U.S. patent application number 14/164623 was filed with the patent office on 2014-05-22 for compositions comprising sphingosine 1 phosphate (s1p) receptor modulators.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Michael AMBUHL, Colleen RUEGGER. Invention is credited to Michael AMBUHL, Colleen RUEGGER.
Application Number | 20140142192 14/164623 |
Document ID | / |
Family ID | 40032615 |
Filed Date | 2014-05-22 |
United States Patent
Application |
20140142192 |
Kind Code |
A1 |
RUEGGER; Colleen ; et
al. |
May 22, 2014 |
Compositions Comprising Sphingosine 1 Phosphate (S1P) Receptor
Modulators
Abstract
The present invention relates to stable compositions comprising
a sphingosine 1 phosphate (S1P) receptor modulator, suitable for
use as a dosage form. The S1P receptor modulators are typically
sphingosine analogues, such as 2-substituted
2-amino-propane-1,3-diol or 2-amino-propanol derivatives, e.g. a
compound comprising a group of formula Y.
Inventors: |
RUEGGER; Colleen; (Morris
Plains, NJ) ; AMBUHL; Michael; (Rheinfelden,
CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
RUEGGER; Colleen
AMBUHL; Michael |
Morris Plains
Rheinfelden |
NJ |
US
CH |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
40032615 |
Appl. No.: |
14/164623 |
Filed: |
January 27, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12682343 |
Jun 9, 2010 |
8673918 |
|
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PCT/US08/79264 |
Oct 9, 2008 |
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14164623 |
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60979482 |
Oct 12, 2007 |
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Current U.S.
Class: |
514/653 |
Current CPC
Class: |
A61P 37/02 20180101;
A61K 47/38 20130101; A61K 47/10 20130101; A61P 25/00 20180101; A61K
31/137 20130101; A61P 29/00 20180101; A61K 36/00 20130101; A61P
9/10 20180101; A61P 43/00 20180101; A61K 9/0056 20130101; A61K
31/133 20130101; A61K 9/7007 20130101; A61P 35/00 20180101; A61P
37/00 20180101; A61P 31/12 20180101; A61P 9/00 20180101; A61K 47/36
20130101; A61P 25/28 20180101; A61K 9/20 20130101; A61P 37/06
20180101 |
Class at
Publication: |
514/653 |
International
Class: |
A61K 31/137 20060101
A61K031/137 |
Claims
1. A method for the treatment of organ or tissue transplant
rejection, graft versus host disease, autoimmune diseases,
inflammatory conditions, viral myocarditis, viral diseases caused
by viral myocarditis or cancers comprising administration of a
stable composition comprising: (i) a compound comprising a group of
formula Y ##STR00018## wherein Z is H, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, phenyl, phenyl substituted by
OH, C.sub.1-6alkyl substituted by 1 to 3 substituents selected from
the group consisting of halogen, C.sub.3-8cycloalkyl, phenyl and
phenyl substituted by OH, or CH.sub.2--R.sub.4z wherein R.sub.4z is
OH, acyloxy or a residue of formula (a) ##STR00019## wherein
Z.sub.1 is a direct bond or O; each of R.sub.5z and R.sub.6z,
independently, is H, or C.sub.1-4alkyl optionally substituted by 1,
2 or 3 halogen atoms; R.sub.1z is OH, acyloxy or a residue of
formula (a); and each of R.sub.2z and R.sub.3z independently, is H,
C.sub.1-4alkyl or acyl; and (ii) one or more of the following
excipients: (a) one or more Fillers selected from the group
consisting of Lactose monohydrate, Lactose anhydrous, Maize starch,
Mannitol, Xylitol, sorbitol, sucrose, and Microcrystalline
cellulose; (b) one or more Binders selected from the group
consisting of HPMC, L-HPC, Povidone, and HPC; (c) one or more
Disintegrants selected from the group consisting of Maize starch,
Crospovidone, Croscarmellose sodium, Sodium carboxymethylstarch,
pregelatinized starch, calcium and silicate; (d) one or more
Lubricants selected from the group consisting of Hydrogenated
castor oil, Glycerol behenate, magnesium stearate, calcium
stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl
sulfate, L-leucine, and sodium stearyl fumarate; (e) one or more
Flow regulators selected from the group consisting of Colloidal
silicone dioxide and Talc; (f) one or more Matrix formers selected
from the group consisting of Hydroxypropyl methyl cellulose,
Hydroxypropyl cellulose, Methyl cellulose, Ethyl cellulose,
Pullulan, Starch; (g) one or more Plastisizers selected from the
group consisting of PEG 400, Dibutyl sebacate, and Sorbitol; (h)
one or more Flavoring agents selected from the group consisting of
Menthol, and tutti fruit; (i) one or more Sweeteners selected from
the group consisting of Sucralose, and Sodium saccharine.
2. The method of claim 1 for the treatment of an autoimmune
disease.
3. The method of claim 1 for the treatment of multiple
sclerosis.
4. The method of claim 1 wherein the compound of formula Y is
selected from the group consisting of
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) in free
form, a pharmaceutically acceptable salt thereof, FTY720-phosphate,
1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-be-
nzyl}-azetidine-3-carboxylic acid, and a prodrug thereof.
Description
[0001] The present invention relates to a composition comprising a
sphingosine 1 phosphate (S1P) receptor modulator.
[0002] In particular, the present invention relates to stable
compositions comprising a sphingosine 1 phosphate (S1P) receptor
modulator suitable for use as a dosage form.
[0003] S1P receptor modulators are typically sphingosine analogues,
such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol
derivatives, e.g. a compound comprising a group of formula Y.
SIP Receptor Modulators
[0004] Sphingosine-1 phosphate (hereinafter "S1P") is a natural
serum lipid. Presently there are eight known S1P receptors, namely
S1P1 to S1P8. S1P receptor modulators are typically sphingosine
analogues, such as 2-substituted 2-amino-propane-1,3-diol or
2-amino-propanol derivatives, e.g. a compound comprising a group of
formula Y
##STR00001##
wherein Z is H, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
phenyl, phenyl substituted by OH, C.sub.1-6 alkyl substituted by 1
to 3 substituents selected from the group consisting of halogen,
C.sub.3-8cycloalkyl, phenyl and phenyl substituted by OH, or
CH.sub.2--R.sub.4z wherein R.sub.4z is OH, acyloxy or a residue of
formula (a)
##STR00002##
wherein Z.sub.1 is a direct bond or O, preferably O; each of
R.sub.5z and R.sub.6z, independently, is H, or C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 halogen atoms; R.sub.1z is OH,
acyloxy or a residue of formula (a); and each of R.sub.2z and
R.sub.3z independently, is H, C.sub.1-4alkyl or acyl.
