Note: Descriptions are shown in the official language in which they were submitted.
CA 022~4411 1998-11-18
TICLOPIDINE HCL FORMULATION
FIELD OF THE INVENTION
This invention relates to pharmaceutical
formulations. More specifically, it relates to orally
administrable dosage formulations of ticlopidine and similar
compounds, an to processes for inhibiting the degradation of
ticlopidine over time.
BACKGROUND OF THE INVENTION
Ticlopidine, the generic name of the pharmaceutical
substance 5-[(2-chlorophenyl)methyl]-4,5,6,7-
tetrahydrothieno-[3,2c]pyridine, of chemical formula:
~ ~
is a known pharmaceutical substance, useful as a platelet
aggregation inhibitor. It is marketed commercially as its
hydrochloride addition salt, in the form of orally
administrable tablets. As an amine compound, it is desirable
to stabilize it against oxidation, by protonation of its
amine group, i.e. by preparing formulations which include an
acid stabilizing compound. Without such stabilizer, and in
the presence of common tablet excipients such as magnesium
stearate, polyvinyl polyvinylpyrrolidone and the like, it
discolors, from white to a grey/brown color through
oxidation.
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BRIEF DESCRIPTION OF THE PRIOR ART
Ticlopidine HCl formulations commonly include a
stabilizing amount of an organic acid to enhance it:s
stability and hence increase its storage life. Thus,
Canadian Patent 1,176,170 Chowhan (Syntex) discloses
stabilized ticlopidine HCl compositions using non-volatile
organic acid, especially citric acid, as a stabilizer.
Canadian Patent Application 2,100,836 Sherman proposes the
use of stearic acid, without any other organic acid, as
stabilized in ticlopidine HCl formulations.
There are significant disadvantages to the use of
these organic acids in ticlopidine HCl formulations. Citric
acid, which is soluble in water so that mixing in compounding
processes using it are relatively simple, is nevertheless
expensive, and relatively large quantities of citric acid are
needed in order to bring the aqueous solution pH of the
formulation into the correct acidity range, pH 3-4. As a
naturally solid, crystalline material, it tends to crystalize
out of solution and upset solution blending procedures.
Stearic acid, on the other hand, is largely insoluble in
water, so that processes which use aqueous formulations for
homogeneous mixing and dispersing of the ingredients cannot
conveniently be used when stearic acid is chosen as
stabilizer. Over-mixing of compositions containing stearic
acid can result in reduced bio-availability, owing to the
fact that stearic acid can act in part as an emulsifier, to
coat and separate individual particles of the mixture from
the bio-available bulk of particles. Organic stabilizers in
general, and stearic and citric acid stabilizers in
particular, have a negative impact on the compressibility of
the final composition, leading to brittle materials which are
very much harder to compress. This is particularly so when
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the acid has to be used in substantial amounts to be
effective as a stabilizer, as in the case of citric acid.
It is an object of present invention to provide
novel formulations of ticlopidine HCl which exhibit good
storage stability without significant discoloration and
without significantly affecting the ln vivo rate and extent
of release of the active ingredient after storage.
SUMMARY OF THE INVENTION
The present invention provides stable, solid,
orally administrable dosage compositions of ticlopidine HCl
and a stabilizing amount of phosphoric acid, along wit:h
pharmaceutically acceptable carrier materials. It has been
found according to the present invention that phosphoric acid
is an effective stabilizer for ticlopidine HCl, and can
readily be incorporated in dosage formulations thereof to
provide storage stable solid compositions such as tablets,
with acceptable bio-availability after storage.
Phosphoric acid is approved as acceptable for use
in various formulations of edible products. However, as far
as is known, it has not been used in practice in any
pharmaceutical formulations. It does however exhibit
significant advantages in practice. As a normally liquid,
water soluble/miscible compound, it is very easy to mix into
intimate, homogeneous mixtures with solid pharmaceutical
compositions. It is inexpensive, readily available,
adequately biocompatible and does not interfere with the bio-
availability of the active pharmaceutical ingredients. As a
strongly acidic compound, only small amounts are required to
bring the ticlopidine HCL formulation pH into the required
low range for stability.
