WO2016153222A2 - Composition pharmaceutique comprenant un sel de potassium de telmisartan et procédé de préparation associé - Google Patents

Composition pharmaceutique comprenant un sel de potassium de telmisartan et procédé de préparation associé Download PDF

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WO2016153222A2
WO2016153222A2 PCT/KR2016/002743 KR2016002743W WO2016153222A2 WO 2016153222 A2 WO2016153222 A2 WO 2016153222A2 KR 2016002743 W KR2016002743 W KR 2016002743W WO 2016153222 A2 WO2016153222 A2 WO 2016153222A2
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telmisartan
potassium
potassium salt
pharmaceutical composition
tablets
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PCT/KR2016/002743
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Korean (ko)
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WO2016153222A3 (fr
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박영준
박상미
조중명
노성구
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크리스탈지노믹스(주)
아주대학교산학협력단
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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
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a pharmaceutical composition containing potassium salt of telmisartan in the form of potassium salt, and a method for preparing the same, wherein the crystalline telmisartan potassium is used to overcome the poor solubility of telmisartan and improve its stability. It relates to a pharmaceutical composition and a preparation method comprising a salt as an active ingredient.
  • Telmisartan is 4 '-[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-ylmethyl] -biphenyl-2 -Angiotensin II antagonist as a substance having a structure of carboxylic acid. Telmisartan is used for the treatment of hypertension, heart failure, diabetic neuropathy, glaucoma, gastrointestinal and bladder diseases, and is generally provided in the form of free acid.
  • basic bases should be used in formulating telmisartan due to low solubility in pH conditions in vivo, and alkali metal hydroxides and meglumine as suitable basic bases. (N-methyl-D-glucamine) is generally used.
  • Korean Patent No. 10-0876302 discloses a method for preparing telmisartan in an amorphous form of 90% or more by preparing telmisartan and a strong deliquescentifying agent in an aqueous solution and then obtaining spray dried granules. .
  • 2009-0119998 limits the specific surface area of sorbitol, but the actual composition is amorphous telmisartan and describes a pharmaceutical composition including a basicizing agent and sorbitol, but such as sodium hydroxide.
  • the tablet may be exposed to moisture due to an increase in hygroscopicity, or may be easily wetted and melted and sticky.
  • the treatment effect may not be satisfactory with only a single component, and thus two or more drugs that change the mechanism of action, for example, angiotensin antagonist (ARB) and calcium channel blocker (CCB). ), Or diuretic class drugs.
  • ARB angiotensin antagonist
  • CCB calcium channel blocker
  • hydrochlorothiazide can be administered in combination. If these co-administered drugs can be in one dosage form, they can bring a variety of benefits, including dosage compliance.
  • telmisartan and CCB class drugs or diuretic class drugs have no clinically interactive drug interactions.
  • CCB-based drug or a diuretic-based drug there are pharmaceutical difficulties. This is because the amlodipine or hydrochlorothiazide mentioned above is incompatible with the basic composition.
  • PCT / EP2002 / 000395 discloses a tablet having a bilayer structure in which telmisartan and hydrochlorothiazide are contained in different layers
  • Korean Patent Application Publication No. 10-2007- 0085801 discloses a tablet having a bilayer structure in which telmisartan and amlodipine are contained in different layers.
  • telmisartan in the case of dissolving poorly soluble telmisartan with a strong deliquescent substance and preparing it as a tablet, other pharmaceutical excipients are contained in a large amount, so that the active ingredient contains less than 20% of the total, increasing the size of the tablet (for example, For example, a product containing 80 mg of telmisartan has a total weight of 480 mg), especially when manufactured in multi-layered tablets, which may be larger in size, considering that most hypertensive patients are old and may suffer from dysphagia. If you need to reduce the size of the product to increase the convenience of taking.
  • composition and method for preparing telmisartan in combination with other effective drugs to produce a single-layered tablet in which the size or size of the single-layered tablet satisfying the stability, hygroscopicity and dissolution rate is reduced and is convenient to take.
  • the present invention is to solve the above-mentioned problems, to provide a telmisartan-containing pharmaceutical composition having a desirable dissolution rate and stability and can reduce the size of the tablet.
  • telmisartan potassium salt 15-70% by weight of telmisartan potassium salt
  • telmisartan potassium salt comprising a potassium salt stabilizer 0.2 to 30% by weight.
  • the potassium salt stabilizer may include one or more from the group consisting of potassium salt adjuvant or anti-gelling agent.