[0005] Group of formula Y is a functional group attached as a
terminal group to a moiety which may be hydrophilic or lipophilic
and comprise one or more aliphatic, alicyclic, aromatic and/or
heterocyclic residues, to the extent that the resulting molecule
wherein at least one of Z and R.sub.1z is or comprises a residue of
formula (a), signals as an agonist at one of more
sphingosine-1-phosphate receptor.
[0006] S1P receptor modulators are compounds which signal as
agonists at one or more sphingosine-1 phosphate receptors, e.g.
S1P1 to S1P8. Agonist binding to a S1P receptor may e.g. result in
dissociation of intracellular heterotrimeric G-proteins into
G.alpha.-GTP and G.beta..gamma.-GTP, and/or increased
phosphorylation of the agonist-occupied receptor and activation of
downstream signaling pathways/kinases.
[0007] Examples of appropriate S1P receptor modulators, comprising
a group of formula Y are, for example:
[0008] Compounds as disclosed in EP627406A1, e.g. a compound of
formula I
##STR00003##
wherein R.sub.1 is a straight- or branched (C.sub.12-22)chain
[0009] which may have in the chain a bond or a hetero atom selected
from a double bond, a triple bond, O, S, NR.sub.6, wherein R.sub.6
is H, C.sub.1-4alkyl, aryl-C.sub.1-4alkyl, acyl or
(C.sub.1-4alkoxy)carbonyl, and carbonyl, and/or [0010] which may
have as a substituent C.sub.1-4alkoxy, C.sub.2-4alkenyloxy,
C.sub.2-4alkynyloxy, arylC.sub.1-4alkyl-oxy, acyl,
C.sub.1-4alkylamino, C.sub.1-4alkylthio, acylamino,
(C.sub.1-4alkoxy)carbonyl, (C.sub.1-4alkoxy)-carbonylamino,
acyloxy, (C.sub.1-4alkyl)carbamoyl, nitro, halogen, amino,
hydroxyimino, hydroxy or carboxy; or
R.sub.1 is
[0010] [0011] a phenylalkyl wherein alkyl is a straight- or
branched (C.sub.6-20)carbon chain; or [0012] a phenylalkyl wherein
alkyl is a straight- or branched (C.sub.1-30)carbon chain wherein
said phenylalkyl is substituted by [0013] a straight- or branched
(C.sub.6-20)carbon chain optionally substituted by halogen, [0014]
a straight- or branched (C.sub.6-20)alkoxy chain optionally
substituted by halogen, [0015] a straight- or branched
(C.sub.6-20)alkenyloxy, [0016] phenyl-C.sub.1-14alkoxy,
halophenyl-C.sub.1-4alkoxy,
phenyl-C.sub.1-14alkoxy-C.sub.1-14alkyl, phenoxy-C.sub.1-4alkoxy or
phenoxy-C.sub.1-4alkyl, [0017] cycloalkylalkyl substituted by
C.sub.6-20alkyl, [0018] heteroarylalkyl substituted by
C.sub.6-20alkyl, [0019] heterocyclic C.sub.6-20alkyl or [0020]
heterocyclic alkyl substituted by C.sub.2-20alkyl, and wherein the
alkyl moiety may have [0021] in the carbon chain, a bond or a
heteroatom selected from a double bond, a triple bond, O, S,
sulfinyl, sulfonyl, or NR.sub.6, wherein R.sub.6 is as defined
above, and [0022] as a substituent C.sub.1-4alkoxy,
C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy, arylC.sub.1-4alkyloxy,
acyl, C.sub.1-4alkyl-amino, C.sub.1-4alkylthio, acylamino,
(C.sub.1-4alkoxy)carbonyl, (C.sub.1-4alkoxy)carbonylamino, acyloxy,
(C.sub.1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxy or
carboxy, and each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5,
independently, is H, C.sub.1-4 alkyl or acyl or a pharmaceutically
acceptable salt or hydrate thereof;
[0023] Compounds as disclosed in EP 1002792A1, e.g. a compound of
formula II
##STR00004##
wherein m is 1 to 9 and each of R'.sub.2, R'.sub.3, R'.sub.4 and
R'.sub.5, independently, is H, C.sub.1-6alkyl or acyl, or a
pharmaceutically acceptable salt or hydrate thereof; [0024]
Compounds as disclosed in EP0778263 A1, e.g. a compound of formula
III
##STR00005##
[0024] wherein W is H; C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl; unsubstituted or by OH substituted phenyl;
R''.sub.4O(CH.sub.2).sub.n; or C.sub.1-6alkyl substituted by 1 to 3
substituents selected from the group consisting of halogen,
C.sub.3-8cycloalkyl, 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
C.sub.1-6alkyl, OH, C.sub.1-6alkoxy, acyloxy, amino,
C.sub.1-6alkylamino, acylamino, oxo, haloC.sub.1-6alkyl, halogen,
unsubstituted phenyl and phenyl substituted by 1 to 3 substituents
selected from the group consisting of C.sub.1-6alkyl, OH,
C.sub.1-6alkoxy, acyl, acyloxy, amino, C.sub.1-6alkylamino,
acylamino, haloC.sub.1-6alkyl and halogen; Y is H, C.sub.1-6alkyl,
OH, C.sub.1-6alkoxy, acyl, acyloxy, amino, C.sub.1-6alkylamino,
acylamino, haloC.sub.1-6alkyl or halogen, Z.sub.2 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.ltoreq.p+q.ltoreq.23, m' is 1, 2 or 3, n is 2 or 3,
each of R''.sub.1, R''.sub.2, R''.sub.3 and R''.sub.4,
independently, is H, C.sub.1-4alkyl or acyl, or a pharmaceutically
acceptable salt or hydrate thereof,
[0025] Compounds as disclosed in WO02/18395, e.g. a compound of
formula IVa or IVb
##STR00006##
wherein X.sub.a is O, S, NR.sub.1s or a group
--(CH.sub.2).sub.na--, which group is unsubstituted or substituted
by 1 to 4 halogen; n.sub.a is 1 or 2, R.sub.1s is H or
