WO2019098540A1

WO2019098540A1 - Formulation having improved hygroscopic property and dissolution rate comprising telmisartan or its pharmaceutically acceptable salt

Info

Publication number: WO2019098540A1
Application number: PCT/KR2018/012191
Authority: WO
Inventors: Dong Jin Lee; Min Kwan Cho; Shin Jung Park; Jong Lae Lim
Original assignee: Chong Kun Dang Pharmaceutical Corp.
Priority date: 2017-11-15
Filing date: 2018-10-16
Publication date: 2019-05-23
Also published as: KR102066832B1; KR20190055471A; TWI734046B; PH12020550597A1; MY196892A; TW202026000A; TW201922242A; SG11202001460TA

Abstract

The present invention relates to a pharmaceutical formulation having improved hygroscopic property and dissolution rate, comprising telmisartan or its pharmaceutically acceptable salt. Specifically, the present invention relates to a tablet comprising telmisartan or its pharmaceutically acceptable salt as an active ingredient, characterized in comprising a high dose of the active ingredient and having a property close to a circular shape. Further, the present invention relates to a pharmaceutical combination comprising a first layer comprising telmisartan or its pharmaceutically acceptable salt; and a second layer comprising (S)-amlodipine or its pharmaceutically acceptable salt, characterized in that the combination has 1:1 to 1:1.6 of a ratio of the short axis to the long axis.

Description

FORMULATION HAVING IMPROVED HYGROSCOPIC PROPERTY AND DISSOLUTION RATE COMPRISING TELMISARTAN OR ITS PHARMACEUTICALLY ACCEPTABLE SALT

The present invention relates to a stable formulation comprising telmisartan or its pharmaceutically acceptable salt. Specifically, the present invention relates a tablet comprising telmisartan or its pharmaceutically acceptable salt as an active ingredient, characterized in comprising a high dose of the active ingredient and having a property close to a circular shape, wherein the tablet has improved hygroscopic property and dissolution rate.

Hypertension refers to a condition in which the blood pressure above the normal range is persistently observed. Hypertension may cause a variety of complications to finally result in death. Hypertension is classified as either primary hypertension or secondary hypertension based on the cause of elevated blood pressure. Primary hypertension is essential hypertension in which the cause of elevated blood pressure is unknown while secondary hypertension refers to the one in which blood pressure is elevated as a result of a specific disease or illness. Secondary hypertension can be treated by identifying the causes of elevated blood pressure. However, pharmacotherapy based on several anti-hypertensive mechanisms is being used to treat patients suffering from primary hypertension, because the cause of primary hypertension, which accounts for about 95% of total hypertension, is not clearly known.

Drugs commonly used in the treatment of hypertension largely include vasodilators, diuretics, and sympatholytic agents depending on the mechanism of action. Vasodilators as currently widely used are divided into, depending on the mechanism of action, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (hereinafter, "ARB"), and a calcium channel blocker (hereinafter, "CCB").

In hypertension, rather than treating blood pressure itself, it is important to maintain blood pressure within the normal range to prevent cardiovascular complications such as stroke, renal failure and coronary artery diseases including heart failure and myocardial infarction, etc. As such, the constant and patient control of the blood pressure is important. Since antihypertensive drugs should be taken over a long period, the treatment agent should cautiously be chosen. Thus, for the purpose of the constant treatment, drugs having different mechanisms should be combined rather than selecting just single drug, so that a better preventive and therapeutic effect is exerted. Further, any side effects that may be caused by drug administration for a long time should be reduced by a combination therapy allowing to decrease the amount of each drug.

In particular, a combination therapy of ARB and CCB in which each mechanism of action is different in the human body is first selected as a combination therapy available in case of the failure of the blood pressure control using a single therapy. This is because the pharmacological actions of the two drugs for lowering blood pressure are different. As such, not only does the combination therapy of the two drugs exert an effective effect for lowering blood pressure, but also it can reduce the used amount of the drug, so that the side effect of each ingredient can greatly be reduced.

Telmisartan, as one of ARB, is currently sold in the market under the trade name of Micardis in the dosage of 20 mg, 40 mg, and 80 mg. Telmisartan is prescribed against essential hypertension where it selectively acts on angiotensin II receptors acting as a strong vasoconstrictor in the renin-angiotensin-aldosterone system, especially AT1 receptors involved in the main physiological action including vasoconstriction.

