WO2016153222A2 - Pharmaceutical composition comprising potassium salt of telmisartan, and preparation method therefor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing a potassium salt of telmisartan, which is an angiotensin II receptor antagonist, and a preparation method therefor. The present invention can provide a granule or powder form of a solid formulation with improved drug dissolution and stability of a telmisartan-containing formulation, and a method for preparing capsules and tablets containing the same. Also, the composition and preparation method according to the present invention are industrially advanced techniques which allow for very easier preparation of telmisartan as a single component or a composite agent combined with other diuretics or high blood pressure-related components compared to a pharmaceutical composition containing telmisartan or salts thereof, thereby achieving significant improvements in terms of production time and cost. The size of a dosage formulation can also be significantly reduced compared to conventional formulations, thereby enhancing medication compliance of patients taking the formulation for a long period of time. In addition, the present invention can provide a composition containing a potassium salt of telmisartan which is capable of significantly improving hygroscopicity of a product, which has been a problem of existing formulations, and maintaining stability in typical packing materials.

Description

Pharmaceutical composition comprising telmisartan potassium salt and method for preparing same

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.

As described in WO 03/059327, 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.

In addition, in order to improve the dissolution rate of the poorly soluble drug telmisartan, it is often prepared in an amorphous form to increase the dissolution rate. In this case, amorphous is very unstable in terms of stability compared to crystalline, which is likely to cause stability problems. Specifically, 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. . In addition, Korean Patent Application Publication No. 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. In the case of using a strong basic base having deliquescent properties, the tablet may be exposed to moisture due to an increase in hygroscopicity, or may be easily wetted and melted and sticky.

In order to solve such a problem, the Republic of Korea Patent No. 10-0960953, Republic of Korea Patent No. 10-1302883, Republic of Korea Patent No. 10-1446603, etc. in the modification of the manufacturing method or using a different basic base solubility or hygroscopic It was intended to improve. However, improvements such as solubility of telmisartan and hygroscopicity of the formulation may not be sufficient, and such limited solubility of the free acid may make it difficult to achieve process simplification of the formulation. In the Republic of Korea Patent No. 10-0929502 has been trying to overcome the existing problems by preparing a crystalline telmisartan sodium salt that does not have a problem in the solubility of the active material, there is a problem that the improvement of stability is not sufficient.

On the other hand, in the field of hypertension drugs, 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. For example, 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.

In addition, the most important point in the development of the combination is that there should be no drug-drug interactions clinically, and that the drug-drugs should have no or minimal chemical interactions. It has been reported that telmisartan and CCB class drugs or diuretic class drugs have no clinically interactive drug interactions. However, in the development of telmisartan as an oral combination with a 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. In order to improve this, International Patent Application No. PCT / EP2002 / 000395 discloses a tablet having a bilayer structure in which telmisartan and hydrochlorothiazide are contained in different layers, and 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.

In addition, 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.

Therefore, the 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.

It is a further object of the present invention to provide a method for preparing such pharmaceutical composition without the use of complicated instruments or methods.

In order to achieve the above object,

Based on composition total weight

15-70% by weight of telmisartan potassium salt and

It provides a pharmaceutical composition comprising telmisartan potassium salt comprising a potassium salt stabilizer 0.2 to 30% by weight.

According to one embodiment, 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.

According to one embodiment, the pharmaceutical composition may further comprise one or more components selected from excipients, disintegrants and lubricants.

In addition, according to one embodiment, 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.

Therefore, 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.

According to another embodiment, 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.

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.

1 and 2 show photographs comparing the sizes of the commercially available telmisartan and amlodipine complex formulations with the formulations according to Example 27.

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. FIG.

As the invention allows for various changes and numerous embodiments, particular embodiments will be illustrated in the drawings and described in detail in the written description. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all transformations, equivalents, and substitutes included in the spirit and scope of the present invention. In the following description of the present invention, if it is determined that the detailed description of the related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.

Hereinafter, 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.

