Note: Descriptions are shown in the official language in which they were submitted.
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DILTIAZEM HYDROCHLORIDE FORMULATION
FIELD OF INVENTION
A pharmaceutical formulation containing diltiazem hydrochloride suitable for
once daily oral administration comprising a blend of beads having three
differing dissolution profiles.
BACKGROUND OF THE INVENTION
Diltiazem is a benzothiazine derivative possessing calcium antagonist
activity.
Diltiazem blocks the influx of calcium ions in smooth and cardiac muscle and
thus exerts potent cardio-vascular effects. Diltiazem has been shown to be
useful in alleviating symptoms of chronic heart disease, particularly angina.
pectoris and myocardial ischemia and hypertension, while displaying a low
incidence of side effects. The first dosage forms of diltiazem sold in the
United States were tablets containing 30 mg or 60 mg of diltiazem
hydrochloride sold under the tradename Cardizem* by Marion Laboratories
Inc. Single oral doses of 30 mg and to 120 mg of Cardizem* tablets result in
peak plasma levels about 2 to 3 hours after ingestion, and the elimination
half life is about 3 to 5 hours. Because of the relatively rapid absorption of
diltiazem hydrochloride from such tablets and rapid elimination, the usual
dosage regimen for immediate release tablets is for a dose to be taken three
or
four times daily. The need for such frequent administration may reduce
patient compliance. Thus adverse therapeutic effects can arise. It thus
became apparent that it would be preferable to administer diltiazem
hydrochloride in a dosage form that releases the diltiazem hydrochloride
much more slowly than Cardizem tablets, so as to enable the frequency of
ingestion by the patient to be reduced to once daily.
* trademark
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A formulation of diltiazem hydrochloride that controls the rate of release to
enable once daily administration is sold in the United States under the
trademark Dilacor* XR by Rhone-Poulenc Rorer Pharmaceuticals Inc.
Dilacor* XR is produced as two-piece hard gelatin capsules, with each
capsule containing a plurality of tablets. The 180 mg strength of Dilacor*
XR contains three tablets and the 240 mg strength contains four tablets. The
same tablets are used in both capsules, and each tablet contains 60 mg of
diltiazem hydrochloride.
The tablets used in Dilacor* XR are made in accordance with the invention of
United States patent 4839177.
Each tablet is comprised of a cylindrical core containing diltiazem
1 S hydrochloride mixed with inactive ingredients which include a polymer that
swells and forms a gel upon contact with aqueous fluids. Because the gel has
high viscosity it swells and dissolves only very slowly in the
gastrointestinal
fluids to thereby retard the rate of release of the diltiazem hydrochloride.
To
further retard the release, insoluble polymeric platforms are affixed to the
top
and bottom of the cylindrical core, thus leaving only the periphery exposed to
the gastrointestinal fluid. The formulation of Dilacor* XR capsules
successfully accomplishes gradual release to enable once daily dosing, but the
Dilacor* XR formulation requires complex and expensive procedures to
produce. In particular, production of the tablets contained in Dilacor* XR
capsules requires production of cores containing the diltiazem hydrochloride
and the affixing thereto of the insoluble platforms.
Another formulation of diltiazem hydrochloride suitable for once daily
administration is now sold in the United States under the trademark
Cardizem*
* trademark
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CD, by Marion Laboratories Inc. Cardizem* CD is sold as capsules
containing a multitude of beads. The composition of the beads contained in
Cardizem* CD capsules is described in U.S. patent 5286497. The beads are
made using core seeds to which is applied a first coating containing the
diltiazem hydrochloride. Over the first coating, further coatings of polymers
are applied which serve to slow down and control the rate at which the
diltiazem hydrochloride is released from the beads in gastrointestinal fluids.
As explained in U.S. patent 5286497, there is a particular dissolution profile
found to be optimum for once daily administration. This desired dissolution
profile, when measured in a type 2 dissolution apparatus according to U.S.
