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WO2011147026A2 - Préparation pharmaceutique stable contenant du telmisartan et de l'hydrochlorothiazide - Google Patents

Préparation pharmaceutique stable contenant du telmisartan et de l'hydrochlorothiazide Download PDF

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Publication number
WO2011147026A2
WO2011147026A2 PCT/CA2011/000621 CA2011000621W WO2011147026A2 WO 2011147026 A2 WO2011147026 A2 WO 2011147026A2 CA 2011000621 W CA2011000621 W CA 2011000621W WO 2011147026 A2 WO2011147026 A2 WO 2011147026A2
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WIPO (PCT)
Prior art keywords
formulation according
telmisartan
cellulose
formulation
diuretic
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Ceased
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PCT/CA2011/000621
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WO2011147026A3 (fr
Inventor
Naresh Talwar
Dean Sebastian
Mathew Philip
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Pharmascience Inc
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Pharmascience Inc
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Priority to CA2801020A priority Critical patent/CA2801020A1/fr
Publication of WO2011147026A2 publication Critical patent/WO2011147026A2/fr
Publication of WO2011147026A3 publication Critical patent/WO2011147026A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/549—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 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical tablet formulation comprising two active ingredients. More specifically the present invention relates to a fonnulation comprising telmisartan / which is an angiotensin ⁇ receptor antagonist and hydrocHorothiazide, which is a diuretic, and methods of manufacturing thereof.
  • Telmisartan was first disclosed in European Patent No. 0,502,314 (issued on May 20, 1998 to Dr. Karl Thomae GmbH) as angiotensin ⁇ receptor antagonist and is indicated for treatment of mild to moderate essential hypertension in patients,
  • Telmisartan is a white to off-white, odorless crystalline powder. It is practically insoluble in water and in the pH range of 3 to 7, sparingly soluble in strong acid (except HC1) and soluble in strong base. As disclosed in PCT Publication WO20000/ 3370 (corresponding to Canadian Patent No.2,352,436, issued on March 23, 2010 to Boehringer I gelheim Pharrna KG) crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.
  • Telmisartan is an orally active, ATI selective angiotensin ⁇ receptor antagonist. By selectively blocking the binding of angiotensin II to the ATI receptors, telmisartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin H
  • Telmisartan blocks ATI receptors, and has essentially no affinity for the AT2 receptors. AT2 receptors have been found in many tissues; to date, they have not been found to be associated with cardiovascular homeostasis. Telmisartan does not inhibit angiotensin converting enzyme (ACE, also known as kininase ⁇ ), the enzyme that converts angiotensin I to angiotensin ⁇ and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis.
  • ACE angiotensin converting enzyme
  • antagonism of angiotensin ⁇ ATI receptors results in two to three-fold increases in plasma renin and angiotensin ⁇ plasma concentrations. Long term effects of increased AT2 receptor stimulation by angiotensin ⁇ are unknown. Telmisartan is known on the market under the trade name Micardis ® by Boehringer Ingelheim Corporation.
  • Hyo ⁇ CKMorothiazide is an orally au ⁇ ninistered thiazide diuretic which was first disclosed in United States Patent No. 3,163,645 (issued on December 29, 1964 to Ciba Corporation) and is indicated in the treatment of edema and hypertension.
  • the chemical name for HCTZ is 6 Woro-3,4Kimydrc ⁇ 2H-l,2 ⁇
  • HCTZ is a white to practically white, crystalline powder which is slightly soluble in water and freely soluble in sodium hydroxide solution.
  • Combination of telmisartan and HCTZ is commercially available under the trade name Micardis Plus ® and is indicated for use in the treatment of hypertension,
  • telmisartan or a pharmaceutically acceptable salt thereof, and HCTZ this approach was not feasible due to the incompatibility of HCTZ with basic compounds such as, e.g., meglumine (N-methyl-D- glucamine) which is a component of conventional telmisartan formulations and the reduced dissolution rate of HCTZ from the dissolving matrix as compared with dissolution from a disintegrating tablet.
  • basic compounds such as, e.g., meglumine (N-methyl-D- glucamine) which is a component of conventional telmisartan formulations and the reduced dissolution rate of HCTZ from the dissolving matrix as compared with dissolution from a disintegrating tablet.
  • Formulations using a combination of these two drugs are described in the following patents: WO2003/059327 (CA2472392), WO2004/096215 (CA2524091), WO2006063737 (CA2589493), WO2007/060170 (CA2625404), WO2007/144175 (CA2654890), WO2009/058950, and WO2009/ 115301.
  • PCT Publication No, WO2003/059327 (corresponds to Canadian Patent No. 2,472,392, issued to Boehringer Ingelheim Pharma on July 14, 2009) discloses a bilayer pharmaceutical tablet comprising a first layer containing telmisartan in substantially amorphous form in a dissolving tablet matrix and a second layer containing a diuretic in a disintegrating tablet matrix.
