Note: Descriptions are shown in the official language in which they were submitted.
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ENTERIC-COATED PHARMACEUTICAL COMPOSrTIONS OF MYCOPHENOLATE
This invention relates to mycophenolic acid.
Mycophenolic acid, also referred to herein as MPA, was first isolated in 1896,
and has been
extensively investigated as a pharmaceutical of potential commercial interest.
It is known
to have anti-tumor, anti-viral, immunosuppressive, anti-psoriatic, and anti-
inflammatory
activity [see e.g. W.A. Lee et al, Pharmaceutical Research ( 1990), 7, p. 161 -
166 anti
references cited therein). Publications have appeared on MPA as an anti-cancer
agent by
Lilly scientists, see e.g. M.J. Sweeney et al., Cancer Research (1972), 32,
1795-1802, and
by ICI scientists, see e.g. GB 1,157,099 and 1,203,328 and as an
immunosuppressant agent
see e.g. A. Mitsui et al. J. Antibiotics { 1969) 22, p. 358-363. In the above-
mentioned article
by W.A. Lee et al it is stated that attempts have been made to increase the
bio-availability
or specificity of MPA by making derivatives. The poor bioavailability of the
acid was
thought to be caused by undetermined factors such as drug complexation in the
gastro-
intestinal lumen, a narrow absorption window, metabolism before absorption
etc.. The
preparation of the morpholinoethyl ester, also known as mycophenolate mofetil
(sometimes
referred to herein as MMF), was described which had considerably higher
bioavailability
than MPA (100% for MMF and 43% for MPA). This derivative has been recently
introduced commercially as an immunosuppressant for the treatment or
prevention of organ
2 0 or tissue transplant rejection, at daily dosages of from about 200 mg to
about 3 grams p.o.,
e.g. about 2 g p.o. Patient compliance with MMF is not ideal, inter alia,
because of side-
effects e.g. gastro-intestinal side effects, the origin of which is not known.
We have now found, after exhaustive testing, that mycophenolate salts when
enteric coated
or adapted to be released in the upper part of the intestines, e.g. in the
duodenum, jejeunum
2 5 and/or ileum, are effective, well-tolerated, pharmaceuticals particularly
for'
immunosuppressive indications especially for the treatment or prevention of
organ, tissue
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or cellular allograft or xenograft rejection, e.g. after
transplant, or the treatment or prevention of immune-
mediated diseases (autoimmune diseases) and have interesting
bioavailability and stability characteristics. Moreover
fewer unit dosage forms are required to be administered than
for MMF, leading to easier administration.
The present invention provides in one aspect a
pharmaceutical composition comprising a mycophenolate salt,
the composition being adapted to release mycophenolate in
the upper part of the intestinal tract (hereinafter referred
to as a composition of the invention). The composition may
be adapted in any conventional manner, preferably with means
adapted to prevent release of the mycophenolate in the
stomach and to ensure release in the upper part of the
intestinal tract. In a further aspect the invention
provides a pharmaceutical composition comprising a coated
pharmaceutically acceptable mycophenolate salt.
According to one aspect of the present invention,
there is provided a pharmaceutical composition comprising an
enteric coated pharmaceutically acceptable mycophenolate
salt and a pharmaceutically acceptable carrier or excipient.
According to another aspect of the present
invention, there is provided a system comprising a
pharmaceutical composition as described herein and an
immunosuppressant for simultaneous, sequential or separate
administration.
Such salts are cationic salts, e.g. of alkali
metals, especially the sodium salts. Sodium mycophenolate
salts are known, e.g. in South African Patent 68/4959. We
prefer to use the mono-sodium salt. This may be obtained in
crystalline form by recrystallization from acetone/ethanol
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if necessary with water; Mpt. 189-191°C.
The invention provides, more specifically, a solid
enteric-coated composition in unit dose form for oral
application, the core of the composition containing sodium
mycophenolate in solid or liquid form.
The term "core" comprises sodium mycophenolate (or
other cationic salt) if desired in admixture with further
physiologically acceptable material, that can be surrounded
by an enteric-coating. The term "core" comprises, in a wide
sense, not only tablets, pellets or granules but also
capsules, e.g. soft or hard capsules of gelatine or starch.