Despite the excellent effect of telmisartan, conventional medicaments containing telmisartan is disadvantageous in that it is highly hygroscopic to provoke a deterioration of the product when exposed to moisture in the air. As such, the deterioration during distribution and storage should be prevented through blister packaging made of aluminum. However, bulky aluminum blister packages are inconvenient to carry. Further, the medicinal drug may be deteriorated in case of the damage of the packaging during storage and transportation.

Telmisartan is featured in having very poor solubility in water in which physiological pH ranges from 1 to 7. As such, in a formulation design, it is preferable to use with an alkaline agent for solubility improvement and solubilization. In this case, if exposed to moisture or administered, it become hygroscopic, and the tablet often turns into being sticky or melted.

Increasing the amount of excipients including calcium silicate to solve the problem results in an increase in the volume of the tablet and in the ratio of the long axis to the short axis of the tablet, whereby the tablet is easily broken.

Therefore, the inventors have accomplished the present invention to provide a high dose tablet having improved hygroscopic property and dissolution rate as well as not being easily broken, when formulating a tablet comprising telmisartan or its pharmaceutically acceptable salt as an active ingredient.

In order to achieve the above objective, the present invention provides a tablet comprising telmisartan or its pharmaceutically acceptable salt as an active ingredient wherein a high dose of the active ingredient is comprised based on the total weight of the tablet and the ratio of the long axis to the short axis is reduced to have a property close to a circular shape.

In Micardis comprising telmisartan as an active ingredient as currently sold in the market, the amount of the active ingredient accounts for about 17% of the total weight of the tablet.

The present invention provides a high dose tablet comprising about at least of 20 wt%, preferably, the range of 25 wt% to 30 wt% of telmisartan based on the total weight of the tablet.

Further, the present invention provides a tablet having a property close to a circular shape by confirming that the smaller the ratio of the long axis to the short axis of the tablet is, the lower the degree of breakage of the tablet is. Accordingly, the present invention provides a tablet wherein the ratio of the short axis to the long axis ranges from 1:1 to 1:1.6.

The tablet of the present invention comprises calcium silicate in order to improve hygroscopic property of telmisartan. As amount of calcium silicate increase, volume of tablet increases. Further, it is difficult to maintain the property of the tablet being a circular shape. As such, in the tablet of the present invention, the weight ratio between telmisartan or its pharmaceutically acceptable salt and calcium silicate is 10:0.5 to 10:5.

Further, the present invention may further comprise a disintegrating agent in order to improve dissolution rate of the tablet. The disintegrating agent may include, but is not limited to, at least one selected from the group consisting of low substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, and sodium starch glycolate. Low substituted hydroxypropyl cellulose may preferably be comprised as the disintegrating agent of the present invention.

Further, the present invention may comprise 3 to 15 wt% of low substituted hydroxypropyl cellulose based on the total weight of the tablet, so that the tablet exerts the improved effect in the disintegration and dissolution of the active ingredient.

Additionally, the present invention may be a pharmaceutical combination comprising a first layer comprising telmisartan or its pharmaceutically acceptable salt; and a second layer comprising another pharmacologically active ingredient.

The present invention provides a pharmaceutical combination comprising a first layer comprising telmisartan or its pharmaceutically acceptable salt; and a second layer comprising another pharmacologically active ingredient, characterized in that telmisartan or its pharmaceutically acceptable salt is comprised in at least 20 wt% based on the total weight of the first layer, and the combination has 1:1 to 1:1.6 of a ratio of the short axis to the long axis.

The pharmacologically active ingredient can be prepared in a combination with telmisartan or its pharmaceutically acceptable salt, which includes, but is not limited to, as a treatment agent of hypertension, atenolol, metoprolol, nadolol and pindolol as a beta receptor blocker; amlodipine, nifedipine, nicardipine, and verapamil as CCB; enalapril, captopril, and ramipril as an ACE inhibitor; losartan and candesartan as ARB; and the like.

Preferably, the first layer comprising telmisartan or its pharmaceutically acceptable salt may further comprise calcium silicate.

More preferably, the first layer comprising telmisartan or its pharmaceutically acceptable salt may further comprise low substituted hydroxypropyl cellulose.

Additionally, the present invention may be a bilayered tablet consisting of a first layer comprising telmisartan or its pharmaceutically acceptable salt; and a second layer comprising (S)-amlodipine or its pharmaceutically acceptable salt.

