(12) United States Patent
`Oomura et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,324,283 B2
`Dec. 4, 2012
`
`US008324283B2
`
`EP
`(54) SOLID PHARMACEUTICAL COMPOSITIONS
`#.
`COMPRISING A SIP RECEPTOR AGONIST
`JP
`AND A SUGAR ALCOHOL
`JP
`e
`-
`JP
`(75) Inventors: Tomoyuki Oomura, Oita (JP);
`WO
`Madhusudhan Pudipeddi, Edison, NJ
`Wº
`(US); Colleen Ruegger, Morris Plains,
`NJ (US) Alan E Rºycºsylºburg, PA WO
`(US); Masaki Sasaki, Oita (JP);
`WO
`Tokuhiro Tamura, Fukuoka (JP)
`(73) Assignees: Novartis AG, Basel (CH), Mitsubishi
`Pharma Corporation, Osaka (JP)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 722 days.
`(21) Appl. No.: 12/189,323
`(22) Filed:
`Aug. 11, 2008
`
`(*) Notice:
`
`4/2003
`1 300 405
`º: A1 ;
`4-2021.31
`7/1992
`11276.191
`10/1999
`2002 24 12 72
`8/2002
`98/03.162
`1/1998
`WO dº ! º: º;
`WO 03/061567
`7/2003
`WO 03/062392
`7/2003
`OTHER PUBLICATIONS
`Kiuchi et al., “Synthesis and immunosuppressive activity of 2-sub
`stituted 2-aminopropane-1,3-diols and 2-aminoethanois”, Journal of
`Med. Chem., 2000, vol.43, pp. 2946-2961.
`Mandala et al., “Alteration of lymphocyte trafficking by sphingosine
`1-phosphate receptor agonists”, Science, 2002, vol. 296, pp. 346
`349.
`Remington’s pharmaceutical sciences (Ed. Alfonso R. Gennaro,
`1990, 18” edn.).
`Parteck M200 MSDS (accessed Jul. 1, 2010 from http://
`setonresourcecenter.com/msdshazcom/htdocs/MSDS/E/EMD/
`Docs/wc.d()0028/wc.dO2803.pdf#search+"granular”).
`Turk (Micronization of Pharmaceutical substances by the rapid
`expansion of Supercritical Solutions (RESS): a promising method to
`improve bioavailability of poorly soluble pharmaceutical agents.
`Journal of Supercritical Fluids, vol. 22, pp. 75-84, 2002).
`Honig et al., “FTY stimulates multidrug transporter and cysteinyl
`leukotriene-dependent T cell chemotaxis to lymph nodes”, The Jour
`nal of Clinical Investigations, 2003, vol. 111, No. 5, p. 627-637.
`Yoshiki, Yanagawa et al., “FTY720, a Novel Immunosuppressant,
`Induces Sequestration of Circulating Mature Lymphocytes by Accel
`eration of Lymphocyte Homing in Rats. II. FTY720 Prolongs Skin
`Allograft Survival by Decreasing T Cell Infiltration into Grafts But
`Not Cytokine Production in Vivo”, The Journal of Immunology, vol.
`160, pp. 5493-5499, (1998).
`Masayuki, Fujino et al., “Amelioration of Experimental Autoimmune
`Encephalomyelitis in Lewis Rats by FTY720 Treatment”, The Jour
`nal of Pharmacology and Experimental Therapeutics, vol. 305, No. 1,
`pp. 70-77, (2003).
`Volker, Brinkmann et al., “The Immune Modulator FTY720 Targets
`Sphingosine 1-Phosphate Receptors”, The Journal of Biological
`Chemistry, vol. 277, No. 24, pp. 21453-21457, (2002).
`English translation of Chemical Engineer, 2000, 2, No. 77, Applica
`tion and Manufacture of Mannitol.
`Remington’s Pharmaceutical Sciences, “Solid Oral Forms”, vol. 2,
`chapter 92, 19 Ed. 1998.
