TW201408283A - Composite formulation for oral administration comprising metformin and rosuvastatin - Google Patents

Abstract

Provided are a composite formulation for oral administration comprising metformin and rosuvastatin and a method for preparing the same. The composite formulation according to the present invention exhibits excellent effects on preventing and treating dyslipidemia and hypercholesterolemia and shows excellent storage stability, and thus can be effectively used for treating dyslipidemia and hypercholesterolemia in a diabetic patient.

Description

Oral administration of metformin (METFORMIN) and rosuvastatin (ROSUVASTATIN) Compound formulation Field of invention

The present invention relates to a compound formulation for oral administration of metformin and rosuvastatin.

Background of the invention

Metformin, a biguanide antidiabetic drug, is an oral antidiabetic agent mainly used for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

The glycemic control mechanism is not associated with insulin secretion, and such mechanisms are known to initiate the delivery of glucose in the liver. Metformin can cause weight loss in diabetic patients, reduce the concentration of triglycerides and low-density lipoproteins in the blood, and increase the concentration of high-density lipoprotein. Therefore, metformin can be used as a main drug for insulin-resistant non-insulin-dependent diabetic patients.

Currently, Glucophage ^® (Mock) hydrochloride tablets have been sold on the market. Glucophage ^® tablets contain 250 mg, 500 mg, or 1,000 mg of metformin hydrochloride, and the maximum required amount is no more than 2,550 mg, depending on effectiveness and resistance. 20 to 30% of patients taking metformin will have side effects associated with taking metformin, such as decreased appetite, bloating, nausea, vomiting, and the like. Most side effects are usually eliminated 2 to 3 weeks after taking metformin for a short time. However, metformin should be stopped immediately when it is not possible to eliminate diarrhea and severe bloating. In a few cases, taking metformin may cause skin rashes, urticaria, and the like. Side effects can be avoided by lowering the minimum dose and/or continuous dose or by using a sustained release formulation that reduces the number of administrations.

Conventional metformin sustained release formulations can be prepared by utilizing polymeric materials or by controlled release of osmotic pressure. For example, Korean Patent No. 1043816 discloses a metformin-based release tablet which is a selective hydrophobic sustained release carrier and a water-swellable polymer which can be made by a water-swellable polymer and by hydrophobicity. The polymer blocks the penetration of water and controls the rate of drug release. In addition, Korean Patent No. 0772980 discloses a natural gum and polyoxyethylene metformin sustained-release formulation for oral administration, which can be maintained by limiting the release rate of metformin having high water solubility when used for oral administration. The constant blood concentration of metformin acts as a hydrophilic polymer for the sustained release carrier.

Meanwhile, an HMG-CoA reductase inhibitor such as rosuvastatin calcium salt is a 3-hydroxy lactone ring or a corresponding ring-opening dihydroxy ring-opening acid, and it is commonly referred to as "statin". Typically, single drug therapy with statins has been used to maintain cholesterol in the normal range of concentrations. Statin inhibits HMG-CoA reductase, which controls the rate of cholesterol production in the body, thereby delaying the production of cholesterol, or promoting its improvement to remove LDL from the blood. Liver function of sterols, and thus lower cholesterol levels, can therefore be used to treat dyslipidemia and hypercholesterolemia.

According to the guidelines of the Korean Diabetes Association, diabetic patients are advised to take a formulation containing statins when dyslipidemia and hypercholesterolemia occur. Thus, the development of co-prescription complex formulations, which typically contain metformin and statin, can be used in place of co-administration, thereby improving patient compliance. At the same time, the use of a composite formulation is economically advantageous compared to taking separate drugs separately.

A pharmaceutical composition containing metformin and rosuvastatin as an active ingredient is disclosed in International Patent Publication No. WO 2011/081493. However, this composition has the disadvantage that the content of rosuvastatin in the formulation is rapidly reduced one month after storage under accelerated conditions. The statin formulation containing rosuvastatin is most stable under alkaline conditions and is unstable under acidic conditions. For this reason, since metformin is acidic, when metformin and rosuvastatin are physically in contact with each other, the interaction will cause deterioration of the stability of rosuvastatin.

