Note: Descriptions are shown in the official language in which they were submitted.
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ORAL PHARMACEUTICAL COMPOSITION OF A POORLY WATER-SOLUBLE ACTIVE SUBSTANCE
Field of the invention.
[0001] The present invention relates to an improved oral pharmaceutical
compositions
comprising at least one poorly water soluble active substance (also referred
to as active
agent), preferably an endothelin conversion enzyme (ECE) inhibitor and/or a
neutral
endopeptidase (NEP) inhibitor in an amount greater than 10% w/w of the
composition,
an alkali system in an amount greater than 10% w/w of the composition
preferably
comprising a mixture of at least two alkaline compounds and optionally one or
more
pharmaceutically acceptable excipients.
[0002] More preferably, with the alkali system comprising a mixture of at
least two
alkaline compounds in the ratio 1:20 to 20:1, the active agent is a compound
of the
R2
R4 O 0 H R3
N Mn+
Ri H H
2 N,
C-COO
0 H2
n
general formula
(I)
wherein:
Ri is selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which
may be substituted by a(Ci-C6)alkoxy, phenyl-(Ci-C6)-alkyl and phenyloxy-
(C1-C6)-alkyl wherein the phenylgroup may be substituted with (C1-C6)alkyl,
(C1-C6)alkoxy or halogen, and naphtyl-(C1-C6)-alkyl,
R2 and R3 are both independently hydrogen or halogen,
R4 is a biolabile ester forming group,
M is a hydrogen or a metal ion, preferably a bivalent metal ion.
n is 1, 2 or 3; or its pharmaceutically acceptable hydrates and solvates.
Even more preferably, with the alkali system comprising a mixture of at least
two
alkaline compounds in the ratio 1:20 to 20:1, the active agent is 1H-1-
Benzazepine-l-
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acetic acid, 3-[[[1-[2-(ethoxycarbonyl)-4-
phenylbutyl]cyclopentyl]carbonyl]amino]-
2,3,4,5-tetrahydro-2-oxo- (SLV 306). An even more preferred compound is said
compound in its 3S,2'R form. The most preferred compound is SLV-306 as its
Ca2+ salt
or its pharmaceutically acceptable hydrates and solvates.
[0003] In the framework of the present invention suitable groups R4 forming
biolabile
esters include lower alkyl groups, phenyl or phenyl-lower-alkyl groups which
are
optionally substituted in the phenyl ring by lower alkyl or by a lower
alkylene chain
bonded to two adjacent carbon atoms, dioxolanylmethyl groups which are
optionally
substituted in the dioxolane ring by lower alkyl, or C2 -C6 -alkanoyloxymethyl
groups
which are optionally substituted on the oxymethyl group by lower alkyl. Where
the
group R4 forming a biolabile ester is lower alkyl, this can be a preferably
unbranched
alkyl group with 1 to 4, preferably 2, carbon atoms. Where the group forming a
biolabile ester is an optionally substituted phenyl-lower-alkyl group, its
alkylene chain
can contain 1 to 3, preferably 1 carbon atoms. Where the phenyl ring is
substituted by a
lower alkylene chain, this can contain 3 to 4, in particular 3, carbon atoms.
Particularly
suitable phenyl-containing substituents R4 are phenyl, benzyl or indanyl.
Where R4 is
an optionally substituted alkanoyloxymethyl group, its alkanoyloxy group can
contain 2
to 6, preferably 3 to 5, carbon atoms and is preferably branched and can be,
for
example, a pivaloyloxymethyl radical (tert-butylcarbonyloxymethyl radical).
[0004] The compositions of the present invention are easy to formulate and
possess
improved solubility and stability. The present invention also describes
process for
preparation of such improved compositions and method of using such
compositions.
Background of the invention.
