U.S. patent application number 14/027943 was filed with the patent office on 2014-01-09 for organic compounds.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Tomoyuki Oomura, Madhusudhan Pudipeddi, Alan Edward Royce, Colleen Ruegger, Masaki Sasaki, Tokuhiro Tamura. Invention is credited to Tomoyuki Oomura, Madhusudhan Pudipeddi, Alan Edward Royce, Colleen Ruegger, Masaki Sasaki, Tokuhiro Tamura.
Application Number | 20140011885 14/027943 |
Document ID | / |
Family ID | 32326722 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140011885 |
Kind Code |
A1 |
Oomura; Tomoyuki ; et
al. |
January 9, 2014 |
Organic Compounds
Abstract
A solid pharmaceutical composition suitable for oral
administration, comprising: (a) S 1 P receptor agonist; and (b) a
sugar alcohol.
Inventors: |
Oomura; Tomoyuki; (Oita,
JP) ; Pudipeddi; Madhusudhan; (Edison, NJ) ;
Ruegger; Colleen; (Morris Plains, NJ) ; Royce; Alan
Edward; (Saylorsburg, PA) ; Sasaki; Masaki;
(Oita, JP) ; Tamura; Tokuhiro; (Fukuoka,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oomura; Tomoyuki
Pudipeddi; Madhusudhan
Ruegger; Colleen
Royce; Alan Edward
Sasaki; Masaki
Tamura; Tokuhiro |
Oita
Edison
Morris Plains
Saylorsburg
Oita
Fukuoka |
NJ
NJ
PA |
JP
US
US
US
JP
JP |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
32326722 |
Appl. No.: |
14/027943 |
Filed: |
September 16, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12987726 |
Jan 10, 2011 |
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14027943 |
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12191098 |
Aug 13, 2008 |
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12987726 |
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10552005 |
Nov 14, 2005 |
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PCT/EP04/03656 |
Apr 6, 2004 |
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12191098 |
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60461215 |
Apr 8, 2003 |
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Current U.S.
Class: |
514/653 |
Current CPC
Class: |
A61K 31/135 20130101;
A61K 31/138 20130101; A61P 9/00 20180101; A61K 9/2054 20130101;
A61K 31/137 20130101; A61K 9/4866 20130101; A61P 25/28 20180101;
A61P 37/00 20180101; A61K 47/26 20130101; A61K 45/06 20130101; A61P
37/06 20180101; A61P 31/12 20180101; A61K 9/0053 20130101; A61K
9/2013 20130101; A61P 41/00 20180101; A61P 31/00 20180101; A61K
47/10 20130101; A61P 43/00 20180101; A61P 29/00 20180101; A61K
9/2018 20130101; A61K 9/4858 20130101; A61P 37/02 20180101; A61P
25/00 20180101; A61K 31/145 20130101; A61K 31/135 20130101; A61K
2300/00 20130101; A61K 31/137 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/653 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 9/48 20060101 A61K009/48; A61K 9/20 20060101
A61K009/20 |
Claims
1. A process for producing a pharmaceutical composition in form of
a solid formulation suitable for oral administration, comprising:
(a) mixing an S1P receptor agonist with a sugar alcohol which is
selected from the group consisting of mannitol, maltitol, inositol,
xylitol, or lactitol; (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, wherein the S1P receptor
agonist is selected from
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a
pharmaceutically acceptable salt thereof, and the phosphate of
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol which has the
formula ##STR00018## in which R.sub.2a is H, R.sub.3a is OH,
X.sub.a is O, and R.sub.1a and R.sub.1b are OH.
2. Process according to claim 1 wherein step (a) comprise the step
of forming a pre-mix by mixing the total amount of S1P receptor
agonist with part of the sugar alcohol.
3. Process according to claim 2 wherein the pre-mix formed in step
(a) comprises from 5 to 25% by weight of the total weight of the
sugar alcohol.
4. Process according to claim 1, wherein the S1P receptor agonist
is micronized and/or pre-screened before step (a).
5. Process according to claim 1, wherein the mixing step (a)
comprises blending the S1P receptor agonist and the sugar alcohol
in a suitable blender or mixer.
