KR101750689B1 - Pharmaceutical combination preparation - Google Patents

Abstract

The present invention relates to a pharmaceutical combination comprising telmisartan and (S) -amlodipine with improved remedies.

Description

≪ RTI ID = 0.0 > Pharmaceutical combination preparation &

The present invention relates to a pharmaceutical combination comprising telmisartan and (S) -amlodipine with improved remedies.

Hypertension refers to a state in which blood pressure beyond the normal range is maintained. Hypertension can lead to many complications and eventually death. Hypertension is classified into primary hypertension and secondary hypertension according to the cause of hypertension. Primary hypertension is an essential hypertension whose cause is unknown, and secondary hypertension is secondary hypertension in which a rise in blood pressure occurs as a result of a specific disease or disease. Secondary hypertension can be cured by identifying the cause of hypertension. However, since the cause of primary hypertension, which accounts for about 95% of total hypertension, is unclear, the treatment of patients with primary hypertension is limited by several factors Based drug therapy.

The most commonly used drugs for the treatment of hypertension are vasodilators, diuretics and sympathomimetics depending on the mechanism of action of the drug. The vasodilators currently used are angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers.

It is important to keep blood pressure in the normal range rather than to treat blood pressure itself, so it is important to prevent cardiovascular complications such as life-threatening stroke, heart failure such as heart failure, myocardial infarction and renal failure, It is important to control your blood pressure. As such, blood pressure medication is required to be taken for a long period of time, so care should be taken in choosing therapeutic drugs. Therefore, rather than choosing one drug for continuous treatment, the combination of drugs with different mechanisms will give better prophylactic and therapeutic effects and can be caused by long-term use of medication by reducing the use of a single drug with concomitant use. There is a need to reduce side effects. In the Hypertension Guideline (JNC7), if sufficient blood pressure control can not be achieved with single-dose administration, it is recommended that patients should be treated with drugs of different mechanisms.

In particular, in the case of a combination prescription of an angiotensin receptor blocker (ARB) and calcium channel blocker (CCB), which are different mechanisms of action in the human body, First, it is selected. Because the pharmacological actions for lowering the blood pressure of the two drug groups are different, it is possible to remarkably reduce the side effects of each ingredient because it can reduce not only the effective blood pressure lowering effect but also the drug use when the two drug groups are administered jointly.

Telmisartan is one of the angiotensin II receptor blockers (ARB) and is available in two doses of 40 mg and 80 mg under the trade name Pritor. Telmisartan is prescribed for essential hypertension and is a receptor for angiotensin II, which acts as a potent vasoconstrictor in the renin-angiotensin-aldostrerone system, in particular the AT1 receptor involved in major physiological functions, such as vasoconstriction It is a selective acting drug.

Amlodipine is one of the calcium channel blockers (CCB) and is marketed as 5 mg and 10 mg under the trade name Norvasc. Separate administration of the pure optical isomer (S) -amlodipine increases the selectivity of the receptor binding, which is lower than that of amlodipine racemic, and can reduce the administration dose by half, thereby reducing the possibility of drug interaction and side effects .

The complex compositions comprising telmisartan and (S) -amlodipine as active ingredients are representative ARB and CCB drugs, respectively, and not only show an effective blood pressure lowering effect, but also reduce the side effects of each component .

However, in order to form telmisartan, it is necessary to use a basic base for solubility improvement and solubilization, and sodium hydroxide and meglumine are mainly used as basic bases. However, when a strongly basic base having a decomposability such as sodium hydroxide is used, there is a problem that the tablets become sticky or melt due to a strong hygroscopicity and are easily invited from the hands when exposed to water or when they are exposed to moisture.

Korean Patent Publication No. 10-2007-0085801 (published on August 27, 2007)

It is an object of the present invention to include a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, microcrystalline cellulose and calcium silicate and a second layer comprising (S) -amlodipine or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, microcrystalline cellulose and calcium silicate, and (S) -amlodipine or a pharmaceutically acceptable salt thereof, And a second layer comprising a pharmaceutically acceptable carrier.

The pharmaceutical combination preparation of the present invention improves the wetting of the first layer containing telmisartan by including microcrystalline cellulose and calcium silicate in the first layer and at the same time enhancing the stability of the (S) -amlodipine contained in the second layer It does not affect the operation.

In the present invention, " telmisartan " refers to 2- (4 - {[4-methyl- 3-benzodiazol-1-yl] methyl} phenyl) benzoic acid as a chemical name.

