WO2007061415A1 - Compositions pharmaceutiques de telmisartan - Google Patents

Compositions pharmaceutiques de telmisartan Download PDF

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Publication number
WO2007061415A1
WO2007061415A1 PCT/US2005/042700 US2005042700W WO2007061415A1 WO 2007061415 A1 WO2007061415 A1 WO 2007061415A1 US 2005042700 W US2005042700 W US 2005042700W WO 2007061415 A1 WO2007061415 A1 WO 2007061415A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
telmisartan
amount
composition according
diluent
Prior art date
Application number
PCT/US2005/042700
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English (en)
Inventor
Gershon Kolatkar
Erela Zisman
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmeceuticals Usa, Inc.
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 Teva Pharmaceutical Industries Ltd., Teva Pharmeceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to AU2005338461A priority Critical patent/AU2005338461A1/en
Priority to CNA2005800521169A priority patent/CN101312714A/zh
Priority to PCT/US2005/042700 priority patent/WO2007061415A1/fr
Priority to CA002623018A priority patent/CA2623018A1/fr
Priority to JP2008541140A priority patent/JP2009515956A/ja
Publication of WO2007061415A1 publication Critical patent/WO2007061415A1/fr
Priority to IL189614A priority patent/IL189614A0/en

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    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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 is directed to pharmaceutical compositions of telmisartan having less than 25% of water soluble diluents.
  • Telmisartan is the common chemical name for the compound 4'-[2-n-propyl-4-methyl-6- ( 1 -methylbenzimidazol-2-yl)benzimidazol- 1 -ylmethyl]biphenyl-2-carboxylic acid. (CAS Registry No.144701-48-4.)
  • the empirical formula of telmisartan is C 33 H 3 oN 4 0 2 and its molecular weight is 514.63.
  • the molecular structure of telmisartan is represented by Formula I.
  • Telmisartan is a non-peptide angiotensin II receptor (type AT 1 ) antagonist.
  • FDA United States Food and Drag Administration
  • telmisartan under the trade name Micardis ® (telmisartan), available as 20, 40 and 80 mg tablets for oral administration.
  • Micardis ® telmisartan
  • Two patents are listed in the FDA's electronic Orange Book for telmisartan, U.S. Patent No. 6,358,986 ("the '986 patent”) and U.S. Patent No. 5,591,762 (“the '762 patent”).
  • telmisartan and the physiologically acceptable salts thereof can also be used to treat cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic neuropathy, glaucoma, gastrointestinal diseases, bladder diseases, and to prevent progression of cardiac insufficiency after myocardial infarct.
  • telmisartan In addition to the above therapeutic applications of telmisartan, the '762 patent discloses other therapeutic applications, including treating diabetic nephropathy, pulmonary diseases, e.g., lung oedema and chronic bronchitis. It also discloses using telmisartan to prevent arterial restenosis after angioplasty, thickening of blood vessel walls after vascular operations, and diabetic angiopathy. The '762 patent further discloses using telmisartan to alleviate central nervous system disorders, such as depression, Alzheimer's disease, Parkinson Syndrome, bulimia, and disorders of cognitive function in view of the effects of angiotensin on the release of acetylchloline and dopamine in the brain.
  • central nervous system disorders such as depression, Alzheimer's disease, Parkinson Syndrome, bulimia, and disorders of cognitive function in view of the effects of angiotensin on the release of acetylchloline and dopamine in the brain.
  • Telmisartan is a white to off-white, odorless crystalline powder. It is practically insoluble in water or an aqueous solution in the pH range of 3 to 9, and sparingly soluble in a strong acid, with the exception of hydrochloric acid in which it is insoluble. Telmisartan is soluble in a strong base.
  • Telmisartan In general, Telmisartan is manufactured and supplied in its free acid form. However, as described in WO 00/43370, crystalline Telmisartan apparently exists in two polymorphic forms which have different melting points. Under the influence of heat and humidity polymorph B of Telmisartan, having the lower melting point, reportedly irreversibly transforms into polymorph A, which has a higher melting point. Both of these forms are apparently very poorly soluble in aqueous systems at the physiological pH range in the gastro-intestinal tract of between pH 1 to 7.
  • the published U.S. patent application 2004/0110813 Al describes that the solubility of Telmisartan can be increased several hundred fold in a pharmaceutical composition
  • a pharmaceutical composition comprising 3 to 50% of Telmisartan dispersed in a dissolving matrix comprising a) a basic agent wherein the molar ratio of basic agent: Telmisartan equals 1:1 to 10:1, b) a surfactant or emulsifier in an amount of about 2 to 3% of the final composition, c) 25 to 70% of a water soluble diluent, and optionally 0 to 20% of further excipients and/or adjuvants.
  • the present invention is directed to pharmaceutical compositions comprising telmisartan in which the solubility of telmisartan is improved, and wherein the composition comprises less than 25% of water soluble diluents.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a) a telmisartan compound, b) a surfactant, c) a basic agent, and d) at least one diluent selected from water soluble and water insoluble diluents, wherein the pharmaceutical composition comprises less than 25% by total weight of the composition of water soluble diluents.
  • the pharmaceutical composition comprises at least one diluent which is water insoluble, preferably microcrystalline cellulose.