  • the antigelling agent may be at least one component selected from magnesium carbonate, sodium carbonate, magnesium oxide, calcium carbonate, sodium phosphate, magnesium phosphate, hard silicic anhydride, and glyceryl behenate.
  • the potassium salt adjuvant includes acesulfame potassium, polyacrylic potassium, potassium alginate, alum, potassium benzoate, potassium hydrogen carbonate, potassium phosphate, potassium carbonate, potassium chloride, potassium hydroxide, potassium citrate, potassium metabisulfite, potassium sorbate and propionic acid One or more components selected from potassium.
  • the pharmaceutical composition may further comprise one or more components selected from excipients, disintegrants and lubricants.
  • the pharmaceutical composition may further comprise at least one second active ingredient selected from diuretics, calcium channel blocker hypertension, angiotensin 1 convertase inhibitor and angiotensin receptor blocker.
  • the pharmaceutical composition according to the present invention may be a pharmaceutical composition for treating hypertension.
  • the second active ingredient may be included in an amount of 1 to 50 wt% based on the total weight of the composition.
  • a capsule or tablet may be provided comprising the pharmaceutical composition according to the invention, and the tablet may be a monolayer or multilayer tablet.
  • telmisartan potassium salt According to the pharmaceutical composition comprising telmisartan potassium salt according to the present invention, it is possible to improve the production time and cost in preparing telmisartan single component or a combination with a diuretic or other high blood pressure components, and By facilitating the size adjustment of the formulation, medication compliance can be improved. In addition, hygroscopicity can be improved while maintaining elution to maintain stability in general packaging.
  • FIG. 3 shows the dissolution rate evaluation results of Example 43 and Comparative Example 1.
  • FIG. 4 shows the dissolution rate evaluation results of Examples 34 and 35 and Comparative Examples 1 and 2.
  • FIG. 5 shows the dissolution rate evaluation results of Examples 32 and 33 and Comparative Examples 1 and 2.
  • telmisartan potassium salt a pharmaceutical composition comprising telmisartan potassium salt and a method of preparing the same according to an embodiment of the present invention will be described in detail.
  • deliquescent basic ingredients such as sodium hydroxide or meglumine
  • telmisartan a compound that is added to elute the poorly soluble telmisartan in free acid form in the body at pH conditions
  • deliquescent basic ingredients such as sodium hydroxide or meglumine
  • telmisartan for example, Difficulty in mixing with calcium channel blockers, diuretics, antihypertensives, other angiotensin receptors and salts thereof, or may cause pharmaceutical stability.
  • telmisartan in the case of dissolving poorly soluble telmisartan with a strong deliquescent substance and preparing it as a tablet. Additional amounts of additional pharmaceutical excipients may occur, resulting in less than 20% of the telmisartan active ingredient, resulting in a total weight of 80 mg of telmisartan. At 480mg, its size can increase.
  • an aluminum-alu foil packaging that prevents the penetration of moisture to prevent degradation of quality due to problems of hygroscopicity and stability by the basic base included in the telmisartan drug according to the prior art. This is more expensive than ordinary blister packaging and can be an increase in cost in industry.
  • the active ingredient telmisartan was prepared in the form of potassium salt.
  • Potassium salt form has higher solubility than telmisartan in free acid form, so there is little solubility problem, and it can help to ensure solubility in the body without using solubilizer, deliquescent or strong basic substance.
  • telmisartan in the form of potassium salt may exhibit superior properties in terms of stability than telmisartan in the form of sodium salt.
  • the telmisartan potassium salt used for this invention is excellent in stability from being crystalline than being amorphous.
  • the content of telmisartan potassium salt in the pharmaceutical composition according to the present invention may include 15 to 70 wt% based on the total weight, preferably 20 to 50 wt%, in consideration of convenience of preparation and ease of preparation. have. Since the effective amount of telmisartan is 40 mg to 80 mg, if telmisartan potassium salt is contained in an amount of 15 wt% or less based on the total weight, it may be difficult to take it in elderly patients due to the increase in the size of the telmisartan tablet. In addition, when using more than 70% by weight of the total weight may cause difficulties in screening and packaging during manufacturing due to the size reduction of the telmisartan-containing tablet.
  • a potassium salt stabilizer may be included to maintain the potassium salt in the product of telmisartan potassium salt.
  • Potassium salts may show high solubility of drugs in solutions of pH 1.2 to 3.0 such as the gastrointestinal tract environment in the body, but in formulations such as tablets or capsules, the drug may form a gel by binding to each other to delay dissolution.
  • the potassium salt stabilizer may be prepared by containing telmisartan potassium salts in the formulation.