[0005] Endothelins (ETs) are potent vasoconstrictors, promitogens, and
inflammatory
mediators. They have been implicated in the pathogenesis of various
cardiovascular,
renal, pulmonary, and central nervous system diseases. Since the final step of
the
biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes
(ECEs),
inhibitors of these enzymes may represent novel therapeutic agents. Currently,
seven
isoforms of these metalloproteases have been identified; they all share a
significant
amino acid sequence identity with neutral endopeptidase (NEP), another
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metalloprotease. Therefore the majority of ECE inhibitors also possess potent
NEP
inhibitory activity. To date, three classes of ECE inhibitors have been
synthesized: dual
ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE
inhibitors. An
agent which suppresses endothelin production, such as an ECE inhibitor, or
which
inhibits the binding of endothelin to an endothelin receptor, such as an
endothelin
receptor antagonist, antagonizes various physiological effects of endothelin
and
produces beneficial effects in a variety of therapeutic areas. Endothelin
receptor
antagonists and ECE inhibitors are therefore useful in treating a variety of
diseases
affected by endothelin. A non-exhaustive list of such diseases includes
chronic heart
failure, myocardial infarction, cardiogenic shock, systemic and pulmonary
hypertension, ischemia-repurfusion injury, atherosclerosis, coronary and
systemic
vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage and the
like.
[0006] SLV-306 (daglutril) is an orally active inhibitor of neutral
endopeptidase (NEP)
and endothelin conversion enzyme (ECE). It belongs to the class of
benzazepine,
benzoxazepine and benzothiazepine-N-acetic acid derivatives which contains an
oxo
group in the alpha position relative to the nitrogen atom and are substituted
in position
3 by a 1-(carboxyalkyl) cyclopentyl-carbonylamino radical. These compound and
their
salts and biolabile esters fall under the scope of protection of the present
invention and
have NEP-inhibitory effects on the heart, as described in Waldeck et al., US
5,677,297
and EP 0733642. The benzazepine-N-acetic acid compounds used in the present
invention are known from EP 0733642, EP 0830863, WO 00/48601 and WO 01/03699,
and can be produced by the methods described in said US 5,677,297 and EP
0733642.
These patents are related to these compounds and their physiologically
acceptable salts
as such and to the use of the compound in heart insufficiency. WO 03/059939
relates to
specific salts of these compounds, especially to the calcium salt. EP 0830863,
W000/48601 and WO01/03699 are related to the use of the above compounds in the
improvement of gastrointestinal blood flow, in the treatment of hypertension
and in the
treatment and prophylaxis of cardiac damages induced by adriamycin and
comparable
anti-cancer drugs, respectively.
[0007] Various active substances have a very poor solubility in the gastric
fluid. When
these active substances are administered to the body, they often have a poor
bio-
availability due to the poor solubility in the digestive fluid. In order to
solve this
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problem several methods were developed, such as micronization, inclusion in
cyclodextrins, the use of inert water-soluble carriers, the use of solid
dispersions (WO
00/00179) or solid solutions or nanocrystalline or amorphous forms of an
active
substance. Also the compounds described in US 5,677,297 and EP 0733642,
including
SLV-306 are poorly bio-available drugs due to the poor solubility in the
gastric fluid.
Even when SLV-306 is used in its salt form, it forms a gel like structure in
the acid
gastric fluid. The gel like structure formed is very difficult to solubilize
again even
under alkaline conditions, leading to a low overall bioavailability.
[0008] WO 03/068266 describes an oral solid solution formulation of compounds
of
formula (I) having enhanced bio-availability compared with said active
substance in a
traditionally formulated form. Although this formulation has superior
bioavailability
properties, it has the draw-back that it is formed via a melt mixture leading
to some
restrictions: it has to be formulated either into a capsule, or into a tablet
via melt-
extrusion technique. Further the size of the formulation will be too large for
higher
dosages.
