KR102066832B1 - Formulation having improved madescent and dissolution rate comprising Telmisartan or its pharmaceutically acceptable salt - Google Patents

Abstract

The present invention relates to pharmaceutical formulations having improved wettability and dissolution rate including telmisartan or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a tablet comprising a telmisartan or a pharmaceutically acceptable salt thereof as an active ingredient, the tablet comprising a high content of the active ingredient and having a shape of a tablet close to the original. . The present invention also provides a pharmaceutical co-formulation comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof and a second layer comprising (S) -amlodipine or a pharmaceutically acceptable salt thereof. The co-formulation relates to a pharmaceutical co-formulation, characterized in that the ratio of short axis to long axis is 1: 1 to 1: 1.6.

Description

Formulation having improved madescent and dissolution rate comprising Telmisartan or its pharmaceutically acceptable salt}

The present invention relates to a stable formulation comprising telmisartan or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a tablet comprising telmisartan or a pharmaceutically acceptable salt thereof as an active ingredient, the tablet comprising a high content of the active ingredient and having a shape of a tablet close to a circular shape. The tablets show improved hygroscopicity and dissolution rate.

Hypertension is a condition in which blood pressure is maintained above a normal range. Hypertension can lead to many complications and eventually death. Hypertension is classified into primary hypertension and secondary hypertension, depending on the cause of the increase in blood pressure. Primary hypertension is essential hypertension with no known cause of blood pressure elevation. Secondary hypertension is secondary hypertension in which blood pressure increases as a result of a specific disease or condition. Secondary hypertension can be treated by identifying the cause of the increase in blood pressure, but since primary hypertension, which accounts for about 95% of all hypertension, is not clear, the treatment of patients with primary hypertension has several mechanisms for lowering blood pressure. Based on drug therapy.

Drugs commonly used in the treatment of hypertension are broadly divided into vasodilators, diuretics, and sympathetic inhibitors depending on the mechanism of action of the drug, and currently widely used vasodilators, depending on the mechanism of action, are an angiotensin converting enzyme (ACE) inhibitor and angiotensin. II Receptor Blocker (ARB) and Calcium Channel Blocker (CCB).

It is important to keep your blood pressure in a normal range rather than to treat the blood pressure itself, so it is important to prevent cardiovascular complications such as coronary artery disease such as life-threatening stroke, heart failure and myocardial infarction, and kidney failure. It is important to control your blood pressure. As such, blood pressure medications are required to be taken for a long time, so be careful when selecting a therapeutic drug. Therefore, the combination of drugs with different mechanisms can be combined with each other, rather than selecting one drug for continuous treatment, resulting in better prophylactic and therapeutic effects, and reduced doses of a single drug in combination, resulting in long-term drug administration. It is necessary to reduce the side effects that are present.

In particular, in the case of a combination prescription of ARB and CCB with different mechanisms of action in the human body, it is selected first as a selective combination regimen when failure to control blood pressure through a single agent. The pharmacological action for lowering the blood pressure of the two drug groups is different, so that not only the effective blood pressure lowering effect when the two drug groups are used in combination, and because the amount of the drug can be reduced, the side effects of each component can be greatly reduced.

Telmisartan is one of the ARBs available in 20 mg, 40 mg and 80 mg doses under the trade name Micardis. Telmisartan is prescribed for essential hypertension and is an angiotensin II receptor that acts as a potent vasoconstrictor in the renin-angiotensin-aldostrerone system, particularly AT1 receptors involved in major physiological functions such as vasoconstriction. It is a drug that acts selectively.

Despite the excellent effect of telmisartan, the conventional drug containing telmisartan has a very high hygroscopic property, so that deterioration of the product occurs when exposed to moisture in the air. Through this, it prevents the deterioration in the distribution and storage process. Blister packaging of bulky aluminum is inconvenient to carry and has the potential of altering the drug due to packaging damage during storage and carrying.

Republic of Korea Patent Publication No. 10-2017-0032681 (Published March 23, 2017)

Telmisartan is characterized by very poor solubility in an aqueous system of pH 1 to 7, which is the physiological pH range of the gastrointestinal tract, and it is preferable to use an alkalizing agent when designing a formulation for improving solubility and solubilization. . In this case, when exposed to water or taken, moisture is often caused by sticky or melting tablets.

In order to solve this problem, when the amount of excipients including calcium silicate is increased, the tablet volume increases and the ratio of the long axis to the short axis of the tablet increases, which results in the tablet being easily broken.

Accordingly, the present inventors have completed the present invention to provide a high content of tablets having excellent hygroscopicity and dissolution rate and at the same time not easily broken when preparing telmisartan or a pharmaceutically acceptable salt thereof as an active ingredient. It was.