  • the potassium salt stabilizer may be included in an amount of 0.2 to 30% by weight based on the total weight of the composition, and preferably 0.5 to 20% by weight, so that the dissolution of telmisartan potassium salt may be increased to 70% or more within 45 minutes.
  • the potassium salt stabilizer may include one or more from the group consisting of potassium salt adjuvant or anti-gelling agent.
  • the potassium salt adjuvant is a substance that serves to maintain a high solubility by continuously forming a form of potassium salt in the formulation, for example, Acesulfame potassium, Polacrilin Potassium Potassium Alginate, Potassium Alum, Potassium Benzoate, Potassium Bicarbonate, Potassium Phosphate, Potassium Carbonate, Potassium Hydroxide, Potassium Citrate, Potassium Metabisulfite Metabisulfite), potassium sorbate (Potassium Sorbate), potassium propionate (Potassium propionate) and the like.
  • These potassium salt adjuvant may fully function as a stabilizer when used in an amount of 0.2 to 30% by weight based on the total weight of the composition, and may be ineffective when the content is low. When the content is excessive, the disintegration may be delayed in the tablet or capsule. There is a possibility that a phenomenon occurs.
  • the anti-gelling agent is a substance that prevents the telmisartan potassium salt from dissolving into a viscous substance and delays dissolution.
  • the gelling agent prevents the formation of a gel by reducing the electrostatic force of the potassium salt.
  • magnesium carbonate, sodium carbonate, magnesium oxide, calcium carbonate, sodium phosphate, magnesium phosphate may play such a role, reducing the electrostatic force of the potassium salt gel
  • a function that can prevent the formation of a light may include a hard silicic anhydride, glyceryl behenate (Glyceryl Behenate) and the like.
  • antigelling agents can be effective when used in 0.2 to 30% by weight based on the total weight of the composition.
  • the content of the anti-gelling agent is low, the effect may be weak, and when the content is excessive, disintegration may occur on tablets or capsules.
  • Potassium salt adjuvant or anti-gelling agent may be included alone as the potassium salt stabilizer, since the effect may be increased when using the two components at the same time may be used together with the potassium salt adjuvant and anti-gelling agent.
  • the pharmaceutical composition comprising the telmisartan potassium salt according to the present invention may further include a diluent, a disintegrant, a lubricant, and the like.
  • the diluent may include water-soluble or water-insoluble excipients, for example lactose, spray dried lactose (Fast-Flo), mannitol, glucose, compressed sugar (Di-pac), dexrate, isomalt, beta cyclo dextrin, microcrystalline cellulose, powdered cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, pregelatinized starch, potato starch, corn starch, microcrystalline cellulose / silicon dioxide composite agent (pro cellosolve TM), lactose / Microcrystalline cellulose complex (Microcell Rock TM ), Rudipures TM , calcium dihydrogen phosphate (Di-Tab), calcium carbonate, potassium carbonate and the like can contain one or more components.
  • lactose spray dried lactose
  • mannitol mannitol
  • glucose compressed sugar
  • dexrate isomalt
  • the disintegrants are, for example, formalin-casein, low-substituted hydroxypropylcellulose (L-HPC), chitin, chitosan, polymerized agar acrylamide, xylan, smecta, key-zo clay ( key-jo clay), crosslinked carboxymethyl guar and modified tapioca starch, alginic acid or alginate, hydroxypropyl cellulose and other cellulose derivatives, potassium chlorine potassium, croscarmellose sodium (Ac-Di-Sol, CLD-2), Starch, gelatinized starch, carboxymethyl starch, gellan gum and the like.
  • L-HPC low-substituted hydroxypropylcellulose
  • chitin chitosan
  • polymerized agar acrylamide xylan
  • smecta key-zo clay
  • key-jo clay key-jo clay
  • crosslinked carboxymethyl guar and modified tapioca starch alg
  • Superdisintegrants are, for example, croscarmellose sodium (AC-Di-Sol), starch sodium glycolate (Primojel and Explotab), crospovidone (Polyplasdone-X1R, polyplasmon-XL 10R, Kollidon CL) or crospovidone (Kollidon CL) and the like.
  • the glidants may include, for example, sodium stearyl fumarate, hydrogenated castor oil, calcium stearate, magnesium trisilicate, magnesium stearate, and the like, in particular sodium stearyl fumarate and the like.
  • excipients and auxiliaries which may additionally be used include, for example, one or more from crystallization retarders, binders, carriers, fillers, flow control agents, solubilizers, colorants, pH regulators, surfactants, lubricants and emulsifiers. You can choose.
