U.S. patent application number 10/512171 was filed with the patent office on 2005-12-01 for high drug load tablet.
Invention is credited to Bianchi, Jean-Claude, Kalb, Oskar, Luftensteiner, Christian-Peter, Ogorka, Jorg.
Application Number | 20050267125 10/512171 |
Document ID | / |
Family ID | 9935351 |
Filed Date | 2005-12-01 |
United States Patent
Application |
20050267125 |
Kind Code |
A1 |
Luftensteiner, Christian-Peter ;
et al. |
December 1, 2005 |
High drug load tablet
Abstract
The present invention pertains to a high drug load tablet
comprising as active ingredient Compound I of formula 1 or a
pharmaceutically acceptable salt thereof in an amount from about
30% to 80% in weight of the active moiety based on the total weight
of the tablet.
Inventors: |
Luftensteiner, Christian-Peter;
(Weil am Rhein, DE) ; Bianchi, Jean-Claude;
(Blotzheim, DE) ; Ogorka, Jorg; (Steinen, DE)
; Kalb, Oskar; (Lorrach, DE) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
9935351 |
Appl. No.: |
10/512171 |
Filed: |
July 12, 2005 |
PCT Filed: |
April 22, 2003 |
PCT NO: |
PCT/EP03/04151 |
Current U.S.
Class: |
514/252.18 ;
424/464 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 9/2072 20130101; A61K 9/2095 20130101; A61K 9/2054 20130101;
A61K 9/28 20130101; A61K 9/2027 20130101; A61K 31/506 20130101;
A61K 31/185 20130101; A61K 9/2013 20130101; A61P 35/02 20180101;
A61P 13/08 20180101; B29C 43/003 20130101; A61P 35/00 20180101;
A61K 31/505 20130101 |
Class at
Publication: |
514/252.18 ;
424/464 |
International
Class: |
A61K 031/506; A61K
009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 23, 2002 |
GB |
0209265.8 |
Claims
1-15. (canceled)
16. A tablet comprising a pharmacologically effective amount of
Compound I of formula (1) 3or a pharmaceutically acceptable salt
thereof in an amount from about 30% to 80% in weight of the active
moiety based on the total weight of the tablet.
17. A tablet according to claim 16 wherein Compound I of formula
(1) or a pharmaceutically acceptable salt thereof is present in an
amount from about 50% to 80% in weight of the active moiety based
on the total weight of the tablet.
18. A tablet according to claim 17 wherein Compound I of formula
(1) is in the monomesylate salt form.
19. A tablet according to claim 18 wherein Compound I of formula
(1) monomesylate is in the beta crystal form thereof.
20. A tablet according to claim 16 wherein the tablet comprises one
or more pharmaceutically acceptable excipients suitable for the
preparation of tablets.
21. A tablet according to claim 20 wherein the excipient comprises
at least one binder.
22. A tablet according to claim 20 wherein the excipients comprise:
at least one binder in a total amount of about 1% to 25% in weight
based on the total weight of the tablet, at least one disintegrant
in a total amount of about 10% to 35% in weight based on the total
weight of the tablet at least one glidant in a total amount of
about 0.5% to 3% in weight based on the total weight of the tablet,
and/or at least one lubricant in a total amount of about 0.5% to 2%
in weight based on the total weight of the tablet.
23. A tablet according to claim 21 wherein the binder comprises
microcrystalline cellulose or hydroxypropylmethyl cellulose or a
mixture thereof.
24. A tablet according to claim 22 wherein the disintegrant
comprises cross-linked polyvinylpyrrolidinone.
25. A tablet according to claim 22 wherein the glidant comprises
colloidal silicon dioxide and/or colloidal anhydrous silica.
26. A tablet according to claim 22 wherein the lubricant comprises
magnesium stearate.
27. A process for the preparation of a tablet according to claim
16, which process comprises (i) mixing the Compound I of formula
(1) or pharmaceutically acceptable salts thereof and
pharmaceutically acceptable excipients; (ii) wet-granulating; (iii)
mixing with pharmaceutically acceptable excipients to form a
mixture; and (iv) compressing the mixture obtained in step (iii) to
form a tablet.
28. The process according to claim 27 wherein the tablet is
coated.
29. A tablet according to claim 16 prepared by a wet-granulation
process.