In order to achieve the above object, the present invention provides a tablet containing a telmisartan or a pharmaceutically acceptable salt thereof as an active ingredient, comprising a high content of the active ingredient based on the total weight of the tablet and The ratio of the major axis to the minor is reduced to give tablets with a near circular shape.

In the case of Mycardis, a commercial product using telmisartan as an active ingredient, the active ingredient content accounts for about 17% of the total weight of the tablet.

In this regard the present invention provides high content tablets in which the content of telmisartan relative to the total weight of the tablet is at least about 20% by weight, preferably 25% to 30% by weight.

In addition, by confirming that the smaller the ratio of the long axis to the short axis of the tablet, the lower the degree of breakage of the tablet, the present invention provides a tablet having a nearly circular shape. Accordingly, the present invention provides tablets in which the ratio of the short axis: long axis of the tablet is in the range of 1: 1 to 1: 1.6.

The tablet of the present invention contains calcium silicate to improve the humidity of telmisartan. At this time, since the volume of the tablet increases as the content of calcium silicate increases and it is difficult to maintain the shape of the tablet, the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof and calcium silicate in the tablet of the present invention is 10: 0.5 to 10: 5.

In addition, the present invention may further include a disintegrant to improve the dissolution rate of the tablet. The disintegrant may include one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, and sodium starch glycolate, but is not limited thereto. The disintegrant of the present invention may preferably include low-substituted hydroxypropyl cellulose.

In addition, the present invention may include 3 to 15% by weight of the low-substituted hydroxypropyl cellulose based on the total weight of the tablet, the tablet has the effect of improved disintegration and dissolution of the active ingredient

The present invention may also be a pharmaceutical co-formulation comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, and a second layer comprising another pharmacologically active ingredient.

The present invention provides a pharmaceutical combination comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof and a second layer comprising another pharmacologically active ingredient, wherein the telmisartan or a pharmaceutically acceptable salt thereof Possible salts are included in at least 20% by weight based on the total weight of the first layer, the co-formulations provide a pharmaceutical co-formation, characterized in that the ratio of the short axis and the long axis is 1: 1 to 1: 1.6.

The pharmacologically active ingredient may form a co-formulation with telmisartan or a pharmaceutically acceptable salt thereof, and beta receptor blockers such as atenolol, metoprolol, nadolol and pindolol as therapeutic agents for hypertension; Amlodipine, nifedipine, nicardipine and verapamil, which are CCBs; ACE inhibitors enalapril, captopril and ramipril; Including but not limited to, ARB rozatan and candesartan.

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

More preferably, the first layer comprising telmisartan or a pharmaceutically acceptable salt thereof may further comprise low-substituted hydroxypropylcellulose.

The present invention may also be a bilayer tablet consisting of a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, and a second layer comprising (S) -amlodipine or a pharmaceutically acceptable salt thereof.

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

The formulations of the present invention contain a high content of active ingredient and have a near-circular property, and thus have excellent pharmaceutical properties with excellent hygroscopicity, stability and dissolution rate and low probability of tablet breakage.

In addition, the two-layered or multi-layered tablets of the present invention have an advantage of easy manufacturing and storage due to the low possibility of layer separation and tablet breakage.

Figure 1 shows the humidity according to the content of calcium silicate of telmisartan tablet.
Figure 2 shows the dissolution rate according to the content of low-substituted hydroxypropyl cellulose of the telmisartan tablet.

“Telmisartan” in the present invention is 2- (4-{[4-methyl-6- (1-methyl-1H-1,3-benzodiazol-2-yl) -2-propyl-1H-1, As a compound which has 3-benzodiazol-1-yl] methyl} phenyl) benzoic acid as a chemical name, the compound of following General formula (1) is meant.

[Formula 1]

In the present invention, telmisartan may be used commercially, or may be synthesized by a method known in the art, but is not limited thereto.

The telmisartan of the present invention can be used in various forms such as telmisartan free acid or pharmaceutically acceptable salts, isomers, racemates, hydrates and solvates thereof as long as the equivalent pharmacological activity is maintained. It is possible.

Such pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable acids or bases. "Pharmaceutically acceptable salt" in the present invention is a concentration that has a relatively nontoxic and harmless effective action in a patient, and any organic or inorganic addition salt in which the side effects caused by this salt do not degrade the beneficial efficacy of the pharmacologically active ingredient. Means.