  • the crystallization retardant is, for example, polyvinylpyrrolidone (povidone), a copolymer of vinylpyrrolidone and other vinyl derivatives, polyvinyl alcohol, glucose, gelatin, hydroxypropylmethylcellulose, hydroxypropyl cellulose It may comprise at least one or more from the group, in particular may comprise povidone.
  • binders include, for example, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxy propylcellulose and It may comprise at least one or more from the group consisting of gelatinized starch, in particular may comprise hydroxypropylmethylcellulose, povidone or mixtures thereof.
  • the carrier, filler, flow regulator, solubilizer, colorant, pH regulator, surfactant, and emulsifier may be those commonly used in the art and are not particularly limited.
  • a granulation solvent for example, methanol, ethanol, isopropyl alcohol or purified water may be used as a liquid having volatility and not remaining in the final product, and in particular, ethanol and purified water may be used as the solvent. have.
  • a drug that can be administered in combination with telmisartan, which is the first drug substance may further include a second drug agent.
  • the second active ingredient for example, diuretics, calcium channel blocker hypertension drugs, angiotensin 1 convertase inhibitors, angiotensin receptor blockers, and the like can be used.
  • the diuretic may include, for example, thiazide and thiazide-homolog diuretics, hydrochlorothiazide, clopamide, zipamide, purosemide, and the like.
  • the calcium channel blocker is, for example, amlodipine, vanidipine, benidipine, diltiazem, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nirendipine, verapamil and pharmaceutically thereof. And one or more of the acceptable salts.
  • the angiotensin 1 convertase inhibitor may include, for example, captopril, ramipril and pharmaceutically acceptable salts thereof, or angiotensin receptor blockers.
  • telmisartan potassium salt and diuretics telmisartan potassium salt and diuretics, telmisartan potassium salt and calcium channel blocker, telmisartan potassium salt and angiotensin I converting enzyme inhibitor, telmisartan potassium salt and other angiotensin receptor blockers, Telmisartan potassium salt and diuretics and calcium channel blockers, including diluents, including one or more in water-soluble excipients such as potassium salt stabilizers, mannitol, isomalt, lactose or non-aqueous excipients such as microcrystalline cellulose, corn starch, etc.
  • Capsules or tablets containing disintegrants, lubricants and the like can be provided.
  • the pharmaceutical composition contains a pharmaceutically acceptable additive such as telmisartan potassium salt, potassium salt stabilizer, water-soluble excipient of saccharide or cellulose-based excipient, excipient, disintegrant, glidant, etc. It can be prepared by tableting directly after mixing.
  • a pharmaceutically acceptable additive such as telmisartan potassium salt, potassium salt stabilizer, water-soluble excipient of saccharide or cellulose-based excipient, excipient, disintegrant, glidant, etc. It can be prepared by tableting directly after mixing.
  • the pharmaceutical composition includes telmisartan potassium salt and potassium salt stabilizer, and further includes active ingredients and excipients that can be commonly co-administered with telmisartan and the like. It can be prepared into granules by one of the methods.
  • a granule comprising one or more of the following steps a to d:
  • a method comprising any one or more of the steps of obtaining granules by dry granulation, and also filling or compressing the capsule by mixing a potassium salt stabilizer, a pharmaceutically acceptable additive, and the like.
  • the pharmaceutical composition comprising telmisartan potassium salt may be added to a pharmaceutical composition including telmisartan potassium salt in addition to a second active ingredient, a pharmaceutically acceptable additive, and the like to prepare a monolayer tablet.
  • telmisartan when two or more drugs are used in combination with telmisartan in order to increase the efficacy, it is possible to improve dosage compliance, process economy, etc. by preparing and administering in one formulation or monolayer tablet. .
  • the inclusion of telmisartan in the form of crystalline potassium salt can overcome the stability and pharmaceutical technical difficulties.
  • telmisartan potassium salt formulations were prepared as tablets using a wet granulation method.
  • the telmisartan potassium salt used in the examples below was obtained from Hwail Chemical (Korea).
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6
  • Example 7 Telmisartan Potassium Salt 91.1 91.1 91.1 91.1 91.1 91.1 91.1 91.1
  • Potassium chloride 10.0 5.0 10.0 10.0 10.0 40.0 60.0 40.0
  • Crospovidone 45.0 50.0 20.0 45.0 60.0 40.0 - 40.0 Croscarmellose sodium - - 10.0 - - 20.0 - - Light anhydrous silicic acid 5.0 5.0 10.0 5.0 - - - - Sodium
  • telmisartan potassium salt and crystalline silicic anhydride are mixed, and then passed through a 20 mesh sieve, and then the potassium chloride, magnesium oxide, spray-dried mannitol, microcrystalline cellulose, and crospovidone 1/2 content compositions according to Table 1 are used.