Accordingly, the present inventors have conducted a comprehensive study to prepare a compound preparation having an excellent storage stability containing oral administration of metformin and rosuvastatin, and as a result, the inventors have found that by containing a functional coating The coating of the cloth material is coated with metformin, and then the metformin is coated with a coating containing an alkaline agent and rosuvastatin to avoid physical contact between the drugs.

Summary of invention

Accordingly, it is an object of the present invention to provide a composite formulation for oral administration with excellent storage stability, wherein the formulation contains metformin or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof .

Another object of the present invention is to provide a method for preparing the oral composite formulation.

According to one aspect of the present invention, there is provided a composite formulation for oral administration comprising: (1) containing metformin or a pharmaceutically acceptable salt thereof and a controlled release agent; (2) a first coating layer formed on the surface of the core And comprising a functional coating material; and (3) a second coating layer formed on the surface of the first coating layer, comprising rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent.

According to another aspect of the present invention, a method for preparing the oral composite formulation is provided, the steps comprising: (1) preparing a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof and a controlled release agent; (2) forming a first cladding layer on the core surface, comprising a functional coating material; and (3) forming a second coating layer on the surface of the first cladding layer, comprising rosuvastatin or a medicament thereof Acceptable salts and an alkalizing agent.

Detailed description of the invention

The present invention provides a composite formulation for oral administration comprising: (1) a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof and a controlled release agent a core (2) a first coating layer formed on the core surface, comprising a functional coating material; and (3) a second coating layer formed on the surface of the first coating layer, comprising Roche Statins or their pharmaceutically acceptable salts and an alkalizing agent.

The nature and type of the various ingredients constituting the composite formulation for oral administration of the present invention will be described in detail hereinafter.

1. A sustained release core containing metformin or a pharmaceutically acceptable salt thereof

According to the composite formulation of the present invention, the sustained release core comprises metformin or a pharmaceutically acceptable salt thereof and a controlled release agent.

The sustained release core comprises metformin as a first pharmaceutically active material or a pharmaceutically acceptable salt thereof, which is preferably metformin hydrochloride. The content of metformin or a pharmaceutically acceptable salt thereof in the unit dosage form per unit dosage form is, but not limited to, 250 mg to 1000 mg, preferably 500 mg to 1000 mg.

In order to control the release rate of metformin, the sustained release core according to the present invention contains a controlled release agent of an expandable polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and ethylcellulose. Preferably, the group consisting of phenol, polyoxyethylene, guar gum, locust bean gum, and mixtures thereof is hydroxypropyl methylcellulose.

The controlled release agent is used in an amount of 25 to 65% by weight, preferably 35 to 55% by weight, based on the total weight of the core.

The sustained release core according to the present invention is preferably in the form of a tablet, and the tablet type sustained release core can be prepared by mixing metformin or a pharmaceutically acceptable salt thereof, a controlled release agent and other pharmaceutically acceptable excipients. And the mixture is made into a tablet.

According to a specific embodiment of the present invention, metformin hydrochloride, hydroxypropylmethylcellulose, lactic acid, and polyvinylpyrrolidone are mixed; a certain amount of pure water is added and mixed; and then the mixture is dried to be granulated. material. Thereafter, a lubricant is added to the granulated material to increase the lubricity for a period of time, and then a custom ingot pressure is applied to form a sustained release core.

Second, the first coating

According to the composite formulation of the present invention, the first coating layer is applied to the coating layer on the surface of the sustained-release core, which functions by preventing physical contact between metformin and rosuvastatin and avoiding the sustained release core contained in metformin The water in the controlled release agent infiltrates rosuvastatin to reduce the release of rosuvastatin-related substances from the interaction between metformin and rosuvastatin. The first coating layer contains a functional (hydrophobic) coating material.

