Note: Descriptions are shown in the official language in which they were submitted.
CA 02637977 2008-10-03
DOSAGE FORM CONTAINING A STATIN
FIELD OF THE INVENTION
The present invention relates to a novel dosage form, a process for the
manufacturing
the same, as well as the composition of the dosage form. More specifically,
the present
invention relates to a dosage form comprising Rosuvastatin calcium as
pharmaceutically
acceptable active ingredient.
BACKGROUND OF THE INVENTION
Rosuvastatin calcium, known under the trade name Crestor , is a synthetic
lipid-
lowering agent for oral administration. The chemical name for rosuvastatin
calcium is
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl]
(3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. It has the following
structural
formula:
F
~..
H OH 0
C$2+
N'` o_
sa~a
2
Rosuvastatin calcium belongs to the class of medications known as "statins",
more
specifically called HMG-CoA reductase inhibitors. HMG-CoA reductase is an
enzyme
involved in regulating cholesterol levels. Statins are used along with changes
to diet and
exercise to help control the amount of cholesterol produced by the body.
Rosuvastatin
calcium can help a persons body decrease LDL (bad) cholesterol and
triglyceride levels;
increase HDL (good) cholesterol levels; and decrease the Total Cholesterol/HDL-
Cholesterol Ratio (TC: HDL-C Ratio). The ratio represents the balance between
good
and bad cholesterol.
Rosuvastatin calcium is indicated as an adjunct to diet, at least equivalent
to the adult
treatment panel III (ATP III TLC diet), for the reduction of elevated total
cholesterol,
(Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for
CA 02637977 2008-10-03
increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response
to diet
and exercise alone has been inadequate including: primary hypercholesterolemia
(Type
Ila including heterozygous familial hypercholesterolemia and severe non-
familial
hypercholesterolemia), combined (mixed) dyslipidemia (Type IIb), homozygous
familial
hypercholesterolemia where rosuvastatin calcium is used either alone or as an
adjunct
to diet and other lipid lowering treatment such as apheresis.
Rosuvastatin calcium is also known to be a synthetic, enantiomerically pure
lipid-
lowering agent. It is a selective, potent and competitive inhibitor of 3-
hydroxy-3-
methylglutaryl-coenzyme A(HMG-CoA) reductase. This enzyme catalyses the
conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step
in
cholesterol biosynthesis. Studies have also shown that rosuvastatin calcium
lowers
plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and
cholesterol synthesis in the liver by increasing the number of hepatic low
density
lipoprotein (LDL) receptors on the cell-surface for enhanced uptake and
catabolism of
LDL. Additionally, rosuvastatin calcium inhibits the hepatic synthesis of very
low density
lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL
particles.
According to Canadian patent application 2,429,263, rosuvastatin can be used
in the
treatment of heterozygous familial hypercholsetrolemia, and according to
Canadian
patent application no. 2,560,167, statins can also be used for the treatment
of ocular
hypertension and glaucoma.
The preparation of rosuvastatin is described in, for example European patent
no.
521 471 and U.S. patent no. 5,260,440 (both 1993 to Shionogi and corresponding
to
Canadian patent no. 2,072,945); by M. Watanabe et al. in Bioorg. Med. Chem. 5,
437
(1997), Canadian patent applications nos. 2,495,296; 2,527,314; 2,543,358; and
2,573,857, and in, for example, International laid open applications
W02007099561,
W02007041666, W02007039287, W02007017117, W02006067456 (corresponding to
CA 2,589,775) and W02006091771 (corresponding to CA 2,594,017).
Canadian patent application no. 2,450,820 is directed to processes for
preparing a
calcium salt of a statin from an ester derivative or protected ester
derivative of the statin
by using calcium hydroxide
2
CA 02637977 2008-10-03
Canadian patent application no. 2,509,619 is directed to a synthetic route of
preparing
rosuvastatin.
Canadian patent application nos. 2,495,296 and 2,527,314 relates to a process
for
manufacture of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt,
which is useful
for the production of a pharmaceutical useful in the treatment of, inter alia,
hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
Canadian patent application no. 2,537,962 relates to two polymorphic forms of
bis[(E)-7-
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-
(3R,5S)-
3,5-dihydroxyhept-6 -enoic acid] calcium salt, processes for making them and
their use
as HMG Co-A reductase inhibitors.