(C.sub.1-4)alkyl, which alkyl is unsubstituted or substituted by
halogen; R.sub.1a is H, OH, (C.sub.1-4)alkyl or O(C.sub.1-4)alkyl
wherein alkyl is unsubstituted or substituted by 1 to 3 halogen;
R.sub.1b is H, OH or (C.sub.1-4)alkyl, wherein alkyl is
unsubstituted or substituted by halogen; each R.sub.2a is
independently selected from H or (C.sub.1-4)alkyl, which alkyl is
unsubstituted or substituted by halogen; R.sub.3a is H, OH, halogen
or O(C.sub.1-4)alkyl wherein alkyl is unsubstituted or substituted
by halogen; and R.sub.3b is H, OH, halogen, (C.sub.1-4)alkyl
wherein alkyl is unsubstituted or substituted by hydroxy, or
O(C.sub.1-4)alkyl wherein alkyl is unsubstituted or substituted by
halogen; Y.sub.a is --CH.sub.2--, --C(O)--, --CH(OH)--,
--C(.dbd.NOH)--, O or S, and R.sub.4a is (C.sub.4-14)alkyl or
(C.sub.4-14)alkenyl; or a pharmaceutically acceptable salt or
hydrate thereof;
[0026] Amino alcohol compounds of formula V
##STR00007##
wherein X is O, S, SO or SO.sub.2; R.sub.1 is halogen,
trihalomethyl, OH, C.sub.1-7alkyl, C.sub.1-4alkoxy,
trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy,
cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH.sub.2--OH,
CH.sub.2--CH.sub.2--OH, C.sub.1-4alkylthio, C.sub.1-4alkylsulfinyl,
C.sub.1-4alkylsulfonyl, benzylthio, acetyl, nitro or cyano, or
phenyl, phenylC.sub.1-4alkyl or phenyl-C.sub.1-4alkoxy each phenyl
group thereof being optionally substituted by halogen, CF.sub.3,
C.sub.1-4alkyl or C.sub.1-4alkoxy; R.sub.2 is H, halogen,
trihalomethyl, C.sub.1-4alkoxy, C.sub.1-7alkyl, phenethyl or
benzyloxy; R.sub.3H, halogen, CF.sub.3, OH, C.sub.1-7alkyl,
C.sub.1-4alkoxy, benzyloxy, phenyl or C.sub.1-4alkoxymethyl; each
of R.sub.4 and R.sub.5, independently is H or a residue of formula
(a)
##STR00008##
wherein each of R.sub.8 and R.sub.9, independently, is H or
C.sub.1-4alkyl optionally substituted by halogen; and n is an
integer from 1 to 4; or a pharmaceutically acceptable salt thereof;
or a compound of formula VI
##STR00009##
wherein [0027] R.sub.1a is halogen, trihalomethyl, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, C.sub.1-4alkylsulifinyl,
C.sub.1-4alkyl-sulfonyl, aralkyl, optionally substituted phenoxy or
aralkyloxy; [0028] R.sub.2a is H, halogen, trihalomethyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy, aralkyl or aralkyloxy; [0029]
R.sub.3a is H, halogen, CF.sub.3, C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio or benzyloxy; [0030] R.sub.4a is H,
C.sub.1-4alkyl, phenyl, optionally substituted benzyl or benzoyl,
or lower aliphatic C.sub.1-5acyl; [0031] R.sub.5a is H,
monohalomethyl, C.sub.1-4alkyl, C.sub.1-4alkoxy-methyl,
C.sub.1-4alkyl-thiomethyl, hydroxyethyl, hydroxypropyl, phenyl,
aralkyl, C.sub.2-4alkenyl or -alkynyl; [0032] R.sub.6a is H or
C.sub.1-4alkyl; [0033] R.sub.7a is H, C.sub.1-4alkyl or a residue
of formula (a) as defined above, [0034] X.sub.a is O, S, SO or
SO.sub.2; and [0035] n.sub.a is an integer of 1 to 4; or a
pharmaceutically acceptable salt thereof.
[0036] With regard to the compounds of formulae (I) and (II), the
term "halogen" encompasses fluorine, chlorine, bromine and iodine.
The term "trihalomethyl group" encompasses trifluoromethyl and
trichloromethyl. "C.sub.1-7 alkyl" encompasses straight-chained or
branched alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, pentyl, hexyl or heptyl. The phrase "substituted or
unsubstituted phenoxy group" encompasses those that have, at any
position of its benzene ring, a halogen atom, such as fluorine,
chlorine, bromine and iodine, trifluoromethyl, C.sub.1-4alkyl or
C.sub.1-4alkoxy. The term "aralkyl group" as in "aralkyl group" or
"aralkyloxy group" encompasses benzyl, diphenylmethyl, phenethyl
and phenylpropyl. Any alkyl moiety as present in "C.sub.1-4alkoxy",
"C.sub.1-4alkylthio", "C.sub.1-4alkylsulfinyl" or
"C.sub.1-4alkylsulfonyl encompasses straight-chained or branched
C.sub.1-4alkyl, e.g. methyl, ethyl, propyl, isopropyl or butyl. The
phrase "substituted or unsubstituted aralkyl group" encompasses
those that have, at any position of its benzene ring, a halogen
atom, such as fluorine, chlorine, bromine and iodine,
trifluoromethyl, lower alkyl having 1-4 carbon atoms, or lower
alkoxy having 1-4 carbon atoms.
[0037] Other compounds of formula V are compounds of formula Va
##STR00010##
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined
above; and Y is O or S and R.sub.6 is hydrogen, halogen,
C.sub.1-7alkyl, C.sub.1-4alkoxy or trifluoromethyl.
[0038] Compounds of formulae V and Va are known and are disclosed
e.g. in WO03/029205, WO 03/029184 and WO04/026817, respectively,
the phosphorylated derivatives being disclosed e.g. in WO04/074297,
the contents of which being incorporated herein by reference in
their entirety. Compounds disclosed may be prepared as disclosed in
the cited references herein.