Such cores may be produced in conventional manner. We have
found that the mycophenolate salts, particularly the sodium
salt, are particularly interesting for the production of
tablets. When tablet cores are used they have preferably a
hardness of from ca. 10 to 70 N.
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The pellets or granules may, after application of the enteric-coating as
described hereinafter
may be used as such or to fill capsules, e.g. hard gelatine capsules. If
desired the capsules
may be alternatively enteric-coated, e.g. in conventional manner.
Other pharmaceutically acceptable ingredients may be present in the cores,
e.g. those
conventionally used in the preparation of pharmaceutically compositions, e.g.
fillers, e.g.
lactose, glidants, e.g. silica, and lubricants, e.g. magnesium stearate.
The term "enteric coating" comprises any pharmaceutically acceptable coating
preventing
the release of the active agent in the stomach and sufficiently disintegrating
in the intestine
tract {by contact with approximately neutral or alkaline intestine juices) to
allow the
resorption of the active agent through the walls of the intestinal tract.
Various in vitro tests
for determining whether or not a coating is classified as an enteric coating
have been
published in the pharmacopoeia of various countries.
More specifically, the term "enteric coating" as used herein refers to a
coating which
remains intact for at least 2 hours, in contact with artificial gastric juices
such as HCl of
pH I at 36 to 38°C and preferably thereafter disintegrates within 30
minutes in artificial
intestinal juices such as a KH~P04 buffered solution of pH 6.8.
The thickness of the coating may vary and depends inter alia on its
permeability in water
and acids. A typical coating may be about 16-30, e.g. 16-20 or to 25, mg on a
size 1
gelatine capsule. Similar thicknesses may be applied in other formulations.
2 0 In general satisfactory results are obtained with a coating of 5 - 100 pm,
preferably 20 - 80
~m thickness. The coating is suitably selected from macromolecular polymers.
Suitable
polymers are listed in e.g. L. Lachman et al. The Theory and Practice of
Industrial
Pharmacy, 3rd Ed, 1986, p. 365 - 373, H. Sucker et al, Pharmazeutische
Technologic,
Thieme, 1991, p. 355 - 359, Hagers Handbuch der pharmazeutischen Praxis, 4th
Ed. Vol.
2 5 7, pages 739 to 742 and 766 to 778, (Springer Verlag, 1971 ) and
Remington's
Pharmaceutical Sciences, 13th Ed., pages 1689 to 1691 (Mack Publ., Co., 1970)
and
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comprise e.g. cellulose ester derivatives, cellulose ethers, acrylic resins,
such as
methylacrylate copolymers and copolymers of malefic acid and phthalic acid
derivatives.
The preferred films are made from cellulose acetate phthalate and
trimellitate; methacrylic
acid copolymers, e.g. copolymers derived from methylacrylic acid and esters
thereof,
containing at least 40% methylacrylic acid; and especially hydroxypropyl
methylcellulose
phthalate.
Methylacrylates include those of molecular weight above 100,000 daltons based
on, e.g.
methylacrylate and methyl or ethyl methylacrylate in a ratio of about 1:1.
Typical products
include Endragit L, e.g. L 100-55, marketed by Rohm GmbH, Darmstadt, Germany.
Typical cellulose acetate phthalates have an acetyl content of 17-26% and a
phthalate
content of from 30-40% with a viscosity of ca. 45-90cP.
Typical cellulose acetate trimellitates have ari acetyl content of 17-26%, a
trimellityl content
from 25 - 35 % with a viscosity of ca. 15-20 cS. An example of an appropriate
cellulose
acetate trimellitate is the marketed product CAT (Eastman Kodak Company, USA).
Hydroxypropyl methylcellulose phthalates, typically have a molecular weight of
from
20,000 to 100,000 daltons e.g. 80,000 to 130,000 daltons, e.g. a hydroxypropyl
content of
from 5 to 10%, a methoxy content of from 18 to 24% and a phthalyl content from
21 to
35%.