U.S. patent no. 7,241,800 relates to anhydrous amorphous forms of rosuvastatin
calcium, fluvastatin sodium and pitavastatin calcium, as well as to processes
for their
preparation, to pharmaceutical compositions containing them and to methods of
treatment using the same.
A problem associated with the chemical compound, rosuvastatin calcium, is that
it
readily undergoes degradation under certain conditions like, exposure to
atmospheric
conditions (i.e. humidity, oxygen, air and light), thereby significantly
reducing the storage
life. Such has been referred to in Canadian patent 2,313,783 and 2,315,141.
The major
degradation products formed are the corresponding (3R,5S) lactone and an
oxidation
product in which the hydroxyl group adjacent to the carbon-carbon double bond
is
oxidized to a ketone functionality. Also another problem associated with
rosuvastatin is
that when it is exposed to light it undergoes photolytic degradation forming
two
diasteriomeric cyclic products. Such has also been referred to in
International laid open
application W02007071357 (which is based on US2005/0187234A1).
To solve this issue of degradation in rosuvastatin calcium, pharmaceutical
manufacturers have used stabilizing agents (or material or substance). For
example,
Canadian patent no. 2,313,783 (corresponding to EP 1 223 918 and U.S. patent
nos.
3
CA 02637977 2008-10-03
6,316,460 and 6,548,513) discloses the use of a tri-basic phosphate salt in
which the
cation is multivalent to provide stability to the composition, thereby
avoiding degradation.
Canadian patent no. 2,315,141 discloses the use of an inorganic salt in which
the cation
is multivalent for stabilizing the rosuvastatin calcium structure.
International laid open application no. W02005041939 (corresponding to
US2005119331A1) discloses formulations comprising therapeutically effective
amounts
of at least one acid-stable, carrier-mediated transport statin, at least one
poorly water-
soluble, carrier-mediated transport statin, or at least one large molecular
weight, carrier-
mediated transport statin, such as atorvastatin and rosuvastatin, or a
pharmaceutically
acceptable salt thereof, and methods of their use.
International laid open application W02007071357 teaches a formulation of (E)-
7-[4-(4-
fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-
(3R,5S)-3,5-
dihydroxyhept-6-enoic acid or a pharmaceutically-acceptable salt thereof for
oral use,
such as tablets, capsules, powders, granules by the use of ingredients chosen
from two
groups. The first group stabilizes rosuvastatin calcium against oxidation and
the other
group inhibits the formation of lactones.
Generally, the rosuvastatin calcium formulations of the prior art require the
use of
stabilizing agents, for example, inorganic salts, tribasic calcium phosphate
in which the
cation is multivalent, and some ingredients which specifically prevents
degradation.
Usage of stabilizing agents inherently renders the manufacturing process more
costly
due to the use of additional pharmaceutical excipients, and which, in turn,
consumes
more time.
There is thus a need for a novel dosage form that overcomes the problems of
the prior
art, such dosage form containing a pharmaceutically acceptable active
substance (i.e.
rosuvastatin calcium), which is substantially free of any stabilizing agents
used to
stabilize the end product from degradation.
4
CA 02637977 2008-10-03
SUMMARY OF THE INVENTION
An object of the present invention is to provide a novel stable pharmaceutical
dosage
form containing an HMG-CoA reductase inhibitor and free of stabilizing agents,
said
dosage form comprising a HMG-CoA reductase inhibitor combined with at least
the
following pharmaceutically acceptable excipients: colloidal silicon dioxide,
microcrystalline cellulose, and lactose monohydrate.
Preferably, wherein the colloidal silicon dioxide is present in an amount
ranging from 0.5
to 1.5%, the microcrystalline cellulose is present in an amount ranging from
25 to 35%
and lactose monohydrate is present in an amount ranging from 50 to 70%.
Preferably, the HMG-CoA reductase inhibitor is a statin. More preferably, the
statin is
rosuvastatin or a pharmaceutically acceptable salt thereof. Most preferably,
the statin is
rosuvastatin calcium.
Another object of the present invention is to provide a rosuvastatin dosage
form that
allows a single daily administration with a prolonged effect, simplified
production and is
cost effective.
Yet another object of the present invention is to provide a process for
manufacturing the
novel dosage form.
