KR20130056818A - Single-layer tablet formulation for combinations comprising telmisartan - Google Patents

Abstract

PURPOSE: A telmisartan composite formulation is provided to ensure high stability despite a single layer tablet and to enable packaging in various methods. CONSTITUTION: A composite formulation for anti-hypertension contains telmisartan and one or more of other anti-hypertension agents selected among an ACE inhibitor, an angiotensin receptor blocker, a calcium channel blocker, and diuretics. The composite formulation contains telmisartan which is adsorbed to an aluminum silicate compound. The aluminum silicate compound is magnesium aluminometasilicate. The composite formulation for anti-hypertension contains telmisartan and the aluminum silicate compound in a weight ratio of 1:0.2-1. The diuretics are hydrochlorothiaxide. The calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

Description

Single-layered composite formulation containing telmisartan {SINGLE-LAYER TABLET FORMULATION FOR COMBINATIONS COMPRISING TELMISARTAN}

The present invention relates to a complex formulation comprising telmisartan, which may be prepared as a monolayer tablet.

Due to the influence of Western diet and the environment, the population of hypertensive patients grows every year, reaching about 1 billion, and it is predicted that the number will exceed 1.5 billion by 2025.

In proportion to the explosive increase in hypertension patients, the market for hypertension drugs is growing rapidly. Currently, the market for hypertension medicine forms about 10% of the global drug market, and the market size is about 42 trillion won.

Existing antihypertensive agents include ACE (Angiotensin-Converting Enzyme) inhibitors, Angiotensin Receptor Blockers (ARBs), and Calcium Channel Blockers (CCBs).

In addition, diuretics that promote sodium ion release and relieve cardiovascular contraction may be used in combination.

ACE inhibitors mitigate cardiovascular contraction by prematurely blocking the formation of angiotensin causing vasoconstriction, angiotensin receptor blockers relieve cardiovascular contractions by interfering with the action of angiotensin, and calcium channel blockers inhibit the influx of calcium ions to prevent cardiovascular In a manner that alleviates contraction, each acts to suppress blood pressure rise.

The JNC-7 Report, a global guideline for diagnosing and treating hypertension, emphasizes strict blood pressure control by simplifying blood pressure classification criteria in four stages. In particular, hypertensive patients are given two or more medications to control their blood pressure. Says it is necessary.

In general, since the angiotensin receptor blocker is expressed in full swing after 4 weeks, it is desirable to co-administer other types of drugs to control blood pressure of hypertensive patients from the beginning of the administration.

In particular, in the absence of other comorbid diseases, combination therapy with thiazide diuretics is recommended.

As the combination therapy of two or more drugs is recommended, in the hypertension drug market, a combination drug is preferred to a single agent in recent years, and in the market scale, the single drug market is decreasing and the combination drug market is gradually expanding (“hypertension”). 'Combination-Single System' Rare Crossover ", Daily Newspaper Medical Newspaper, June 29, 2012, http://www.bosa.co.kr/umap/sub.asp?news_pk=185979, August 13, 2012 ).

Angiotensin receptor blockers (ARBs) are telmisartan, valsartan, olmesartan, losarartan, candesartan, irbesartan, eprosar Eprosartan.

However, among these ARB drugs, telmisartan has been shown to have a cardiovascular protective effect, according to a TRANSCEND clinical study published at the European Society of Cardiology (Munich, Germany).

In addition, Park Rae Woong (2012), “Comparison of Hyperkalemic Risk in Hospitalized Patients Treated with Different Angiotensin Receptor Blockers: A Retrospective, has shown a lower risk of hyperkalemia side effects than other angiotensin receptor blockers. Cohort Study Using a Korean Clinical Research Database ”, American Journal of Cardiovascular Drugs), and among the existing ARB drugs, telmisartan is considered to be the best drug.

Combination products containing telmisartan are available from Boehringer Ingelheim's Mycardis Plus ^® (combination of telmisartan and hydrochlorothiazide) and the company's Twinstar ^® (combination of telmisartan and amlodipine). It is gaining great boom in the market.

