FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10 and rule 13)
"A Stabilized Pharmaceutical Composition of Pravastatin and
method for preparation thereof."
(a) Astron Research Ltd.
(b)NATIONALITY: an Indian company
(c) 2nd Floor, Premier House l,
Bodakdev, Ahmedabad-380054.
Gujarat, ïndia.
The following specification particularly describes the invention
and the manner in which it is tb be performed.
l


FIELD OF THE INVENTION
The present invention relates to a stabilized phannaceutical composition
comprising Pravastatin or its pharmaceutically acceptable salts along with
suitable adjuvants. This composition is stable in the acidic pH environment
of the gastric lumina.
The invention also relates to a process for making the pharmaceutical
composition.
BACKGROUND OF THE INVENTION
Pravastatin, chemically known as (+)- (3R, 5R)-3,5-dihydroxy-7- [(1S, 2S,
6S, 8S,8aR)-6-hydroxy-2-methyl-8- [(S)-2-methylbutyryloxy] -l, 2, 6, 7, 8,
8a-hexahydro -Inaphthyl] heptanoate, and its pharmaceutical acceptable
salts has been described in U.S.patent No. 4,346,227 which is incorporated
herein by reference.
The statins are the most effective drug agents for treating dyslipidemia. The
statins includes mevastatin, lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, and cerivastatin. Alberts and colleagues at Merck isolated
lovastatin (formerly known as mevinolin) from Aspergillus terrus that was
the first statin approved for use in human beings. Pravastatin and
simvastatin are the chemically modified derivatives of lovastatin.
Pravastatin contains a hexahydronapthalene ring. Because of its structural
similarity with 3-hydroxy-3-methyIgIutaryI coenzyme A (HMG-CoA),
pravastatin is reversible competitive inhibitor of the enzyme HMG-CoA
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reductase. HMG-CoA catalyzes the conversion of HMG-CoA to
mevalonate, which is the early rate limiting step in cholesterol biosynthesis.
Pravastatin also reduces LDL levels by enhancing the removal of LDL
precursors (VLDL and IDL) and by decreasing hepatic VLDL production.
Pravastatin inhibit cholesterogenesis in the liver and this result in increase
expression of LDL receptor gene. Because of reduced free cholesterol in
hepatocytes, membrane-bound SREBPs (sterol-responsive element
bounded proteins) are cleaved by a protease and translocated to the nucleus.
This results in increase in synthesis of LDL receptors. At the same time
degradation of LDL receptor is reduced. On account of this reason there is
increasein number of LDL receptors on the surface of hepatocytes that
results in increased removal of LDL from the blood, thereby lowering
LDL-choIesterol levels. This is described in 'The Pharmacological Basis of
Therapeutics' by Goodman & Gilman (10th ed).
The therapeutic efficacy of any drug depends to a considerable extent on
the design of its pharmaceutical formulation. The physico-chemical
attributes and biopharmacological characteristics account for the
formulation of a stable and bioavailable pharmaceutical composition.
Pravastatin sodium is relatively polar and hydrophilic in nature. It is
susceptible to heat, light and moisture. It is also sensitive to a low pH
environment and is very unstable at pH 3 or less as found in the stomach
wherein the hydroxy acids degrade to form lactone and an inactive isomer
primarily, 3-a-hydroxyisopravastatin (Triscari et.al., J. Clin. Pharmacol,
3