6. Process according to claim 5 wherein the blending of the S1P
receptor agonist and the sugar alcohol is performed for a total of
100 to 400 revolutions.
7. Process according to claim 1, wherein the components are dry
mixed.
8. Process according to claim 7, wherein the milling step (b)
comprises passing the mixture obtained in (a) through a screen.
9. Process according to claim 1, wherein step (a) further comprises
the step of adding a binder solution to the mixture.
10. Process according to claim 1, wherein step (a) further
comprises the step of adding a binder to the mix dry and water is
added in the granulation step.
11. Process according to claim 1, wherein the milled mixture
obtained in (b) is blended before mixing with the lubricant.
12. Process according to claim 1, wherein the lubricant is
pre-screened before mixing.
13. Process according to claim 1, wherein an additional amount of
binder is added in step (c) to the mixture obtained in (b).
14. Process according to claim 1, wherein steps (a) and (b)
comprise the following steps: within step (a) i) the S1P receptor
agonist is dry-mixed with the sugar alcohol, ii) the obtained sugar
alcohol/S1P receptor agonist mixture is dry-mixed with a binder,
iii) water is added, and, within step (b), iv) the mixture is
granulated, and v) the granulation is dried and milled.
15. Process according to claim 1, wherein the composition contains
0.01 to 20% by weight of S1P receptor agonist, based on the total
weight of the composition.
16. Process according to claim 1, wherein the composition contains
75 to 99.99% by weight of the sugar alcohol, based on the total
weight of the composition.
17. Process according to claim 1, wherein the S1P receptor agonist
is selected from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
and a pharmaceutically acceptable salt thereof.
18. Process according to claim 1, wherein the S1P receptor agonist
is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, or the
hydrochloride salt thereof.
19. Process according to claim 1, wherein the sugar alcohol is
mannitol.
20. Process according to claim 1, wherein the sugar alcohol is
D-mannitol.
21. Process according to claim 18 wherein the sugar alcohol is
D-mannitol
22. Process according to claim 1, wherein the sugar alcohol is a
mixture of mannitol and xylitol.
Description
[0001] The present invention relates to pharmaceutical compositions
comprising a sphingosine-1 phosphate receptor agonist.
Sphingosine-1 phosphate (hereinafter "S1P") is a natural serum
lipid. Presently there are 8 known S1P receptors, namely S1P1 to
S1P8. S1P receptor agonists have accelerating lymphocyte homing
properties.
[0002] S1P 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-cells from the blood are
stimulated to migrate into lymph nodes (LN) and Peyer's patches
(PP), and thus infiltration of cells into transplanted organs is
inhibited.
[0003] The various known S1P receptor agonist show structural
similarities, which result in related problems in providing a
suitable formulation. In particular, there is a need for an S1P
receptor agonist containing formulation which is well-adapted for
oral administration in a solid form, e.g. as a tablet or
capsule.
[0004] Accordingly, the present invention provides a solid
pharmaceutical composition suitable for oral administration,
comprising a S1P receptor agonist and a sugar alcohol.
[0005] It has surprisingly been found that solid compositions
comprising a sugar alcohol provide formulations which are
particularly well suited to the oral administration of S1P receptor
agonists. The compositions provide a convenient means of systemic
administration of S1P receptor agonists, do not suffer from the
disadvantages of liquid formulations for injection or oral use, and
have good physiochemical and storage properties. In particular, the
compostions 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.
