KR20190023938A - Pharmaceutical composition comprising rosuvastatin with improved stability - Google Patents

Abstract

Provided is a pharmaceutical composition including rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient, an iron oxide as a photostabilizer, an edible tar color, an edible tar color aluminum lake, a natural pigment, or a combination thereof. According to an embodiment, the pharmaceutical composition can significantly improve light stability of rosuvastatin, which is sensitive to light, and can further ensure stability of the active ingredient against temperature and humidity conditions as well.

Description

[0001] The present invention relates to pharmaceutical compositions comprising rosuvastatin with improved stability,

The present invention relates to a pharmaceutical composition containing rosuvastatin having improved stability, more specifically, rosuvastatin or a pharmaceutically acceptable salt thereof which can improve the light stability of rosuvastatin and shorten the manufacturing process ≪ / RTI >

Rosuvastatin, or a pharmaceutically acceptable salt thereof, is one of the HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treat dyslipidemia. In particular, rosuvastatin is widely used as a drug for the treatment of hyperlipidemia. In addition, rosuvastatin is superior to atorvastatin or simvastatin, which is commonly used as a drug of the same mechanism, to lower the LDL-cholesterol concentration in the blood as well as to increase the concentration of HDL-cholesterol in the body I am interested. It is important to maintain the stability of the active ingredient as the therapeutic effect is excellent and the drug having a small amount of usage is unfortunate. Unfortunately, rosuvastatin has poor stability due to temperature, humidity, especially light. 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 order to solve such a problem, there has been developed a technique of coating the outer surface of a pharmaceutical composition containing rosuvastatin by shading, but such a coating can not completely block the influence of light on the preparation, Humidity, which can lead to stability problems with rosuvastatin.

Patent Document 1 discloses a technique for forming a coating layer by spray coating rosuvastatin on a tablet, pellet, or granular core. However, it is difficult to secure the stability of the active ingredient, the loss is large in the spray drying process, There is a problem that efficiency is low.

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.

The inventors of the present invention have surprisingly found that the stability of light is remarkably improved in a pharmaceutical composition to which a specific coloring matter is added in comparison with a non-coloring matter preparation agent while continuing research for improving the stability of rosuvastatin.

Korean Patent Publication No. 2014-0037873

One aspect includes a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient and having improved light stability and a simple manufacturing process.

One aspect provides a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient and as a light stabilizer, iron oxide, an edible tar pigment, an edible tar pigment aluminum rake, a natural pigment, or a combination thereof do.

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 pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient and having improved light stability and a simple manufacturing process.

One aspect provides a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient and as a light stabilizer, iron oxide, an edible tar pigment, an edible tar pigment aluminum rake, a natural pigment, or a combination thereof do.

As used herein, the term " rosuvastatin "refers to [(E) -7- [4- (4-fluorophenyl) -6-isopropyl- 2- [methyl (methylsulfonyl) amino] pyrimidin- -Yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic acid]. The compound acts as a HMG-CoA reductase inhibitor as a statin-based drug, inhibiting the synthesis of cholesterol, and also reducing blood LDL-cholesterol and triglyceride levels. In addition, rosuvastatin exhibits excellent efficacy in the treatment of hypercholesterolemia, hyperlipidemia, or atherosclerosis, and is marketed as a product such as AstraZeneca's "CRESTOR ^TM ".

The term " pharmaceutically acceptable salts of rosuvastatin "refers to salts prepared according to methods conventional in the art, and such methods of preparation are 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 alkali metals such as sodium or potassium, alkaline earth metals such as calcium and magnesium and include, for example, rosuvastatin calcium salts, rosuvastatin hydrochloride, But are not limited to, rosuvastatin acetylsalicylate, rosuvastatin fumarate, rosuvastatin succinate, rosuvastatin maleate, or rosuvastatin malate, and the like.

