Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

• the present invention relates to pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
• the present invention particularly relates to pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient that show desired stability as well as dissolution profile.
• the present invention also relates to a method of preparing pharmaceutical compositions comprising azilsartan medoxomil that are stable and has desired dissolution profile.
• the present invention relates to a simple and cost effective process for the preparation of pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof.
• the present invention also relates to stable pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).
• the present invention further relates to use of the pharmaceutical compositions for the treatment of hypertension and associated disorders.
• Blood pressure is the pressure of circulating blood on the walls of blood vessels. It is usually expressed in terms of the Systolic blood pressure (SBP) and Diastolic blood pressure (DBP). SBP is the peak pressure exerted on the walls of the arteries during the contraction phase of the ventricles of the heart while DBP is the minimum pressure exerted on the vessel walls when the heart muscle relaxes between two heart beats. BP is influenced by multiple factors like the muscular efficiency of the heart, the blood volume and viscosity, the age and health of the individual, and the state of the vascular wall. The mean arterial blood pressure is the product of cardiac output and peripheral vascular resistance.
• Hypertension also referred to as high blood pressure and sometimes called arterial hypertension, is a condition in which the arteries have persistently elevated blood pressure. It is defined as a SBP of at least 140 mmHg and/or a DBP of at least 90 mmHg. Blood pressure between 120/80 mmHg and 139/89 mmHg is called prehypertension to denote increased risk of hypertension.
• Hypertension affects about 20% of the adult population in developed countries. In the adult population aged 60 years or older, this percentage increases to about 60% to 70% in general. Hypertension is also associated with an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. (Fagard, R. H., Am. J. Geriatric Cardiology, 11 (1), 23-28 (2002); Brown, M J and Haycock, S; Drugs, 59 (Suppl 2), 1-12 (2000)).
• Hypertension may be classified as primary (essential) or secondary.
• Primary hypertension is the term for high blood pressure with unknown cause that accounts for about 95% of cases and Secondary hypertension is the term for high blood pressure with a known direct cause, such as kidney disease, tumors. It is also caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma.
• Hypertension can be managed by non-medication measures such as lifestyle changes such as dietary changes, physical exercise, weight loss and alike as well as medication measures.
• Several classes of medications called as 'antihypertensive drugs' belong to various chemical and pharmacological categories have been developed for the management of hypertension. However, the efficacy and safety of such drugs vary from patient to patient and there remains need for more effective treatment.
• Angiotensin II receptor blockers ARB or antagonists.
• Angiotensin II can act directly on blood vessels to cause increase in blood pressure. It also stimulates the release of aldosterone which is a potent vasoconstrictor that causes significant increase in blood pressure, but can also change the baseline filtering activity of the kidneys. Aldosterone causes the kidneys to retain both salt and water, which, over time, increases the amount of water in the body resulting into rise in blood pressure.
• ARBs specifically antagonize or block the action of angiotensin II type 1 receptors resulting in vasodilation, reduced secretion of vasopressin, and reduced production and secretion of aldosterone. The combined effect is a reduction in blood pressure.
• Azilsartan is a selective ATi subtype angiotensin II receptor antagonist. It is approved by USFDA as Edarbi ® immediate release oral tablets containing azilsartan medoxomil for the treatment of hypertension. Azilsartan medoxomil is a prodrug, which is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Each Edarbi ® tablet contains 42.68 or 85.36 mg azilsartan kamedoxomil, as the potassium salt of azilsartan medoxomil, which is equivalent to containing 40 mg or 80 mg respectively of azilsartan medoxomil.
• Azilsartan medoxomil is chemically described as (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 - ⁇ [2'-(5 -oxo-4, 5 -dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl ⁇ - 1H- benzimidazole-7-carboxylate monopotassium salt.
• Azilsartan kamedoxomil is a white to nearly white powder which is practically insoluble in water and freely soluble in methanol.
• US 5583141 patent discloses the compound azilsartan.