[0006] S1P 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: [0007] Compounds as disclosed in EP627406A1, e.g. a
compound of formula I
##STR00001##
[0007] wherein R.sub.1 is a straight- or branched
(C.sub.12-22)carbon chain [0008] 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, alkyl, aralkyl, acyl or
alkoxycarbonyl, and carbonyl, and/or [0009] which may have as a
substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl,
alkylamino, alkylthio, acylamino, alkoxycarbonyl,
alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen,
amino, hydroxylmino, hydroxy or carboxy; or
R.sub.1 is
[0009] [0010] a phenylalkyl wherein alkyl is a straight- or
branched (C.sub.6-20)carbon chain; or [0011] a phenylalkyl wherein
alkyl is a straight- or branched (C.sub.1-30)carbon chain wherein
said phenylalkyl is substituted by [0012] a straight- or branched
(C.sub.6-20)carbon chain optionally substituted by halogen, [0013]
a straight- or branched (C.sub.6-20)alkoxy chain optionally
substituted by halogen, [0014] a straight- or branched
(C.sub.6-20)alkenyloxy, [0015] phenylalkoxy, halophenylalkoxy,
phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, [0016]
cycloalkylalkyl substituted by C.sub.6-20alkyl, [0017]
heteroarylalkyl substituted by C.sub.6-20alkyl, [0018] heterocyclic
C.sub.6-20alkyl or [0019] heterocyclic alkyl substituted by
C.sub.2-20alkyl, and wherein the alkyl moiety may have [0020] 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 [0021] as a substituent alkoxy,
alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,
alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each
of R.sub.2, R.sub.3, R.sub.4 and R.sub.6, independently, is H,
C.sub.1-4 alkyl or acyl or a pharmaceutically acceptable salt
thereof; [0022] Compounds as disclosed in EP 1002792A1, e.g. a
compound of formula II
##STR00002##
[0022] 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, alkyl or acyl, or a
pharmaceutically acceptable salt thereof; [0023] Compounds as
disclosed in EP0778263 A1, e.g. a compound of formula III
##STR00003##
[0023] 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.1-6
alkyl, 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.11, R.sub.12, R.sub.13 and R.sub.14, independently, is H,
C.sub.1-4alkyl or acyl, or a pharmaceutically acceptable salt
thereof, [0024] Compounds as disclosed in WO02/18395, e.g. a
compound of formula IVa or IVb
##STR00004##
[0024] 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.1-4alkyl 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
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--, --C(O)--, --CH(OH)--, --C(.dbd.NOH)--,
O or S, and R.sub.48 is (C.sub.4-14)alkyl or (C.sub.4-14)alkenyl;
or a pharmaceutically acceptable salt or hydrate thereof; [0025]
Compounds as disclosed in WO 02/076995, e.g. a compound of formula
V
##STR00005##
[0025] wherein [0026] m.sub.c is 1, 2 or 3; [0027] X.sub.c is O or
a direct bond; [0028] R.sub.1c is H; C.sub.1-6 alkyl optionally
substituted by OH, acyl, halogen, C.sub.3-10cycloalkyl, phenyl or
hydroxy-phenylene; C.sub.2-6alkenyl; C.sub.2-6alkynyl: or phenyl
optionally substituted by OH; [0029] R.sub.2c is
[0029] ##STR00006## [0030] wherein R.sub.5c is H or C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 halogen atoms, and R.sub.6c is
H or C.sub.1-4alkyl optionally substituted by halogen; each of
R.sub.3c and R.sub.4c, independently, is H, C.sub.1-4alkyl
optionally substituted by halogen, or acyl, and [0031] R.sub.c is
C.sub.13-20alkyl 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)
[0031] ##STR00007## [0032] wherein R.sub.7c is H, C.sub.1-4alkyl or
C.sub.1-4alkoxy, and R.sub.8c is substituted C.sub.1-20alkanoyl,
phenylC.sub.1-14alkyl wherein the C.sub.1-14alkyl is optionally
substituted by halogen or OH, cycloalkylC.sub.1-14alkoxy or
phenylC.sub.1-14alkoxy wherein the cycloalkyl or phenyl ring is
optionally substituted by halogen, C.sub.1-4alkyl and/or
C.sub.1-4alkoxy, phenylC.sub.1-14alkoxy-C.sub.1-14alkyl,
phenoxyC.sub.1-14alkoxy or phenoxyC.sub.1-14alkyl, [0033] R.sub.c
being also a residue of formula (a) wherein R.sub.8c is
C.sub.1-14alkoxy when R.sub.1c is C.sub.1-4alkyl, C.sub.2-6alkenyl
or C.sub.2-6alkynyl, or a compound of formula VI
##STR00008##
[0033] wherein [0034] n is 2, 3 or 4 [0035] R.sub.1x is H;
C.sub.1-6alkyl optionally substituted by OH, acyl, halogen,