The bilayered tablet or multi-layered tablet of the present invention has a property close to a circular shape, so that a possibility of the layer separation and breakage of the tablet is low.

The formulation of the present invention comprises a high dose of an active ingredient and has a property close to a circular shape, whereby having good pharmaceutical properties being not only improved hygroscopic property, stability and dissolution rate, but also a low possibility of breakage of the tablet.

Further, the bilayered tablet or multi-layered tablet of the present invention has a low possibility of the layer separation and breakage of the tablet, so that the preparation and storage are advantageously easy.

Fig. 1 depicts the hygroscopic property of the telmisartan tablet depending on the amount of calcium silicate.

Fig. 2 depicts the dissolution rate of the telmisartan depending on the amount of low substituted hydroxypropyl cellulose.

"Telmisartan" according to the present invention refers to a compound called as a chemical name of 2-(4-{[4-methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid, i.e., a compound of the following formula 1:

[Formula 1]

Telmisartan used in the present invention may be commercially sold or synthesized by a method known in the art, which is not limited thereto.

Telmisartan according to the present invention may be used in different forms including a free acid of telmisartan or its pharmaceutically acceptable salt, isomer, racemate, hydrate, and solvate as long as the equivalent pharmacological activity is maintained.

The pharmaceutically acceptable salt includes a salt derived from a pharmaceutically acceptable acid or base. A "pharmaceutically acceptable salt" according to the present invention refers to any and all organic or inorganic addition salts in a concentration exerting a relatively non-toxic and innocuous effective action in a patient where a side effect resulting from the salt does not decrease a beneficial effect of the pharmacological active ingredient.

Preferably, the pharmaceutically acceptable salt of telmisartan according to the present invention may be, but is not limited to, a sodium salt, a potassium salt, a magnesium salt, and a calcium salt.

More preferably, the pharmaceutical formulation of the present invention includes a free acid of telmisartan.

Telmisartan is primarily used as an agent for treating essential hypertension where it selectively acts on angiotensin II receptors acting as a strong vasoconstrictor in the renin-angiotensin-aldosterone system, especially AT1 receptors involved in the main physiological action such as vasoconstriction. Since telmisartan constantly exhibits anti-hypertensive effect for 24 hours, the blood pressure-controlling effect of a drug administered the day before maintains even the next morning when the blood pressure is sharply increased. Further, since the renal excretion rate is less than 2%, the dose adjustment is not required for patients suffering from mild and even severe renal failure.

"(S)-amlodipine" according to the present invention refers to a compound called as a chemical name of 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, i.e., a compound of the following formula 2:

[Formula 2]

(S)-amlodipine used in the present invention may be commercially sold or synthesized by a method known in the art, which is not limited thereto.

(S)-amlodipine according to the present invention may be used in different forms including a free base of (S)-amlodipine or its pharmaceutically acceptable salt, isomer, racemate, hydrate, and solvate as long as the equivalent pharmacological activity is maintained.

Preferably, the pharmaceutically acceptable salt of (S)-amlodipine according to the present invention may include, but is not limited to, (S)-amlodipine besylate, (S)-amlodipine maleate, (S)-amlodipine orotate, (S)-amlodipine camsylate, (S)-amlodipine adipate, or (S)-amlodipine mesylate.

More preferably, the pharmaceutical combination of the present invention includes (S)-amlodipine besylate.

Amlodipine, as one type of CCB, having 30 to 50 hours of a half-life, is a very useful calcium channel blocker exhibiting an activity very consistently over a long period. Amlodipine blocks calcium influx into vascular smooth muscle to lead to peripheral arterial vasodilation, whereby lowering blood pressure, as well as being effective for vasospastic angina.

Amlodipine is a chiral compound having a chiral center. (S)-enantiomer of amlodipine as a strong calcium channel blocker is known as exerting a higher activity than a mixture of the enantiomers (racamate) (Arrowsmith et al., J. Med. Chem., 29, 1696 (1986)). The activity of (R)-enantiomer is 1000 times lower than (S)-enantiomer while kinin-mediated nitrogen oxide mechanism is observed as presumed as being related to a side effect (Hintze et al., J. Cardiovasc. Pharmacol., 39(2):208-14 (2002)).

Thus, once (S)-amlodipine separated as a pure enantiomer is administered, a selectivity to the receptor binding is higher than the amlodipine racemates while the dosage can be lowered in half. Therefore, there is an advantage that the possibility of drug interaction and side effects can be lowered.