`* cited by examiner
`Primary Examiner – Benjamin Packard
`(74) Attorney, Agent, or Firm — Karen DeBenedictis
`(57)
`ABSTRACT
`A solid pharmaceutical composition suitable for oral admin
`istration, comprising:
`(a) a S1P receptor agonist; and
`(b) a sugar alcohol.
`32 Claims, No Drawings
`
`(65)
`
`Prior Publication Data
`|US 2008/0311 188 A1
`Dec. 18, 2008
`
`Related U.S. Application Data
`(62) Division of application No. 10/552,005, filed as
`application No. PCT/EP2004/003656 on Apr. 6, 2004,
`now abandoned.
`(60) Provisional application No. 60/461,215, filed on Apr.
`8, 2003.
`
`(51) Int. Cl.
`(2006.01)
`A0IN 33/02
`(2006.01)
`A6 IK 31/135
`(52) U.S. Cl. ....................................................... 514/649
`(58) Field of Classification Search ................... 514/649
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`|U.S. PATENT DOCUMENTS
`4,110,322 A
`8/1978 Greven et al. .......... 260/112.5 R.
`5,112,616 A
`5/1992 McCarty
`6,277,888 B1* 8/2001 Sakai et al. ................... 514/653
`6,476,004 B1 11/2002 Sakai et al.
`7,151,093 B2 12/2006 Kishikawa et al. ........... 514/114
`2002/0155512 A1
`10/2002 Liao et al.
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`
`FOREIGN PATENT DOCUMENTS
`0.142078
`5/1985
`() 812 588
`12/1997
`() 627 406
`10/1998
`() 990 440
`4/2000
`1 002 792
`5/2000
`1 050 301
`11/2000
`1 195 165
`4/2002
`
`TEVA EX. 1037
`Page 1
`
`

`

`US 8,324,283 B2
`
`1
`SOLID PHARMACEUTICAL COMPOSITIONS
`COMPRISING A SIP RECEPTOR AGONIST
`AND A SUGAR ALCOHOL
`
`This is a divisional of application Ser. No. 10/552,005 filed
`on Nov. 14, 2005, which is National Stage of International
`Application No. PCT/EP2004/003656 filed on Apr. 6, 2004,
`which claims benefit of provisional Application 60/461,215
`filed on Apr. 8, 2003, the entire disclosures of which are
`hereby incorporated by reference.
`The present invention relates to pharmaceutical composi-
`tions comprising a sphingosine-l phosphate receptor agonist.
`Sphingosine-l phosphate (hereinafter “SlP”) is a natural
`serum lipid. Presently there are 8 known S] P receptors,
`namely SlPl to SlPS. SlP receptor agonists have accelerat-
`ing 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 sec-
`ondary lymphatic tissue, evoking a generalized immtmo sup-
`pression. Naive cells are sequestered, CD4 and CD8 T—cells
`and B-cells from the blood are stimulated to migrate into
`lymph nodes (LN) and Peyer’s patches (PP), and thus infil-
`tration of cells into transplanted organs is inhibited.
`The various known S 1P 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 wcll-
`adaptcd for oral administration in a solid form, e.g. as a tablet
`or capsulc.
`Accordingly, the present invention provides a solid phar—
`maceutical composition suitable for oral administration,
`comprising a SlP receptor agonist and a sugar alcohol.