  • This bilayer tablet structure overcomes the stability problem caused by the incompatibility of a diuretic like HCTZ with basic constituents of the telmisartan formulation. At the same time such a formulation provides for immediate release of the diuretic from the fast disintegrating matrix.
  • bilayer tablets as per PCT PubUcation No. WO2003/059327 tend to be slightly hygroscopic and, therefore, need to be packaged using a moisture-proof packaging material such as aluminium foil blister packs, or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
  • PCT Publication No. WO2004/096215 (corresponds to Canadian Patent Application No. 2,524,091, filed April 27, 2004 by Boehringer Ingelheim Pharma) relates to a medicament formulation of the crystalline sodium salt of 4'-[2-n-propyl-4-methyl-6-(l- memylberizimida..ol-2-yl) beruirnida2ol-l-ylmethyl]biphenyl-2-carboxy]ic acid (i.e., telmisartan) and methods for production thereof.
  • the patent discloses pharmaceutical composition containing the telmisartan sodium salt and a diuretic.
  • PCT Publication No. WO2006/063737 (corresponds to Canadian Patent Application No. 2,589,493, filed December 9, 2005 by Boehringer Ingelheim Pharma) discloses a pharmaceutical composition comprising telmisartan and HCTZ for the treatment of hypertension in patients with an insufficient blood pressure reduction upon treatment either with an angiotensin ⁇ receptor antagonist, or a pharmaceutical composition of an angiotensin II receptor antagonist and a low dose of HCTZ, wherein the pharmaceutical composition contains the component telmisartan in a dissolving tablet matrix having instant release characteristics and wherein the diuretic HCTZ is in a separate layer in a disintegrating pharmaceutical matrix.
  • PCT Publication No, WO2007/144175 (corresponds to Canadian Patent Application No. 2,654,890, filed June 14, 2007 be Lek Pharmaceuticals D.D.) discloses a stable formulation of telmisartan and HCTZ having both substances in separate units is prepared, exhibiting exceptional stability when subjecting to stress conditions.
  • PCT PubEcation No. WO2009/058950 discloses the pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of HCTZ from a dissolving matrix, methods for producing tablets and methods of use for treating hypertension.
  • PCT Publication No. WO2009/115301 discloses a solid pharmaceutical composition comprising at least two layers, wherein the first layer contains a non-peptide angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof in a dissolving matrix and the second layer contains a diuretic or a pharmaceutically acceptable salt thereof, characterized in that the second layer contains the diuretic or the pharmaceutically acceptable salt thereof in a dissolving matrix and the pharmaceutical composition is substantially free of disintegrants.
  • the solid pharmaceutical composition according to the present invention preferably in the form of a tablet, provides an immediate release of the non-peptide angiotensin ⁇ receptor antagonist, in particular of the poorly water soluble telmisartan or pharmaceutically acceptable salts thereof, and also provides an immediate release of a diuretic from the tablet matrix.
  • the tablet structure overcomes the stability problem caused by the incompatibility of diuretics, like HCTZ, with basic excipients of conventional telmisartan formulations, e.g. meglumine. It is known from the literature that tdrnisartan has very poor aqueous solubility in the physiological pH range of the gastroin estirial tract between pH 1 and 7, and is soluble in strong base.
  • HCTZ degrades in alkaline conditions i.e undergoes alkaline hydrolysis in the presence of heat and moisture.
  • the major degradation product of HCTZ is 4-aminc ⁇ 6-ddoro-l benzenesulfonarni (“DSA”) It is advantageous to administer both drugs concomitantly or even better to administer a composition comprising both, to treat hypertension.
  • the present invention provides a stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt and a diuretic dispersed in a matrix, said matrix comprising:
  • dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from about 1:1 to about 10:1;
  • the preferred diuretic of the present invention is HCTZ.
  • a stable pharmaceutical formulation wherein the in vitro dissolution rate of said formulation is at least about 80 % by weight of telmisartan dissolved within 30 minutes and at least about 80% of the diuretic dissolved within 30 minutes as measured by using USP type II apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.
  • mere is provided a process for the preparation of a stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt thereof, and a diuretic dispersed in a matrix, wherein said process comprises the following steps:
  • a stable pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form, for the treatment or prevention of hypertension is provided.
  • telmisartan or acceptable salts
  • HCTZ HCTZ
  • active agent active ingredient
  • active pharmaceutical ingredient active pharmaceutical ingredient
  • drug drug
  • pharmacologically active agent pharmaceutically acceptable active agent
  • pharmaceutically acceptable active substance pharmaceutically acceptable active substance