30. A method of treating a subject which comprises administering a
tablet according to claim 16 comprising a pharmacologically
effective amount of Compound I of formula (1) to a subject in need
of such a treatment.
Description
[0001] The present invention relates to pharmaceutical tablets
Comprising
4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin--
2-ylamio)phenyl]-benzamide or pharmaceutically acceptable salts
thereof and is hereinafter referred as Compound I.
[0002] Compound I has the formula (1) 2
[0003] Compound I free base and its acceptable salts thereof are
disclosed in the European Patent application 0564409. Compound I
mesylate and Compound I mesylate alpha and beta crystal forms are
disclosed in International Patent application WO 99/03854.
[0004] Typically, prescribed daily dosages of Compound I mesylate
for the treatment of leukemia are high, e.g. 400-800 mg in adults.
Thus, there is a need for an oral dosage form which is convenient
to administer and provides a daily dosage amount of Compound I.
[0005] Accordingly, the present invention provides a tablet with
high drug loading comprising a pharmacologically effective amount
of Compound I or a pharmaceutically acceptable salt thereof present
in an amount of from about 30% to 80%, e.g. at least about 35, 40,
45, 50 or 55% to about e.g. 60, 65, 70, 75 or 80%, preferably more
than 55%. In particular, the amount of Compound I may vary from 45
to 80%, e.g. 50 to 70% in weight based on the total weight of the
tablet.
[0006] Compound I may be in the free base form or pharmaceutically
acceptable salts thereof, e.g. monomesylate form. The active moiety
corresponds to Compound I in the free base form. For example, 119.5
mg of Compound I mesylate salt correspond to 100 mg of Compound I
free base active moiety.
[0007] The present invention also provides a tablet comprising
[0008] (a) a pharmacologically effective amount of Compound I,
and
[0009] (b) at least one pharmaceutically acceptable excipient
suitable for the preparation of tablets wherein the amount of
Compound I or pharmaceutically acceptable salt thereof, calculated
as the percentage of the content in weight of the active moiety
based on the total the tablet, is from about 30% to 80%, e.g. at
least about 35, 40, 45, 50 or 55% to about e.g. 60, 65, 70, 75 or
80%, preferably more than 55%. In particular the amount of Compound
I may vary from 45 to 80%, e.g. 50 to 70% in weight of the active
moiety based on the total weight of the tablet.
[0010] In another aspect, the present invention provides a tablet
wherein the Compound I is in crystalline form.
[0011] In a further aspect of the invention, the monomesylate salt
of Compound I is used.
[0012] In a preferred embodiment of the invention, the monomesylate
salt of Compound I is in crystalline form, e.g. alpha or beta
crystal form, most preferably, the monomesylate salt of Compound I
is in the beta crystal form.
[0013] One or more pharmaceutically acceptable excipients may be
present in the tablets, e.g. those conventionally used, e.g. (1.1)
at least one binder, e.g. microcrystalline cellulose,
hydroxypropylmethyl cellulose, (1.2) at least one disintegrant,
e.g. cross-linked polyvinylpyrrolidinone, e.g. Crospovidone.RTM.,
(13) at least one glidant, e.g. colloidal silicon dioxide, (1.4) at
least one lubricant, e.g. magnesium stearate and/or (1.5) basic
coating. In the tablet according to the present invention,
microcrystalline cellulose is used as a binder.
[0014] Reference is made to the extensive literature on the subject
for these and other excipients and procedures mentioned herein, see
in particular Handbook of Pharmaceutical Excipients, Third Edition,
edited by Arthur H. Kibbe, American Pharmaceutical Association,
Washington, USA and Pharmaceutical Press, London; and Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete edited
by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier
editions which are incorporated herein by reference.
[0015] Binders (1.1) include but are not restricted to starches,
e.g. potato, wheat or corn starch; microcrystalline cellulose, e.g.
products such as Avicel.RTM., Filtrak.RTM., Heweten.RTM. or
Pharmacel.RTM.; hydroxypropyl cellulose; hydroxyethyl cellulose;
hydroxypropylmethyl cellulose, e.g. hydroxypropylmethyl
cellulose-Type 2910 USP, hypromellose, and polyvinylpyrrolidone,
e.g. Povidone.RTM. K30 from BASF. Preferably, hydroxypropylmethyl
cellulose-Type 2910 USP is used.