Pharmacopoeia XXII, in O.1NHCL at 100 rpm is as follows:
a) from 20-45 % released after 6
hours
b) from 25-50 % released after 12
hours
c) from 35-70 % released after 18
hours
d) not less than 70 % released after
24 hours
e) not less than 85 % released after
30 hours
The invention of U.S. patent 5286497 achieves this dissolution profile by
using a mixture of beads with two differing amounts of coating.
The beads with the lesser amount of coating are referred to as "rapid release
diltiazem beads" and the beads with the greater amount of coating are
referred to as "delayed release diltiazem beads" .
It is disclosed that by making each of these types of beads so as to comply
with particular dissolution requirements, the mixture of the two types of
beads produces the desired dissolution profile for the final composition.
* trademark
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A difficulty with the invention of U.S. patent 5286497 is that it is difficult
to
reliably make the two types of beads so as to get the required dissolution
profile for the final mixture.
In particular, the desired dissolution profile requires that the amount
released
must exceed 20 % after 6 hours, but must not exceed 50 % after 12 hours.
This requires that the "rapid release diltiazem beads" give a sharp step-like
release of the diltiazem. Otherwise, if the amount released increases only
gradually with time, beads formulated to assure that at least 20 % of the
diltiazem is released from the final mix after 5 hours will also cause more
than
50% to be released after 10 hours, thus causing the final composition to fail
to
meet requirements.
In view of the aforesaid problems with prior art formulations, it is an object
of
the invention to produce a composition of diltiazem hydrochloride suitable for
once daily administration, in the form of a blend of beads that overcomes the
difficulty in achieving the required dissolution profile that results from
using
a mixture of only two types of beads.
The new formulation is characterized in the following way. Beads containing
diltiazem hydrochloride are made by processes the same as or similar to those
disclosed in U.S. patent 5286497.
However, instead of mixing only two types of beads, referred to as "rapid
release beads" and "delayed release beads", three types of beads are made,
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which will be referred to herein as "rapid release beads", "intermediate
release
' beads", and "delayed release beads".
By using an appropriate mixture of these three types of beads, with three
S different amounts of coating, it is possible to obtain the desired
dissolution
profile for the final mix, without the need for the individual types of beads
to
have the sharp step-like release profile required by the invention of U.S.
patent
5286497.
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The rapid release, intermediate release, and delayed release beads of the
invention will typically exhibit in vitro dissolution profiles as shown in
Table
1 when measured in O.1NHCL using a type 2 apparatus at 100 rpm according
to U.S. Pharmacopoeia XXII.
TABLE 1
RAPID INTERMEDIATE DELAYED
RELEASE RELEASE RELEASE
BEADS BEADS BEADS
Hours ical cceptable TwicalAcceptableTvn~calAcceptable
3 70% 40% Io 5% 0% Io 15% 3% 0% to 10%
100%
6 ~ 95% 80% to 17% 0% to 30% 12% 0% to 20%
100%
12 100% 90% to 55% 35% to 25'ir U% co 35%
100% 75%
18 100% 90% to 85% 65% Io 45 ~a 30% Io
100% 95% fi0%
24 100 95 % to 95 75 % to 68 ~ 50 '% 10
~ 100 % % 100 % 90
100% 95% to 100 80% to ~~ % ?0/. to
100a % 100%
25
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All three types of beads will usually be made by taking the same cores
containing diltiazem hydrochloride and applying different amounts of
polymeric coating to slow down the release. The intermediate release beads
will typically have more coating than the rapid release beads, and similarly
the delayed released beads will typically have more coating than the .
intermediate release beads.
It follows that the intermediate release beads will contain a smaller percent
diltiazem hydrochloride by weight than the prompt release beads, and
similarly the delayed release beads will contain a smaller percent diltiazem
hydrochloride by weight than the intermediate release beads.
The final blend of beads will typically contain about 15 % by weight rapid
release beads, about 20% by weight intermediate release beads and about
65 % by weight delayed released beads.
In view of the differences in percent diltiazem hydrochloride content as
aforesaid, it follows that in the final blend, about 18 % of the diltiazem
hydrochloride content will be in the rapid release beads, about 20%~ in the
intermediate release beads, and about 62% in the delayed release beads.