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DESCRIPTION OF THE ~RED EMBODIMENTS
To be effective as a stabilizer, the phosphoric
acid used in the formulations of the invention should be used
in amounts effective to provide formulations having pH from
about l to about 5.5 in aqueous solution. Thus, the precise
amount of phosphoric acid to be used depends upon the tablet
size, the amount of active ingredient and the acidity of any
other ingredients included in the formulation. When all of
the ingredients except the ticlopidine HCl and the phosphoric
stabilizing agent are substantially neutral, such an
effective amount of phosphoric acid is from about 0.5 to
about 3 parts by weight of 85% phosphoric acid per l00 parts
by weight of ticlopidine HCl, preferably from about l-l.5
parts by weight per l00 parts by weight of ticlopidine HCl.
Some routine experimentation may be required to determine the
optimum amount of phosphoric acid, for each individual dosage
formulation, but this is well within the skill of the art.
Typical additional ingredients for use in
formulations according to the invention are those commonly
used in pharmaceutical tablets, such as microcrystalline
cellulose or other cellulose derivatives, starch and starch
derivatives, crosslinked polyvinylpyrrolidone (povidone), to
act as carriers or excipients, vegetable oils to provide the
necessary binding characteristics for the tablets, and
magnesium stearate and the like, to act as a lubricant in
forming the tablets. Typically, the active ingredient
ticlopidine HCl constitutes more than 50% of the total
weight, preferably from 55-75%, of the formulation.
Mixing procedures for preparing compositions
according to the invention are generally in accordance with
standard procedures known in the art. Typically, the active
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ingredient, ticlopidine HC1 and carriers, e.g.
microcrystalline cellulose, corn starch and sodium starch
glycolate, are initially mixed to form a dry homogeneous
powder. The phosphoric acid stabilizer and the povidone are
added slowly to water, and mixed at slow speed to form a
solution. Then the solution is added slowly to the powder
mixture in, for example, a ribbon blender and mixed to form
a uniform wet mass, optionally with the addition of more
water. After thorough mixing in this way, the wet mass is
dried, e.g. on trays in a forced air drying oven, to obtain
dry granules of the mixed formulation.
The preparation of tablets from such a granular
formulation can be conducted in standard tableting apparatus,
e.g. by compression into cores of appropriate size. After
tablets have been prepared, they are suitably film coated,
using a solution of film forming colored or clear material.
The coating solution or suspension is appropriately sprayed
onto the tablets, followed by drying.
Specific examples of the most preferred embodiments
of the invention will now be described in detail, these to be
viewed as illustrative of the present invention and not
limiting.
EXAMPLE 1
Film coated tablets of ticlopidine HCl active
ingredient 250 mg were prepared according to the following
formulation:
Ticlopidine HCl 250 mg (63.29%)
Microcrystalline cellulose 66.60 mg (16.86%)
Corn Starch 33.57 mg (8.50%)
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Sodium Starch Glycolate 9.88 mg (2.5)
Purified Water (Retained) 7,90 mg (2.00%)
Phosphoric acid (85%) 3.35 mg (0.85%)
Povidone 15.80 (4.00%)
Hydrogenated vegetable oil (Sterotex) 5.93 mg
(1.50%)
Magnesium Stearate 1.97 mg (0.50%)
Initially, there was prepared a dry granular
mixture of the microcrystalline cellulose, ticlopidine HCl,
corn starch and a portion of the sodium starch glycolate, in
a ribbon blender, with mixing for 15 minutes, in a batch size
sufficient to make 150,000 tablets (59.25 kg of active
ingredient). There was separately prepared, in a mixer, a
solution of phosphoric acid and povidone in purified water,
the phosphoric acid and povidone being added slowly into the
water during mixing, and mixing being continued until a clear
solution was obtained. Then the solution was slowly added
evenly over the mixing powders in the ribbon blender, and
mixing was continued, at room temperature, until a uniform
wet mass was obtained. The wet granules were screened and
then spread evenly onto drying trays and placed on racks for
forced air drying at 43~C. for 2-5 hours. After further
screening, the granules were fed into a ribbon blender and
mixed for a further three minutes. Then the remainder of the
sodium starch glycolate was added and mixed in, followed by
the addition of the hydrogenated vegetable oil and magnesium
stearate, with mixing for a further minute. This composition
was tableted into round modified concave tablets with a
conventional punch tableting apparatus, to give tablets of
395 mg average individual weight. The tablets were film
coated by spraying with an aqueous solution of Dri-Klear-042
~Trade-mark
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(825 g in 5525 g water) for sealing purposes. Dri-Klear-042
is a commercially available, proprietary composition of
hydroxypropyl methylcellulose, talc and triethyl citrate. The
tablets had acceptable hardness and disintegration
S resistance.