[Chemical Formula 1]

In the present invention, telmisartan can be commercially available or synthesized by methods 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 its pharmaceutically acceptable salts, isomers, racemates, hydrates and solvates, as long as the equivalent pharmacological activity is maintained It is possible.

The pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable acids or bases. The term "pharmaceutically acceptable salt" in the present invention means any organic or inorganic additive salt which is relatively non-toxic to the patient and has a harmless effective action, the side effect of which is not adversely affected by the beneficial effects of the pharmacologically active ingredient .

Preferably, the pharmaceutically acceptable salts of telmisartan of the present invention may be sodium salts, potassium salts, magnesium salts and calcium salts of telmisartan, but are not limited thereto.

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

Telmisartan is mainly used as a therapeutic agent for essential hypertension and is a receptor for angiotensin II acting as a strong vasoconstrictor in the renin-angiotensin-aldostrerone system, particularly, AT1 which is involved in the main physiological action such as vasoconstriction It is a drug that selectively acts on the receptor. Telmisartan has a blood pressure lowering effect continuously for 24 hours. Therefore, blood pressure control effect is effective until the morning when the blood pressure rises due to the effect of the drug taken on the previous day, and the excretion rate of kidney is less than 2% It also has a strength that does not require dose control for patients with renal impairment. In addition, telmisartan has been shown to be the best drug of the existing ARB because of the low risk of hyperkalemia side effects compared to other ARB (Angiotensin receptor blocker) (Park Rae Woong, American Journal of Cardiovascular Drugs, 2012).

Telmisartan is characterized by its very poor solubility in aqueous systems 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 the formulation for solubility improvement and solubilization.

Therefore, it is preferable that the first layer of the pharmaceutical combination preparation of the present invention contains an alkalizing agent. Suitable alkalizing agents that may be used include metal hydrides, basic amino acids, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydrogen phosphate and mixtures thereof. The metal hydrates include, for example, sodium hydroxide or calcium hydroxide; As the basic amino acid, for example, arginine, lysine or meglumine (N-methyl-D-glucamine) may be used. Preferably, the pharmaceutical combination of the present invention includes dry sodium carbonate.

However, since the alkalizing agent has deliquescence and moisture resistance, when the formulation containing the alkalizing agent is exposed to moisture or moisture, the formulation becomes sticky or melts.

Meanwhile, the second layer of the pharmaceutical combination preparation of the present invention contains (S) -amlodipine as an active ingredient.

In the present invention, "(S) -amlodipine" refers to 3-ethyl-5-methyl-2- (2- aminoethoxymethyl) -4- (2- chlorophenyl) 3,5-pyridinedicarboxylate " means a compound of the following formula (2): < EMI ID =

(2)

In the present invention, (S) -amlodipine can be commercially available or synthesized by methods known in the art, but not limited thereto.

(S) -amlodipine of the present invention may be formulated as a free base of (S) -amlodipine or a pharmaceutically acceptable salt, isomer, racemate, hydrate and solvate thereof, as long as the 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. The term "pharmaceutically acceptable salt" in the present invention means any organic or inorganic additive salt which is relatively non-toxic to the patient and has a harmless effective action, the side effect of which is not adversely affected by the beneficial effects of the pharmacologically active ingredient .

Preferably, the pharmaceutically acceptable salts of the (S) -amlodipine of the present invention are (S) -amlodipine besylate, (S) -amlodipine maleate, (S) -amlodipine orthoate, , (S) -amlodipine adipate or (S) -amlodipine mesylate.

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

Amlodipine, one of the calcium channel blockers (CCB), is a very useful calcium channel blocker with a half-life of 30 to 50 hours, which is very persistent and active over a long period of time. Amlodipine is a drug effective in lowering blood pressure and inducing angina pectoris due to spastic vasoconstriction by inducing peripheral arterial dilation by blocking calcium influx into the vascular smooth muscle. Amlodipine is a chiral compound with a chiral center, and the (S) -enantiomer of amlodipine is known to exhibit higher activity than the isomeric mixture (racemic form) as a potent calcium channel blocker (Arrowsmith et al., J (R) -enantiomer is 1000-fold less active than the (S) -enantiomer and exhibits a kinin-mediated nitric oxide mechanism presumed to be associated with adverse effects Hintze et al., J. Cardiovasc. Pharmacol., 39 (2): 208-14 (2002)). Therefore, when the pure optical isomer (S) -amlodipine is administered separately, the selectivity of the receptor binding exhibiting the drug effect can be enhanced and the administration dose can be reduced to about half that of amlodipine racemic, so that the drug interaction and the possibility of side effects can be lowered There is an advantage.

