-12 + 10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCb, 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer. After centrifugation at Stooge, the supernatant is diluted with HME without sucrose and centrifuged at 100,000>«g for 1h. The resulting pellet is rehomogenized and centrifuged a second hour at 100,000xg, This crude membrane pellet is resuspended in HME with sucrose, liquored, and snap-frozen by immersion in liquid nitrogen. The membranes are stored at 70'C. Protein concentration is determined spectroscopic ally by Bradford protein assay.
GTPvS binding assay using SIP receptor/HEK293 membrane preparations
GTPvS binding experiments are performed as described by DS. Im et al., Mol. Pharmacology. 2000; 57:753. Ligand-mediated GTPyS binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl2, pH 7.5) using 25 pg of a membrane preparation from transiently transfected HEK293 cells. Ligand is added to membranes in the presence of 10 ppm GDP and 0.1 nM (1200 /mmol) and incubated at 30**C for 30 min. Bound GTPyS is separated from unbound using the Branded harvester (Gaithersburg, MD) and counted with a liquid scintillation counter.

The composition of the invention preferably contains 0.01 to 20% by weight of SI P receptor agonists, more preferably 0.1 to 10%, e.g. 0.5 to 5% by weight, based on the total weight of the composition.
The sugar alcohol may act as a diluent, carrier, filler or bulking agent, and may suitably be mannitol, maltitol, instill, xyiitol or lactitol, preferably a substantially non-hygroscopic sugar alcohol, e.g. mannitol (D-mannitol). A single sugar alcohol may be used, or a mixture of two or more sugar alcohols, e.g a mixture of mannitol and xyiitol, e.g. in a ratio of 1:1 to 4:1.
In a particularly preferred embodiment, the sugar alcohol is prepared from a spray-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 SIP receptor agonist throughout the mannitol in the composition. A higher surface 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, e.g. with a mean particle size of 300 pm or less, has also been found to improve compressibility and hardness of tablets formed from the composition.
Preferably the single point surface area of the sugar alcohol preparation, e.g. mannitol, is 1 to 7 m^/g, e.g. 2 to 6 m^/g or 3 to 5 m^/g. The mannitol preparation may suitably have a mean particle size of 100 to 300 pm, e.g. 150 to 250 pm and a bulk density of 0.4 to 0.6 g/mL, e.g. 0.45 to 0.55 g/mL. A suitable high surface area mannitol is Partake M200, available commercially from E. Merck.
The composition preferably contains 75 to 99.99% by weight of the sugar alcohol, more preferably 85 to 99.9%, e.g 90 to 99.5% by weight, based on the total weight of the composition.
The composition preferably further comprises a lubricant Suitable lubricants include stearic acid, magnesium stearate, calcium stearate. zinc stearate, glycerol palmitostearate, sodium smeary fumigates, canola oil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g. Cutina® or Labia® 101), mineral oil, sodium laurel sulfate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer, or a mixture of any of the above. Preferably the lubricant

comprises magnesium stearate, hydrogenated castor oil or mineral oil. Colloidal silicon dioxide and polyethylene glycol are less preferred as the lubricant.
The composition preferably contains 0.01 to 5% by weight of the lubricant, more preferably 1 to 3% by weight, e.g. about 2% by weight, based on the total weight of the composition.
The composition may comprise one or more further excipients such as carriers, binders or diluents. In particular, the composition may comprise microcrystalline cellulose (e.g. Advice®), methylceilulose, hydroxypropylcellulose, hydroxypropylmethylceilulose, starch (e.g. corn starch) or dicalcium phosphate, preferably in an amount of from 0.1 to 90 % by weight, e.g. 1 to 30% by weight, based on the total weight of the composition. Where a binder, e.g. microcrystalline cellulose, methylceilulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose is used, it is preferably 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 particularly important for fine granulations. Microcrystalline cellulose and methylceilulose are particularly preferred where a high tablet hardness and/or longer disintegration time is required. Hydroxypropyl cellulose is preferred where faster disintegrations 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 20% by weight of the sugar alcohol, e.g. xylitol.
In one embodiment, the composition further comprises a stabilizer, preferably glycine HCl or sodium bicarbonate. The stabiliser may be present in an amount of e.g. 0.1 to 30%, preferably 1 to 20% by weight.
The composition may be in the form of a powder, granule or pellets or a unit dosage form, for example as a tablet or capsule. The compositions of the present invention are well-adapted for encapsulation into an orally administrable capsule shell, particularly a hard gelatin shell.
Alternatively the compositions may be compacted into tablets. The tablets may optionally be coated, for instance with talc or a polysaccharide (e.g. cellulose) or hydroxypropylmethylceilulose coating.

