FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition compnsmg
Azilsartan kamedoxomil which is free from pH control agent and process of
manufacturing the same. It further relates to a method of reducing an unpleasant odor
from the pharmaceutical composition by packaging the said pharmaceutical
composition in a pharmaceutical package, wherein pharmaceutical package is free
from desiccant.
BACKGROUND OF THE INVENTION
Azilsartan kamedoxomil which has a chemical name a~ (5-Methyl-2-oxo-1 ,3-dioxol-
4-yl)methyl 2-ethoxy-1-{ [2'-(5-oxo-4,5-dihydro-1 ,2,4-oxadiazol-3-yl)biphenyl-4-
yl]methyl}-lH-benzimidazole-7-carboxylate monopotassium salt 1s a novel
angiotensin receptor antagonist disclosed in U.S, Patent No. 7, 157,584. It is a class TV
molecule (low solubility and low permeability) as per Biopharmaceutics
Classification System and its chemical structure is shown below:
Azilsartan kamedoxomil is marketed as tablets for oral administration under the brand
names ED ARB I® in strengths of 40 and 80 mg. Inactive ingredients in the ED ARB I®
tablet consist of mannitol, fumaric acid, sodium hydroxide, hydroxypropyl cellulose,
croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.
Pharmaceutical products sometimes emit unpleasant odor which originates due to
vanous groups like sulfhydryl, sulphur, biacetyl etc. For example, Captopril and
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IPO DELHI 24-09-2815 17-34
r-------------------------------------------------------------------------------------------
Fursiltiamine emit odor due to sulphur compounds; Rimatil and L-cysteine give smell
due to sulfhydryl group and in Olmesartan medoxomil smell originates due to
biacetyl compound. Other active pharmaceutical ingredients like Bupropion,
isometheptene, bucillamine, valerian extracts and garlic pearls also emit unpleasant
odor. Patient compliance is less wherein pharmaceutical products emit unpleasant
odor.
Compounds having medoxomil group such as Olmesartan medoxomil and Azilsartan
kamedoxomil undergo hydrolysis at the ester linkage to produce a low molecular
weight compound, 2,3-butanedione (also called biacetyl or diacetyl). Generation of
2,3-butanedione leads to emission of unpleasant odor. To overcome this unpleasant
odor, commercially available EDARBI® tablets are packaged in high-density
polyethylene (HDPE) bottles with desiccants.
It is desirable to prepare alternate pharmaceutical compositions of Azilsartan
kamedoxomil which is stable and devoid of unpleasant odor.
US 2010/0121071 suggests that Azilsartan kamedoxomil has a better stability profile
at an acidic pH but its solubility is low at an acidic pH. The publication also discloses
use of a pH control agent showing pH of about 2 to about 5 to stabilize the
pharmaceutical formulation comprising Azilsartan kamedoxomil.
The following publications have proposed alternatives for stable composition and
methods to reduce unpleasant odor of pharmaceutical composition:
WO 20141102628 discloses use of polymeric carrier such as polyvinyl pyrrolidone,
copovidone, or a mixture thereof as a solublizer and a stabilizer for Azilsartan
medoxomil formulation. The polymeric carrier is intimately mixed with Azilsartan
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IPO DELHI 24-09-2015 17 34
medoxomil. Pharmaceutical composition as per the invention is prepared by using
anhydrous solvents without the use of water.
US 8,541,024 discloses a film-coated scored tablet of Azilsartan and discloses various
water-soluble film coating base which include cellulose-based polymer such as
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose or
methylhydroxyethyl cellulose; a synthetic polymer such as polyvinyl acetal diethyl
aminoacetate, amino alkyl methacrylate copolymer or polyvinylpyrrolidone; and a
-
polysaccharide such as pullulan. The publication also discloses use of pH adjusting
agent to stabilize the formulation.
US 201110201658 teaches a method of decreasing an unpleasant odor of a
pharmaceutical preparation comprising Azilsartan kamedoxomil with the help of a
desiccant.
US 2012/0100093 discloses a method for reducing smell of a medicinal preparation
which comprises using a chemical absorption-type desiccant, wherein the chemical
absorption-type desiccant for reducing smells of said medicinal preparation is a
metallic oxide.
WO 2014/080365 covers a pharmaceutical composition compnsmg an active
pharmaceutical ingredient with an unpleasant odor and a melt-processable polymer,
wherein said composition is prepared by a hot-melt extrusion process.