`It has surprisingly been found that solid compositions com—
`prising a sugar alcohol provide formulations which are par—
`ticularly well suited to the oral administration of S l P receptor
`agonists. The compositions provide a convenient means of
`systemic administration of SIP receptor agonists, do not suf-
`fer from the disadvantages ofliquid formulations for injection
`or oral use, and have good physicochemical and storage prop—
`erties. In particular, the compositions ofthe present invention
`may show a high level of uniformity in the distribution of the
`SIP 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 a gonists are typically sphjngosine analogues,
`such as 2-substitutcd 2-amino-propanc-l ,3-diol or 2-amino-
`propanol derivatives. Examples of appropriate SlP receptor
`agonists are, for example:
`Compounds as disclosed in EP627406A1 , e.g. a compound
`of formula I
`
`CHZOR;
`
`R4R5N
`
`CHZORZ
`
`R1
`
`wherein R1 is a straig‘rt- or branched (C1 2_22)carbon chain
`which may have in the Chain a bond or a hctcro atom
`selected from a double bond, a triple bond, 0, S, NR6,
`wherein R6 is H, alkyl, aralkyl, acyl or alkoxycarbonyl,
`and carbonyl, and/or
`
`2
`which may have as a substituent alkoxy, alkenyloxy,
`alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
`acylamino, alkoxycarbonyl, alkoxycarbonylamino,
`acyloxy, alkylcarbamoyl, nitro, halogen, amino,
`hydroxyimino, hydroxy or carboxy; or
`
`R1 is
`a phenylalkyl wherein alkyl is a straight— or branched
`(C6720)carbon chain; or
`a phenylalkyl wherein alkyl is a straight- or branched
`(C 1_3U)carbon chain wherein said phenylalkyl is substi-
`tuted by
`a straight- or branched (C6_2U)carbon chain optionally sub-
`stituted by halogen,
`a straight- or branched (C6_Zn)alkoxy chain optionally sub-
`stituted by halogen,
`a straight— or branched (C5_20)alkenyloxy,
`phenylalkoxy, halophenylalkoxy, phenylalkoxyallq‘l, phe-
`noxyalkoxy or phenoxyalkyl,
`cycloallxylalkyl substituted by C16_20alkyl,
`hctcroarylalkyl substitutcd by C6_2Oalkyl,
`heterocyclic Céiloalkyl or
`heterocyclic alkyl substituted by C2_2Ualkyl,
`and wherein
`the alkyl moiety may have
`in the carbon chain, a bond or a heteroatom selected from
`a double bond, a triple bond, 0, S, sulfinyl, sulfonyl. or
`NR5, wherein R6 is as defined above, and
`as a substituent alkoxy, alkenyloxy, alkynyloxy, aralky-
`loxy, acyl, alkylamino, alkylthio, acylamino, alkoxycar-
`bonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl,
`nitro, halogen, amino, hydroxy or carboxy, and
`each of R2, R3, R4 and R5, independently, is H, C 1.4 alkyl or
`acyl
`or a pharmaceutically acceptable salt thereof;
`Compounds as disclosed in EP 1002792A1, e.g. a com-
`pound of formula II
`
`II
`
`R’4R’5N
`
` CIHZOR’g (I)
`
`I
`< >
`0
`(CH2);
`C
`(”him
`
`CHZOR’Z
`
`\ /
`
`wherein m is l to 9 and each of R‘z, R'3, R'4 and R‘s, indepen-
`dently, is H, alkyl or acyl,
`or a pharmaceutically acceptable salt thereof;
`Compounds as discloscd in EP0778263 A1, e.g. a com-
`pound of formula III
`
`III
`
`NR” JRNZ
`
`w_t
`Z, 7)"
`I
`\ /\X
`(CsztvaR’g
`
`wherein W is H; C1_6alkyl, C2_6alkenyl or C2_6alkynyl;
`unsubstituted or by OH substituted phenyl: R"4O(CH2)M; or
`C 1_5alkyl substituted by 1 to 3 substituents selected from the
`group consisting of halogen, C3_Scycloalkyl, phenyl and phe-
`nyl substitutcd by OH;
`X is H or unsubstituted or substituted straight chain alkyl
`having a number p of carbon atoms or unsubstituted or sub-
`stituted straight chain alkoxy having a number (p-l ) ofcarbon
`
`5
`
`10
`
`15
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`6O
`
`65
`
`TEVA EX. 1037
`
`Page 2
`
`TEVA EX. 1037
`Page 2
`
`

`

`US 8,324,283 B2
`
`4
`Compounds as disclosed in WO 02/076995, e.g. a com
`pound of formula V
`
`3
`atoms, e.g. substituted by 1 to 3 substitutents selected from
`the group consisting of Cile alkyl, OH, Cigalkoxy, acyloxy,
`amino, C1-galkylamino, acylamino, oxo, haloC1-galkyl, halo
`gen, unsubstituted phenyl and phenyl substituted by 1 to 3
`substituents selected from the group consisting of C1-calkyl,
`OH, C1-galkoxy, acyl, acyloxy, amino, Claalkylamino, acy
`lamino, haloCi-galkyl and halogen; Y is H, C1-calkyl, OH,
`C1-galkoxy, acyl, acyloxy, amino, C1-galkylamino, acy
`lamino, haloCi-galkyl 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 6sp+q=23, m' is 1, 2 or 3, n is 2 or 3,
`each of R", R", R", and R", independently, is H, C, alkyl
`or acyl,
`or a pharmaceutically acceptable salt thereof,
`Compounds as disclosed in WOO2/18395, e.g. a compound
`of formula IVa or IVb
`
`10
`
`15
`
`20
`
`IV a
`
`*
`CH2R3a
`ºs------- Or
`º
`R1b.
