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WO2006013545A1 - Compositions pharmaceutiques d'irbesartan - Google Patents

Compositions pharmaceutiques d'irbesartan Download PDF

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Publication number
WO2006013545A1
WO2006013545A1 PCT/IB2005/052549 IB2005052549W WO2006013545A1 WO 2006013545 A1 WO2006013545 A1 WO 2006013545A1 IB 2005052549 W IB2005052549 W IB 2005052549W WO 2006013545 A1 WO2006013545 A1 WO 2006013545A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
pharmaceutical composition
granules
irbesartan
cellulose
Prior art date
Application number
PCT/IB2005/052549
Other languages
English (en)
Inventor
Deepak Murpani
Praveen Raheja
Shanmugam Kumar
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006013545A1 publication Critical patent/WO2006013545A1/fr

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Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to pharmaceutical compositions comprising irbesartan and hydrochlorothiazide and processes for the preparation thereof.
  • antihypertensive drugs When given as monotherapy, antihypertensive drugs normalize blood pressure in only a fraction of hypertensive patients. Treatment with two or more agents from different pharmacological classes is often necessary to achieve adequate blood pressure control.
  • the rationale for using combination therapy is to obtain increased blood pressure control by employing two antihypertensive agents with different modes of action and to enhance compliance by using a single tablet that is taken once or twice daily.
  • Irbesartan a long-acting angiotensin-II receptor antagonist, is useful in the treatment of various cardiovascular ailments including hypertension and heart failure.
  • Sanofi Synthelabo markets a combination of irbesartan and hydrochlorothiazide as oral tablets under the brand name AVALIDE®. These tablets comprise two different strengths of irbesartan (150 mg and 300 mg) and one strength of hydrochlorothiazide (12.5 mg). The average weight of the tablet comprising 300 mg irbesartan and 12.5 mg hydrochlorothiazide is 600 mg and the average weight of the tablet comprising 150 mg irbesartan and 12.5 mg hydrochlorothiazide is 300 mg. These tablets have an irbesartan content of approximately 50% based on the tablet weight, which indicates that the tablets are large and contain a large proportion of excipients.
  • U.S. Patent No. 5,994,348 discloses that the physical properties of irbesartan and hydrochlorothiazide present difficulties in developing formulations suitable for preparing a tablet having both a substantial quantity of active agent and a small size to allow for easy swallowing.
  • Both irbesartan and hydrochlorothiazide are fluffy materials with low densities, poor flow characteristics, a resistance to blending and dispersion in liquids due to agglomeration and poor wetting qualities. These powders are also likely to exhibit static charge effects.
  • Irbesartan also exhibits poor aqueous solubility and has a tendency to stick to the punches and dies used in the tabletting procedure.
  • compositions comprising irbesartan alone or in combination with hydrochlorothiazide, which has a high content of the active, maintains a small sized dosage form and still exhibits a rapid onset of action.
  • a pharmaceutical composition that includes more than about 70% by weight of irbesartan or salt thereof, alone or in combination with about 2% to about 20% by weight of hydrochlorothiazide, wherein the irbesartan and the hydrochlorothiazide comprise granules with a bulk density of between about 0.35 g/ml to about 0.65 g/ml.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • Suitable pharmaceutically acceptable excipients may include one or more of diluents, binders, disintegrants, anti- adherents and lubricants.
  • Suitable diluents may include one or more of dibasic calcium phosphate, sugars, cellulose derivatives and mixtures thereof.
  • the diluents may be lactose hydrous, lactose anhydrous and microcrystalline cellulose.
  • the diluents may be present at a concentration from about 1% to about 15% by weight of the tablet.
  • Suitable binders may include one or more of alginic acid, sodium alginate, hy- droxypropyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methylcellulose, ethyl cellulose, gelatin, starch or starch derivatives and mixtures thereof.
  • the binders may be present at a concentration of from about 1% to about 10% by weight of the tablet.
  • Suitable disintegrants may include one or more of cross-linked carboxymethyl cellulose sodium, sodium starch glycolate, pregelatinized starch, cross-linked polyvinyl pyrrolidone, low-substituted hydroxy propyl cellulose and mixtures thereof.
  • the disintegrants may be present at a concentration of from about 1% to about 6% by weight of the tablet.
  • Suitable lubricants may include one or more of calcium stearate, magnesium stearate, glyceryl monostearate, glyceryl palmitostearate, zinc stearate, sodium stearyl fumarate and stearic acid; sodium lauryl sulphate, polyethylene glycol, hydrogenated vegetable oil, talc, sodium benzoate and mixtures thereof.
  • the lubricants may be present at a concentration of from about 0.2% to about 2% by weight of the tablet.
  • Suitable antiadherents may include one or more of silicon dioxide, magnesium trisilicate, talc and mixtures thereof.
  • the antiadherents may be present at a con ⁇ centration of from about 0.2% to about 2% by weight of the tablet.