The aforementioned publications involve use of desiccants and expensive as well as
. complex manufacturing process like hot melt extrusion to reduce the unpleasant odor
from the dosage forms. However, all these techniques can increase the manufacturing
cost of marketed formulation.
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IPO DELRI 24-09-2015 17:34
The present inventors have developed a stable· pharmaceutical composition
comprising Azilsartan kamedoxomil which is free from pH control agent. The dosage
form of the present invention may optionally contain flavoring agents. The present
invention further provides a method of reducing an unpleasant odor from the
pharmaceutical composition by packaging the said pharmaceutical composition in a
pharmaceutical package, wherein the pharmaceutical package is free from desiccant.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a stable pharmaceutical composition compnsmg
Azilsartan kamedoxomil which is free from pH control agent and process of
manufacturing the same. It further relates to a method of reducing an unpleasant odor
from the pharmaceutical composition by packaging the pharmaceutical composition
in a pharmaceutical package, wherein the pharmaceutical package is free from
desiccant.
Pharmaceutical compositions are coated for a variety of reasons, including masking
objectionable flavors or odors, protecting unstable composition, providing protection
of the composition through the stomach with enteric coatings, improving appearance
of the composition or separating medicine ingredients into a core segment and coaring
segment.
According to one embodiment of the present invention, base of the coating is selected
form the group consisting of a cellulose-based polymer such as hydroxypropyl
cellulose, hydroxypropylmethyl celJulose, 1 hydroxyethyl cellulose or
methylhydroxyethyl cellulose; a synthetic polymer such as polyvinyl acetal diethyl
aminoacetate, ammo alkyl methacrylate copolymer, polyvinyl acohol or
polyvinylpyrrolidone; and a polysaccharide such as pullulan. Preferably, base of the
coating is synthetic polymer which is polyvinyl alcohol.
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IPO DELHI 24-09-2915 17;34
Polyvinyl alcohol (PV A) is a synthetic water soluble polymer, a white powder, which
melts, with decomposition and .pyrolysis, at 230°C. PV A is a :film-forming agent
produced by the hydrolysis of polyvinyl acetate and used in a number of
pharmaceutical formulations for coating. An optimized instant release :film coating
formulation based on PV A, can be applied on the tablets with a solid matter content
of up to 25 percent, which is a major step towards achieving highly efficient film
coating processes. Besides the increased solids content of the formulations, other
properties, like reduced permeability of water vapour or oxygen through a :film, have
also been achieved. The versatility and excellent :film-forming properties of PV A
itself, e.g., biodegradability, good strength, and superior appearance, make it a highly
suitable polymer for the application of tablet :film coating.· PV A-based coatings have
been found to increase tablet coating efficiency, reduced process time, and enhance
. tablet-to-tablet uniformity over cellulose-based coatings. Additionally, PV A-based
coatings also exhibit increased :film adhesion compared to cellulose-based coatings.
Ideally, :film coatings should be inert, have minimal interaction with the active species
and formulation components, and maintain functionality in the presence of drug
molecules (can be acidic or alkaline salts) and common impurities found in
excipients.
According to another embodiment of the invention, flavoring agents are added either
in the core or in the coating. Flavoring may be obtained from a variety of sources
with the relevant criteria being strength and pleasing nature of the flavor. The
preferred flavoring amount is readily determined by balancing the goal of adding an
amount sufficient to mask the unpleasant odor and provide a distinct, characteristic
and pleasing odor. The desired strength of the flavoring may vary depending on the
type of composition and the intended recipients and the identity of the flavoring. In
addition to the natural flavorants, many synthetic flavorants are also used. Preferred
flavouring agents used are selected from anise oil, cinnamon oil, cocoa, menthol,
orange oil, lemon oil, peppermint oil and vanillin.
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IPO DELHI 24-09-2815 17:34
The coating composition may comprise pharmaceutically acceptable excipients such
as binders, plasticizers, coloring agents, and opacifiers. The total weight gain after
coating may be about 1% wlw to about 5% w/w of uncoated composition.
Examples of binders for coating include cellulose or cellulose derivatives such as
~ .
carboxymethylcellulose sodium, alginic acid or sodium alginate, microcrystalline·
cellulose, methylcellulose, gelatin, povidone, starch, or pregelatinized starch.