  • the mixture was put in a high speed granulator and mixed at 500 rpm for 2 minutes. After ethanol was added while stirring at a speed of 500rpm in the granulator was granulated for 3 minutes.
  • the granules were dried in a hot air dryer at 60 ° C. until the drying loss was less than 2%, and granules were formed into 18 mesh sieves using an oscillator.
  • the granules thus obtained were mixed with prosolve and the remaining amount of crospovidone for 5 minutes, and sodium stearyl fumarate was passed through a 40 mesh sieve and mixed for 2 minutes to obtain a final mixture.
  • the final mixture was compressed by the total amount of tablets per tablet with a compression tableting machine to prepare a rectangular tablet.
  • a tablet was prepared in the same manner as in Example 1 except for changing the contents of potassium chloride and prosolve.
  • Tablets were prepared in the same manner as in Example 1 except that croscarmellose sodium was further added in the same manner as crospovidone.
  • Tablets were prepared in the same manner as in Example 1, except that polypyrrolidone was further added when mixing potassium chloride.
  • Tablets were prepared in the same manner as in Example 1 except that magnesium oxide and hard silicic anhydride were not added.
  • Tablets were prepared in the same manner as in Example 5, except that croscarmellose sodium was further added.
  • Tablets were prepared in the same manner as in Example 5 except that prosolve and crospovidone were not added.
  • Tablets were prepared in the same manner as in Example 5 except for changing the contents of potassium chloride, prosolve and crospovidone.
  • Example 9 Example 10
  • Example 11 Telmisartan Potassium Salt 91.1 91.1 91.1 91.1 Potassium chloride 10.0 - 20.0 - Precipitated Calcium Carbonate 20.0 40.0 - - Magnesium carbonate - - 20.0 40.0 Spray drying mannitol 143.9 143.9 143.9 143.9 Microcrystalline cellulose 30.0 30.0 30.0 30.0 Crospovidone 20.0 40.0 20.0 40.0 Croscarmellose sodium 20.0 - 20.0 - Light anhydrous silicic acid 10.0 10.0 10.0 10.0 10.0 Sodium stearyl fumarate 5.0 5.0 5.0 Total amount of tablets per tablet (mg) 350 360 360 360 360 360 360
  • telmisartan potassium salt preparation was prepared by tablets by a wet granulation method. After mixing telmisartan potassium salt and hard silicic anhydride with 1/2 content, the mixture is passed through a 20 mesh sieve, and then potassium chloride, precipitated calcium carbonate, spray-dried mannitol, microcrystalline cellulose, and crospovidone according to Table 2 are used. 1/2 content Croscarmellose sodium 1/2 content was placed in a high speed rotary granulator and mixed at 500 rpm for 2 minutes. After ethanol was added while stirring at a speed of 500rpm in the granulator was granulated for 3 minutes. The granules were dried in a hot air dryer at 70 ° C.
  • Tablets were prepared as in Example 9 except for potassium chloride and light silicic anhydride.
  • Tablets were prepared as in Example 1 except for potassium chloride and croscarmellose sodium.
  • telmisartan potassium salt formulations were prepared as tablets using a dry granulation method.
  • Example 13 Example 14
  • Example 15 Example 16
  • Example 17 Telmisartan Potassium Salt 91.10 91.10 91.10 91.10 91.10 91.10
  • Magnesium Stearate 3.00 3.00 3.00 3.00 3.00 3.00 3.00 Total amount of tablets per tablet (mg) 362.10 352.10 352.10 327.10 342.10
  • telmisartan potassium salt, magnesium oxide, polypyrrolidone, spray-dried mannitol, and croscarmellose sodium were added thereto, mixed for 5 minutes, and then passed through a 20-mesh sieve.
  • One third portion of magnesium stearate was passed through a 40 mesh sieve and placed in the mixture and mixed for 3 minutes.
  • the mixture was compressed with a mini-compress granulator (Glatte), and granules were prepared by passing through an oscillator equipped with an 18 mesh sieve. 2/3 portions of magnesium stearate was appleed into the granules in a 40 mesh sieve, and the mixture was mixed well for 3 minutes to obtain a final mixture.
  • the final mixture was compressed by the total amount of tablets per tablet with a compression tableting machine to prepare a rectangular tablet.
  • a tablet was prepared in the same manner as in Example 13 except that hard silicic anhydride was added except for magnesium oxide.
