WO2014017833A1

WO2014017833A1 - Composite formulation for oral administration comprising metformin and rosuvastatin

Info

Publication number: WO2014017833A1
Application number: PCT/KR2013/006637
Authority: WO
Inventors: Jin Cheul Kim; Ki Woo Jeong; Jae Ho Kim; Yong Il Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2012-07-24
Filing date: 2013-07-24
Publication date: 2014-01-30
Also published as: UY34931A; AR092356A1; KR20140013436A; TW201408283A; TWI573587B

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

COMPOSITE FORMULATION FOR ORAL ADMINISTRATION COMPRISING METFORMIN AND ROSUVASTATIN

FIELD OF THE INVENTION

The present invention relates to a composite formulation for oral administration comprising metformin and rosuvastatin.

BACKGROUND OF THE INVENTION

Metformin, a biguanide-based antidiabetic agent, is an oral anti-hyperglycemic drug which is mainly used for treating a non-insulin dependent diabetes mellitus (NIDDM). A glycemic control mechanism is irrelevant to insulin secretion, and it is known that such a mechanism activates a glucose transporter in the liver. Metformin induces weight loss in diabetic patients, decreases the level of blood triglycerides and low density lipoprotein, and increases the level of high density lipoprotein. Thus, metformin can be used as a primary drug for a non-insulin dependent diabetic patient having an insulin resistance.

Currently, metformin is commercially available on the market in the form of hydrochloride tablets as Glucophage^® (Merck). The Glucophage^® tablet contains 250 mg, 500 mg, or 1,000 mg of metformin hydrochloride, and its administration is carried out within a range that does not exceed 2,550 mg, a maximum demand volume in consideration of both aspects of effectiveness and tolerance. A side effect associated with taking metformin is a decrease of appetite, abdominal distension, nausea, diarrhea, and the like that occur in 20 to 30% of the patients who take metformin. Most side effects often clear up after 2 to 3 weeks of taking metformin transiently. However, it is preferable to stop taking metformin when diarrhea and serious abdominal distension does not clear up. In rare cases, taking metformin may cause a skin rash, hives, and the like. The side effects may be avoided by decreasing the minimal dose and/or continuous dose or using a sustained release formulation capable of reducing the number of administration.

A conventional metformin sustained release formlation is prepared by using a polymer material or performing controlled release depending on osmotic pressure. For example, Korean Patent No. 1043816 discloses a metformin sustained release tablet using metformin, a selected hydrophobic sustained release carrier and a water-swellable polymer, in which the drug release rate is controlled by water swelling caused by a water-swellable polymer and by blocking of water permeation induced by a hydrophobic polymer. In addition, Korean Patent No. 0772980 discloses a sustained release formulation of metformin for oral administration containing natural gums and polyethylene oxide, which is a hydrophilic polymer, as a sustained release carrier, which is capable of maintaining a consistent blood concentration of metformin by restricting the release rate of metformin having high water solubility when being administered orally.

Meanwhile, a HMG-CoA reductase inhibitor such as rosuvastatin calcium salts is a 3 -hydroxy lactone ring or the corresponding ring-opened dihydroxy open acid, and is often referred to as "statin". Typically, a single-drug therapy using statin has been used to maintain a cholesterol level within the normal range. Statin suppresses a HMG-CoA reductase, which controls the rate of cholesterol production in the body, resulting in a delay in the production of cholesterol, or promotes an improvement in liver function of removing blood LDL cholesterol, and thereby reducing the level of cholesterol, and thus can be used to treat dyslipidemia and hypercholesterolemia.

According to Guidelines of Korean Diabetes Association, diabetic patients are advised to first take a formulation containing statin when they have dyslipidemia and hypercholesterolemia. Accordingly, in case of developing a composite formulation comprising metformin and statin, which are often prescribed together, it is possible to substitute the co-administration, and thus can improve patient compliance. Also, taking the composite formulation is financially advantageous as compared with the case of taking each of the single drugs together.