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

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

Telmisartan is primarily used to treat essential hypertension and is selective for the angiotensin II receptor, which acts as a potent vasoconstrictor in the renin-angiotensinaldostrerone system, particularly AT1 receptors involved in major physiological functions such as vasoconstriction. Is a drug that acts as a. Since telmisartan has a continuous blood pressure-lowering effect for 24 hours, it has a blood pressure control effect until the next morning when blood pressure rises by the effect of the drug taken the day before, and the renal excretion rate is less than 2%, mild and severe renal impairment The patient also has the advantage that no dose adjustment is required.

In the present invention, "(S) -amlodipine" is 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl- A compound having the chemical name of 3,5-pyridinedicarboxylate, means a compound represented by the following Chemical Formula 2:

[Formula 2]

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

(S) -Amlodipine of the present invention is a free base of (S) -Amlodipine or pharmaceutically acceptable salts, isomers, racemates, hydrates and solvates thereof as long as equivalent pharmacological activity is maintained It can be used in various forms.

The pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable acids or bases. "Pharmaceutically acceptable salt" in the present invention is a concentration that has a relatively nontoxic and harmless effective action for a patient, and any organic or inorganic addition salt in which the side effects caused by this salt do not degrade the beneficial efficacy of the pharmacologically active ingredient. Means.

Preferably, the pharmaceutically acceptable salts of (S) -amlodipine of the present invention are (S) -amlodipine besylate, (S) -amlodipine maleate, (S) -amlodipine orate, (S) -amlodipine camsylate , (S) -amlodipine adipate or (S) -amlodipine mesylate, but is not limited thereto.

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

Amlodipine is one of the CCBs and is a very useful calcium channel blocker with a half-life of 30 to 50 hours and a very long lasting activity. Amlodipine is effective in lowering blood pressure and blocking angina due to convulsive vasoconstriction by blocking calcium inflow into vascular smooth muscle and inducing peripheral artery dilation.

Amlodipine is a chiral compound with asymmetric carbon, and the (S) -optical isomer of amlodipine is a potent calcium channel blocker and is known to exhibit higher activity than isomer mixtures (racemic form) (Arrowsmith et al., J Med. Chem., 29, 1696 (1986)), (R) -optical isomers are 1000 times less active than (S) -optical isomers and exhibit kinin-mediated nitric oxide mechanisms presumably associated with adverse events ( Hintze et al., J. Cardiovasc. Pharmacol., 39 (2): 208-14 (2002)).

Therefore, when the pure optical isomer (S) -amlodipine is separated and administered, it can increase the selectivity of receptor binding, which is more effective than amlodipine racemics, and can reduce the dose of the drug by about half, thereby reducing the possibility of drug interaction and side effects. There is an advantage to that.

Tablets of the invention may further comprise at least one pharmaceutically acceptable additive. The additive may use conventional additives known in the art within the range that does not cause interaction with telmisartan, a pharmaceutically acceptable salt thereof, and does not interfere with drug efficacy.

The pharmaceutically acceptable additive may be, for example, any one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and a coating agent, but is not limited thereto.

By "diluent" is meant herein an inert material used as a filter to produce the desired bulk, flow and compression properties in the preparation of solid dosage formulations. For example, lactose monohydrate, lactose anhydrous, white sugar, corn starch, or calcium dihydrogen phosphate, but is not limited thereto.

By "binder" is meant herein a substance which can impart elasticity and tackiness to increase the strength of the formed formulations, in particular the strength of the formed tablets. For example, the binder may be carboxymethyl cellulose-sodium (CMC-Na), starch solution, polyvinylpyrrolidone (PVP), gum arabic and hydroxypropyl cellulose (HPC), but is not limited thereto.

As used herein, "disintegrant" means a substance used to accelerate the disintegration of a solid formulation so that the active agent exhibiting efficacy in the formulation is released in a short time. For example, carboxymethyl cellulose calcium (CMC-Ca), crospovidone, sodium starch glycolate, croscarmellose sodium or low-substituted hydroxypropyl cellulose may be used as the disintegrant, but is not limited thereto. .

In the present invention, "lubricant" is a substance that imparts improved flow properties to the formulation. For example, colloidal silica, magnesium stearate, stearic acid, talc, or stearyl fumarate may be used as the lubricant, but is not limited thereto.

In one embodiment of the present invention, the pharmaceutical combination preparation of the present invention may be an oral solid preparation, preferably, the pharmaceutical combination preparation of the present invention is a two-layer tablet.

In another aspect of the present invention, the present invention provides a method for preparing a telmisartan single agent or a complex comprising telmisartan and (S) -amlodipine. The pharmaceutical mono- and co-formulations of the present invention can be prepared by tablets and the like using methods known in the art to those skilled in the art, for example, wet granulation, direct firing, dry granulation and the like.