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 food color 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 ). The sodium tetraoxide catalyst includes, 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 above-mentioned "Iron sesquioxide" refers to a compound containing 98.0% or more ferric oxide (Fe ₂ O ₃ ) and shows a red to yellowish powdery state (Korean Food Safety Association Notice No. 2016-32, Standards and specifications). 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.

In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable additive selected from the group consisting of a colorant, a diluent, a binder, a disintegrant, a lubricant, and combinations thereof.

The pigments may be added to facilitate identification of the tablets and may include, for example, brown iron oxide, yellow iron oxide, black iron oxide, red iron oxide, green No. 201, green No. 2, green No. 3, , Red No. 104, Red No. 18, Red No. 1, Red No. 227, Red No. 2, Red No. 3, Red No. 3 Aluminum Lake, Red No. 40, Red No. 40 Aluminum Lake, Red No. 4, No. 1, Blue No. 1 Aluminum Lake, Blue No. 203, Blue No. 2, Blue No. 2 Aluminum Lake, Blue No. 4, Blue No. 4 Aluminum Lake, Blue No. 5, Yellow No. 1, Yellow No. 203, Yellow No. 203 Aluminum Lake , Yellow No. 205, Yellow No. 4, Yellow No. 4 Aluminum Lake, Yellow No. 5, Yellow No. 5 Aluminum Lake, Yellow No. 6, Gardenia Blue, Gardenia Yellow, Caramel Color, Edible Orange Pigment, Edible Orange Pigment, White pigments, but are not limited thereto. For example, the white pigment may include titanium oxide or calcium carbonate.

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 .

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

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.

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.

In one embodiment, the pharmaceutical composition may further comprise a medicament for treating a metabolic syndrome disease that can be used in combination with a pharmaceutical. The term " Metabolic syndrome "refers to a pathological phenomenon in which various metabolic abnormalities are present simultaneously. For example, the metabolic syndrome includes cardiovascular diseases, hypertension, hyperglycemia, hypertriglyceridemia, diabetes, nonalcoholic fatty liver, hyperuricemia, obesity, insulin resistance, impaired glucose regulation, It is not. In the above metabolic syndrome diseases, it is often accompanied by an increase in dyslipidemia, total cholesterol (TC) and high density lipoprotein cholesterol (HDLC), and rosuvastatin or a pharmaceutically acceptable salt thereof inhibits the synthesis of cholesterol Is effective in the treatment of metabolic syndrome diseases accompanied by various symptoms when used together.

In one embodiment, the pharmaceutical composition may be formulated into powders, granules, tablets, pellets, capsules, or oral tablets, depending on the intended use, but is not limited thereto.

The pharmaceutical composition according to one aspect significantly improves the light stability of rosuvastatin, which is vulnerable to light, and can secure the stability of the active ingredient even under temperature and humidity conditions.

In addition, since coating or spray-drying steps in the prior art, which have been attempted to complement the stability of rosuvastatin, can be omitted, the manufacturing method is simple and the loss in the manufacturing process can be reduced, which is economical and efficient.

Fig. 1 is a photograph showing the characteristics before and after the light stability test of Example 2, Light Comparative Example 1. 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.

Examples 1 to 5 and Comparative Examples 1 to 2: Preparation of pharmaceutical composition

The pharmaceutical compositions of Examples 1 to 5 and Comparative Examples 1 to 3 were prepared.

Specifically, the content ratio of rosuvastatin calcium, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate, crospovidone, light silicic anhydride, stearic acid magnesium oxide, yellow iron oxide, blue No. 2 aluminum lake, and red No. 3 aluminum lake To prepare Examples and Comparative Examples.

Example 1)

21 mg of rosuvastatin calcium, 50 mg of microcrystalline cellulose, 142 mg of mannitol, 22 mg of anhydrous calcium hydrogen phosphate, 18 mg of crospovidone, 2 mg of light silicic anhydride, 15 mg of magnesium stearate, 0.21 mg of yellow iron oxide, 0.08 mg of aluminum lake were mixed.