In the prior art, deliquescent basic ingredients such as sodium hydroxide or meglumine, which are added to elute the poorly soluble telmisartan in free acid form in the body at pH conditions, are generally administered in combination with telmisartan, for example, Difficulty in mixing with calcium channel blockers, diuretics, antihypertensives, other angiotensin receptors and salts thereof, or may cause pharmaceutical stability.

In addition, 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.

In addition, when preparing a combination formulation containing diuretics, calcium channel antagonists, etc., due to the solubility of telmisartan, various excipients and solubilizing agents have to be used. Difficult to manufacture, due to the production of a multi-layered tablet containing each active ingredient, the production is complicated and the yield may be reduced.

In addition, in the packaging, 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.

In the present invention, in order to improve the conventional problems, 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. In addition, telmisartan in the form of potassium salt may exhibit superior properties in terms of stability than telmisartan in the form of sodium salt. In addition, 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.

In the present invention, 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. In order to overcome the above problems, 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. Can play a role. In addition, as a material for continuously maintaining the properties of the potassium salt, for example, 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 As a function that can prevent the formation of a light may include a hard silicic anhydride, glyceryl behenate (Glyceryl Behenate) and the like. These antigelling agents can be effective when used in 0.2 to 30% by weight based on the total weight of the composition. When 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.

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. 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.

According to one embodiment, other 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.

Such 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.

In addition, according to one embodiment, as 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.

According to one embodiment of the present invention, a drug that can be administered in combination with telmisartan, which is the first drug substance, may further include a second drug agent.

As 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.

According to one embodiment, 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.

According to one embodiment, 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.

According to one embodiment, 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.

Specifically, to prepare granules comprising telmisartan potassium salt and a potassium salt stabilizer, obtaining a granule comprising one or more of the following steps a to d:

a) spray-drying to obtain spray dried granules,

b) fluid bed granulation to obtain granules,

c) obtaining granules by Wet granulation,

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. To prepare a single-layer tablets; can be prepared through further.

According to one embodiment, 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.

According to the above method, 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. . In addition, the inclusion of telmisartan in the form of crystalline potassium salt can overcome the stability and pharmaceutical technical difficulties.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily practice the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.

Examples 1-8

According to the content and composition of Table 1, 1,000 tablets of 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).

Ingredient / Unit mg Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 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 Magnesium oxide 20.0 20.0 30.0 40.0 - - - - Polypyrrolidone - - - 5.0 - - - - Spray drying mannitol 100.0 100.0 20.0 15.0 100.0 100.0 100.0 100.0 Prosolve 45.0 50.0 41.0 45.0 60.0 40.0 - 40.0 Microcrystalline cellulose 18.9 18.9 113.9 108.9 38.9 38.9 58.9 38.9 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 stearyl fumarate 5.0 5.0 4.0 5.0 5.0 5.0 5.0 5.0 Total amount of tablets per tablet (mg) 340 345 350 370 365 375 315 355

Example 1

First, 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.

Example 2

According to the composition of Table 1, a tablet was prepared in the same manner as in Example 1 except for changing the contents of potassium chloride and prosolve.

Example 3

Tablets were prepared in the same manner as in Example 1 except that croscarmellose sodium was further added in the same manner as crospovidone.

Example 4

Tablets were prepared in the same manner as in Example 1, except that polypyrrolidone was further added when mixing potassium chloride.

Example 5

Tablets were prepared in the same manner as in Example 1 except that magnesium oxide and hard silicic anhydride were not added.

Example 6

Tablets were prepared in the same manner as in Example 5, except that croscarmellose sodium was further added.

Example 7

Tablets were prepared in the same manner as in Example 5 except that prosolve and crospovidone were not added.

Example 8

Tablets were prepared in the same manner as in Example 5 except for changing the contents of potassium chloride, prosolve and crospovidone.

Examples 9-12

According to the content and composition of Table 2 below, 1,000 tablets of telmisartan potassium salt formulations were prepared.

Ingredient / Unit mg Example 9 Example 10 Example 11 Example 12 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 Sodium stearyl fumarate 5.0 5.0 5.0 5.0 Total amount of tablets per tablet (mg) 350 360 360 360

Example 9

First, 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. until the loss on drying was less than 2%, and granules were formed into 18 mesh sieves using an oscillator. The remaining granules were added with the remaining amount of hard silicic anhydride, crospovidone, and croscarmellose sodium, and 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.