cycloalkyl, phenyl or hydroxy-phenylene; C.sub.2-6alkenyl;
C.sub.2-6alkynyl; or phenyl optionally substituted by OH; [0036]
R.sub.2x is H, C.sub.1-4 alkyl or acyl [0037] each of R.sub.3x and
R.sub.4x, independently is H, C.sub.1-4alkyl optionally substituted
by halogen or acyl, [0038] R.sub.5x is H, C.sub.1-4alkyl or
C.sub.1-4alkoxy, and [0039] R.sub.6x is C.sub.1-20 alkanoyl
substituted by cycloalkyl; cyloalkylC.sub.1-14alkoxy wherein the
cycloalkyl ring is optionally substituted by halogen,
C.sub.1-4alkyl and/or C.sub.1-4alkoxy; phenylC.sub.1-14alkoxy
wherein the phenyl ring is optionally substituted by halogen,
C.sub.1-4alkyl and/or C.sub.1-4alkoxy, [0040] R.sub.6x being also
C.sub.4-14alkoxy when R.sub.1x is C.sub.2-4alkyl substituted by OH,
or pentyloxy or hexyloxy when R.sub.1x is C.sub.1-4alkyl, provided
that R.sub.6x is other than phenyl-butylenoxy when either R.sub.5x
is H or R.sub.1x is methyl, or a pharmaceutically acceptable salt
thereof; [0041] Compounds as disclosed in WO02/06268AI, e.g. a
compound of formula VII
##STR00009##
[0041] 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
##STR00010##
R.sub.4d is lower alkyl; n.sub.d is an integer of 1 to 6;
[0042] 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 substitutents 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 substitutents 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, 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 R.sub.6d and R.sub.7d, independently,
is H or a substituent 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-lower alkylamino, lower aliphatic
acylamino, cyano or nitro; and <group b> is cycloalkyl, aryl,
heterocycle, 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 group exclusive of single bond
and linear C.sub.1-10 alkylene, or a pharmacologically acceptable
salt or ester thereof; [0043] Compounds as disclosed in JP-14316985
(JP2002316985), e.g. a compound of formula VIII:
##STR00011##
[0043] 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-1431595; or a pharmacologically acceptable salt or ester
thereof; [0044] Compounds as disclosed in WO 03/29184 and WO
03/29205, e.g. compounds of formula IX
##STR00012##
[0044] wherein X.sub.f is O or S, and R.sub.1f, R.sub.2f, R.sub.3f
and n.sub.f are as disclosed in WO 03/29184 and 03/29205, each of
R.sub.4f and R.sub.5f, independently is H or a residue of
formula
##STR00013##
wherein each of R.sub.8f and R.sub.9f, independently, is H or
C.sub.1-4alkyl optionally substituted by halogen; e.g.
2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-dol
or
2-amino-2-[4-(benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-propane-d-
iol, or a pharmacological salt thereof. [0045] Compounds as
disclosed in WO03/062252A1, e.g. a compound of formula X
##STR00014##
[0045] wherein Ar is phenyl or naphthyl; each of mg and ng
independently is 0 or 1; A is selected from COOH, PO3H2, PO2H,
SO3H, PO(C1-3alkyl)OH 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 optionally
substituted by halogen or OH; each R4g Independently 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 WO03/062252A1; [0046] Compounds as disclosed in WO
03/062248A2, e.g. a compound of formula XI
##STR00015##
[0046] 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 or phenyl 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.
[0047] According to a further embodiment of the Invention, a S1P
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 S1P1 receptor over the S1P3 receptor of at
least 20 fold, e.g. 100, 500, 100) 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-GTP.gamma.S binding assay, said
compound having an EC50 for binding to the S1P1 receptor of 100 nM
or less as evaluated by the 35S-GTP.gamma.S 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
##STR00016##
[0048] 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.
[0049] Acyl may be a residue R.sub.y--CO-- wherein R.sub.y is
C.sub.1-6alkyl, C.sub.3-6cycloacyl, phenyl or
phenyl-C.sub.1-4alkyl. Unless otherwise stated, alkyl, alkoxy,
alkenyl or alkynyl may be straight or branched.
[0050] 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.
[0051] 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.1-4alkyl 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 pare, preferably
in para.
[0052] Preferably each of R.sub.2 to R.sub.5 is H.
