Pharmaceutical Composition Comprising Azilsartan

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 2 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 3 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. 4 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. 5 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. 6 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. 7 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. 8 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 10 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 11 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.