  • telmisartan containing pharmaceutical compositions of the present invention provide sufficient solubility of telmisartan for use in a physiological environment while the amount of water soluble diluents is less than 25% of the composition by weight. Telmisartan is released from said pharmaceutical compositions with sufficient solubility for gastro-intestinal absorption in the slightly acidic and neutral pH region.
  • dissolution of the pharmaceutical composition in an aqueous solution of neutral pH dissolves at least 80% of the Telmisartan contained therein within 45 minutes.
  • At least 80% of the Telmisartan is dissolved from the pharmaceutical composition in such aqueous solution within 30 minutes, and most preferably at least 80% of the Telmisartan is dissolved from the pharmaceutical composition in such aqueous solution within 20 minutes.
  • a pharmaceutical composition comprising about 12.5% to about 15.5% weight percent of telmisartan; about 40% to about 70% weight percent microcrystalline cellulose; about 2.0% to about 3.5% weight percent of a surfactant, preferably Poloxamer 188; about 9% to about 12% weight percent of a basic agent, preferably Meglumine; about 1.0% to about 1.5% weight percent of a binder; about 7.5% to about 10% weight of a disintegrant; about 0% to 17% weight percent of a water soluble filler and about 0.5% to about 1% weight of a lubricant, all weight percentages are based upon the total weight of the pharmaceutical composition.
  • a surfactant preferably Poloxamer 188
  • a method of preparing a pharmaceutical composition comprising the following steps of 1) mixing a disintegrant, preferably sodium starch glycolate, and one or more diluents, preferably at least one water insoluble diluent, more preferably wherein at least one diluent is microcrystalline cellulose, in a high shear mixer to form a homogeneous mixture; 2) preparing a granulation suspension of purified water, alcohol, a basic agent, a surfactant, and telmisartan; 3) combining the homogeneous mixture and the granulation suspension to form a combined mixture; 4) preparing a granulation solution of water and a binder, preferably Povidone (preferably PVP K-30); 5) adding the granulation solution to the combined mixture to form a granulate; 6) drying the formed granules; 7) sizing the dried granules; 8) mixing the dried granulate with a disintegrant, preferably sodium starch glycolate, and optionally
  • a method of treating a patient suffering from hypertension comprising administering an effective amount of a telmisartan compound in a pharmaceutical composition comprising about 12.5% to about 15.5% of a telmisartan compound; about 2.0 to about 3.5% of a surfactant; about 9% to about 12% of a basic agent; and at least one diluent, wherein the pharmaceutical composition comprises less than 25% of water soluble diluents.
  • the pharmaceutical composition comprises about 40% to about 70% of a water insoluble diluent.
  • water soluble diluent refers to a compound, used in the art as a diluent, for use in a pharmaceutical composition which is soluble in an aqueous environment.
  • water insoluble diluent refers to a compound, used in the art as a diluent, for use in a pharmaceutical composition which is insoluble or very poorly soluble in an aqueous environment.
  • the pharmaceutical composition according to the invention comprises: a) a telmisartan compound, in admixture with b) a surfactant, c) a basic agent, and d) at least one diluent selected from water soluble and water insoluble diluents, wherein the amount of water soluble diluents in the pharmaceutical composition is less than 25% by weight of the pharmaceutical composition.
  • the amount of water soluble diluents in the pharmaceutical composition is less than 20%, more preferably less than 17.5%, by weight of the pharmaceutical composition.
  • Said pharmaceutical composition preferably comprises at least one water insoluble diluent.
  • a pharmaceutical composition of the invention is in tablet dosage form containing telmisartan as the active ingredient in an amount of 20, 40 or 80 mg in each tablet, and wherein the total weight of the pharmaceutical composition is from about 130mg to about 160mg. More preferably, such tablets contain 20 mg of telmisartan.
  • the relative amount of the telmisartan compound typically varies from about 12.5% to about 15.5% by weight of the pharmaceutical composition.
  • telmisartan as used in the pharmaceutical composition of the present invention may be in any suitable form such as for example in the form of polymorph A or B.
  • Suitable diluents for use in the pharmaceutical composition of the invention include microcrystalline cellulose (e.g. Avicel ® ), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • the total amount of water soluble diluents in the pharmaceutical composition is less than 25% by weight of the pharmaceutical composition.
  • At least one diluent for use in the pharmaceutical composition is a water insoluble diluent such as microcrystalline cellulose.
  • the insoluble diluent for use in the pharmaceutical composition of the invention is microcrystalline cellulose (e.g. Avicel ® PH 102).
  • the relative amount of the water insoluble diluent is preferably from about 40% to about 70% by weight of the pharmaceutical composition.
  • Suitable surfactants for use in the pharmaceutical composition of the invention include poloxamers, polyethylene glycols, polysorbates, sodium lauryl sulfate, polyethoxylated castor oil, and hydroxylated castor oil.
  • a preferred surfactant for use in the pharmaceutical composition of the invention is Poloxamer 188.
  • the pharmaceutical composition comprises an amount of about 2.0% to about 3.5% by total weight of the composition of the surfactant.
  • Suitable basic agents for use in the pharmaceutical composition of the invention include alkaline hydroxides, alkaline carbonates, alkaline phosphates, basic amino acids, and Meglumine.
  • a preferred basic agent for use in the pharmaceutical composition of the invention is Meglumine.
