COMBINATION FORMULATION CONTAINING SUSTAINED RELEASE METFORMIN AND IMMEDIATE RELEASE HMG-COA REDUCTASE INHIBITOR

Abstract

The present invention relates to a combination formulation containing metformin for treating non-insulin-dependent diabetes and an HMG-CoA reductase inhibitor for treating dyslipidemia. The present invention provides a combination formulation and a method for preparing the combination formulation, wherein the combination formulation contains metformin and an HMG-CoA reductase inhibitor.

Claims

1. A combination formulation comprising: a first sustained-release composition, which comprises granules comprising metformin or a pharmaceutically acceptable salt thereof and a swellable polymer, and a water-insoluble polymer film for coating the granules; and a second immediate-release composition comprising an HMG-CoA reductase inhibitor.

2. The combination formulation of claim 1, wherein the swellable polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth, acacia gum, locust bean gum, xanthan gum, polyvinyl alcohol, and polyvinylpyrrolidone.

3. The combination formulation of claim 1, wherein the swellable polymer has a viscosity of 100 cps or higher.

4. The combination formulation of claim 1, wherein the water-insoluble polymer is at least one selected from the group consisting of methacrylic acid copolymer, ethylcellulose, cellulose acetate succinate, cellulose acetate phthalate, fatty acids, fatty acid esters, fatty acid alcohols, and waxes.

5. The combination formulation of claim 4, wherein the fatty acid and fatty acid ester are at least one selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate, stearic acid, and a mixture thereof; the fatty acid alcohol is at least one selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and a mixture thereof; and the wax is at least one selected from the group consisting of carnauba wax, beeswax, microcrystalline wax, and a mixture thereof.

6. The combination formulation of claim 1, wherein metformin or a pharmaceutically acceptable salt thereof is contained in an amount from 250 mg to 1000 mg.

7. The combination formulation of claim 1, wherein the water-insoluble polymer is contained in an amount from 1 wt % to 20 wt % based on the total weight of the first sustained-release composition.

8. The combination formulation of claim 1, wherein the swellable polymer is contained in an amount from 1 wt % to 40 wt % based on the total weight of the first sustained-release composition.

9. The combination formulation of claim 1, wherein the HMG-CoA reductase inhibitor is at least one selected from the group consisting of rosuvastatin, atorvastatin, pitavastatin, lovastatin, simvastatin, pravastatin, and fluvastatin.

10. The combination formulation of claim 1, wherein the HMG-CoA reductase inhibitor is contained in an amount from 5 mg to 160 mg.

11. The combination formulation of claim 1, wherein the second immediate-release composition is completely disintegrated in distilled water at 37 C. within 5 minutes.

12. The combination formulation of claim 1, the combination formulation is formulated so that physical contact or chemical reaction between the swellable polymer in the first sustained-release composition and the HMG-CoA reductase inhibitor is inhibited by the water-insoluble polymer film.

13. The combination formulation of claim 1, wherein the combination formulation is an uncoated tablet, a film-coated tablet, a double-layer tablet, a multi-layer tablet, or a core tablet.

14. The combination formulation of claim 1, wherein the first sustained-release composition and the second immediate-release composition are in a form of a double-layer tablet.

15. A method of preparing the combination formulation of claim 1, comprising: preparing the first sustained-release composition by preparing granules comprising metformin or a pharmaceutically acceptable salt thereof, and a swellable polymer, followed by forming a water-insoluble polymer film on the granules; preparing the second immediate-release composition comprising an HMG-CoA reductase inhibitor; and formulating the first sustained-release composition and the second immediate-release composition into a unit formulation.

16. The method of claim 15, further comprising forming a film layer on the external surface of the combination formulation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows the results of a release test for the combination formulations prepared in Examples 1 and 2 of the present invention and a Glucophage XR 500 mg tablet.

[0028] FIG. 2 shows the results of a release test for the combination formulations prepared in Examples 1 and 2 of the present invention and a Lipitor 10 mg tablet.

[0029] FIG. 3 shows the results of a release test for the combination formulations prepared in Examples 3 and 4 of the present invention and a Crestor 10 mg tablet.

BEST MODE

[0030] Preferred embodiments of the present invention will be described below in more detail with reference to the accompanying drawings. The present invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present invention to those skilled in the art.

[0031] To solve the above problems, the present invention provides a combination formulation including a first sustained-release composition which includes granules containing metformin or a pharmaceutically acceptable salt thereof and a swellable polymer and a water-insoluble polymer film for coating the granules, and a second immediate-release composition containing an HMG-CoA reductase inhibitor.

[0032] As used herein, the term a first sustained-release composition refers to a composition containing metformin or a pharmaceutically acceptable salt thereof capable of long-acting release of the same by preventing its rapid release. For sustained-release, metformin or a pharmaceutically acceptable salt thereof is formed into granules along with a swellable polymer, and each individual granule is coated with a water-insoluble polymer film.