[0053] A preferred compound of formula I is
2-amino-2-tetradecyl-1,3-propanedlol. A particularly preferred S1P
receptor agonist of formula I 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 V is phosphoric acid
mono-[(R)-2-amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]ester.
[0058] A preferred compound of formula VIII is
(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbuta-
n-1-ol.
[0059] 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.
[0060] Examples of pharmaceutically acceptable salts of the
compounds 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, 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 present invention encompass hydrate and solvate forms.
[0061] Binding to S1P receptors can be determined according to the
following assays.
A. Binding Affinity of S1P Receptor Agonists to Individual Human
S1P Receptors
[0062] Transient Transfection of Human S1P Receptors into HEK293
Cells
[0063] S1P receptors and G.sub.i proteins are cloned, and equal
amounts of 4 cDNAs for the EDG receptor, G.sub.i-.alpha.,
G.sub.i-.beta. and G.sub.i-.gamma. 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 containing
25 .mu.g of DNA and 0.25 M CaCl.sub.2 is added to HEPES-buffered 2
mM Na.sub.2HPO.sub.4. Subconfluent 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 refed media (90% 1:1 Dulbecco'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 MgCl.sub.2, 1 EDTA, pH 7.4)
containing 10% sucrose on ice, and disrupted using a Dounce
homogenizer. After centrifugation at 800.times.g, the supernatant
is diluted with HME without sucrose and centrifuged at
100,000.times.g for 1 h. The resulting pellet is rehomogenized and
centrifuged a second hour at 100,000.times.g. This crude membrane
pellet is resuspended in HME with sucrose, aliquoted, and
snap-frozen by immersion in liquid nitrogen. The membranes are
stored at 70.degree. C. Protein concentration is determined
spectroscopically by Bradford protein assay.
GTP.gamma.S Binding Assay Using S1P Receptor/HEK293 Membrane
Preparations
[0064] GTP.gamma.S binding experiments are performed as described
by DS. Im et al., Mol. Pharmacol. 2000; 57:753. Ligand-mediated
GTP.gamma.S binding to G-proteins is measured in GTP binding buffer
(in mM: 50 HEPES, 100 NaCl, 10 MgCl.sub.2, pH 7.5) using 25 .mu.g
of a membrane preparation from transiently transfected HEK293
cells. Ligand is added to membranes in the presence of 10 .mu.M GDP
and 0.1 nM [.sup.35S]GTP.gamma.S (1200 Ci/mmol) and incubated at
30.degree. C. for 30 min. Bound GTP.gamma.S is separated from
unbound using the Brandel harvester (Gaithersburg, Md.) and counted
with a liquid scintillation counter.
[0065] 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.
[0066] The sugar alcohol may act as a diluent, carrier, filler or
bulking agent, and may suitably be mannitol, maltitol, inositol,
xylitol 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 xylitol, e.g. in a ratio of 1:1 to 4:1.
[0067] 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 S1P 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 .mu.m or less, has also been
found to improve compressibility and hardness of tablets formed
from the composition.
[0068] Preferably the single point surface area of the sugar
alcohol preparation, e.g. mannitol, is 1 to 7 m.sup.2/g, e.g. 2 to
6 m.sup.2/g or 3 to 5 m.sup.2/g. The mannitol preparation may
suitably have a mean particle size of 100 to 300 .mu.m, e.g. 150 to
250 .mu.m 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 commercially from E. Merck.
[0069] 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.
[0070] The composition preferably further comprises a lubricant.
Suitable lubricants include stearic add, magnesium stearate,
calcium stearate, zinc stearate, glyceryl palmitostearate, sodium
stearyl fumarate, canola oil, hydrogenated vegetable oil such as
hydrogenated castor oil (e.g. Cutina.RTM. or Lubriwax.RTM. 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 lubricant.
[0071] 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.
[0072] 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.
Avicel.RTM.), methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, 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,
methylcellulose, 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 methylcellulose are
particularly preferred where a high tablet hardness and/or longer
disintegration time is required. Hydroxypropyl cellulose is
preferred where faster distintegration is required. Where
appropriate, xylitol may also be added as an additional binder, for
example in addition to microcrystalline cellulose, e.g. In an
amount up to 20% by weight of the sugar alcohol, e.g. xylitol.