However, in terms of stability, (S) -amlodipine is considerably more unstable than its racemic mixture, and it is known experimentally that the dissolution of (S) -amlodipine is faster than that of racemic and that the amount of the substance due to an increase in degradation products is also increased. This is because the thermodynamically separated optical isomer form is unstable (Hadzidedic et al., J. Pharm. Dev. Technol., 19 (8): 930.941 (2014)).

Such (S) -amlodipine is easily hydrolyzed by the alkalizing agent used for the solubility and solubilization of telmisartan, and the stability is deteriorated.

The pharmaceutical combination preparation of the present invention has an advantage of improving both the problem of invasiveness of the above-mentioned telmisartan preparation and the problem of lowering the stability of (S) -amlodipine. Specifically, the effect of improving the conventionality of the pharmaceutical combination comprising the first layer containing the microcrystalline cellulose as an excipient, the first layer containing calcium silicate as the adsorbent, and the first layer in the first layer containing telmisartan as an active ingredient At the same time, does not affect the stability of the (S) -amlodipine contained in the second layer by the addition of the microcrystalline cellulose and calcium silicate as described above.

In a specific experimental example, the degree of the irritation of the medicament containing telmisartan according to the present invention was tested under accelerated conditions (at a humidity of 75% at a temperature of 40 DEG C), and as a result, after one day, , But the tablets containing microcrystalline cellulose were hardly changed and it was confirmed that the effect of improving the moisture resistance was excellent (Experimental Example 1).

Preferably, the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to microcrystalline cellulose in the pharmaceutical combination preparation of the present invention is 10:25 to 10:35.

Preferably, the microcrystalline cellulose in the pharmaceutical combination preparation of the present invention may be contained in an amount of 50 to 60% by weight based on the total weight of the first layer.

In a specific example, the proper range of content of microcrystalline cellulose contained in the preparation was tested. As a result, when the weight ratio of telmisartan and microcrystalline cellulose was 10:25, 10:30, the degree of fineness of the tablet was small and the maximum hardness And the maximum hardness of the tablets was increased and the degree of abrasion was also decreased as the amount of microcrystalline cellulose in the preparation was increased.

Preferably, the pharmaceutical combination of the present invention has a weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate of from 10: 1 to 10: 6.

More preferably, the pharmaceutical combination preparation of the present invention has a weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to microcrystalline cellulose of from 10: 25 to 10: 30, and includes telmisartan or a pharmaceutically acceptable salt thereof and silicic acid Calcium is from 10: 1 to 10: 5.

More preferably, the pharmaceutical combination of the present invention has a weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate of from 10: 2 to 10: 3.

In a specific experimental example, the effect of the amount of calcium silicate in the formulation on the degree of improvement in the degree of permeability and on the stability of the (S) -amlodipine layer was examined. As a result, it was found that the calcium silicate contained in the telmisartan layer was effective for the improvement of the hygroscopicity, but it was confirmed that the amount of (S) - amlodipine was increased as the amount of calcium silicate was increased. Thereby, it is possible to improve the moisture-permeability of the telmisartan layer, while appropriately adjusting the content of telmisartan or its pharmaceutically acceptable salt and calcium silicate in the range of not lowering the stability of the (S) -amlodipine layer to 10: 1 to 10: 5, preferably from 10: 2 to 10: 3, by weight of the calcium silicate.

The pharmaceutical combination of the present invention may further comprise at least one pharmaceutically acceptable additive. The additive may be added to the composition in a manner known to those skilled in the art without causing interactions with telmisartan, its pharmaceutically acceptable salts, (S) -amlodipine and its pharmaceutically acceptable salts, Can be used.

The pharmaceutically acceptable additive may be, for example, but not limited to, a diluent, a binder, a disintegrant, a lubricant, and a skin care agent.

In the present invention, the term "diluent" means an inert material used as a filter to produce bulk, flow properties and compression characteristics desirable for the preparation of solid dosage forms. For example, it may be, but is not limited to, lactose hydrate, anhydrous lactose, white sugar, corn starch, or calcium monohydrogen phosphate.

As used herein, the term "excipient " means a material added to impart a suitable hardness or shape to a drug, or to be of a size that is easy to handle by giving a constant dose weight when the amount of the active ingredient is small. For example, it may be a sugar derivative such as mannitol or sorbitol, an inorganic excipient such as corn starch, potato starch, low substituted hydroxypropylcellulose, a cellulose derivative such as methylcellulose, carbonate such as calcium carbonate, and the like, but is not limited thereto .