[0009] WO 06/067150 (not pre-published) describes an oral immediate release
formulation of compounds of formula (I) comprising the active substance in an
amount
up to 60% of the total weight of the formulation, at least 10 % w/w of an
alkaline
compound or a mixture of alkaline compounds, between 0.1 and 10% w/w of one
ore
more surfactants and optionally auxiliary materials in an amount of between 1%
and
45% of the total weight of the formulation. Especially when docusate sodium is
used as
the surfactant a good bioavailability of the active substance is obtained.
Summary of the invention
[0010] It is the objective of the present invention to provide an alternative
oral
formulation for the compounds with a low oral bio availability, especially for
endothelin
conversion enzyme (ECE) inhibitors and/or neutral endopeptidase (NEP)
inhibitors
with a significant increase in bio-availability compared with said active
substance in a
traditionally formulated form, the new oral formulation being sufficiently
stable for
commercial use and also being useful in the preparation of formulations with a
high
content of active substance with a reasonable size and optionally without the
use of a
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surfactant. It is a further objective of the present invention to provide a
formulation
which can be prepared using normal formulation procedures and equipment, so
that no
substantial investment is not necessary.
[0011 ] It is another objective of the present invention to provide a process
for the
preparation of such improved compositions.
[0012] It is also an objective of the present invention to provide an improved
oral
pharmaceutical composition comprising at least one poorly soluble active
agent,
preferably an endothelin conversion enzyme (ECE) inhibitor and/or a neutral
endopeptidase (NEP) inhibitor other than a compound of the above general
Formula (I)
in an amount greater than 10% w/w of the composition, a alkali system in an
amount
greater than 20% w/w of the composition and optionally one or more
pharmaceutically
acceptable excipients.
[0013] It is a further objective of the present invention to provide an
improved oral
pharmaceutical composition comprising at least one poorly soluble active
agent,
preferably endothelin conversion enzyme (ECE) inhibitor and/or neutral
endopeptidase
(NEP) inhibitor, other than a compound of the above general Formula (I), in an
amount
greater than 10% w/w of the composition, an alkali system in an amount greater
than
20% w/w of the composition comprising a mixture of at least two alkaline
compounds,
and optionally one or more pharmaceutically acceptable excipients.
[0014] It is an even further objective of the present invention to provide an
improved
oral pharmaceutical composition comprising at least one poorly soluble active
agent,
preferably endothelin conversion enzyme (ECE) inhibitor and/or neutral
endopeptidase
(NEP) inhibitor, preferably a compound of the above general Formula (I), in an
amount
greater than 10% w/w of the composition, an alkali system in an amount greater
than
20% w/w of the composition comprising a mixture of at least two alkaline
compounds
in the ratio 1:20 to 20:1 and optionally one or more pharmaceutically
acceptable
excipients.
[0015] It is a further objective of the present invention to provide an
improved oral
pharmaceutical composition comprising SLV-306 or its pharmaceutically
acceptable
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salts, esters, hydrates, solvates, isomers or derivatives as active agent in
an amount
greater than 10% w/w of the composition, a alkali system in an amount greater
than
20% w/w of the composition comprising a mixture of at least two alkaline
compounds
in the ratio 1:20 to 20:1 and optionally one or more pharmaceutically
acceptable
excipients.
[0016] It is another objective of the present invention to provide a process
for the
preparation of such improved compositions which comprises of the following
steps:
i) mixing the active agent and alkali system optionally with one or more
pharmaceutically acceptable excipients, and
ii) formulating of the mixture produced in (i) into a suitable dosage form.
[0017] It is yet another objective of the present invention to provide a
method of using
such composition which comprises administering to a patient in need thereof an
effective amount of the composition.
[0018] The improved compositions of the present invention are easier to
formulate and
possess improved solubility and stability.
Detailed description of the invention.
[0019] The present invention provides improved oral pharmaceutical
compositions
comprising at least one, in acid, poorly soluble active agent, preferably
endothelin
conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP)
inhibitor, other
than a compound of the above general Formula (I), in an amount greater than
10% w/w
of the composition, an alkali system in an amount greater than 10% w/w of the
composition and optionally one or more pharmaceutically acceptable excipients.