Example 2)

The procedure of Example 1 was repeated except that 0.42 mg of yellow iron oxide was used.

Example 3)

The procedure of Example 1 was repeated except that the amount of yellow iron oxide was changed to 3 mg.

Example 4)

The procedure of Example 1 was repeated except that 10.5 mg of rosuvastatin calcium, 56 mg of microcrystalline cellulose, 157.5 mg of mannitol, 11 mg of anhydrous calcium phosphate, and 0.42 mg of yellow iron oxide were used.

Example 5)

0.42 mg of yellow iron oxide, and 0 mg of blue No. 2 aluminum lake were prepared in the same manner as in Example 1.

Comparative Example 1)

The procedure of Example 1 was repeated except that 0 mg of yellow iron oxide and 0 mg of blue No. 2 aluminum lake were used.

Comparative Example 2)

Except that 0.1 mg of yellow iron oxide and 0 mg of blue No. 2 aluminum lake were used.

Comparative Example 3)

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 prepared in the same manner as in Example 1.

Experimental Example 1:

The light stability tests of Examples 1 to 5 and Comparative Examples 1 to 3 were conducted under the following conditions according to the Guideline for Evaluation of Photostability of Pharmaceutical Drugs (December 2015).

The specimens of Examples 1 to 5 and Comparative Examples 1 to 3 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 1 Very light green Very light green Example 2 Light green Light green Example 3 Light yellow Light yellow Example 4 Light green Light green Example 5 Light yellow Light yellow Comparative Example 1 White Brown Comparative Example 2 Very light yellow Light yellow Comparative Example 3 Light red Light red

Fig. 1 shows properties before and after the light stability test for Example 2 and Comparative Example 1. Fig.

As shown in Table 1 and FIG. 1, the compositions of Examples 1 to 5 according to the present invention showed no change in properties before and after the light stability test. In comparison, in Comparative Examples 1 and 2, changes in properties were observed before and after the photostability test, indicating that photostigration of suvastatin occurred.

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

In the 11th edition of the European Pharmacopoeia, the contents and the substances were measured for the compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 according to the test method of suvastatin. The results are shown in Table 2 below.

division Content reduction (%) Flexible Substance Growth Rate (%) Example 1 7.9 14.9 Example 2 2.1 18.3 Example 3 3.1 15.4 Example 4 3.3 18.0 Example 5 6.3 54.0 Comparative Example 1 33.9 91.9 Comparative Example 2 15.6 110.0 Comparative Example 3 7.3 50.4

As shown in Table 2, in Examples 1 to 5 according to the present invention, the amount of decrease in content (%) and the amount of increase in content of flexible material (%) were much smaller than those in Comparative Examples 1 to 3 under acceleration conditions over time, And the production of the flexible substance was remarkably improved.

Claims (7)

A pharmaceutical composition comprising rosuvastatin as an active ingredient or a pharmaceutically acceptable salt thereof and iron oxide, edible tar pigment, edible tar pigment aluminum rake, natural pigment, or a combination thereof as a light stabilizer. The pharmaceutical composition according to claim 1, wherein the light stabilizing agent comprises ferric iron oxide, an indigo guidder tar pigment, an indigo guid tar pigment aluminum flake, or a combination thereof. The pharmaceutical composition according to claim 1, wherein the light stabilizer comprises yellow iron oxide, edible pigment blue No. 2, edible pigment blue No. 2 aluminum lake, or a combination thereof. The pharmaceutical composition according to claim 1, wherein the light stabilizer comprises yellow iron oxide and a food color blue No. 2 aluminum lake. The pharmaceutical composition according to claim 1, wherein the light stabilizer is included in an amount of 0.005 to 1 part by weight per part by weight of rosuvastatin. The pharmaceutical composition 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. The pharmaceutical composition according to claim 1, further comprising a drug for treating a metabolic syndrome disease which can be used in combination with a pharmaceutical.

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