Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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DIRECT COMPRESSION POLYMER TABLET CORE
This application is a divisional application of Canadian
Patent Application No. 2,387,915 filed on October 13, 2000.
BACKGROUND OF THE INVENTION
A number of polymeric materials having useful therapeutic
activity have been described for treatment of various conditions
such as hyperlipidemia and hyperphosphatemia. Many of these
polymeric materials function as non-absorbed ion exchange resins
in the digestive tract. Such non-absorbed polymeric materials
bind or otherwise sequester a target molecule and facilitate its
removal from the body via the gastrointestinal tract. Examples
of such resins include: Colestipol and Cholestyramine useful as
orally administered cholesterol lowering agents; a variety of
aliphatic amine polymers disclosed in U.S. Patent Nos. 5,496,545
and 5,667,775 useful as phosphate binders particularly for
removing phosphate from patients suffering from renal failure;
and other aliphatic amine polymers disclosed in U.S. Pat. No.
5,624,963, U.S. Pat. No. 5,679,717, WO 98/29107 and WO 99/22721
useful as cholesterol lowering agents.
Non-absorbed polymer therapeutics have traditionally
presented a number of formulation challenges as the dosages are
generally very large (gram quantities), and the resins tend to be
extremely hydrophilic. The most desirable formulation for oral
delivery of a therapeutic is a direct compression tablet
formulation. However, not all therapeutics, particularly given
the high dose requirements of polymeric ion exchange
therapeutics, lend themselves to a tablet formulation. Even if
such materials could be rendered into a tablet, it is generally
not possible without the significant addition of other materials
which assist in the tableting process. Ultimately the addition
of any materials other than the active ingredient is undesirable
given the dose requirement of the active ingredient. Ideally the
tablet should contain as much active ingredient as possible with
little else in the way of additional materials such that the
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tablet is as small as possible and easy to administer to the
patient.
In addition, once the polymeric materials are compressed
into a tablet, the tablet requires a coating for ease of
administration to the patient. It has been discovered that the
core polymeric material tends to be very hygroscopic, and thus
will swell immediately upon contact with the inside of the mouth.
Most coatings contain water, and thus it was believed that
coating such tablets with a water-based coating would be
impossible because the hygroscopic tablets would swell during the
coating process. Thus providing a tablet core comprising a
hygroscopic material such that a suitable coating may be used in
conjunction with that core, is another significant challenge to
providing the polymeric active ingredient in tablet form.
There is a need to provide suitable dosage forms for
polymeric ion exchange materials, particularly for hydrophilic
aliphatic amine polymers useful as therapeutic agents, which
minimize the overall amount of material administered to the
patient, which are easy to administer orally, and which are
stable upon production and storage.
SUMMARY OF THE INVENTION
The invention of the parent application provides a tablet
core which comprises at least about 95% by weight of an aliphatic
amine polymer. In a preferred embodiment, the aliphatic amine
polymer resin is a cross-linked polyallylamine resin. The
aliphatic amine polymer is preferably hydrated. The hydrated
polymer can, for example, comprise from about 5o water by weight
or greater.
The parent invention also provides a method of producing a
tablet core comprising at least about 95% by weight of an
aliphatic amine polymer resin. The method comprises the step of
compressing the aliphatic amine polymer to form the tablet core.
The tablet core can further include one or more excipients. In
this embodiment, the method of producing the tablet core
comprises the steps of: (1) hydrating or drying the aliphatic
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amine polymer to the desired moisture level; (2) blending the
aliphatic amine polymer with the excipients in amounts such that
the polymer comprises at least about 95% by weight of the
resulting blend; and (3) compressing the blend to form the tablet
core.
The parent invention further relates to a coated tablet
wherein the coating comprises a water-based coating. The
invention of this divisional application relates to a compressed
tablet comprising a pharmaceutically active agent and an
effective disintegrating amount of polyallylamine or a salt
thereof with a pharmaceutically acceptable acid.
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BRIEF DESCRIPTION OF'THE DRAWINGS
The Figure is a table comprising data showing formulations
and responses for sevelamer hydrochloride compressed tablet cores.
DETAILED DESCRIPTION OF THE INVENTION
A number of polymeric materials having useful therapeutic
activity have been discussed above. In particular, aliphatic amine
polymers have been disclosed which are useful in methods of
lowering the serum phosphate level of a patient and lowering the
serum cholesterol level of a patient. For example an
epichorohydrin-cross-linked poly(allylamine hydrochloride) resin
(U.S. Patent Nos. 5,496,545 and 5,667,775), also referred to as
sevelamer hydrochloride or sevelamer and marketed as Renagel , has
been shown to be effective at removing phosphate from human
patients suffering from renal failure. Therapeutically effective
dosages of sevelamer hydrochloride are large, typically on the
order of 4 to 6 grams per day. Consequently, development of a
dosage form of this and similar resins which minimizes the amount
of excipient material is desirable.