  • stability refers to the extent to which a product retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture. There are five general types of stability defined by the United States Pharmacopoeia: diemical, physical, microbiological, therapeutic and toxicological.
  • the present invention discloses a pharmaceutical formulation comprising a combination of telrnisaxtan and HCTZ in a single layer, preferably with magnesium oxide, that does not degrade or contribute to degradation of HCTZ, and a manufacturing process in order to get suitable stability properties without the need of expensive packing.
  • the active ingredients are present in a monouthic tablet or a single layer tablet,
  • bilayer pharmaceutical formulation comprising two active ingredients, wherein the first active ingredient is telrnisartan or a pharmaceutically acceptable salt thereof, which is practically insoluble in water (pH 3- 9), though soluble in strong base.
  • the second active ingredient is HCTZ, which is slightly soluble in water, though soluble in sodium hydroxide solution.
  • the first layer is a placebo layer and the second layer comprises telrnisartan, or a pharmaceutically acceptable salt thereof, and the diuretic (e.g., HCTZ).
  • the formulation of the present invention further comprise pharmaceutically acceptable excipients.
  • excipients are added to the formulations for a variety of purposes.
  • One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, such as for example diluents, binders, lubricants, disintegrants, glidants, and addifying agents.
  • Some of the preferred pharmaceutically acceptable excipients of the formulations of the present invention include: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90 (Frosolv®), colloidal silicon dioxide (Aerosil ®), dibasic calcium phosphate hydrous, croscarmellose sodium, magnesium oxide heavy, magnesium stearate, rnicrocrystalline cellulose and iron oxides.
  • Suitable diluents include for example pharmaceutically acceptable inert fillers such as microciystalline cellulose, lactose, pregektinized starch, dibasic calcium phosphate, saccharides, and/ or mixtures of the foregoing.
  • Suitable binders include, for example, the followmg: povidone; copovidone; alginic acid; sodium alginate; cellulose derivatives such as hydroxypropyl memylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methylcellulose and ethyl cellulose; gelatin; starch or starch derivatives; and mixtures thereof.
  • Suitable lubricants include, for example, the following: magnesium-, ahuxununv or calcium-stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate hydrogenated vegetable oil, polyethylene glycol, and mixtures thereof.
  • Suitable disintegrants include, for example, the following: croscarmellose sodium, sodium starch glycolate, maize starch, CMCCa, CMC-Na, micrc ⁇ stalline cellulose, cross-linked PVP, alginic acid, sodium alginate, pregelatinized starch and low- substituted hydroxy propyl cellulose,
  • Suitable anti-adherents include, for example, one or more compounds that are capable of preventing stickiness to surfaces of the punches.
  • anti-adherents include suicon ⁇ ontainin,g compounds such as colloidal silicon dioxide, magnesium trisilicate and talc.
  • the stable pharmaceutical formulations of the present invention can be used to treat or prevent hypertension.
  • the pharmaceutical formulations of the present invention containing the two active ingredients in a single layer, in an immediate release form can be used to treat or prevent hypertension.
  • the stable pharmaceutical formulations comprise telmisartan, or a pharmaceutically acceptable salt, and a diuretic (preferably HCTZ), dispersed in a matrix.
  • the matrix comprises: o at least one disintegrant in an amount ranging from about 0,5% to about 20% by weight;
  • dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telimsartan of from about 1 : 1 to about 10:1;
  • the disintegrant in the formulations of the present invention include, for example, the following: crospovidone, croscarmellose sodium, sodium starch glycolate, starch, modified starch, maize starch, macrocrystalline cellulose, cross-linked
  • polyvinylpolypyrrolidone PVP
  • alginic acid sodium alginate
  • pregelatinized starch carboxymethyl cellulose (CMC)
  • CMC carboxymethyl cellulose
  • CMC-calcium CMC-calcium
  • CMC-sodium low-substituted hydroxyl propyl cellulose
  • the disintegrant is croscarmellose sodium
  • the dissolution enhancing agent in the formulations of the present invention include, for example, the following: NaHC0 3j KHC0 3 , NA 2 C0 3 , Na 2 HP0 4 , K 2 HP0 4 , tromethamine, triethanolamine, MgO, and MgC ⁇ 3 ⁇ 4.
  • the dissolution enhancing agent is MgO.
  • the water insoluble diluent in the formulations of the present inventions include, for example, the following; rmcrocrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin®), kaolin, starch, starch derivatives, and co-processed excipients.
  • the co-processed excipient is preferably Ludipress(® (mixture of lactose and 3.2% Povidone K30), Cellactose® (mixture of lactose and cellulose), and Silicifi ed MCC Prosolv® (mixture of macrocrystalline cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified niicrocryslalline cellulose Prosolv®.
  • the formulation further comprises a solubilizing agent selected from the group consisting of: alkali metal hydroxide such as NaOH and KOH. More preferably, the solubilizing agent is NaOH.