  • the pharmaceutical composition comprises an amount of about 9% to about 12% by total weight of the composition of the basic agent.
  • the telmisartan pharmaceutical composition of the invention may also include pharmaceutically acceptable excipients.
  • pharmaceutical excipients are routinely incorporated into solid dosage forms. This is done to ease the manufacturing process as well as to improve the performance of the dosage form.
  • Common excipients include fillers, binders, lubricants, etc. Such excipients could be used in the dosage forms of this invention.
  • Fillers are added in order to increase the mass of an individual dose to a size suitable for tablet compression.
  • suitable fillers include for example powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride, dry starch, sorbitol, and talc.
  • a water soluble filler may optionally be used.
  • a preferred filler of this type for use in the pharmaceutical composition of the invention is sorbitol in an amount not exceeding 25% by total weight of the composition.
  • the pharmaceutical composition comprises an amount of about 0% to about 17% by total weight of the composition of the optional filler.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ® ), hydroxypropyl methyl cellulose (e.g. Methocel ® ), liquid glucose, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
  • Povidone PVP K-30 Kollidon ® , Plasdone ® ), pregelatinized starch, sodium alginate and starch.
  • a preferred binder for use in the pharmaceutical composition of the present invention is Povidone (e.g. PVP K-30).
  • the pharmaceutical composition comprises an amount of about 1.0% to about 1.5% by total weight of the composition of the binder.
  • a compacted solid pharmaceutical composition may also include the addition of a disintegrant to the composition.
  • Disintegrants include croscarmellose sodium (e.g. Ac Di Sol ® , Primellose ® ), crospovidone (e.g. Kollidon ® , Polyplasdone ® ), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab ® , Primoljel ® ) and starch.
  • a preferred disintegrant for use in the pharmaceutical composition of the invention is sodium starch glycolate.
  • the pharmaceutical composition comprises an amount of about 7.5% to about 10% by total weight of the composition of the disintegrant.
  • Glidants can be added to improve the flowability of a non compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc.
  • a lubricant can be added to the composition to reduce adhesion and/or ease the release of the product from e.g. the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • a preferred lubricant for use in the pharmaceutical composition of the invention is magnesium stearate.
  • the pharmaceutical composition comprises an amount of about 0.5% to about 1.0% by total weight of the composition of the lubricant.
  • excipients that may be incorporated into the formulation include preservatives, antioxidants, or any other excipient commonly used in the pharmaceutical industry.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, and rectal administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and homges.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions of the invention are described in Table 1 infra, wherein all weight percentages are based upon the total weight of the composition.
  • Table 1 Preferred Pharmaceutical Compositions of the Invention
  • telmisartan dissolves from the pharmaceutical composition of the present invention at a suitable rate.
  • at least 80% of the telmisartan in the pharmaceutical composition dissolves in a neutral aqueous environment within 45 minutes.
  • at least 80% of the telmisartan in the pharmaceutical composition dissolves in a neutral aqueous environment within 30 minutes, and most preferably at least 80% of the Telmisartan is dissolved from the pharmaceutical composition in such aqueous solution within 20 minutes.
  • compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules.
  • the compacted granules may subsequently be compressed into a tablet.
  • the granulates and powder blends produced by these methods can alternatively be filled into capsules or sachets for example.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include macrocrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • a preferred method of preparing a telmisartan pharmaceutical composition of the invention comprises the steps of 1) mixing a disintegrant, preferably sodium starch glycolate, and one or more diluents, preferably at least one water insoluble diluent, more preferably wherein at least one diluent is microcrystalline cellulose, in a high shear mixer to form a homogeneous mixture; 2) preparing a granulation suspension of purified water, alcohol, a basic agent, a surfactant, and telmisartan; 3) combining the homogeneous mixture and the granulation suspension to form a combined mixture; 4) preparing a granulation solution of water and a binder, preferably Povidone (e.g.
  • step 10 will typically be replaced by the step of filling capsule shells.
  • the method of the present invention is however not limited to these mixing procedures or their order, and several of the steps involved can be combined into a single step.
  • the amount of disintegrant used preferably results in a pharmaceutical composition comprising about 7.5% to about 10% of a disintegrant.
  • the amount of a telmisartan compound used in said method preferably results in a pharmaceutical composition comprising about 12.5% to about 15.5% of a telmisartan compound.
  • the amount of a basic agent used in said method preferably results in a pharmaceutical composition comprising about 9% to about 12% of a basic agent.
  • the amount of a binder used in said method preferably results in a pharmaceutical composition comprising about 1.0% to about 1.5% of a binder.
  • the amount of surfactant used in said method preferably results in a pharmaceutical composition comprising about 2.0% to about 3.5% of a surfactant.