International Patent Publication No. WO 201 1/081493 discloses a pharmaceutical composition including metformin and rosuvastatin as active ingredients. However, said composition has a disadvantage that the amount of rosuvastatin contained in the formulation sharply decreases at the time of one month after being stored under accelerated conditions. The statin formulation comprising rosuvastatin is mostly stable in a basic condition and unstable in an acidic condition. For this reason, it is expected that since metformin is acidic, when the metformin and rosuvastatin physically contact each other, the stability of rosuvastatin deteriorates due to their interaction.

Accordingly, the present inventors have conducted a thorough investigation to prepare a composite formulation for oral administration comprising metformin and rosuvastatin having excellent storage stability, and as a result, the inventors have found that it is possible to prevent physical contact between said drugs by coating metformin with a coating layer comprising a functional coating material, and then coating metformin with a coating layer comprising an alkalizing agent and rosuvastatin.

SUMMARY OF THE INVENTION

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

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

In accordance with one aspect of the present invention, there is provided a composite formulation for oral administration comprising:

1) a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof and a release-controlling agent;

2) a first coating layer formed on a surface of the core, which comprises a functional coating material; and

3) a second coating layer formed on a surface of the first coating layer, which comprises rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent.

In accordance with another aspect of the present invention, there is provided a method for preparing the composite formulation for oral administration, which comprises the steps of:

1) preparing a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof and a release-controlling agent;

2) forming a first coating layer formed on a surface of the core, which comprises a functional coating material; and

3) forming a second coating layer on a surface of the first coating layer, which comprises rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent. BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are graphs showing the changes in rosuvastatin assays of the formulations prepared in Comparative Examples and Examples, respectively, under accelerated storage conditions; and

FIG. 3 is a graph showing a dissolution rate of metformin depending on an assay of ethylcellulose (EC) in the coating of the formulations prepared in Comparative Examples and Examples. 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 release-controlling agent; 2) a first coating layer formed on a surface of the core, which comprises a functional coating material; and 3) a second coating layer formed on a surface of the first coating layer, which comprises rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent.

Hereinafter, properties and types of each of the components constituting the composite formulation for oral administration of the present invention will be described in detail.

1) Sustained release core comprising metformin or a pharmaceutically acceptable salt thereof In accordance with the composite formulation of the present invention, the sustained release core comprises metformin or a pharmaceutically acceptable salt thereof and a release-controlling agent.

The sustained release core comprises, as a first pharmacologically active material, metformin or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride. The composite formulation may comprise metformin or a pharmaceutically acceptable salt thereof in an amount of 250 mg to 1000 mg, preferably

500 mg to 1000 mg per unit dosage form, but not limited thereto.

In order to control release rate of metformin, the sustained release core according to the present invention may comprise a release-controlling agent that is a swelling polymer, which is selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, polyethylene oxide, guar gum, locust bean gum, and a mixture thereof, preferably hydroxypropyl methylcellulose.

The release-controlling agent may be employed 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 tablet, and the sustained release core in the form of tablet may be prepared by mixing metformin or a pharmaceutically acceptable salt thereof, a release-controlling agent and other pharmaceutically acceptable excipients, granulating and tableting the mixture.

According to an embodiment of the present invention, metformin hydrochloride, hydroxypropyl methylcellulose, lactose, and polyvinylpyrrolidone are mixed; a certain amount of purified water is added and mixed; and then the mixture is dried to prepare a granular material. Subsequently, a lubricant is added to the granular material to enhance lubricating properties for a certain period of time, and then a certain compression pressure is applied to prepare a sustained release core.

2) First coating layer (functional barrier coating layer)

In accordance with the composite formulation of the present invention, the first coating layer is a coating layer applied onto a surface of the sustained release core which functions to minimize the production of rosuvastatin-related materials produced by the interaction between metformin and rovasutatin by avoiding physical contact of metformin and rovasutatin and to prevent migration of water, which is contained in a release-controlling agent comprised in the metformin sustained release core, into rosuvastatin. The first coating layer comprises a functional (hydrophobic) coating material.