Preferably the alkaline system comprises a mixture of at least two alkaline
compounds.
[0020] In the framework of the present description surfactants are defined as
molecules
with well defined polar and non-polar regions that allow them to aggregate in
solutions
to form micelles. Depending on the nature of the polar area, surfactants can
be non-
ionic, anionic, cationic and zwitterionic. Examples of non-ionic hydrophilic
surfactants
are polyoxyethylene sorbitan esters, cremophores and poloxamers. Examples of
anionic
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surfactants are sodium lauryl sarcosinate, docusate and pharmaceutically
acceptable
docusate salts such as docusate calcium, docusate sodium and docusate
potassium.
[0021] Inhibitors of neutral endopeptidase (NEP) and/or endothelin conversion
enzyme
(ECE) within the scope of this invention, include but are not limited to CGS
26303,
phosphoramidon, FR901533, TMC-66, SM-19712, SLV-306, KC-12615, KC-90095-1-
AC, CGS-26303, CGS-30440, CGS-31447, CGS-26670, Sch-54470, and the
pharmaceutically acceptable salts, esters, isomers, derivatives and prodrugs
thereof.
[0022] In a further embodiment of the present invention, the alkali system
comprises an
alkaline compound or a mixture of at least two alkaline compounds selected
from but
not limited to the group consisting of sodium bicarbonate, sodium carbonate,
potassium
bicarbonate, potassium carbonate, magnesium carbonate, calcium carbonate, tris
buffer,
triethanolamine; alkaline hydroxides such as sodium hydroxide, potassium
hydroxide
or magnesium hydroxide; alkaline phosphates such as disodium hydrogen
phosphate,
dipotassium hydrogen phosphate, dicalcium phosphate; and meglumine or mixtures
thereof.
[0023] Preferably the alkali system is present in an amount greater than 10%
w/w of the
composition, more preferably greater than 20% w/w, or is present in an amount
greater
than 30% w/w, 40% w/w, 50% w/w, 55% w/w or 60% w/w of the composition.
[0024] In a preferred embodiment of the present invention, the alkali system
of the
composition comprises a mixture of at least two alkaline compounds in the
ratio 1:20 to
20:1 w/w.
[0025] In another embodiment, with the alkali system comprising a mixture of
at least
two alkaline compounds in the ratio 1:20 to 20:1 w/w, the endothelin
conversion
enzyme (ECE) inhibitor or neutral endopeptidase (NEP) inhibitor has the
general
formula (Formula-1)
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R2
R4 p p Rs
y N Mn+
Ri H H N
2 C- COO-
O H2
n
Formula-1
Wherein:
Ri is a selected from the group consisting of (C1-C6) alkoxy(C 1 -C6) alkyl
which
may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-
(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl,
(C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl,
R2 and R3 are both independently hydrogen or halogen,
R4 is a biolabile ester forming group,
M is a hydrogen or a metal ion, preferably a bivalent metal ion
nisl,2or3;
[0026] In a preferred embodiment, with the alkali system comprising a mixture
of at
least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is
the
endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP)
inhibitor, SLV-306, of chemical formula 3-(1-(2'-(Ethoxycarbonyl)-4'-phenyl-
butyl)-
cyclopentan-l- carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-l-benzazepin-l-
acetic
acid or at least one pharmaceutically acceptable salt, esters hydrate,
solvate, isomer or
derivative thereof.
[0027] In a more preferred embodiment, with the alkali system comprising a
mixture of
at least two alkaline compounds in the ratio 1:20 to 20:1 w/w, the active
agent is SLV-
306 in its calcium salt form .
