KR20190023940A - Composite formulation comprising telmisartan, amlodipine and rosuvastatin with improved stability and dissolution rate, and a process for the preparation thereof - Google Patents

Abstract

An aspect provides a composite formulation and a manufacturing method thereof. The composite formulation comprises: a first layer containing rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; and a second layer containing telmisartan or a pharmaceutically acceptable salt thereof and a basification agent. The composite formulation according to the aspect exhibits excellent dissolution rate, stability, content uniformity, and tablet compressibility.

Description

[0001] The present invention relates to a combination preparation comprising telmisartan, amlodipine and rosuvastatin having improved stability and dissolution rate and a preparation method thereof,

The present invention relates to a combination preparation containing telmisartan, amlodipine and rosuvastatin, and a preparation method thereof, and more particularly to a combination preparation comprising telmisartan, amlodipine and rosuvastatin, which are improved in stability and dissolution rate, And rosuvastatin, and a process for producing the same.

A mixture of telmisartan [4 '- [2-n-propyl-4-methyl-6- (1-methylbenzimidazol- -Carboxylic acid] is commercially available as a product of GlaxoSmithKline's "Prito ^™ " and is an angiotensin II receptor blocker (ARB), which is highly potent in the renin-angiotensin-aldosterone It selectively acts on angiotensin II receptors, which act as vasoconstrictors, especially AT1 receptors, which are involved in major physiological functions, such as vasoconstriction. In addition, telmisartan is an effective antihypertensive drug, mainly prescribed for essential hypertension, and recent studies have shown that it is the most superior of the existing ARBs because of the lower risk of hyperkalemia side effects compared to other ARBs have.

Amlodipine [3-Ethyl 5-methyl 2 - [(2-aminoethoxy) methyl] -4- (2- chlorophenyl) -6-methyl-1,4-dihydropyridine- Is commercially available as a product of Pfizer's "NovaSM ^™ " and is a calcium channel blocker (CCB), which is effective in preventing systolic hypertension and stroke. In addition, calcium channel blockers such as amlodipine are effective in angina pectoris due to coronary artery dilatation, and are particularly useful for variant angina in which coronary artery spasm is involved.

- (3R (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - , 5S) -3,5- dihydroxy-hept-6-enoic acid] are commercially available in products such as' Crestor ^TM "AstraZeneca Corp., statins (statin) acts as a HMG-CoA reductase inhibitor as a drug in the series Inhibits the synthesis of cholesterol, and also reduces blood LDL-cholesterol and triglyceride levels. In addition, rosuvastatin has excellent efficacy in treating hypercholesterolemia, hyperlipidemia, or atherosclerosis.

Unfortunately, rosuvastatin is poorly tolerated by temperature, humidity, and especially by light, despite its excellent therapeutic efficacy. Drugs such as rosuvastatin, nifedipine, and acetaminophen, which are vulnerable to light, are easily decomposed by light and may be deteriorated in stability. As a result, the product does not achieve the desired therapeutic effect, There is a risk of harm or unexpected side effects. These drugs should be stored in a cool place or packed in a special way to prevent the decrease of drug efficacy and protect against moisture, direct sunlight, and heat. It is known. Furthermore, rosuvastatin could not sufficiently prevent the degradation of stability due to light by adding a generally known stabilizer.

In addition, hypertension and hyperlipidemia, which are typical target diseases of drugs such as rosuvastatin, amlodipine, and telmisartan, have a very high rate of disease incidence of about 49%, and thus the proportion of hypertension drugs and hyperlipemia drugs It is frequent. Furthermore, patients taking hypertension drugs or hyperlipidemia medicines often have diabetes, kidney disease, heart / cerebrovascular disease, or other metabolic disorders. However, patients who actually need to take various amounts of medication often do not take proper medication because of the inconvenience of taking many medicines. Therefore, it is urgent to develop a combination preparation capable of effectively treating a cardiovascular disease with a high rate of concomitant diseases, having a high combined prescription rate, reducing the inconvenience in taking the medicines, and improving the light stability of the medicament.