Examples of plasticizers for coating include propylene glycol, triethyl citrate, tributyl
citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, or acetylated
monoglycerides.
Examples of opacifiers for coating include titanium dioxide, talc, calcium carbonate,
behenic acid, or cetyl alcohol.
Examples of coloring agents for coating include colorants such as iron oxide, Lake of
Tartrazine, Allura Red, Lake of Quinoline Yellow, Lake of Erythrosine, or Titanium
dioxide. The other known pigments, colorants, lakes are also contemplated within the
scope of this invention.
Suitable solvents for the coating include water, ethanol, methanol, isopropyl alcohol,
dichloromethane, acetone, or mixture thereof.
According to another embodiment of the invention, the pharmaceutical composition
is free from pH control agent.
According to yet another embodiment, the pharmaceutical composition is a solid oral
dosage form in the form of tablets, capsules, pill, caplets, granules or pellets.
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IPO DELHI 24-09-2015 17 34
The present invention provides a stable pharmaceutical composition free of pH
control agent and free of desiccant in pharmaceutical package wherein said
pharmaceutical composition is prepared by wet granulation, dry granulation or direct
compressiOn process.
The pharmaceutical composition of the present invention further comprises· one or
more pharmaceutically acceptable excipients selected from the group consisting of
diluents, binders, disintegrants, or lubricants. These excipients may be added
intragranularly or extragranularly in the pharmaceutical composition. The excipients
are not present in intimate admixture with Azilsartan kamedoxomil. Intimate
admixture is obtained by techniques such as co-precipitation, co-milling etc.
The diluent is selected from the group consisting of starch, lactose, sucrose,
maltodextrin, microcrystalline cellulose, dextrose, sucrose, mannitol, sorbitol, xylitol,
isomalt, erythritol, or mixtures thereof.
The binder is selected from the group consisting of alginic acid; sodium alginate;
cellulose derivatives such as carboxy methyl cellulose sodium, microcrystalline
cellulose, hydroxypropylcellulose, hydroxy propyl methyl· cellulose or
methylcellulose; gelatin; povidone; starch; pregelatinized starch; or mixtures thereof.
The disintegrant is selected from the group consisting of crospovidone, sodium starch
glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose,
calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose,
magnesium aluminum silicate, or mixtures thereof.
The lubricant is selected from the group consisting of magnesium stearate, calcium
stearate, sodium stearyl fumarate, stearic acid, talc, or mixtur'es thereof.
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IP 0 DEL HT 2 .!i: - 0 9 - 2 0 1 5 1 7 3 .!L
Co-processed excipients are also contemplated within the scope of this invention.
Pharmaceutical package of the present invention is selected from the group consisting
of HDPE bottles, multilayer HDPE bottles, Alu-Alu blisters. Preferably,
pharmaceutical package is multilayer HDPE bottle.
Multilayer bottles offer high oxygen and moisture barrier thus improving sensitive
product shelf life over time and reduce the need for desiccants. Bottles are produced
from combination of HDPE (high density polyethylene) or polypropylene in
conjunction with a layer resistant to oxygen permeation such as EVOH (ethylenevinyl
alcohol copolymer). Other suitable multi-layer bottles could be prepared using
polymers such as of "COC" or "COP" (cyclic olefin copolymers- COC, cyclic olefin
polymer - COP) with a layer resistant to oxygen permeation such as nylon. These
multi-layer bottles may consist of two or more layers and may have additional
additives to promote the adhesion and structural integrity of the bottle itself. Bottles
having high resistance to air and/or moisture are often referred to as barrier bottles.
Azilsartan kamedoxomil may be used in combination with one or more therapeutic
agents. These therapeutic agents include antihypertensive agents or hypoglycemic
agents. Antihypertensive agents may be further selected from diuretics, calcium
channel blockers (CCB), and ACE inhibitors.
The following examples illustrate the invention but are not to be construed as limiting
the scope of the invention.