The terms "diluent" and "excipient" in the present invention may be used interchangeably.

In the present invention, the term "binder" means a material capable of imparting elasticity and tackiness in order to increase the strength of the formed preparation, especially the strength of the formed tablet. For example, the binder may be, but is not limited to, carboxymethylcellulose-sodium (CMC-Na), starch hydrolyzate, polyvinylpyrrolidone (PVP), gum arabic and hydroxypropylcellulose (HPC).

The term " disintegrating "in the present invention means a substance used to accelerate the disintegration of a solid preparation so that the active agent exhibiting drug efficacy in the preparation is released in a short time. For example, carboxymethylcellulose calcium (CMC-Ca), crospovidone, sodium starch glyconate, croscarmellose sodium or low-substituted hydroxypropylcellulose may be used as the disintegrant, but the present invention is not limited thereto.

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

As an example of the present invention, the pharmaceutical combination preparation of the present invention may be an oral solid preparation, and preferably, the pharmaceutical combination preparation of the present invention is a two-layered preparation.

In another aspect of the present invention, the present invention provides a method for preparing a pharmaceutical combination comprising telmisartan and (S) -amlodipine. The pharmaceutical combination of the present invention can be produced by a method known to those skilled in the art, for example, by using a wet granulation method, a direct method, a dry granulation method, or the like.

Illustratively, the method for preparing a pharmaceutical combination of the present invention by the wet granulation method comprises the steps of: preparing a binding solution; Mixing the active ingredient with a diluent (or excipient) to prepare a mixture; Associating the mixture with the binding solution; And drying and sizing and lubricating the association.

In addition, a method for producing a pharmaceutical combination preparation of the present invention by an exemplified direct method includes the steps of preparing a mixture by mixing a main ingredient and an excipient, adding a disintegrant and a lubricant to the mixture, .

The pharmaceutical combination preparation of the present invention can be prepared by, for example, spray drying a solution prepared by dissolving a basic component, preferably dry sodium carbonate, in an appropriate solvent to provide a telmisartan layer to an inactive excipient to form amorphous telmisartan A granule composition of the layer containing (S) -amlodipine may be prepared, and the two granule compositions may be tableted to prepare the pharmaceutical combination of the present invention.

In another aspect of the present invention, the pharmaceutical combination preparation of the present invention is used for prevention or treatment of cardiovascular diseases selected from the group consisting of hypertension, angina pectoris, arterial spasm, heart arrhythmia, cerebral infarction, cardiomyopathy, congestive heart failure and myocardial infarction And can be used particularly for prevention or treatment of essential hypertension.

The pharmaceutical combination preparation of telmisartan and (S) -amlodipine of the present invention significantly improves the impermeability of the telmisartan layer by including microcrystalline cellulose and calcium silicate in the telmisartan layer, It is possible to secure the stability of the battery.

FIG. 1 is a graph showing the results of Examples 1 to 5, in which the flexible substance D of (S) -amlodipine was measured after storage for 2 weeks under accelerated conditions (40 ° C., 75% relative humidity,
FIG. 2 is a graph showing the results of Examples 1 to 5 in which individual soft substances of (S) -amlodipine were measured after storage for 4 weeks under accelerated conditions (40 ° C., 75% relative humidity, open).
FIG. 3 is a graph showing the results of Examples 1 to 5, in which the total soft substances of (S) -amlodipine were measured after storage for 4 weeks under accelerated conditions (40 ° C., 75% relative humidity,
4 is a graph showing the results of Examples 10 to 16 in which the flexible substance D of (S) -amlodipine was stored under acceleration conditions (40 ° C, 75% relative humidity, open) for 2 weeks.
FIG. 5 is a graph showing the results of Examples 10 to 16 in which individual flexible substances of (S) -amlodipine were measured after storage for 4 weeks under accelerated conditions (40 ° C., 75% relative humidity, open).
FIG. 6 is a graph showing the results of Examples 10 to 16, in which the total flexible substances of (S) -amlodipine were measured after storage for 4 weeks under acceleration conditions (40 ° C., 75% relative humidity, open).

Hereinafter, production examples, examples and experimental examples will be described in detail to facilitate understanding of the present invention. It should be understood, however, that the following examples and experimental examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The embodiments and experimental examples of the present invention are provided to enable those skilled in the art to more fully understand the present invention.

≪ Preparation Example > Preparation of telmisartan and (S) -amlodipine granules

Preparation Example 1: Preparation of a mixture of a customary improved telmisartan granule

The telmisartan granule mixture was prepared by the following method with the composition shown in Table 1 below.