Patent Document 1 discloses a two-layered tablet containing telmisartan and amlodipine. However, even in this case, patients having hypertension and hyperlipemia are inconvenient to prescribe and administer a therapeutic agent for hyperlipidemia separately. In addition, in the case of the telmisartan and rosuvastatin combination agents, it is inconvenient to prescribe and administer amlodipine separately for hypertension patients not controlled by telmisartan.

Patent Document 2 discloses a technique for forming a coating layer by spray coating rosuvastatin on tablets, pellets or granular cores to improve the stability of rosuvastatin, but it is difficult to secure the stability of the active ingredient, There is a problem in that there is a lot of loss in the spray drying process and the efficiency is low because of the complicated process.

In addition, a method for producing a nucleophilic tablet containing a drug-unstable drug-containing drug and an outer layer covering the inner core tablets comprises preparing a tablet first, placing the inner core tablet on the tablet of the outer layer, Is inefficient, and the drug elution can be inhibited.

Therefore, we will develop a combination drug that improves compliance with medication, improves drug stability and dissolution rate, and further reduces national insurance financing for patients with cardiovascular disease with hypertension and hyperlipidemia that are not controlled by telmisartan or amlodipine monotherapy. There is a need. However, pharmaceutical preparations containing rosuvastatin, amlodipine and telmisartan are unlikely to be commercialized despite their necessity because of the possibility of lowering the dissolution rate and stability due to interactions between drugs and the difficulty of development.

The inventors of the present invention have developed a combination preparation containing telmisartan, amlodipine and rosuvastatin, which have improved stability and solubility as well as improved uniformity in content and stability after the repeated studies.

Korean Patent Publication No. 2007-0085801 Korean Patent Publication No. 2014-0037873

All technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the relevant art, unless otherwise defined. Also, preferred methods or samples are described herein, but similar or equivalent ones are also included in the scope of the present specification. Also, the numerical values set forth herein are considered to include the meaning of "about" unless explicitly stated. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect includes a first layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; And

A second layer comprising telmisartan or a pharmaceutically acceptable salt thereof and a basic agent.

Another aspect includes the steps of preparing a first layer that incorporates rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; And

There is provided a method of preparing the combination preparation of claim 1, comprising the step of preparing a second layer which comprises admixing telmisartan or a pharmaceutically acceptable salt thereof and a basic agent.

One aspect includes a first layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; And

A second layer comprising telmisartan or a pharmaceutically acceptable salt thereof and a basic agent.

The combined preparation according to the present invention can solve the problem of lowering of stability due to the interaction of amlodipine and telmisartan, and it is possible to reduce the dissolution rate due to the interaction of the two drugs even though amlodipine and rosuvastatin are contained in the same preparation Not shown.

The term "light stabilizer" is used to mean that the active ingredient is exposed to sunlight during processing, storage and distribution, thereby preventing degradation, degradation, oxidation or discoloration of the active ingredient, Refers to the contributing substance.

The term " light stabilization "refers to any action that blocks or alleviates possible physicochemical changes due to exposure to visible light and ultraviolet light.

The term " Tar pigment "refers to a pigment synthesized from benzene or naphthalene contained in coal tar, which is a by-product of coal gasification. The term "edible tar pigment" refers to a tar pigment which can be used as a food additive and includes, for example, edible color red No. 2, yellow No. 4, yellow No. 5, red No. 40, Red No. 3, Green No. 3, Blue No. 1, or Blue No. 2. In addition, the edible tar pigment may be a chemical structural azo dye (for example, Red No. 2, Yellow No. 4, Yellow No. 5, Red No. 40, or Red No. 102), xant- (For example, red No. 3), triphenylmethane-based edible pigments (for example, green No. 3, blue No. 1), or indigoid type pigments (for example, blue No. 2) . ≪ / RTI >

The above-mentioned "Indigo dye" is an organic compound which exhibits blue color, and includes 2,2'-bis (2,3-dihydro-3-oxoindolylidene), indigotine (2,2'- 2,3-dihydro-3-oxoindolyliden), Indigotin).

[Chemical Formula 1]

In addition, the "indigo-based coloring matter pigment" refers to an indigoid-based coloring matter which can be used as a food additive, and includes, for example, Indigo Carmine. The indigocarmin is a 3,3'-dioxo-2,2'-bisindoledene-5,5'-disulfonic acid disodium salt (3,3'-dioxo-2,2'-bisindolyden- , 5'-disulfonic acid disodium salt), also referred to as edible color blue No. 2.