[0039] Phosphorylated derivatives of compounds described herein can
be prepared utilizing the procedures for synthesizing
phosphorylated compounds described known in the art, e.g., in WO
2005/021503 (see, e.g., pages 11 and 12).
[0040] Optically active compounds of and phosphorylated derivatives
thereof can be prepared in high purity utilizing procedure
described in the art, e.g. in Hinterding et al., Synthesis, Vol.
11, pp. 1667-1670 (2003).
[0041] Compounds as disclosed in WO02/06268AI, e.g. a compound of
formula VI
##STR00011##
wherein each of R.sub.1d and R.sub.2d, independently, is H or an
amino-protecting group; R.sub.3d is hydrogen, a hydroxy-protecting
group or a residue of formula
##STR00012##
R.sub.4d is C.sub.1-4alkyl; n.sub.d is an integer of 1 to 6;
X.sub.d is ethylene, vinylene, ethynylene, a group having a formula
-D-CH.sub.2-- (wherein D is carbonyl, --CH(OH)--, O, S or N), aryl
or aryl substituted by up to three substituents selected from group
a as defined hereinafter; Y.sub.d is single bond,
C.sub.1-10alkylene, C.sub.1-10alkylene which is substituted by up
to three substituents selected from groups a and b,
C.sub.1-10alkylene having O or S in the middle or end of the carbon
chain, or C.sub.1-10alkylene 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; R.sub.5d is hydrogen,
C.sub.3-6cycloalkyl, aryl, heterocyclic group, C.sub.3-6cycloalkyl
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 heterocyclic group substituted by up to three
substituents selected from groups a and b; each of R.sub.6d and
R.sub.7d, independently, is H or a substituents selected from group
a; each of R.sub.8d and R.sub.9d, independently, is H or
C.sub.1-4alkyl optionally substituted by halogen; <group a>
is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, lower
alkylthio, carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic
acyl, amino, mono-lower alkylamino, di-C.sub.1-4alkylamino,
acylamino, cyano or nitro; and <group b> is
C.sub.3-6cycloalkyl, aryl or heterocyclic group, each being
optionally substituted by up to three substituents selected from
group a; with the proviso that when R.sub.5d is hydrogen, Y.sub.d
is a either a single bond or linear Cl.sub.10 alkylene, or a
pharmacologically acceptable salt, ester or hydrate thereof;
[0042] Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a
compound of formula VII
##STR00013##
wherein R.sub.1e, R.sub.2e, R.sub.3e, R.sub.4e, R.sub.5e, R.sub.6e,
R.sub.7e, n.sub.e, X.sub.e and Y.sub.e are as disclosed in
JP-14316985; or a pharmacologically acceptable salt, ester or
hydrate thereof;
[0043] Compounds as disclosed in WO03/062252A1, e.g. a compound of
formula VIII
##STR00014##
wherein Ar is phenyl or naphthyl; each of m.sub.g and n.sub.g
independently is 0 or 1; A is selected from COOH, PO.sub.3H.sub.2,
PO.sub.2H, SO.sub.3H, PO(C.sub.1-3alkyl)OH and 1H-tetrazol-5-yl;
each of R.sub.1g and R.sub.2g independently is H, halogen, OH, COOH
or C.sub.1-4alkyl optionally substituted by halogen; R.sub.3g is H
or C.sub.1-4alkyl optionally substituted by halogen or OH; each
R.sub.4g independently is halogen, or optionally halogen
substituted C.sub.1-4alkyl or C.sub.1-3alkoxy; and each of R.sub.g
and M has one of the significances as indicated for B and C,
respectively, in WO03/062252A1; or a pharmacologically acceptable
salt, solvate or hydrate thereof;
[0044] Compounds as disclosed in WO 03/062248A2, e.g. a compound of
formula IX
##STR00015##
wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH,
1H-tetrazol-5-yl, PO.sub.3H.sub.2, PO.sub.2H.sub.2, --SO.sub.3H or
PO(R.sub.5h)OH wherein R.sub.5h is selected from C.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl, phenyl, --CO--C.sub.1-3alkoxy and
--CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionally
substituted; each of R.sub.1h and R.sub.2h independently is H,
halogen, OH, COOH, or optionally halogeno substituted
C.sub.1-6alkyl or phenyl; R.sub.3h is H or C.sub.1-4alkyl
optionally substituted by halogen and/OH; each R.sub.4h
independently is halogen, OH, COOH, C.sub.1-4alkyl, S(O).sub.0,1 or
2C.sub.1-2alkyl, C.sub.1-3alkoxy, C.sub.3-6cycloalkoxy, aryl or
aralkoxy, wherein the alkyl portions may optionally be substituted
by 1-3 halogens; and each of R.sub.h and M has one of the
significances as indicated for B and C, respectively, in
WO03/062248A2 or a pharmacologically acceptable salt, solvate or
hydrate thereof.
[0045] Compounds as disclosed in WO 04/103306A, WO 05/000833, WO
05/103309 or WO 05/113330, e.g. compounds of formula Xa or Xb
##STR00016##
wherein A.sub.k is COOR.sub.5k, OPO(OR.sub.5k).sub.2,
PO(OR.sub.5k).sub.2, SO.sub.2OR.sub.5k, POR.sub.5kOR.sub.5k or
1H-tetrazol-5-yl, R.sub.5k being H or C.sub.1-6alkyl; W.sub.k is a
bond, C.sub.1-3alkylene or C.sub.2-3alkenylene; Y.sub.k is
C.sub.6-10aryl or C.sub.3-9heteroaryl, optionally substituted by 1
to 3 radicals selected from halogene, OH, NO.sub.2,
C.sub.1-16alkyl, C.sub.1-6alkoxy; halo-substituted C.sub.1-6alkyl
and halo-substituted C.sub.1-6alkoxy; Z.sub.k is a heterocyclic
group as indicated in WO 04/103306A, e.g. azetidine; R.sub.1k is
C.sub.6-10aryl or C.sub.3-9heteroaryl, optionally substituted by
C.sub.1-6alkyl, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.3-9heteroaryl, C.sub.3-9heteroarylC.sub.1-4alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-4alkyl,
C.sub.3-8heterocycloalkyl or
C.sub.3-8heterocycloalkylC.sub.1-4alkyl; wherein any aryl,
heteroaryl, cycloalkyl or heterocycloalkyl of R.sub.1k may be
substituted by 1 to 5 groups selected from halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy and halo substituted-C.sub.1-6alkyl or
--C.sub.1-6alkoxy; R.sub.2k is H, C.sub.1-6alkyl, halo substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl: and each of
R.sub.3k or R.sub.4k, independently, is H, halogen, OH,
C.sub.1-6alkyl, C.sub.1-6alkoxy or halo substituted C.sub.1-6alkyl
or C.sub.1-6alkoxy; and the N-oxide derivatives thereof or prodrugs
thereof, or a pharmacologically acceptable salt, solvate or hydrate
thereof.