By taking into account these percentages along with the typical dissolution
data given in Table 1, it can be seen that in the final mix, the dissolution
at
6 hours will be about 27 %, and at 12 hours will be about 44 % .
There is thus achieved a final mix which has dissolution over 20 % at 6
hours and under 50% at 12 hours, in accordance with the ohjectivc of this
invention.
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Similarly, it can be seen that in final mix the dissolution will be under 70%
at 18 hours, over 70 % at 21 hours, and over 85 % at 30 hours.
The final mix can thus be made to meet the dissolution specifications
disclosed in U.S. patent 5286497 as being particularly desired to ensure
uniform blood levels, these specifications being as follows:
a) from 20 % to 40 % after 6 hours
b) from 25 % to 50 % after 12 hours
c) from 35 % to 70 % after 18 hours
d) not less than 70% after 24 hours
e) not less than 85 % after 30 hours
As aforesaid, all three types of beads will usually be made by first making
core beads containing the diltiazem hydrochloride and then applying a
polymeric coating to slow down the dissolution rate.
The core beads may be made by any of a number of techniques well known
to persons skilled in the art of pharmaceutical formulations.
In one technique, the core beads are made beginning with sugar spheres
having a diameter ranging from about 12 to 45 mesh and more preferably
from 35 to 45 mesh. The spheres are loaded into a f7uidized bed coating
apparatus. In that apparatus there is sprayed onto the spheres a solution
containing diltiazem hydrochloride, a polymeric binder and optionally other
excipients. As the solvent is evaporated, a film containing diltiazem
hydrochloride is built up to result in the core beads containing diltiazem
hydrochloride.
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Another technique suitable to produce core beads containing diltiazem
hydrochloride is the technique known in the art as extrusion-spheronization.
In the extrusion part of this process, a mixture of diltiazem hydrochloride,
a binder, water and optionally other excipients is forced through a screen
to product moist strands. The moist strands are then transferred to the
spheronizer. In the spheronizor the strands are placed on a rotating disc
where they are forced to roll outward by centrifugal force. In the process,
the strands break into pieces with length approximately equal to diameter,
and they also become rounded as they roll. They are then dried and thus
become dry core beads containing diltiazem hydrochloride.
As aforesaid, the second part of the process of producing the final beads is
to apply to the core beads one or more polymeric coatings to slow down the
dissolution rate.
Such coating or coatings may be applied by loading the core beads into a
fuidized bed coating apparatus and spraying onto the core beads a solution
or suspension of suitable polymers, and other excipients in a solvent, and
evaporating the solvent. The solvent preferably will be water, but organic
solutions also may be used.
This polymeric coating or coatings may be made using any number of
polymers known in the art to be useful as slow-release coatings. Such
polymeric coating may be produced, for example, using polymerized
acrylates or copolymers of acrylic acid and methacrylic acid or esters of
either monomer (hereinafter called polymerized acrylates). These materials
are available from several commercial sources.
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Examples of such copolymers include poly (methyl methacrylate), poly (ethyl
methacrylate), poly(butyl methacrylate), poly (isobutyl methacrylate), poly
(isobutyl methacrylate), and poly (phenyl methacrylate).
The amount of polymerized acrylate contained within the polymeric coating
can vary. Typically, the polymeric coating will contain from 10 to 75 w/w%
of polymerized acrylate and preferably about 55-65% w/w% based on the
total weight of the polymeric coating, the balance being a plasticizer and
other excipients.
Preferred polymerized acrylates are those which are water insoluble, slightly
water permeable copolymers of acrylic acid lower alkyl ester and methacrylic
acid lower alkyl ester in which some ester moieties are further substituted
with a tri(alkyl)ammonium group. The tri(alkyl)ammonium group is typically
present in the range of about 1:30 to 1:50 relative to the amount of neutral
ester present. One such preferred copolymer is a copolymer of ethyl acrylate
and methyl methacrylate which contains trimethylammoniumethyl
methacrylate in a range of about 1:40 relative to neutral monomers. This
copolymer is commercially available from Rohm Pharma GmbH under the
tradename Eudragit* RS. The same copolymer is available in an easy to use
aqueous dispersion sold under the tradename Eudragit* RS30D.