The above-mentioned "edible pigment blue No. 2" refers to 3,3'-dioxo-2,2'-bisindolidine-5,5'-disulfonic acid disodium salt (C ₁₆ H ₈ O ₈ N ₂ S ₂ Na ₂ ) a coloring matter containing a compound as a main component, and refers to a coloring matter containing 85.0% or more of the above compound (Korea Food and Drug Administration Notice No. 2016-32, standards and standards for food additives).

The term " edible tar pigment aluminum lake "refers to a coloring pigment obtained by reacting an edible tar pigment with an alkali such as aluminum sulfate or aluminum chloride, and precipitating it with an aluminum lake. For example, "Food Blue No. 2 Aluminum Lake" refers to a pigment obtained by applying basic aluminum to Food Blue No. 2.

The edible pigment blue No. 2 aluminum lake is also referred to as Indigo Carmine Aluminum Lake. According to the standards and specifications of food additives (Food and Drug Administration Notice No. 2016-32), the food color blue No. 2 aluminum lake is prepared by reacting an aqueous solution of an aluminum salt with an alkali and then adsorbing the blue color No. 2 Means a pigment obtained by filtration, drying and pulverization. In addition, the edible pigment blue No. 2 contained 10.0% of 3,3'-dioxo-2,2'-biindoliden-5,5'-disulfonic acid (C ₁₆ H ₁₀ N ₂ O ₈ S ₂ = 422.40) Or more. It is a fine powder of blue with violet color and has no odor. In the present specification, the edible pigment blue No. 2 aluminum lake is commercially available, and those obtained by a known method or the like may be used. The edible pigment blue No. 2 aluminum lake was prepared by dissolving 3,3'-dioxo-2,2'-biindoliden-5,5'-disulfonic acid (C ₁₆ H ₁₀ N ₂ O ₈ S ₂ = 422.40) % Or more, for example, 10.0% to 40.0% can be used.

The term "natural pigment" refers to a pigment obtained mainly from an animal or a plant, and can be obtained by a method such as extraction from a natural origin material. For example, depending on the raw material of the production, there may be used a red pigment, a red pigment yellow pigment, a red pigment yellow pigment or a mineral pigment derived from plant origin, such as gardenia yellow color, beryllium color, turmeric pigment or animal derived rock color, squid ink color, And gold leaf derived from pigment.

The term "iron oxide" refers to an oxide of iron and includes iron oxide (FeO), iron (III) oxide (Fe ₃ O ₄ ), or ferric oxide ₂ O ₃ ). Sodium tetraoxide can include, for example, black iron oxide.

The term "black iron oxide" refers to a compound containing Fe ₃ O ₄ (231.53) and containing 67.1% or more of iron (Fe: 55.85) when quantified (Korean Pharmacopoeia 7 part pharmaceutical additive) .

The term "iron sesquioxide" refers to a compound containing not less than 98.0% of ferric oxide (Fe ₂ O ₃ ) and shows characteristics of red to yellowish brown powder (Korea Food and Drug Administration Notice 2016-32, Standards and specifications for additives). Further, the ferric iron oxide or ferric oxide includes, for example, yellow iron oxide or red iron oxide.

The "red iron oxide" is Fe ₂ O ₃ , also referred to as ferric iron or iron oxide. The above-mentioned "yellow iron oxide" is Fe ₂ O ₃ (H ₂ O) and is also referred to as yellow ferric oxide. In this specification, commercially available yellow iron oxide may be used, and those obtained by a known method or the like may be used.

According to an aspect of the present invention, there is provided a composition for improving the light stability of rosuvastatin or a pharmaceutically acceptable salt thereof, comprising the iron oxide, edible tar pigment, edible tar pigment aluminum lake, natural pigment, or a combination thereof as the light stabilizer .

In one embodiment, the light stabilizer may include ferric iron oxide, an indigo-derivatized tar pigment, an indigo-derivatized tar pigment aluminum lake, or a combination thereof. For example, the ferric iron oxide may be yellow iron oxide or red iron oxide.