  • the pharmaceutical composition may further include from about 1% to about 10% by weight of diluent; from about 1% to about 10% by weight of binder; from about 1% to about 6% by weight of disintegrant; from about 0.2% to about 2% by weight of lubricant; and from about 0.2% to about 2% by weight of anti-adherent.
  • the pharmaceutical composition may further include 8% by weight of micro- crystalline cellulose, 2% by weight of hydroxypropyl methylcellulose, 2% by weight of cross-linked carboxyr ⁇ ethyl cellulose sodium, 1% by weight of colloidal silicon dioxide and 0.85% by weight of calcium stearate.
  • irbesartan or salt thereof 70% by weight of irbesartan or salt thereof, alone or in combination with about 2% to about 20% by weight of hydrochlorothiazide, wherein the granules have a bulk density of between about 0.35 g/ml to about 0.65 g/ml.
  • a process for the preparation of a phar ⁇ maceutical composition includes blending irbesartan with one or more pharmaceutically acceptable excipients and optionally hydrochlorothiazide; granulating to obtain a wet mass; screening the wet mass to form granules; drying and sizing the granules, wherein the granules have a bulk density of between about 0.35 g/ ml to about 0.65 g/ml; and compressing the granules into tablets.
  • Embodiments of the process may include one or more of the following features.
  • the granulation may be carried out by wet or dry granulation.
  • a process for the preparation of a phar ⁇ maceutical composition includes preparing an intragranular composition by:
  • the process includes preparing an extra granular composition by:
  • Embodiments of the process may include one or more of the following features.
  • the granulation may be carried out by wet or dry granulation.
  • a method for the treatment of hy ⁇ pertension in a patient in need thereof comprises administering a phar ⁇ maceutical composition comprising more than 70% by weight of irbesartan or salt thereof, alone or in combination with about 2% to about 20% by weight of hy ⁇ drochlorothiazide, wherein the irbesartan and hydrochlorothiazide comprise granules with a bulk density of between about 0.35 g/ml to about 0.65 g/ml.
  • tablet dosage forms comprising irbesartan alone, or in combination with hydrochlorothiazide, may be formulated, wherein the tablet is small even though the amount of active ingredient is high.
  • the tablet may include more than 70% by weight of irbesartan or salt thereof alone or in combination with about 2% to about 20% by weight of hydrochlorothiazide, wherein the bulk density of the granules is between 0.35 g/ml to 0.65 g/ml.
  • granules prepared according to the present invention which may be formulated into a suitable pharmaceutical composition.
  • the granules have good flowability, reduced sticking tendency and good compressibility. Further, they result in a dosage form that is smaller in size than was previously possible for a given unit dose.
  • the tablets prepared may include (per tablet) from about 25 mg to about 300 mg of irbesartan, more particularly, from about 75 mg to 300 mg of irbesartan and, optionally, from about 1 mg to about 25 mg of hydrochlorothiazide, particularly from about 6.25 mg to about 12.5 mg of hydrochlorothiazide.
  • the total weight of the tablets prepared may be from about 50 mg to about 430 mg.
  • the tablet may be a unit dose of about 150 mg of irbesartan and a unit dose of 12.5 mg hydrochlorothiazide, wherein the total weight of the tablet does not exceed 215 mg.
  • the tablet may also be a unit dose of about 300 mg of irbesartan and optionally, a unit dose of 12.5 mg hydrochlorothiazide, wherein the total weight of the tablet does not exceed 430 mg.
  • the tablets possess desirable physical properties (hardness, friability and disin- tegration) and are prepared in a size easy to swallow while still containing the entire required dose for single administration, thereby encouraging patient compliance.
  • These improved tabletting and flow properties are not only observed in a lab-scale batch but also in a scale-up batch, thus indicating reproducibility and consistency.
  • the high active ingredient content in the composition is achieved by incorporating lesser amounts of excipients.
  • the tablets may further include one of more pharma ⁇ ceutically excipients, which impart the desired cohesiveness, lubrication and free flowing properties to the active ingredients.
  • excipients may include one or more of binders, lubricants, diluents, anti-adherents and disintegrants.
  • Suitable diluents may include one or more of dibasic calcium phosphate, sugars, such as, lactose hydrous or lactose anhydrous; and cellulose or cellulose derivatives, such as, microcrystalline cellulose.
  • the diluent may be microcrystalline cellulose.
  • the diluents may be present at a concentration from about 1% to about 15% by weight of the tablet.
  • Suitable binders may include alginic acid, sodium alginate; cellulose derivatives, such as hydroxypropyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methylcellulose and ethyl cellulose; gelatin and starch or starch derivatives.
  • the binder may be hydroxypropyl methylcellulose.
  • the binders may be present at a concentration from about 1% to about 10% by weight of the tablets.
  • Suitable disintegrants may include one or more of carboxymethyl cellulose sodium
  • the dis- integrant may be cross-linked carboxy methylcellulose sodium.
  • the disintegrants may be present at a concentration from about 1% to about 6% by weight of the tablets.
  • Suitable lubricants may include one or more of fatty acids or fatty acid derivatives, such as, calcium stearate, magnesium stearate, glyceryl monostearate, glyceryl palmi- tostearate, zinc stearate, sodium stearyl fumarate, stearic acid, sodium lauryl sulphate, polyethylene glycol, hydrogenated vegetable oil, talc and sodium benzoate.