`CH2
`
`(CH3)3CH3
`
`IVb
`
`º
`CH2R35
`ºs-------
`º
`R1b.
`CH2
`
`Ya - R4a
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Ric
`
`Re
`
`wherein
`m, is 1, 2 or 3;
`X, is O or a direct bond;
`R1, is H; CO-e alkyl optionally substituted by OH, acyl,
`halogen, Cs-locycloalkyl, phenyl or hydroxy-phenylene;
`C2-calkenyl; C2-calkynyl; or phenyl optionally substituted
`by OH:
`R22 is
`
`wherein Rs is Hor Claalkyl optionally substituted by 1, 2
`or 3 halogen atoms, and Racis H or Claalkyl optionally
`substituted by halogen;
`each of Rs...and Raº, independently, is H. Claalkyl optionally
`substituted by halogen, or acyl, and
`R., is C1s 20alkyl 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 Rze is H. Claalkyl or Claalkoxy, and r is substi
`tuted C1-20alkanoyl, phenylC1-14alkyl wherein the
`C1-14alkyl is optionally substituted by halogen or OH,
`cycloalkylC1-14alkoxy or phenylC1-14alkoxy wherein
`the cycloalkyl or phenyl ring is optionally substituted by
`halogen, C1-4alkyl and/or CO1-adlkoxy, phenylc, 14
`alkoxy-C1-14alkyl, phenoxyC-1aalkoxy or phen
`OxyC1-14alkyl,
`R., being also a residue of formula (a) wherein Rs is
`C1-14alkoxy when R.I., is C1-4alkyl, C2-galkenyl or
`C2-calkynyl,
`or a compound of formula VI
`
`wherein X, is O, S, NRIs or a group –(CH2),a_, which
`group is unsubstituted or substituted by 1 to 4 halogen; n., is 1
`or 2, R1, is H or (Cla)alkyl, which alkyl is unsubstituted or
`substituted by halogen; Ria is H, OH, (Cla)alkyl or O(Cla)
`alkyl wherein alkyl is unsubstituted or substituted by 1 to 3
`halogen; R1, is H, OH or (Cla)alkyl, wherein alkyl is unsub
`stituted or substituted by halogen; each R2, is independently
`selected from Hor(Cla)alkyl, which alkyl is unsubstituted or
`substituted by halogen; Rs, is H, OH, halogen or O(Cla)alkyl
`wherein alkyl is unsubstituted or substituted by halogen; and
`Rs, is H, OH, halogen, (Cla)alkyl wherein alkyl is unsubsti
`tuted or substituted by hydroxy, or O(Cla)alkyl wherein alkyl
`is unsubstituted or substituted by halogen; Y, is –CH2—,
`—C(O)—, -CH(OH)—, -C(=NOH-, O or S, and Ra, is
`(C4-1a)alkyl or (C4-1a)alkenyl;
`or a pharmaceutically acceptable salt or hydrate thereof;
`
`60
`
`65
`
`R4x R33 N.