An example of an appropriate cellulose acetate phthalate is the marketed
product CAP
2 0 (Eastman Kodak, Rochester N.Y., USA).
Examples of suitable hydroxypropyl methylcellulose phthalates are the marketed
products
having a hydroxypropyl content of from 6-10%, a methoxy content of from 20-
24%, a
phthalyl content of from 21-27%, a molecular weight of about 84,000 daltons
known under
~.
the trade mark HP50 and available from Shin-Etsu Chemical Co. Ltd., Tokyo,
Japan, and
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having a hydroxypropyl content, a methoxy content, and a phthalyl content of 5-
9%, 18-
22% and 27-35% respectively, and a molecular weight of 78,000 daltons, known
under the
trademark HP55 and available from the same supplier.
A preferred coating is HP S0.
The enteric coating may be carried out in conventional manner, e.g. so that
the cores are
sprayed with a solution of the enteric-coating.
Suitable solvents for the enteric-coating are for example organic solvents,
e.g. an alcohol
such as ethanol, a ketone such as acetone, halogenated hydrocarbons such as
CH~CI~ or
mixtures of such solvents, e.g. ethanol /acetone, e.g. 1:1 to 10:1.
Conveniently a softener such as di-n-butylphthalate or triacetin is added to
such a solution,
e.g. in a ratio of coating material to softener of from 1: about 0.05 to about
0.3.
If desired for cellulose phthalates and other acidic coating materials an
ammonium salt may
be found and an aqueous solution may be used.
A fluidized bed coater may be used for coating.
Conveniently the cores are treated at room temperature or warmed up to
40°C e.g. by means
of warm air of 40° up to 70°C, before spraying. To avoid a
sticking of the cores the spray
procedure is preferably interrupted at certain time intervals and the cores
then warmed up
again. It is, however, also possible to proceed without interruption of the
spray procedure,
e.g. by automatic regulation of the spray amount taking into account the
temperature of
2 0 exhaust air and/or cores.
The spray pressure may vary within wide ranges, in general satisfactory
results are obtained
with a spray pressure of from about 1 to about 1.5 bar.
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The compositions of the invention are useful as imrriunosuppressants as
indicated by
standard tests.
The activity and characteristics of the compositions of the invention may be
indicated in
standard
a) clinical trials, e.g. observing the first acute rejection episodes or
treatment failure
six months after transplant of kidneys or maintaining a rejection - free state
within
6 months after initiation of treatment with the invention. The compositions of
the
invention are administered at a dose in the range of 0.5 to 2.0 g/day e.g.
about 1.5
g /day and decrease the acute rejection rates when administered during the
period
around transplant surgery, and maintain a rejection-free state in patients who
are 3
months or more after transplantation. Thus the compositions of the invention
may
be administered during the initial 72 hours after transplantation at dose of
about 0.5
g administered twice a day in combination with a conventional steroid and
cyclosporin, e.g, as NEORAL for which the cyclosporin dose is the conventional
dose e.g. ca. 8 ~ 3 mg/kg for renal transplants. The steroid dose is to be
administered at about 2.5 mg /kg for 4 days after transplant, 1 mg/kg
thereafter for
1 week, ~0.6 mg/kg thereafter for 2 weeks thereafter 0.3 mg/kg for 1 month for
prednisone.
and in
2 0 b) animal trials e.g. observing the kidney allograft reaction in rat. In
this test one
kidney from a female fisher 344 rat is transplanted onto the renal vessel of a
unilaterally (left side) nephrectomized WF recipient rat using an end-to-end
anastomosis.Ureteric anastomosis is also end-to-end. Treatment commences on
the
day of transplantation and is continued for 14 days. A contralateral
nephrectomy is
2 5 done seven days after transplantation, leaving the recipient relying on
the
performance of the donor kidney. Survival of the graft recipient is taken as
the
parameter for a functional graft. Typical doses of the compbsitions of the
invention
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are from about 1 to 30 mg/kg p.o.