  • Tablets were prepared in the same manner as in Example 13, except that potassium chloride was further added when telmisartan potassium salt was added.
  • Tablets were prepared in the same manner as in Example 15, except that the contents of potassium chloride and prosolve were changed.
  • Tablets were prepared in the same manner as in Example 16, except for potassium chloride.
  • the formulation was prepared by a wet granulation method using a telmisartan potassium salt fluidized bed granulator of 1,000 tablet scale.
  • Example 18 Telmisartan Potassium (Tel. K) 91.10 91.10 91.10 91.10 91.10 Magnesium Oxide (Light) - 20.0 40.0 20.0 Potassium chloride 20.0 10.00 - - Polar Green Potassium - - 10.0 - Potassium alginate - - - 20.0 Polypyrrolidone 10.0 10.0 10.0 10.0 Prosolve - 98.0 108.0 Spray drying mannitol 146.0 146.0 80.0 80.0 Microcrystalline cellulose 52.9 32.9 - - Croscarmellose sodium 40.0 40.0 20.0 20.0 Crospovidone - - 20.0 20.0 Light anhydrous silicic acid 10.0 10.0 - - Magnesium Stearate - - 4.0 Sodium stearyl fumarate 5.0 5.0 - - Total amount of tablets per tablet (mg) 375.0 365.0 373.1 373.1
  • polypyrrolidone was dissolved in purified water. Separately, telmisartan potassium salt, hard silicic anhydride, and spray-dried mannitol were mixed and passed through 20 mesh sieves. Then, potassium chloride, microcrystalline cellulose, and croscarmellose sodium 1/2 were added to a plastic bag and mixed for 5 minutes to prepare a fluidized bed mixture. Prepared. Granules were prepared in a fluidized bed granulator at an intake temperature of 60 ° C. while adding a fluidized bed mixture in a fluidized bed granulator (Glatte) and spraying a polypyrrolidone solution. In a fluidized bed granulator, drying was carried out at 50 ° C.
  • Tablets were prepared in the same manner as in Example 18, except that magnesium oxide was further added when potassium chloride was added.
  • tablets were prepared in the same manner as in Example 20 except for further adding potassium alginate when spray-dried mannitol was added.
  • tablets were prepared using a wet granule manufacturing method of telmisartan potassium salt formulation of 1,000 tablets.
  • Example 22 Example 23
  • Example 24 Example 25 Telmisartan Potassium Salt 91.1 91.1 91.1 91.1 Potassium chloride 10.0 10.0 10.0 10.0 Spray drying mannitol 146.0 146.0 120.0 40.0 Microcrystalline cellulose 57.9 50.0 77.0 133.9 Croscarmellose sodium - - 36.0 - Crospovidone 40.0 40.0 - 50.0 Light anhydrous silicic acid 20.0 17.0 20.0 - Glyceryl Vehicle - - - 20.0 Sodium stearyl fumarate 5.00 5.9 5.9 5.00 Total amount of tablets per tablet (mg) 370.0 360.0 360.0 350.0
  • telmisartan potassium salt and hard silicic anhydride were mixed and passed through a 20 mesh sieve. Then, potassium chloride, spray-dried mannitol, microcrystalline cellulose, and half of the content of crospovidone were placed in a high-speed rotating granulator and mixed at 500 rpm for 2 minutes. Then, ethanol was added while stirring at a speed of 500 rpm in the granulator for 3 minutes. The granules were dried in a hot air dryer at 60 ° C. until the loss on drying was less than 2%, and granules were formed into 18 mesh bodies using an oscillator.
  • the remaining granules were added to the granulated granules, mixed for 5 minutes, sodium stearyl fumarate was passed through a 40 mesh sieve, and mixed for 2 minutes to obtain a final mixture.
  • the final mixture was compressed by the total amount of tablets per tablet with a compression tableting machine to prepare a rectangular tablet.
  • Tablets were prepared in the same manner as in Example 22 except for changing the contents of microcrystalline cellulose, hard silicic anhydride, and sodium stearyl fumarate.
  • Tablets were prepared in the same manner as in Example 22, except that croscarmellose sodium was added instead of crospovidone.
  • tablets were prepared in the same manner as in Example 22, except that glyceryl bicarbonate was added to the light silicic anhydride.
  • telmisartan potassium salt and amlodipine complex preparation 1,000 tablets were prepared.