1995; 35: 142). The acid instability of pravastatin reduces its bioavailability
and results in degradation of pravastatin following oral administration.
The literatute discloses various approaches to obviate problems related to
unfavorable absorption characteristics of pravastatin due to acid sensitivity.
One such approach mentioned in the prior art pertains to the use of agents
that are basic in nature and impart alkaline pH. US 51890589, for example,
discloses stabilized pravastatin pharmaceutical composition comprising
pravastatin about 1-60% by weight, one / more basifying agents from about
1-75 % by weight of composition compatible with pravastatin, to impart a
desired pH of at least 9 to an aqueous dispersion of said composition.
Basifying agents used in the formulation includes an alkali metal oxide, an
alkali metal hydroxide or ammonium hydroxide.
Patent no. WO 02076376 describes a stable pharamceutical composition of
pravastatin by the addition of basifying agent sodium stearyl fumarate (also
as lubricant) and Calcium carbonate (also as diluent) to impart a pH
between 6.5 and 8.5 to an aqueous dispersion of the product.
Japan patent no. 20022080430 describes method for stabilized pravastatin
medicinal composition by the addition of basifying agents like magnesium
aluminosilicate or magnesium metaaluminosüicate to the pravastin.
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Japan patent no. 2000229855 relates to pravastatin composition, in which
the product is stabüized by addition of a substance having buffer action or
antacid action as a part of the vehicle component, mannitol as a base.
Patent WO 9949896 describes a drug composition containing sodium
pravastatin and cyclodextrin as a stabilizer, Cyclodextrin surrounds the
drug molecules and prevents its exposure to the acidic environment. The
amount of cyclodextrin is advantageously used in the range of 50-5000
weight parts in proportion to 100 weight parts of pravastatin, below which
the drug is insufficiently stabüized and degrades at high humidity and
temperature. It is well recognized by those skilled in the art that the desired
stability may be achieved by application of such an approach but not
without compromising the release of the drug,
Still other techniques are directed towards use of protective coatings to
prevent release of pravastatin in the stomach. U. S. Patent No. 5,225,202
discloses an enteric coated pharmaceutical composition of pravastatin in the
form of tablet, beadlet, pellet or partiële that is enteric coated with
neutralized hydroxypropylmethyl cellulose phthalate and a plasticizer
which affords protection in a low pH environment of 3 or less while release
medicament at a pH of 4,5 or higher. It is well known to the formulation
scientist that phthalate polymers are prone to hydrolysis.
Also, due to aging, the properties of the polymer change which could have
significant effect on both ultimate dissolution behaviour and mechanical
properties of the applied coating. Further, with time, under ambient
5