Specifically, when rosuvastatin is directly coated onto the surface of the sustained release core comprising metformin hydrochloride, there are disadvantages in that lactone is produced by the physical contact of metformin and rosuvastatin, and the water contained in the release-controlling agent comprised in the metformin sustained release core accelerates the production of lactone. In the present invention, however, the first coating layer comprising a functional coating material is formed between the sustained release core comprising metformin and a second coating layer comprising rosuvastatin, i.e., on the surface of the sustained release core, so that it can prevent a decrease in the rosuvastatin assay during a storage period.

The functional coating material which can be used in the present invention may be selected from the group consisting of ethyl cellulose, cellulose acetate, (meth)acrylic acid copolymer (Eudragit), and a mixture thereof, preferably ethyl cellulose.

The functional coating material may be employed in an amount of from 16 to less than 48 % by weight, preferably 16 to 32 % by weight, based on the total weight of the first coating layer. When the functional coating material is used in an amount of less than 16 % by weight, the functional coating material (e.g., ethyl cellulose) may not be able to cover the whole area of the sustained release core, and thus, the assay of rosuvastatin may be reduced over a certain time period. On the contrary, when the functional coating material is used in an amount of 48 % by weight or more, drug release is delayed, and with more excessive amount used, more delay in drug release is expected.

The first coating layer may further comprise a general coating material known in the art, e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl alcohol in addition to the functional coating material. Moreover, if necessary, it may further comprise a pharmaceutically acceptable additive. Examples of the pharmaceutically acceptable additive include a disintegrant, a diluent, a stabilizer, a binder, and a lubricant.

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

The first coating layer may be applied on to the surface of the sustained release core in an amount of 2 parts by weight or more and preferably 4 parts to 10 parts by weight, based on 100 parts by weight of the sustained release core. 3) Second coating layer (rosuvastatin coating layer)

In the composite formulation of the present invention, a second coating layer comprises, as a second pharmacologically active ingredient, rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent. For rosuvastatin or the pharmaceutically acceptable salt thereof in accordance with the present invention, rosuvastatin calcium is preferred, and may be employed in an amount of 1 mg to 50 mg, preferably 5 to 40 mg per unit dosage form, but not limited thereto.

In the present invention, the second coating layer comprises an alkalizing agent that suppresses the production of lactone which is the main degradation product of rosuvastatin. The alkalizing agent may be selected from the group consisting of magnesium carbonate (MgC0₃), magnesium hydroxide (Mg(OH)₂), sodium bicarbonate (NaHC0₃), calcium carbonate (CaC0₃), and a mixture thereof.

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

When the alkalizing agent is employed in an amount of more than 8 % by weight, no further suppressing effect against the production of the lactone can be achieved, but a relative assay of the coating material is reduced, so that the adhesion rate of the second coating layer is decreased.

Additionally, in the composite formulation of the present invention, the second coating layer may further comprise a general coating material such as polyethylene glycol, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol graft polymer, or a mixture thereof. Said polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft polymer or the mixture thereof may be employed in an amount of 25 to 85% by weight, preferably 25 to 80% by weight, based on the total weight of the second coating layer.

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

The second coating layer may be applied on to the surface of the first coating layer in an amount of 3 parts to 30 parts by weight, preferably 5 parts to 20 parts by weight, based on 100 parts by weight of the sustained release core.

Further, the present invention provides a method for preparing a composite formulation for oral administration, which comprises the steps of: 1) preparing a sustained release core including metformin or a pharmaceutically acceptable salt thereof and a release-controlling agent; 2) forming a first coating layer on a surface of the core, which comprises a functional coating material; and 3) forming a second coating layer on the first coating layer, which comprises rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent.

