.
ORAL PHARMACEUTICAL COMPOSITION OF ALIPHATIC AMINE POLYMER
OR SALTS THEREOF
Field of the Invention
The present invention relates to an oral pharmaceutical composition of aliphatic
amine polymer or salts thereof comprising less than of about 10% of plasticizing
agent in the coating composition and/or mixture of water and organic solvent(s)
as coating solvent. By using a mixture of water and organic solvent(s) and/or less
than of about 10% of plasticizer in the coating, a robust coat which can control
the swelling of the composition can be prepared.
Background of the Invention
The aliphatic amine polymer is a cross-linked polyallylamine with a
pharmaceutically acceptable acid. The aliphatic amine polymer is an
epichlorohydrin-cross-linked polyallylamine with a pharmaceutically acceptable
acid, such as sevelamer, sevelamer hydrochloride, colesevelam or its
hydrochloride salt.
The colesevelam hydrochloride is a non-absorbable, polymeric and a highcapacity
bile acid-binding molecule. It is also a lipid-lowering and glucoselowering
agent intended for oral administration. Colesevelam hydrochloride is
poly (allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated
with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide.
Colesevelam hydrochloride is hydrophilic and insoluble in water. Chemically,
allylamine polymer with 1-chloro-2, 3-epoxypropane, [6-(allylamino)-hexyl]
trimethylammonium chloride and N-allyldecylamine, hydrochloride and is
represented by the following formula:
In the structure, m represents a number > 100 to indicate an extended polymer
network.
Colesevelam hydrochloride is approved in United States under the proprietary
name Welchol ® as oral tablet and marketed by Daiichi Sankyo.
Welchol ® is indicated as an adjunct to diet and exercise to reduce elevated lowdensity
lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia
(Fredrickson Type Ila) as monotherapy or in combination with HMG CoA)
reductase inhibitor (statin) and as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.
U.S. Patent No. 7,229,61 3 discloses a method for treating hyperglycemia and/or
reducing serum glucose levels in a patient that includes administering to the
patient a therapeutically effective amount of colesevelam or salts thereof.
U.S. Patent No. 6,733,780 discloses a compressed tablet comprising a
hydrophilic core comprising at least or about 95 weight % of poly (allylamine) or a
salt thereof and a water-based coating comprising cellulose derivative and
plasticizing agent. The patent discloses coating composition comprising
hydroxypropylmethylcellulose and a plasticizer. The disclosed coating
composition contains at least 23% of diacetylated monoglyceride as a plasticizing
agent.
The U.S. Patent Application No. 201 0/0008988 discloses pharmaceutical
compositions comprising less than about 95% by weight of aliphatic amine
polymers of sevelamer hydrochloride, sevelamer carbonate and colesevelam
hydrochloride, and methods of preparing pharmaceutical compositions thereof.
The U.S. Patent Application No. 201 0/03301 75 discloses a pharmaceutical
composition comprising dry cross-linked polyallylamine and water soluble
excipient comprising polyols and polyethylene glycol.
The U.S. Patent Application No. 201 1/01 59087 discloses a pharmaceutical
composition comprising wet granulated bile acid sequestrants composition,
wherein the composition is free of reducing sugar.
The colesevelam hydrochloride tends to be very hygroscopic and thus will swell
immediately upon contact with the inside of the mouth. Thus it was believed that
coating such tablets with aqueous based coating would be difficult because the
hygroscopic tablets would swell during the coating process.
The prior arts disclosure suggests that use of a relatively high amount of
diacetylated monoglyceride as plasticizing agent in coating composition to
overcome the tablet-swelling problem and to stabilize the pharmaceutical
compositions of poly allylamines or a salt thereof.
Thus, there still exists an enduring need to develop an improved and stable
pharmaceutical composition of aliphatic amine polymers which will provides an
alternative to existing formulation of colesevelam hydrochloride.