The tablet of the present invention may further comprise at least one pharmaceutically acceptable excipients. The excipient may be a conventional excipient as known in the art unless it interacts with telmisartan or its pharmaceutically acceptable salt and disrupts a medicinal effect.

For example, the pharmaceutically acceptable excipient may be, but is not limited to, at least one selected from the group consisting of a diluent, a binder, a disintegrating agent, a glidant, and a coating agent.

The "diluent" according to the present invention refers to an inactive substance used as a filter to provide a desired bulk, fluidity, and compressibility when preparing a solid dosage form. For example, the diluent may be, but is not limited to, lactose hydrate, anhydrous lactose, sucrose, corn starch, anhydrous dibasic calcium phosphate, or dibasic calcium phosphate hydrate.

The "binder" according to present invention refers to a substance to provide elasticity and adhesion so that a strength of a formulation as formed, especially, a tablet as formed is increased. For example, the binder may be, but is not limited to, carboxymethyl cellulose-sodium (CMC-Na), starch paste, polyvinyl pyrrolidone (PVP), gum arabic, or hydroxypropyl cellulose (HPC).

The "disintegrating agent" according to the present invention refers to a substance used to accelerate the disintegration of a solid form so that an active ingredient exerting the medicinal effect is released from the form within a short time. For example, as the disintegrating agent, carboxymethyl cellulose calcium (CMC-Ca), crospovidone, sodium starch glycolate, croscarmellose sodium, or low-substituted hydroxypropyl cellulose may be used without limitation.

The "glidant" according to the present invention is a substance with which improved flowability is provided to a formulation. For example, as the glidant, colloidal silica, magnesium stearate, stearic acid, talc, or sodium stearyl fumarate may be used without limitation.

In one embodiment according to the present invention, the pharmaceutical combination of the present invention may be a solid formulation for oral administration. Preferably, the pharmaceutical combination of the present invention is a bilayered tablet.

In another embodiment according to the present invention, a process for preparing a single agent comprising telmisartan or a combination comprising telmisartan and (S)-amlodipine is provided. The pharmaceutical single agent and combination of the present invention can be prepared as a tablet, etc., by using a preparation process known to skilled in the art, for example, a wet granulation, a direct compression, a dry granulation, etc.

Hereinafter, a better understanding of the present invention may be obtained through the following experimental examples and examples which are set forth to illustrate, but are not to be construed as the limitation of the present invention. The following examples are merely provided to explain in details to those skilled in the art.

[Experimental Example 1]

Experiment on breakage of a telmisartan tablet depending on the ratio of the short axis to the long axis of the tablet

Prepare tablets of Examples 1 to 6 comprising telmisartan as an active ingredient where the composition is as described in [Table 1] and the ratio of the short axis to the long axis is as described in [Table 2].

[Example 1 to 6] Preparation of a tablet comprising telmisartan

Telmisartan, dried sodium carbonate, povidone, and yellow iron oxide were added into water, heated, stirred, and dissolved, to prepare a first binding solution. Separately, calcium silicate was added into water and homogenously stirred to prepare a secondary binding solution. Microcrystalline cellulose was introduced into a fluidized bed granulator to be fluidized, followed by spraying the first binding solution and the secondary binding solution sequentially to prepare a granule, which was dried, the dried materials being sized by using the co-mill sizing machine. The sized materials were sieved into 30 mesh, followed by introducing sodium stearyl fumarate and mixing the same to prepare the granulation mixture of telmisartan. By using a tableting machine, the tablets (Examples 1 to 6) were prepared wherein each has 1:1, 1:1.3, 1:1.5, 1:1.6, 1:1.7, or 1:1.8 of the ratio of the short axis to the long axis.

Ingredients	mg/tablet
Telmisartan
	80
Microcrystalline cellulose	169.84
Dried sodium carbonate	30
Povidone	20
Yellow iron oxide	0.16
Calcium silicate	4
Sodium stearyl fumarate	6
Total weight	310

The tablets of Examples 1 to 6 prepared above were subjected to a free fall drop test in the following manner.