Specifically, when rosuvastatin is directly applied to the surface of the sustained-release core containing metformin hydrochloride, it will cause physical contact with metformin and rosuvastatin to produce lactone, as well as internal control of metformin sustained-release core. The water of the release will accelerate the disadvantages of lactone production. However, the first coating layer containing the functional coating material in the present invention is formed between the sustained release core containing metformin and the second coating layer containing rosuvastatin, that is, on the surface of the sustained release core. Therefore, the reduction of rosuvastatin content during storage can be avoided.

The functional coating material which can be used in the present invention is selected from the group consisting of ethyl cellulose, cellulose acetate, (meth)acrylic copolymer (Eudragit), and mixtures thereof, preferably B. Cellulose.

The functional coating material is based on the total weight of the first cladding layer The amount is from 16 to less than 48%, preferably from 16 to 32% by weight. When the amount of the functional coating material is less than 16% by weight, the functional coating material (eg, ethyl cellulose) will not cover the entire surface area of the sustained-release core, resulting in a decrease in Luo after a certain period of time. Sulvastatin content. On the other hand, when the amount of the functional coating material exceeds 48% by weight, the drug is delayed to be released, and when a larger amount is used, the release of the drug is further delayed.

The first coating layer further contains, in addition to the functional coating material, general coating materials conventionally known in the art, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinyl alcohol. Further, it may further contain a pharmaceutically acceptable additive as needed. Examples of pharmaceutically acceptable additives include decomposers, diluents, stabilizers, binders, and lubricants.

In the present invention, the first coating layer may be formed on the surface of the sustained-release core by applying a coating solution by dispersing or dissolving the functional coating material in water, ethanol, or a mixed solvent thereof. A mixed solvent of water and ethanol is preferred.

The first coating layer applied to the surface of the sustained-release core is 2 parts by weight or more, and preferably 4 parts by weight to 10 parts by weight, based on 100 parts by weight of the sustained-release core.

Third, the second coating layer (rosuvastatin coating)

In the composite formulation of the present invention, the second coating layer as a pharmaceutically active ingredient contains rosuvastatin or a pharmaceutically acceptable salt thereof, and an alkalizing agent.

In the case of rosuvastatin or a pharmaceutically acceptable salt thereof according to the present invention, it is preferred to use rosuvastatin calcium, and per unit dosage form thereof. The amount is, but not limited to, 1 mg to 50 mg, preferably 5 to 40 mg.

In the present invention, the second coating layer contains an alkalizing agent which inhibits the production of a lactone which is a main decomposition product of rosuvastatin. The alkalizing agent may be selected from the group consisting of magnesium carbonate (MgCO ₃ ), magnesium hydroxide (Mg(OH) ₂ ), sodium hydrogencarbonate (NaHCO ₃ ), calcium carbonate (CaCO ₃ ), and mixtures thereof.

The alkalizing agent may be used in an amount of 2 to 8% by weight, preferably 4 to 8% by weight, based on the total mass of the second coating layer.

When the amount of the alkalizing agent exceeds 8% by weight, the effect of suppressing the lactone production cannot be further produced, but when the relative content of the coating material is lowered, the adsorption rate of the second coating layer is also lowered.

Further, in the composite formulation of the present invention, the second coating layer may further contain a general coating material such as polyethylene glycol, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol graft polymer, or Its mixture. The polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft polymer or a mixture thereof is used in an amount of 25 to 85% by weight, preferably 25, based on the total weight of the second coating layer. Up to 80% by weight.

In the composite formulation of the present invention, the second coating layer can be prepared by dispersing or dissolving rosuvastatin or a pharmaceutically acceptable salt thereof, polyethylene glycol, polyvinyl alcohol (PVA), polyvinyl alcohol- A polyethylene glycol graft polymer or a mixture thereof, and an alkalizing agent in water, ethanol or a mixture thereof are then coated on the surface of the first coating layer.

The second coating layer applied to the surface of the first coating layer is from 3 parts to 30 parts by weight, preferably 5 parts by weight to 100 parts by weight of the sustained release core. 20 parts by weight.