Ingredients Weight (mg / tablet) Telmisartan 80.00 D-sorbitol 242.00 Dry sodium carbonate 30.00 Povidone 20.00 Calcium silicate 20.00 Sodium stearyl fumarate 8.00 Total amount 400.00

1) Preparation of primary binding solution

Telmisartan, dried sodium carbonate, povidone and calcium silicate were added to the water, heated and stirred to dissolve completely.

2) granule manufacture and drying

D-sorbitol was added to the fluidized bed granulator and fluidized. Then, the primary binding liquid of 1) was sprayed to prepare granules and dried.

3) Preparation of secondary binding solution

Calcium silicate was added to the water and completely dissolved by stirring.

4) Manufacturing and sizing of granules

After the granulation of 2) was fluidized in the fluidized bed, granules were prepared by spraying the secondary binding solution of 3). It was dried and settled with a co-mitt conditioner.

5) After mixing and final mixing

4) and D-sorbitol were put into a mixer and mixed. Sodium stearyl fumarate was sieved through 30 mesh, and final mixing was performed to prepare a final mixture of telmisartan granules.

Preparation Example 2: Preparation of (S) -amlodipine granule mixture

(S) -amlodipine granule mixture was prepared by the following preparation method with the composition shown in Table 2 below.

Ingredients Weight (mg / tablet) (S) -amlodipine besylate
((S) -amlodipine) 3.69
(2.5) Microcrystalline cellulose 126.55 Anhydrous calcium hydrogen phosphate 64.00 Starch glycolate sodium 2.00 Blue No. 2 dye 0.26 Magnesium stearate 3.5 Total amount 200.00

1) Deduction of main ingredient

(S) -amlodipine besylate was added with anhydrous calcium hydrogen phosphate.

2) mixing of granules

1) were mixed with microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

3) Hitting and sizing of granules

2) were crushed and crushed with a 16 mesh sieving machine to prepare granules, which were then fixed with a co-miller.

4) Pigment Reduction

Microcrystalline cellulose was added to the blue No. 2 dye, mixed and pulverized with a sample mill.

5) final mixing

3), and 4) microcrystalline cellulose, sodium starch glycolate, and anhydrous calcium phosphate were mixed and mixed with magnesium stearate, followed by final mixing to obtain a final mixture (S ) -Amlodipine granulation mixture.

Production Examples 3 to 6: Preparation of telmisartan granule mixture

The telmisartan granule mixture was prepared with the composition shown in Table 3 below. At this time, the preparation method was the same as that of Preparation Example 1, except that the excipient was replaced with D-mannitol, erythritol, microcrystalline cellulose and starch to prepare granules of Production Examples 3 to 6.

Ingredients (unit: mg / tablet) Production Example 3 Production Example 4 Production Example 5 Production Example 6 Telmisartan 80.00   80.00  80.00   80.00 D-mannitol 262.00 - - - Erythritol -  262.00 - - Microcrystalline cellulose - -  262.00 - Starch - - - 262.00 Dry sodium carbonate 30.00 30.00 30.00 30.00 Povidone 20.00 20.00 20.00 20.00 Sodium stearyl fumarate 8.00 8.00 8.00 8.00 Total amount 400.00 400.00  400.00 400.00

Preparation Examples 7 to 10: Preparation of telmisartan granule mixture

The telmisartan granule mixture was prepared with the composition shown in Table 4 below. The granules of Preparation Examples 7 to 10 were prepared in the same manner as in Preparation Example 1 except that the amount of microcrystalline cellulose as an excipient was changed to 30%, 40%, 50% and 60% by weight.

Ingredients
(Unit: mg / tablet) Production Example 7 Production Example 8 Production Example 9 Production Example 10 Telmisartan 80.00  80.00 80.00 80.00 D-mannitol 142.00 102.00 62.00 22.00 Microcrystalline cellulose 120.00 160.00 200.00 240.00 Dry sodium carbonate 30.00 30.00 30.00 30.00 Povidone 20.00 20.00 20.00 20.00 Sodium stearyl fumarate 8.00 8.00 8.00 8.00 Total amount 400.00 400.00  400.00  400.00

Production Examples 11 to 17: Preparation of telmisartan granule mixture

The telmisartan granule mixture was prepared with the composition shown in Table 5 below. The preparation method was the same as in Preparation Example 1 except that the weight ratio of telmisartan and calcium silicate was changed to 10: 0, 10: 1, 10: 2, 10: 3, 10: 4, 10: 5, The granules of Examples 11 to 17 were prepared.