  • the formulation according to the present invention further comprises a surfactant or emulsifier present in an amount ranging from about 0.5% to about 1 % by weight.
  • the water insoluble diluent is selected from the group consisting of:
  • microcrystallme cellulose di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate
  • the co-processed excipient is selected from the group consisting of:
  • Ludipress (mixture of lactose and 3.2% Povidone K30), Cellactose(® (mixture of lactose and cellulose), and Silicified MCC Prosolv® (mixture of microcrystallme cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified microcrystallme cellulose Prosolv®.
  • the in vitro dissolution rate of the formulation is at least 80% w/w of telmisartan dissolved within 30 minutes and at least 80% of the diuretic dissolved within 30 minutes as measured by using USP type II apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.
  • the in vitro dissolution rate of the formulations of the present invention is at least about 60% of telmisartan is dissolved within 5 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37°C; at least about 80% of telmisartan is dissolved within 10 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37°C; and at least about 90% of telmisartan is dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37°C.
  • the in vitro dissolution rate of the HCTZ in the formulations of the present invention is at least about 55% dissolved within 5 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 3 C; at least about 75% dissolved within 10 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37°C; at least about 80% dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37*0; and at least about 85% dissolved within 60 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37°C
  • the formulations of the present invention comprise less than about 0.5% by weight of 4-amino-6-chloro-l,3 benzenedisulfonamide (DSA) impurity in comparison to the initial HCTZ content when exposed to 40°C /75% RH conditions in Blister as well as HDPE pack.
  • DSA 4-amino-6-chloro-l,3 benzenedisulfonamide
  • the in vitro dissolution rate remains similar to the initial value for telmisartan and for the diuretic on stabiliy as measured by using USP type ⁇ apparatus at 75 rpm in 900ml of pH 7, 5 phosphate buffer.
  • a wet granulation process preferably a low shear granulation process, is preferred for preparing the stable pharmaceutical formulations of the present invention.
  • the process has for starting material a salt form of an angiotensin II receptor antagonist (ie. telmisartan) the process comprises a dry mixing step and direct compression.
  • the step of preparation of a granulation solution further comprises dissolving telmisartan under stirring in purified water with sodium hydroxide.
  • step (1) further comprises dissolving povidone (K-30) in isopropyl alcohol. Furthermore, the process preferably further comprises mixing the content of step (1) with the content of step (2) for 15 minutes.
  • the step of dry mixing (step (2)) further comprises dry mixing silicified MCC 90 (Prosolv®), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide in a ribbon blender for 5 min.
  • silicified MCC 90 Prosolv®
  • dibasic calcium phosphate hydrous croscarmellose sodium
  • colloidal silicon dioxide in a ribbon blender for 5 min.
  • step (2) further comprises screening the content obtained from step (2) through a comill equipped with 0.045R screen (1190 ⁇ ) and then mix for 5 minutes to yield a telmisartan blend.
  • step (3) further comprises adding to the blend obtained from step (2) (the dry mixing step) the granulation solution.
  • step (3) further comprises drying the wet granules in a fluid bed drier at an inlet temperature of 50°C ⁇ 5°C until a loss on drying value of 3.8% ⁇ 0.4% is obtained on a moisture analyzer set at 105°C for 10 minutes.
  • the step (3) further comprises screening the dried granules through a comill equipped with 0.039R screen (1000 ⁇ ).
  • step (4) comprises mixing magnesium oxide heavy and the colloidal silicon dioxide (Aerosil®) and screening through #30 sieve (600um).
  • step (4) further comprises screening HCTZ, macrocrystalline cellulose PHI 02 (Avicel®) and croscarmellose sodium through #40 sieve (400 ⁇ ) and adding to the granules of telmisartan and blending to yield a HCTZ blend.
  • step (4) further comprises dispersing a portion of the HCTZ blend with magnesium stearate and screening the obtained content through #40 sieve (400 ⁇ ) to yield a lubricated HCTZ blend.
  • step (4) further comprises adding the lubricated HCTZ blend to the telmisartan granules and blending for 3 minutes to yield the actives blend.
  • the process comprises a step of blending placebo involving screening macrocrystalline cellulose, yellow or red iron oxide, colloidal silicon dioxide and croscarmellose sodium, through #40 sieve (400 ⁇ _) and blending the content for 15 minutes to obtain an excipient placebo blend.
  • the step of compression (step (5)) further comprises compressing the excipient blend and actives blend, to form a bilayer pharmaceutical formulation.
  • the present invention provides a process for the preparation of a pharmaceutical formulation containing two active ingredients in a monolithic tablet comprising the following steps:
  • step (5) granulating the blend of step (4) with the content of step (3);
  • step (7) mixing the granules of step (7) with additional pharmaceutically acceptable excipients;
  • step (10) adding the content of step (9) to the content of step (8);
  • silicified MCC 90 (Prosolv®), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide; 5) screening the content obtained from step (4) and then blending;
  • step (6) adding to the blend of step (5) to the granulation solution of step (3);
  • step (8) mixing the granules of step (8) with magnesium oxide heavy and the colloidal silicon dioxide (Aerosil® ) and screening the obtained mixture;
  • step 9 screening HCTZ, microcrystalline cellulose PHI 02 (Avicel®) and croscarmellose sodium, and blending with the granules of step (9);
  • step (12) blending the content of step (11) together with the granules of step (9);
  • step (12) screening magnesium stearate and blending with the blend of step (12);
  • step 15) compressing the lubricated blend of step (14) and the blend of step (12), using a bilayer compression machine.
  • the granulation solution is prepared by dissolving the telimisartan gradually by stirring in purified water with sodium hydroxide.
  • the isopropyl alcohol and povidone (K-30) is dissolved in a separate vessel. Then, the content of solution of step (1) is mixed with the content of the solution of step (2).
  • the obtained content is dry mixed and then screened with the following pharmaceutical excipients: silicified MCC 90 (Prosolv ®), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide.
  • step (3) is added to the blend of step (5) and the granulation is carried out in a ribbon blender.
  • the wet granules are dried in a fluid bed drier at inlet temperature of
  • step (7) 50°C ⁇ 5°C until a loss on drying value of 3.8% ⁇ 0.4% is obtained on a moisture analyzer set at 105°C for 10 minutes.
  • the dried granules obtained from step (7) are screened through a comill equipped with 0.039R screen (1000 ⁇ ) (step (8)).
  • the granules of step (8) are mixed with magnesium oxide heavy and colloidal silicon dioxide (Aerosil®) and screened through #30 sieve (600 ⁇ ) (step (9)).
  • Alignil® magnesium oxide heavy and colloidal silicon dioxide
  • HCTZ, microcrystaUine cellulose PHI 02 (Avicel®) and croscannellose sodium are screened through #40 sieve (400 ⁇ ), added to the granules of step (9) and blended for 20 minutes (step (10)).
  • a portion of the blend obtained from step (10) is dispersed with magnesium stearate, and then screened manually through #40 sieve (400 ⁇ ) and blended for 3 minutes (step (11)).
  • microcrystalline cellulose PHI 02, yellow iron oxide, colloidal silicon dioxide and croscannellose sodium are screened through #40 sieve (400um) and blended for 1 minutes (step (13)).
  • magnesium stearate is passed through a 40 (400um) mesh screen, is introduced into the bin blender and blended for 3 minutes with mixture obtained from step (12), prior to compression (step (14)).
  • the lubricated blend is compressed using capsule shaped tooling at average weight of 700 mg on a stokes bilayer compression machine (step (15)).
  • the granulation solution is prepared by adding to the content of telmisartan solution (1) the Povidone K-30 solution (2) and mixing for 15 minutes.
  • Silicified MCC 90 (Prosolv®), dibasic calcium phosphate hydrous, Croscarmellose sodium and Colloidal Silicon Dioxide (Aerosil ®) was introduced into a ribbon blender and blended for 5 minutes. The blend was screened through a comill screen 0.045R (1190 ⁇ ). This blend was reintroduced into the ribbon blender and blended for 5 minutes.
  • step 4 was granulated with solution of step 3 in a ribbon blender.
  • step 7 The dried screened granules of step 7 was added to a bin blender.
  • HCTZ Microcrystalline Cellulose PH102 (Avicel®)and croscarmellose sodium was screened through #40 sieve (400 ⁇ ). ⁇ sieved dispersion was introduced into the bin blender of step 8 and blended for 20 minutes.
  • Magnesium stearate was dispersed with a portion of the blend of step 10 in a polyethylene bag and screened manually through #40 sieve (400Mm).lr s sieved dispersion was introduced into the bin blender of step 8 and blended for 3 minutes.
  • Cellulose PH 102 (Avicel®), Yellow oxide iron, Colloidal Silicon Dioxide (Aerosil ®) and croscarmellose sodium was screened through #40 sieve (400 ⁇ ) and introduced into the bin blender and blended for 15 minutes.
  • Magnesium stearate was screened through #40 sieve (400um) and introduced into the bin blender of step 12 and blended for 3 minutes.
  • step 14 The lubricated blend of step 11 and step 13 was compressed using capsule shaped tooling at an average weight of 700 mg on a stokes bilayer compression inachine.
  • Example 1 The tablets obtained from Example 1 were subsequently tested for in vitro dissolution rate, measured by Apparatus ⁇ (USP Paddle Method), using the following parameters:
  • Examplel The stability of the illustrated embodiment of the formulation of present invention (Examplel) was evaluated in two types of packaging at 40 " /75% relative humidity conditions. The following parameters were evaluated,
  • Table VII Comparative Degradation of Example I and Micardis plue® in ALU/ALU Blisters at 0 e Q75% RH.