[0016] Suitable disintegrants (1.2) according to the invention
include but are not restricted to maize starch; CMC-Ca; CMC-Na;
microcrystalline cellulose; cross-linked PVP, e.g. as known and
commercially available under the trade names Crospovidone.RTM.,
Polyplasdone.RTM., available commercially from the ISP company, or
Kollidon.RTM. XL; alginic acid; sodium alginate; and guar gum.
Preferably, cross-linked PVP, e.g. Crospovidone.RTM. is used.
[0017] As glidants (1.3), one or more of the following may be used:
silica; colloidal silica, e.g. colloidal silica anhydrous, e.g.
Aerosil.RTM. 200, magnesium trisilicat, powdered cellulose, starch
and talc. Preferably colloidal silica anhydrous or/and colloidal
silicon dioxide are used.
[0018] As lubricants (1.4) one or more of the following may be used
Mg-, Al- or Ca-stearate, PEG 4000-8000 and/or talc. Preferably
magnesium stearate is used.
[0019] One or more of these excipients can be selected and used
having regard to the particular desired properties of the tablet by
routine experimentation.
[0020] According to the present invention, the amount of binder
(1.1) may vary within a range of from about 1 to 40%, preferably 1
to 30%, in particular 1 to 25% in weight based on the total weight
of the tablet.
[0021] The amount of disintegrant (1.2) may vary within a range of
from to 5 to 40%, e.g. 10 to 35% in weight based on the total
weight of the tablet.
[0022] The amount of glidant (1.3) may vary within ranges of from
0.1 to 10%, in particular 0.1 to 5%, e.g. 0.5 to 3% in weight based
on the total weight of the tablet or 2 to 4% in weight based on the
total weight of the tablet.
[0023] The amount of lubricant (1.4) may vary within a range of
from 0.1 to 5%, e.g. 0.5 to 2% in weight based on the total weight
of the tablet.
[0024] The amount of basic coating (1.5) may vary from 1 to 10%,
preferably from 1.5 to 5% in weight based on the total weight of
the tablet.
[0025] It will be appreciated that any given excipient may serve
more than one function e.g. as disintegrant, binder, glidant,
and/or lubricant.
[0026] In a preferred aspect of the invention, the tablet comprises
the following excipients, one or more binders in a total amount of
about 1% to 25% in weight based on the total weight of the tablet,
one or more disintegrants in a total amount of about 10% to 35% in
weight based on the total weight of the tablet, one or more
glidants in a total amount of about 0.5% to 3% in weight based on
the total weight of the tablet, and/or one or more lubricants in a
total amount of about 0.5% to 2% in weight based on the total
weight of the tablet.
[0027] The absolute amounts of each excipient and the amounts
relative to other excipients is similarly dependent on the desired
properties of the tablet and may also be chosen by routine
experimentation. For example, the tablet may be chosen to exhibit
accelerated and/or delayed release of Compound I with or without
quantitative control of the release of active agent. Preferably the
tablet is chosen to exhibit immediate release of the Compound I,
e.g. the Compound I monomesylate salt beta crystal form.
[0028] The present inventors have encountered difficulties in the
production of Compound I tablets due to high friability values and
poor abrasion resistance. Further, the flexibility in the quantity
of excipients, e.g. disintegrants, is limited due to the high drug
load of the product Thus, there still exists a need for
commercially acceptable Compound I dosage forms for oral
administration with good patient convenience and acceptance.
[0029] In accordance with the present invention, it has now
unexpectedly been found that stable and convenient galenic tablets
comprising Compound I are obtainable. The present Applicants have
found that pharmaceutically acceptable oral solid dosage forms in
the form of tablets, being particularly convenient to administer
and stable, may be obtained by preparation of tablets by
compression methods. More specifically, the tablets of the
invention may be prepared by granulation, preferably
wet-granulation, followed by compression methods. Compound I,
especially the mesylate salt, exhibits high particle size, e.g. 60%
of the Compound I starting material having a particle size greater
or equal to 100 .mu.m, e.g. 90% of the particles are smaller or
equal to 420 .mu.m Wet-granulation process is usually performed
with a starting material of particle size lower than 100 .mu.m.
[0030] It is a characteristic of the tablet according to the
invention that it contains a high content of Compound I given the
relatively small amount of excipients. This enables the production
of physically small tablets. The total amount of excipients in a
given unit dosage may be about 70% or less by weight based on the
total weight of the tablet, more particularly about 50% or less.