[0028] The most preferred compound, with the alkali system comprising a
mixture of at
least two alkaline compounds in the ratio 1:20 to 20:1 w/w, is the SLV-306
calcium salt
in its 3S, 2'R form. This compound is referred to as Compound S-Ca, the
corresponding acid (1H-1-Benzazepine-l-acetic acid, 3[[[1-[2-(ethoxycarbonyl)-
4-
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phenylbutyl] -cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-) is
referred to as
Compound S-H, the corresponding sodium salt is referred to as Compound S-Na.
[0029] In one embodiment, the active agent of Formula-1 is present in the
composition
in an amount between about 10% and 80% by weight of the composition,
preferably in
an amount between about 15 and 75% by weight of the composition. The active
agent
is or may optionally be used in a micronized form.
[0030] In further preferred embodiment, the alkali system comprises a mixture
of
sodium bicarbonate and sodium carbonate (Effer-SodaTM-12) marketed by SPI
Pharma.
Effer-SodaTM-12 is a highly stable, surface modified sodium bicarbonate
powder. It is
produced by converting the surface of sodium bicarbonate particles to sodium
carbonate. Primarily, Effer-SodaTM-12 contains 83-90% w/w sodium bicarbonate
and
10-17% w/w sodium carbonate. The outer layer of sodium carbonate absorbs
moisture
(from the atmosphere or composition) and forms sodium sesquicarbonate, which
is
stable up to 70 C temperature. This protection mechanism provided by the heat
stable
sodium sesquicarbonate prevents early effervescent reaction at ambient and
elevated
temperature storage conditions.
[0031] Surprisingly the inventors of the present invention have found that
using an
alkaline compound in the formulation, alone or in a mixture e.g. Effer-SodaTM-
12, even
without any surfactant in the composition prevents the difficult to solubilize
gel
formation in the acid gastric fluid, thereby enhancing the solubility of SLV-
306 as
evidenced during in vitro dissolution studies in a biphasic dissolution model
(see
Example 1a), which indicates an improvement in the in vivo solubility as well
and thus
improvement in bioavailability. Further the compositions have a good stability
upon
storage. Further since the Effer-SodaTM-12 is granular in nature, its use in
formulating
the compositions of the present invention has improved the flow properties and
compressibility of material used to formulate the desired dosage form and also
improved its machinability.
[0032] Specific solid alkaline compounds like the bicarbonates and carbonates
as
indicated above are often used in combination with solid acidic compounds
(e.g. citric
acid, tartaric acid, adipic acid, fumaric acid, succinic acid, ascorbic acid,
nicotinic acid,
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saccharin, aspirin, malic acid, sodium dihydrogen phosphate, disodium
dihydrogen
pyrophosphate, sodium dihydrogen citrate and disodium hydrogen citrate) in
effervescent compositions. In the present invention the composition preferably
does not
contain an acidic compound.
[0033] In another embodiment of the present invention, the pharmaceutical
compositions of present invention optionally comprise one or more
pharmaceutically
acceptable excipients selected from but not limited to a group comprising
diluents,
disintegrants, binders, polymers, solubilizers, fillers, bulking agents, anti-
adherants,
anti-oxidants, buffering agents, colorants, flavoring agents, coating agents,
plasticizers,
surfactants, organic solvents, stabilizers, preservatives, lubricants,
glidants, chelating
agents, and the like known to the art used either alone or in combination
thereof.
[0034] Diluents that can be used in the present invention include lactose,
calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate,
microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran,
starches,
pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, and the
like or
mixtures thereof.
[0035] Binders that can be used in the present invention include acacia,
alginic acid and
salts thereof, cellulose derivatives, methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, polyethylene glycol, gums, polysaccharide acids,
gelatin,
polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer,
polymethacrylates, hydroxypropyl-methylcellulose, ethylcellulose, starch,
pregelatinized starch, tragacanth, dextrin, microcrystalline cellulose,
sucrose, or
glucose, and the like or mixtures thereof can be used.