Where the pharmaceutical capsule is in unit dosage form, each unit dosage will suitably contain 0.5 to 10 mg of the SIP receptor agonist.
The compositions of the invention may show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics may be determined, e.g. by measuring decomposition products by HPLC analysis after storage for particular times, at particular temperatures, e.g. 20°, 40"* or 60°C.
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 at. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische Technologie, Thieme, 1991. Hagers Handbuch dear phamiazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ,, Co., 1970) or later editions.
In one aspect, the present invention relates to a process for producing a pharmaceutical composition, comprising:
(a) mixing an SIP receptor agonist with a sugar alcohol;
(b) milling and/or granulating the mixture obtained in (a); and
(c) mixing the milled and/or granulated mixture obtained in (b) with a lubricant.
By using this process, a preparation having a good level of content and blend uniformity (i.e. a substantially uniform distribution of the S1P receptor agonist throughout the composition), dissolution time and stability is obtained.
The S1P receptor agonist, e.g. 2-amino-2-[2-(4-octyiphenyl)ethyl]propane-1,3-diol. hydrochloride, may optionally be micron zed, and/or pre-screened, e.g, with a 400 to 500 mesh screen, before step (a) in order to remove lumps. The mixing step (a) may suitably comprise blending the SIP receptor agonist and the sugar alcohol, e.g. mannitol in any suitable blender 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 (b) may suitably comprise passing the mixture obtained in (a) through a screen, which preferably has a mesh size of 400 to 500 pm. Process step (a) may comprise the step of mixing the total amount of SIP receptor agonist at first with a low amount of sugar alcohol, e.g. from 5 to 25% by weight of the total weight of sugar alcohol, in order to form a pre-mix. Subsequently the remaining amount of sugar alcohol is added to the pre-mix. Step (a) may also comprise the step of adding a binder solution, e.g. methyl cellulose and/or xylitol, e.g. an aqueous solution, to the mixture. Alternatively the binder is added to the mix dry and water is added in the granulation step.
The milled mixture obtained in (b) may optionally be blended once more before mixing with the lubricant. The lubricant, e.g. magnesium stearate, is preferably pre-screened, e.g. with a 800 to 900 Mm screen, before mixing.
Alternatively, a wet granulation process is employed. In this embodiment, the SIP receptor agonist is preferably first dry-mixed with the desired sugar alcohol, e.g. mannitol, and the obtained sugar alcohol/S1P receptor agonist mixture is then dry-mixed with a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose. Water is then added and the mixture granulated, e.g. using an automated granulator. The granulation is then dried and milled.
If desirable, an additional amount of binder may be added in step (c) to the mixture obtained in (b).
The process may comprise a further step of tabletting or encapsulating the mixture obtained in (c), 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 include corticoids, iron oxides, and chlorophyll. Preferably, the capsules of the invention are marked using a code.
The pharmaceutical compositions of the present invention are useful, either alone or in combination with other active agents, for the treatment and prevention of conditions e.g. as

disclosed in US 5,604,229, WO 97/24112, WO 01/01978, US 6,004,565, US 6,274,629 and JP-14316985, 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, iiver, kidney, pancreatic, sl b) treatment and prevention of autoimmune disease or of inflammatory conditions, e.g. multiple sclerosis, arthritis (for example rheumatoid arthritis), inflammatory bowel disease. hepatitis, etc.;
c) treatment and prevention of viral myocarditis and viral diseases caused by viral mycocarditis, including hepatitis and AIDS.
Accordingly, in further aspects the present invention provides:
1. A composition as defined above, for use in treating or preventing 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 defined 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 invention will now be described with reference to the following specific embodiments.

Example 1
Micronized Compound A, e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol. hydrochloride salt (FTY720), is screened and 116.7 g of the screened compound is mixed with 9683.3 g mannitol (Patrick M200 from E. Merck). The mixture is then milled in a Fruit MGI device (Key International Inc. USA) using a 30 mesh screen. Magnesium stearate is screened using a 20 mesh screen and 200 g of the screened compound blended with the FTY720/mannitol mixture to produce a product composition.
The product composition is then compacted on a tablet press using a 7 mm die to form 120 mg tablets, each containing:

* 1 mg of Compound A in free form is equivalent to 1.12 mg of FTY720.
Example 2
In a further example, the process of example 1 is repeated except that the magnesium
stearate is replaced by Cutina® (hydrogenated castor oil).
Example 3
Compound A, e.g. FTY720, and mannitol (Parteck M200 from E. Merck) are each screened separately using an 18 mesh screen. 1.9 g screened FTY720 is mixed with 40 g screened mannitol for 120 revolutions in a blender at 32 rpm. The FTY720/mannitol mixture is then screened through a 35 mesh screen.
The screened FTY720/mannitol mixture is added to a granulator along with a further 340.1 g mannitol and 12 g hydroxypropylcellulose. The mixture is mixed for 3 minutes. Water is then added at a rate of 100 ml/minute and the mixture granulated for 2 minutes. The granulation is transferred into a tray dryer and dried at 50°C for 150 minutes.