Example 10

Tablets were prepared as in Example 9 except for potassium chloride and light silicic anhydride.

Example 11

Except for precipitated calcium carbonate, tablets were prepared in the same manner as in Example 9 except that magnesium carbonate was further added during precipitation of precipitated calcium carbonate.

Example 12

Tablets were prepared as in Example 1 except for potassium chloride and croscarmellose sodium.

Examples 13-17

According to the content and composition of Table 3, 1,000 tablets of telmisartan potassium salt formulations were prepared as tablets using a dry granulation method.

Ingredient / Unit mg Example 13 Example 14 Example 15 Example 16 Example 17 Telmisartan Potassium Salt 91.10 91.10 91.10 91.10 91.10 Magnesium oxide 60.00 - 20.00 20.00 40.00 Potassium chloride - 40.00 10.00 5.00 - Polypyrrolidone 5.00 5.00 5.00 5.00 5.00 Prosolve 98.00 98.00 118.00 98.00 98.00 Spray drying mannitol 80.00 80.00 80.00 80.00 80.00 Croscarmellose sodium 25.00 25.00 25.00 25.00 25.00 Light anhydrous silicic acid - 10.00 - - - Magnesium Stearate: 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

Example 13

First, 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.

Example 14

A tablet was prepared in the same manner as in Example 13 except that hard silicic anhydride was added except for magnesium oxide.

Example 15

Tablets were prepared in the same manner as in Example 13, except that potassium chloride was further added when telmisartan potassium salt was added.

Example 16

Tablets were prepared in the same manner as in Example 15, except that the contents of potassium chloride and prosolve were changed.

Example 17

Tablets were prepared in the same manner as in Example 16, except for potassium chloride.

Examples 18-21

According to the content and composition of Table 4, the formulation was prepared by a wet granulation method using a telmisartan potassium salt fluidized bed granulator of 1,000 tablet scale.

Ingredient / Unit mg Example 18 Example 19 Example 20 Example 21 Telmisartan Potassium (Tel. K) 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 4.0 Sodium stearyl fumarate 5.0 5.0 - - Total amount of tablets per tablet (mg) 375.0 365.0 373.1 373.1

Example 18

First, 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. until the loss on drying was 2% or less, and the granules were formed into 18 mesh bodies using an oscillator. The remaining granules were added with the remaining amount of croscarmellose sodium and mixed 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.

Example 19

Tablets were prepared in the same manner as in Example 18, except that magnesium oxide was further added when potassium chloride was added.

Example 20

Except for potassium chloride, microcrystalline cellulose, light silicic anhydride, and sodium stearyl fumarate, additional polar green potassium and prosolve were added when spray-dried mannitol was added, and crospovidone was added in the same manner as the croscarmellose sodium addition method, stearyl Tablets were prepared in the same manner as in Example 19, except that magnesium stearate was added instead of sodium fumarate.

Example 21

Except for polar green potassium, tablets were prepared in the same manner as in Example 20 except for further adding potassium alginate when spray-dried mannitol was added.

Examples 22-25

According to Table 5 below, tablets were prepared using a wet granule manufacturing method of telmisartan potassium salt formulation of 1,000 tablets.

Ingredient / Unit mg 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

Example 22

First, 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.

Example 23

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.

Example 24

Tablets were prepared in the same manner as in Example 22, except that croscarmellose sodium was added instead of crospovidone.

Example 25

Except for light silicic anhydride, tablets were prepared in the same manner as in Example 22, except that glyceryl bicarbonate was added to the light silicic anhydride.

Examples 26-30

According to the content and composition of Table 6, 1,000 tablets of telmisartan potassium salt and amlodipine complex preparation, telmisartan potassium salt and hydrochlorothiazide complex preparation were prepared.