• US 7157584 patent discloses azilsartan medoxomil or a pharmaceutically acceptable salt thereof.
• US 20110201658 patent application discloses a pharmaceutical package including a preparation containing azilsartan or a salt thereof, and a desiccant.
• US 20120100093 patent application discloses a medicinal package comprising an azilsartan preparation capable of giving out smells, a packaging component and a chemical absorption-type desiccant.
• US 9066936 patent further discloses a solid pharmaceutical composition comprising azilsartan or a salt thereof and a pH control agent, wherein the pH control agent has pH of about 2 to about 5. This patent teaches that azilsartan is unstable in the neutral pH range, at which pharmaceutical preparations are generally produced and solubility of azilsartan is low at a pH range where it is stable.
• WO 2014102628 patent application discloses a stable pharmaceutical composition comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, and a polymeric carrier which is selected from the group consisting of polyvinyl pyrrolidone, copovidone, or a mixture thereof.
• compositions of the present invention are stable when prepared without the use of pH control agent(s) and also simultaneously achieve desired solubility profile. This is contrary to the teachings of the existing prior arts that require use of the pH control agent(s) which provide the pH in a strict narrow range of about 2 to about 5 to prepare stable pharmaceutical compositions of azilsartan with desired dissolution characteristics.
• the present invention provides pharmaceutical compositions comprising therapeutically effective amount of angiotensin II receptor blocker and one or more other pharmaceutically acceptable excipient(s).
• the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipient(s).
• compositions of the present invention comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof are stable and when subjected to conditions of 40°C/75% RH for a period of three months, results in less than 0.5% of desethyl azilsartan, desethyl azilsartan medoxomil, azilsartan medoxomil amide, ethyl azilsartan and other related substances originating from the decomposition of azilsartan medoxomil. Contrary to the existing prior arts, these pharmaceutical compositions are prepared without the use of pH control agent(s).
• An aspect of the present invention provides pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipient(s), the compositions are stable and also achieve desired dissolution.
• Another aspect of the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin component and one or more other pharmaceutically acceptable excipient(s).
• An aspect of the present invention further provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, hydroxypropyl beta-cyclodextrin and one or more other pharmaceutically acceptable excipient(s).
• the compositions of the present invention simultaneously achieve desired stability characteristics and dissolution profile.
• the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
• step iii) granulating the blend of step i) using granulating agent prepared in step ii) iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
• step iii) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or filling into suitable sized capsules.
• the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin component and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
• step iii) granulating the blend of step i) using granulating agent prepared in step ii) iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
• step iii) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or filling into suitable sized capsules.
• Present invention further provides a simple and cost effective process to prepare the stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipient(s).
• One aspect of the present invention relates to stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by an anhydrous granulation process.
• Another aspect of the present invention provides stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using an anhydrous solvent(s), which further optionally contains a hydrous solvent(s).
• Another aspect of the present invention relates to stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using a mixture of an anhydrous solvent(s) and a hydrous solvent(s). Another aspect of the present invention also relates to the application of specified compression force to prepare pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof that are stable and also shows desired dissolution characteristics.
• An aspect of the present invention further relates to method of using these compositions for the treatment of hypertension and associated disorders.
• the present invention provides pharmaceutical compositions comprising therapeutically effective amount of angiotensin II receptor blocker and one or more other pharmaceutically acceptable excipient(s).
• Particularly present invention provides pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil as an angiotensin II receptor blocker and one or more other pharmaceutically acceptable excipient(s).
• the "azilsartan” unless indicated otherwise in the specification refers to azilsartan in the form of free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof.
• azilsartan is in the form of azilsartan medoxomil which is a prodrug of azilsartan active.
• Azilsartan medoxomil is hydrolyzed to azilsartan in the gastrointestinal tract during absorption.
• therapeutically effective amount is defined to mean the amount or quantity of the active drug azilsartan, which is sufficient to elicit an appreciable biological response when administered to the patient. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.