Hereinafter, examples and experimental examples will be described in detail to help the understanding of the present invention. However, the following Examples and Experimental Examples are merely to illustrate the content of the present invention is not limited to the scope of the following Examples and Experimental Examples. Examples and experimental examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

Experimental Example 1

Tablet failure test according to the ratio of short axis and long axis of telmisartan tablet

The tablets of Examples 1 to 6 having the ratio of the short axis and the long axis of [Table 2] were prepared using the composition of Table 1 containing telmisartan as an active ingredient.

Examples 1 to 6 Preparation of Tablets Containing Telmisartan

Telmisartan, dried sodium carbonate, povidone, and yellow iron oxide were added to water, warmed, stirred, and dissolved to prepare a primary binder solution. Separately, calcium silicate was added to water and stirred homogeneously to prepare a secondary binder solution. After the microcrystalline cellulose was put into the fluidized bed granulator and fluidized, the first binding liquid and the second binding liquid were sprayed sequentially to prepare granules, followed by drying. The sieved material was sieved through 30 mesh, and then mixed with sodium stearyl fumarate to prepare a telmisartan granule mixture. Tablets (Examples 1 to 6) having a ratio of short axis and long axis of 1: 1, 1: 1.3, 1: 1.5, 1: 1.6, 1: 1.7, and 1: 1.8 were prepared using a tablet press.

Free fall test was carried out in the same manner as described below for the tablets of Examples 1 to 6 prepared above.

Thirty tablets of 90 tablets were packed in HDPE (high density polyethylene) bottles and dropped 10 times at a location of 1 m on a flat, solid floor. After the drop test, the bottle was opened to determine whether or not the tablet was broken. At this time, the test conditions were maintained at a relative humidity of 75% or less at a temperature room temperature (1 ~ 30 ℃). The rate at which the tablets were broken was measured, and the measurement results are shown in the following [Table 2].

As shown in Table 2, Examples 1 to 4, it was found that the tablets were not broken and the durability increased. In addition, it can be seen that the degree of tablet breakdown increases as the ratio of the long axis to the short axis increases.

Therefore, as the ratio of the short axis to the long axis of the tablet approaches 1: 1, it was confirmed that the possibility of tablet breakage decreases.

Experimental Example 2

Tablet breakdown experiment according to the ratio of short axis and long axis of telmisartan and amlodipine

The tablets of Examples 7 to 12 having the ratio of short axis and long axis of [Table 4] were prepared using the composition of [Table 3] including telmisartan and amlodipine as active ingredients.

Examples 7 to 12 Preparation of Tablets Containing Telmisartan and Amlodipine

Telmisartan, dry sodium carbonate, povidone, and yellow iron oxide were added to water, warmed, stirred, and dissolved to prepare a primary binder solution. Separately, calcium silicate was added to water and stirred homogeneously to prepare a secondary binder solution. After the microcrystalline cellulose was put into the fluidized bed granulator and fluidized, the first binding liquid and the second binding liquid were sprayed sequentially to prepare granules, followed by drying. The sieved material was sieved through 30 mesh, and then mixed with sodium stearyl fumarate to prepare a telmisartan granule mixture. Anhydrous calcium hydrogen phosphate was added to (S) -amlodipine besylate and dispersed, and microcrystalline cellulose, sodium starch glycolate, and sodium stearyl fumarate were added and mixed. The mixture was struck with a stirrer equipped with a 16 mesh sieve and sieved to prepare granules, and the granules were stipulated with a comil sizer. Microcrystalline cellulose was added to the blue No. 2 dye, and the pigment was dispersed. Microcrystalline cellulose, sodium starch glycolate, and anhydrous calcium hydrogen phosphate were added to the sieved product and the dye product, and then mixed with sodium stearyl fumarate, which was sieved through 30 mesh, to prepare a (S) -amlodipine granule mixture. It was. The telmisartan granules mixture and the (S) -amlodipine granules mixture were tableted using a tablet press such that the ratio of the short axis and the long axis was 1: 1, 1: 1.3, 1: 1.5, 1: 1.6, 1: 1.7 and 1: 1.8, respectively. (Examples 7 to 12) were prepared.

The free fall test was performed on the tablets of Examples 7 to 12 prepared above, and the ratio of tablet breakage and layer separation was measured. The measurement results are shown in the following [Table 4].

As shown in Table 4, in Examples 7 to 10 it was found that the tablets were not broken and the layer separation did not occur, thereby increasing the durability. In addition, as the ratio of the long axis to the short axis was found to increase the degree of tablet breakage.

Therefore, it can be seen that the ratio of tablet breakage decreases as the ratio of the short axis to the long axis of the tablet approaches 1: 1.