In addition, the conventional technique regarding a telmisartan composite agent can also be understood with reference to following patent document 1-patent document 2 (therefore, all the content of patent document 1-patent document 2 is incorporated in the content of this specification as a prior art document. do).

Patent Literature 1 discloses a first layer formulated for the instantaneous release of angiotensin II receptor antagonist telmisartan from a soluble tablet matrix and a formulation formulated for the instantaneous release of amlodipine, a calcium channel blocker from a disintegrating or erosive tablet matrix. A two-layer tablet of telmisartan and amlodipine containing two layers is disclosed.

Patent document 2 relates to a pharmaceutical composition containing telmisartan and hydrochlorothiazide, specifically, a first coating with a mixture containing polyvinylpyrrolidone as an inert water-soluble polymer in a telmisartan core Secondary coating with a mixture of hydrochlorothiazide and polyvinylpyrrolidone, which are diuretic in the stomach, can have an excellent dissolution rate of diuretic, and the size and weight of the pharmaceutical composition is much smaller than that of conventional commercially available preparations. Since it is easy, it discloses the two-layer tablet which can be used more effectively for the medical industry.

As can be seen from the patent literature regarding the commercially available telmisartan complex or telmisartan complex, the telmisartan complex is currently made only of a double-layer tablet, that is, a pH In the physiological pH range of the gastrointestinal tract of 1 to 7, it is due to the use of strong alkalizing agents such as sodium hydroxide to increase the solubility of telmisartan, which is characterized by very low solubility in aqueous systems.

Strong basic substances, such as sodium hydroxide, absorb moisture in the air and dissolve themselves, ie, have strong deliquescent properties, and as a result, telmisartan preparations are deliquescent, and in the case of telmisartan tablets, a few hours after opening It will not melt and will cause a big problem in chemical storage stability.

In addition, strong alkalis may lead to softening of the second medicinal component other than telmisartan, causing problems in formulation stability.

In order to solve these problems, studies on a method of coating and blending components other than telmisartan have been attempted, but another problem arises in that the dissolution rate is lowered due to the gel formation properties of the coated components (Patent Documents). See Background 2).

WO publication 2006/048208 (2006.05.11.) KR Registration 10-1010325 B1 (2011.01.25.)

As described above, the conventional telmisartan composite agent has a problem in that a soft substance of hydrochlorothiazide is generated due to the alkali hydroxide and a strong alkalizing agent of an alkali component that acts as a solubilizer in telmisartan, and elution of each component. Because of the pattern problem, it was necessary to take the form of a bilayer tablet.

However, double tablets require expensive equipment such as double tableting machines in manufacturing, yields of about 80-90%, low production yields, and two to three times the working time compared to single-layer tablets. There is a problem that is very high.

Accordingly, the present invention is to provide a telmisartan composite formulation, which can be prepared in a single layer, to solve the above problems.

The present invention has been made to solve the above problems of the prior art,

In an antihypertensive complex formulation comprising telmisartan and at least one other antihypertensive agent selected from ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, telmisartan and other antihypertensive agents are included together in the same layer The present invention provides an antihypertensive complex preparation characterized in that telmisartan is adsorbed on an aluminum silicate compound.

In addition, in the present invention, telmisartan adsorbed on the aluminum silicate compound provides an antihypertensive complex preparation, characterized in that the granulated.

In the present invention, the aluminum magnesium silicate compound provides an antihypertensive complex preparation, characterized in that the magnesium metasilicate aluminate.

In the present invention, the telmisartan: aluminum magnesium silicate compound = 1: provides an antihypertensive complex preparation, characterized in that contained in a weight ratio within the range.

In addition, in the present invention, the diuretic agent provides an antihypertensive complex preparation, characterized in that the hydrochlorothiazide.

In addition, in the present invention, the calcium channel blocker provides an antihypertensive complex preparation, characterized in that amlodipine or a pharmaceutically acceptable salt thereof.