Summary of the Invention
In one aspect, there is provided an oral pharmaceutical composition comprising a
core, which comprises of an aliphatic amine polymer or salt thereof and
optionally with one or more pharmaceutically acceptable excipients, and at least
one layer coated over said core, which comprises mixture of water and organic
solvent(s) in the ratio of about 90:1 0 to about 10:90 and/or less than about of
10% w/w of one or more plasticizing agents and optionally one or more
pharmaceutically acceptable excipients.
In another aspect, there is provided an oral pharmaceutical composition
comprising a core, which comprises of colesevelam or salt thereof and optionally
with one or more pharmaceutically acceptable excipients, and at least one layer
coated over said core, which comprises of less than about of 10% w/w of one or
more plasticizing agents, and optionally one or more pharmaceutically
acceptable excipients.
In another aspect, the amount of plasticizer in the coating composition is less
than about 8% w/w, preferably less than about 5% w/w.
In another aspect, there is provided an oral pharmaceutical composition
comprising a core, which comprises of an aliphatic amine polymer or salt thereof
and optionally with one or more pharmaceutically acceptable excipients, and at
least one layer coated over said core, which comprises of less than about of 10%
w/w of diacetylated monoglyceride, and optionally one or more pharmaceutically
acceptable excipients.
In another aspect, there is provided a process for the preparation of an oral
pharmaceutical composition of an aliphatic amine polymer or salt thereof, which
process comprises steps of:
(a) mixing the aliphatic amine polymer or salt thereof with one or more
pharmaceutically acceptable excipients; compressing the mixture to form a core;
and
(b) coating the said core with a composition which comprises of mixture of water
and organic solvent(s) in the ratio of about 90:1 0 to about 10:90 and/or less than
10% w/w of one or more plasticizing agents, and optionally one or more
pharmaceutically acceptable excipients.
In another aspect, there is provided a process for the preparation of an oral
pharmaceutical composition of an aliphatic amine polymer or salt thereof, which
process comprises steps of:
(a) preparing a core which comprises of an aliphatic amine polymer or salt
thereof, and optionally one or more pharmaceutically acceptable excipients; and
(b) coating the said core with a composition which comprises of less than about
10% w/w of one or more plasticizing agents, water, one or more organic solvent,
and optionally one or more pharmaceutically acceptable excipients.
In another aspect, there is provided an oral pharmaceutical composition
comprising a core, which comprises of an aliphatic amine polymer or salt thereof
and optionally with one or more pharmaceutically acceptable excipients, and at
least one layer coated over said core, which comprises of less than about of 10%
w/w of plasticizing agent, polymer and optionally one or more pharmaceutically
acceptable excipients.
In another aspect, there is provided an oral pharmaceutical composition
comprising a core, which comprises of an aliphatic amine polymer or salt thereof
and optionally with one or more pharmaceutically acceptable excipients, and at
least one layer coated over said core, which comprises plasticizing agent and
aliphatic amine polymer in the ratio of about 1:4 to about 1:45, preferably 1:43
w/w of the total weight of the coating composition.
In another aspect, there is provided an oral pharmaceutical composition used for
the Primary Hyperlipidemia and Type 2 Diabetes Mellitus as an adjunct to diet
and exercise.
Detailed Description of the Invention
The inventors of the present invention have surprisingly found that by using the
mixture of water and organic solvent(s) in the range of about 90:1 0 to about
10:90 and/or less than about of 10% w/w of plasticizing agent in coating
composition, the tablet-swelling problem can be avoided significantly and also
provides ease to coating operation.
The inventors of the present invention empirically found that using mixture of
water and organic solvent(s) and/or a judicial amount of plasticizing agent in the
coating compositions has a direct effect on the tablet swelling and practical
operations. In particular, the inventors have found that judicially using mixture of
water and organic solvent(s) in coating solution or dispersion in the range of
about 10:90 to about 90:1 0 and less than about of 10% w/w of plasticizing agent,
for example, diacetylated monoglyceride can effectively curb the tablet swelling
and provides ease to coating operation of aliphatic amine polymers (e.g.
colesevelam hydrochloride) and eventually may control generation of impurities.