Ingredients
(Unit: mg / tablet) Production Example 11 Production Example 12 Production Example 13 Production Example 14 Production Example 15 Production Example 16 Production Example 17 Telmisartan 80.00  80.00 80.00 80.00  80.00 80.00 80.00 D-mannitol 62.00 54.00 46.00 38.00 30.00 22.00 14.00 Microcrystalline cellulose 200.00 200.00 200.00 200.00 200.00 200.00 200.00 Dry sodium carbonate 30.00 30.00 30.00 30.00 30.00 30.00 30.00 Povidone 20.00 20.00 20.00 20.00 20.00 20.00 20.00 Calcium silicate 0.00 8.00 16.00 24.00 32.00 40.00 48.00 Sodium stearyl fumarate 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Total amount 400.00 400.00  400.00 400.00 400.00  400.00 400.00

EXAMPLES Preparation of a bilayer preparation comprising telmisartan and (S) -amlodipine

Example 1

A mixture of the telmisartan granule mixture prepared according to Preparation Example 1 and the (S) -amlodipine granule mixture prepared according to Preparation Example 2 was tableted with a double layer tablet machine (manufactured by Sejong Pharmatech, model: GRC-25D) mg < / RTI > The obtained two-layer tablets contained 80 mg of telmisartan and 2.5 mg of (S) -amlodipine for each layer.

Examples 2 to 5

The two-layered tablets of Examples 2 to 5 were obtained according to the method of Example 1 using the telmisartan granule mixture prepared according to Preparation Examples 3 to 6 and the (S) -amlodipine granule mixture prepared according to Preparation Example 2. [

Example  6 to 9

The two-layered tablets of Examples 6 to 9 were obtained according to the method of Example 1 using the telmisartan granule mixture prepared according to Preparation Examples 7 to 10 and the (S) -amlodipine granule mixture prepared according to Preparation Example 2. [

Examples 10 to 16

The sediments of Examples 10 to 16 were obtained according to the method of Example 1 using the telmisartan granule mixture prepared according to Preparation Examples 11 to 17 and the (S) -amlodipine granule mixture prepared according to Preparation Example 2. [

EXPERIMENTAL EXAMPLES Improvement of the Properties and Stability of Telmisartan and (S) -amlodipine in Two-layer Definite Custom Properties

Experimental Example 1: Confirmation of the improvement effect of the demonstration of the telmisartan layer

1) Experimental method

The deliquescent properties of the two-layered tablets obtained in Examples 1 to 5 according to the present invention were compared with telmisartan preparations (Mirardis tablets, Boehringer Ingelheim) as comparison examples, and the effect of improving the specificity was evaluated. It was found through the FDA label that it contains telmisartan, sodium hydroxide, meglumine, sorbitol, povidone and magnesium stearate. Specifically, each drug was exposed to accelerated conditions (humidity 75%, temperature 40 ℃) without wrapping, and the degree of disturbance after 1 day was compared with the statistical observation.

2) Experimental results

As a result, the tablets of Examples 2 to 5 showed a somewhat lowered gloss, but no change was observed, unlike the case of the micardis tablets of the control sample melted to an undetectable form as shown in [Table 6] below.

Mikardis jung

Example 1

Example 2

Example 3

Example 4

Example 5

Experimental Example 2: Confirmation of stability improvement of (S) -amlodipine layer according to the type of excipient

1) Experimental method

(S) -amlodipine, the preparations prepared in Examples 1 to 5 were stored in an HDPE bottle in an open state for 4 weeks under accelerated conditions (humidity: 75%, temperature: 40 ° C) S) -amlodipine was measured. The specific measurement method is as follows:

- Column: C18 (3.9 mm x 150 mm, 4 m)

- Detector: Ultraviolet absorptiometer (measuring wavelength: 237 nm)

- mobile phase: a mixture of acetonitrile, methanol, pH 3.0 buffer (180: 250: 570)

- Flow rate: 1.0 mL / min

- Column temperature: 30 ° C

- Sample temperature: 5 ° C

2) Experimental results

The results of the flexo matter content of the (S) -amlodipine layer of Examples 1 to 5 in which the types of excipients in the first layer are different are shown in Tables 7 to 9 and Figs.