Even if the telmisartan composite formulation of the present invention is prepared in a single layered tablet, there is no problem in dissolution of each component, and no softening material is generated so that the stability is very high. In addition, since the stability to moisture is high, various packaging methods such as PE bottles and PTP packaging are possible in the packaging of tablets. In addition, since it can be simply manufactured by a single stroke method, there is an effect of reducing the manufacturing cost and time.

1 is a photograph showing the results of leaving room temperature for 2 days in the deliquescent experiments of Examples and Comparative Examples.
Fig. 2 is a photograph showing the result of the accelerated two-day standing in the deliquescent experiments of Examples and Comparative Examples.

The present invention enjoys the priority benefit of the 10-2011-0122362 application filed with the Korean Patent Office on November 22, 2011, and the content of the 10-2011-0122362 application filed to the Korean Patent Office is All content is quoted as content on this specification within the range which is not arrange | positioned with the content.

Hereinafter, the present invention will be described in detail.

According to the present invention,

In an antihypertensive complex formulation comprising telmisartan and at least one other antihypertensive agent selected from ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics,

Telmisartan is adsorbed on the aluminum silicate compound,

It relates to an antihypertensive complex preparation characterized in that telmisartan and other antihypertensive agents are included together in the same layer.

In particular, the present invention is characterized in that telmisartan and other antihypertensive agents are not included in different layers, but included in the same layer, unlike the conventional invention.

According to the prior art, when telmisartan and other antihypertensive agents are included in the same layer, there is a problem in that the tablets themselves melt due to the strong alkalinity of the solubilizer of telmisartan, or due to softening or deliquescent.

The prior art has solved this problem by making a multi-layered tablet which is a tablet having a first layer containing telmisartan and a second layer containing another antihypertensive agent, that is, a tablet having two or more layers.

However, as described above, double tablets require expensive equipment, have low yields, and have a long process time, so that production is degraded and production costs are drastically increased.

Accordingly, the inventors of the present application have found that when telmisartan dissolved in a strong alkaline solubilizer is adsorbed to an aluminum silicate compound, even if it is prepared as a single layer crystal, it does not cause a soft material or a deliquescent problem. Reached.

Included together in the same layer means that telmisartan and other antihypertensive agents are not isolated in tablets in the form of the core and its coating, and telmisartan and the other term in the form of a multi-layered tablet such as double tablets. It is to say that a hypertensive agent is not isolate | separated (the prior art and meaning with respect to a double well can be understood with reference to patent document 1-patent document 2 of the prior art mentioned above).

That is, the inclusion in the same layer means that, on the monolayer side of the tablet, it is not partitioned as a region where only telmisartan exists as a main component and only another antihypertensive agent as a main component, Tells us that telmisartan and other antihypertensive agents are present at the same time.

In particular, the present invention is characterized in that telmisartan and other antihypertensive agents are included together in the same layer, but substantially includes a layer containing telmisartan as a main component, or substantially another antihypertensive agent as a main component. Layers may be further provided, but not excluded (ie, the present invention is merely characterized by having layers comprising telmisartan and other antihypertensive agents which the prior art could not realize, In addition, it does not exclude the further inclusion of another additional layer).

In the present invention, the telmisartan may be adsorbed to the aluminum magnesium silicate compound by placing the aluminum magnesium silicate compound and the excipient in a high speed coalescing unit or a fluidized bed granulator and associating with telmisartan at high speed. The present invention is not limited thereto, and the adsorption method that is obvious to those skilled in the art (hereinafter, referred to as a person skilled in the art) can be used without limitation without departing from the object of the present invention.

The term 'telmisartan' includes not only telmisartan itself, which is a pharmacologically active ingredient, but also a pharmaceutically acceptable salt of telmisartan or an isomer of telmisartan.