[0036] Disintegrants useful in the present invention are selected from but not
limited to
starches, pregelatinized starch, celluloses, cross-linked
carboxymethylcellulose,
crospovidone, crosslinked polyvinylpyrrolidone, a calcium or a sodium alginate
complex, clays, alginates, sodium starch glycolate, croscarmellose sodium and
the like
or mixtures thereof.
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[0037] Lubricants that can be used in the present invention include magnesium
stearate,
sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl
behenate,
stearates, waxes and the like or mixtures thereof can be used. Stabilizers
such as
antioxidants, buffers, or acids, and the like are useful in the present
invention. Glidants
such as talc, colloidal silicon dioxide or the like.
[0038] Polymers that can be used in formulating a composition according to the
present
invention include cellulosic derivatives, polyalkylene oxides, acrylic acid
and
methacrylic acid polymers, crosslinked polyacrylic acids, polysaccharide gums
such as
xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum,
alginic
acid, alginates, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan,
dextran,
amylose, amylopectin, dextrin, and the like or mixtures thereof can also be
additionally
used in formulating the compositions of the present invention. Solubilizers
such as
polyethylene glycol and their derivatives, for example, Gelucire such as
Gelucire
50/13 (Gattefosse); polyoxyethylene alkyl ethers such as polyoxyethylene
stearyl ether,
polyoxyethylene oleyl ether and polyoxyethylene cetyl ether which are
available under
the Brij and Cetomacrogol series trade names; polyvinylpyrrolidone K-30,
polyvinylpyrrolidone K-90 or Kollidon(t VA 64; polar solvent; and the like
used either
alone or in combination.
[0039] The present invention also relates to a process of preparing the
formulation as
described above. In a first embodiment of this aspect of the present
invention, the
process for the preparation of such improved compositions comprises of the
following
steps:
i) mixing the active agent and alkali system optionally with one or more
pharmaceutically acceptable excipients, and
ii) formulating the mixture produced in (i) into a suitable dosage form.
[0040] In a preferred embodiment of the process of the present invention, this
process
comprises the following steps:
i) mixing the active agent, alkali system, and lubricant,
ii) optionally adding one or more other pharmaceutically acceptable
excipients,
forming a mixture, and
iii) formulating the mixture produced in (i) and (ii) into a suitable dosage
form.
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[0041] In a further preferred embodiment of the process of the present
invention, the
process comprises:
i) mixing SLV-306 or at least one pharmaceutically acceptable salt, ester,
hydrate, solvate, isomer or derivative thereof; the alkali system, the
disintegrant and the lubricant,
ii) optionally adding one or more other pharmaceutically acceptable
excipients,
forming a mixture, and
iii) formulating the mixture produced in (i) and (ii) into a suitable dosage
form.
[0042] In a further embodiment, the composition of the present invention is in
the form
of a solid dosage form such as tablets, capsules, patches or the like,
preferably as
tablets. The tablets can be prepared by either direct compression, dry
compression
(slugging), or by granulation. In a preferred embodiment of the present
invention, the
oral composition is prepared by compression or compaction. The granulation
technique
is either aqueous or non-aqueous. The non-aqueous solvent used is selected
from a
group comprising ethanol, isopropyl alcohol, ethyl acetate, methyl t-butyl
ether
(MTBE), and methylene chloride. In an embodiment, the compositions of the
present
invention are in the form of compacted tablets, compressed tablets, moulded
tablets,
and the like.
[0043] When the formulations of the present invention are provided in the form
of
tablets, these tablets have disintegration times of between 5 minutes and 90
minutes.
Preferably the disintegration times are below 60 minutes and most preferably
they are
below 45 minutes. Formulations with short disintegration times can be prepared
by
using a mixture of sodium bicarbonate and sodium carbonate as available, e.g.,
in
Effer-SodaTM-12.
[0044] The present invention also provides a method of using such composition
which
comprises administering to a patient in need thereof an effective amount of
the
composition. The compositions can be used in the treatment of chronic heart
failure,
myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension,
ischemia-repurfusion injury, atherosclerosis, coronary and systemic
vasospastic
disorders, cerebral vasospasm, and subarachnoid hemorrhage.