Specifically, the present invention provides a method for preparing a composite formulation for oral administration, which comprises the steps of: 1) preparing a sustained release core by using metformin or a pharmaceutically acceptable salt thereof and a release-controlling agent according to a conventional method for preparing a tablet; 2) forming a first coating layer by applying a coating solution prepared by dissolving a functional coating material in a suitable solvent for enteric coating (e.g., a mixed solvent of ethanol and water) on to a surface of the sustained release core, and then drying; and 3) forming a second coating layer by applying a coating solution prepared by dissolving a coating material such as polyethylene glycol, polyvinyl alcohol-polyethylene glycol graft polymer, or a mixture thereof, an alkalizing agent, and rosuvastatin or a pharmaceutically acceptable salt thereof, along with any pharmaceutically acceptable additives in a suitable solvent (e.g., a mixed solvent of ethanol and water) on to the surface of the first coating layer and then drying. The composite formulation of the present invention thus obtained may be formulated in the form of a coated tablet according to a conventional preparation method, and then used for an oral administration.

The composite formulation for oral administration prepared in accordance with the method of the present invention can maintain the assay of rosuvastatin of 90% or more, which is the requirement set forth in International Conference on Harmonisation (ICH) Guideline, after being stored under accelerated storage conditions of 40 °C and 75% relative humidity for 6 months. The composite formulation for oral administration has excellent storage stability and drug release rate, so that it can be effectively used as a composite formulation.

The composite formulation for oral administration of the present invention comprises two pharmacologically active components, i.e., metformin and rosuvastatin, in one tablet, and thus can be used to treat dyslipidemia and hypercholesteremia in a diabetic patient at the same time. Accordingly, the composite formulation for oral administration can reduce inconvenience that a patient takes two tablets separately and significantly improve patient compliance. EXAMPLES

Hereinafter, the present invention is described more specifically by the following Examples. However, these are provided only for illustration purpose, and the present invention is not limited thereto.

Examples 1 and 2 and Comparative Examples 1 and 2: Preparation of sustained release tablet coated with functional barrier and rosuvastatin

Step 1 : Metformin sustained release core

Metformin hydrochloride, hydroxypropyl methylcellulose HPMC 2208 (Shin-Etsu Chemical), lactose, and polyvinyl pyrrolidone PVP K30 (BASF, Germany) were first admixed according to the composition listed in the Table 1 below. Subsequently, a certain amount of purified water was added thereto, and the mixture was mixed, and dried to obtain a granular product. Magnesium stearate was added to the prepared mixture, the mixture was modified to enhance its slip properties for 5 minutes, and then a compression pressure of 10 kN was applied to prepare a sustained release tablet.

[Table 1]

Composition of metformin sustained release core

Ethyl cellulose (Dow Chem., USA), hydroxypropyl methylcellulose HPMC

2910 (Shin-Etsu, Japan), polyethylene glycol PEG 6000 (SANYO Chem., Japan), and polyvinyl pyrrolidone PVP K-30 (BASF, Germany) were admixed in a mixed solvent of ethanol and water according to the composition listed in Table 2 below. Subsequently, the mixture was coated on a surface of the sustained release core prepared in Step 1 above using 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 to be 45 °C and the product temperature was controlled to be 30 °C. After the coating process was completed, the tablet was dried for 30 minutes to remove remaining ethanol and water.

[Table 2]

Composition of functional barrier coating

Step 3 : Rosuvastatin drug coating

Rosuvastatin calcium, polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat^® IR, BASF, Germany), magnesium carbonate and Povidone K30 (BASF, Germany) were admixed in a mixed solvent of ethanol and water according to the composition listed in Table 3 below. The mixture was secondarily coated on the surface of the sustained release tablet coated with functional barrier prepared in Step 2 above using a coater (SEJONG, SFC-30), and then dried to prepare the composite formulation of the present invention. During the coating process, the supply air temperature was controlled to be 45 °C and product temperature was controlled to be 30 °C. After the coating process was completed, the tablet was dried for 30 minutes to remove remaining ethanol and water.