The parent invention provides a tablet core comprising at
least about 95% by weight of an aliphatic amine polymer. The
aliphatic amine polymer resin can be any of the aliphatic amine
resins described in U.S. Patent Nos. 5,496,545;5,667,775;
5,624,963; 5,703,188; 5,679,717; 5,693,675; 5,607,669; 5,618,530;
5,487,888; and 5,702,696. Other suitable aliphatic amine polymers
are disclosed in U.S. Patent Nos. 5,840,766; 6,034,129 and
6,423,754 . In particular preferred embodiment, the aliphatic
amine polymer is polyallylamine, polyvinylamine,
poly(diallylamine) or poly(ethyleneimine) or a salt thereof with a
pharmaceutically acceptable acid. The aliphatic amine polymer is
optionally substituted at one or more nitrogen atoms with an alkyl
group or a substituted alkyl group such as a trialkylammonioalkyl
group. For example, the N-substituents may be unsubstituted or
substituted Cl-Cõ-alkyl groups. The aliphatic amine polymer maybe
linear or can optionally be cross-linked, for example via a
multifunctional monomer or a bridging group which connects two
amino nitrogen atoms from two different polymer strands.
Preferably, the polyallylamine is from about 1t to about 10t
cross-linked.
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In a preferred embodiment, the aliphatic amine polymer resin is
hydrated. For sevelamer hydrochloride, in particular, the
compressibility is strongly dependent upon the degree of hydration
(moisture content) of the resin. Preferably, the resin has a
moisture content of about 3% to about 10% by weight, preferably 5%
by weight or greater, more preferably, the moisture content is
from 5% to about 8% or 9% by weight, and most preferably about 7%
by weight. It is to be understood that in embodiments in which the
polymer resin is hydrated, the water of hydration is considered to
be a component of the resin. Thus, in this embodiment, the tablet
core comprises at least about 95%, preferably at least about 96%,
and more preferably at least about 98% by weight of the hydrated
polymer, including the water of hydration.
The tablet can further comprise one or more excipients, such
as hardeners, glidants and lubricants, which are well known in the
art. Suitable excipients include colloidal silicon dioxide,
stearic acid, magnesium silicate, calcium silicate, sucrose,
calcium stearate, glyceryl behenate, magnesium stearate, talc,
zinc stearate and sodium stearylfumarate. The excipients can
represent from 0 to about 5% of the tablet core by weight.
The tablet core of the parent invention is prepared by a method
comprising the steps of: (1) hydrating or drying the aliphatic
amine polymer to the desired moisture level; (2) blending the
aliphatic amine polymer with any excipients to be included in
amounts such that the polymer comprises at least about 95% by
weight of the resulting blend; and (3) compressing the blend using
conventional tableting technology.
The parent invention also relates to a stable, swallowable coated
tablet, particularly a tablet comprising a hydrophilic core, such
as a tablet comprising an aliphatic amine polymer, as described
above. In one embodiment, the coating composition comprises a
cellulose derivative and a plasticizing agent. The cellulose
derivative is, preferably, hydroxypropylmethylcellulose (HPMC).
The cellulose derivative can be present as an aqueous solution.
Suitable hydroxypropylmethylcellulose solutions include those
containing HPMC low viscosity and/or HPMC high viscosity.
Additional suitable cellulose derivatives include cellulose ethers
useful in film
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coating formulations. The plasticizing agent can be, for example, an
acetylated
monoglyceride such as diacetylated monoglyceride, The coating composition can
further include a pigment selected to provide a tablet coating of the desired
color.
For example, to produce a white coating, a white pigment can be selected, such
as
titanium dioxide.
In one embodiment, the coated tablet of the parent invention can be prepared
by a
method comprising the step of contacting a tablet core of the invention, as
described
above, with a coating solution comprising a solvent, at least one coating
agent
dissolved or suspended in the solvent and, optionally, one or more
plasticizing
agents. Preferably, the solvent is an aqueous solvent, such as water or an
aqueous
buffer, or a mixed aqueous/organic solvent. Preferred coating agents include
cellulose derivatives, such as hydroxypropylmethylcellulose. Typically, the
tablet
core is contacted with the coating solution until the weight of the tablet
core has
increased by an amount ranging from about 4% to about 6%, indicating the
deposition of a suitable coating on the tablet core to form a coated tablet.