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[0045] The improved compositions of the present invention are easier to
formulate and
possess improved solubility and stability.
[0046] The following examples are only intended to further illustrate the
invention, in
more detail, and therefore these Examples are not deemed to restrict the scope
of the
invention in any way.
[0047] EXAMPLES.
[0048] Example 1. Materials and methods
[00491 Materials.
S-Ca were prepared according to the prescription given in Examples 2 and 3 of
W003/059939 starting with the acid prepared according to Example 2 of EP
0733642.
In all Examples the actual amount of S-Ca is given. 103.75 mg S-Ca corresponds
with
100 mg S-H which is the active principle.
Sodium bicarbonate can be obtained from Sigma Aldrich or Canton Labs, India.
Effer-SodaTM-12 can be obtained from SPI Pharma, Newcastle, Delaware US.
All other auxiliary materials are readily commercially available.
[00501 Methods.
Description of the bi-phase in-vitro dissolution method.
The bi-phase dissolution was performed with the USP apparatus 2 configuration.
The
paddle speed was 50 rpm and the temperature of the vessels (and so the
dissolution
medium) was maintained at 37.0 C using Vankel VK7010 equipment.
The dissolution of the formulations was started in 500 m10.1 M hydrochloric
acid (4.2
ml concentrated hydrochloric acid (HC1) in 500 ml water)(phase 1). After 0, 5,
15 and
minutes a sample was taken. After 30 minutes 500 ml 1 M phosphate buffer (32.4
gram sodium di-hydrogen phosphate NaH2PO4 and 124.8 gram di-sodium hydrogen
phosphate (NazHPO4) in 1000 ml water was added to phase 1. Addition of the
30 phosphate buffer changed the pH of the dissolution medium from pH 1 in
phase 1 to pH
6.8 in phase 2. During the dissolution test the pH of both phases remained
unchanged.
Samples were taken after 35, 45 and 60 minutes.
All the samples were filtered through a Pall Zymark Acrodisc PSF, GxF/GHP,
0.45 m
or a Millipore Millex-FH (hydrophobic PTFE 0.45 m) filter.
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The quantity of the dissolved daglutril in the filtered samples was analyzed
by off-line
UV measurements at 240 nm using external standardization.
In an earlier comparative study with the calcium salt of the compound SLV306
(S-Ca),
it has been shown that this bi-phase in vitro dissolution method has a good
correlation
with in-vivo results.
[0051 ] Example 2: Preparation of a traditionally formulated coated tablet of
SLV-
306.
Ingredients Quantity (mg/tablet)
S-Ca 414.25
Micro crystalline cellulose PH301 249.00
Cross-linked polyvinylpyrrolidon 14.00
Sodium stearyl fumarate 1.75
Opadry II Yellow coating 21.00
Tablet weight 700.00
[0052] Procedure:
i) Compact S-Ca and pass the compact through a 1.0 mm sieve.
ii) Mix material of step (i) with micro crystalline cellulose PH301, cross-
linked
polyvinylpyrrolidon and sodium stearyl fumarate to obtain a uniform
mixture.
iii) Compress the material of step (ii) using a tablet compression machine.
iv) Coat the tablets from step (iii) in suitable coating equipment.