• Therapeutically effective amount of azilsartan medoxomil in the respect of this invention is usually between 40 and 80 mg, usually administered once daily, although amounts outside this range and different frequencies of administration are feasible for use in therapy under prescribed medical conditions.
• dosage forms of the present invention are useful, inter alia, in the prevention and/or treatment of hypertension and associated disorders.
• Azilsartan medoxomil or its pharmaceutically acceptable salt(s) may be present in crystalline or amorphous forms and may include salts with inorganic bases and organic bases.
• Inorganic bases may include, but not limited to, salts with alkali metals such as sodium or potassium, or alkaline earth metals such as calcium or magnesium.
• Organic bases may include, but not limited to, salts of ethanolamines, tromethamine, trimethylamine, triethylamine, tertiary butylamine, pyridine and dicyclohexylamine.
• azilsartan medoxomil is in the form of azilsartan kamedoxomil in the present invention, which is a potassium salt of azilsartan medoxomil.
• concentration of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, used in the pharmaceutical composition ranges from 10% w/w to 50% w/w by weight of the pharmaceutical composition.
• An important aspect of the present invention provides compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof that are stable.
• compositions comprising azilsartan as an active are chemically stable as degradation by oxidation, hydrolysis, isomerization, photolysis, polymerization, or any other method of degradation, could lead to a change in bioavailability and could also lead to toxicity.
• Chemical stability can be measured by a suitable, stability indicating chromatographic method for determining degradation products.
• stable refers to the pharmaceutical composition of the present invention, when subjected to conditions of 40°C/75% RH for a period of three months, results in less than 0.5% of desethyl azilsartan, desethyl azilsartan medoxomil, azilsartan medoxomil amide, ethyl azilsartan and other related substances originating from the decomposition of azilsartan medoxomil.
• Pharmaceutical compositions of the present invention comprising azilsartan medoxomil are found to be stable. The stability of the compositions achieved without using any pH control agent which is contrary to the prior art mentioned in the earlier paragraphs and it is one of the important aspect of the present invention.
• stable compositions of the azilsartan medoxomil or pharmaceutically acceptable salt thereof comprise one or more cyclodextrin component(s).
• the cyclodextrin component as used herein, is intimately mixed with azilsartan medoxomil.
• Cyclodextrin component acts as a solubilizer and stabilizer for azilsartan medoxomil.
• cyclodextrins that can be used in the present invention include but not limited to cyclodextrin, a- cyclodextrin, b- cyclodextrin, g- cyclodextrin, hydroxypropyl-b- cyclodextrin, sulfobutyl ether b-cyclodextrin sodium salt, methylated b-cyclodextrin, branched b and g- cyclodextrin, hydroxypropyl-y-cyclodextrin or combination thereof.
• Cyclodextrin component may further include, but not limited to, chemically modified cyclodextrins, for example, methylated, acetylated, hydroxypropylated cyclodextrins or alike.
• cyclodextrin component is selected from the group comprising of b- cyclodextrin, hydroxypropyl ⁇ -cyclodextrin, hydroxypropyl- g- cyclodextrin or mixtures thereof.
• the ratio of azilsartan medoxomil or a pharmaceutically acceptable salt thereof to a cyclodextrin component is selected from about 1 : 10 to about 10: 1 based on weight.
• Another important aspect of the present invention provides a stable pharmaceutical composition
• a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by an anhydrous granulation process comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof.
• Yet another important aspect of the present invention provides a stable pharmaceutical composition
• a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using a mixture of an anhydrous solvent(s) and a hydrous solvent(s).
• Another embodiment of the present invention provides a stable pharmaceutical composition
• a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using an anhydrous granulation solvent(s) which further optionally contains a hydrous solvent(s) and comprises a cyclodextrin component selected from group comprising of hydroxy propyl b -cyclodextrin, hydroxy propyl g - cyclodextrin or a mixture thereof, wherein the ratio of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, to the cyclodextrin component is from about 1 : 10 to about 10: 1 based on weight.