conditions, the enteric coating gives an acidic residue, which may degrade
pravastatin within the formulation itself.
Furthermore, an enteric-coated formulation requires prolonged time to
attain the effective serum concentration. Additionally, the application of the
enteric coating is an additional operation which increases the length of the
manufacturing process and thereby the cost of the product.
As aforementioned, several pharmaceutical compositions have been
described which relate to the means to improve the stability, absorption and
thus bioavailability profile of pravastatin. However, none of the solutions
described above are completely satisfactory.
As aforesaid, one of the requirements for an acceptable pharmaceutical
composition is that it must be sufficiently stable so as not to exhibit
substantial decomposition of the active ingrediënt during the time between
manufacture of the composition and absorption of the drug in the body.
In light of the foregoing, the primary object of the present invention is to
provide a process for the preparation of a pharmaceutical composition of
pravastatin, which is stable upon prolonged storage and provides the
desired therapeutic effect while avoiding the heretofore-mentioned
disadvantages.
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SUMMARY OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical
composition of pravastatin which effects better stability and bioavailability.
More particularly, the present invention provides a pharmaceutical
composition, which is stable and suitable for oral administration,
comprising an effective amount of pravastatin or its pharmaceutical
acceptable salts and suitable adjuvants.
According to another aspect of the present invention, it provides a stable
formulation of pravastatin in the form of beads, pellets, granules, tablets
and capsules, comprising pravastatin or its pharmaceutical acceptable salts
and other adjuvants such as diluent, binder, glidant, anti-adherent,
disintegrant, alkalizing agents and the like. Also, the pharmaceutical
composition in solid dosage form may be optionally coated.
The present invention is directed to a pharmaceutical composition
exhibiting enhanced stability and bioavailability of pravastatin or its
pharmaceutical acceptable salts which is attained through the use of
processing techniques and adjuvants that do not adversely affect the
stability of the drug.
Insofar as the techniques of formulation of pharmaceutical composition are
concerned, two preparative routes are known, which are wet granulation
and dry process, which includes dry granulation (compaction or slugging)
and direct compression. The comparative experimentation'revealed that wet
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granulation of pravastatin resulted in deleterious effect on the stability of
formulation. A dry processing technique instead, stabüized the formulation
remarkably.
The present invention also provides a dry process for the preparation of
pharmaceutical composition which is stable and suitable for oral
administration, comprising mixing an effective amount of pravastatin or its
pharmaceutical acceptable salts and adjuvants comprising at least one
diluent, binder, glidant, anti-adherent, disintegrant, alkalizing agents,
Also, in the course of developing the present invention, many different
pharmaceutical compositions containing pravastatin were formulated and
tested for stability. Since this hydroxy acid compound (pravastatin) is
susceptible to degradation to the lactone form in an acidic environment, it
was necessary to stabilize its structural integrity in pharmaceutical
formulatiöns. Through extensive comparative experiments using various
combinations of excipients, it was found that the use of either mono / di-
sodium glycine carbamate or Formaxx 70 (Co-precipitated Calcium
carbonate and sorbitol) as a diluent and/or 1-Arginine as an alkalizing agent
aided in stabilizing the formulation. The total related substances and the
lactone formation was much lower when either of the two mentioned
adjuvants were used.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, the pharmaceutical composition may
contain one or more of diluents as a granulation substrate or filler.
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Examples of such diluents that may be used in the present invention
include, but are not limited to, Microcelac 100 (co-precipitated
microcrystalline cellulose and Lactose) lactose, sucrose, compressible
sugar, sorbitol, mannitol, Formax 70 (Co-precipitated Calcium carbonate
and sorbitol) and mono / di-sodium glycine carbamate.
In preferred embodiments of the present invention, the pharmaceutical
composition contains mono-sodium glycine carbamate, Microcelac 100 and
Lactose as the diluent.
The amount of diluents relative to the drug may vary depending on the
nature of diluent, their physiochemical characteristics, total weight of the
formulation, and other adjuvants that may be present as the integral part of
the formulation. However, the total diluent may be present in an amount
from about 5 % to about 95% by weight, more preferably from about 20 %
to about 85% by weight of the total weight of the pharmaceutical
composition, Individually the preferred diluents may be present preferably
from about 2 % to 60 % by weight of the total weight of the pharmaceutical
composition.
In accordance with this invention, the pharmaceutical composition may
contain a alkalizing agent for providing better stabüity to the product. The
alkalizers, which are amenable to the pharmaceutical composition of the
present invention, include 1-Arginine.
The composition of the invention may contain a alkalizing agent, 1-arginine
9