`
`Rix
`
`R5,
`- |=
`CH2)n,
`Ty
`t -Q.
`
`CH2—OR2,
`
`3.
`
`VI
`
`TEVA EX. 1037
`Page 3
`
`

`

`US 8,324,283 B2
`
`6
`<group b- is cycloalkyl, aryl, heterocycle, each being option
`ally substituted by up to three substituents selected from
`group a.
`with the proviso that when Rs., is hydrogen, Y., is a group
`exclusive of single bond and linear C1-io alkylene, or a phar
`macologically acceptable salt or ester thereof;
`JP-1431 6985
`Compounds
`&lS
`disclosed
`in
`(JP2002316985), e.g. a compound of formula VII:
`
`VIII
`
`wherein R12, R22, Rae, Rae, Rse, Roe, R72, n., X, and Y, are as
`disclosed in JP-14316985;
`or a pharmacologically acceptable salt or ester thereof;
`Compounds as disclosed in WO 03/29184 and WO
`03/29206, e.g. compounds of formula IX
`
`R1
`f
`
`X
`| S ºf.
`
`|
`
`S/S
`
`NH2
`
`2%
`R2,
`
`CH2OR4,
`2 (CH2)
`* CH.OR,
`
`IX
`
`5
`
`wherein
`n, is 2, 3 or 4
`R1, is H; C1-calkyl optionally substituted by OH, acyl, halo
`gen, cycloalkyl, phenyl or hydroxy-phenylene; C2-galk
`enyl; C2-calkynyl; or phenyl optionally substituted by OH:
`R2, is H, Cia alkyl or acyl
`each of Rs, and Ray, independently is H. Claalkyl optionally
`substituted by halogen or acyl,
`Rs, is H. Claalkyl or C1 aalkoxy, and
`Ra, is C1.20alkanoyl substituted by cycloalkyl; cylo
`alkylC1-14alkoxy wherein the cycloalkyl ring is optionally
`substituted by halogen, Claalkyl and/or Claalkoxy; phe
`nylc? 14alkoxy wherein the phenyl ring is optionally sub
`stituted by halogen, C1-1aalkyl and/or Claalkoxy,
`Ray being also Ca.14alkoxy when R1, is C2 aalkyl substituted
`by OH, or pentyloxy or hexyloxy when R1, is Calla-alkyl,
`provided that Ra, is other than phenyl-butylenoxy when
`either Rs, is H or R1, is methyl,
`or a pharmaceutically acceptable salt thereof;
`Compounds as disclosed in WOO2/06268A1, e.g. a com
`20
`pound of formula VII
`
`10
`
`15
`
`A.Å.
`NR1aR2d
`/\!\ v-v –
`(CH2)ad Q 2. X4–Ya–Rs.4
`S
`
`R4d
`
`R34C)
`
`VII
`
`25
`
`30
`
`wherein each of R1a and R22, independently, is Horanamino
`protecting group;
`Rs, is hydrogen, a hydroxy-protecting group or a residue of
`formula
`
`35
`
`wherein X, is O or S, and R, R2, Ryand n, are as disclosed
`in WO 03/29184 and 03/29205,
`each of Ra, and Rs, independently is Hora residue of formula
`
`— P |NOR,
`
`O
`
`Ra, is lower alkyl;
`nº is an integer of 1 to 6;
`X, is ethylene, vinylene, ethynylene, a group having a for
`mula -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;
`Y., is single bond, C1-ioalkylene, Cl-loalkylene which is sub
`stituted by up to three substitutents selected from groupsa and
`b, Cl-loalkylene having O or S in the middle or end of the
`carbon chain, or C1-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 Raº, and R74, independently, is H or a substituent
`selected from group a?
`each of Rs., and Roº, independently, is H or Claalkyl option
`ally substituted by halogen;
`<group a- is halogen, lower alkyl, halogeno lower alkyl,
`lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbo
`nyl, hydroxy, lower aliphatic acyl, amino, mono-lower alky
`lamino, di-lower alkylamino, lower aliphatic acylamino,
`cyano or nitro; and
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2ORs.