  • the amount of an optional filler used in said method preferably results in a pharmaceutical composition comprising about 0% to about 17% of a filler.
  • the amount of a lubricant used in said method is preferably from about 0.5% to about 1.0%.
  • Telmisartan is used for the treatment of hypertension in patients, either alone or in combination with other hypertensive agents.
  • the pharmaceutical compositions of the present invention provide an effective delivery system for the administration of telmisartan to patients in need of such treatment.
  • Treatment of hypertensive patients may comprise administering an effective amount of telmisartan in a pharmaceutical composition comprising about 12.5% to about 15% telmisartan, about 2.0 to about 3.5% of a surfactant; about 9% to about 12% of a basic agent; and at least one diluent, wherein the pharmaceutical composition comprises less than 25% of water soluble diluents.
  • the pharmaceutical composition comprises about 40% to about 70% of a water insoluble diluent.
  • Example 1 Telmisartan formulations comprising 41% of a water insoluble diluent.
  • Telmisartan tablets were prepared containing 41% of a water insoluble diluent. Sorbitol, a filler in these formulations, may also be considered a water soluble diluent and is thus present in less than 25%, i.e. 16.7%, of the composition.
  • the tablets were prepared in three potencies, 20, 40 and 80 mg Telmisartan tablets. The tablet compositions are presented in Table 2.
  • Table 2 Telmisartan formulations comprising 41% of a water insoluble diluent.
  • the tablets were prepared by mixing a homogeneous mixture of microcrystalline cellulose and sodium starch glycolate with a granulation suspension of purified water, Poloxamer 188, Meglumine, and telmisartan in a high shear mixer to form a partial granulate mixture.
  • This partial granulate mixture was granulated with a granulation solution of alcohol and Povidone (PVP K-30).
  • PVP K-30 granulation solution of alcohol and Povidone
  • the obtained granules were dried in a Fluid Bed dryer until the observed "loss on drying” (LOD) was 2% or less.
  • the dried granules were then milled by passing them through an oscillating granulator. Subsequently, the milled granulates were mixed with Sorbitol and sodium starch glycolate in a blender.
  • the obtained blend was then mixed with magnesium stearate and tablets were prepared by compressing this mixture.
  • Example 2 Telmisartan formulations comprising 53% of a water insoluble diluent.
  • Telmisartan tablets were prepared containing 53% of a water insoluble diluent. Sorbitol, a filler in these formulations, may also be considered a water soluble diluent and is thus present in an amount less than 25%, i.e. 13.4%, of the composition.
  • the tablets were prepared in three potencies, 20, 40 and 80 mg Telmisartan tablets.
  • the tablet compositions are presented in Table 3.
  • Table 3 Telmisartan formulations comprising 53% of a water insoluble diluent.
  • the tablets were prepared by wet granulation by mixing a homogeneous mixture of microcrystalline cellulose and sodium starch glycolate with a granulation suspension of purified water, Poloxamer 188, Meglumine, and telmisartan in a high shear mixer to form a partial granulate mixture.
  • This partial granulate mixture was granulated with a granulation solution of alcohol and Povidone (PVP K-30).
  • PVP K-30 Povidone
  • the obtained granules were dried in a Fluid Bed dryer until the observed "loss on drying” (LOD) was 2% or less.
  • the dried granules were then milled by passing them through an oscillating granulator. Subsequently, the milled granulates were mixed with Sorbitol and sodium starch glycolate in a blender. The obtained blend was then mixed with magnesium stearate and tablets were prepared by compressing this mixture.
  • Example 3 Telmisartan formulations comprising 66% of a water insoluble diluent.
  • Telmisartan tablets were prepared containing 66% of a water insoluble diluent. Moreover, these formulations do not comprise water soluble diluents. The tablets were prepared in three potencies, 20, 40 and 80 mg Telmisartan tablets. The tablet compositions are presented in Table 4. Table 4: Telmisartan formulations comprising 66% of a water insoluble diluent.
  • the tablets were prepared by wet granulation through a method analogous to the method used to prepare the tablets of example 1.
  • Example 4 Dissolution tests with Telmisartan pharmaceutical tablet dosage forms.
  • Dissolution tests with the Telmisartan pharmaceutical tablet dosage formulations of examples 1 to 3 were performed. In these tests the dissolution of the tablets of examples 1 to 3 was compared with the dissolution of the reference tablet formulation, a Micardis ® tablet. These in vitro dissolution tests were conducted using an Apparatus II (Paddle Method) as described in the United State Pharmacopeia XXI/National Formulary XVI. The comparative dissolution tests were conducted under the following conditions. Micardis ® tablets and Telmisartan tablets of examples 1, 2, and 3 were dissolved in a USP type II apparatus at a paddle speed of 75 rpm, at a temperature of 37°C, in 900ml of a buffer at pH 7.5. The results of these dissolution tests are presented in Table 5.
  • the pharmaceutical tablet formulations of the present invention and the reference Micardis ® tablet all dissolve at least 80% of the telmisartan contained therein well within the desired 45 minutes. In fact, all dissolve at least 80% of the telmisartan contained in the formulation within 30 minutes, and some formulations even achieve that at least 80% of the telmisartan from the pharmaceutical composition is dissolved in such aqueous solution within 20 minutes.
  • the results further demonstrate that the pharmaceutical tablet formulations of the invention have a similar dissolution profile compared to the reference formulation.