Ingredient / Unit mg 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 6.94 - Hydrochlorothiazide - - - - 12.5 Magnesium oxide 20.0 20.0 40.0 20.00 10.0 Potassium chloride - 10.0 10.0 15.00 20.0 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 Light anhydrous silicic acid 6.0 5.0 5.0 10.0 - Sodium stearyl fumarate 4.96 5.0 5.0 5.0 5.0 Total amount of tablets per tablet (mg) 340.0 350.0 350.0 360.00 340.0

Example 26

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. In the granulated granules, 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.

Example 27

Except for spray-dried mannitol, additional potassium chloride was added when magnesium oxide was added, granules were formed into 18 mesh sieves in an oscillator, followed by addition of prosolve, and crospovidone instead of croscarmellose sodium. Tablets were prepared in the same manner.

Example 28

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.

Example 29

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.

Example 30

Except for amlodipine besylate and light silicic anhydride, tablets were prepared in the same manner as in Example 27, except that hydrochlorothiazide was further added when the telmisartan potassium salt was added.

Examples 31-37

According to the content and composition shown in Table 7, 1,000 tablets of telmisartan potassium salt and amlodipine complex preparations were prepared.

Ingredient / Unit mg Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 Example 37 Telmisartan Potassium (Tel. K) 91.1 91.1 91.1 91.1 91.1 91.1 45.55 Amlodipine Besylate 6.94 6.94 6.94 6.94 6.94 6.94 13.88 Magnesium oxide 30.0 - - 20 40 30.0 15.0 Potassium chloride 10.0 5 10 - - 10.0 5.0 Pro cellosolve ^TM 34.06 34.06 34.06 34.06 34.06 32.06 17.56 Spray drying mannitol 20.0 20.0 20.0 20.0 20.0 20.0 11.84 Microcrystalline cellulose 113.9 145.9 140.9 130.9 110.9 113.9 64.53 Croscarmellose sodium 20.0 20.0 20.0 20.0 20.0 20.0 11.33 Crospovidone 10.0 10.0 10.0 10.0 10.0 10.0 5.67 Light anhydrous silicic acid 10.0 10.0 10.0 10.0 10.0 10.0 5.67 Sodium stearyl fumarate 7.00 7.00 7.00 7.00 7.00 - - Magnesium Stearyl Acid - - - - - 6.00 3.98 Total amount of tablets per tablet (mg) 353.0 350.0 350.0 350.0 350.0 350.0 200.0

Example 31

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. In the granulated granules, 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.

Examples 32 and 33

A tablet was prepared in the same manner as in Example 31, except for magnesium oxide.

Examples 34 and 35

Tablets were prepared in the same manner as in Example 32, except for potassium chloride.

Examples 36 and 37

Tablets were prepared in the same manner as in Example 31, except that magnesium stearyl acid was added instead of sodium stearyl fumarate.

Examples 38-42

According to the content and composition of Table 8, 1,000 tablets of telmisartan potassium salt and amlodipine complex preparation, telmisartan potassium salt and hydrochlorothiazide complex preparation were prepared in a two-layer tablet.

step Ingredient / Unit mg 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 2) two-story Amlodipine Besylate 6.94 6.94 6.94 13.88 - Hydrochlorothiazide - - - - 12.5 Light anhydrous silicic acid 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 20.0 Sodium stearyl fumarate 4.00 4.00 4.00 4.00 4.00 Total amount of tablets per tablet (mg) 400.0 400.0 350.4 350.3 400.0

Example 38

1) One layer of 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. Sodium stearyl fumarate was added thereto, followed by mixing for 2 minutes to prepare a single-crystal final mixture. 2) Among the components of the second layer, amlodipine besylate, hard silicic anhydride, and prosolvevtab were mixed and passed through a 20 mesh sieve, followed by mixing croscarmellose sodium, followed by mixing for 2 minutes with sodium stearyl fumarate. A positive final mixture was prepared. In the first layer, the final mixture of 1) of Table 8 was placed in the hopper using a double-layer tablet press, and the final mixture of 2) in Table 8 was administered to the hopper in the second layer, and then compressed by one tablet with a double-layer tablet compression tablet press. Prepared as rectangular tablets.