in an amount from about 0.5 % to about 25% and preferably from about 2%
to about 10% by weight of the total weight of the composition.
Other possible and supplemental adjuvants such as binders, disintegrants,
glidants, anti-adherents, colourants, and the like known as conventional by
those skilied in the art may be included, optionally, in the inventive
formulation. The present invention is not to be construed as being limited to
any particular excipient or class of pharmaceutical excipients.
Pharmaceutical adjuvants used must be of high purity and low toxicity to
render them suitable for incorporation and administration thereof. The
choices of these adjuvants and the amounts to be used are considered to be
within the purview of one skilled in the art and would depend on the type of
dosage form.
The pharmaceutical composition may contain a binder so as to form a
cohesive mass of the powder blend. It may be any pharmaceutical
acceptable, non-toxic, water-soluble and/or water insoluble agent showing
binding properties.
The composition may contain a binder selected from among several
applicable substances such as corn starch, microcrystalline cellulose,
povidone, modified corn starch, sugars, gums, methyl cellulose,
hydroxypropyl cellulose, and the like.
The requisite amount of binding agent used in this invention is an amount
needed to obtain a cohesive mass of desirable strength that allows for the
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formation of granules or tablets of optimum hardness. The binding agent
may be present in an amount from about 0.1 % to about 10% by weight and
preferably from about 0.5% to about 7.5% by weight of the composition.
According to the present invention the composition may contain a
disintegrating agent. Suitable disintegrating agents that can be used in the
present invention include staren, croscarmellose sodium, sodium starch
glycollate, crospovidone, cross-linked carboxymethyl starch, and the like.
The disintegrating agent may be present in an amount from about 1% to
about 10%, preferably from about 2% to about 7% by weight of the total
weight of the composition.
In addition to the above ingredients, colloidal silicon dioxide, and the like
as glidants, talc, and the like as an anti-adherent, magnesium stearate and
the like as lubricant and iron oxides, and the like as colorants may be
incorporated into the carrier.
The present invention is not to be construed as being limited to any
particular excipient or class of pharmaceutical excipients. The choice of
adjuvants and the amounts to be used are considered to be within the
purview of one skilled in the art.
According to the present invention the pharmaceutical composition may be
prepared either in the form of pellets, beads, granules, tablets and capsules.
The pharmaceutical composition in accordance to the present invention
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may be optionally coated with rapidly dissolving water soluble film coat.
The examples of water-soluble polymers include hydroxypropyl
methylcellulose, hydroxypropyl cellulose and the like. The solid unit
dosage form in accordance with the present invention may be coated to a
weight build up of about 1% to about 10% by weight, preferabiy from
about l % to about 4% by weight of the total weight of the composition.
According to the present invention wherein the pharmaceutical composition
is in the form of capsule dosage form, the capsule shell may be of a hard
gelatin or a soft gelatin type.
Stability studies for the different pharmaceutical compositions were
performed using the technique known as accelerated stability testing. In
such studies, samples were stored at the conditions of elevated temperature
and high humidity(40 C/15% RH). At the end of the desired time schedule,
the samples were analyzed for the drug content and total related substances
(degradation products) using high performance liquid chromatographic
techniques (HPLC).
According to the present invention, the pharmaceutical composition is
prepared by blending pravastatin sodium with adjuvants such as at least one
diluent and/or at least one alkalizing agent and the optionally added
adjuvants including anti adherents, disintegrant and glidants. The blend is
directly compressed into tablets or may be filled into capsules.
Alternatively, the pharmaceutical composition is prepared by blending the
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aforementioned ingredients with only a portion of the lubricant. The blend
is roll compacted and then sized to obtain granules. The granules raay be
filled into capsules or compressed into tablets.
In those embodiments of the present invention wherein the foregoing
composition is in the form of spherical pellets or beads, the art of producing
such dosage forms by extrusion and spheronisation techniques or
techniques based on high shear granulation or fluidized bed techniques raay
be used. Single unit pellets can be produced on industrial scale using
lozenge and troches cutting machines.
The foïlowing examples further illustrate this invention and are not to be
construed as limiting the scope but read in conjunction with the description
above, provide further understanding of the present invention and an
outline of the process for preparing the composition of the invention.
Example l
This example illustrates the present invention in the form of tablets using a
dry process (direct compression) for preparation and using mono-sodium
glycine carbamate, Lactose and Microcelac 100 as düuents, with a
composition as given in Table 1.
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Table 1: Composition

S.NO. Ingrediënt Name Function % w/w
i. Pravastatin Sodium Active 10.00
2. Microcelac 100 Diluent 28.87
3, Mono-sodium Glycine Carbamate Diluent 3.75
4. Lactose Monohydrate Diluent 48.75
5. Croscarmellose Sodium Disintegrant 4.00
6. Povidone Binder 3.00
7. Ferric oxide yellow Colorant 0.13
8. Magnesium Stearate Lubricant 1.50
All the ingredients were sifted through a sieve # 40 (ASTM std., 425
microns). The sifted materials are then mixed in a blender and compressed
into tablets of réspective weights for the desired strength.
The compressed tablets were packed in High Density Polyethylene (HDPE)
bottles which were induction sealed and stored at 40 C and 75% RH. A
stability indicating assay procedure was used to determine the drug content
and the total related substances. The results are recorded in Table 2
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Table 2: Stability Data

S.No. Parameter Results - Initial Results - 3 months
(40°C / 75 % RH)
1. rAssay 99.5 % 96.3 %
2. Related Substances