`— P |NOR,
`
`O
`
`wherein each of Rs, and Roa independently, is H or C, alkyl
`optionally substituted by halogen; e.g. 2-amino-2-[4-(3-ben
`zyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol or
`2-amino-2-[4-(benzyloxyphenylthio)-2-chlorophenyl]pro
`pyl-1,3-propane-diol, or a pharmacological salt thereof.
`Compounds as disclosed in WOO3062252A1, e.g. a com
`pound of formula X
`
`X
`
`R3g
`
`As (R4g)0-4 sº
`
`|
`(CH2)ng
`
`Re–M
`
`(CH2)ng
`M
`
`Rig
`
`wherein
`Aris phenyl or naphthyl; each of mg and ng independently is
`0 or 1: A is selected from COOH, PO3H2, PO2H, SO3H,
`PO(C1-3alkyl)0H and 1H-tetrazol-5-yl; each of R1g and
`R2g independently is H, halogen, OH, COOH or C1-4alkyl
`optionally substituted by halogen; R3g is H or C1-4alkyl
`
`TEVA EX. 1037
`Page 4
`
`

`

`US 8,324,283 B2
`
`7
`optionally substituted by halogen or OH; each R4g indepen
`dently is halogen, or optionally halogen substituted
`C1-4alkyl or C1-3alkoxy; and each of R9 and M has one of
`the significances as indicated for B and C, respectively, in
`WOO3/062252A1;
`Compounds as disclosed in WO 03/062248A2, e.g. a com
`pound of formula XI
`
`8
`Acyl may be a residue R,-CO—wherein R, is C, alkyl,
`Cs-acycloalkyl, phenyl orphenyl-Cu-aalkyl. Unless otherwise
`stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or
`branched.
`When in the compounds offormula I the carbon chain as Ri
`is substituted, it is preferably substituted by halogen, nitro,
`amino, hydroxy or carboxy. When the carbon chain is inter
`rupted by an optionally substituted phenylene, the carbon
`chain is preferably unsubstituted. When the phenylene moi
`ety is substituted, it is preferably substituted by halogen,
`nitro, amino, methoxy, hydroxy or carboxy.
`Preferred compounds of formula I are those wherein R, is
`Cis-3oalkyl, optionally substituted by nitro, halogen, amino,
`hydroxy or carboxy, and, more preferably those wherein R, is
`phenylalkyl substituted by Ca.14-alkyl chain optionally sub
`stituted by halogen and the alkyl moiety is a C-calkyl option
`ally substituted by hydroxy. More preferably, R is phenyl
`C1-galkyl substituted on the phenyl by a straight or branched,
`preferably straight, Ca.14alkyl chain. The Ca.14alkyl chain
`may be in ortho, meta or para, preferably in para.
`Preferably each of R, to Rs is H.
`A preferred compound of formula I is 2-amino-2-tetrade
`cyl-1,3-propanediol. A particularly preferred S1P receptor
`agonist of formula I is FTY720, i.e. 2-amino-2-[2-(4-oc
`tylphenyl)ethyl] propane-1,3-diol in free form or in a phar
`maceutically acceptable salt form (referred to hereinafter as
`Compound A), e.g. the hydrochloride, as shown:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`HO
`
`OH
`
`wherein Ar is phenyl or naphthyl; n is 2, 3 or 4: A is COOH,
`1H-tetrazol-5-yl, PO3H2, PO2H2, —SO3H or PO(R5h)OH
`wherein R5h is selected from C1-4alkyl, hydroxyC1-4alkyl,
`phenyl, -CO-C1-3alkoxy and —CH(OH)-phenyl wherein
`said phenyl orphenyl moiety is optionally substituted; each of
`R1h 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 or 2C1-3alkyl, C1-3alkoxy, C3-6cycloalkoxy, aryl
`or aralkoxy, 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 S1P
`receptoragonist 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 S1P1 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 S1P1 receptor of 100 nM or less as evaluated by the
`35S-GTPyS binding assay. Representative S1P1 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
`
`35
`
`40
`
`45
`
`XII
`
`50
`
`55
`
`XIII
`
`60
`
`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.