[0033] As used herein, the term metformin refers to a compound with a chemical name of N,N-dimethylimidodicarbonimidic diamide (Formula 1 below), which is used as a therapeutic agent for preventing or treating non-insulin-dependent diabetes.

##STR00001##

[0034] Metformin may be used by separation from natural resources, by manufacturing via chemical modification after obtainment thereof from natural resources, or easily by a chemical synthesis according to a known method by a skilled person in the art. Alternatively, commercially available metformin may be purchased for use.

[0035] Preferably, metformin or a pharmaceutically acceptable salt thereof may be contained in the combination formulation of the present invention in an amount from 250 mg to 1000 mg.

[0036] As used herein, the term a swellable polymer refers to a pharmaceutically acceptable polymer which becomes swollen in an aqueous solution, thereby allowing control of drug release. In the present invention, the swellable polymer forms granules along with metformin or a pharmaceutically acceptable salt thereof and exhibits the sustained-release characteristic of the same. The swellable polymer that can be used in the present invention may include at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth, acacia gum, locust bean gum, xanthan gum, polyvinyl alcohol, and polyvinylpyrrolidone, and preferably, hydroxypropyl methylcellulose or polyethylene oxide, but is not limited thereto as long as it is a pharmaceutically acceptable swellable polymer enabling controlled release according to the purposes of the present invention. Preferably, the swellable polymer has a viscosity of 100 cps or higher.

[0037] Preferably, the swellable polymer may be contained in the combination formulation in an amount from 10 wt % to 40 wt % based on the total weight of the first sustained-release composition. When the swellable polymer is contained at less than 10 wt %, it becomes difficult to achieve effective control of drug release, whereas when the swellable polymer is contained at more than 40 wt %, the size of tablets becomes too large to be administered, and is thus not appropriate.

[0038] The granules of the present invention containing metformin or a pharmaceutically acceptable salt thereof and the swellable polymer are formed by coating the external surface with a water-insoluble polymer.

[0039] As used herein, the term a water-insoluble polymer refers to a pharmaceutically acceptable polymer capable of controlling drug release, which is water-insoluble or hardly soluble in water. Additionally, the purposes of the water-insoluble polymer of the present invention not only include prevention of the release of metformin or a pharmaceutically acceptable salt thereof, but also prevention of the HMG-CoA reductase inhibitor contained in the second immediate-release composition from being in contact with the swellable polymer. That is, the combination formulation according to the present invention is formed such that the swellable polymer can be prevented from physical contact and chemical reaction with the HMG-CoA reductase inhibitor by the water-insoluble polymer film coating.

[0040] The present invention relates to a combination formulation which contains an HMG-CoA reductase inhibitor in addition to metformin, and the swellable polymer used for the sustained-release of metformin or a pharmaceutically acceptable salt thereof inhibits the release of the HMG-CoA reductase inhibitor, and also increases the amount of impurities of the HMG-CoA reductase inhibitor, thereby significantly deteriorating the stability of the formulation. Accordingly, the type of the formulation, which contains a swellable polymer for sustained-release metformin but does not affect the HMG-CoA reductase inhibitor, should be considered. For this purpose, in the present invention, the external surface of the granules, which contain metformin or pharmaceutically acceptable salt and a swellable polymer, is coated with a water-insoluble polymer, thereby preventing the contact between the swellable polymer and the HMG-CoA reductase inhibitor.

[0041] In an exemplary embodiment of the present invention, when the water-insoluble polymer was absent, the swellable polymer exhibited an impact on the HMG-CoA reductase inhibitor, thereby reducing the release rate of the HMG-CoA reductase inhibitor and increasing the formation of impurities. On the contrary, in the case of a combination formulation of the present invention using a water-insoluble polymer film, the first sustained-release composition and the second immediate-release composition of respectively showed a release pattern similar to that of a single-formulation type, and there was no increase in the formation of impurities. Since the first sustained-release composition according to the present invention did not cause a high viscosity problem by the swellable polymer while effectively controlling the sustained-release metformin, these results suggest that the sustained-release agent for metformin did not affect the immediate release of the second immediate-release composition.

[0042] The water-insoluble polymer that can be used in the present invention may include at least one selected from the group consisting of methacrylic acid copolymer, ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, fatty acids, fatty acid esters, fatty acid alcohols, and waxes, and preferably, methacrylic acid copolymer or ethylcellulose, but the water-insoluble polymer is not limited thereto as long as it is a pharmaceutically acceptable water-insoluble polymer enabling controlled release according to the purposes of the present invention.

[0043] Preferably, the water-insoluble polymer according to the present invention may be contained in the amount from 1 wt % to 20 wt % based on the total weight of the first sustained-release composition. When the polymer content exceeds 20 wt %, it will increase the film thickness and slow hydration of the swellable polymer, and thus is not suitable for controlling the initial release of drug.