  • Example 26 Example 27
  • Example 28 Example 29
  • Example 30 Telmisartan Potassium (Tel. K) 91.1 91.1 91.1 91.10 91.1 Amlodipine Besylate 6.94 6.94 6.94 - Hydrochlorothiazide - - - - 12.5
  • Prosolve - 38.06 38.06 38.06 48.0 Spray drying mannitol 140.0 - 15.0 100.00 - Microcrystalline cellulose 31.0 123.9 88.9 18.90 123.4
  • Croscarmellose sodium 40.0 - - 15.0 - Crospovidone - 50.0 50.0 40.00 30.0
  • telmisartan potassium salt After mixing telmisartan potassium salt, amlodipine besylate, light anhydrous silicic acid, and spray-dried mannitol, it is passed through a 20 mesh sieve, and magnesium oxide, microcrystalline cellulose, and 1/2 part of croscarmellose sodium are placed in a high speed mixing granulator at 500 rpm. Mix for 3 minutes. Then, granules were prepared by adding ethanol while stirring at a speed of 500 rpm in the granulator. Then, the water was dried in a hot air dryer until 2% or less, and granules were formed into 18 mesh bodies in an oscillator.
  • the prosolve and the remaining amount of croscarmellose sodium were added and mixed firstly.
  • Sodium stearyl fumarate was added and mixed for 2 minutes to prepare a final mixture.
  • the final mixture was compressed into tablets by compression tablet press to prepare rectangular tablets.
  • Tablets were prepared in the same manner as in Example 27 except that the spray-dried mannitol was further added when the hard silicic anhydride was added.
  • a tablet was prepared in the same manner as in Example 28, except that croscarmellose sodium was further added in the same manner as the addition of crospovidone.
  • tablets were prepared in the same manner as in Example 27, except that hydrochlorothiazide was further added when the telmisartan potassium salt was added.
  • telmisartan potassium salt After mixing telmisartan potassium salt, amlodipine besylate, 1/2 part of hard silicic anhydride and 1/2 part of spray-dried mannitol, it is passed through a 20 mesh sieve, and magnesium oxide, microcrystalline cellulose, and crospovidone are passed through a high-speed mixing granulator. The mixture was mixed at 500 rpm for 3 minutes. Then, granules were prepared by adding ethanol while stirring at a speed of 500 rpm in the granulator. Then, the water was dried in a hot air dryer until 2% or less, and granules were formed into 18 mesh bodies in an oscillator.
  • Prosolve TM croscarmellose sodium, potassium chloride
  • the remaining amount of hard silicic anhydride and spray-dried mannitol were mixed firstly, sodium stearyl fumarate was added, and mixed for 2 minutes to prepare a final mixture.
  • the final mixture was compressed into tablets by compression tablet to prepare a rectangular tablet.
  • a tablet was prepared in the same manner as in Example 31, except for magnesium oxide.
  • Tablets were prepared in the same manner as in Example 32, except for potassium chloride.
  • Tablets were prepared in the same manner as in Example 31, except that magnesium stearyl acid was added instead of sodium stearyl fumarate.
  • telmisartan potassium salt and amlodipine complex preparation 1,000 tablets were prepared in a two-layer tablet.
  • Example 38 Example 39
  • Example 40 Example 41
  • Example 42 1) first floor Telmisartan Potassium (Tel. K) 91.1 91.1 40.5 40.5 91.1
  • Magnesium oxide 20.0 40.0 20.0 20.0 20.0 Potassium chloride 10 10 10 10 10 Spray drying mannitol 20 20 20 20 20 Microcrystalline cellulose 110.9 90.9 115.9 115.9 110.9 Croscarmellose sodium 20.0 20.0 20.0 20.0 20.0 Crospovidone 20.0 20.0 20.0 20.0 20.0 Sodium stearyl fumarate 4.00 4.00 4.00 4.00 4.00 4.00 2) two-story Amlodipine Besylate 6.94 6.94 13.88 - Hydrochlorothiazide - - - - 12.5 Light anhydrous silicic acid 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Pro Solve Easy Tab 67.06 67.06 63.06 56.06 61.5 Croscarmellose sodium 20.0 20.0 20.0 20.0 Sodium stearyl fum
  • telmisartan potassium salt spray-dried mannitol, magnesium oxide, potassium chloride, microcrystalline cellulose, and croscarmellose sodium in Table 8 were placed in a high speed mixing granulator and mixed at 500 rpm for 3 minutes. Then, granules were prepared by adding ethanol while stirring at a speed of 500 rpm in the granulator. Then, the water was dried in a hot air dryer until 2% or less, and granules were formed into 18 mesh bodies in an oscillator. Crospovidone was added to the granulated granules, followed by primary mixing.