[0046] The compounds of formulae I to Xb may exist in free or salt
form. Examples of pharmaceutically acceptable salts of the
compounds of the formulae III to VIII include 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 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 combination of the present invention encompass hydrate
and solvate forms.
[0047] Acyl as indicated above may be a residue R.sub.y--CO--
wherein R.sub.y is C.sub.1-6alkyl, C.sub.3-6cycloalkyl, phenyl or
phenyl-C.sub.1-4alkyl. Unless otherwise stated, alkyl, alkoxy,
alkenyl or alkynyl may be straight or branched.
[0048] Aryl may be phenyl or naphthyl, preferably phenyl.
[0049] When in the compounds of formula I the carbon chain as
R.sub.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 by halogen, nitro, amino,
methoxy, hydroxy or carboxy.
[0050] Preferred compounds of formula I are those wherein R.sub.1
is C.sub.13-20alkyl, optionally substituted by nitro, halogen,
amino, hydroxy or carboxy, and, more preferably those wherein
R.sub.1 is phenylalkyl substituted by C.sub.6-14-alkyl chain
optionally substituted by halogen and the alkyl moiety is a
C.sub.1-6alkyl optionally substituted by hydroxy. More preferably,
R.sub.1 is phenyl-C.sub.1-6alkyl substituted on the phenyl by a
straight or branched, preferably straight, C.sub.6-14alkyl chain.
The C.sub.6-14alkyl chain may be in ortho, meta or para, preferably
in para.
[0051] Preferably each of R.sub.2 to R.sub.5 is H.
[0052] In the above formula of VII "heterocyclic group" represents
a 5- to 7 membered heterocyclic group having 1 to 3 heteroatoms
selected from S, O and N. Examples of such heterocyclic groups
include the heteroaryl groups indicated above, and heterocyclic
compounds corresponding to partially or completely hydrogenated
heteroaryl groups, e.g. furyl, thienyl, pyrrolyl, azepinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl,
thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, 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.
[0053] A preferred compound of formula I is
2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred S1P
receptor agonist of formula III is FTY720, i.e.
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:
##STR00017##
[0054] A preferred compound of formula II is the one wherein each
of R'.sub.2 to R'.sub.5 is 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 (referred
to hereinafter as Compound B), e.g the hydrochloride.
[0055] A preferred compound of formula III is the one wherein W is
CH.sub.3, each of R''.sub.1 to R''.sub.3 is H, Z.sub.2 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 hydrochloride. The R-enantiomer is
particularly preferred.
[0056] A preferred compound of formula IVa is the FTY720-phosphate
(R.sub.2a is H, R.sub.3a is OH, X.sub.a is O, R.sub.1a and R.sub.1b
are OH). A preferred compound of formula IVb is the Compound
C-phosphate (R.sub.2a is H, R.sub.3b is OH, X.sub.a is O, R.sub.1a
and R.sub.1b are OH, Y.sub.a is O and R.sub.4a is heptyl). A
preferred compound of formula V is Compound B-phosphate.
[0057] A preferred compound of formula VII is
(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbuta-
n-1-ol.
[0058] A preferred compound of formula Xa is e.g.
1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-be-
nzyl}-azetidine-3-carboxylic acid, or a prodrug thereof.
[0059] It will be appreciated that the compounds as described
herein may be the direct active substances, or may be prodrugs. For
example, the compounds may be phosphorylated forms.
Oral Formulations
[0060] The dosage form of a composition of the present invention,
e.g. the final dosage form, may be a solid dosage form, e.g. a
tablet. In another embodiment of the present invention the dosage
form is granular, e.g. powder form and may comprise part of a
suspension or gel. Another dosage forms may comprise of small
multiparticulate pellets/beads. Other dosage forms may comprise a
solid or granular composition which is soluble in a liquid to
produce a liquid formulation prior to administration. Examples of
such formulations are soluble tablets, capsules and sachets. The
final liquid formulation may be consumed as a drink.
[0061] The oral route is often the most convenient route for drug
administration. This may be in the form of a standard tablet, a
conventional orally disintegrating tablet, a lyophilized tablet, or
a thin film.
[0062] It has been found that compounds comprising a group of
formula Y, e.g. amino-propane-1,3-diols, e.g. those that have S1P
agonist activity, are not easy to formulate. In particular, these
are not easy to formulate in a solid oral formulation.
[0063] As such, the present inventors have surprisingly found that
only a limited number of excipients are potentially feasible with
such amino diols.
The Maillard Reaction
[0064] The Maillard reaction is a chemical reaction between an
amino acid and a reducing sugar [Sugars that contain aldehyde
groups that are oxidised to carboxylic acids are classified as
reducing sugars.
[0065] 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. The
reactive carbonyl group of the sugar interacts with the
nucleophilic amino group of the amino acid, and interesting but
poorly characterized odor and flavor molecules result. This process
accelerates in an alkaline environment because the amino groups do
not neutralize. This reaction is the basis of the flavouring
industry, since the type of amino acid determines the resulting
flavour.
[0066] The potentially feasible excipients are classified into e.g.
fillers, binders, disintegrants, lubricants, flow regulators,
plastisizers, and matrix formers. Some excipients can be listed in
more than one class.
[0067] Typical ranges found in a final formulation comprising a
compound as described herein are as follows:
Fillers: 10-97%
Binders: 1-15%
Disintegrants: 1-15%
Lubricants: 0.5-2%
[0068] Flow regulators: 0.5-3% Matrix formers: 3-50%
Plastisizers: 5-30%
[0069] Flavoring agents: 1-20%
Sweeteners: 1-20%
[0070] The present invention therefore relates to stable blends
comprising a compound having a group of formula Y and at least one
other excipient.