EXAMPLE 2
Tablets prepared as described above in Example 1
were tested for stability in an accelerated stability test.
For this test, the tablets were stored for 4 weeks at 40"C
under conditions of 75% relative humidity, to represent
accelerated storage conditions.
15Assays of the tablets before and after the
accelerated stability test showed no difference in their bio-
availability, and no significantly difference in their
appearance. Whilst the initial appearance of the tablets
was, in color, white to off-white, after the 4 week stability
test they were more off-white. Otherwise there was no
difference, indicating that the formulation is stable.
EXAMPLE 3
25A stock standard solution of ticlopidine HCl
reference standard was prepared, by accurately weighing out
55.5 mg of the solid material and transferring it to 200 mL
volumetric flask. It was dissolved in 50 mL water and
diluted to 300 mL volume, with thorough mixing, to give a
30concentration of 0.2775 mg/mL. The solution was filtered
through a 1.2 ~m Acrodisc filter, discarding the first 100 mL
of filtrate.
A working standard solution was prepared from the
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stock standard solution, by transferring 5.0 mL of stock
standard solution filtrate to a 500 mL volumetric flask,
diluting to 50 mL volume with water and thorough mixing
(concentration - 0.02776 mg/mL).
Sample preparation was conducted using a standard
USP Apparatus 2 (paddles). One 250 mg tablet was placed into
each of the six dissolution vessels, the paddles lowered to
a distance of 2.5 cm from the bottom of each vessel, with the
10shaft centered. 900 mL of water at 37~C+0.5~C was added to
each vessel, and the paddles rotated at 50 rpm to effect
dissolution. An aliquot of solution was withdrawn, from the
mid-zone, filtered immediately through 1.2 ~m Acrodisc
filters, and the first 10 mL of each filtrate was discarded.
The remainders were collected in individual containers. 5.0
mL of each filtrate solution was transferred to a 50 mL
volumetric flask, diluted to 50 mL with water and thoroughly
mixed. Concentration - 0.02778 mg/mL.
20The amount of ticlopidine HCL dissolved was
determined by UV spectrophotometry, measuring UV absorbances
of solution under test at the wavelength of maximum
ticlopidine HCl absorbance, about 232 nm, in comparison with
the working standard solution.
In all samples, not less than 95% of the active
ingredient had dissolved after 45 minutes (range 95-99%).
Comparative, similar testing on a commercial ticlopidine HCl
formulation stabilized with citric acid showed almost exactly
the same dissolution characteristics - of six separate
samples, not less than 95% of the active ingredient had
dissolved at 45 minutes in each case, range 95-100%.
Assays conducted on tablets promptly after their
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manufacture and on tablets after the four week accelerated
storage described in Example 2, showed no differences in
their dissolution rates. Also, very similar results were
obtained when the dissolving medium was O.lN hydrochloric
S acid instead of water.