In one preferred embodiment, the solids composition of the coating solution
is:
Material %W/W
HPMC low viscosity Type 2910, cUSP 38.5%
HPMCE high viscosity Type 2910, cUSP 38.5%
diacetylated mono 1 ceride 23.0%
Tablets may be coated in a rotary pan coater as is known in the art or any
other conventional coating apparatus such as a column coater or a continuous
coater.
Astonishingly, it has been found that an aqueous coating dispersion is
suitable as a coating solution for tablets comprising a hygroscopic, or water-
swellable substance, such as an aliphatic amine polymer tablet. For example,
the
coating composition provides a strong, elastic and moisture-permeable coating
without causing significant concomitant swelling of the tablet core during the
coating process. In a preferred embodiment, the coating composition provides a
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tablet coating which withstands the swelling and contraction of
sevelamer hydrochloride tablets during exposure to varying
humidity levels and other known stability tests. Further, the
coating composition can be used to coat other aliphatic amine
polymer tablets without excessive uptake by the tablet core of
water from the coating solution during the coating process.
The parent invention also relates to the use of an aliphatic
amine polymer as a disintegrant in a tablet. In general, in this
embodiment the aliphatic amine polymer is not the active
ingredient in the tablet, but is added to the tablet to enhance
the rate of disintegration of the tablet following administration.
This allows a more rapid release of the active agent or agents.
The tablet will generally include the aliphatic amine polymer, one
or more active ingredients, such as therapeutic agents
(medicaments), and, optionally, one or more additional excipients.
The aliphatic amine polymer can be one of the aliphatic amine
polymers disclosed above, such as polyethyleneimini,
polyvinylamine, polyallylamine, polydiallylamine or any of the
aliphatic amine polymers disclosed in U.S. Patent No. 5,496,545,
5,667,775, 6,203,785 and WO 99/2243. In one embodiment, the
aliphatic amine polymer is a cross-linked polyallylamine or a salt
thereof with a pharmaceutically acceptable acid. Preferably, the
aliphatic amine polymer is an epichlorohydrin-cross-linked
polyallylamine or salt thereof with a pharmaceutically acceptable
acid, such as sevelamer or sevelamer hydrochloride.
The tablet which includes an aliphatic amine as a disintegrant
will, generally, include a sufficient amount of the aliphatic
amine polymer to effectively enhance the rate of tablet
= disintegration under conditions of use. For example, if the tablet
is an oral dosage form and it is desired that the tablet
disintegrate in the stomach of the patient, the tablet should
include a sufficient amount of the polymer to enhance the
disintegration rate of the tablet under the conditions encountered
in the stomach. The appropriate amount of the polymer to be
included in the tablet can be determined by one skilled in the art
using known methods. Typically, the polymer, the active ingredient
or ingredients and any additional fillers or excipients are
combined by mixing, and the resulting mixture is compressed to
form a tablet using
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conventional methods. The tablet core formed in this way can then be coated,
for
example, as described above, or by other methods and other coating
compositions
which are known in the art and suitable for the intended use of the tablet.
In one embodiment, the tablet which includes an aliphatic amine polymer as
a disintegrant is intended for administration in vivo, for example, to a
patient, such
as a human. Preferably, the tablet is intended to be administered orally. In
this
embodiment, the active ingredient or ingredients will be a therapeutic or
diagnostic
agent. The tablet can also be intended for use in vitro, for example, to
deliver an
active ingredient to an aqueous environment, such as a swimming pool.
The inventions of the parent and divisional application will now be described
in detail by reference to the following examples.
EXAMPLES
Example 1 Preparation and characterization of 400 mg and 800 mg sevelamer
hydrochloride direct compression tablet cores.
Preparation of tablet cores
400 mg sevelamer hydrochloride tablet cores were prepared from a blend
consisting of 5000.0 g sevelamer hydrochloride, 50.0 g colloidal silicon
dioxide, NF
(Aerosil 200) and 50.0 g stearic acid. The sevelamer hydrochloride was
hydrated to
moisture content of 6% by weight. The blend was prepared by passing the
sevelamer hydrochloride and colloidal silicon dioxide through a #20 mesh
screen,
transferring the mixture to a 16 quart PK blender and blending for five
minutes. The
stearic acid was then passed through an oscillator equipped with a #30 mesh
screen,
transferred into the 16 quart PK blender and blended for five minutes with the
sevelamer hydrochloride/ colloidal silicon dioxide mixture. The resulting
blend was
discharged into a drum and weighed. The final blend was then compressed on a
16
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station Manesty B3B at 4 tons pressure using 0.280" x 0.620" punches to give
tablet
cores with an average weight of 434 mg. The resulting tablets consisted of 425
mg
6% hydrated sevelamer hydrochloride (equivalent to 400 mg anhydrous sevelamer
hydrochloride), 4.25 mg colloidal silicon dioxide and 4.25 mg stearic acid.