Preferably the excipient content is in the range of about 30 to
55%, more particularly 35 to 50% in weight based on the total
weight of the tablet
[0031] Tablets according to the invention surprisingly provide for
the administration of Compound I in a smaller size than was
hitherto possible for a given unit dose of Compound I. The tablets
of the invention are, despite the high drug loading, small, and,
therefore, convenient to administer. This leads to a better patient
compliance.
[0032] In another embodiment this invention provides a tablet
comprising from 50 mg to 600 mg Compound I, e.g. of from 100 mg to
about 400 mg. Most preferably, tablets according to the invention
are tablets containing 100 mg and/or tablets containing 400 mg of
Compound I.
[0033] Accordingly, the present invention provides for tablets
containing an amount of Compound I mesylate, e.g. Compound I
mesylate alpha crystal form and/or Compound I mesylate beta crystal
form, equal to 100 mg and/or 400 mg of Compound I free base. Most
preferably, the Compound I mesylate form used for the tablet
according to the invention is the beta crystal form.
[0034] According to the invention, the process for the preparation
of the tablets consists in forming an inner phase, mixing it
together with an outer phase, compressing the obtained mixture and
optionally coating the tablet.
[0035] The inner phase comprises Compound I. Preferably, the inner
phase comprises Compound I and one or more excipients, more
preferably one or more binders and most preferably the amount of
one or more binders in the inner phase is ranging from about 1 to
30%, preferably 1 to 20% and more preferably 1 to 15%. The binders
of the inner phase according to the invention are preferably
microcrystalline cellulose and hydroxypropylmethyl cellulose. The
amount of microcrystalline cellulose in the inner phase may vary
from about 10 to 29%, in particular 12 to 14% in weight based on
the total weight of the tablet The amount of hydroxypropylmethyl
cellulose in the inner phase may vary from 1 to 5%, preferably 1 to
2% in weight based on the total weight of the tablet. The Compound
I and the pharmaceutically acceptable excipients of the inner phase
are mixed together with water and the mixture is processed for
granulation, e.g. using a wet high-shear granulator to form the
wet-granulates. The wet-granulates may be then, dried, e.g. using a
fluid bed dryer.
[0036] The present invention pertains to a process for the
preparation of tablets comprising an outer phase. The outer phase
consists in a mixture of the inner phase with one or more
excipients. The inner phase and one or more excipients of the outer
phase are mixed together using, e.g. a diffusion mixer. Preferably,
one or more binders are added. Most preferably cellulose
microcrystalline is added. Even more preferably, microcrystalline
cellulose is added in the range of 1 to 10% in weight based on the
total weight of the tablet. In a preferred embodiment of the
invention, in the outer phase, the amount of microcrystalline
cellulose is around 5% in weight based on the total weight of the
tablet. The outer phase according to the invention may also contain
one or more disintegrants, most preferably Crospovidone.RTM.. In a
preferred embodiment, the amount of disintegrant in the outer phase
is ranging from about 10 to 30%, preferably 12 to 25%, most
preferably about 15%.
[0037] In a particular aspect of the invention, one or more
glidants are incorporated into the outer phase.
[0038] According to the invention, one or more lubricants are
incorporated into the outer phase.
[0039] In a further aspect of the invention, tablets are performed
by compression of the mixture of the inner and the outer phases
using, e.g. a tablet press.
[0040] Optionally, the tablets may be coated, preferably as
described herein after.
[0041] In one embodiment of the invention, the process for the
preparation of a tablet which comprises
[0042] (a) forming an inner phase comprising
[0043] (i) mixing the Compound I together with pharmaceutically
acceptable excipients
[0044] (ii) wet-granulating
[0045] (b) forming an outer phase comprising
[0046] (iii) adding further pharmaceutically acceptable excipients
to the inner phase and mixing;
[0047] (e) forming the tablet by
[0048] (iv) compressing the mixture obtained in step (iii) and,
optionally
[0049] (d) coating.
[0050] More specifically, in one aspect the present invention
provides a process comprising:
[0051] (i) mixing the Compound I and pharmaceutically acceptable
excipients, e.g. one or more binders, e.g. microcrystalline
cellulose, in a high shear mixer,
[0052] (ii) adding water, subjecting the mixture to
wetting/kneading, e.g. in a high shear mixer, screening using a
screening mill with a rotating impeller, and drying, e.g. in a
fluidized bed dryer,
[0053] (iii) adding pharmaceutically acceptable excipients, e.g.
sieved excipients, such as one or more disintegrants, e.g.