The mixture is then milled in a Frewitt MGI device using a 35 mesh screen. Magnesium stearate is screened and 6 g of the screened compound is blended for 90 revolutions at 32 rpm vita the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the
blend.
The product composition is then filled into size 3 hard gelatin shells on an Howling & Kari 400 encapsulation device. 120 mg of the product composition is added to each capsule. Therefore each capsule contains:

Example 4
In a further example, the process of example 3 is repeated except that the magnesium
stearate is replaced by Cutina® (hydrogenated castor oil).
Example 5
In a further example, the process of example 3 is repeated except that the hydroxypropyl
cellulose is replaced by hydroxypropylmethyl cellulose.
Example 6a
Micronized Compound A, e.g. FTY720, is screened using a 400 \}n) (40 mesh) screen. 58.35 g of the screened compound is mixed with 4841.65 g mannitol (Parteck M200 from E. Merck) in a 25L Bole bin blender for 240 blending revolutions. The mixture is then milled in a Frewitt MGI device using a 400 mesh screen, and the milled mixture is blended once more. Magnesium stearate is screened and 100 g of the screened compound is blended with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the blend.

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

Example 6b
In an alternative embodiment, capsules are manufactured using the components and in the amounts as described in Example 6a, but the FTY720 is first mixed with 14 mg mannitol (before screening). This mixture is then screened as described above. The screened mixture is then blended with the remaining mannitol and the magnesium stearate is added, followed by additional blending and filling into capsules.
Examples 7 and 8
In further examples, capsules are prepared as described in example 6, except that each
capsule contains each component in the following amounts:

Examples 9 to 11
In further examples, capsules are prepared as described in examples 6 to 8, except that the
magnesium stearate is replaced in each case by Cutina® (hydrogenated castor oil).
Examples 12 to 22

In further examples, capsules or tablets are prepared as described in examples 1 to 11. except that FTY720 is replaced in each case by 2-aminO"2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol hydrochloride.
Examples 23 and 24
Capsules containing the following ingredients are prepared, by weighing each component
and mixing in a mortar, then filling into capsules:

The FTY720 and a proportion of the D-mannitol equal to twice the weight of the FTY720 are mixed in a Micro speed Mixer MS-5 type (Palmer, USA) for 2 minutes at 1200 rpm. The remaining D-mannitol is added to the mixture and mixed for another 2 minutes. 80 or 60 milliliters of 5% methyl cellulose SM-25 solution is supplied from a hopper and granulated under the same conditions. The mixture is extruded through a screen with 0.4 mm apertures

using an extruder RG-5 type. The extruded material is dried at 65°C by a fluidized-bed granuiator STREA I Type (Patheon, Canada) and then sieved through a 24 mesh sieve. Fine particles which pass through a 60 mesh sieve are removed. The obtained fine granules are filled into capsules by a Zima capsule-filling machine (100 mg per capsule).

FTY720, D-mannitol and xylitol are placed in a fluid-bed granuiator (MP-01 model, Powrex), mixed for five minutes, and granulated under spray of binder solution, followed by drying till the exhaust temperature reaches 40°C. The granulation conditions are as shown below. Dried powder is passed through a 24-mesh sieve, added to the specified amount of filler and lubricant, and mixed in a mixer (Tubular Mixer, WAB) for three minutes to make the powder for compression.
The resulting powder is compressed by a tabletting machine (Clean press correct 12 HUK, Kyushu Seisakusho) with a punch of 7 mm i.v. x 7.5 mm R at a compression force of 9800 N.
Granulation condition;

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








WE CLAIM:
1. A solid pharmaceutical composition suitable for oral administration, comprising:
(a) a S1P receptor agonist; and
(b) a sugar alcohol.
2. A composition according to claim 1, wherein the S1P receptor agonist comprises 2-
amino-2-[2-(4-octylphenyl)ethyl]propane-1.3-diol or 2-amino-2-{2"[4-(1"OXO-5-phenylpentyl)-
phenyl]ethyl}propane-1,3-diol or a pharmaceutically acceptable salt thereof.
3. A composition according to claim 1 or claim 2, wherein the sugar alcohol comprises
mannitol.
4. A composition according to any preceding claim, further comprising a lubricant.
5. A composition according to claim 4, wherein the lubricant comprises magnesium stearate.
6. A composition according to any preceding claim, comprising 0.5 to 5% by weight of the S1P receptor agonist.
7. A composition according to any preceding claim, comprising 90 to 99.5% by weight of
the sugar alcohol.
8. A composition according to any of claims 4 to 7, comprising 1.5 to 2.5% by weight of the lubricant.
9. A composition according to any preceding claim, in the form of a tablet,
10. A composition according to any of claims 1 to 9 in the foment of a capsule.