The aluminum magnesium silicate compound is a compound in which silica (SiO ₂ ), aluminum oxide (Al ₂ O ₃ ), and magnesium oxide (MgO) are mixed. It is intended to include all of the various types of compounds present. Representative examples thereof include magnesium aluminosilicate, magnesium aluminometasilicate, magnesium aluminum silicate, and the like. For a more detailed definition and content of this, see USP34 NF 29, The United States Pharmacopoeia, Aug. 01, 2011, pp. 1568-1570, which is hereby incorporated by reference as a part of the disclosure.

In addition, telmisartan adsorbed on the aluminum silicate compound is preferably granulated after being mixed with an excipient, a binder, a disintegrant, or other additives in terms of lowering the possibility of interference with other antihypertensive agents, but is not necessarily limited thereto. It doesn't happen.

The aluminum magnesium silicate compound may be one that is magnesium metasilicate aluminate, and telmisartan: aluminum magnesium silicate compound = 1: 1: It is suitably included in the weight ratio within the range of 0.2 ~ 1. If the amount of the aluminum magnesium silicate compound is too high out of the above range, it is easy to adsorb the telmisartan solution, but the dissolution rate may be lowered, and the size of the tablet may increase, which may cause inconvenience when taking. have. On the contrary, if the amount of the aluminum magnesium silicate compound is too small out of the above range, it may be difficult to adsorb the telmisartan solution, making the manufacturing difficult, and the initial dissolution rate may be too large.

The type of the ACE inhibitor is not particularly limited, and non-limiting examples include captopril, enalapril, quinapril, ramipril, lysinopril, and benase Benzepril and fosinopril.

The type of angiotensin receptor blocker (ARB) is not particularly limited, and non-limiting examples include telmisartan, valsartan, olmesartan, losarartan, candesartan ( candesartan, irbesartan, eprosartan.

The type of the calcium channel blocker (CCB) is not particularly limited, and as a non-limiting example, nifedipine, nimodipine, nisoldipine, felodipine, amlodipine, darodipine, floridipine, lasidipine, isradipine, nigul Dipine, niludipine, oxadipine, elgodipine, riodipine, nilvadipine, lemdipine, nitrendipine, nicardipine, verapamil, diltiazem and flunarizine, among which amlodipine is preferred. Do.

The type of diuretic is not particularly limited, and examples thereof include, but are not limited to, chlorothiazide, hydrochlorothiazide, furosemide, bumetanide, spironolactone, and triamterin ( triamterene), of which hydrochlorothiazide is preferred.

Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are merely for the purpose of detailed description of the invention and are not intended to limit the scope of the claims thereby.

Example

Example  One - Telmisartan  And Hydrochlorothiazide  Composite

(1) Preparation of Telmisartan Granules

Telmisartan was prepared by dissolving telmisartan in an aqueous sodium hydroxide solution in which sodium hydroxide was dissolved in purified water.

Magnesium aluminate, mannitol, microcrystalline cellulose, calcium carboxymethyl cellulose, colloidal silicon oxide were added to a high speed coalescing machine, and the telmisartan solution prepared above was added and mixed.

After the association was dried and sieved to 25 mesh, carboxymethyl cellulose calcium, colloidal silicon oxide, and sodium stearyl fumarate were added to the formulation and mixed.

Compounded ingredients and ratios were as shown in Table 1 below.

(2) Preparation of Hydrochlorothiazide Granules

Povidone was dissolved in purified water to prepare a binding solution.

Hydrochlorothiazide, mannitol, and crospovidone were added to the high speed coalescing unit, and the above-mentioned binder solution was added and combined.

The association was dried and sieved to a 25 mesh sieve, sodium stearyl fumarate was added thereto, and mixed.

(3) Preparation of tablets

The telmisartan granules and the hydrochlorothiazide granules were mixed and compressed into tablets.

Example  2 - Telmisartan  And Hydrochlorothiazide  Composite

(1) Preparation of Telmisartan Granules

It was prepared in the same manner as in Example 1.

(2) hydrochlorothiazide mixture

Hydrochlorothiazide and mannitol were added to the mixer in the same formulation as in Table 3 and mixed.