Examples 39-41

It was prepared in the same manner as in Example 36 except that each component of the content shown in Table 8 was used.

Example 42

It was prepared in the same manner as in Example 38 except that hydrochlorothiazide was added instead of amlodipine besylate.

Example 43, Comparative Examples 1 and 2

Example 43

After 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.

Comparative Example 1

Except for potassium chloride and magnesium oxide was prepared in the same manner as in Example 43.

Ingredient / Unit mg 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

Comparative Example 2

A commercially available telmisartan / amlodipine complex formulation, Tweensta TAB, 80/5 mg was set as Comparative Example 2.

Test Example 1: Tablet Size Comparison

As shown in Figures 1 and 2, comparing the size of the commercial twin star tablet 80 / 5mg according to the present invention Example 27, it can be seen that the formulation of the present invention is much smaller.

Test Example 2: Dissolution Rate Evaluation

The tablets of 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.

According to the results of FIG. 3, it can be seen that the dissolution rate of the tablet of Example 43 is superior to the tablet of Comparative Example 1.

4 is a result of evaluating the dissolution rate for the tablets of Comparative Examples 1 and 2 and the Examples 34 and 35 tablets to which 20 mg and 40 mg of magnesium oxide as a potassium salt stabilizer were added, respectively.

5 is a result of evaluating the dissolution rate for the tablets of Comparative Example 1 and Comparative Example 2 and the tablets of Examples 32 and 33 to which 5 mg and 10 mg of potassium chloride as a potassium salt stabilizer were added, respectively.

As can be seen in the results of Figures 4 and 5, it can be seen that the dissolution rate of the telmisartan tablet according to the present invention is improved compared to Comparative Examples 1 and 2.

The 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. In addition, 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.

The specific parts of the present invention have been described in detail above, and it should be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (14)

Based on composition total weight 15-70% by weight of telmisartan potassium salt and A pharmaceutical composition comprising telmisartan potassium salt comprising from 0.2 to 30% by weight of a potassium salt stabilizer. The method of claim 1, Pharmaceutical composition comprising telmisartan potassium salt wherein the potassium salt stabilizer comprises at least one from the group consisting of potassium salt adjuvant or anti-gelling agent. The method of claim 2, The gelling agent comprises telmisartan potassium salt selected from magnesium carbonate, sodium carbonate, magnesium oxide, calcium carbonate, sodium phosphate, magnesium phosphate, hard silicic anhydride, glyceryl behenate and combinations thereof. Pharmaceutical compositions. The method of claim 2, The potassium salt adjuvant includes potassium acesulfame, potassium polyacryline, 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 Pharmaceutical composition comprising telmisartan potassium salt which is at least one selected from the group consisting of potassium. The method of claim 1, A pharmaceutical composition comprising telmisartan potassium salt further comprising at least one component selected from excipients, disintegrants and glidants. The method of claim 1, A pharmaceutical composition comprising telmisartan potassium salt further comprising at least one second active ingredient selected from diuretics, calcium channel blocker hypertension, angiotensin 1 convertase inhibitors, and angiotensin receptor blockers. The method of claim 1, Pharmaceutical composition comprising telmisartan potassium salt wherein the second active ingredient comprises 1 to 50% by weight based on the total weight of the composition. The method of claim 6, Pharmaceutical composition comprising telmisartan potassium salt for the treatment of hypertension. A capsule comprising the pharmaceutical composition according to any one of claims 1 to 8. Tablets comprising the pharmaceutical composition according to any one of claims 1 to 8. The tablet according to claim 10, which is a monolayer or multilayer tablet. A method for preparing a tablet by direct tableting using the pharmaceutical composition according to any one of claims 1 to 8. A method for preparing a capsule, wherein the pharmaceutical composition according to any one of claims 1 to 8 is granulated by spray drying, fluidized bed granulation, wet granulation, or dry granulation to fill the capsule. The pharmaceutical composition according to any one of claims 1 to 8 is granulated by spray drying, fluidized bed granulation, wet granulation, or dry granulation, followed by mixing and tableting with a pharmaceutically acceptable additive. Method of making tablets.

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