[0053] Example 3: Preparation of tablets of SLV-306 containing Effer-SodaTM-12
Ingredients Quantity (mg/tablet)
Tablet I Tablet II
S-Ca 622.5 622.5
Effer-SodaTM-12 299.5 599.5
Magnesium stearate 10.0 13.0
Sodium starch glycolate 33.0 65.0
Opadry II Yellow coating 35.0 47.2
Tablet weight 1000.0 1347.2
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[0054] Procedure:
i) Sift S-Ca, Effer-SodaTM-12, Magnesium stearate and Sodium starch
glycolate through an appropriate sieve, e.g. a #40 mesh sieve.
ii) Mix the S-Ca, Effer-SodaTM-12 and a portion of Magnesium stearate and
Sodium starch glycolate sifted above to obtain a uniform mixture.
iii) Compact the material of step (ii) and pass the compact through an
appropriate sieve, e.g. a #30 mesh sieve.
iv) Mix material of step (iii) with the remaining quantity of Magnesium
stearate
and Sodium starch glycolate.
v) Compress the material of step (iv) using a tablet compression machine
vi) Coat the tablets of step (v) by spraying an Opadry II Yellow 85F22185
aqueous suspension on the tablets followed by drying the tablets.
[00551 Example 4. Comparative dissolution study for SLV306 formulation with
Effer-SodaTM-12 and a traditionally formulated tablet
A comparative dissolution study according to the method described in Example 1
was
carried out on one batch of a traditionally formulated tablet (Tablet A,
prepared as
described in Example 2) and two batches of the calcium salt of SLV-306 (S-Ca)
(Tablet
B, prepared as described in Example 3(I) and Tablet C, prepared as described
in
Example 3 (II)).
The release profile of these formulations is given in the Table below and
depicted in
Figure 1. From this study it can be concluded that a formulation of S-Ca with
a high
drug load and a favorable release profile can be prepared.
Time Drug Release in %
(min)
Tablet A Tablet B Tablet C
0 0 -0.02 0.00
5 1.1 -0.02 0.10
15 1.6 -0.03 0.15
1.9 -0.07 0.08
30 35 31.4 51.99 60.88
45 49.1 76.76 75.73
60 57.4 88.27 87.79
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[0056] Example 5: Preparation of film-coated tablets of SLV-306 containing
Effer-
Soda.
Ingredients Quantity (mg/ tablet)
S-Ca 311.25
Effer-SodaTM-12 300.00
Microcrystalline cellulose (Avicel 310.00
Croscarmellose sodium 20.00
Isopropyl alcohol q.s (lost in processing)
Hydrogenated castor oil (Lubritab(t) 7.50
Purified talc 7.50
Colloidal silicon dioxide 7.50
Opadry II Yellow 85F22185 30.00
Purified water q.s. (lost in processing)
[0057] Procedure:
i) Sift S-Ca, Effer-SodaTM-12, Microcrystalline cellulose (Avicel(t PH 101)
and Croscarmellose sodium through an appropriate sieve, e.g. a #40 mesh
sieve and mix.
ii) Granulate the mixture using Isopropyl alcohol followed by sifting through
an appropriate sieve, e.g. a #24 mesh sieve and drying.
iii) Sift Hydrogenated castor oil (Lubritab(t), Purified talc and Colloidal
silicon
dioxide through an appropriate sieve, e.g. a #40 mesh sieve and mix.
iv) Add the material of step (iii) to the material of step (ii) and mix.
v) Compress the material of step (iv) using a tablet compression machine.
vi) Coat the tablets of step (v) by spraying an Opadry II Yellow 85F22185
suspension in water on the tablets followed by drying the tablets.
[0058] Example 6: Preparation of capsules of SLV-306.
Ingredients Quantity (mg/ capsule)
S-Ca 311.25
Magnesium carbonate 150.00
Dicalcium phosphate 131.25
Sodium starch glycolate 30.00
Magnesium stearate 10.00
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[0059] Procedure:
i) Sift S-Ca, Magnesium carbonate, Dicalcium phosphate, Sodium starch
glycolate and Magnesium stearate through an appropriate sieve, e.g. a #40
mesh sieve and mix.
ii) Compact the material of step (i) and pass the compacts through #30 mesh
sieve.
iii) Lubricate the material of step (ii) with #60 mesh sieve passed Magnesium
stearate.
iv) Fill the material of step (iii) into a hard gelatin capsule.
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