90 tablets are packed in high density polyethylene (HDPE) bottles where each bottle includes 30 tablets. The drop test was carried out ten times at a position of 1 m above a flat and solid floor. After the drop test, the bottle was opened to determine whether the tablet was broken or not wherein as the test conditions, a room temperature (1 to 30°C) and up to 75% of relative humidity were kept. The rate where the tablet is broken was measured. The measurement results are shown in [Table 2].

Example	Ratio of the short axis to the long axis	Tablet breakage rate(%)	Result
1	1:1	None	Conformed
2	1:1.3	None	Conformed
3	1:1.5	None	Conformed
4	1:1.6	None	Conformed
5	1:1.7	3.3% (3/90)	Non-conformed
6	1:1.8	5.6% (5/90)	Non-conformed

As shown in [Table 2] above, the tablets of Examples 1 to 4 were not broken and the durability was increased. Further, the breakage rate(%) of the tablet increased as the ratio of the long axis to the short axis increased.

Thus, it was confirmed that a possibility of the tablet breakage is reduced as the ratio of the short axis to the long axis is closer to 1:1.

[Experimental Example 2]

Experiment on breakage of a combination tablet of telmisartan and amlodipine depending on the ratio of the short axis to the long axis of the tablet

Prepare tablets of Examples 7 to 12 comprising telmisartan and amlodipine as active ingredients where the composition is as described in [Table 3] and the ratio of the short axis to the long axis is as described in [Table 4].

[Example 7 to 12] Preparation of a tablet comprising telmisartan and amlodipine

Telmisartan, dried sodium carbonate, povidone, and yellow iron oxide were added into water, heated, stirred, and dissolved, to prepare a first binding solution. Separately, calcium silicate was added into water and homogenously stirred to prepare a secondary binding solution. Microcrystalline cellulose was introduced into a fluidized bed granulator to be fluidized, followed by spraying the first binding solution and the secondary binding solution sequentially to prepare a granule, which was dried, the dried materials being sized by using the co-mill sizing machine. The sized materials were sieved into 30 mesh, followed by introducing sodium stearyl fumarate and mixing the same to prepare the granulation mixture of telmisartan. Anhydrous dibasic calcium phosphate was added to (S)-amlodipine besylate to triturate, followed by adding microcrystalline cellulose, sodium starch glycolate, and sodium stearyl fumarate and mixing the same. The mixture was compacted and sieved by using a roller compactor equipped with a 16-mesh sieve to prepare granules, which was sized by the co-mill sizing machine. Microcrystalline cellulose was added into Blue No. 2 dye and pulverized, to triturate the dye. Microcrystalline cellulose, sodium starch glycolate, and anhydrous dibasic calcium phosphate were added into the sized granules and the dye-triturated mixture, and mixed, followed by introducing sodium stearyl fumarate sieved to 30 mesh and mixing the same, to prepare the granulation mixture of (S)-amlodipine. By using a tableting machine for the granulation mixture of telmisartan and the granulation mixture of (S)-amlodipine, the tablets (Examples 7 to 12) were prepared wherein each has 1:1, 1:1.3, 1:1.5, 1:1.6, 1:1.7, or 1:1.8 of the ratio of the short axis to the long axis.

Telmisartan layer
Ingredients	mg/tablet
Telmisartan
	80
Microcrystalline cellulose	169.84
Dried sodium carbonate	30
Povidone	20
Yellow iron oxide	0.16
Calcium silicate	4
Sodium stearyl fumarate	6
Total weight	310
Amlodipine layer
Ingredients	mg/tablet
(S)-amlodipine besylate ((S)-amlodipine)	7.38 (5.00)
Microcrystalline cellulose	115.07
Anhydrous dibasic calcium phosphate	20
Sodium starch glycolate	4.5
Blue No. 2 dye	0.45
Sodium stearyl fumarate	2.6
Total weight	150

The tablets of Examples 7 to 12 prepared above were subjected to a free fall drop test, so that the rate where the tablet is broken and the layers are separated was measured. The measurement results are shown in [Table 4].

Example	Ratio of the short axis to the long axis	Tablet breakage rate(%)	layer separation rate(%)	Result
7	1:1	None	None	Conformed
8	1:1.3	None	None	Conformed
9	1:1.5	None	None	Conformed
10	1:1.6	None	None	Conformed
11	1:1.7	3.3% (3/90)	2.2(2/90)	Non-conformed
12	1:1.8	5.6% (5/90)	3.3(3/90)	Non-conformed

As shown in [Table 4] above, the tablets of Examples 7 to 10 were not broken and no separation between the layers was found. As such, it was found that the durability was increased. Further, the breakage rate(%) of the tablet increased as the ratio of the long axis to the short axis increased.