800 mg sevelamer hydrochloride tablet cores were prepared from 19.0 kg
sevelamer hydrochloride, 0.19 kg colloidal silicon dioxide, and 0.19 kg
stearic
acid,. The sevelamer hydrochloride had a moisture content of 6% by weight. The
blend was prepared by passing the sevelamer hydrochloride and colloidal
silicon
dioxide through a #20 mesh screen, transferring the mixture to a PK blender
and
blending for five minutes. The stearic acid was then passed through an
oscillator
equipped with a #30 mesh screen, transferred into the PK blender and blended
for
five minutes with the sevelamer hydrochloride/colloidal silicon dioxide
mixture.
The resulting blend was then discharged into a drum and weighed. The final
blend
was then compressed in on a 16 station Manesty B3B at 4 tons pressure using
0.3125" x 0.750" punches to give tablets with an average weight of 866 mg. The
resulting tablets consisted of 850 mg 6% hydrated sevelamer hydrochloride
(equivalent to 800 mg anhydrous sevelamer hydrochloride), 8.0 mg colloidal
silicon
dioxide and 8.0 mg stearic acid.
Characterization of tablet cores
The tablets prepared as described above were white to off-white, oval
shaped, compressed tablets. The variation of the tablets prepared from each
blend
with respect to weight, thickness, friability, hardness, disintegration time
and density
was assessed.. Standard methods in the art were employed for each of the
measurements. The results, (not shown), indicate that the hardness,
friability,
thickness, and disintegration behavior of the sevelamer hydrochloride tablets
all met
industry-standard criteria.
Example 2 Coating of sevelamer hydrochloride tablet cores.
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Compressed core tablets prepared as described in Example 1 were coated in a
coating pan with an aqueous coating solution having a solids composition
comprising:
Material %W/W
HPMC low viscosity Type 2910, cUSP 38.5%
HPMCE high viscosity Type 2910 cUSP 38.5%
diacetylated mono 1 ceride 23.0%
The coating solution was applied to the compressed cores until a weight gain
of approximately 4 to 6% was achieved. Stability studies - controlled room
temperature, accelerated conditions, freeze/thaw and photosensitivity - for
the coated
sevelamer hydrochloride tablets were conducted in accordance with those
procedures known in the art and described in the following references:
International
Committee on Harmonization (ICH) guidance "Q I A-Stability Testing of New Drug
Substances and Products" (June 1997); ICH "Q 1 B-Guidelines for the
Photostability
Testing of New Drug Substances and Products" (November 1996);and ICH
guidance "Q1C-Stability Testing for New Dosage Forms" (November 1996. The
results (not shown) indicate that the coated tablets all met industry standard
criteria.
Example 3 Factors affecting the Processing and Performance Characteristics of
Compressed Tablets (prior to coating)
In order to maintain consistently acceptable compressed tablet on a per
batch basis, a number of correlative tests were performed in order to
deterrnine
which factors most strongly impact the quality and integrity of the tablets.
Studies
such as weight variation, tablet hardness, friability, thickness,
disintegration time,
among others are known to those skilled in the art and are described in the
United
States Pharmacopeia (U.S.P.). "Hardness" means the measure of the force
(measured herein in Newtons) needed to fracture a tablet when such tablet is
placed
lengthwise on a Hardness Tester. "Friability" is the measure of the mechanical
strength of the tablet needed to withstand the rolling action of a coating pan
and
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packaging. It is measured using a friabiliator. "Thickness" is the measure of
the
height of the tablet using a micrometer. "Disintegration Time" is the time
necessary
for the tablet to break apart in an appropriate solution at 37 C and is
measured in
minutes.
Attainment of appropriate hardness (150-170 N hardness range) and friability
(no more than 0.8%) is important to the success of the formulation. Having
tablets
with high hardness and low friability is particularly important when the
tablets are to
be coated as is the case with sevelamer hydrochloride tablets
Fig. 1 provides a table listing several different sevelamer hydrochoride
tablet
core formulations that vary by a number of factors including (actual) moisture
content, and compression force used, excipient content among other variations.
The
data in
Fig. I indicates that the most important factor affecting the processing and
performance characteristics of compressed tablets is the moisture content. All
formulations provided good flow with little weight variation throughout the
entire
range of compositions. In addition, disintegration times were less than 5
minutes
across the range of compositions. Thus, it appears that moisture content and
compression force provide the most appropriate factors on which to establish
operating ranges for hardness and friability.
EQUIVALENTS
Wtvile this invention has been particularly shown and described with
references to preferred embodiments thereof, it will be understood by those
skilled
in the art that various changes in form and details may be made therein
without
departing from the spirit and scope of the invention as defined by the
appended
claims.