It is also worth mentioning that the present invention is considered to be
inventive
because the manufacturing process is simple and less time consuming. The
dosage
forms according to the present invention substantially decrease the formation
of lactone
or oxidation degradation products in comparison to the commercially available
dosage
form containing rosuvastatin, hence they present greater stability than what
was
achieved in the Crestor@) product.
Other embodiments and further scope of applicability of the present invention
will
become apparent from the detailed description and examples given hereinafter.
It should
be understood, however, that this detailed description and examples, while
indicating
preferred embodiments of the invention, are given by way of illustration only,
since
CA 02637977 2008-10-03
various changes and modifications within the spirit and scope of the invention
will
become apparent to those skilled in the art.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Nomenclature
Before the present formulations and methods of use are disclosed and
described, it is to
be understood by a person skilled in the art that unless otherwise indicated
this invention
is not limited to specific pharmacologically active agents, specific
pharmaceutical
carriers, or to particular administration regimens, as such may vary. It is
also to be
understood that the terminology used herein is for the purpose of describing
particular
embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims,
the singular
forms "a," "an" and "the" include plural referents unless the context clearly
dictates
otherwise. Thus, for example, reference to "an active agent" includes mixtures
of active
agents, reference to "a pharmaceutical carrier" includes combinations of two
or more
carriers, and the like.
"Optional" or "optionally" means that the subsequently described circumstance
may or
may not occur, so that the description includes instances where the
circumstance occurs
and instances where it does not.
The terms or expressions "active agent," "drug", "pharmacologically active
agent",
"pharmaceutically acceptable active agent" and/or "pharmaceutically acceptable
active
substance" are used interchangeably herein to refer to a chemical material or
compound
which, when administered to an organism (human or animal, generally human)
induces
a desired pharmacologic effect. In the context of the present invention, the
terms or
expressions refer to a compound that is capable of being delivered orally.
According to the present invention, the pharmaceutically active substance can
be a
statin, for example, rosuvastatin. The term "rosuvastatin" as used herein
includes all
optical isomers, racemic mixtures and the like of the compound and all
pharmaceutically
acceptable salts, amides, prodrugs and analogs thereof.
6
CA 02637977 2008-10-03
Similarly, a "pharmaceutically acceptable salt" or a "pharmaceutically
acceptable ester"
of the compound as provided herein is a salt or ester which is not
biologically or
otherwise undesirable. A pharmaceutically acceptable salt of rosuvastatin is,
for
example, rosuvastatin calcium.
By the terms "effective amount" or "pharmaceutically effective amount" of an
agent as
provided herein are meant a nontoxic but sufficient amount of the agent to
provide the
desired therapeutic effect. The exact amount required will vary from subject
to subject,
depending on age, general condition of the subject, the severity of the
condition being
treated, and the particular active agent administered, and the like. Thus, it
is not possible
to specify an exact "effective amount." However, an appropriate "effective"
amount in
any individual case may be determined by one of ordinary skill in the art
using routine
experimentation.
The term "excipient" refers to a generally pharmaceutically inactive or inert
substance
used as a diluent or vehicle for a drug. Different forms of drug
administration may require
a different excipient and a "pharmaceutically acceptable excipient" includes a
"pharmaceutically acceptable carrier." For example, tablets, troches, pills,
capsules, and
the like, may contain excipients including binders, such as gum tragacanth,
acacia, corn
starch or gelatin; a disintegrating agent such as corn starch, potato starch,
alginic acid; a
lubricant such as magnesium stearate. Capsules may contain additional
excipients such
as a liquid carrier.
By "pharmaceutically acceptable carrier" is meant a carrier comprised of a
material that
is not biologically or otherwise undesirable, i.e., the material may be
administered to an
individual along with the selected active agent without causing any
undesirable biological
effects or interacting in a deleterious manner with any of the other
components of the
pharmaceutical composition in which it is contained. The term "carrier" is
used
generically herein to refer to any components present in the pharmaceutical
formulations
other than the active agent or agents, and thus includes diluents, binders,
lubricants,
disintegrants, fillers, coloring agents, wetting or emulsifying agents, pH
buffering agents,
preservatives, and the like.
7
CA 02637977 2008-10-03
The expression "substantially free" is intended to mean that the present
invention does
not contain any specific amount of stabilizing agent that is sufficient to
stabilize the
active substance, formulation or end product .