Crospovidone.RTM., one or more binders, e.g. microcristalline
cellulose, one or more glidant, e.g. colloidal silicon dioxide, and
mixing, e.g. in a diffusion mixer;
[0054] (iv) adding pharmaceutically acceptable excipients such as
one or more lubricant e.g. magnesium stearate, sieving, e.g.
hand-sieving, e.g. at 900 .mu.m, and mixing, e.g. in a diffusion
mixer,
[0055] (v) tabletting the mixture obtained in step (iv) by
compression, e.g. in a conventional tablet press, e.g. in an EK-0
Korsch eccentric tabletting machine or a rotary tabletting machine,
preferably a rotary machine and
[0056] (vi) coating, e.g. in a pan coater, e.g. Glatt, Accela.
[0057] By "core" is meant the granulate phase (steps (i) and (ii))
including the active drug Compound I and the outer phase consisting
of the excipients.
[0058] By "total weight of the tablet" is meant the weight of a
tablet being the inner and the outer phases and the coating (if
any).
[0059] According to the invention, the coating process may be
performed at low temperature, e.g. between 30 and 40.degree. C.,
preferably between 32 and 39.degree. C., most preferably at a
temperature ranging from around 35 to around 38.degree. C. The
coating process may be performed with a spray rate preferably in
the range of 30 to 105 g of coating dispersion per kg of cores per
hour, preferably of 35 to 105 g. It has surprisingly been found
that swelling of the disintegrants, e.g. Crospovidone.RTM., nor
sticking of the cores occurred during spraying of the coating
mixture, as it would be expected by the person skilled in the art
by processing at low temperatures.
[0060] Moreover, the tablets exhibit improved abrasion resistance.
The physical and chemical stability may be tested in conventional
manner, e.g. the tablets may be tested as such by measurement of
dissolution, friability, disintegration time, assay for Compound I
degradation products, appearance and/or microscopy, e.g. after
storage at room temperature, i.e. 25.degree. C., and/or storage at
40.degree. C.
[0061] The tablet cores may vary in shape and be, for example,
round, oval, oblong, cylindrical or any other suitable shape. A
characteristic of tablets according to the invention is their small
size having regard to the amount of Compound I or Compound I salt
contained therein.
[0062] In a preferred embodiment of the invention tablets obtained
by the compression method described above are round or oval. The
edges of the tablets may be beveled or rounded. Most preferably,
the tablets are ovaloid and/or round. The tablets according to the
invention may be scored. The ovaloid tablet may be small in
dimension e.g. 10 to 20 mm in length, preferably 15 to 20 mm, most
preferably 17 to 19 mm; 5 to 10 nun in width, preferably 6.5 to 8
mm. The thickness of the tablet is from 4 to 8 mm, preferably 6 to
8 mm. Compression forces of between 10 to 20 kN are used to prepare
the compressed tablet, preferably, 12 to 18 kN. Preferably, the
ovaloid tablet contains 400 mg of Compound I. The round tablet may
be of the following dimensions, e.g. 5 to 15 mm in diameter,
preferably 7 to 10 mm, most preferably about 9 mm. The thickness of
the tablet may be from 2 to 5 mm, preferably 2.5 to 4 mm
Compression forces of between 6 to 18 kN are used to prepare the
compressed tablet, preferably, 8 to 14 kN. Preferably, the round
tablet contains 100 mg of Compound I. Preferably the 100 mg tablet
is a scored tablet, most preferably the tablet has a break score on
one side.
[0063] The tablets of the invention comprising about 100 mg of
Compound I may furthermore have a hardness of from about 30 to 140
N, e.g. 40 to 140 N, 30 to 100 N, 40 to 100 N, preferably 50 to 80
N. The tablets of the invention comprising about 400 mg of Compound
I may have a hardness of 100 to 270 N, e.g. 100 to 250 N, 160 to
270 N, 160 to 250 N, preferably 195 to 235 N.
[0064] The disintegration time of the tablet may be of about 20 min
or less. Preferably, for the 100 mg Compound I tablet, the
disintegration time is ranging from about 2 to 10 min, preferably 4
to 10 min, e.g. 4 to 8 min. For the 400 mg Compound I tablet, the
disintegration time is, preferably ranging from about 7 to 15 min,
preferably 8 to 15 min, e.g. 8 to 14 min.