The compositions of the invention are particularly useful for the following
conditions:
a) Treatment and prevention of native or transgenic organ, tissue or cellular
allograft or
xenograft transplant rejection, e.g. for the treatment of recipients of e.g.
heart, lung,
combined heart-lung, liver, kidney, pancreatic, skin, pancreatic islet cell,
neural cell
or corneal transplant; including treatment and prevention of acute rejection;
treatment
and prevention of hyperacute rejection, e.g. as associated with xenograft
rejection; and
treatment and prevention of chronic rejection, e.g. as associated with graft-
vessel
disease. The compositions of the invention are also indicated for the
treatment and
prevention of graft-versus-host disease, such as following bone marrow
transplantation.
b) Treatment and prevention of autoimmune diseases, e.g. immune-mediated
diseases and
inflammatory conditions, in particular inflammatory conditions with an
etiology
including an immunological component such as arthritis (for example rheumatoid
arthritis, arthritis chronica progrediente and arthritis deformans) and
rheumatic
diseases. Specific immune-mediated diseases for which the compositions of the
invention may be employed include, autoimmune hematological disorders,
including,
but not limited to hemolytic anaemia, aplastic anaemia, pure red cell anaemia
and
idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis,
sclerodoma, Wegener granulosis, dermatomyositis, polymyositis, chronic active
2 0 hepatitis, primary bilary cirrhosis, myasthenia gravis, psoriasis, Steven-
Johnson
syndrome, pemphigus, idiophatic spree, inflammatory bowel diseases (including
e.g.
ulcerative colitis and Crohn's disease), endocrine ophthalmophathy, Graves
disease,
sarcoidosis, multiple sclerosis, juvenile diabetes (diabetes mellitus type I),
non-
infectious uveitis (anterior and posterior}, keratoconjunctivitis sicca and
vernal
2 5 keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis,
vasculitis,
glomerulonephritides (with and without nephrotic syndrome, e.g. including
idiophatic
nephrotic syndrome or minimal change nephropathy) and juvenile
dermatomyositis.
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Appropriate dosages of the compositions of the invention will of course vary,
e.g.
depending on the condition to be treated (for example the disease type or the
nature of
resistance), the MPA salt used, the effect desired and the mode of
administration.
In general however satisfactory results are obtained on administration e.g.
orally at dosages
on the order of from about 1 to about 30 mg salt per kg animal body weight per
day,
administered once or in divided doses up to 4 times per day. Suitable daily
dosages for
patients are thus in the order of 200 mg to 3 g p.o. salt e.g. from about 50
to 100% that of
mycophenolate mofetil. For the preferred mono sodium salt the dosage of the
salt is about
two thirds that of mycophenolate mofetil.
Representative unit dosage forms contain from about 50 mg, e.g. 100 mg, to
about 1.5 g
of the pharmaceutically acceptable mycophenolate salt.
The bioavailability characteristics of compositions of the invention may be
determined in
conventional manner, e.g. by oral administration to beagle dogs. Dosages are
typically 50
mg salt animal e.g. ca 3- 5 mg salt /kg animal body weight. Dogs are adult
(ca. 10 kg e.g.
6 - 14 kg) and fasted. Three hours after administration ca. 200 g food is
administered.
Blood samples are taken from the cephalic vein, before administration and 10,
30, and 45
minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours, after administration. Plasma
levels of free
MPA are determined by HPLC analysis (with UV detection).
In a relative bioavailability trial as described above in male beagle dogs
dosages of 3.8 mg
2 0 salt/kg animal body weight p.o. were administered with the Example 1
composition as
described hereinafter and with a MPA or MMF formulation corresponding to the
Example
1 composition but containing an identical amount of MPA or commercially
available MMF.
Results are as follows:-
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MPA (AUC Relative Ex 1 MPA MMF
Bioavailability, Frel
[ng.hr.ml-']
Mean 4612 (218) 3579 ( I74) 2709 (
100)
Median 4204 ( 168) 2911 ( 182) 2513 (
100)
SD 939 1889 1363
CV 20 53 50
Cmax
[ng/ml] (Relative Cmax)
Mean 5391 (3I3) 3683 (227) 2052 ( 100)
Median 5359 (367) 2719 ( 172) 1462 ( 100)
SD 1847 2504 945
CV (%) 34 (46) 68 (87) 46 (0)
The coefficients of variation (CV) of AUC (20%) and Cmax (34%) of the Example
1
composition are significantly less than those of the reference compositions,
indicating less
inter-subject and intra-subject variability with the Example 1 composition.