Furthermore, the present invention provides a method for preparing a composite formulation for oral use, the steps comprising: (1) preparing a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof and a controlled release agent; (2) at the core Forming a first coating layer comprising a functional coating material; and (3) forming a second coating layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent on the first coating layer .

Specifically, the present invention provides a method for preparing a composite formulation for oral use, the steps comprising: (1) preparing a sustained release core by using metformin or a pharmaceutically acceptable salt thereof and a controlled release agent according to a conventional method to form a tableting agent; (2) applying a coating solution prepared by dissolving a functional coating material in a suitable enteric coating solvent (for example, a mixed solvent of ethanol and water) to the surface of the sustained-release core To form a first cladding layer and then to dry; and (3) to dissolve a coating material such as polyethylene glycol, polyvinyl alcohol-polyethylene in a suitable solvent such as a mixed solvent of ethanol and water. An alcohol grafted polymer or a mixture thereof, an alkalizing agent, and a coating solution prepared from rosuvastatin or a pharmaceutically acceptable salt thereof, together with any pharmaceutically acceptable additive, applied to the surface of the first coating layer A second cladding layer is formed and then dried. The obtained complex formulation of the present invention can be formulated into an oral dosage form of a coated tablet according to a conventional preparation method.

After 6 months of storage under accelerated storage conditions of 40 ° C and 75% relative humidity, the oral composite formulation Nairoshu made by the method of the present invention according to the requirements described in the International Drug Regulatory Association (ICH) guidelines The content of statin is more than 90%. The compound formulation for oral administration has a pole Good storage stability and drug release rate, as well as can be effectively used as a composite formulation.

The oral complex formulation of the present invention contains two pharmacologically active ingredients, namely metformin and rosuvastatin, in a lozenge, and thus can be used for simultaneous treatment of dyslipidemia and hypercholesterolemia in diabetic patients. Thus, the combination formulation for oral administration reduces the inconvenience of requiring two separate tablets for the patient and significantly improves patient compliance.

Figure 1 and Figure 2 show the changes in the rosuvastatin content of the formulations prepared in the comparative examples and the examples under accelerated storage conditions, respectively; and Figure 3 shows that the elution rate of metformin depends on the comparative examples and the examples. The ethylene cellulose (EC) content in the coating of the formulation.

Detailed description of the preferred embodiment

Hereinafter, the present invention will be more specifically illustrated by the following examples. However, it is provided for illustrative purposes only, and the invention is not limited to only these embodiments.

Examples 1 and 2 and Comparative Examples 1 and 2: Preparation of a sustained release lozenge for coating a functional barrier agent and rosuvastatin Step 1: Metformin sustained release core

Metformin hydrochloride, hydroxypropylmethylcellulose HPMC 2208 (Shin-Etsu Chemical Co.), lactose, and polyvinylpyrrolidone PVP K30 (BASF, Germany) were premixed according to the compositions listed in Table 1 below. Connect Then, a certain amount of pure water is added, and then the mixture is stirred, and dried to obtain a granulated product. Magnesium stearate was added to the prepared mixture for 5 minutes to enhance the slip to improve the mixture, and then a pressure of 10 kN was applied to prepare a sustained release tablet.

Step 2: Functional barrier coating

Ethylcellulose (Dow's Chemical, USA), hydroxypropylmethylcellulose HPMC 2910 (Shin-Etsu, Japan), Polyethylene II were mixed according to the composition listed in Table 2 below in a mixed solvent of ethanol and water. Alcohol PEG 6000 (SANYO Chemical, Japan), and polyvinylpyrrolidone PVP K-30 (BASF, Germany). Next, the mixture was applied onto the surface of the sustained release core prepared in the step 1 by a coater (SEJONG, SFC-30), and then dried to obtain a functional barrier coated tablet. During the coating process, the supply air temperature was controlled at 45 ° C and the product temperature was controlled at 30 ° C. After the coating process was completed, the tablet was dried for 30 minutes to remove residual ethanol and water.