The ferric iron oxide, indigoide-based tar pigments, and indigoide-based tar pigments of aluminum lake can significantly reduce photodegradation of rosuvastatin, among iron oxides, edible tar pigments, and edible tar pigments aluminum rakes.

Also, in one embodiment, the light stabilizer may include yellow iron oxide, a food color blue No. 2, a food color blue No. 2 aluminum lake, or a combination thereof. The yellow iron oxide, the edible pigment blue No. 2, and the edible pigment blue No. 2 aluminum lake are particularly useful as an antioxidant in the production of iron oxide, edible tar pigment, and edible tar pigment aluminum lake, Can be remarkably reduced.

In one embodiment, the light stabilizer may include yellow iron oxide and a food grade blue No. 2 aluminum lake. The yellow iron oxide and the edible pigment blue No. 2 aluminum lake can remarkably reduce the photodegradation of rosuvastatin particularly among iron oxide, edible tar pigment, and edible tar pigment aluminum lake, and yellow oxides of iron and edible pigment blue No. 2 It exhibits a synergistic effect depending on the combination of aluminum rake. For example, the use of yellow iron oxide as the light stabilizer and the blue No. 2 aluminum lake as the food coloring agent is more preferable than the use of the yellow iron oxide and the food color red No. 3 aluminum lake as the photosensitizing agent and the content The change and the rate of increase of the flexible substance can be remarkably reduced. The pharmaceutical composition containing the light stabilizer according to one embodiment is also useful for increasing the shelf life of a medicine and securing an effective period since stability in a light and temperature condition as well as in a light and temperature condition is improved.

In one embodiment, the light stabilizer may be included in an amount of from 0.005 to 1 part by weight per part by weight of rosuvastatin. In yet another embodiment, the light stabilizer may be included in an amount of 0.01 to 0.5 parts by weight per 1 part by weight of rosuvastatin. If the content is less than the above range, the light stabilizing effect is insufficient.

The first layer according to one embodiment may be in the form of a powder mixture comprising rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof.

The particle size of mannitol contained in the first layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof is in the range of the mean particle size, that is, 50% of the weight percentage in the particle size distribution curve (D50) or a mean value.

In one embodiment, the mannitol contained in the first layer has a particle size of 10 to 300 [mu] m (d50 or mean value). The mannitol may be, for example, 10 to 300 占 퐉 (d50 or mean value), 20 to 200 占 퐉 (d50 or mean value), 30 to 100 占 퐉 (d50 or mean value), or 33 to 65 占 퐉 (d50 or mean value) Lt; / RTI > By using mannitol having a specific particle size in these ranges, it is possible to improve the stability of the combined preparation and prevent the content of the active ingredient from decreasing, without deteriorating the dissolution rate of the drug contained in the combined preparation.

In one embodiment, the mannitol in the first layer may be included in an amount of 5 to 15 parts by weight, for example 5 to 10 parts by weight, per 1 part by weight of rosuvastatin. When the amount is less than these contents, the effect of improving the dissolution rate and the fixability and reducing the content of the active ingredient is insufficient.

Wherein the composition comprises rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and mannitol in a first layer of the combination preparation, wherein the second layer comprises telmisartan or a pharmaceutically acceptable salt thereof And a basic agent, and by controlling the specific particle size or content of mannitol contained in the first layer, the dissolution rate, precision, and stability of the combined preparation can be remarkably improved. In addition, such an effect does not exhibit the dissolution rate, the stability, and the stability improving effect equivalent to the valsartan as a special effect of the combination preparation, for example, when valsartan is used instead of rosuvastatin.

The second layer according to one embodiment may be in the form of a granulate comprising telmisartan or a pharmaceutically acceptable salt thereof and a basic agent.

In one embodiment, the basicizing agent contained in the second layer comprising telmisartan or a pharmaceutically acceptable salt thereof includes basic amino acids such as, for example, arginine, lysine and the like, for example, sodium hydroxide, potassium hydroxide , Alkaline earth metal oxides such as magnesium oxide, zinc oxide, meglumine, sodium carbonate, sodium bicarbonate, or combinations thereof, but are not limited thereto. It is not.