The area under the curve (AUC) and Cmax with the Example 1 composition are
higher
than those of the reference compositions.
Naturally the advantageous bioavailability characteristics of the present
compositions may
2 0 be ascertained in standard clinical bioavailability trials. For example,
doses from 200 mg
to 1.5 g of the Example 1 composition and MPA, and MMF may be administered to
12
healthy volunteers in single doses in a cross-over trial. Increased AUC and
C~"~x may be
observed for the Example 1 composition.
The compositions of the present invention are surprisingly tolerated better
than MMF,
2 5 inducing less gastro-intestinal side effects such as diarrhoea and
burning. They show less
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long term side effects e.g. in the colon.
The compositions of the invention may be administered as the sole active
ingredient or with
another immunosuppressant e.g. together with simultaneous or separate
administration of
other immunosuppressants, for example, in immunosuppressive applications such
as
prevention and treatment of graft vs. host disease, transplant rejection, or
immune-mediated
disease, the compositions of the invention may be used in combination with
cyclosporins
or ascomycins, or their immunosuppressive analogs, e.g. cyclosporin A, FK- 506
(tacrolimus), etc., rapamycin; corticosteroids; cyclophosphamide;
azathioprine; methotrexate;
brequinar; leflunomide; mizoribine; deoxyspergualin; analogues thereof, and
immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to
leukocyte
receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, CTLA4, B7, CD45, or CS58
or their ligands; or other immunomodulatory compounds.
When the compositions of the invention are co-administered with such other
immunosuppressants the dosages of the other immunosuppressants may be reduced
e.g. to
one-half to one-third their dosages when used alone.
Representative doses for ciclosporin to be used are e.g. 1 to 10, e.g. 1 to 2
mg/kg/day.
The present invention provides in another aspect the use, method and
compositions as
defined hereinafter in the claims.
Insofar as details of excipients are not described herein, these are known, or
available e.g.
2 0 in the Handbook of Pharmaceutical Excipients, Second Edition, edited by
Ainley Wade and
Paul J. Weller, 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.
2 5 Following is a description by way of example only of compositions of this
invention:
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EXAMPLE 1:
COMPOSITION
Capsule contents
MPA mono sodium salt 53.43 mg (= 50 mg MPA)
Lactose ( 1:1 mixture of 100/200 mesh) 256.57 mg
Silica (Aerosil) 3.1 mg
Magnesium stearate 1.5_ 5 m~
314.65 m~
Capsule is size 1
Enteric coatine (ca 17 mg)
,. Hydroxypropyl methyl cellulose phthalate (HP50) 9 parts
Triacetin 1 part
Procedure
The capsule ingredients are mixed and filled into size 1 capsules. The
capsules are coated
in a fluidized bed coater with a solution of the enteric coating ingredients
in ethanol
(containing 10% acetone). The coating on each capsule is about 17 mg. The
capsules meet
the enteric coating test described herein and do not disintegrate within 2
hours in artificial
gastric juices (pH 1, HCl). The compositions are stable, e.g for 2 years at
room temperature.
If desired larger capsules containing 534.3 mg MPA mono sodium salt may be
made in
2 0 analogous manner, reducing the amount of lactose. These are well tolerated
in clinical trials.
EXAMPLE 2:
Capsules of size 1 are made up as in Example 1. A solution for enteric coating
is made up
as follows:
Hydroxypropyl methyl cellulose phthalate (HP50) 270 g
2 5 Triacetin ~ 30 g
Acetone 900 g
Ethanol 1800 g
600 g of this enteric coating solution are used. for 1 kg of caps'les (ca.
2400). The amount
of coating applied to each capsule is about 25 mg giving a film 'thickness of
5-6 mg/cm2.