The term "stabilizing agent" refers to any substance or a mixture of
substances which
when in contact with the active agent in appropriate quantities will improve
the physical
and chemical characteristics of the active agent.
According to the present invention, the expression "dosage form" may consist
of
granules, spheroids, beads, pellets, capsules, tablets or any other suitable
unit. In the
present invention, the dosage form is preferably a tablet.
As aforementioned, the present invention relates to a novel stable
pharmaceutical
dosage form containing an HMG-CoA reductase inhibitor, wherein the dosage form
is
free of stabilizing agents, said dosage form comprising an HMG-CoA reductase
inhibitor
combined with at least the following pharmaceutically acceptable excipients:
colloidal
silicon dioxide, microcrystalline cellulose, and lactose monohydrate.
(i) Core Composition (or tablet composition)
The tablet composition of the present invention is made of several components,
such as
for example at least one pharmaceutically acceptable active substance (i.e. a
statin,
rosuvastatin or pharmaceutically acceptable salt thereof) combined with and at
least one
pharmaceutically acceptable excipient.
(a) Pharmaceutically acceptable active substance
Pharmaceutically acceptable active agents or substances include and are not
limited to
statins. Suitable statins include, for example, atorvastatin, cerivastatin,
fluvastatin,
lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and
simvastatin.
Rosuvastatin and salts thereof are particularly preferred pharmaceutically
acceptable
active agents.
It is worth mentioning that the pharmaceutically acceptable active agent or
substance
could be co-administered with another active agent known to a person skilled
in the art,
8
CA 02637977 2008-10-03
such as, for example, simvastatin and ezetimibe (Vytorin ), lovastatin and
niacin
(advicor@) and atorvastatin and amlodipine (caduet ).
Each of the active agents in the individual tablets may be in the form of a
pharmaceutically acceptable salt, ester, amide, prodrug or other derivative or
analog,
including active agents modified by appending one or more appropriate
functionalities to
enhance selected biological properties. Such modifications are known in the
art and/or
are described in the pertinent texts and literature.
(b) Pharmaceutically acceptable excipients
As aforementioned the pharmaceutically acceptable active substance can be
combined
with and at least one pharmaceutically acceptable excipient. Acceptable
pharmaceutically acceptable excipients, include for example diluents,
disintegrants,
binders, lubricants, glidants, and the like.
Diluents, also termed "fillers," are typically necessary to increase the bulk
of a tablet so
that a practical size is provided for compression. Suitable diluents include,
for example,
lactose, spray dried lactose ,a-lactose, R-lactose , Tabletose , various
grades of
Pharmatose , Microtose , Fast Flow , sorbitol, microcrystalline cellulose,
various
grades of Avicel, Vivacel , Vivapur , powdered cellulose, kaolin, starch,
hydrolyzed
starches, pregelatinized starch, alumina, sucrose, dextrins, dextrose,
fructose,
maltodextrins, and the like.
Disintegrants are used to facilitate tablet disintegration or "breakup" after
administration,
and are generally starches, clays, cellulose and cellulose derivatives,
alginic acid or
alginates, gums, crospovidone, polarcrillin potassium, sodium starch
glycollate,
pregelatinized starch, and the like.
Binders are used to impart cohesive qualities to a tablet formulation, and
thus ensure
that a tablet remains intact after compression. Suitable binder materials
include, but are
not limited to starch (including corn starch and pregelatinized starch),
gelatin, sugars
(including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene
glycol, waxes,
natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate,
celluloses, and
Veegum, and synthetic polymers such as polymethacrylates and
polyvinylpyrrolidone
9
CA 02637977 2008-10-03
(povidone), ethylcellulose, hydroxyethyl cellulose,
hydroxypropylmethylcellulose
(HPMC), methylcellulose, polyethylene oxide, and the like.
Lubricants are used to facilitate tablet manufacture; examples of suitable
lubricants
include, for example, magnesium stearate, calcium stearate, stearic acid,
glyceryl
behenate, and polyethylene glycol, talc, stearic acid (chemically designated
as
octadecanoic acid, C18H3602), zinc stearate, sodium stearyl fumerate, calcium
stearate,
light mineral oil and are preferably present at no more than approximately 0.5
to 2.5 wt.