[0071] The compound having a group of formula Y may, in one
embodiment, be mixed together with one or more of the following
excipients:
(a) Fillers selected from Lactose monohydrate, Lactose anhydrous,
Maize starch, Mannitol, Xylitol, sorbitol, sucrose,
Microcrystalline cellulose, e.g. Avicel PH101, Dibasic calcium
phosphate, Maltodextrin, gelatin, e.g. DE 12 and/or (b) Binders
selected from HPMC, e.g. 3cPs, L-HPC, e.g. HP-Cellulose LH-22,
Povidone. and/or (c) Disintegrants selected from Maize starch,
Crospovidone, Croscarmellose sodium, Sodium carboxymethylstarch
e.g. Primojel, pregelatinized starch, e.g. Starch 1500 (Sta RX),
calcium silicate and/or (d) Lubricants selected from Hydrogenated
e.g. ricinoleic, 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 Aerosil 200Colloidal silicone
dioxide, e.g. Aerosil 200, Talc and/or (f) Matrix formers selected
from Hydroxypropyl methyl cellulose, Hydroxypropyl cellulose,
Methyl cellulose, Ethyl cellulose, Pullulan, Starch, e.g. Pure
Cote, Povidone and/or (g) Plastisizers selected from PEG 400,
Dibutyl sebacate, Sorbitol and/or (h) Flavoring agents selected
from Menthol, tutti fruti and/or (i) Sweeteners selected from
Sucralose, Sodium saccharine.
[0072] Fillers are preferably selected from Fillers selected from
Lactose monohydrate, Lactose anhydrous, Maize starch, Xylitol,
sorbitol, sucrose, Microcrystalline cellulose, e.g. Avicel PH101,
Dibasic calcium phosphate, Maltodextrin and gelatin.
[0073] According to one embodiment of the invention preferred
fubricants are selected from magnesium stearate and calcium
stearate.
[0074] In a second embodiment, the present invention relates to a
binary blend comprising 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 an hydrous, calcium silicate, colloidal silicone
dioxide, talc, magnesium stearate, calcium stearate.
[0075] Preferably, no moisture is present.
[0076] In particular, the excipients are selected from:
Dicalcium phosphate, HPC, crospovidone, calcium silicate, magnesium
stearate.
[0077] In particular, the formulation or blend of the present
invention does not comprise a reducing sugar, e.g glucose,
glyceraldehyde, lactose, arabinose and maltose.
[0078] In a further preference, the formulation or blend of the
present invention does not comprise PEG, stearic acid,
[0079] Where necessary, stabilizers may be added to increase or
decrease the pH. By modifying the pH, the composition may be
adapted to optimize the reduction of likelihood of a malliard
reaction, or other side reactions taking place. An example of a
stabilizer is citric acid.
[0080] In a preferred embodiment of the compositions of the present
invention are binary blends, i.e. a mixture of a compound
comprising a group of formula Y and one excipient as listed
herein.
[0081] A particular advantage of the stable binary blends as
disclosed herein is that they may be transported and stored prior
to final formulation, without forming degredation products. The
blends of the present invention, e.g. binary blends, therefore
provide a commercially viable option for storing the S1P modulator
as described herein in stable conditions.
[0082] Prior to the surprising findings of the present invention,
the instability of the compounds comprising a group Y would not
have been able to be safely stored, without the possibility of
impurities being formed. With the present invention, the skilled
person is now shown which excipients may be used with the S1P
modulators for storage and, most importantly, which excipients may
be used to reduce the risk of impurities contaminating a final drug
product, such impurities being formed by a malliard reaction.
Levels of Impurities Tolerated:
[0083] Compositions of the present invention, e.g. binary blends
and/or final dosage forms, are preferably free from impurities. It
will be understood that the level of impurities tolerated will be
judged using pharmaceutically acceptable standards.
[0084] However, it is also understood the pharmaceutical standards
may only apply to a final dosage form, i.e. the final product. The
present invention, in a preferred embodiment provides binary blends
containing an S1P receptor modulator as definated herein, i.e. a
compound comprising a group of formula Y, which are low, e.g. free,
of impurities. Preferably the binary blends of the present
invention meet the following criteria for level of impurities:
[0085] No more than 4.5 wt % of impurities and/or but no more than
2 wt % for an individual impurity. [0086] Preferably, impurities
are at 2 wt % or lower with no individual impurity being more than
0.5 wt %
[0087] The "wt %" measurements above are indicators of amount of
impurities tolerated. The term "wt %" means the percentage in
relation to the amount of the whole formulation, for example 4 wt %
means 4 mg in a 100 mg tablet.
Example of Impurity Tolerances, Using the Compound FTY720 as a
Reference
[0088] There are three qualified degradation products observed in a
dosage form: acetyl amide, palmitate amide and stearate amide.
[0089] The mechanism for the formation of these degradation
products is postulated to be due to a nucleophilic attack of the
primary amine of the FTY720 molecule at the carbonyl carbon of the
acetic, palmitic or stearic acid.
[0090] Based on tox qualification study, the three primary
degradation products, acetyl amide, palmitate amide and stearate
amide were qualified at levels of 4.6%, 4.5% and 4.8%,
respectively.
[0091] In order to adequately control the quality and efficacy of
the final dosage product each qualified degradation product was
assigned a specification of equal to or less than 2.0% of label
strength.
[0092] The specified degradation products were assigned a
specification of equal to or less than 1.0% of label strength.
[0093] The unspecified degradation products were assigned a
specification of equal to or less than 0.5% of label strength as
per the Novartis drug product purity policy.
[0094] The sum of all the degradation products above the limit of
quantitation (0.1% label strength) was set at equal or less than a
total of 4.5%.
FTY720: An Example of a Compound Comprising a Group of Formula
Y:
[0095] A chemical stability program using binary mixtures of FTY720
and excipients (1% drug substance was stored for 1 month in closed
vials at 50.degree. C.) was performed using FTY720 drug
substance.
[0096] General Method to Prepare Binary Mixtures:
1. 10 mg drug substance and 1000 mg excipient were filled into a
glass vial (=binary mixture). 2. The closed vials were stored for 1
month at 50.degree. C.
[0097] The analytical characterization was performed using gradient
HPLC with UV detection.