(3) Preparation of tablets

The telmisartan granules and the hydrochlorothiazide mixture were mixed and compressed into tablets.

Example  3 - Telmisartan  And Amlodipine besylate  Composite

(1) Preparation of Telmisartan Granules

It was prepared in the same manner as in Example 1.

(2) amlodipine besylate mixtures

Amlodipine besylate and mannitol were mixed in a mixer as shown in Table 4 below.

(3) Preparation of tablets

The telmisartan granules and the amlodipine besylate mixture were mixed and then compressed in a tablet press.

Comparative example

Comparative example  One - Telmisartan  And Hydrochlorothiazide  Composite

Commercially available Mikradis Plus tablets 80 / 12.5 mg ^TM (Manufacturing / importing: Boehringer Ingelheim Korea, Ingredient name: Hydrochlorothiazide 12.5mg, Telmisartan 40mg)

Comparative example  2 - Telmisartan  And Amlodipine besylate  Composite

Commercially available twin-star tablets 80 / 5mg ^TM (manufacture / import: Boehringer Ingelheim Korea, amlodipine besylate 13.87mg, telmisartan 40mg)

Experimental Example

1. Dissolution test

  (1) elution test conditions

    -Eluent: pH 1.2 solution (1st solution of disintegration test method of the Korean Pharmacopoeia)

     pH 4.0 solution (KFDA 2011-57 pH 4.0 acetate buffer solution)

     pH6.8 solution (2nd solution of disintegration test method of the Korean Pharmacopoeia General Test Methods)

     Water solution (purified water)

    Elution temperature: 37 ℃

    Paddle rotation speed: 50 rpm

    Under the above experimental conditions, each of the six specimens, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60, 90, 120, 180 minutes (pH 1.2 liquid 120 minutes, pH 4.0 liquid 180 minutes, pH6.8 liquid and water solution up to 45 minutes), the eluate was collected and filtered to obtain a sample solution. Separately, 89 mg of telmisartan standard and 14 mg of hydrochlorothiazide were precisely weighed, dissolved in 0.1 mol / L sodium hydroxide solution, and methanol was added to make 100 ml. 10 ml of this solution was taken as the eluent and used as the standard solution.

    -Detector: UV-visible spectrophotometer (wavelength: 270nm)

    Mobile phase: pH6.0 phosphate buffer: acetonitrile = 50: 50

    pH6.0 Phosphate Buffer: A solution made up to 1000 mL by dissolving 7.87 g of sodium dihydrogen phosphate monohydrate and 2.86 g of sodium dihydrogen phosphate dihydrate in water.

    Column: C18, 4.6 × 150 mm, 5 μm or equivalent column

    Flow rate: 1 ml / min

    -Column temperature: 35 ℃

    Injection volume: 10µl

(2) Experimental results

Table 5 shows the dissolution rate of hydrochlorothiazide of Comparative Example 1.

Table 6 shows the dissolution rate of telmisartan of Comparative Example 1.

Table 7 below shows the dissolution rate of amlodipine besylate of Comparative Example 2.

Table 8 below shows the dissolution rate of telmisartan of Comparative Example 2.

Table 9 below shows the dissolution rate of hydrochlorothiazide of Example 1.

Table 10 below shows the dissolution rate of telmisartan of Example 1.

Table 11 below shows the dissolution rate of amlodipine besylate of Example 3.

Table 12 below shows the dissolution rate of telmisartan of Example 3.

In Example 1 and Example 3, it was confirmed that telmisartan elutes the telmisartan elution individual deviation quickly and rapidly in a pH 1.2 solution. T _max of telmisartan can be problematic in the event of deviation of the object from 0.5 to 1.5 hours.

The dissolution rate of hydrochlorothiazide in Example 1 tends to be somewhat slow due to the characteristics indicated by the change from double tablet to monolayer tablet, but during the bioequivalence test, the T _max of hydrochlorothiazide is 2 hours, so the dissolution pattern Delays of 10 to 15 minutes are not a problem. Hydrochlorothiazide eluted within 30 minutes.