  • telmisartan potassium salt amlodipine besylate, spray-dried mannitol for 5 minutes in a content as shown in Table 9, and then passed through a 20 mesh sieve, potassium chloride, magnesium oxide, Prosolve TM , croscarmellose sodium was added and further mixed for 5 minutes.
  • Magnesium stearyl acid was passed through a 40 mesh sieve and mixed for 2 minutes to obtain a final mixture. The final mixture was compressed by the total amount of tablets per tablet with a compression tableting machine to prepare a rectangular tablet.
  • Example 43 Comparative Example 1 Telmisartan Potassium (Tel. K) 91.9 91.1 Amlodipine Besylate 6.94 6.94 Magnesium oxide 40.0 - Potassium chloride 5.0 - Prosolve 98.0 98.0 Spray drying mannitol 80.0 80.0 Croscarmellose sodium 25.0 25.0 Magnesium Stearyl Acid 3.0 3.0 Total amount of tablets per tablet (mg) 349.84 304.04
  • telmisartan / amlodipine complex formulation Tweensta TAB, 80/5 mg was set as Comparative Example 2.
  • Example 43 and Comparative Example 1 were eluted at a rate of 50 revolutions in 900 mL of the pH 1.2, pH 4.0, and pH6.8 elution test solutions according to the second method of the KEPCO dissolution test method, followed by telmisar
  • the result of measuring the dissolution rate of the potassium potassium salt is shown in FIG.
  • composition and method according to the present invention can be prepared using a relatively small amount of excipients compared to the conventional telmisartan single agent, can reduce the size of the tablet when administered, and when preparing a complex containing another compound The method can be facilitated and improved in terms of manufacturing time and cost.
  • it is possible to provide a telmisartan potassium salt-containing composition which can maintain stability even in a general packaging material by remarkably improving the hygroscopicity of the product, which is a problem of the existing formulation.

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Abstract

La présente invention concerne une composition pharmaceutique contenant un sel de potassium de telmisartan, qui est un antagoniste du récepteur de l'angiotensine II, et un procédé de préparation associé. La présente invention peut fournir une forme de granule ou de poudre d'une formulation solide présentant une dissolution et une stabilité de médicament meilleures d'une formulation contenant du telmisartan, et un procédé de préparation de gélules et de comprimés la contenant. Aussi, la composition et le procédé de préparation selon la présente invention sont des techniques avancées sur le plan industriel qui permettent une préparation très facile du telmisartan en tant que composant unique ou agent composite combiné avec d'autres diurétiques ou autres composants lié à la pression artérielle élevée, par rapport à une composition pharmaceutique contenant du telmisartan ou des sels de celui-ci, ce qui permet d'obtenir des améliorations significatives en termes de temps et de coût de production. La taille d'une formulation posologique peut également être considérablement réduite par rapport aux formulations classiques, ce qui permet d'améliorer l'observance thérapeutique de patients prenant la formulation pendant une longue période de temps. En outre, la présente invention peut fournir une composition contenant un sel de potassium de telmisartan qui est capable d'améliorer considérablement l'hygroscopicité d'un produit, ce qui a été un problème des formulations existantes, et de maintenir la stabilité dans les matériaux d'emballage classiques.
PCT/KR2016/002743 2015-03-20 2016-03-18 Composition pharmaceutique comprenant un sel de potassium de telmisartan et procédé de préparation associé WO2016153222A2 (fr)

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WO2021148347A1 (fr) * 2020-01-20 2021-07-29 Zakłady Farmaceutyczne POLPHARMA S.A. Comprimé bicouche comprenant du telmisartan et de l'amlodipine

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CN101039917A (zh) * 2004-10-15 2007-09-19 特瓦制药工业有限公司 制备替米沙坦的方法
SI22297A (sl) * 2006-06-23 2007-12-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Priprava soli telmisartana
CN104958273B (zh) * 2009-05-27 2017-10-13 株式会社茶山医化 含有泡腾层的多层片
KR101171375B1 (ko) * 2010-01-20 2012-08-13 한올바이오파마주식회사 난용성 약물을 함유하는 경구 제형
KR101302883B1 (ko) * 2012-07-23 2013-09-05 삼일제약주식회사 텔미사르탄을 유효성분으로 포함하는 안정성이 증가된 약제학적 조성물 및 그 제조방법

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021148347A1 (fr) * 2020-01-20 2021-07-29 Zakłady Farmaceutyczne POLPHARMA S.A. Comprimé bicouche comprenant du telmisartan et de l'amlodipine

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