Step 3: Rosuvastatin drug layer

Mix rosuvastatin calcium, polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat ^® IR, BASF, Germany), magnesium carbonate and Povidone according to the composition listed in Table 3 below in a mixed solvent of ethanol and water. K30 (BASF, Germany). The mixture is applied to the surface of the coated sustained release tablet of the functional barrier layer produced in the above step 2 by a coater (SEJONG, SFC-30) for a second time, and then dried to prepare the composite formulation of the present invention. Things. During the coating process, the supply air temperature was controlled at 45 ° C and the product temperature was controlled at 30 ° C. After the coating process was completed, the tablet was dried for 30 minutes to remove residual ethanol and water.

Examples 3 and 4 and Comparative Examples 3 and 4: Preparation of coated functional barriers (using different functional coating materials) and rosuvastatin sustained release tablets Functional barrier coating

According to the composition listed in Table 4 below, hydroxypropylmethylcellulose HPMC 2910 (Shin-Etsu, Japan), polyethylene glycol PEG 6000 (SANYO Chemical, Japan), and poly were mixed in a mixed solvent of ethanol and water. Vinyl pyrrolidone PVP K-30 (BASF, Germany) together with ethyl cellulose, cellulose acetate (Eastmal, USA), (meth)acrylic acid copolymer (Evonik, Germany), polyvinyl alcohol (Astro, USA) or White sugar (CJ, Korea). The procedure of Example 1 was repeated except that a functional barrier coated tablet was prepared by coating a mixture using a coater (SEJONG, SFC-30) to prepare a sustained release tablet.

Examples 5 to 7 and Comparative Example 5: Preparation of a sustained release lozenge coated with rosuvastatin using different kinds of alkalizing agents Rosuvastatin drug layer

According to the composition listed in Table 5 below, rosuvastatin calcium, polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat IR, BASF, Germany) and Povidone K30 (BASF, were mixed in a mixed solvent of ethanol and water. Germany) together with magnesium hydroxide (Ilyang Pharmaceutical Co., Ltd., Korea, Korea), sodium bicarbonate (Duksan, Korea) or calcium carbonate (Sankyo, Japan). In addition to using a coater (SEJONG, SFC-30) by applying a secondary coating mixture to a sustained release tablet coated with a functional barrier layer prepared in Step 2 and then drying to prepare a composite formulation of the present invention The procedure of Example 1 was repeated to prepare a sustained release tablet.

Examples 8 to 10 and Comparative Examples 6 to 8: Preparation of a sustained release lozenge coated with rosuvastatin using different amounts of an alkalizing agent

In addition to the rosuvastatin drug layer described in Step 3 of Example 1, a sustained release tablet was prepared by the same method as in Example 1, and the content of magnesium carbonate (BASF, Germany) was changed according to the following Table 6. A composite formulation is prepared.

Comparative Example 9: Preparation of a sustained release lozenge containing metformin

The procedure of Step 1 of Example 1 was repeated to prepare a sustained release tablet containing metformin, and then a non-functional barrier layer was formed as described in Step 3 of Example 1 to form a coating containing rosuvastatin to prepare a sustained release tablet.

Comparative Example 10: Preparation of a sustained release lozenge for coating a functional barrier layer and rosuvastatin

The procedure of Example 1 was repeated to prepare a sustained release tablet, except that the composition of the functional barrier layer listed in Table 7 below was used.

Experimental Example 1: Rosuvastatin stability in the presence of a drug barrier

The formulations prepared in Comparative Examples 9 and 10 were packaged in high density polyethylene (HDPE) bottles and then stored at 50 ° C and 75% relative humidity under accelerated conditions. After 1, 3, and 6 months of storage, samples were taken and tested against the sustrovastatin control formulation of the Suvast (Hanmi Pharmaceutical Co., Ltd.) standard and test method. Specifically, 100 mg of rosuvastatin sample was added to a 500 mL-flask and then mixed well. Next, the liquid was passed through a 0.45 μm filter, followed by HPLC and the absorbance at 242 nm to measure the concentration of rosuvastatin. The results are shown in Table 8 (unit: %) and Figure 1.