In one embodiment, the first layer may further comprise a light stabilizer. The light stabilizing agent is not limited as long as the drug contained in the first layer is rosuvastatin or amlodipine, particularly, a substance which can improve the stability of rosuvastatin which is vulnerable to light and can be added pharmaceutically. In one embodiment, the light stabilizer may be iron oxide, an edible tar pigment, an edible tar pigment aluminum lake, a natural pigment, or a combination thereof. In one embodiment, the light stabilizer may be yellow iron oxide, a food color blue No. 2, a food color blue No. 2 aluminum lake, or a combination thereof.

In one embodiment, the light stabilizer may be included in an amount of from 0.005 to 1 part by weight per part by weight of rosuvastatin. In yet another embodiment, the light stabilizer may be included in an amount of 0.01 to 0.5 parts by weight per 1 part by weight of rosuvastatin. If the content is less than the above range, the light stabilizing effect is insufficient.

The pharmaceutically acceptable salts of rosuvastatin, amlodipine, or telmisartan as used herein refer to salts prepared according to methods conventional in the art, and such methods of preparation are well known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, hydrobromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium or potassium, alkaline earth metals such as calcium and magnesium.

In one embodiment, the first layer may further comprise a binder, a lubricant, a disintegrant, or a combination thereof.

In one embodiment, the second layer may further comprise a diluent, a binder, a lubricant, or a combination thereof.

The binder includes, but is not limited to, polyvinylpyrrolidone, copovidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose, It is not.

The lubricant may be selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium benzoate, sodium stearyl fumarate, glyceryl monolate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, zinc stearate , Paraffins, and mixtures thereof.

The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glyconate, low-substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, Mixtures thereof, and the like.

Such diluents include, but are not limited to, lactose, dextrin, mannitol, sorbitol, starch, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, light silicic anhydride, sugars and mixtures thereof .

In one embodiment, the combined preparation may be formulated into tablets, pellets, capsules, or oral tablets, depending on the intended use, but is not limited thereto. In one embodiment, the combined preparation may be formulated into a multi-layer tablet, such as a two-layer tablet or a three-layer tablet, and may preferably be formulated in a two-layer tablet.

Said first layer according to one embodiment is in the form of a powder mixture comprising rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, said second layer being a mixture of telmisartan or pharmacologically acceptable salts Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt thereof and a basic agent.

Another aspect includes the steps of preparing a first layer that incorporates rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; And

There is provided a method of preparing the combination preparation of claim 1, comprising the step of preparing a second layer which comprises admixing telmisartan or a pharmaceutically acceptable salt thereof and a basic agent.

In one embodiment, a method is provided for further comprising mannitol in the first layer. In one embodiment, the particle size of the mannitol can be 20 to 200 탆 (d50 or mean value).

In one aspect, the other combination preparation is useful for patients who exhibit excellent dissolution rate, stability, uniformity, and saturation, and are required to take many drugs with hypertension and hyperlipemia.

In addition, since the combined preparation of telmisartan, amlodipine and rosuvastatin is used as a combined preparation, the number of medicines that have to be taken three or more times a day can be reduced to one tablet per day, If the effect is insufficient, there is no burden to administer additional drugs of other ingredients.

Fig. 1 shows properties before and after the light stability test for Example 3 and Comparative Example 4. Fig.
Fig. 2 shows photographs of the tablets prepared in Example 3, Comparative Example 1 and Comparative Example 3, observed. Fig.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Preparation of the combination preparation of Examples 1 to 8 and Comparative Examples 1 to 7

The following Examples and Comparative Examples illustrate the preparation of a first layer in which rosuvastatin, amlodipine and mannitol are mixed; And a second layer comprising a mixture of telmisartan and a basicizing agent.

I) Production of the second layer

First, to obtain the composition of the second layer, sodium hydroxide and meglumine were added to purified water (q.s), and then ethanol (q.s) was added. Telmisartan was added thereto to dissolve povidone. The solution was poured into a fluidized bed granulator together with mannitol (d50 or mean value: 200 μm or less), sprayed and dried to obtain a fluidized bed granule and mixed with sorbitol, light anhydrous silicic acid, and magnesium stearate.