• a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and a cyclodextrin component selected from above group which is prepared by a granulation process using a mixture of an anhydrous solvent(s) and a hydrous solvent(s).
• Granulating solvent used in the present invention include, but not limited to, anhydrous, hydrous, or mixture thereof.
• anhydrous granulation refers to a wet granulation process carried out using anhydrous solvents without the use of water.
• Suitable anhydrous solvents include, but not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, toluene, tetrahydrofuran, chloroform, methylene chloride, or mixtures thereof.
• acetone is preferred as an anhydrous solvent.
• the anhydrous solvent as a wet granulating agent is used in an amount of 10% to 80% w/w.
• the present invention also incorporates the use of a granulation process using an anhydrous solvent(s), which further optionally contains a hydrous solvent such as water.
• the present invention further incorporates the use of a granulation process that uses a mixture of an anhydrous solvent(s) and a hydrous solvent(s). In an embodiment of the present invention, a mixture of acetone and water is a preferred granulating solvent.
• the present invention provides stable pharmaceutical compositions comprising azilsartan medoxomil as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).
• Second active agent(s) that can be used in the present invention include, but not limited to, antihypertensive agent(s) or a hypoglycemic agent(s).
• Antihypertensive agents may be further selected from, but not limited to, diuretics, calcium channel blockers, and ACE inhibitors.
• Diuretics include, but not limited to, chlorthalidone, chlorothiazide, hydrochlorothiazide, and alike or pharmaceutically acceptable salts thereof.
• Calcium channel blockers include, but not limited to, amlodipine, felodipine, isradipine, nicardipine, nifedipine, diltiazam, verapamil or a pharmaceutically acceptable salts thereof.
• ACE inhibitors include, but not limited to, benazepril, benazeprilat, captopril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, or a pharmaceutically acceptable salt thereof.
• Hypoglycemic agents include, but not limited to, repaglinide, nateglinide, glimepiridum, glibenclamidum, gliclazidum, metformin, miglitol, acarbose, pioglitazone, rosiglitazone or a pharmaceutically acceptable salt thereof.
• the said second active is selected from diuretics that include, but not limited to, chlorthalidone, chlorothiazide and hydrochlorothiazide or pharmaceutically acceptable salts thereof.
• the said second active agent is used in a therapeutically effective amount that is useful for the prevention and/or treatment of hypertension and associated disorders and may further shows synergistic therapeutic effect when combined with azilsartan medoxomil or a pharmaceutically acceptable salt thereof.
• One embodiment of the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
• step iii) granulating the blend of step i) using granulating agent prepared in step ii) iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii) v) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or fdling into suitable sized capsules.
• the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin component and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
• step iii) granulating the blend of step i) using granulating agent prepared in step ii) iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
• step iii) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or fdling into suitable sized capsules.
• a pharmaceutical composition of the present invention is prepared according to the processes described above and comprises azilsartan medoxomil as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).
• a specified compression force to prepare the dosage forms of the present invention is another important aspect of present invention. Applying the specified compression force to the granules or the blend prepared according to the present invention results into dosage forms having desired dissolution as well as stability profile.
• the compression force is applied by an upper and lower punch to carry out the compression step.
• the compression force (N) applied during the compression step of the process of the present invention is in the range of from 50 to 300 N, preferably from 50 to 200 N, more preferably from 50 to 150 N.
• stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof of the present invention show desired dissolution characteristics.
• composition(s) according to the present invention when tested for in- vitro dissolution profile, exhibits dissolution such that the amount of the drug equivalent to 85 % dissolves within 30 minutes.
• the suitable dissolution test is selected and it is carried out in an aqueous media non-buffered or buffered to a pH range (1 to 7.8) found in the gastrointestinal tract and controlled at 37°C ( ⁇ l0°C), that maintain a physiological relevance.