As shown in Table 8 and Figure 1, all rosuvastatin levels in the formulations of Comparative Examples 9 and 10 were reduced according to storage time. The formulation of Comparative Example 9 which did not contain a functional barrier coating failed to meet the requirements of the ICH guidelines 3 months after the initial storage period, while the formulation of Example 10 was compared and could not be used 6 months after the initial storage period. Accepted for the ICH guidelines.

The cause of rosuvastatin breakdown is expected to be physical contact between rosuvastatin, which is stable in an alkaline environment and in metformin hydrochloride. Specifically, it is expected that the decomposition of rosuvastatin in Comparative Example 10 will be affected by HPMC 2208 containing a large amount of water in the sustained release core of metformin. Based on the above results, it can be demonstrated that the stability of rosuvastatin cannot be rescued only by physically blocking the active ingredient.

Experimental Example 2: Rosuvastatin stability of EC content in functional barrier coatings

The rosuvastatin content according to the same method as Experimental Example 1 was confirmed using the formulations prepared in Examples 1 and 2 and Comparative Examples 1 and 2. The results are shown in Table 9 (unit: %) and Figure 2.

Compared with the formulations prepared in the absence of EC in Comparative Examples 9 and 10, the formulations prepared by adding the EC of the functional coating material in Examples 1 and 2 and Comparative Examples 1 and 2 can significantly improve the stability of the content. Sex. However, in Comparative Example 1 (containing 8% by weight), the rosuvastatin content after initial storage for 6 months under accelerated conditions was 91.6% of the initial amount, which was not in the commercial metformin sustained release lozenge content standard. It is in the range of 95 to 105%, so its stability is not guaranteed. On the other hand, when the EC content in the mass of the functional barrier layer is 16% by weight or more, the stability can be maintained up to 6 months under accelerated conditions.

From the above results, it was confirmed that when the content of the functional coating material was 16% by weight or more, it was effective in preventing the decrease in the content of rosuvastatin due to the water contained in the sustained release core of metformin.

Experimental Example 3: Metformin elution rate of EC content in a functional barrier coating

When the functional barrier coating contains a high EC content, the EC content can affect the elution rate of metformin. Therefore, the elution test of metformin was carried out using the formulations obtained in Examples 1 and 2 and Comparative Examples 1 and 2. Test.

Specifically, the elution test was carried out according to the second method (paddle method) of the Korean Pharmacopoeia dissociation test at 37 ° C according to the dissociation test of the Korean Pharmacopoeia using 900 mL of the second liquid (artificial intestinal secretion). The time-based elution solution after the elution was started, and then the elution rate was measured by high performance liquid chromatography. The results are shown in Table 10 (unit: %) and Figure 3.

In Comparative Example 2, it was confirmed that when the EC content of the functional barrier coating layer was 48%, the elution rate of metformin was delayed. However, when the EC content is 32% or less, there is no elution delay due to the presence of the functional barrier coating.

The non-trademark product Megaformin SR ingot (Hanmi Pharmaceutical Co., Ltd.) is a product that is bioequivalent to Glucophage XR ingot (Mock) and is commercially available, and its standard elution rate is set at 1 The hour is 20 to 40%, 40 to 60% at 3 hours, and 80% or higher at 12 hours. The elution rate of the comparative example 12 did not fall at the standard elution rate at the reference time, so it can be easily expected that it is not easy to protect. Bioequivalent and not applicable by product standards.

Therefore, based on the results of Experimental Examples 2 and 3, it can be concluded that the preferred EC amount in the functional barrier coating is 16 to 32% for maintaining the stability of rosuvastatin by blocking water and also does not affect metformin. The amount of drug released.

Experimental Example 4: Rosuvastatin stability depends on the type of coating material of the functional coating

The content of rosuvastatin was confirmed by the same method as Experimental Example 1 by using the formulations prepared in Examples 3 and 4 and Comparative Examples 3 and 4. The results are shown in Table 11 (unit: %).