  • the lubricant may be calcium stearate.
  • the lubricants may be present a con ⁇ centration from about 0.2% to about 2% by weight of the tablets.
  • Suitable antiadherents may include one or more of silicon-containing compounds, such as, colloidal silicon dioxide, magnesium trisilicate and talc.
  • the anti- adherent may be colloidal silicon dioxide.
  • the antiadherents may be present at a con ⁇ centration from about 0.2% to 2% by weight of the tablets.
  • the tablets may be prepared using either wet granulation or dry granulation processes.
  • a process for preparing tablets comprising more than 70% by weight of irbesartan or salt thereof, alone or in combination with 2 to 20% by weight of hydrochlorothiazide, wherein the bulk density of the granules is between 0.35 g/ml to 0.65 g/ml.
  • the process includes:
  • the process for preparing tablets 'containing irbesartan alone or in combination with hydrochlorothiazide includes: [60] preparing an intragranular composition by:
  • the wet granulation may also be performed with an aqueous solution of the binder.
  • the tablets may be prepared using a dry granulation process.
  • the process includes: [72] blending irbesartan with one or more pharmaceutically acceptable excipients, and optionally, hydrochlorothiazide to form a blend; [73] compacting or slugging the blend;
  • the tablets prepared according to the present invention exhibit a dissolution profile wherein at least 60% of the hydrochlorothiazide is released in 30 minutes and at least 90% of the irbesartan releases in 30 minutes in a 900 ml of 0.1 N hydrochloric acid at 37°C, with paddle speed of 50 rpm using USP Apparatus II.
  • the powder blend of actives and excipients is formed using a mixer, such as a planetary or high shear granulator.
  • a mixer such as a planetary or high shear granulator.
  • Conventional powder mixers such as, double cone blenders, V-shell blenders, ribbon and paddle mixers may also be used.
  • Dry granulation may be carried out using roller compactors or conventional tabletting machines to prepare compacts or slugs.
  • wet granulation is carried out using a granulator selected from amongst shear granulators, such as planetary mixers and oscillating granulators; high-speed mixer/ granulators such as diosna and collette-gral mixer; and fluidized bed granulators.
  • shear granulators such as planetary mixers and oscillating granulators
  • high-speed mixer/ granulators such as diosna and collette-gral mixer
  • fluidized bed granulators such as fluidized bed granulators.
  • the granules may be dried using conventional drying ovens, tray dryers or fluidized bed granulators.
  • the dried granules may be milled and sized in a hammer mill or by screening.
  • the bulk density of the granules is determined by measuring the volume of a known mass of a test sample that has passed through a screen into a graduated cylinder (Method I described in US Pharmacopoeia). A quantity of granules 'M' having an untapped apparent volume of 150 to 250 ml is selected. According to the test, these granules are passed through a screen into a dry graduated cylinder without compacting. The material is carefully leveled without tamping and the unsettled apparent volume 'V to the nearest graduated unit is noted. The bulk density (g/ml) is calculated by the formula:
  • the tablets may also contain one or more additional ingredients including flavors, sweeteners, colorants and preservatives. Tablets may additionally be provided with non-functional coatings.
  • the coatings may include film-forming polymers, such as cellulose ethers, acrylic polymer or a mixture of polymers. Suitable cellulose ethers may include hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • a method for the treatment of hypertension in a patient in need thereof includes administering to a patient in need of a pharmaceutical composition comprising more than 70% by weight of irbesartan or salt thereof, alone or in combination with 2 to 20% by weight of hydrochlorothiazide, wherein the bulk density of the granules is between 0.35 g/ml to 0.65 g/ml.
  • the powder blend was granulated with purified water to form a wet mass. 3. The wet mass was screened to form granules. 4. The granules were dried and the dried granules were screened. 5. The remaining portion of microcrystalline cellulose and colloidal silicon dioxide were blended with cross-linked carboxymethyl cellulose.
  • step 5 The powder blend of step 5 was mixed with the granules of step 4 and then lubricated with calcium stearate.
  • step 6 The mixture of step 6 was compressed into tablets.
  • Tables 1 and 2 provide the in- vitro dissolution profiles of irbesartan and hy ⁇ drochlorothiazide, respectively, prepared by the composition and process of Example 1 in 0.1N Hydrochloric acid (900 ml) at 37 ⁇ 0.5°C, using USP 2 apparatus at 50 rpm.
  • Table 1 Dissolution profile of irbesartan from tablets prepared as per Example 1 in 0.1N Hydrochloric acid (900 ml), USP 2 at 50 rpm.
  • Table 2 Dissolution profile of hydrochlorothiazide from tablets prepared as per Example 1 in 0.1N Hydrochloric acid (900 ml), USP 2 at 50 rpm.
  • Table 3 provides the bulk density of the granules prepared for a lab-scale batch and scale-up batch (1,00,000 tablets).
  • Table 4 provides the physical properties of the tablets prepared for a lab-scale batch and a scale-up batch.
  • step 6 Mix the powder blend of step 5 with the granules of step 4 and lubricate with calcium stearate.