The polymeric coating will preferably contain a quantity of a suitable
plasticizer. Examples of such plasticizers are acetyl triethyl citrate,
dibutyl
phthalate, tributyl citrate, triethyl citrate, acetyl triethyl citrate,
propylene
glycol, triacetin, polyethylene glycol and diethyl phthalate. Preferred
plasticizers are triethyl citrate, tributyl citrate, and acetyl tributyl
citrate.
* trademark
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The amount of plasticizer will typically be 5 to 30 w/w% based on the total
weight of polymeric coating.
In addition to containing polymerized acrylate and optionally a plasticizer,
the polymeric coating may contain other conventional excipients including
antifoaming agents such as simethicone, in the range of 0 to 2 w/w % based
on the total weight of the polymeric coating. It may also contain an anti-
adherent such as talc in the range of 0 to 70 w/w% and preferably 25 to 35
w/w % based on the total weight of polymeric coating.
A sufficient quantity of polymeric coating must be utilized to substantially
envelope the core beads in order to give them the desired release (i.e.
dissolution) profile. The exact quantity will depend on the composition and
size of the core beads, the composition of the coating, and whether the
coated beads are intended to be the rapid release, intermediate release or
delayed release beads. A suitable amount for each of the three types of
buds can readily be determined by trial and error by persons skilled in the
art. That is to say, various amounts can be applied and the dissolution
profiles can be determined for the various amounts and a suitable amount
thereby selected to give the desired profile.
For ease of handling the beads after application of the coating to the core
beads it is desirable that the dried coating not be tacky, so that the beads
will not stick together. Coatings of Eudragit RS and other similar polymers
may be found to be excessively tacky. To solve lhls problem, a further
coating may be applied over the tacky coating using another polymer that
is not so tacky.
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There are many suitable non-tacky polymers well-known in the art,
including for example cellulose derivatives such as hydroxypropyl
methylcellulose, which are water-soluble polymers. Another suitable
nontacking polymer for such overcoat is a copolymer of methacrylic acid
and methacrylic acid methyl esters sold by Rohm Pharma Gmbh under the
tradename Eudragit L. This polymer is insoluble in gastric fluid but soluble
in neutral to weakly alkaline intestinal fluid. As with Eudragit RS, Eudragit
L is available in an easy to use aqueous dispersion sold under the tradename
Eudragit L30D.
If an overcoat is used, unless it is rapidly soluble it will further delay the
dissolution of the beads, and accordingly the amount of both the primary
coating and the overcoating must be selected to achieve the desired
dissolution profile for each of the three types of beads.
In the case of the rapid release beads, a coating as aforesaid is desirable
but
not necessary. That is to say, the rapid release beads may take the form of
the core beads without coating. Alternatively, the rapid release beads may
consist of core beads coated with only a thin coating of a polymer that need
not significantly delay dissolution, since there is no upper limit on the
dissolution rate of the rapid release beads within the scope of the present
tnventlon.
After completion of coating and drying of the beads, the three types of
beads are blended together in the required proportions for incorporation into
the final dosage form.
The proportions of the three types of beads by weight will preferably be
about 15% for the rapid release beads, about 20% for the intermediate
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release beads, and about 65% for the delayed release beads. However, the
percentages may differ from these preferred amounts depending on the exact
dissolution profile for each of the three types of beads.
The blended diltiazem beads may be administered in a number of dosage
forms known in the art. For example, they may be placed into a gelatin
capsule. The blended beads may also be mixed with a binder such as
microcrystalline cellulose and compressed into tablets.
The quantity of beads that are placed in each dosage unit will typically be
such as to produce a dosage unit containing from 90 mg to 540 mg of
diltiazem hydrochloride, and more preferably from 120 mg to 360 mg.