Experimental Example 3

Humidity Test of Telmisartan Tablets with Calcium Silicate Contents

The telmisartan tablets of Examples 13 to 17 were prepared according to the preparation method described in Experimental Example 1 with the composition shown in Table 5 below.

For the tablets of Examples 13 to 17 prepared above, the wettability was evaluated. In the method of evaluating humidity, the gloss and color change of the surface of the tablet were observed after one day by exposing each drug to the accelerated condition (relative humidity 75 ± 5%) and temperature 40 ± 2 ℃ without packaging.

As a result of the humidity evaluation, the gloss change and the color change are shown in the following [Table 6], and the change in appearance is shown in [Fig. 1].

As shown in Table 6, the tablets of Examples 13 to 15 could hardly observe the change in gloss and color. As shown in Fig. 1, the tablets of Examples 13 to 15 showed little change in appearance.

Therefore, it was found that the tablets of Examples 13 to 15 had almost no change in gloss, color, and properties, and were excellent in humidity.

Experimental Example 4

Dissolution Rate Experiments of Telmisartan Tablets with Different Disintegrants

According to the preparation method disclosed in Experimental Example 1 in the composition of [Table 7], the telmisartan tablets of Examples 18 to 21 were prepared.

Disintegration time was measured for the tablets of Examples 18 to 21 prepared above. The disintegration time was measured based on the disintegration test method of the Korean Pharmacopoeia, purified water was used as the disintegration solution, and the water temperature was maintained at 37 ± 2 ° C. Disintegration time was defined as the time at which the tablet completely disappeared from the bottom of the disintegrator. The disintegration time measurement results are shown in the following [Table 8].

As shown in Table 8, the tablet of Example 18 exhibited the shortest disintegration time, from which it was confirmed that low-substituted hydroxypropyl cellulose was the most suitable disintegrant.

Experimental Example 5

Dissolution Rate Experiment of Telmisartan Tablets with Disintegrant Content

The telmisartan tablets of Examples 22 to 24 were prepared according to the preparation method disclosed in Experimental Example 1 with the composition shown in Table 9 below.

For the tablets of Example 18 and Examples 22-24, the dissolution rate over time was measured.

The dissolution rate was measured based on the second method (paddle method) of the Korean Pharmacopoeia. The eluate was 900 mL of phosphate buffer (pH 7.5), and the dissolution temperature was 37 ± 0.5 ℃ and the rotation speed was 75 rpm. Proceeded. The eluate was taken at 5, 10, 15, and 30 minutes after the start of the elution. The eluate was taken as a sample solution and analyzed by liquid chromatography with a standard solution 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].

As shown in Table 10, as the content of low-substituted hydroxypropyl cellulose was increased, the dissolution rate was increased, and the dissolution rate of Example 24 containing 9 wt% was the best.

Claims (14)

A tablet comprising telmisartan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient is contained in an amount of 25 to 30 wt% based on the total weight of the tablet, and the ratio of the short axis to the long axis of the tablet is 1: 1 to 1: 1.6, wherein the tablet comprises a low-substituted hydroxypropyl cellulose as a disintegrant, 3 to 15% by weight based on the total weight of the tablet.
delete The tablet according to claim 1, further comprising calcium silicate.
The tablet according to claim 3, wherein the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof and calcium silicate is 10: 0.5 to 10: 5.
delete delete delete delete A pharmaceutical combination comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof and a second layer comprising a pharmacologically active ingredient, wherein the telmisartan or a pharmaceutically acceptable salt thereof 25 to 30% by weight based on the total weight of the first layer, the composite formulation has a ratio of uniaxial to long axis of 1: 1 to 1: 1.6, the first layer is a low-substituted hydroxypropyl disintegrant A pharmaceutical combination comprising cellulose in an amount of 3 to 15% by weight, based on the total weight of the first layer.
The pharmaceutical composition of claim 9, wherein the pharmacologically active ingredient is atenolol, metoprolol, nadolol, pindolol, amlodipine, nifedipine, nicardipine, verapamil, enalapril, captopril, ramipril, rozatan and candesartan, and these Pharmaceutical combinations, characterized in that selected from the group consisting of pharmaceutically acceptable salts.
The pharmaceutical combination according to claim 9, wherein the pharmacologically active ingredient is (S) -amlodipine or a pharmaceutically acceptable salt thereof.
10. The combination formulation of claim 9, wherein the first layer comprising telmisartan or a pharmaceutically acceptable salt thereof further comprises calcium silicate.
delete The pharmaceutical combination according to claim 9, wherein the combination is a bilayer tablet.

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