[0065] The friability of the tablets is measured according to the
US Pharmacopeia. The friability of the tablets according to the
invention monitored following the recommendation of the US
Phramacopeia is 0%.
[0066] The tablets of the invention may furthermore be colored
and/or the tablets or coating 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
tablets. Dyes suitable for use in pharmacy typically include
carotinoids, iron oxides or chlorophyll. The tablets of the
invention may be marked using an imprint code.
[0067] Procedures which may be used may be conventional or known in
the art or based on such procedures 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 pharmazuetischen Praxis, 4th Ed.
(Springer Verlag, 1971) and Remington's Pharmaceutical Sciences,
13th Ed., (Mack Publ., Co., 1970) or later editions.
[0068] The tablets of the invention are useful for human indication
of Compound I, e.g. anti-tumor treatment, as indicated by standard
tests. The activity and characteristics of the tablets of the
invention may be indicated in standard clinical trials and/or
animal trials.
[0069] The tablets of the invention are particular useful for, e.g.
treatment of non-malignant and malignant proliferative disorders,
e.g. leukemias, gliomas, sarcomas, prostate-, breast-,
gastro-intestinal-, lung-, ovary tumors.
[0070] The tablets of the invention comprising a pharmacologically
effective amount of Compound I or Compound I salt may be
administered as the sole active drug or with another active drug
may be envisaged, e.g. together with simultaneous or separate
administration of other drugs.
[0071] Furthermore, the tablets of the invention obtained are
stable both to the production process and during storage, e.g. for
2 years or even 3 years in conventional packaging, e.g. sealed
aluminium blister packs. Less than about 5%, e.g. 2 or 3% or less
of Compound I or Compound I salt may degrade during this time as
determined in conventional tests.
[0072] The tablets of the invention, e.g. the 100 and 400 mg
tablets, are bioequivalent with the marketed hard gelatine capsules
(100 mg) of Compound I. The administration of 400 mg of Compound I
in hard gelatine capsules (4.times.100 mg) in the form of a single
film coated tablet is well tolerated.
[0073] Depending on age, individual condition, mode of
administration, and the clinical picture in question, effective
doses, for example daily dosing of tablets of the invention
comprising, e.g. 100-1000 mg, e.g. 100 to 800 mg, preferably 100 to
600 mg, especially 400 mg of Compound 1, are administered to
patients of about 70 kg bodyweight
[0074] The invention relates also to a method for administering to
a human subject in need of such a treatment, Compound I or a
pharmaceutically acceptable salt thereof in the form of a tablet,
once daily for a period exceeding 3 months. The invention relates
especially to such method wherein a daily dose of 100 to 1000 mg,
preferably 100 to 800 mg, especially 200 to 600 mg, preferably 400
mg, of Compound I is administered to an adult. It will be
understood that the specific dose level for any particular patient
will depend upon a variety of factors including the age, the body
weight, general health, drug combination with one or more active
drugs, type and severity of the disease.
[0075] Accordingly in a further aspect the present invention
provides a method of treating a subject which comprises
administering a tablet according to the invention comprising a
pharmacologically effective amount of Compound I salt to a subject
in need of such a treatment, optionally with the simultaneous,
sequential or separate administration of another drug e.g. a
cyclosporin, a rapamycin, an ascomycin, corticosteroids,
cyclophosphamide, azathioprine, methotrexate, brequinar,
leflunomide, mizoribine, mycophenolic acid and/or mycophenolate
mofetil.
[0076] When the tablets of the invention are co-administered within
a combined therapy the dosages of the Compound I mesylate may be
reduced e.g. to one-half to one-third their dosages when used
alone.
[0077] The medicament package comprises tablets according to the
invention and printed instructions directing that one or more
tablets of Compound I be administered orally.
[0078] Following non-limitative examples illustrate the
invention.