Ii) Production of the first layer

In order to obtain the composition of the first layer, amlodipine besylate, rosuvastatin calcium, microcrystalline cellulose, mannitol (d50 or mean value: 20 m to 200 m), anhydrous calcium hydrogen phosphate, crospovidone, light silicic anhydride, stearic acid Magnesium, blue No. 2 aluminum lake, and yellow iron oxide were mixed.

The powder mixture of the granules of the second layer and the first layer prepared above was tableted with a tablet press to prepare a tablet.

Example 1)

I) Production of the second layer

7 mg of sodium hydroxide and 24 mg of meglumine were dissolved in purified water (q.s), and 80 mg of telmisartan was dissolved by adding ethanol (q.s) to dissolve 24 mg of povidone. The solution was mixed with 300 mg of mannitol to make fluidized bed granules, mixed with 40 mg of sorbitol and 1 mg of light silicic anhydride and 5 mg of magnesium stearate to prepare granules.

Ii) Production of the first layer

Separately from the second layer, 14 mg of amlodipine besylate, 21 mg of rosuvastatin calcium, 50 mg of microcrystalline cellulose, 142 mg of mannitol (20 m, d50 or mean value), 22 mg of anhydrous calcium hydrogen phosphate, 18 mg of crospovidone, 2 mg of anhydrous silicic acid, 15 mg of magnesium stearate, 0.08 mg of blue No. 2 aluminum lake, and 0.42 mg of yellow iron oxide were mixed to prepare a powder mixture.

The granules of the second layer and the powder mixture of the first layer were kneaded to prepare an alum.

Example 2)

The same procedure as in Example 1 was carried out except that the particle size of mannitol used in the first layer was changed to 33 mu m (d50 or mean value).

Example 3)

The procedure of Example 1 was repeated except that the particle size of mannitol used in the first layer was changed to 65 占 퐉 (d50 or mean value).

Example 4)

The procedure of Example 1 was repeated except that the particle size of mannitol used in the first layer was changed to 200 탆 (d50 or mean value).

Example 5)

The procedure of Example 3 was repeated except that the amount of yellow iron oxide in the first layer was changed to 0.21 mg.

Example 6)

The procedure of Example 3 was repeated except that the amount of yellow iron oxide in the first layer was changed to 3 mg.

Example 7)

In the first layer, 10.5 mg of rosuvastatin calcium, 56 mg of microcrystalline cellulose, 157.5 mg of mannitol and 11 mg of anhydrous calcium phosphate were prepared in the same manner as in Example 3.

Example 8)

0.42 mg of yellow iron oxide in the first layer and 0 mg of blue No. 2 aluminum lake were prepared in the same manner as in Example 3.

Comparative Example 1)

The procedure of Example 1 was repeated except that 192 mg of microcrystalline cellulose and 0 mg of mannitol were mixed in the first layer.

Comparative Example 2)

The procedure of Example 1 was repeated except that the particle size of mannitol used in the first layer was changed to 3 mu m (d50 or mean value).

Comparative Example 3)

The procedure of Example 1 was repeated except that the particle size of mannitol used in the first layer was changed to 354 탆 (d50 or mean value).

Comparative Example 4)

The procedure of Example 3 was repeated except that 0 mg of yellow iron oxide was used in the first layer and 0 mg of blue No. 2 aluminum lake was used.

Comparative Example 5)

The procedure of Example 3 was repeated except that 0.1 mg of yellow iron oxide and 0 mg of blue No. 2 aluminum lake were used in the first layer.

Comparative Example 6)

Except that 0.42 mg of yellow iron oxide, 0 mg of blue No. 2 aluminum lake, and 0.08 mg of Red No. 3 aluminum lake were used in the first layer.

Comparative Example 7)

The procedure of Example 3 was repeated except that 21 mg of valsartan was used instead of rosuvastatin calcium in the first layer.

Experimental Example 1:

The optical stability tests of Examples 3, 5 to 8, and Comparative Examples 4 to 6 were conducted under the following conditions in accordance with the Guideline for Optical Stability Evaluation (December 2015) of pharmaceutical drugs for drug use.