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Abstract

L'invention concerne une préparation pharmaceutique stable contenant du telmisartan, ou un sel pharmaceutiquement acceptable de celui-ci, et un diurétique dispersé dans une matrice. La matrice contient au moins un délitant dans une quantité comprise entre 0,5 % et 20% en poids ; un agent d'amélioration de dissolution présent dans un rapport molaire agent d'amélioration de dissolution - telmisartan compris entre 1:1 et 10:1 ; et un diluant hydro-insoluble dans une quantité comprise entre 15% et 75% en poids et au moins un autre excipient ou adjuvant pharmaceutiquement acceptable dans une quantité comprise entre 0 et 25% en poids.
PCT/CA2011/000621 2010-05-28 2011-05-27 Préparation pharmaceutique stable contenant du telmisartan et de l'hydrochlorothiazide Ceased WO2011147026A2 (fr)

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CA2801020A CA2801020A1 (fr) 2010-05-28 2011-05-27 Preparation pharmaceutique stable contenant du telmisartan et de l'hydrochlorothiazide

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CA2,706,292 2010-05-28
CA2706292A CA2706292A1 (fr) 2010-05-28 2010-05-28 Une formulation pharmaceutique stable renfermant du telmisartan et de l'hydrochlorothiazide

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WO2011147026A2 true WO2011147026A2 (fr) 2011-12-01
WO2011147026A3 WO2011147026A3 (fr) 2012-01-26

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Cited By (12)