Flexible Substance D
(unit : %) Early 1 week 2 weeks Example 1 0.04 0.38 0.59 Example 2 0.04 0.33 0.51 Example 3 0.02 0.34 0.56 Example 4 Non-detection 0.23 0.56 Example 5 0.05 0.41 0.66

Other individual flexible substances
(unit : %) Early 1 week 2 weeks 3 weeks 4 weeks Example 1 0.04 0.39 0.44 0.61 0.89 Example 2 0.05 0.24 0.43 0.62 0.77 Example 3 0.03 0.31 0.49 0.66 0.75 Example 4 Non-detection Non-detection 0.37 0.42 0.48 Example 5 0.05 0.34 0.58 0.64 0.86

Total flexible material
(unit : %) Early 1 week 2 weeks 3 weeks 4 weeks Example 1 0.05 0.51 0.88 1.29 1.46 Example 2 0.07 0.46 0.81 1.02 1.24 Example 3 0.06 0.41 0.88 1.10 1.38 Example 4 Non-detection Non-detection 0.56 0.63 0.77 Example 5 0.12 0.45 0.94 1.22 1.38

(Total flexible substance: sum of flexible substances excluding flexible substance D)

As can be seen in Table 7, as a result of the stability test of the (S) -amlodipine layer according to the type of excipient of the telmisartan layer, the flexible substance D was confirmed to similar degree in all of the tablets of Examples 1 to 5. However, as can be seen in Tables 8 and 9, the amounts of other individual flexible substances and total flexible substances were found to be lowest in Example 4 compared to Examples 1 to 3 and Example 5 at four-week accelerated conditions, The difference reached a maximum of about two times. As a result, it was confirmed that when the microcrystalline cellulose was used as the excipient in the first layer, that is, the telmisartan layer, the (S) -amlodipine layer as the second layer was the most stable.

Experimental Example 3: Effect of amount of microcrystalline cellulose on granularity

1) Experimental method

The angles of repose and the cost of production examples 7 to 10 prepared by varying the amounts of microcrystalline cellulose were measured. The hardness and the degree of abrasion of the tablets of Examples 6 to 9 were measured by the following methods.

[Cost Measurement]

- Device used: PT-TDI (Pharmatest Apparate, Germany)

- Measurement method: Measured by tapping 1250 times

[Measurement of Repose Angle]

- Equipment: PTG-S4 + PTG-NIR (Pharmatest Apparatebau, Germany)

- Measuring method: Measured using a measuring instrument with prepared sample

[Measurement of hardness]

- Hardness tester: TBH-225 (Pharmatest Apparatebau, GmbH, Germany)

- Measurement method: Average calculation after 10 repetitions

[Measuring the degree of wear]

- Marsonometer: SVM-102 (Pharmatest Apparatebau, GmbH, Germany)

- Measuring method: Measuring 20 marks, 100 marks after measuring the degree of wear

2) Experimental results

The evaluation results of the properties of each granule and tablets are shown in [Table 10] and [Table 11].

Item Production Example 7 Production Example 8 Production Example 9 Production Example 10 Cost-effective (ml / g) bulk 1.80 1.78 1.9 2.0 tapped 1.4 1.5 1.6 1.6 Angle of repose 34 35 34 33

Item Example 6 Example 7 Example 8 Example 9 Maximum Hardness (Kp) 10 12 15 17 Marson (%) 0.27 0.20 0.15 0.07

As can be seen in Table 10, the cost and angle of repose of the granules showed similar results in all of Examples 7 to 10. However, the maximum hardness and the degree of fretting of Examples 6 to 9, in which the granular mixture of Production Examples 7 to 10 were prepared in a two-layer form together with (S) -amlodipine, showed different results as shown in Table 11. Specifically, as the amount of microcrystalline cellulose was increased, the maximum hardness of the tablet was increased and the wrinkle was also decreased. As a result, the higher the content by weight of the microcrystalline cellulose, the more the problem of the customary and stability of the telmisartan and S- When we consider it, we can confirm the advantage.

Experimental Example 4: Influence of the amount of calcium silicate on the moisture content

1) Experimental method

The aging-improving effects of the granules obtained in Production Examples 11 to 17 were evaluated. Specifically, each granule was exposed to accelerated conditions (humidity 75%, temperature 40 ° C), and after 1 day, the moisture content (dry weight loss) was measured and measured according to the following test method.

[Measurement of moisture (dry weight loss)]

- Equipment used: HB43-S (METTLER TOLEDO, USA)

- Measurement method: Measure the weight loss by heating at 105 ℃ for 30 minutes.

2) Experimental results

It was confirmed that the moisture (losing weight loss) measured in Production Examples 12 to 17 containing calcium silicate was smaller than that of Production Example 11 containing no calcium silicate as shown in the following [Table 12] It is confirmed that it is effective for improvement of sex.