[0073] In one embodiment, the composition further comprises a
stabiliser, 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.
[0074] 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.
[0075] 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
hydroxypropylmethylcellulose coating.
[0076] 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.
[0077] 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.degree., 40.degree. or 60.degree. C.
[0078] The pharmaceutical compositions of the present invention may
be produced by standard processes, for instance by conventional
mixing, granulating, sugar-coating, dissolving or lyophilizing
processes. Procedures which may be used are known in the art, e.g.
those described in L. Lachman et al. The Theory and Practice of
Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische
Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen
Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's
Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later
editions.
[0079] 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.
[0080] 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.
[0081] The S1P receptor agonist, e.g.
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride,
may optionally be micronized, and/or pre-screened, e.g. with a 400
to 500 .mu.m 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.
[0082] 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 .mu.m. Process step (a)
may comprise the step of mixing the total amount of S1P 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. methylcellulose 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.
[0083] 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 .mu.m screen, before mixing.
[0084] Alternatively, a wet granulation process is employed. In
this embodiment, the S1P 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.
[0085] If desirable, an additional amount of binder may be added in
step (c) to the mixture obtained in (b).
[0086] 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 carotinoids, iron
oxides, and chlorophyll. Preferably, the capsules of the invention
are marked using a code.
[0087] 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
U.S. Pat. No. 5,604,229, WO 97/24112, WO 01/01978, U.S. Pat. No.
6,004,565, U.S. Pat. No. 6,274,629 and JP-14316985, the contents of
which are incorporated herein by reference.
[0088] In particular, the pharmaceutical compositions are useful
for:
a) treatment and prevention of organ or tissue transplant
rejection, for example for the treatment of the recipients of
heart, lung, combined heart-lung, liver, kidney, pancreatic, skin
or corneal transplants, and the prevention of graft-versus-host
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 myocarditis, including hepatitis and AIDS.
[0089] 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.
[0090] The invention will now be described with reference to the
following specific embodiments.
EXAMPLE 1
[0091] 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 (Parteck M200 from E. Merck). The
mixture is then milled in a Frewitt 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.
[0092] The product composition is then compacted on a tablet press
using a 7 mm die to form 120 mg tablets, each containing:
TABLE-US-00001 Compound A, e.g. FTY720* 1.4 mg Mannitol M200 116.2
mg Magnesium stearate 2.4 mg Total 120 mg *1 mg of Compound A in
free form is equivalent to 1.12 mg of FTY720.
EXAMPLE 2
[0093] In a further example, the process of example 1 is repeated
except that the magnesium stearate is replaced by Cutina.RTM.
(hydrogenated castor oil).
EXAMPLE 3
[0094] 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.
[0095] 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.degree. C. for 150 minutes.
[0096] 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 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.
[0097] The product composition is then filled into size 3 hard
gelatin shells on an Hoflinger & Karg 400 encapsulation device.
120 mg of the product composition is added to each capsule.
Therefore each capsule contains:
TABLE-US-00002 FTY720 * 0.56 mg Mannitol M200 114.04 mg
Hydroxypropylcellulose 3.6 mg Magnesium stearate 1.8 mg Total 120
mg
EXAMPLE 4
[0098] In a further example, the process of example 3 is repeated
except that the magnesium stearate is replaced by Cutina.RTM.
(hydrogenated castor oil).
EXAMPLE 5
[0099] In a further example, the process of example 3 is repeated
except that the hydroxypropyl cellulose is replaced by
hydroxypropylmethyl cellulose.
EXAMPLE 6A
[0100] Micronized Compound A, e.g. FTY720, is screened using a 400
.mu.m (40 mesh) screen. 58.35 g of the screened compound is mixed
with 4841.65 g mannitol (Parteck M200 from E. Merck) in a 25 L
Bohle bin blender for 240 blending revolutions. The mixture is then
milled in a Frewitt MGI device using a 400 .mu.m 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.
[0101] The product composition is then filed into size 3 hard
gelatin shells on an Hoflinger & Karg 400 encapsulation device.
120 mg of the product composition is added to each capsule.