% relative to tablet weight.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02)
(aerosil ),
magnesium silicate, starch, talc, magnesium trisilcate, etc. Colloidal
silicion dioxides are
also known to function as an absorbent; anti-caking agent; emulsion
stabilizer; glidant;
suspending agent; and tablet disintegrant.
If desired, the tablets may also contain minor amounts of nontoxic auxiliary
substances
such as antioxidants, such as for example, ascorbic acid, ascorbyl palmitate,
butylated
hydroxyl anisole, butylated hydroxyl toulene, potassium meta bisulfite, propyl
gallate,
sodium thiosulfate, tocopherol, tocopherol acetate, tocopherol hemisuccinate,
TPGS or
other tocopherol derivatives, hypophosphorous acid, fumaric acid,
monothioglycerol;
coloring agents, flavouring agents, surface active agents, such as for
example, Sodium
lauryl sulfate, poly oxyethylene sorbitan fatty acid esters (Tween series),
Myrj
series, Solutol HS, poly oxyethylene alkyl ethers (Byrj series), poly
oxyethylene, castor
oil derivatives, polyoxyethylene stearates, sorbitan esters (i.e. sorbitan
fatty acid esters),
poloxamers, sucrose fatty acid ester, vitamin E TPGS, polyethylene glycol
fatty acid
esters, wetting or emulsifying agents, buffering agents, including for
example, citric acid,
sodium citrate, dilute HCI, sodium hydroxide, fumaric acid, tartaric acid,
malic acid,
succinic acid, preservatives, such as methyl and propyl parabens, BKC,
thiomersal, and
the like. Examples of each the aforementioned agents can also be found in for
example,
the Handbook of Pharmaceutical Excipients (5th edition) by Raymond C. Rowe,
Paul J.
Sheskey and Sian C. Owen.
CA 02637977 2008-10-03
(ii) Coating Composition
The coating composition of the present invention can be made of several
components.
For example, the coating composition can include a coating agent, alone or in
combination with any other pharmaceutically acceptable excipient, including
for
example, film forming polymer, anti-tacking agents, glidants, diluents,
lubricants,
plasticizers, additives, surface active agents, and solvents.
For example, the coating composition of the present invention can comprise of
a coating
agent, such as Opadry II manufactured by Colorcon.
(iii) Additional coats
It is worth mentioning that the end product can further be coated with a non-
functional or
top coat so as to improve the appearance of the dosage form, i.e. a tablet. In
this
connection, conventional coating procedures and equipment may be used to coat
the
dosage units, i.e., the drug-containing tablets, beads or particles.
For detailed information concerning materials, equipment and processes for
preparing
tablets, beads, drug particles, and delayed release dosage forms, reference
may be had
to Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York:
Marcel
Dekker, Inc., 1989), and to Ansel et al., Pharmaceutical Dosage Forms and Drug
Delivery Systems, 6th Ed. (Media, PA: Williams & Wilkins, 1995).
Utility
The novel drug dosage forms are to be administered orally to a mammal and can
be
used to administer rosuvastatin calcium to treat or prevent a variety of
disorders,
conditions and diseases. In accordance with the present invention,
administration of
rosuvastatin calcium may be carried out in order to treat any disorder,
condition or
disease for which rosuvastatin calcium is generally indicated. Such disorders,
conditions
and diseases include, for example, described in the background of the
invention.
For administration of rosuvastatin calcium, the typical daily dose is in the
range of
approximately 5 mg to 100 mg, preferably 5 mg to 60 mg, and more preferably 40
mg;
although the exact dosage regimen will depend on a number of factors,
including age,
11
CA 02637977 2008-10-03
the general condition of the patient, the particular condition or disorder
being treated, the
severity of the patient's condition or disorder, and the like. A standard dose
of 10 mg for
oral administration, once daily, is recommended in most patients.
It is to be understood that while the invention has been described in
conjunction with the
preferred specific embodiments thereof, that the description above as well as
the
examples which follow are intended to illustrate and not limit the scope of
the invention.
Other aspects, advantages and modifications within the scope of the invention
will be
apparent to those skilled in the art to which the invention pertains.
EXAMPLES
The following examples are illustrative of the wide range of applicability of
the present
invention and are not intended to limit its scope. Modifications and
variations can be
made therein without depending from the spirit and scope of the invention.
Although any
method and material whether similar or equivalent to those described herein
can be
used in the practice for testing the present invention, the preferred methods
and
materials as described.