9
I'P 0 D-E L HI: 2: 4 - () g, - 2 0 1 5 I 7 3 4
Exam[!le 1
Ingredients
Azilsartan kamedoxomil
Mannitol/Lactose
Low substituted hydroxypropyl cellulose
Croscarmellose sodium/Crospovidone
Microcrystalline cellulose
Magnesium stearate
Coating containing flavouring agent
Exam[!le 2
Ingredients
Azilsartan kamedoxomil
Mannitol/Lactose
Low substituted hydroxypropyl cellulose
Croscarmellose sodium/Crospovidone
Microcrystalline cellulose
Magnesium stearate
Flavoring agent
·Exam[!le 3
Ingredients
Azilsartan kamedoxomil
Manni to !/Lactose
Low substituted hydroxypropyl cellulose
Croscarmellose sodium/Crospovidone
Microcrystalline cellulose
Magnesium stearate
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IPO DELHI 24-09-2015 17 34
------------ ---
Percent
Concentration (w/w)
15-30%
25-55%
1-5%
1-10%
5-15%
0.25-2.5%
1-5%
Percent
Concentration (w/w) ·
15-60%
25-70%
1-20%
1-15%
5-50%
0.25-5%
0.01-5%
Percent
Concentration (w/w)
15-60%
25-70%
1-20%
1-15%
5-50%
0.25-5%
Manufacturing process:
i) Azilsartan kamedoxomil and croscarmellose sodium/crospovidone were sifted
through a suitable sieve.
ii) Mannitol/lactose were sifted through a suitable sieve along with blend of step
l.
iii) The blend of step ii was compacted using roller compactor.
iv) The compacts of step iii were passed through a mesh of suitable size to
achieve desired fraction of granules.
v) Microcrystalline cellulose was sifted through a suitable sieve and blended
with granules of step iv.
vi) Blend of step v was lubricated with mixed with Magnesium stearate and
compressed to form tablets.
vii) The tablets of step vi may be optionally coated.
The coated tablets prepared using quantitative formula as given in Example I and
commercially available EDARBI® tablets were subjected to dissolution studies using
USP dissolution apparatus II containing 900 ml of deaerated Phosphate buffer pH 7.8
as the dissolution medium with paddle speed of 50 Revolutions Per Minute (RPM).
The dissolution data is provided in the following Table.
Time point % drug released
(min.) ED ARB I® Example I
10 85 91
15 102 92
20 106 92
30 108 91
45 107 89
60 104 89
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IPO DELHI 24-09-2015 17 34
Since more than 85% of the drug is released in 15 minutes from both the coated
tablets prepared using quantitative formula as given in Example 1 and commercially
available EDARBI® tablets, dissolution profile of coated tablets prepared using
quantitative formula as ~given in Example 1 was similar to the dissolution profile of
EDARBI® tablets.
Coated tablets prepared using quantitative formula as given in Example 1 exhibited
better formulation technical attributes when packaged in a desiccant free multilayer
HDPE bottle in comparison to a tablet packaged in a desiccant free single layer
HDPE bottle.
Many modifications of this invention can be made without departing from its spirit
and scope, as will be evident to those skilled in the art. The specific embodiments
described herein are provided by way of example only, and the invention is to be
limited only by the terms of the appended daims, along with the full scope of
equivalents to which such claims are entitled.

WE CLAIM:
1. A stable pharmaceutical composition compnsmg Azilsartan kamedoxomil
free from pH control agent, wherein the pharmaceutical package is devoid of
desiccant.
2. The pharmaceutical composition of claim I, wherein Azilsartan kamedoxomil
is present in an amount ranging from 15 to 60% by weight with respect to
total weight of the pharmaceutical composition.
3. The pharmaceutical composition of claim 2, wherein the composition
comprises at least one or more pharmaceutically acceptable excipient.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutically
acceptable excipient is selected from diluent, binder, disintegrant, lubricant,
glidant, plasticizer, opacifier, coloring agent and flavoring agent.
5. The pharmaceutical composition of claim 4, wherein the exci"pients are not in
intimate admixture with Azilsartan kamedoxomil.
6. The pharmaceutical composition of claim 5, wherein flavoring agent is added
in the coating.
7. A method of reducing odor of a pharmaceutical composition compnsmg
Azilsartan kamedoxomil free from pH control agent, the method comprising a
pharmaceutical package devoid of desiccant.
8. The pharmaceutical composition of claim 1 or 7, wherein the pharmaceutical
composition is prepared by aqueous wet granulation, dry granulation, direct
compression or dry blending process.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical
composition is packaged in multilayer high density polyethylene (HDPE)
bottles.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical
composition is selected from the group consisting of tablets, capsules, pill,
caplets, granules or pellets.