Also, in the case of amlodipine, since the T _max of the amlodipine besylate is 6 to 12 hours, the delay of about 10 to 15 minutes on the dissolution pattern is not a problem. Amlodipine besylate eluted within 30 minutes.

Both Example 1 and Example 3 showed a final dissolution rate of at least 85% in all solutions except pH 4.0.

2. Leading material experiment

  (1) About Example 1

For Example 1, the materials were stored at accelerated (40 < 0 > C, 75% RH) according to USP, Telmisartan and Hydrochlorothiazide tablets and packed in HDPE bottle.

The results were as in Table 13 below.

Accelerated (40 ℃, 75% RH) storage, Alu-bag packaging was tested for a flexible material, the results were as shown in Table 14.

  (2) About Example 3

Experimental Method

-Sample solution: 2 tablets of Yellow No. 1 in a 100 mL flask, add 5 mL of 0.1N NaOH, and shake to disintegrate. After disintegration, add 80 mL of methanol, ultrasonically treat for 10 minutes, and shake for 30 minutes to extract. Adjust the temperature to room temperature and adjust the temperature to 100 mL with methanol. 10 mL of this solution is diluted to 50 mL with diluent solution.

-Standard Solution: 160 mg of telmisartan and 28 mg of amlodipine besylate are precisely weighed and dissolved in a 100 mL flask. 10 mL of this solution is diluted to 50 mL with diluent solution.

-Diluent Buffer: Solution = 1: 1

-Buffer: A solution of 2.0g ammonium dihydrogen phosphate dissolved in 1L water and adjusted to pH3.0 with phosphoric acid

Solution: Acetonitrile: Methanol =: 1: 1

-Detector: UV-visible spectrophotometer (Telmisartan: 298nm, Amlodipine besylate: 237nm)

Column: C18, 4.6 × 150 mm, 5 μm or equivalent column

Flow rate: 1 ml / min

-Column temperature: 40 ℃

Injection volume: 10µl

Acceleration (40 ℃, 75% RH) storage for Example 3, HDPE bottles (bottle) packaging and the result of the flexible material was as shown in Table 15.

For Example 3, accelerated (40 ° C., 75% RH) storage, packaging in an aluminum bag (Alu-bag), the flexural material test results were as shown in Table 16 below.

3. Detoxification Experiment

Comparative Example 1 and Example 1 were left unpacked at room temperature to perform deliquescent experiments.

FIG. 1 is a photograph showing the result after 2 days of room temperature, and FIG. 2 is a photograph showing the result after 2 days of acceleration.

In both FIG. 1 and FIG. 2, from the left side of a photograph, the comparative example 1 (initial stage: 0 hours left) is performed before the comparative example 1 after 2 days of leaving, and the comparative example 1 after 2 days of leaving, and after 2 days of leaving. Example 1 is the order.

As can be seen in Figures 1 and 2, the comparative example shows the deliquescent property and the tablet melts, whereas in the case of the example did not show the deliquescent property, showed excellent storage stability.

Claims (6)

In an antihypertensive complex formulation comprising telmisartan and at least one other antihypertensive agent selected from ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics,
Telmisartan is adsorbed on the aluminum silicate compound,
Antihypertensive complex formulation, characterized in that telmisartan and other antihypertensive agents are included together in the same layer. The antihypertensive complex preparation according to claim 1, wherein the telmisartan adsorbed on the aluminum silicate compound is granulated. The antihypertensive complex preparation according to claim 1, wherein the aluminum magnesium silicate compound is magnesium metasilicate aluminate. The antihypertensive complex preparation according to claim 1, wherein the telmisartan: aluminum magnesium silicate compound is contained in a weight ratio within the range of 1: 0.2 to 1. The antihypertensive complex preparation according to claim 1, wherein the diuretic is hydrochlorothiazide. The antihypertensive complex formulation of claim 1, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

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