All of the percentages given hereinabove and below are percentages by weight.
Examples of various formulations of rosuvastatin calcium capsules and/or
tablets are
provided herein below.
12
CA 02637977 2008-10-03
Table I
Comparative Formula of the dosage form according to preferred embodiments of
the
present invention vs. Crestor@ (Astra Zeneca)
Rosuvastatin %w/w Function Crestor Function
tablets of present
invention
1 Rosuvastatin as 5.0%- Active Rosuvastatin as Active
Rosuvastatin 14% Rosuvastatin
calcium calcium
2 Collloidal Silicon 0.5- Glidant Calcium Stabilizer
Dioxide Aerosil 1.5% phosphate
3 Microcrystalline 25-35% Diluent Lactose Diluent
cellulose Avicel Monohydrate
4 Lactose 50-70% Diluent Microcrystalline Diluent
Monohydrate cellulose
Crospovidone 3-5.0% Disintegrant Crospovidone Disintegrant
6 Magnesium stearate 0.5- Lubricant Magnesium Lubricant
1.0% stearate
7 Opadry II Pink Coating Ferric oxide Red Colorant
agent
8 Opadry II Yellow Coating Ferric oxide Yellow Colorant
agent
9 - - - Hydroxy propyl Film former
methyl cellulose
- - - GI ce I triacetate Plasticizer
11 - - - Titanium Dioxide Opacifier
Example #1
Table 2
Lot Size - 974 Tablets
Rosuvastatin 5 mg (ROST 025) %w/w Qty for the lot (gm)
1 Rosuvastatin as Rosuvastatin 5.21 5.329
calcium
2 Collloidal Silicon Dioxide Aerosil 0.5 0.487
3 Microcrystalline cellulose Avicel 34.0 33.116
4 Lactose Monohydrate 54.54 52.88
5 Crospovidone 5.0 4.870
6 Magnesium stearate 0.75 0.731
7 Opadry II Yellow 3.0% of the
tablet weight
Manufacturing Process:
13
CA 02637977 2008-10-03
In a first step (i.e. step #1), rosuvastatin calcium and portion of lactose
monohydrate
(10.0 Gm) are blended together and screened through 420 pm mesh (blend #1). In
a
second step (i.e. step #2), aerosil, microcrystalline cellulose (Avicel ) and
crospovidone
are screened through 420 pm and blended with blend of step # 1 for 1 minute
(blend #2).
In a third step (step #3), the remaining portion of lactose monohydrate was
screened
through 600 pm mesh and blended with blend #2 for 1 to 2 minutes (blend #3).
In a
fourth step (step #4), magnesium stearate is screened through 420 pm mesh (425
pm)
and is then blended with blend # 3 for several minutes (i.e. 1-2 minutes).
Afterwards, in a
fifth step #5, the final blend, containing the elements of steps #1 to # 4,
was compressed
using a rotary press, so as to form, for example, tablets. The resulting
tablets were then
coated with, for example Opadry II (from colorcon) to a weight gain of 2% to
3.0%w/w.
The coating process can be performed with conventional coating equipment, for
example O'HARA Lab CoatT"".
Example #2
Table 3
Lot Size - 123 Tablets
Rosuvastatin 40 mg ( ROST 026) %w/w Qty for the lot (gm)
1 Rosuvastatin as Rosuvastatin 9.80 5.41
calcium
2 Collloidal Silicon Dioxide Aerosil 0.5 0.261
3 Microcrystalline cellulose Avicel 34.0 17.8
4 Lactose Monohydrate 50.0 25.82
Crospovidone 5.0 2.61
6 Magnesium stearate 0.75 0.392
7 Opadry II Pink 3.0% of the
tablet weight
Manufacturing Process:
In a first step (i.e. step #1), rosuvastatin calcium and portion of lactose
Monohydrate
(10.0 Gm) are blended together and screened through 420 pm mesh (blend #1). In
a
second step (i.e. step #2), aerosil, microcrystalline cellulose (Avicel ) and
crospovidone
are screened through 420 pm and blended with blend of step # 1 for 1 minute
(blend #2).
In a third step (step #3), remaining portion of Lactose Monohydrate was
screened
14
CA 02637977 2008-10-03
through 600 pm mesh and blended with blend #2 for 1 to 2 minutes (blend #3).