[Experimental Example 3]

Experiment on hygroscopic property of a telmisartan tablet depending on the amount of calcium silicate

Prepare telmisartan tablets of Examples 13 to 17 in accordance with the preparation process described Experimental Example 1, provided that the composition is as described in [Table 5].

Ingredients	Example 13	Example 14	Example 15	Example 16	Example 17
Telmisartan	80 mg	80 mg	80 mg	80 mg	80 mg
Microcrystalline cellulose	164 mg	168 mg	170 mg	172 mg	174 mg
Dried sodium carbonate	30 mg	30 mg	30 mg	30 mg	30 mg
Povidone	20 mg	20 mg	20 mg	20 mg	20 mg
Calcium silicate	8 mg	6 mg	4 mg	2 mg	-
Sodium stearyl fumarate	8 mg	6 mg	6 mg	6 mg	6 mg
Total weight	310 mg	310 mg	310 mg	310 mg	310 mg
The weight ratio of telmisartan to calcium silicate	10:1	10:0.75	10:0.5	10:0.25	-

Hygroscopic property of the tablets of Example 13 to 17 prepared above was evaluated. As a specific method for evaluating hygroscopic property, each drug without any packaging was exposed to an accelerated condition (relative humidity: 75±5%, temperature: 40±2°C). After one day, the change of gloss and color of the tablet surface were observed.

The change of gloss and color as the result of evaluating hygroscopic property are shown in [Table 6] below. The change of property is shown in [Fig. 1].

	Example 13	Example 14	Example 15	Example 16	Example 17
Change of gloss	0	0	1	3	4
Change of color	0	0	0	2	3

As shown in [Table 6] above, few changes of gloss and color were observed in the tablets of Example 13 to 15. Further, as shown in [Fig. 1], few changes of property were also observed in the tablets of Example 13 to 15.

As such, the tablets of Example 13 to 15 exhibited few changes of gloss, color, and property. Accordingly, improved hygroscopic property was confirmed.

[Experimental Example 4]

Experiment on dissolution rate of a telmisartan tablet depending on the type of disintegrating agent

Prepare telmisartan tablets of Examples 18 to 21 in accordance with the preparation process described Experimental Example 1, provided that the composition is as described in [Table 7].

Ingredients	Example 18	Example 19	Example 20	Example 21
Telmisartan	80 mg	80 mg	80 mg	80 mg
Microcrystalline cellulose	154.5 mg	154.5 mg	154.5 mg	154.5 mg
Dried sodium carbonate	30 mg	30 mg	30 mg	30 mg
Povidone	20 mg	20 mg	20 mg	20 mg
Calcium silicate	4 mg	4 mg	4 mg	4 mg
Low substituted hydroxypropyl cellulose (LH-21) (w/w %)	15.5 mg(5%)	-	-	-
Croscarmellose sodium	-	15.5 mg(5%)	-	-
Crospovidone	-	-	15.5 mg(5%)	-
Sodium starch glycolate	-	-	-	15.5 mg(5%)
Sodium stearyl fumarate	6 mg	6 mg	6 mg	6 mg
Total weight	310 mg	310 mg	310 mg	310 mg

The　disintegration　times　of the tablets of　Examples　18 to 21　prepared above　were measured.　　　The　disintegration　time was measured in accordance with the disintegration test method included in the Korean Pharmacopeia　where a purified water was used as a disintegration medium and the temperature of the water　was kept at 37±2°C. The disintegration time was determined as the time period for which the tablets completely disappeared from the bottom of the　disintegrator.　The result of the disintegration time as measured is shown in [Table 8] below.

	Example 18	Example 19	Example 20	Example 21
Disintegration time	14 min.	26 min.	22 min.	20 min.

As shown in [Table 8] above, the tablet of Example 18 exerted the shortest disintegration time. As such, it was confirmed that low substituted hydroxypropyl cellulose is the most suitable disintegrating agent.

[Experimental Example 5]

Experiment on dissolution rate(%) of a telmisartan tablet depending on the amount of disintegrating agent

Prepare telmisartan tablets of Examples 22 to 24 in accordance with the preparation process described Experimental Example 1, provided that the composition is as described in [Table 9].