• Various dosages, such as tablets, capsules can be studied for dissolution profile, in a standard prescribed manner. When the dosage form is a tablet, typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets.
• the amount of dissolved active can be determined using suitable analytical techniques such as UV or HPLC.
• the dissolution ( in-vitro ) test in addition to its application as a quality control technique, can more preferably be used to predict the biological ( in-vivo ) performance of the tablet.
• the dissolution test is performed in 900 mL of dissolution medium at 37° C., using USP Apparatus 2 (paddles) method at a rotation speed of 50 rpm. Samples are removed after 5, 10, 15, 20, 30, 45, and 60 minutes from test initiation and analyzed for azilsartan medoxomil. Phosphate buffer, pH 7.8 deaerated solution has been used as dissolution medium.
• compositions or “formulation” or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
• solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles and the like
• liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
• excipient means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, disintegrant, lubricant, glidant, surfactant, colourant or the like.
• the excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human use.
• Reference to an excipient includes both one and more than one such excipients and the said excipients may be added intragranularly or extragranularly.
• Fillers or diluents may be selected from, but not limited to, carbohydrates, confectioners sugar, compressible sugars, dextrose, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof. Fillers or diluents may be used in the range of 10-90 % w/w of total weight of stable oral pharmaceutical composition.
• Binders may be selected from, but not limited to, potato starch, wheat starch, com starch, microcrystalline cellulose, celluloses such as hydroxy propyl cellulose, hydroxy propyl methylcellulose, povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums like acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, or combinations thereof. Binders may be used in the range of 1-15 % w/w of total weight of stable oral pharmaceutical composition.
• Disintegrants may be selected from, but not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate, starches or combinations thereof. Disintegrants may be used in the range of 1-50 % w/w of total weight of stable oral pharmaceutical composition.
• “Lubricants” may be selected from, but not limited to, aluminium stearate, zinc stearate, calcium stearate, magnesium stearate, polyethylene glycol, mineral oil, talc, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate, glyceryl behenate, sodium benzoate or mixtures thereof. Lubricant may be used in the range of 0.1 - 5 % w/w of total weight of stable oral pharmaceutical composition.
• “Glidants” may be selected from, but not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel or mixtures thereof. Glidant may be used in the range of 0.01 - 4 % w/w of total weight of stable oral pharmaceutical composition.
• “Surfactants” are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution.
• the surfactants can be selected from, but not limited to, hydrophilic surfactants or lipophilic surfactants or mixtures thereof.
• the surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants.
• Surfactants according to the present invention are selected from, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like, used either alone or in combination thereof. “Colorants” may be selected from, but not limited to, iron oxide yellow, iron oxide red, titanium dioxide or mixtures thereof
• compositions in accordance with the present invention can be prepared either by direct compression, dry granulation like slugging or roller compaction, or by wet granulation.
• the wet granulation method may comprise use of non- aqueous organic solvent(s) such as dichloromethane, ethanol, acetone, methylene chloride and the like, or a mixture thereof, as the granulating aid.
• compositions in accordance with the present invention can also be prepared using a granulation method, which may comprise use of an anhydrous solvent(s), hydrous solvent(s) or mixture thereof as granulating solvent(s).
• compositions of the present invention may be further coated with a functional or nonfunctional coating.
• the coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers.
• the total weight gain after coating may be about 1% w/w to 10% w/w of the uncoated pharmaceutical composition.
• Coating agents which are useful in coating process, may be selected from, but not limited to, water soluble polymers such as, but not limited to, polyvinylpyrrolidone or water soluble cellulose such as, but not limited to, hydroxy propyl methyl cellulose or hydroxy propyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, com, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non- aqueous systems or combinations of aqueous and non-aqueous system as appropriate.
• water soluble polymers such as, but not limited to, polyvinylpyrrolidone or water soluble cellulose such as, but not limited to, hydroxy
• binders for coating include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, copovidone, starch, pregelatinized starch, or mixtures thereof.