As a result, inventors of the present invention have found a novel way of
preparing the pharmaceutical composition of aliphatic amine polymers which can
significantly control tablet swelling and meets the desired parameters.
The present invention relates to a novel coated pharmaceutical composition of
aliphatic amine polymer or salt thereof which coating comprises mixture of water
and organic solvent(s) and/ or less than about 10% of plasticizing agent.
The term "aliphatic amine polymer" used throughout the specification refers to
not only aliphatic amine polymer per se, but also its free base, other
pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers,
pharmaceutically acceptable derivatives, pharmaceutically acceptable
polymorphs and pharmaceutically acceptable prodrugs thereof.
Aliphatic amine polymer suitable for use in the composition of the present
invention may include, but not limited to bile acid sequestrants such as
colesevelam and sevelamer.
The compositions of the present invention are oral compositions of colesevelam
hydrochloride that improve shelf-life and provide palliative pharmaceutical
composition of colesevelam hydrochloride.
In an another embodiment, the pharmaceutical composition of aliphatic amine
polymer comprises a core comprising aliphatic amine polymer and one or more
pharmaceutically acceptable excipients and at least one layer coated over said
core comprises water, one or more organic solvents, one or more plasticizing
agents, and optionally one or more pharmaceutically acceptable excipients;
wherein the composition is stable when stored for real time study condition at
25°C and 60% relative humidity or for accelerated study condition at 40°C and
75% relative humidity for at least 3 months.
In an embodiment, the pharmaceutical composition of the present invention
comprising colesevelam hydrochloride and coating comprising less than 10%
w/w of plasticizing agent and optionally with one or more pharmaceutically
acceptable excipients, wherein the composition is stable when stored at 25°C
and 60% relative humidity or at 40°C and 75% relative humidity for at least 3
months.
In another embodiment, the pharmaceutical composition of the present invention
comprises aliphatic amine polymer in an amount of less than of about 80% of the
core weight.
In a further embodiment, the composition substantially free of impurities like
unknown or degradation products when stored at 25°C and 60% relative humidity
or at 40°C and 75% relative humidity for 3 months.
The pharmaceutical composition of the present invention may be developed in
the form of a dosage form suitable of oral administration.
Dosage forms include solid dosage forms but not limited to tablets, powders,
capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups,
suspensions and elixirs. The tablet can be coated or uncoated tablet.
The term "pharmaceutically acceptable excipient" includes a pharmaceutically
acceptable material, composition or vehicle, suitable for administering an active
pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and not injurious to
the patient. Excipients include diluents, binders, disintegrants, glidants,
lubricants, flavoring, and others.
Diluents increase the bulk of a solid pharmaceutical composition. Exemplary
diluents for solid compositions include, but are not limited to, microcrystalline
cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium
carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,
magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such
as a tablet, may include excipients whose functions include helping to bind the
active ingredient and other excipients together after compression. Exemplary
binders for solid pharmaceutical compositions include, but are not limited to,
acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl
cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose,
magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates,
povidone, pregelatinized starch, sodium alginate and starch.
Disintegrants increase the dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach, for example. Exemplary disintegrants
include, but are not limited to, alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium,
crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose,
microcrystalline cellulose, polacrilin potassium, powdered cellulose,
pregelatinized starch, sodium alginate, sodium starch glycolate and starch.
Glidants can be added to improve the flowability of a non-compacted solid
composition and to improve the accuracy of dosing. Exemplary excipients that
may function as glidants include colloidal silicon dioxide, magnesium trisilicate,
powdered cellulose, starch, talc and tribasic calcium phosphate.