In a
fourth step (step #4), magnesium stearate is screened through 420 pm mesh and
is then
blended with blend # 3 for 1-2 minutes. Afterwards, in a fifth step #5, the
final blend,
containing the elements of steps #1 to # 4, was compressed using a rotary
press, so as
to form, for example, tablets. The resulting tablets were then coated with,
for example
Opadry II (from colorcon) to a weight gain of 2% to 3.0%w/w.
The coating process can be performed with conventional coating equipment, for
example O'HARA Lab CoatTM.
Example #3
Table 4
Lot Size - 25000 Tablets
Rosuvastatin 20 mg ( P-1751) %w/w Qty for the lot (gm)
1 Rosuvastatin as Rosuvastatin 6.946 521.0
calcium
2 Collloidal Silicon Dioxide Aerosil 0.5 37.5
3 Microcrystalline cellulose (Avicel 10.0 750.0
101)
4 Microcrystalline cellulose (Avicel 15.0 1125.0
102)
Lactose Monohydrate 63.8 4785.3
6 Crospovidone 3.0 225.0
7 Magnesium stearate 0.75 56.3
8 Opadry II Pink 3.0% of the
tablet weight
Manufacturing Process:
In a first step (i.e. step #1), rosuvastatin calcium Microcrystalline
cellulose Avicel Ph 101
are blended together in a V blender for 3 minutes and screened through 225-250
pm
mesh (blend #1). In a second step (i.e. step #2), aerosil, microcrystalline
cellulose
(Avicel 102) and crospovidone are blended together in a V -blender for 3
minutes and
screened through 1000-1200 pm mesh (blend #2). In a third step (step #3),
Lactose
Monohydrate was screened through 1000-1200 pm mesh and blended with blend # 1&
blend #2 for 21 minutes in a Bin Blender (blend #3). In a fourth step (step
#4),
magnesium stearate is screened through 420 pm mesh and is then blended with
blend #
3 for 3 minutes in a Bin Blender. Afterwards, in a fifth step #5, the final
blend, containing
CA 02637977 2008-10-03
the elements of steps #1 to # 4, was compressed using a rotary press, so as to
form, for
example, tablets. The resulting tablets were then coated with, for example
Opadry II
(from colorcon) to a weight gain of 2% to 3.0%w/w.
The coating process can be performed with conventional coating equipment, for
example O'HARA Lab CoatT"".
In other words, the process for manufacturing the novel dosage form according
to the
present invention generally comprises:
- a first step of combining an HMG-CoA reductase inhibitor with at least the
following pharmaceutically acceptable excipients: colloidal silicon dioxide,
microcrystalline cellulose, and lactose monohydrate so as to form a blend;
- a second step of compressing said blend obtained in step 1; and
- optionally, a third step of applying a coating composition.
Direct compression of powder is a preferred manufacturing technique. However,
it is
worth mentioning that other dosage forms can be envisaged; though for the
purposes of
the present invention, the tablet form is preferred.
It is worth mentioning that the dosage form, for example a tablet, of the
present invention
was subjected to accelerated stability studies as per ICH conditions in their
primary
packaging. A primary packaging includes tablets packed in HDPE packs with a
dessicant and further induction sealed and also in blister packs. One (1)
month and
three (3) months stability studies were conducted and tested for degradation.
A
comparative study of the stability results for the composition of the present
invention
versus compositions stabilized by tribasic calcium phosphate are provided in
the
following tables.
16
CA 02637977 2008-10-03
Table 5
Comparative stability of the dosage form according to a preferred embodiment
of the
present invention (i.e. Rosuvastatin 40 mg) vs. Crestor@ 40mg (Astra Zeneca)
Composition according to a Crestor 40 mg
preferred embodiment of the Lot No( 103960A)
present invention
Rosuvastatin 40 mg
Lot No : ROST 026
Exposed condition 40 C/75% RH 40 C/75% RH
Pack HDPE Pack* Blister pack
T=0 1 Month 3 Months T=0 1 Month 3 Month
Degradation Known com ounds
Comp 1 0.10% 0.11% 0.10% 0.13% 0.13% 0.25%
Comp 2 0.04% 0.04% 0.04% ND ND ND
Comp 3* ND 0.04% 0.10% 0.53 % 0.64% 0.85%
Comp 4* 0.06% 0.07% 0.13% 0.03% 0.11% 0.22%
Comp 5 ND ND ND ND ND ND
Total Known 0.20% 0.26% 0.36% 0.69% 0.88% 1.32%
Individual unknown compounds
0.05% 0.05% 0.05% 0.05% 0.05% 0.05%
0.03% 0.03% 0.05% 0.04%
Total unknown 0.08% 0.08% 0.05% 0.10 % 0.09% 0.05%
Total Related 0.27% 0.34 /u 0.41% 0.79% 0.97% 1.37%
*HDPE pack - 50 tablets in 60 cc HDPE bottle with 1 x 1.0 g Trisorb and
induction
sealed.