The specimens of Examples 3, 5 to 8 and Comparative Examples 4 to 6 were visually observed before and after light exposure, and the results are shown in Table 1 below.

division Before the test After the test Example 3 Light green Light green Example 5 Very light green Very light green Example 6 Light yellow Light yellow Example 7 Light green Light green Example 8 Light yellow Light yellow Comparative Example 4 White Brown Comparative Example 5 Very light yellow Light yellow Comparative Example 6 Light yellow Light yellow

Fig. 1 shows properties before and after the light stability test for Example 3 and Comparative Example 4. Fig.

As shown in Table 1 and FIG. 1, the compositions of Examples 3, 5 to 8 according to the present invention showed no change in properties before and after the light stability test. In comparison, in Comparative Examples 4 to 5, changes in properties were observed before and after the photostability test, and it was confirmed that photostigration of suvastatin occurred.

Experimental Example 2: Purity determination test (content and flexible substance measurement)

In the 11th revision of the European Pharmacopoeia, the contents and the substances were measured for the compositions prepared in Examples 3, 5 to 8 and Comparative Examples 4 to 6 according to the test method of suvastatin. The results are shown in Table 2 below.

division Content reduction (%) Flexible Substance Growth Rate (%) Example 3 7.5 13.1 Example 5 2.3 17.4 Example 6 3.2 14.9 Example 7 3.4 17.0 Example 8 6.2 52.7 Comparative Example 4 34.5 93.1 Comparative Example 5 17.3 127.0 Comparative Example 6 7.6 51.9

As shown in Table 2, in Examples 3 and 5 to 8 according to the present invention, the amount of decrease in content (%) and the rate of increase in the amount of softening material (%) were much smaller than those in Comparative Examples 4 to 6 , The content was reduced and the production of the flexible material was remarkably improved.

Experimental Example 3: Determination of dissolution rate of telmisartan

The dissolution test of Examples and Comparative Examples was carried out under the following two test conditions in accordance with the drug equivalence test standard (Food and Drug Safety Notification No. 2016-135). [Test Conditions]

(1) Telmisartan dissolution test conditions based on FDA

According to 'Telmisartan tablet' in Dissolution Methods for Drug Products (FDA)

(2) dissolution test conditions of telmisartan reflecting gastrointestinal environment ( pH 7.5, 300 mL, 50 rpm / min)

The two test conditions are the comparative dissolution test conditions according to the drug equivalence test standard, and the test condition (2) is a more severe condition, so that the equivalence in the clinical test results can be better guaranteed.

The similarity of the dissolution profile between the test results obtained under the above conditions and the reference drug (Twins tablet ^TM ) can be compared using the similarity factor (f ₂ ). The similarity factor (f ₂ ) is calculated using the dissolution rate (%) between two elution curves. The calculation formula is as follows.

(Where n is the number of time points, R _t is the mean dissolution rate of the reference drug and T _t is the mean dissolution rate of the test drug)

The similarity factors (f ₂ ) of Examples 1 to 5 and Comparative Example 1 calculated according to the above results are shown in Table 3 below. When the value of the similarity factor (f ₂ ) is 50 or more, it can be judged that the dissolution profile is equivalent. In addition, the larger the similarity factor value, the more similar dissolution rate to the reference drug.

division
The dissolution rate similarity factor (f ₂ ) Test conditions (1)
pH 7.5, 900 mL, 75 rpm Test conditions (2)
pH 7.5, 300 mL, 50 rpm Example 1 51 62 Example 2 54 74 Example 3 52 79 Example 4 55 63 Example 5 53 57 Comparative Example 1 50 32

As shown in Table 3, all of Examples 1 to 5 according to the present invention showed similarity factor values of 50 or more. Thus, in Examples 1 to 5, not only the dissolution test conditions of the standard and test methods but also the dissolution rate equivalent to that of the reference drug were observed under the test conditions reflecting the gastrointestinal environment.

However, in Comparative Example 1 in which no mannitol (20 mu m, d50 or mean value) according to the present invention is contained in the first layer, a test that is more severe than the test condition (1) the value of the similarity factor (f ₂₎ in the condition (2) was very low at 50 or less.

Experimental Example 4: Confirmation of tablet qualities

Tablets prepared in Examples 1 to 4, 7 and Comparative Examples 1 to 3 were observed for tablet pressurization through observation of discharge pressure and properties of the apparatus. The discharge pressure is a value indicating the force received by the device when the tablet is discharged. Generally, the higher the value, the more difficult the device will be, and the tablet is less stable. The pressure of the device displayed on the pressure gauge connected to the device when the tablet was pressed was checked. In addition, visual properties including the extent of refining of the tablet were visually observed and confirmed.