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Abstract

La présente invention concerne une composition pharmaceutique de telmisartan comprenant a) un composé de telmisartan, b) un tensioactif, c) un agent basique et d) au moins un diluant, la composition comprenant moins de 25 % de diluants solubles dans l’eau. Le composé de telmisartan est de préférence présent en une quantité comprise entre environ 12,5 % et environ 15,5 %. Il est préférable d’utiliser dans la composition pharmaceutique au moins un diluant insoluble dans l’eau en une quantité comprise entre environ 40 % et environ 70 % du poids total de la composition pharmaceutique. La cellulose microcristalline constitue un diluant insoluble dans l’eau préféré.
PCT/US2005/042700 2005-11-22 2005-11-22 Compositions pharmaceutiques de telmisartan WO2007061415A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU2005338461A AU2005338461A1 (en) 2005-11-22 2005-11-22 Pharmaceutical compositions of telmisartan
CNA2005800521169A CN101312714A (zh) 2005-11-22 2005-11-22 替米沙坦的药用组合物
PCT/US2005/042700 WO2007061415A1 (fr) 2005-11-22 2005-11-22 Compositions pharmaceutiques de telmisartan
CA002623018A CA2623018A1 (fr) 2005-11-22 2005-11-22 Compositions pharmaceutiques de telmisartan
JP2008541140A JP2009515956A (ja) 2005-11-22 2005-11-22 テルミサルタンの医薬組成物
IL189614A IL189614A0 (en) 2005-11-22 2008-02-19 Pharmaceutical compositions of telmisartan