Lactone impurity 0.034 % 0.055 %

Total impurities 0.203 % 0.376 %
The results indicate that even after 3 months there was no significant
difference in assay, total related substances or lactone impurity.
Example 2
This example illustrates the present inventkm in the form of tablets using a
dry process (direct compression) for preparation and using Lactose and
Microcelac 100 as diluents; 1-Arginine as a alkalizing agent, with a
composition as given in Table 1.
Table 1; Composition

S.No. Ingrediënt Name Function % w/w
1. Pravastatin Sodium Active 10.00
2. Microcelac 100 Diluent 28.87
3. Lactose Monohydrate Diluent 48.75
4. I-Arginine Alkalizing agent 3.75
5. Croscarmellose Sodium Disintegrant 4.00
6. Povidone Binder 3.00
7. Ferric oxide yellow Colorant 0.13
8, Magnesium Stearate Lubricant 1.50
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All the ingredients were sifted through a sieve # 40 (ASTM std., 425
microns). The sifted materials are then mixed in a blender and compressed
into tablets of respective weights for the desired strength.
The compressed tablets were packed in High Density Polyethylene (HDPE)
bottles which were induction sealed and stored at 40 C and 75% RH. A
stability indicating assay procedure was used to determine the drug content
and the total related substances. The results are recorded in Table 2
Table 2: Stability Data

S.No. Parameter Results - Initial Resuits - 3 months
(40°C/ 75% RH)
1. Assay 97.3 % 96.4 %
2. Related Substances

Lactone impurity 0.017 % 0.067 %

Total impurities 0.150 % 0.483 %
The results indicate that even after 3 months there was no significant
difference in assay, total related substances or lactone impurity.
While this invention has been described with an emphasis upon preferred
embodiments, it will be obvious to those of ordinary skill in the art that
variations in the preferred methods of the present invention may be used
and that it is intended that the invention may be practiced otherwise than as
specifically described herein.
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Accordingly, this invention includes all modifications encompassed within
the spirit and scope of the invention as defined by the following claims.
While the present invention has been described in terras of its specific
embodiments, 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.
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We Claim:
1. A pharmaceutical composition which is stable and suitable for oral
administration, comprising an effective amount of pravastatin or its
pharmacetuically acceptable salts and suitable adjuvants including at
least diluents, and/or alkalizing agents.
2. The pharmaceutical composition according to claim l wherein the
diluents comprises about 5% to about 95% by weight of said
composition may be selected from the group consisting of lactose,
compressible sugar, sucrose, sorbitol, mannitol, cellulose, mono / di -
sodium glycine carbamate, cellulosic derivatives, Formax 70 (co-
precipitated calcium carbonate and sorbitol), Microcelac 100 (co-
precipitated lactose and cellulose), staren, starch derivatives, and
mixtures thereof.
3. The pharmaceutical composition according to claim.2 wherein the
diluents are mono-sodium glycine carbamate, lactose and Microcelac
100, wherein the total diluents.
4. The pharmaceutical composition according to claim 3 wherein the
individual diluents comprises about 2 % to 60 % by weight of the total
weight of the pharmaceutical composition.
5. The pharmaceutical composition according to claim l wherein the
alkalizing agent are amino acids such as 1-arginine or other such amino
acids or salts thereof.
6. The pharmaceutical composition according to claim 5 wherein the
alkalizing agent comprises about 0.5 % to about 25% by weight of said
composition.
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7. The pharmaceutical composition according to claim l wherein the
composition may include other adjuvants such as binders, disintegrants,
lubricants, glidants, antiadherants and mixtures thereof comprising of
concentrations of binder 0.1 - 10 % and disintegrant l - 10 %.
8. The pharmaceutical composition according to claim l wherein the
dosage form being formed into a physical form selected from the group
consisting of pellets, beads, granules, tablets and capsules.
9. The pharmaceutical composition according to claim 8 wherein tablet
dosage form further comprises coating with a fast dissolving film
10. A dry or wet process for the preparation of a pharmaceutical
composition which is stable and suitable for oral administration,
comprising an effective amount of pravastatin or its pharmaceutical
acceptable salts and suitable adjuvants including at least diluents and
alkalizing agent.
11. A pharmaceutical composition as claimed is herein described with
foregoing description and examples.
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Dated this on 15th of September 2005