[Table 3]

Composition of rosuvastatin drug coating Component Assay (mg)

Rosuvastatin calcium 10.4

Kollicoat IR 75.8

Magnesium carbonate 5.0

Povidone K30 8.8

(Ethanol) 500.0

Distilled water (DW) 500.0

Total mass of coating material 100.0

Examples 3 and 4 and Comparative Examples 3 and 4: Preparation of sustained release tablet coated with functional barrier (using different functional coating material) and rosuvastatin

Functional barrier coating

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

[Table 4]

Composition of functional barrier coating

Polyvinyl alcohol - - - 16 -

White sugar - - - - 16

(Ethanol) <1040> <1040> <1040> <1040> <1040>

Distilled water

<440> <440> <440> <440> <440> (DW)

Total mass of

100 100 100 100 100 coating material

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

Rosuvastatin calcium, polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat IR, BASF, Germany), and Povidone K30 (BASF, Germany) were admixed along with magnesium hydroxide (Ilyang pharmaceutical Co., LTD, Korea), sodium bicarbonate (Duksan Company, Korea) or calcium carbonate (Sankyo, Japan) in a mixed solvent of ethanol and water according to the composition listed in Table 5 below. The procedures of Example 1 were repeated, except that the composite formulation of the present invention was prepared by secondarily coating the mixture on the sustained release tablet coated with the functional barrier prepared in Step 2 using a coater (SEJONG, SFC-30) and then drying, to prepare a sustained release tablet.

[Table 5]

Distilled water (DW) <500> <500> <500> <500> <500>

Total mass of coating

100 100 100

material 100 100

Examples 8 to 10 and Comparative Examples 6 to 8: Preparation of sustained release tablet coated with rosuvastatin using different amounts of alkalizing agents A sustained release tablet was prepared by using the same method as Example 1 , except that in the rosuvastatin drug coating described in Step 3 of Example 1 , the assay of magnesium carbonate (BASF, Germany) was changed as listed in the following Table 6 to prepare the complex formulation. [Table 6]

Comparative Example 9: Preparation of sustained release tablet comprising metformin The procedures of Step 1 of Example 1 were repeated to prepare a sustained release tablet comprising metformin, and then a coating comprising rosuvastatin was formed as described in Step 3 of Example 1 without a functional barrier coating to prepare the sustained release tablet.

Comparative Example 10: Preparation of sustained release tablet coated with functional barrier and rosuvastatin

The procedures of Example 1 were repeated, except that the composition of the functional barrier coating as listed in Table 7 below was used, to prepare a sustained release tablet. [Table 7]

Experimental Example 1: Stability of rosuvastatin according to the presence of a functional barrier coating layer The formulations prepared in Comparative Examples 9 and 10 were packaged in a high density polyethylene (HDPE) bottle, and then stored under accelerated conditions of 50 °C and 75% relative humidity. After 1, 3, and 6 months of storage, the samples were taken and tested with reference to a standard and test method of Suvast (Hanmi Pharm. Co., Ltd.) that is a rosuvastatin control formulation. Specifically, 100 mg of a rosuvastatin sample was added to a 500 ml-flask and then shaken to mix thoroughly. Subsequently, the liquid was passed through a 0.45 μηι filter and then was subjected to a HPLC and its absorbance was measured at 242 nm to measure the concentration of rosuvastatin. The results are shown in Table 8 (unit: %) and FIG. 1. [Table 8]

As illustrated in Table 8 and FIG. 1, all of the rosuvastatin assays in the formulations of Comparative Examples 9 and 10 were reduced in proportion to a storage period. The formulation of Comparative Example 9, which does not comprise a functional barrier coating layer, failed to meet the requirement of ICH guideline 3 months after the initial period, whereas the formulation of Comparative Example 10 dissatisfied ICH guideline 6 months after the initial period.