[0098] For the analysis, the stored samples were dissolved in 40 ml
of 0.0005N hydrochloric acid in isopropanol and stirred with a
magnetic stirrer for 30 minutes. This solution was centrifuged and
an aliquot of the clear supernatant was used as the test
solution.
[0099] The limit of quantitation (loq) of the method was 0.1%. The
rel. standard deviation S.sub.rel of the assay determinations was
2%.
TABLE-US-00001 Apparatus HPLC system with gradient capability,
autosampler and UV detector Column Waters Xterra .TM. MS C.sub.8
Length 50 mm, internal diameter 4.6 mm, particle size 2.5 .mu.m,
Part number 186000603. Chromatographic conditions Mobile phase A
100 mM NaClO.sub.4 buffer, pH 2.8:methanol = 93:7 (v/v) Mobile
phase B Acetonitrile Time [min.] Phase A [%] Phase B [%] Gradient
program 0 70 30 (linear) 1.0 70 30 15.0 58 42 28.0 5 95 30.0 5 95
30.1 70 30 35.0 70 30 Flow rate 1.5 ml/min Detection UV detection
at 215 nm Column temperature 30.degree. C. Auto-sampler Temperature
Ambient Injection volume 10 .mu.l Run time 35 min
[0100] The tables below provide a list of potentially feasible
excipients including the results of the stability program.
EXAMPLE 1
FTY720 Stability Test with Selected Fillers
TABLE-US-00002 [0101] Excipient Assay in % .SIGMA. impurities in %
Lactose anhydrous 101.4 0.0 Maize starch 102.2 0.0 Mannitol 102.3
0.0 Mannitol granulated (SD 200) 99.5 0.3 Avicel 97.9 0.2 Citric
acid + Mannitol (10 + 90) 102.4 0.0 Sodium hydrogen carbonate +
Mannitol 102.7 0.0 (10 + 90)
EXAMPLE 2
FTY720 Stability Test with Selected Binders
TABLE-US-00003 [0102] Excipient Assay in % .SIGMA. impurities in %
HPMC 3cPs 97.8 0.0 HP-Cellulose LH-22 99.8 0.4
EXAMPLE 3
FTY720 Stability Test with Selected Disintegrants
TABLE-US-00004 [0103] Excipient Assay in % .SIGMA. impurities in %
Maize starch 102.2 0.0 Crosscarmellose sodium 102.4 0.0 Sodium
carboxymethylstarch (Primojel) 103.2 0.0 Starch 1500 (Sta RX) 101.3
0.0
EXAMPLE 4
FTY720 Stability Test with Selected Lubricants
TABLE-US-00005 [0104] Excipient Assay in % .SIGMA. impurities in %
Hydrogenated ricinoleic oil (Cutina) 103.6 0.0 Mg stearate +
Manitol (1 + 99) 103.5 0.5
EXAMPLE 5
FTY720 Stability Test with Selected Flow Regulators
TABLE-US-00006 [0105] Excipient Assay in % .SIGMA. impurities in %
Aerosil 200 101.5 0.6
EXAMPLE 6
FTY720 Stability Test with Selected Matrix Formers
TABLE-US-00007 [0106] Excipient Assay in % .SIGMA. impurities in %
Hydroxypropyl methyl cellulose 97.8 0.0 Hydroxypropyl cellulose
99.8 0.4 Methyl cellulose -- -- Ethyl cellulose -- -- Pullulan --
-- Starch, e.g. Pure Cote 102.2 0.0 Povidone 95.4 0.5
[0107] Polymers having different molecular weights may be used in
the same formulation, e.g. having a low and a high molecular
weight, i.e. one can use a mixture of e.g. cellulose type polymers
having a low and a high MW to provide for different properties.
EXAMPLE 7
FTY720 Stability Test with Selected Plastisizers
TABLE-US-00008 [0108] Excipient Assay in % .SIGMA. impurities in %
PEG 400 -- -- Dibutyl sebacate -- -- Sorbitol -- --
EXAMPLE 8
FTY720 Stability Test with Selected Flavoring Agents
TABLE-US-00009 [0109] Excipient Assay in % .SIGMA. impurities in %
Menthol -- -- Tutti frutti
EXAMPLE 9
FTY720 Stability Test with Selected Sweeteners
TABLE-US-00010 [0110] Excipient Assay in % .SIGMA. impurities in %
Sucralose -- -- Sodium saccharine -- --
EXAMPLE 10
Non-Feasible Excipients
[0111] An example of a non-feasible excipient is shown below. The
method to prepare the binary mixtures and the analytical
characterization are the same as describe before.
TABLE-US-00011 Excipient Assay in % .SIGMA. impurities in %
Glycerylbehenat 96.2 >2 (Compritol)
EXAMPLE 10
S1P Assays
[0112] The binding affinity of S1P receptor modulators to
individual human S1P receptors may be determined in following
assay:
[0113] S1P receptor modulator activities of compounds are tested on
the human S1P receptors S1P.sub.1, S1P.sub.2, S1P.sub.3, S1P.sub.4
and S1P.sub.5. Functional receptor activation is assessed by
quantifying compound induced GTP [.gamma.-.sup.35S] binding to
membrane protein prepared from transfected CHO or RH7777 cells
stably expressing the appropriate human S1P receptor. The assay
technology used is SPA (scintillation proximity based assay).
Briefly, DMSO dissolved compounds are serially diluted and added to
SPA-bead (Amersham-Pharmacia) immobilised S1P receptor expressing
membrane protein (10-20 .mu.g/well) in the presence of 50 mM Hepes,
100 mM NaCl, 10 mM MgCl.sub.2, 10 .mu.M GDP, 0.1% fat free BSA and
0.2 nM GTP [.gamma.-.sup.35S](1200 Ci/mmol). After incubation in 96
well microtiterplates at RT for 120 min, unbound GTP
[.gamma.-.sup.35S] is separated by a centrifugation step.
Luminescence of SPA beads triggered by membrane bound GTP
[.gamma.-.sup.35S] is quantified with a TOPcount plate reader
(Packard). EC.sub.50s are calculated using standard curve fitting
software. In this assay, the S1P receptor modulators preferably
have a binding affinity to S1P receptor <50 nM.
[0114] Preferred S1P receptor modulators are e.g. compounds which
in addition to their S1P binding properties also have accelerating
lymphocyte homing properties, e.g. compounds which elicit a
lymphopenia resulting from a re-distribution, preferably
reversible, of lymphocytes from circulation to secondary lymphatic
tissue, without evoking a generalized immunosuppression. 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).