Item Production Example 11 Production Example 12 Production Example 13 Production Example 14 Production Example 15 Production Example 15 Production Example 17 Loss on drying (%) 11.4 9.8 9.1 8.9 8.5 8.7 8.4

Experimental Example 5: Confirmation of improving effect of stability of (S) -amlodipine layer on calcium silicate amount

1) Experimental method

(S) -amlodipine, the preparations prepared in Examples 10 to 16 were stored in an HDPE bottle in an open state under accelerated conditions (at a humidity of 75% and a temperature of 40 ° C) for 4 weeks, S) -amlodipine was measured. The measurement method is as follows:

- Column: C18 (3.9 mm x 150 mm, 4 m)

- Detector: Ultraviolet absorptiometer (measuring wavelength: 237 nm)

- mobile phase: a mixture of acetonitrile, methanol, pH 3.0 buffer (180: 250: 570)

- Flow rate: 1.0 mL / min

- Column temperature: 30 ° C

- Sample temperature: 5 ° C

2) Experimental results

The results of the flexographic properties of the (S) -amlodipine layers of Examples 10 to 16 prepared by varying the amount of calcium silicate are shown in Tables 13 to 15 and FIGS.

Flexible Substance D
(unit : %) Early 1 week 2 weeks Example 10 Non-detection 0.21 0.55 Example 11 Non-detection 0.18 0.57 Example 12 Non-detection 0.20 0.57 Example 13 0.01 0.21 0.54 Example 14 0.01 0.24 0.59 Example 15 Non-detection 0.21 0.52 Example 16 0.02 0.24 0.60

Other individual flexible substances
(unit : %) Early 1 week 2 weeks 3 weeks 4 weeks Example 10 Non-detection 0.13 0.32 0.42 0.47 Example 11 Non-detection 0.10 0.29 0.40 0.44 Example 12 0.01 0.14 0.33 0.43 0.46 Example 13 Non-detection 0.12 0.31 0.47 0.48 Example 14 0.02 0.14 0.37 0.46 0.51 Example 15 Non-detection 0.17 0.37 0.50 0.54 Example 16 0.03 0.24 0.42 0.57 0.62

Total flexible material
(unit : %) Early 1 week 2 weeks 3 weeks 4 weeks Example 10 Non-detection 0.14 0.38 0.54 0.79 Example 11 Non-detection 0.17 0.34 0.57 0.72 Example 12 0.01 0.15 0.39 0.60 0.81 Example 13 0.01 0.16 0.36 0.57 0.83 Example 14 0.03 0.17 0.42 0.63 0.87 Example 15 0.01 0.20 0.45 0.61 0.89 Example 16 0.05 0.28 0.54 0.72 0.98

(Total flexible substance: sum of flexible substances excluding flexible substance D)

As can be seen in Tables 13 to 15, the stability test of the (S) -amlodipine layer according to the weight ratio of telmisartan and calcium silicate showed that the content of the flexible substance D was similarly increased regardless of the amount of calcium silicate. In comparison with other individual softening materials, unknown softening substances were detected the most in Example 16 in which the amount of calcium silicate was the highest. Also, as the amount of calcium silicate increased, the detection of unknown softening material increased and the total softening material also increased. As a result, it was found that calcium silicate had an excellent effect on improving the moisture permeability through Experimental Example 4, but as the amount of calcium silicate increased, the inclusion of proper amount in the preparation was preferable.

Claims (9)

Comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, calcium silicate, and an alkalizing agent and a second layer comprising (S) -amlodipine or a pharmaceutically acceptable salt thereof, As a pharmaceutical combination preparation,
The weight ratio of said telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate is from 10: 1 to 10: 5,
Wherein the alkalizing agent is any one or more selected from the group consisting of basic amino acids, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, and mixtures thereof. The pharmaceutical combination according to claim 1, wherein the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to microcrystalline cellulose is 10:25 to 10:35. delete The pharmaceutical composition of claim 1, wherein the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to microcrystalline cellulose is 10:25 to 10:30 and the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate is from 10: 1 to 10: 5. The pharmaceutical combination according to claim 4, wherein the microcrystalline cellulose is contained in an amount of 50 to 60% by weight based on the total weight of the first layer. The pharmaceutical combination according to claim 4, wherein the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate is 10: 2 to 10: 3. delete delete The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of (S) -amlodipine is (S) -amlodipine besylate, (S) -amlodipine maleate, (S) (S) -amlodipine adipate, and (S) -amlodipine < RTI ID = 0.0 > mesylate. ≪ / RTI >

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