It can be predicted that the reason for the breakdown of rosuvastatin is due to physical contact between the rosuvastatin, which is stable in a basic condition, and metformin hydrochloride. Particularly, it can be expected that in the case of Comparative Example 10, the breakdown of rosuvastatin is influenced by a large amount of moisture assay included in HPMC 2208 which is contained in the metformin sustained release core. From the above results, it could be confirmed that it is difficult to secure the stability of rosuvastatin by physically blocking the active ingredients only.

Experimental Example 2: Stability of rosuvastatin according to EC assay in functional barrier coating layer

The rosuvastatin assays were confirmed according to the same method used in Experimental Example 1 using the formulations prepared in Examples 1 and 2 and Comparative Examples 1 and 2. The results are listed in Table 9 (unit: %) and FIG. 2. [Table 9]

Accelerated 1 98.4 ± 1.0 99.0 ± 1.2 98.7 ± 0.7 100.6 ± 0.3 month

Accelerated 3 96.6 ± 1.2 100.3 ± 1.1 98.4 ± 1.6 98.9 ± 1.4 months

Accelerated 6 91.6 ± 1.1 98.4 ± 5.7 99.2 ± 1.2 100.7 ± 1.6 months

The formulations prepared by adding EC that is a functional coating material in Examples 1 and 2 and Comparative Examples 1 and 2 exhibited significantly improved assay stability as compared to the formulations prepared without EC in Comparative Examples 9 and 10. However, in the case of Comparative Example 1 (containing 8% by weight), the rosuvastatin assay after 6 months under acceleration conditions was 91.6% of the initial amount, which does not fall in the range of 95 to 105%, an assay standard of commercially available metformin sustained release tablet, and thus the stability was not secured. On the other hand, when the assay of EC was 16% by weight or more in a functional barrier coating mass, the stability was maintained until 6 months of accelerated conditions.

From the above results, it could be confirmed that when the functional coating material was comprised in an amount of 16% by weight or more, it is effective to prevent a decrease in rosuvastatin assay due to water contained in a metformin sustained release core.

Experimental Example 3: Dissolution rate of metformin according to EC assay in functional barrier coating layer When the EC assay was high in a functional barrier coating layer, the EC assay could have an influence on a dissolution rate of metformin. Therefore, a metformin dissolution test was performed by using the formulations obtained in Examples 1 and 2 and Comparative Examples 1 and 2.

Specifically, the dissolution test was performed using 900 mL of the second liquid (artificial intestinal secretion) in accordance with the dissolution test of the Korean Pharmacopoeia as a solution at 37 °C by using the Second Method (paddle method) used in dissolution test according to the Korean Pharmacopoeia. Time-based dissolution solutions were collected after dissolution was initiated, and then metformin was analyzed with a high-performance liquid chromatography to measure a dissolution rate. The results are shown in Table 10 (unit: %) and FIG. 3. [Table 10]

It could be confirmed that in the case of Comparative Example 2, when the EC assay of the functional barrier coating layer was 48%, the dissolution of metformin was delayed. However, when the EC assay was 32% or less, no delay in dissolution due to the functional barrier coating layer was observed.

As for Megaformin SR Tab. (Hanmi Pharm. Co., Ltd), a generic product that is verified as a product having bioequivalence to Glucophage XR Tab. (Merck) and is commercially available, and its standard dissolution rate was set to be 20 to 40% at 1 hour, 40 to 60% at 3 hours, and 80% or more at 12 hours. The dissolution rates for Comparative Example 2 did not fall in the standard dissolution rate at all of the base times, so that it could be easily expected that it is difficult to secure a bioequivanlence and it is unsuitable in view of a product standard.

Accordingly, based on the results of Experimental Examples 2 and 3, it could be concluded that as an effective assay, the preferable amount of the EC in the functional barrier coating layer was in the range of 16 to 32% for securing an assay stability of rosuvastatin by blocking water and also for not affecting on metformin drug release.

Experimental Example 4: Stability of rosuvastatin depending on the type of a coating material of functional barrier coating layer The assay of rosuvastatin was confirmed according to 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 1 1 (unit: %).

