U.S. patent application number 10/785322 was filed with the patent office on 2004-08-26 for direct compression polymer tablet core.
This patent application is currently assigned to Genzyme Corporation. Invention is credited to Petersen, John S., Tyler, Joseph.
Application Number | 20040166156 10/785322 |
Document ID | / |
Family ID | 27388413 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040166156 |
Kind Code |
A1 |
Tyler, Joseph ; et
al. |
August 26, 2004 |
Direct compression polymer tablet core
Abstract
The present invention provides a tablet core which comprises at
least about 95% by weight of an aliphatic amine polymer. The
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 the aliphatic 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 present invention further relates to a
coated tablet comprising an aliphatic amine polymer core wherein
the coating is a water based coating.
Inventors: |
Tyler, Joseph; (Somerville,
MA) ; Petersen, John S.; (Acton, MA) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD
P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Assignee: |
Genzyme Corporation
Cambridge
MA
|
Family ID: |
27388413 |
Appl. No.: |
10/785322 |
Filed: |
February 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10785322 |
Feb 24, 2004 |
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09691429 |
Oct 18, 2000 |
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6733780 |
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60160258 |
Oct 19, 1999 |
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60174227 |
Jan 3, 2000 |
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Current U.S.
Class: |
424/465 |
Current CPC
Class: |
A61K 9/2866 20130101;
A61K 9/2009 20130101; A61K 9/28 20130101; A61K 9/2013 20130101;
A61K 9/2027 20130101; A61K 9/282 20130101; A61K 31/785
20130101 |
Class at
Publication: |
424/465 |
International
Class: |
A61K 009/20; A61K
009/24 |
Claims
What is claimed is:
1. A compressed tablet comprising an effective disintegrating
amount of polyallylamine or a salt thereof with a pharmaceutically
acceptable acid.
2. The compressed tablet of claim 1, wherein the polyallylamine or
salt thereof is cross-linked.
3. The tablet of claim 2, wherein the polyallylamine or salt
thereof is cross-linked with epichlorohydrin.
4. The tablet of claim 1, wherein the polyallylamine or the salt
thereof is not an active ingredient.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 09/691,429, filed Oct. 18, 2000, which claims the benefit of
U.S. Provisional Application No. 60/160,258, filed Oct. 19, 1999,
and U.S. Provisional Application No. 60/174,227, filed Jan. 3,
2000. The entire teachings of the above applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 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 U.S. Pat. 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, WO98/29107 and WO99/22721 useful as cholesterol lowering
agents.
[0003] 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 tablet is as small as
possible and easy to administer to the patient.
[0004] 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.
[0005] 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
[0006] The present invention 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 5% water by weight or greater.
[0007] The 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 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 present invention further
relates to a coated tablet wherein the coating comprises a water
based coating.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The FIGURE is a table comprising data showing formulations
and responses for sevelamer hydrochloride compressed tablet
cores.
DETAILED DESCRIPTION OF THE INVENTION
[0009] 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. Pat. Nos. 5,496,545 and 5,667,775), also referred to as
sevelamer hydrochloride or sevelamer and marketed as RENAGEL.RTM.,
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.
[0010] The present 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. Pat. 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, each of which is hereby incorporated herein by
reference in its entirety. Other suitable aliphatic amine polymers
are disclosed in U.S. Ser. Nos. 08/670,764; 08/959,471, and
08/979,096, each of which is hereby incorporated by reference
herein in its entirety. In a particularly 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. The aliphatic amine polymer 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. 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 5% by weight or greater, more preferably,
the moisture content is from about 5% to about 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.
[0011] 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 stearylflumarate. The excipients can represent
from 0 to about 5% of the tablet core by weight.
[0012] The tablet core of the 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.
[0013] The 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 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.
[0014] In one embodiment, the coated tablet of the 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.
[0015] In one preferred embodiment, the solids composition of the
coating solution is:
1 Material % W/W HPMC low viscosity Type 2910, cUSP 38.5% HPMCE
high viscosity Type 2910, cUSP 38.5% diacetylated monoglyceride
23.0%
[0016] 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.
[0017] 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 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.
[0018] The present 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.
[0019] The aliphatic amine polymer can be one of the aliphatic
amine polymers disclosed above, such as polyethyleneimine,
polyvinylamine, polyallylamine, polydiallylamine or any of the
aliphatic amine polymers disclosed in U.S. Pat. Nos. 5,496,545 and
5,667,775 and U.S. Ser. Nos. 08/777,408 and 08/964,498, the
teachings of each of which are incorporated herein by reference. 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.
[0020] 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 doseage 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 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.
[0021] 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.
[0022] The invention 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
[0023] Preparation of Tablet Cores
[0024] 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 station Manesty B3B at 4 tons pressure
using 0.280".times.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.
[0025] 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".times.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.
[0026] Characterization of Tablet Cores
[0027] 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
[0028] 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:
2 Material % W/W HPMC low viscosity Type 2910, cUSP 38.5% HPMCE
high viscosity Type 2910, cUSP 38.5% diacetylated monoglyceride
23.0%
[0029] 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
"Q1A-Stability Testing of New Drug Substances and Products" (June
1997); ICH "Q1B-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)
[0030] In order to maintain consistently acceptable compressed
tablet on a per batch basis, a number of correlative tests were
performed in order to determine 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 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.degree. C.
and is measured in minutes.
[0031] 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.
[0032] The FIGURE 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
[0033] The FIGURE 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.
[0034] Equivalents
[0035] While 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.
* * * * *