[0115] The lymphocyte homing property may be measured in following
Blood Lymphocyte Depletion assay:
[0116] A S1P receptor modulator or the vehicle is administered
orally by gavage to rats. Tail blood for hematological monitoring
is obtained on day -1 to give the baseline individual values, and
at 2, 6, 24, 48 and 72 hours after application. In this assay, the
S1P receptor agonist or modulator depletes peripheral blood
lymphocytes, e.g. by 50%, when administered at a dose of e.g.
<20 mg/kg.
Final Product Manufacture:
[0117] The manufacture of final pharmaceutical products may be
carried out using conventional techniques. Examples of such
techniques are described below, by way of example.
Compressed Tablets
[0118] Compressed tablets are exerted to great pressure in order to
compact the material. If a sufficiently homogeneous mix of
components cannot be obtained with simple mixing, the ingredients
must be granulated prior to compression to ensure an even
distribution of the active compound in the final tablet. Two basic
techniques are used to prepare powders for granulation into a
tablet: wet granulation and dry granulation.
[0119] Powders that can be mixed well and therefore do not require
granulation can be compressed in to a tablet through a technique
called Direct Compression.
Lyophilised Tablets
[0120] These tablets may be manufactured by way of creating a
suspension containing the active ingredient and other excipients,
for example Gelatin in an amount, for example, of about 3 wt %,
structure forming agents, such as mannitol or sorbitol, for example
and in an amount, for example, of about 1.5 wt %, sweeteners and
flavouring agents.
[0121] An example of a lyophilised tablet formulation is provided
below:
[0122] The Gelatin/Mannitol solution is cooled to 23.degree. C. and
mixed with the active substance. The total solid content is
preferably less than 50%. The suspension is then cooled to
15.degree. C. to prevent sedimentation of the suspension before the
start of lyophilisation.
Thin Films
[0123] The compositions of the present invention may be further
mixed with additional excipients to form final products. The final
products may be made from the binary compositions using standard
techniques, such as the ones below:
[0124] Possible manufacturing comprises casting, drawing, extrusion
or coating/lamination processes:
[0125] Casting is a manufacturing process by which the
drug/excipient mixture is introduced into a mold, allowed to
solidify within the mold, and then ejected or broken out to make
the individual thin film.
[0126] Drawing produces a roll by pulling on a molten
drug/excipient mixture until it increases in length. This is
typically accompanied by a thinning out of the material. The single
units are then cut or punched out of these roles and packed, e.g.
into pouches.
[0127] Extrusion creates rolls by pushing and/or drawing through a
die of the desired profile shape. Extrusion may be continuous
(producing indefinitely long material) or semi-continuous
(producing many short pieces). The single units are then cut or
punched out of these roles and packed, e.g. into pouches.
[0128] Coating/lamination could be described as manufacturing a
laminate first by coating and lamination. The resulting roll is
then splitted into smaller rolls. The single units are then cut or
punched out of these roles and packed, e.g. into pouches.
[0129] According to the invention, the compositions of the present
invention, e.g. the final dosage form, are useful for:
a) treatment and prevention of organ or tissue transplant
rejection, for example for the treatment of the recipients of
heart, lung, combined heart-lung, liver, kidney, pancreatic, skin
or corneal transplants, and the prevention of graft-versus-host
disease, such as sometimes occurs following bone marrow
transplantation; particularly in the treatment of acute or chronic
allo- and xenograft rejection or in the transplantation of insulin
producing cells, e.g. pancreatic islet cells; b) treatment and
prevention of 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. d)
treatment and prevention of cancer, e.g. solid tumors, carcinoma,
e.g. for preventing metastatic spread of tumours or for preventing
or inhibiting growth of micrometastasis
[0130] By "solid tumors" are meant tumors and/or metastasis
(whereever located) other than lymphatic cancer, e.g. brain and
other central nervous system tumors (eg. tumors of the meninges,
brain, spinal cord, cranial nerves and other parts of central
nervous system, e.g. glioblastomas or medulla blastomas); head
and/or neck cancer; breast tumors; circulatory system tumors (e.g.
heart, mediastinum and pleura, and other intrathoracic organs,
vascular tumors and tumor-associated vascular tissue); excretory
system tumors (e.g. kidney, renal pelvis, ureter, bladder, other
and unspecified urinary organs); gastrointestinal tract tumors
(e.g. oesophagus, stomach, small intestine, colon, colorectal,
rectosigmoid junction, rectum, anus and anal canal), tumors
involving the liver and intrahepatic bile ducts, gall bladder,
other and unspecified parts of biliary tract, pancreas, other and
digestive organs); oral cavity (lip, tongue, gum, floor of mouth,
palate, and other parts of mouth, parotid gland, and other parts of
the salivary glands, tonsil, oropharynx, nasopharynx, pyriform
sinus, hypopharynx, and other sites in the lip, oral cavity and
pharynx); reproductive system tumors (e.g. vulva, vagina, Cervix
uteri, Corpus uteri, uterus, ovary, and other sites associated with
female genital organs, placenta, penis, prostate, testis, and other
sites associated with male genital organs); respiratory tract
tumors (e.g. nasal cavity and middle ear, accessory sinuses,
larynx, trachea, bronchus and lung, e.g. small cell lung cancer or
non-small cell lung cancer); skeletal system tumors (e.g. bone and
articular cartilage of limbs, bone articular cartilage and other
sites); skin tumors (e.g. malignant melanoma of the skin,
non-melanoma skin cancer, basal cell carcinoma of skin, squamous
cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); and tumors
involving other tissues including peripheral nerves and autonomic
nervous system, connective and soft tissue, retroperitoneum and
peritoneum, eye and adnexa, thyroid, adrenal gland and other
endocrine glands and related structures, secondary and unspecified
malignant neoplasm of lymph nodes, secondary malignant neoplasm of
respiratory and digestive systems and secondary malignant neoplasm
of other sites.
[0131] Where hereinbefore and subsequently a tumor, a tumor
disease, a carcinoma or a cancer is mentioned, also metastasis in
the original organ or tissue and/or in any other location are
implied alternatively or in addition, whatever the location of the
tumor and/or metastasis is.
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