[Table 1 1]

The formulations prepared in Examples 1 , 3 and 4, which comprise ethyl cellulose, cellulose acetate, and (meth)acrylic acid copolymer as a functional coating material, respectively, exhibited a significantly improved assay stability unlike the formulations prepared in Comparative Examples 3 and 4, which comprise polyvinyl alcohol and white sugar, respectively.

Experimental Example 5: Stability of rosuvastatin depending on the type of an alkalizing agent

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

The formulations prepared in Examples 1 , and 5 to 7, which comprises magnesium carbonate, magnesium hydroxide, sodium bicarbonate, and calcium carbonate as an alkalizing agent, respectively, exhibited a significantly improved assay stability as compared to the formulation prepared in Comparative Example 5, which did not contain any alkalizing agent to suppress the production of lactone, a main degradation product of rosuvastatin. Experimental Example 6: Stability test of the formulation according to 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 under acceleration conditions of 50 °C and 75% relative humidity. After 1 month of storage, the samples were taken, and then an amount of a lactone-related compound that is a main degradation product of rosuvastatin was measured. The results are shown in the following Table 13. [Table 13]

Related compound test (Impurity Lactone %, Criteria: within 1.5%)

As compared to the formulations of Examples 8 to 10, the formulations of Comparative Examples 6 and 7 which did not contain any alkalizing agent, or had only a small assay thereof, had relatively low stability, and thus contained a large amount of lactone-related materials. Meanwhile, the formulation in Comparative Example 8 which had a larger amount of the alkalizing agent than that of the formulation in Example 10, produced greater amounts of related materials. Accordingly, it could be concluded that the preferred amount of alkalizing agent is in the range of 4 to 8% by weight, based on the total weight of the second coating layer.

Claims

What is claimed is:

1. A composite formulation for oral administration, comprising:

1) a sustained release core comprising metformin or a pharmaceutically acceptable salt thereof, and a release-controlling agent;

2) a first costing layer formed on a surface of the core, which comprises a functional coating material; and

2. The composite formulation of claim 1 , wherein the release-controlling agent is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, polyethylene oxide, guar gum, locust bean gum, and a mixture thereof.

3. The composite formulation of claim 1 , wherein the metformin or pharmaceutically acceptable salt thereof is comprised in an amount of 250 mg to 1000 mg.

4. 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 copolymer, and a mixture thereof.

5. The composite formulation of claim 1, wherein the functional coating material is comprised in an amount of from 16 to less than 48 % by weight, based on a total weight of the first coating layer.

6. The composite formulation of claim 5, wherein the functional coating material is comprised in an amount of 16% to 32% by weight, based on a total weight of the first coating layer.

7. The composite formulation of claim 1 , wherein the alkalizing agent is selected from the group consisting of magnesium carbonate (MgC0₃), magnesium hydroxide (Mg(OH)₂), sodium bicarbonate (NaHC0₃), calcium carbonate (CaC0₃), and a mixture thereof.

8. The composite formulation of claim 1 , wherein the alkalizing agent is comprised in an amount of 4% to 8% by weight, based on a total weight of the second coating layer.

9. The composite formulation of claim 1, wherein the rosuvastatin or pharmaceutically acceptable salt thereof is comprised in an amount of 1 mg to 50 mg per unit dosage form.

10. The composite formulation of claim 1, wherein the first coating layer is used in an amount of 4 parts to 10 parts by weight, based on 100 parts by weight of the sustained release core.

1 1. The composite formulation of claim 1 , wherein the second coating layer is used in an amount of 3 parts to 30 parts by weight, based on 100 parts by weight of the sustained release core.

12. A method for preparing the composite formulation of claim 1, which comprises the steps of:

2) forming a first coating layer on a surface of the core, which comprises a functional coating material; and

3) forming a second coating layer on a surface of the first coating layer, which comprises rosuvastatin or a pharmaceutically acceptable salt thereof and an alkalizing agent.