• plasticizers for coating include, but not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof.
• opacifiers for coating include, but not limited to, titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.
• Antitacking agents such as, but not limited to, talc, stearic acid, magnesium stearate, colloidal silicon dioxide or the like.
• coloring agents for coating include, but not limited to, FDA approved colorants such as iron oxide, lake of tartrazine, allura red, lake of quinoline yellow, lake of erythrosine, titanium dioxide, or mixtures thereof.
• Suitable solvents for the coating include, but not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.
• compositions comprising azilsartan medoxomil packed or stored into the bottle or blister pack or pouch or any corresponding packing known to a person skilled in the art in which the dosage form or the pharmaceutical compositions are packed or stored.
• azilsartan medoxomil compositions are packed or stored into the bottle or blister pack or pouch which comprises a desiccant.
• the term "desiccant" is referred herein to a substance used to remove or suppress or decrease the odor or to absorb moisture which prevents degradation and/or decomposition of the active agent(s).
• the desiccant may be placed in the internal space of the package containing the composition, in an amount sufficient to remove the odorous material or to suppress or reduce the smell.
• the desiccants are selected from, but not limited to, a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof.
• azilsartan medoxomil compositions are packed or stored into the bottle or blister pack or pouch which comprises a desiccant and optionally antioxidant(s).
• antioxidant is intended to mean an agent that inhibits oxidation, and thus is used to prevent the deterioration of preparations by oxidation due to the presence of oxygen free radicals or free metals in the composition.
• antioxidants that can be used in the present invention include, but not limited to ascorbic acid, butylated hydroxyl anisole, butylated hydroxyl toluene, or a mixture thereof.
• the amount of antioxidants used in the pharmaceutical compositions of the present invention ranges from 0.01% w/w to 2% w/w.
• An aspect of the present invention provides a method of using the compositions of the present invention comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof for the treatment of hypertension and associated disorders. Another aspect of the present invention further provides a method of using the compositions of present invention comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and optionally second active agent for the treatment of hypertension and associated disorders.
• the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.
• step 2 Hydroxy propyl cellulose was dissolved in acetone under stirring 3. Dry mixture of step 1 was granulated with binder solution of step 2
• step 3 was dried
• step 4 Dried granules of step 4 were milled through suitable screen
• step 7 material was lubricated with sifted magnesium stearate for suitable time in blender
• step 3 Dry mixture of step 1 was granulated with binder solution of step 2 using rapid mixing granulator
• step 3 was dried
• step 4 Dried granules of step 4 were milled through suitable screen
• Microcrystalline cellulose, vanillin, mannitol and croscarmellose sodium were sifted through suitable sieve
• step 7 material was lubricated with sifted magnesium stearate for suitable time in blender
• step 3 Dry mix of step 1 was granulated with binder solution of step 2
• step 3 was dried
• step 4 Dried granules of step 4 were milled through suitable screen
• step 7 material was lubricated with sifted magnesium stearate for suitable time in blender
• step- 1 Dry mix of step- 1 was granulated with binder solution of step- 2
• step- 3 was dried
• step- 4 Dried granules of step- 4 were milled through suitable screen by Quadro co mill
• Microcrystalline cellulose, croscarmellose sodium and crospovidone were sifted through suitable sieve 7. Milled material of step- 5 and sifted material of step- 6 were blended for suitable time in blender
• step- 7 material was lubricated with sifted magnesium stearate for suitable time in blender

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=65278423

Family Applications (1)

Country Status (2)

Cited By (1)

Families Citing this family (1)

Citations (12)

• 2018
  • 2018-12-29 IN IN201721047406A patent/IN201721047406A/en unknown
  • 2018-12-29 WO PCT/IB2018/060716 patent/WO2019130277A1/en active Application Filing

Patent Citations (13)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events