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

Abstract

L'invention concerne des compositions pharmaceutiques comprenant de l'irbésartan et de l'hydrochlorothiazide, et des procédés de préparation de celles-ci.
PCT/IB2005/052549 2004-07-28 2005-07-28 Compositions pharmaceutiques d'irbesartan WO2006013545A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1396/DEL/2004 2004-07-28
IN1396DE2004 2004-07-28

Publications (1)

Publication Number Publication Date
WO2006013545A1 true WO2006013545A1 (fr) 2006-02-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/052549 WO2006013545A1 (fr) 2004-07-28 2005-07-28 Compositions pharmaceutiques d'irbesartan

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007080074A1 (fr) * 2006-01-09 2007-07-19 Krka, D.D. Novo Mesto Composition pharmaceutique solide comprenant de l’irbesartan
WO2007093168A2 (fr) * 2006-02-13 2007-08-23 Ratiopharm Gmbh Composition pharmaceutique contenant de l'irbesartan à libération rapide
WO2011141783A2 (fr) 2010-04-13 2011-11-17 Micro Labs Limited Composition pharmaceutique comprenant de l'irbésartan
CN116115578A (zh) * 2023-03-06 2023-05-16 广州白云山天心制药股份有限公司 含有厄贝沙坦和氢氯噻嗪的药用组合物及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0747050A1 (fr) * 1995-06-07 1996-12-11 Bristol-Myers Squibb Company Compositions pharmaceutiques d'irbésartan
US20020076437A1 (en) * 2000-04-12 2002-06-20 Sanjeev Kothari Flashmelt oral dosage formulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0747050A1 (fr) * 1995-06-07 1996-12-11 Bristol-Myers Squibb Company Compositions pharmaceutiques d'irbésartan
EP1275391A1 (fr) * 1995-06-07 2003-01-15 Sanofi-Synthelabo Composition pharmaceutique contenant de l'irbesartan et un diurétique
US20020076437A1 (en) * 2000-04-12 2002-06-20 Sanjeev Kothari Flashmelt oral dosage formulation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007080074A1 (fr) * 2006-01-09 2007-07-19 Krka, D.D. Novo Mesto Composition pharmaceutique solide comprenant de l’irbesartan
EA016579B1 (ru) * 2006-01-09 2012-06-29 Крка, Д.Д. Ново Место Твердый фармацевтический препарат, содержащий гидрохлорид ирбесартана, и способ его изготовления
WO2007093168A2 (fr) * 2006-02-13 2007-08-23 Ratiopharm Gmbh Composition pharmaceutique contenant de l'irbesartan à libération rapide
WO2007093168A3 (fr) * 2006-02-13 2007-10-04 Ratiopharm Gmbh Composition pharmaceutique contenant de l'irbesartan à libération rapide
US8309607B2 (en) 2006-02-13 2012-11-13 Ratiopharm Gmbh Rapid release irbesartan-containing pharmaceutical composition
WO2011141783A2 (fr) 2010-04-13 2011-11-17 Micro Labs Limited Composition pharmaceutique comprenant de l'irbésartan
CN116115578A (zh) * 2023-03-06 2023-05-16 广州白云山天心制药股份有限公司 含有厄贝沙坦和氢氯噻嗪的药用组合物及其制备方法

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