`
`65
`
`A preferred compound of formula II is the one wherein
`each of R'2 to R', is H and m is 4, i.e. 2-amino-2-(2-[(1-oxo
`5-phenylpentyl)phenyl]ethyl)propane-1,3-diol, in free form
`or in pharmaceutically acceptable salt form (referred to here
`inafter as Compound B), e.g. the hydrochloride.
`A preferred compound of formula III is the one wherein W
`is CHA, each of R", to R", is H, Z, is ethylene, X is heptyloxy
`and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl
`butanol, in free form or in pharmaceutically acceptable salt
`form (referred to hereinafter as Compound C), e.g. the hydro
`chloride. The R-enantiomer is particularly preferred.
`A preferred compound of formula IVa is the FTY720
`phosphate (R22 is H, Rs., is OH, X, is O, Ria and R1a are OH).
`A preferred compound of formula IVb is the Compound
`C-phosphate (R22 is H. Rs, is OH, X, is O, R1, and Riº, are
`OH, Y, is O and Ra, is heptyl). 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)-bu
`tyl]ester.
`A preferred compound of formula VIII is (2)-R-2-amino
`4-[3-(4-cyclohexyloxybutyl)benzo[b]thien-6-yl)-2-meth
`ylbutan-1-ol.
`When the compounds of formulae I to XIII have one or
`more asymmetric centers in the molecule, the various optical
`isomers, as well as racemates, diastereoisomers and mixtures
`thereof are embraced.
`Examples of pharmaceutically acceptable salts of the com
`pounds of formulae I to XIII include salts with inorganic
`acids, such as hydrochloride, hydrobromide and sulfate, salts
`with organic acids, such as acetate, fumarate, maleate, ben
`zoate, citrate, malate, methanesulfonate and benzene
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`10
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`
`sulfonate 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 S1P receptors can be determined according to
`the following assays.
`A. Binding Affinity of S1P Receptor Agonists to Individual
`Human S1P Receptors
`Transient Transfection of Human S1P Receptors into
`HEK293 Cells
`S1P receptors and G, proteins are cloned, and equal
`amounts of 4 clNAs for the EDG receptor, G-O, G-6 and
`G-Y are mixed and used to transfect monolayers of HEK293
`cells using the calcium phosphate precipitate method (M.
`Wigler et al., Cell. 1977; 11; 223 and DS. Im et al., Mol.
`Pharmacol. 2000, 57; 753). Briefly, a DNA mixture contain
`ing 25 pig of DNA and 0.25 M CaCl2 is added to HEPES
`buffered 2 mM Na2HPO4. Subconfluent monolayers of
`HEK293 cells are poisoned with 25 mM chloroquine, and the
`20
`DNA precipitate is then applied to the cells. After 4 h, the
`monolayers are washed with phosphate-buffered saline and
`refed media (90% 1:1 Dulbecco’s modified essential media
`(DMEM):F-12+10% fetal bovine serum). The cells are har
`vested 4872 h after addition of the DNA by scraping in HME
`25
`buffer (in mM: 20 HEPES, 5 MgCl2, 1 EDTA, pH 7.4) con
`taining 10% sucrose on ice, and disrupted using a Dounce
`homogenizer. After centrifugation at 800×g, the supernatant
`is diluted with HME without sucrose and centrifuged at 100,
`000×g for 1 h. The resulting pellet is rehomogenized and
`30
`centrifuged a second hour at 100,000×g. This crude mem
`brane pellet is resuspended in HME with sucrose, aliquoted,
`and snap-frozen by immersion in liquid nitrogen. The mem
`branes are stored at 70° C. Protein concentration is deter
`mined spectroscopically by Bradford protein assay.