A lubricant can be added to the composition to reduce adhesion and ease the
release of the product from the dye. Exemplary lubricants include, but are not
limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl
palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil,
polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl
fumarate, stearic acid, talc and zinc stearate.
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.
The coating composition comprises polymer and plasticizing agent. The polymer
can be selected from but not limited cellulosic ethers such as
hydroxypropylmethylcellulose (HPMC) and hydroxypropyl cellulose. The
plasticizing agent selected from group comprising acetylated monoglyceride,
triacetin, polyethylene glycol, triethyl citrate, a polysorbate, preferably
diacetylated monoglyceride either alone or in combination thereof. The coating
composition can further include a pigment 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 an embodiment, the ratio of amount of plasticizing agent and polymer in the
coating composition according to the present invention is in the range of about 1:
4 to about 1: 45, preferably 1: 43 w/w.
In an embodiment, the ratio of amount of water and organic solvent(s) in the
coating composition according to the present invention is in the range of about
90:1 0 to about 10:90, preferably 70:30 to 30:70, more preferably 40:1 0 to 10:40
v/v.
The present invention is further illustrated by the following examples which are
provided merely to be exemplary of the invention and do not limit the scope of
the invention. Certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.
Example : Colesevelam Hydrochloride tablet
Table 1
Process for preparing uncoated core:
The weighed amount of colesevelam Hydrochloride was co sifted with colloidal
silicon dioxide and Microcrystalline Cellulose (MCC) through 30# mesh. To this
magnesium stearate passed through # 60 mesh was added and blended for 5
minutes in double cone blender. The obtained blend was compacted using roll
compactor using suitable compaction parameters. The obtained flakes were
milled using oscillating granulator through # 25 mesh so that all granules of
below 25 #. The # 25 mesh passed granules were further sifted through 60#
mesh and fraction above # 60 collected separately. Compaction process was
repeated for below 60 # fraction till 50 to 60 % of above 60 # granules are
obtained. These obtained granules were blended in double cone blender for 5
minutes with MCC and Colloidal silicon dioxide, previously passed through # 40
mesh. These obtained granules were lubricated with pre sifted (through 60 mesh)
magnesium stearate, in Double Cone Blender for 3 minutes and then
compressed into tablet using suitable punches.
The Colesevelam Hydrochloride tablet obtained from example 1 was coated with
various coating composition comprising hydroxypropylmethylcellulose and
diacetylated monoglycerides present in different proportion. The various
illustrative examples are as follows:
Example 2: Coating composition
Table 2
*** Removed during processing of drying.
Example 3: Tablet coating with hydro-alcoholic dispersion
Table 3
* Checked on 6 tablets in purified water
Process for coating with hydro-alcoholic dispersion:
The weighed amount of Hydroxypropylmethylcellulose and Di-Acetylated
Monoglycerides were dissolved or dispersed in hydro-alcoholic solvent. The
obtained coating solution or dispersion was applied to compressed cores until a
weight gain of approximately about 7 to about 15 percent was achieved. The
coating composition was prepared by using water: alcohol in the ratio of about
90:1 0 to about 10:90.The hydro-alcoholic solvent used in coating solution was
completely removed during drying process.
Example 4: Tablet coating with aqueous dispersion
Table 4
* Checked on 6 tablets in purified water
Process for coating tablet with aqueous dispersion:
The required amount of HPMC and DAMG was dispersed in water and stirred for
40 minutes till clear solution or dispersion without lumps was obtained. The
compressed core tablet obtained in Example 1 was added in coating pan. The
coating was started after setting the desired parameters (RPM, temperature and
atomization speed) and continued the coating till the target weight gain was
achieved.
Example 5: Tablet coating with Non-aqueous dispersion
Table 5
* * Removed during processing of drying.