* Cited by examiner, † Cited by third party
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WO2014068507A1 (fr) * 2012-11-02 2014-05-08 Abbott Healthcare Pvt. Ltd. Compositions pharmaceutiques orales solides de telmisartan essentiellement exemptes de tensioactifs
JP2019502741A (ja) * 2016-01-22 2019-01-31 エックス４ ファーマシューティカルズ， インコーポレイテッド がんを処置するための方法
WO2019033969A1 (fr) * 2017-08-15 2019-02-21 中国科学院上海药物研究所 Eutectique de telmisartan et de chlorhydrothiazide
US10548889B1 (en) 2018-08-31 2020-02-04 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
US10610527B2 (en) 2015-12-22 2020-04-07 X4 Pharmaceuticals, Inc. Methods for treating immunodeficiency disease
US10759796B2 (en) 2016-06-21 2020-09-01 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US10953003B2 (en) 2015-12-14 2021-03-23 X4 Pharmaceuticals, Inc. Methods for treating cancer
US10988465B2 (en) 2016-06-21 2021-04-27 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11332470B2 (en) 2016-06-21 2022-05-17 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11337969B2 (en) 2016-04-08 2022-05-24 X4 Pharmaceuticals, Inc. Methods for treating cancer
US11357742B2 (en) 2015-12-14 2022-06-14 X4 Pharmaceuticals, Inc. Methods for treating cancer
US12285424B2 (en) 2020-03-10 2025-04-29 X4 Pharmaceuticals, Inc. Methods for treating neutropenia

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CN102885789A (zh) * 2012-04-05 2013-01-23 常州制药厂有限公司 一种治疗高血压的复方制剂的制备方法

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DE10244681A1 (de) * 2002-09-24 2004-04-08 Boehringer Ingelheim International Gmbh Neue feste Telmisartan enthaltende pharmazeutische Formulierungen und deren Herstellung
DE10319450A1 (de) * 2003-04-30 2004-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmazeutische Formulierung des Telmisartan Natriumsalzes
US20090142398A1 (en) * 2007-11-21 2009-06-04 Pharmascience Inc. Novel pharmaceutical compositions comprising a disintegration matrix
TR200906506A2 (tr) * 2009-08-24 2011-03-21 Bi̇lgi̇ç Mahmut Telmisartan içeren katı dozaj formları.

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014068507A1 (fr) * 2012-11-02 2014-05-08 Abbott Healthcare Pvt. Ltd. Compositions pharmaceutiques orales solides de telmisartan essentiellement exemptes de tensioactifs
US11357742B2 (en) 2015-12-14 2022-06-14 X4 Pharmaceuticals, Inc. Methods for treating cancer
US10953003B2 (en) 2015-12-14 2021-03-23 X4 Pharmaceuticals, Inc. Methods for treating cancer
US11219621B2 (en) 2015-12-22 2022-01-11 X4 Pharmaceuticals, Inc. Methods for treating immunodeficiency disease
US10610527B2 (en) 2015-12-22 2020-04-07 X4 Pharmaceuticals, Inc. Methods for treating immunodeficiency disease
JP2019502741A (ja) * 2016-01-22 2019-01-31 エックス４ ファーマシューティカルズ， インコーポレイテッド がんを処置するための方法
JP2022082565A (ja) * 2016-01-22 2022-06-02 エックス４ ファーマシューティカルズ， インコーポレイテッド がんを処置するための方法
US11337969B2 (en) 2016-04-08 2022-05-24 X4 Pharmaceuticals, Inc. Methods for treating cancer
US11306088B2 (en) 2016-06-21 2022-04-19 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US10988465B2 (en) 2016-06-21 2021-04-27 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11332470B2 (en) 2016-06-21 2022-05-17 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US10759796B2 (en) 2016-06-21 2020-09-01 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11780837B2 (en) 2016-06-21 2023-10-10 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
WO2019033969A1 (fr) * 2017-08-15 2019-02-21 中国科学院上海药物研究所 Eutectique de telmisartan et de chlorhydrothiazide
US11045461B2 (en) 2018-08-31 2021-06-29 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
US10548889B1 (en) 2018-08-31 2020-02-04 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
US11672793B2 (en) 2018-08-31 2023-06-13 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
US12115156B2 (en) 2018-08-31 2024-10-15 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
US12285424B2 (en) 2020-03-10 2025-04-29 X4 Pharmaceuticals, Inc. Methods for treating neutropenia
US12377090B1 (en) 2020-03-10 2025-08-05 X4 Pharmaceuticals, Inc. Methods for treating neutropenia

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CA2706292A1 (fr) 2011-11-28
WO2011147026A3 (fr) 2012-01-26
CA2801020A1 (fr) 2011-12-01

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