Therefore each capsule contains:
TABLE-US-00003 FTY720 * 1.4 mg Mannitol M200 116.2 mg Magnesium
stearate 2.4 mg Total 120 mg
EXAMPLE 6B
[0102] 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
[0103] In further examples, capsules are prepared as described in
example 6, except that each capsule contains each component in the
following amounts:
TABLE-US-00004 Example 7 Example 8 FTY720 * 2.8 mg 5.6 mg Mannitol
M200 114.8 mg 112 mg Magnesium stearate 2.4 mg 2.4 mg Total 120 mg
120 mg
EXAMPLES 9 TO 11
[0104] 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.RTM. (hydrogenated castor oil).
EXAMPLES 12 TO 22
[0105] 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
[0106] Capsules containing the following ingredients are prepared,
by weighing each component and mixing in a mortar, then filling
into capsules:
TABLE-US-00005 Example 23 Example 24 FTY720 5 mg 1 mg D-mannitol
83.7 mg 117 mg Corn starch 24 mg -- Avicel .RTM. PH101 12 mg --
Hydroxypropylcellulose 0.3 mg 7 mg Talc 3 mg 3 mg Lubri wax
.RTM.101 2 mg 2 mg Total 130 mg 130 mg
EXAMPLES 25 TO 27
[0107] Pharmaceutical compositions containing the following
ingredients are produced:
TABLE-US-00006 Example 25 Example 26 Example 27 FTY720 5 g 10 g 100
g D-mannitol 991 g 986 g 897 g Methylcellulose SM-25 4 g 4 g 3 g
Total 1000 g 1000 g 1000 g
[0108] The FTY720 and a proportion of the D-mannitol equal to twice
the weight of the FTY720 are mixed in a Microspeed 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% methylcellulose 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.degree. C. by a
fluidized-bed granulator 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 Zuma capsule-filling machine (100 mg per
capsule).
EXAMPLES 28 TO 31
[0109] Tablets containing the following ingredients (in mg) are
produced:
TABLE-US-00007 Example Example 28 Example 29 Example 30 31 FTY720 1
1 1 1 D-mannitol 62.3 62.3 62.0 62.0 Xylitol* 26.7 (5.4) 26.7 (5.4)
26.6 26.6 Methylcellulose -- -- 0.4 0.4 Microcrystalline 24.0 --
24.0 -- cellulose Low-substituted -- 24.0 -- 24.0 Hydroxypropyl-
cellulose Hydrogenated oil 6.0 6.0 6.0 6.0 Total 120.0 120.0 120.0
120.0 *The amount of xylitol indicated in brackets was used as a
binder.
[0110] FTY720, D-mannitol and xylitol are placed in a fluid-bed
granulator (MP-01 model, Powrex), mixed for five minutes, and
granulated under spray of binder solution, followed by drying till
the exhaust temperature reaches 40.degree. 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.
[0111] The resulting powder is compressed by a tabletting machine
(Cleanpress correct 12 HUK, Kikushui Seisakusho) with a punch of 7
mm i.d..times.7.5 mm R at a compression force of 9800 N.
Granulation Conditions:
TABLE-US-00008 [0112] Item Setting Charge-in amount 1170 g Volume
of intake-air 50 m.sup.3/min Temperature of intake-air 75.degree.
C. Flow rate of spray solution 15 mL/min Spray air pressure 15
N/cm.sup.2 Spray air volume 30 L/min Volume of binder solution 351
mL
EXAMPLES 32 TO 39
[0113] Tablets containing the following ingredients (in mg) are
produced:
TABLE-US-00009 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. 32 33 34 35 36 37 38
39 FTY720 1 1 1 1 1 1 1 1 D-mannitol 116.6 114.2 104.6 114.2 104.6
116.6 115.4 113 magnesium 2.4 2.4 2.4 2.4 2.4 -- -- -- stearate
glycine HCl -- 2.4 12 -- -- -- -- -- sodium -- -- -- 2.4 12 -- --
-- bicarbonate zinc -- -- -- -- -- 2.4 -- -- stearate silicone
fluid -- -- -- -- -- -- 3.6 -- mineral oil -- -- -- -- -- -- -- 6
Total 120.0 120.0 120.0 120.0 120.0 120.0 120.0 120.0
* * * * *