Table 4 shows the results of observation of discharge pressures and properties of the tablets prepared in Examples 1 to 4 and 7 and Comparative Examples 1 to 3.

division Discharge pressure (kgf) Appearance Example 1 51 Good Example 2 47 Good Example 3 36 Good Example 4 36 Good Example 7 35 Good Comparative Example 1 243 Bad Comparative Example 2 102 Bad Comparative Example 3 145 Bad

 Fig. 2 shows photographs of the tablets prepared in Example 3, Comparative Example 1 and Comparative Example 3, observed. Fig.

As shown in Table 4 and FIG. 2, the tablets of Examples 1 to 4 and 7 according to the present invention had a high discharge pressure of 35 to 51 kgf, a small amount of tablet corroding, Accordingly, the decrease in the content of the active ingredient can be prevented. In comparison, the tablets of Comparative Examples 1 to 3 had very high discharge pressures of 102 to 243 kgf, and the appearance of the tableted tablets was severely impaired and showed poor stability.

Experimental Example 5: Content uniformity test

The content uniformity test for Examples 1 to 5 and 7 and Comparative Examples 1 to 4 and 7 of the present invention was carried out according to the content uniformity test in the formulation uniformity test method of the Korean Test Method (Article 11) Respectively.

The results of the content uniformity test are shown in Table 5 as relative standard deviation (% RSD).

division Amlodipine Rosuvastatin Valsartan Example 1 2.4 2.6 - Example 2 1.9 0.1 - Example 3 1.1 0.4 - Example 4 3.3 1.0 - Example 7 2.5 0.5 - Comparative Example 1 15.7 16.0 - Comparative Example 2 8.9 8.3 - Comparative Example 3 17.2 16.1 - Comparative Example 7 18.7 - 19.4

As shown in Table 5, the tablets of Examples 1 to 4 and 7 according to the present invention had very low relative standard deviation (RSD) values of 0.1 to 3.3, indicating that the contents were very uniform. In comparison, the tablets of Comparative Examples 1 to 3 and 7 had a high RSD value of 8.3 to 19.4, indicating that the content was uneven.

Claims (14)

A first layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; And
A second layer comprising telmisartan or a pharmaceutically acceptable salt thereof and a basic agent. The combined preparation according to claim 1, wherein the light stabilizing agent comprises ferric iron oxide, an indigo guidder tar pigment, an indigo guidder type tar pig silver alum lake, or a combination thereof. The combined preparation according to claim 1, wherein the light stabilizer comprises yellow iron oxide, a food color blue No. 2, a food color blue No. 2 aluminum lake, or a combination thereof. The combined preparation according to claim 1, wherein the light stabilizer comprises yellow iron oxide and a blue color No. 2 aluminum lake. The combined preparation according to claim 1, wherein the light stabilizer is contained in an amount of 0.005 to 1 part by weight per part by weight of rosuvastatin. The combined preparation according to claim 1, wherein the light stabilizer is contained in an amount of 0.01 to 0.5 parts by weight per 1 part by weight of rosuvastatin. 2. The combination preparation according to claim 1, further comprising mannitol in the first layer. The combined preparation according to claim 7, wherein the particle size of the mannitol contained in the first layer is 20 to 200 mu m (d50 or mean value). The combined preparation according to claim 7, wherein the particle size of the mannitol contained in the first layer is 30 to 100 mu m (d50 or mean value). The combined preparation according to claim 7, wherein the first layer contains 5 to 15 parts by weight of mannitol per 1 part by weight of rosuvastatin. The combination preparation according to claim 1, wherein the combination preparation is a multilayer tablet. The combined preparation according to claim 1, wherein the combination preparation is a two-layer tablet formulation. A step of preparing a first layer which is admixed with rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and a light stabilizer; And
A method for preparing the combination preparation of claim 1, comprising the step of preparing a second layer which admixes telmisartan or a pharmaceutically acceptable salt thereof and a basic agent.  The method according to claim 1, further comprising adding mannitol to the first layer.

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