Table 6
Comparative Stability of the dosage form according to a preferred embodiment
of the
present invention (Rosuvastatin 5 mg) vs. Crestor 5mg (Astra Zeneca)
Composition according to a Crestor 5mg
preferred embodiment of the Lot No( 104063C)
present invention
Rosuvastatin 5 mg
Lot No : ROST 025
Exposed condition 40 C/75% RH 40 C/75% RH
Pack HDPE Pack * Blister pack
T=0 lMonth 3 Months T=0 1 Month 3 Month
Degradation Known com ounds
Comp 1 0.11% 0.12% 0.09% 0.12% 0.12% 0.25%
Com 2 ND ND ND ND ND ND
Comp 3* 0.04% 0.09% 0.22% 0.75% 0.87% 1.04%
Comp 4* 0.05% 0.06% 0.10% 0.06% 0.26% 0.61%
Comp 5
17
CA 02637977 2008-10-03
Total Known 0.20% 0.27% 0.41% 0.93% 1.25% 1.90%
Individual unknown compounds
0.03% 0.03% 0.08% 0.03% 0.04%
0.03% 0.04% 0.06% 0.03%
0.04%
Total unknown 0.06% 0.03% 0.12% 0.13% 0.07%
Total Related 0.26% 0.30% 0.41% 1.06% 1.38% 1.97%
*HDPE pack - 45 tablets in 150 cc HDPE bottle with 1.0 g Trisorb and induction
sealed.
Table 7
Comparative stability data of the dosage form according to a preferred
embodiment of
the present invention (i.e. Rosuvastatin 20mg) in different packaging
Composition according to a Composition according to a
preferred embodiment of the preferred embodiment of the
present invention present invention
Rosuvastatin 20 mg Rosuvastatin 20 mg
Lot No: P-1751 Lot No : P-1751
Exposed condition 40 C/75% RH 40 C/75% RH
Pack HDPE Pack* Blister pack**
T=0 lMonth 3 Months T=0 1 Month 3 Month
Degradation (Known compounds)
Comp 1 0.09% 0.13% 0.11% 0.09% 0.12% 0.12%
Comp 2 <0.06% <0.06% <0.06% <0.06% <0.06% <0.06%
Comp 3* <0.06% 0.09% 0.16% <0.06% <0.06% 0.06%
Comp 4* <0.06% 0.06% 0.09% <0.06% 0.08% 0.13%
Comp 5 <0.06% <0.06% <0.06% <0.06% <0.06% <0.06%
Individual unknown compounds
<0.06% <0.06% <0.06% <0.06% <0.06% <0.06%
Total Related 0.09% 0.28% 0.36% 0.09% 0.20% 0.31%
*HDPE pack - 100 tablets in 150 cc HDPE bottle with 1.0 g Trisorb and
induction
sealed.
**Blister pack - Cold Forming blister with push-through aluminum foil.
ND - Not Detected
T=O - Time Zero Analysis
Comp 3 - Keto acid (Major degradation product)
Comp 4 - Lactone (Major degradation product)
Excellent chromatographic resolution between the main peak and its degradation
products or impurities was achieved using a C18 reversed column with acidic
ammonium acetate and an increasing gradient using acetonitrile and
tetrahydrofuran.
18
CA 02637977 2008-10-03
Degradation products were quantified at 280 nm. The reporting limit of the
degradation
products was set at 0.03 %.
From the results provided in tables 5 to 7, it can clearly be understood that
the
composition (or formulation) of the present invention is stable without the
addition of any
stabilizers. The major degradation products, being the lactone and the keto-
acid
(oxidation product), are well controlled.
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