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WO2010012248A1 (fr) * 2008-07-31 2010-02-04 Zentiva, K.S. Comprimés de telmisartan
JP2010535212A (ja) * 2007-08-01 2010-11-18 テバ ファーマシューティカル インダストリーズ リミティド 改良されたカンデサルタンの製剤
WO2010057449A3 (fr) * 2008-11-24 2011-03-17 Zentiva, K.S. Composition pharmaceutique solide comprenant de l'atorvastatine et du telmisartan en tant que substances actives
WO2012043709A1 (fr) 2010-09-30 2012-04-05 塩野義製薬株式会社 Préparation pour améliorer la solubilité d'un médicament médiocrement soluble
WO2014100639A1 (fr) * 2012-12-21 2014-06-26 Teva Pharmaceutical Industries Ltd. Administration transmucosale d'acétate de glatiramère
US9789059B2 (en) 2014-07-30 2017-10-17 Boehringer Ingelheim International Gmbh Oral disintegrating tablet
WO2019130049A1 (fr) 2017-12-29 2019-07-04 Grünenthal GmbH Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur

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CN102532033A (zh) * 2012-02-29 2012-07-04 江西杏林白马药业有限公司 替米沙坦成盐工艺
JP6379044B2 (ja) * 2013-01-31 2018-08-22 沢井製薬株式会社 テルミサルタンとヒドロクロロチアジドとを含有する多層錠剤
JP6218664B2 (ja) * 2013-04-04 2017-10-25 沢井製薬株式会社 テルミサルタン含有錠剤
CN104688696B (zh) * 2013-12-04 2017-12-19 长春海悦药业股份有限公司 一种含有坎地沙坦酯的药物组合物
JP5871294B1 (ja) * 2015-02-27 2016-03-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 即時放出経口錠剤
CN110934848B (zh) * 2019-12-20 2022-02-15 江西杏林白马药业股份有限公司 一种替米沙坦胶囊及其制备方法
CN115245497A (zh) * 2021-04-26 2022-10-28 武汉伯睿科医药科技有限公司 替米沙坦胶囊及其制备工艺

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Cited By (15)

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Publication number Priority date Publication date Assignee Title
WO2007060170A2 (fr) * 2005-11-24 2007-05-31 Boehringer Ingelheim International Gmbh Comprimé bicouche comprenant du telmisartan et un diurétique
WO2007060170A3 (fr) * 2005-11-24 2007-09-13 Boehringer Ingelheim Int Comprimé bicouche comprenant du telmisartan et un diurétique
JP2010535212A (ja) * 2007-08-01 2010-11-18 テバ ファーマシューティカル インダストリーズ リミティド 改良されたカンデサルタンの製剤
WO2010012248A1 (fr) * 2008-07-31 2010-02-04 Zentiva, K.S. Comprimés de telmisartan
EA019374B1 (ru) * 2008-07-31 2014-03-31 Зентива, К.С. Композиция телмисартана и способ ее получения
WO2010057449A3 (fr) * 2008-11-24 2011-03-17 Zentiva, K.S. Composition pharmaceutique solide comprenant de l'atorvastatine et du telmisartan en tant que substances actives
EP2623100A1 (fr) * 2010-09-30 2013-08-07 Shionogi & Co., Ltd. Préparation pour améliorer la solubilité d'un médicament médiocrement soluble
WO2012043709A1 (fr) 2010-09-30 2012-04-05 塩野義製薬株式会社 Préparation pour améliorer la solubilité d'un médicament médiocrement soluble
EP2623100A4 (fr) * 2010-09-30 2014-04-02 Shionogi & Co Préparation pour améliorer la solubilité d'un médicament médiocrement soluble
US9427402B2 (en) 2010-09-30 2016-08-30 Shionogi & Co. Ltd. Preparation for improving solubility of poorly soluble drug
KR101849808B1 (ko) 2010-09-30 2018-04-17 시오노기세이야쿠가부시키가이샤 난용성 약물의 용해성 개선 제제
WO2014100639A1 (fr) * 2012-12-21 2014-06-26 Teva Pharmaceutical Industries Ltd. Administration transmucosale d'acétate de glatiramère
US9789059B2 (en) 2014-07-30 2017-10-17 Boehringer Ingelheim International Gmbh Oral disintegrating tablet
US10918595B2 (en) 2014-07-30 2021-02-16 Boehringer Ingelheim International Gmbh Oral disintegrating tablet
WO2019130049A1 (fr) 2017-12-29 2019-07-04 Grünenthal GmbH Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur

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IL189614A0 (en) 2008-06-05
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JP2009515956A (ja) 2009-04-16
AU2005338461A1 (en) 2007-05-31

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