`35
`GTPYS Binding Assay Using S1P Receptor/HEK293 Mem
`brane Preparations
`GTPYS binding experiments are performed as described by
`DS. Im et al., Mol. Pharmacol. 2000; 57:753. Ligand-medi
`ated GTPYS binding to G-proteins is measured in GTP bind
`ing buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl2, pH 7.5)
`using 25 pig of a membrane preparation from transiently
`transfected HEK293 cells. Ligand is added to membranes in
`the presence of 10 puM GDP and 0.1 nM [*S]GTPYS (1200
`Ci/mmol) and incubated at 30° C. for 30 min. Bound GTPYS
`is separated from unbound using the Brandel harvester
`(Gaithersburg, Md.) and counted with a liquid scintillation
`COunter.
`The composition of the invention preferably contains 0.01
`to 20% by weight of S1P 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, inosi
`tol, xylitol or lactitol, preferably a substantially non-hygro
`scopic 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 xylitol, e.g. in a ratio
`of 1:1 to 4:1.
`In a particularly preferred embodiment, the sugar alcoholis
`60
`prepared from a spray-dried composition, e.g. mannitol com
`position, having a high specific surface area. The use of this
`type of mannitol composition may assist in promoting uni
`form distribution of the S1P receptor agonist throughout the
`mannitol in the composition. A higher surface area may be
`achieved by providing a sugar alcohol, e.g. mannitol, prepa
`ration consisting of particles having a smaller mean size
`
`45
`
`50
`
`55
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`65
`
`US 8,324,283 B2
`
`10
`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 pum or less, has also been found to improve com
`pressibility and hardness of tablets formed from the compo
`sition.
`Preferably the single point surface area of the sugar alcohol
`preparation, e.g. mannitol, is 1 to 7 mi/g, e.g. 2 to 6 mº/g or 3
`to 5m’?g.The mannitol preparation may suitably have a mean
`particle size of 100 to 300 pum, e.g. 150 to 250 pum 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 Parteck M200, available com
`mercially 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, glyceryl palmitostearate,
`sodium stearyl furnarate, canola oil, hydrogenated vegetable
`oil such as hydrogenated castor oil (e.g. Cutina R or Lubri
`wax(R) 101), mineral oil, sodium lauryl 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 lubricants.
`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 excipi
`ents such as carriers, binders or diluents. In particular, the
`composition may comprise microcrystalline cellulose (e.g.
`Avicel R), mathylcellulose, hydroxypropylcellulose, hydrox
`ypropylmethylcellulose, starch (e.g. corn starch) or dical
`cium 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, mathylcellulose, hydroxypropyl cellulose, hydrox
`ypropylmethyl 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 mathylcellulose are particularly preferred where a high
`tablet hardness and/or longer disintegration time is required.
`Hydroxypropyl cellulose is preferred where faster disintegra
`tion is required. Where appropriate, xylitol may also be added
`as an additional binder, for example in addition to microcrys
`talline 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
`stabiliser, preferably glycine HC1 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 pallets 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 cap
`sule shelf, 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 hydroxypro
`pylmethylcellulose coating.
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`11
`Where the pharmaceutical capsule is in unit dosage form,
`each unit dosage will suitably contain 0.5 to 10 mg of the S1P
`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 deter
`mined, e.g. by measuring decomposition products by HPLC
`analysis after storage for particular times, at particular tem
`peratures, e.g. 20°, 40° or 60° C.
`The pharmaceutical compositions of the present invention
`may be produced by standard processes, for instance by con
`ventional 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 pharmazeutischen 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 S1P 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
`30
`distribution of the S1P receptor agonist throughout the com
`position), dissolution time and stability is obtained.
`The S1P receptor agonist, e.g. 2-amino-2-[2-(4-octylphe
`nyl)ethyl] propane-1,3diol, hydrochloride, may optionally be
`micronized, and/or pre-screened, e.g. with a 400 to 500 pum
`mesh screen, before step (a) in order to remove lumps. The
`mixing step (a) may suitably comprise blending the S1P
`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 compo
`40
`ments. 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 pum.
`Process step (a) may comprise the step of mixing the total