Such a dosage unit is suitable for once daily oral ingestion for a variety of
cardiovascular indications such as angina, hypertension, and arrhythmias.
As used in this application, any reference to dissolution profile should be
construed as referring to the results of a dissolution test in which the
amount
of diltiazem hydrochloride released is measured as specified in the United
States Pharmacopoeia XXII, using a type 2 apparatus at 100 rpm, a
temperature of 37°C and a test solution of O.1NHC1.
The following examples are presented to further illustrate the invention but
should not be considered as limiting the invention.
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EXAMPLE 1
A quantity of core beads were made by the extrusion and spheronization
process containing 90% by weight diltiazem hydrochloride, on a dried basis,
the balance being microcrystalline ceh.ulose together with methylcellulose
as a binder.
EXAMPLE 2
Rapid release beads were made by coating the core beads of example 1 with
a polymeric coating using Eudragit RS30D along with plasticizer and talc.
An overcoating was then applied using Eudragit L30D along with plasticizer
and talc. The total amount of coating applied was such as to give finished
beads with the content of diltiazem hydrochloride being 77.3 % by weight.
Gelatin capsules were filled with these beads, and the dissolution profile was
measured and found to be as shown in table 2, the results shown being the
approximate average for several capsules.
TABLE 2
Time 3 hrs. 6 hrs. 12 hrs.18 hrs. 24 hrs.30 hrs.
Amount 95 % 100 100 % 100 100
2S released73% % % ~~
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EXAMPLE 3
Intermediate release beads were made by coating the core beads of example
2 with a polymeric coating using Eudragit RS30D along with plasticizer and
talc. An overcoating was then applied using Eudragit L30D along with
plasticizer and talc. The total amount of both coatings was such as to give
finished beads with the content of diltiazem hydrochloride being 63.9% by
weight.
Gelatin capsules were filled with these beads, and the dissolution profile was
measured and found to be as shown in table 3, the results shown being the
approximate average for several capsules.
TABLE 3
Time 3 hrs. 6 hrs. 12 hrs.18 hrs.24 hrs. 30 hrs.
Amount 3 % 16 % 54 % 85 % 95 % 99 %
~
Released
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EXAMPLE 4
Delayed release beads were made by coating the core beads of example 2
with a polymeric coating using Eudragit RS30D along with plasticizer and
talc. An overcoating was then applied using Eudragit L30D along with
plasticizer and talc. The amount of Eudragit RS30D used was less than that
used in making the beads of example 3, and the amount of Eudragit L30D
used was more than that used in making the beads of example 3. The total
amount of both coatings was such as to give finished beads with the content
of diltiazem hydrochloride being 63 % by weight.
Gelatin capsules were filled with these beads, and the dissolution profile was
measured and found to be as shown in table 3, the results shown being the
approximate average for several capsules.
TABLE 4
Time 3 hrs. 6 hrs. 12 hrs. 18 hrs.24 hrs. 30 hrs.
~
Amount 3 % 12 %a 26 % 44 % 68 % R8 %
Released
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EXAMPLE 5
The beads of examples 2, 3, and 4 were mixed in the following proportion.
Rapid release beads from example 2 - 1 S
Intermediate release beads from example 3 - 20 %
Delayed release beads from example 4 - S~
Total - 100%
In view of the diltiazem hydrochloride percentage content contained in each
of the three types of beads as stated in examples 2, 3, and 4, it will be seen
that the diltiazem hydrochloride percentage conten~ in the above mix is:
15% x77.3% +20%a x63.9% +65%x63% =65.3%
To achieve a dose of 300 mg of diltiazem hydrochloride thus requires 300
mg/65.3 % = 459mg of the mix of beads.
Gelatin capsules were filled each with 459mg of this mixture of beads. The
dissolution profile was measured and found to be as shown in table 5, the
results shown being the approximate average for several capsules.
TABLE 5
lime 3 hrs. 6 hrs. 12 hrs. 18 hrs.24 hrs. 30 hrs.
Amount 15 % 25 % 42 % 61 ~~ 79 %a 9 I
Released %
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