Process for coating tablet with aqueous dispersion:
The required amount of HPMC and DAMG was dispersed in Isopropyl alcohol
and Dichloromethane and stirred for 40 minutes till clear solution or dispersion
without lumps was obtained. The compressed core tablet obtained in Example 1
was added in coating pan. The coating was started after setting the desired
parameters (RPM, temperature and atomization speed) and continued the
coating till the target weight gain was achieved.
The various coated tablets obtained from examples 4 illustrates that tablets do
not match the disintegration time (DT) when compared with Reference product.
The disintegration time (DT) for Reference product is as follows in various media:
Table 6
The coated tablets obtained from example 5 illustrate that tablets match the
disintegration time (DT) when compared with Reference product. But the various
problems like logo bridging, change in film property like from transparent film to
opaque film were observed.
The various coated tablets obtained from examples 3 illustrative that tablets
according to present invention match the Disintegration time (DT) when
compared with Reference product and various problems like logo bridging,
change in film property like from transparent film to opaque film were not
observed.
Claims:
1. An oral pharmaceutical composition comprising a core which comprises of
an aliphatic amine polymer and optionally one or more pharmaceutical
excipients, and at least one layer coated over said core, which comprises
mixture of water and organic solvent(s) in the ratio of about 90:1 0 to about
10:90.
2. An oral pharmaceutical composition comprising a core which comprises of
an aliphatic amine polymer and optionally one or more pharmaceutical
excipients, and at least one layer coated over said core, which comprises
of less than about 10% w/w of one or more plasticizing agents, and
optionally one or more pharmaceutically acceptable excipients.
3. The oral pharmaceutical composition of claim 1, wherein the composition
comprises less than about 10% w/w of one or more plasticizing agents.
4. The oral pharmaceutical composition of claim 2, wherein the layer coated
over the core comprises a mixture of water and organic solvent(s) in the
ratio of about 90:1 0 to about 10:90 and optionally one or more
pharmaceutically acceptable excipients.
5. The oral pharmaceutical composition of claim 1 or 2, wherein the aliphatic
amine polymer selected from sevelamer, colesevelam or pharmaceutically
acceptable salts thereof.
6. The oral pharmaceutical composition of claim 1 or 2, wherein the aliphatic
amine polymer is present in an amount of less than of about 80% of the
core weight.
7. The oral pharmaceutical composition of claim 1 or 4 , wherein the organic
solvent(s) comprises isopropyl alcohol, methanol, ethanol and
dichloromethane or mixture thereof.
8. The oral pharmaceutical composition of claim 2 or 3, wherein the
plasticizing agent is selected from group comprising acetylated
monoglyceride, triacetin, polyethylene glycol, triethyl citrate and
polysorbate.
9. The oral pharmaceutical composition of claim 2, 3 or 8, wherein the ratio
of the amount of aliphatic amine polymer and plasticizing agent is about
45: 1 to about 4:1 .
10.The oral pharmaceutical composition of claim 1, wherein the composition
is prepared by a process, which process comprises steps of:
(a) preparing a core comprising mixing aliphatic amine polymer with one
or more pharmaceutically acceptable excipients;
(b) coating the core prepared in step (a) with a composition which
comprises of water, one or more organic solvents, one or more plasticizing
agents, and optionally one or more pharmaceutically acceptable
excipients; and
(c) optionally, drying the coated core prepared in step (b).
11.The oral pharmaceutical composition of claim 2, wherein the composition
is prepared by a process, which process comprises steps of:
(a) preparing a core which comprises of an aliphatic amine polymer or salt
thereof, and optionally one or more pharmaceutically acceptable
excipients; and (b) coating the said core with a composition which
comprises of less than about 10% w/w of one or more plasticizing agents,
water, one or more organic solvent, and optionally one or more
pharmaceutically acceptable excipients.
1 .Use of oral pharmaceutical composition of claim 1 or 2, for the
treatment/prevention of Primary Hyperlipidemia and Type 2 Diabetes
Mellitus as an adjunct to diet and exercise.