EXAMPLE 1
Tablet Formulation (100 mg Tablet)
[0079]
1 Composition Quantity Component per unit (mg) per batch (kg)
Compound I .sup.2119.500 167.300 mesylate.sup.1 Microcrystalline
(1.1) 25.000 35.000 cellulose.sup.1 Hypromellose/ (1.1) 2.500 3.500
Hydroxypropyl methylcellulose.sup.1 Microcrystalline
.sup.3(1.1).sup. 9.850 13.790 cellulose Crospovidone (1.2) 28.000
39.200 Silica, colloidal (1.3) 1.250 1.750 anhydrous/ Colloidal
silicon dioxide Magnesium (1.4) 1.400 1.960 stearate Basic coating
(1.5) 7.125 8.550.sup.4 9.975 14.364.sup.4 premix yellow Basic
coating (1.5) 0.375 0.450.sup.4 0.525 0.756.sup.4 premix red Total
weight 195.000 196.500 273.000 .apprxeq.275.000 .sup. Units/batch
1'400'000 .sup.1Components of the granulate, .sup.2119.5 mg
Compound I mesylate equals 100 mg Compound I free base,
.sup.3Microcrystalline cellulose is added in the outer phase as a
dry binder, .sup.4a 20% manufacturing overage of the coating
dispersion is included to cover spray losses during the coating
process step.
[0080] Tablets of 100 mg of Compound I free base according to the
invention and of the above tablet were prepared by wet granulation
of a mixture of Compound I salt with (1.1), mixing with
.sup.3(1.1), (1.2), (1.3) and (1.4), compressing and coating the
resultant tablets with an aqueous dispersion of the coating mixture
(1.5).
[0081] The coating process may be performed at low temperature,
e.g. ranging from around 35 to around 38.degree. C. The coating
process may be performed with a spray rate preferably in the range
of 30 to 105 g of coating dispersion per kg of cores ("core"
corresponds to the compressed inner and outer phase) per hour, e.g.
35 to 105 g per kg of cores per h.
EXAMPLE 2
Tablet Formulation (400 mg Tablet)
[0082] Tablets of 400 mg of Compound I according to the invention
and of the following tablet were prepared by wet granulation of a
mixture of Compound I salt with (1.1), mixing with .sup.3(1.1),
(1.2), (1.3) and (1.4), compressing and coating the resultant
tablets with an aqueous dispersion of the coating mixture
(1.5).
[0083] Composition per dosage form unit and quantity per batch
2 Composition Quantity Component per unit (mg) per batch (kg)
Compound I .sup.2478.000 167.300 mesylate.sup.1 Microcrystalline
(1.1) 100.000 35.000 cellulose.sup.1 Hypromellose/ (1.1) 10.000
3.500 Hydroxypropyl methylcellulose.sup.1 Microcrystalline
.sup.3(1.1).sup. 39.400 13.790 cellulose Crospovidone (1.2) 112.000
39.200 Silica, colloidal (1.3) 5.000 1.750 anhydrous/ Colloidal
silicon dioxide Magnesium (1.4) 5.600 1.960 stearate Basic coating
(1.5) 17.100 20.425.sup.4 5.985 8.588.sup.4 premix yellow Basic
coating (1.5) 0.900 1.075.sup.4 0.315 0.452.sup.4 premix red Total
weight 768.000 771.500 268.800 .apprxeq.270.000 .sup. Units/batch
350'000 .sup.1Components of the granulate, .sup.2478 mg Compound I
mesylate equals 400 mg Compound I free base, .sup.3Microcrystalline
cellulose is added in the outer phase as a dry binder, .sup.4a 20%
manufacturing overage of the coating dispersion is included to
cover spray losses during the coating process step.
[0084] The coating process may be performed at low temperature,
e.g. ranging from around 35 to around 38.degree. C. The coating
process may be performed with a spray rate preferably in the range
of 30 to 105 g of coating dispersion per kg of cores ("core"
corresponds to the compressed inner and outer phase) per hour, e.g.
35 to 105 g per kg of cores per h.
EXAMPLE 3
Dimensions of the Tablets
[0085]
3 Compound I free base/tablet Shape and Dimensions 100 mg Round,
9.1-9.3 mm diameter, curved, bevelled edges, thickness: 2.8-3.4 mm
break score on one side 400 mg Ovaloid, 18.1-18.3 .times. 7.2-7.4
mm, curved, bevelled edges, thickness: 6.6-7.2 mm 100 mg Round,
9.1-9.4 mm diameter, curved, bevelled edges, thickness: 2.8-3.4 mm
break score on one side 400 mg Ovaloid, 18.1-18.4 .times. 7.2-7.5
mm, curved, bevelled edges, thickness: 6.6-7.2 mm
* * * * *