Ethyl cellulose, cellulose acetate, and (meth)acrylic copolymer were used as functionalities in Examples 1, 3 and 4, respectively, compared to the formulations prepared in Comparative Examples 3 and 4 containing polyvinyl alcohol and white sugar, respectively. The formulation prepared by the coating material has a significant improvement in content stability.

Experimental Example 5: Rosuvastatin stability depends on the type of alkalizing agent

The content of rosuvastatin was confirmed by the same method as Experimental Example 1 by using the formulations prepared in Examples 5 and 7 and Comparative Example 5. The results are shown in Table 12 (unit: %).

And without any alkalizing agent, which can inhibit the lactone which produces the main decomposition product of rosuvastatin, compared with the preparation prepared in the comparative example 5, respectively containing magnesium carbonate, magnesium hydroxide, sodium hydrogencarbonate and calcium carbonate as a base. The formulation prepared in Example 1, and 5 to 7 significantly improved the stability of the content.

Experimental Example 6: Stability test according to the formulation of an alkalizing agent

The formulations prepared in Examples 8 to 10 and Comparative Examples 6 to 8 were packaged in a high density polyethylene (HDPE) bottle and then stored at 50 ° C and 75% relative humidity under accelerated conditions. After storage for 1 month, the sample was taken out and the amount of the relevant compound of the lactone of the main decomposition product of rosuvastatin was determined. The results are shown in Table 13 below.

When there is no, or only a small amount of alkalizing agent, Comparative Example 6 and The formulation of 7 has a relatively low stability when compared to the formulations of Examples 8 to 10, and thus contains a large amount of lactone-related substances. At the same time, the formulation in Comparative Example 8 containing a greater amount of basifying agent than the formulation of Example 10 produced a greater amount of lactone related material. Therefore, it is inferred that the preferred amount of the alkalizing agent ranges from 4 to 8% by weight, based on the total weight of the second coating layer.

Claims (12)

An oral complex formulation comprising: 1) a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof, and a controlled release agent; 2) a first coating layer formed on the surface of the core, comprising a a functional coating material; and 3) a second coating layer formed on the surface of the first coating layer, comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and an alkalizing agent. The composite formulation of claim 1, wherein the controlled release agent is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, polyoxyethylene, guar gum, hedgehog a group of soybean gum, and mixtures thereof. The complex formulation of claim 1, wherein the metformin or a pharmaceutically acceptable salt thereof is present in an amount of from 250 mg to 1000 mg. The composite formulation of claim 1, wherein the functional coating material is selected from the group consisting of ethyl cellulose, cellulose acetate, (meth)acrylic acid copolymers, and mixtures thereof. The composite formulation of claim 1 wherein the functional coating material is present in an amount between 16 and less than 48% by weight based on the total weight of the first coating. The composite formulation of claim 5, wherein the functional coating material is present in an amount between 16% and 32% by weight based on the total weight of the first coating. The composite formulation of claim 1, wherein the alkaline agent is selected from the group consisting of magnesium carbonate (MgCO ₃ ), magnesium hydroxide (Mg(OH) ₂ ), sodium hydrogencarbonate (NaHCO ₃ ), calcium carbonate (CaCO ₃ ), And a group of mixtures thereof. The composite formulation of claim 1, wherein the alkalizing agent is present in an amount of from 4% to 8% by weight based on the total weight of the second coating layer. The complex formulation of claim 1, wherein the rosuvastatin or a pharmaceutically acceptable salt thereof is contained in an amount of from 1 mg to 50 mg per unit dosage form. The composite formulation of claim 1, wherein the first coating layer is used in an amount of from 4 parts by weight to 10 parts by weight based on 100 parts by weight of the sustained release core. The composite formulation of claim 1, wherein the second coating layer is used in an amount of from 3 parts to 30 parts by weight based on 100 parts by weight of the sustained release core. A method for the preparation of a composite formulation according to claim 1, which comprises the steps of: 1) preparing a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof and a controlled release agent; 2) forming on the surface of the core a first coating layer comprising a functional coating material; and 3) forming a second coating layer on the surface of the first coating layer, comprising rosuvastatin or a pharmaceutically acceptable salt thereof and a base Chemical agent.