Ingredients	Example 22	Example 23	Example 24
Telmisartan	80 mg	80 mg	80 mg
Microcrystalline cellulose	160.7 mg	148.3 mg	142.1 mg
Dried sodium carbonate	30 mg	30 mg	30 mg
Povidone	20 mg	20 mg	20 mg
Calcium silicate	4 mg	4 mg	4 mg
Low substituted hydroxypropyl cellulose (LH-21) (w/w %)	9.3 mg(3%)	21.7 mg(7%)	27.9 mg(9%)
Sodium stearyl fumarate	6 mg	6 mg	6 mg
Total weight	310 mg	310 mg	310 mg

The dissolution rate depending on the unit time was measured on the tablets of Examples 18 and 22 to 24.

The dissolution rate was tested on the basis of Method II (paddle method) included in the Korean Pharmacopoeia. 900 mL of phosphate buffer (pH 7.5) was used as a dissolution medium, the dissolution temperature was 37±0.5°C, and the rotation speed was 75 rpm. Dissolution mediumwas taken out at 5, 10, 15, and 30 minutes after the dissolution started. The filtered solution was then used as a test solution, which was analyzed, with a standard solution, by using a liquid chromatograph to measure the dissolution rate.

The dissolution rate per hour is shown in [Fig. 2] and the dissolution rate for 30 minutes is shown in [Table 10].

	Example 22	Example 18	Example 23	Example 24
1	55.8	71.8	89.7	94.7
2	53.6	87.6	84.8	96.8
3	59.6	76.4	93.8	84.2
4	65.1	75.2	94.6	92.8
5	57.8	72.8	94.5	93.4
6	61.0	82.4	94.3	94.7
Average	58.8	77.7	92.0	92.8
Maximum	65	88	95	97
Minimum	54	72	85	84

As shown in [Table 10] above, the dissolution rate was elevated as the amount of low substituted hydroxypropyl cellulose increased. Example 24 containing 9 wt% of disintegrating agent showed the most superior dissolution rate.

Claims

A tablet comprising telmisartan or its pharmaceutically acceptable salt as an active ingredient, characterized in that the active ingredient is comprised in at least 20 wt% based on the total weight of the tablet and the tablet has 1:1 to 1:1.6 of a ratio of the short axis to the long axis.
The tablet according to Claim 1, characterized in that the active ingredient is comprised in a range from 25 wt% to 30 wt% based on the total weight of the tablet.
The tablet according to Claim 1, characterized in further comprising calcium silicate.
The tablet according to Claim 3, characterized in that the weight ratio of telmisartan or its pharmaceutically acceptable salt to calcium silicate is 10:0.5 to 10:5.
The tablet according to Claim 1, characterized in further comprising a disintegrating agent.
The tablet according to Claim 5, characterized in that the disintegrating agent is at least one selected from the group consisting of low substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, and sodium starch glycolate.
The tablet according to Claim 5, characterized in that the disintegrating agent is low substituted hydroxypropyl cellulose.
The tablet according to Claim 7, characterized in comprising 3 to 15 wt% of low substituted hydroxypropyl cellulose based on the total weight of the tablet.
A pharmaceutical combination comprising a first layer comprising telmisartan or its pharmaceutically acceptable salt; and a second layer comprising a pharmacologically active ingredient, characterized in that telmisartan or its pharmaceutically acceptable salt is comprised in at least 20 wt% based on the total weight of the first layer, and the combination has 1:1 to 1:1.6 of a ratio of the short axis to the long axis.
The pharmaceutical combination according to Claim 9, characterized in that the pharmacologically active ingredient is selected from the group consisting of atenolol, metoprolol, nadolol, pindolol, amlodipine, nifedipine, nicardipine, verapamil, enalapril, captopril, ramipril, losartan, and candesartan, and a pharmaceutically acceptable salt thereof.
The pharmaceutical combination according to Claim 9, characterized in that the pharmacologically active ingredient is (S)-amlodipine or its pharmaceutically acceptable salt.
The pharmaceutical combination according to Claim 9, characterized in that the first layer comprising telmisartan or its pharmaceutically acceptable salt further comprises calcium silicate.
The pharmaceutical combination according to Claim 9, characterized in that the first layer comprising telmisartan or its pharmaceutically acceptable salt further comprises low substituted hydroxypropyl cellulose.
The pharmaceutical combination according to Claim 9, characterized in that the combination is a bilayered tablet.