Documents:

5941-CHENP-2007 FIRST PAGE OF IPRP 22-10-2012.pdf

5941-CHENP-2007 AMENDED PAGES OF SPECIFICATION 25-03-2013.pdf

5941-CHENP-2007 AMENDED CLAIMS 17-07-2013.pdf

5941-CHENP-2007 AMENDED CLAIMS 25-03-2013.pdf

5941-CHENP-2007 AMENDED PAGES OF SPECIFICATION 29-07-2013.pdf

5941-CHENP-2007 AMENDED PAGES OF SPECIFICATION 12-03-2012.pdf

5941-CHENP-2007 ASSIGNMENT 27-03-2013.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS 15-07-2013.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS 03-07-2013.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS 20-05-2013.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS 27-03-2013.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS. 17-07-2013.pdf

5941-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 22-10-2012.pdf

5941-CHENP-2007 FORM-1 25-03-2013.pdf

5941-CHENP-2007 FORM-1 29-07-2013.pdf

5941-CHENP-2007 FORM-3 20-05-2013.pdf

5941-CHENP-2007 FORM-3 25-03-2013.pdf

5941-CHENP-2007 FORM-5 25-03-2013.pdf

5941-CHENP-2007 OTHER DOCUMENT 12-03-2012.pdf

5941-CHENP-2007 OTHER PATENT DOCUMENT 25-03-2013.pdf

5941-CHENP-2007 OTHER PATENT DOCUMENT 1 25-03-2013.pdf

5941-CHENP-2007 OTHERS 25-03-2013.pdf

5941-CHENP-2007 POWER OF ATTORNEY 17-07-2013.pdf

5941-CHENP-2007 POWER OF ATTORNEY 25-03-2013.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS 12-03-2012.pdf

5941-CHENP-2007 CORRESPONDENCE OTHERS 29-07-2013.pdf

5941-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 25-03-2013.pdf

5941-CHENP-2007 FORM-1 12-03-2012.pdf

5941-CHENP-2007 FORM-13 12-03-2012.pdf

5941-CHENP-2007 FORM-13-1 12-03-2012.pdf

5941-CHENP-2007 FORM-6 12-03-2012.pdf

5941-chenp-2007-abstract.pdf

5941-chenp-2007-claims.pdf

5941-chenp-2007-correspondnece-others.pdf

5941-chenp-2007-description(complete).pdf

5941-chenp-2007-form 1.pdf

5941-chenp-2007-form 26.pdf

5941-chenp-2007-form 3.pdf

5941-chenp-2007-form 5.pdf


Patent Number 256766
Indian Patent Application Number 5941/CHENP/2007
PG Journal Number 31/2013
Publication Date 02-Aug-2013
Grant Date 26-Jul-2013
Date of Filing 24-Dec-2007
Name of Patentee MITSUBISHI TANABE PHARMA CORPORATION
Applicant Address 2-6-18 KITAHAMA CHUO-KU OSAKA-SHI OSAKA 541-8505
Inventors:
# Inventor's Name Inventor's Address
1 ROYCE, ALAN EDWARD RR4 BOX 9LE, SAYLORSBURG, PA 18353.
2 OOMURA, TOMOYUKI 11-9 USHIGAMI 1-CHOME, MAKATSU-SHI, OITA 871-0015, JAPAN.
3 SASAKI, MASAKI 1852 MORO-MACHI, NAKATSU-SHI, OITA 871-0048, JAPAN.
4 TAMURA, TOKUHIRO 632-4, OAZA-KOUJI, YOSHITOMI-CHO, CHIKUJOU-GUN, FUKUOKA 871-0821, JAPAN.
5 PUDIPEDDI, MADHUSUDHAN 51 CALVERT AVENUE EAST, EDISON, NJ 08826, USA.
6 RUEGGER, COLLEEN 89 POPLAR DRIVE, MORRIS PLAINS, NJ 07950, USA.
PCT International Classification Number A61K 31/135
PCT International Application Number PCT/EP04/03656
PCT International Filing date 2004-04-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/461,215 2003-04-08 U.S.A.