[0044] As used herein, the term a second immediate-release composition refers to a composition containing an HMG-CoA reductase inhibitor which can be completely disintegrated in distilled water at 37 C. within 5 minutes.

[0045] As used herein, the term HMG-CoA, as an acronym for 3-hydroxy-3-methylglutaryl-coenzyme A, refers to a precursor for biosynthesis of sterols including cholesterols. As used herein, the term HMG-CoA reductase inhibitor refers to compounds which provide the effect of lowering the levels of in vivo total cholesterol and LDL-cholesterol by inhibiting the activity of HMG-CoA reductase, which is involved in the early stages of the conversion of HMG-CoA into mevalonate during the process of cholesterol biosynthesis. For example, the HMG-CoA reductase inhibitor may be at least one selected from rosuvastatin, atorvastatin, pitavastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, or a pharmaceutically acceptable salt, but it is not limited thereto. Additionally, the formulation of the present invention may further include a pharmaceutically acceptable alkalifying agent. The HMG-CoA reductase inhibitor according to the present invention is preferably atorvastatin or rosuvastatin. Preferably, the HMG-CoA reductase inhibitor may be contained in the combination formulation of the present invention in an amount from 5 mg to 160 mg. Additionally, in the case of rosuvastatin, it may be contained in the combination formulation of the present invention in an amount from 5 mg to 40 mg.

[0046] The second immediate-release composition may further contain a pharmaceutically acceptable disintegrant and/or a dissolution adjuvant for the purpose of being completely disintegrated in distilled water at 37 C. within 5 minutes. The disintegrant and/or the dissolution adjuvant that can be used in the present invention may include at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polysorbate, poloxamer, and sodium lauryl sulfate, and preferably, croscarmellose sodium or crospovidone may be used, but the disintegrant and/or the dissolution adjuvant are not limited thereto as long as they are pharmaceutically acceptable additives capable of controlling the disintegration according to the purposes of the present invention.

[0047] The combination pharmaceutical formulation according to the present invention can maintain stability without any changes in characteristics even when the two drugs of metformin or a pharmaceutically acceptable salt thereof and an HMG-CoA reductase inhibitor are manufactured and stored in a combination process.

[0048] As used herein, the term a pharmaceutically acceptable salt refers to a formulation type that does not damage the biological activities and physical properties of metformin or an HMG-CoA reductase inhibitor to be administered. The pharmaceutically acceptable salt may include acid addition salts which can form non-toxic acid addition salts containing pharmaceutically acceptable anions, e.g., inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydriodic acid; organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; etc. For example, the pharmaceutically acceptable salt may include metal salts or alkali earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine; etc.

[0049] Additionally, the combination pharmaceutical formulation of the present invention may further include a film layer on the external surface. The film layer may be, for example, a shield film layer, a moisture-proofing film layer, or a glucose film layer, etc. Preferably, the external film layer is formed of a water-soluble material, which may include hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, ethylcellulose, methylcellulose, polymethacrylate, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat; BASF, Germany), polyvinyl alcohol (Opadry; Colorcon, USA), or a combination thereof, but are not limited thereto.

[0050] Additionally, the combination pharmaceutical formulation of the present invention may be formulated by further using additives conventionally used in the art within the scope of not damaging the effects of the present invention, such as a diluent, a binder, a lubricant, a pH adjuster, an antifoaming agent, a dissolution adjuvant, an antioxidant, etc.

[0051] The combination pharmaceutical formulation of the present invention may be prepared in various formulation types, e.g., tablets such as uncoated tablets, film-coated tablets, single-layer tablets, double-layer tablets, multi-layer tablets, or core tablets; powders; granules; capsules; etc. Preferably, the combination pharmaceutical formulation of the present invention is prepared in the form of a double-layer tablet consisting of the first sustained-release composition and the second immediate-release composition.

[0052] The thus-prepared combination pharmaceutical formulation of the present invention can provide appropriate release features suitable for each of the pharmaceutical active ingredients by continuously releasing metformin and rapidly releasing HMG-CoA reductase inhibitor during in vivo administration. Additionally, administration convenience was improved by reducing the contents of sustained-release agents necessary for sustained-release metformin, whereas the drug for immediate-release was rapidly dissolved and the stability of the HMG-CoA reductase inhibitor was improved by including a stabilizing agent. Accordingly, the combination pharmaceutical formulation of the present invention can be effectively used for the prevention and treatment of dyslipidemia, dyslipidemia, atherosclerosis, diabetes, and diabetes complications.

[0053] In another exemplary embodiment, the present invention provides a method of preparing the combination formulation including preparing the first sustained-release composition, by preparing granules containing metformin or a pharmaceutically acceptable salt thereof, and a swellable polymer, followed by forming a water-insoluble polymer film on the granules;

[0054] preparing the second immediate-release composition containing an HMG-CoA reductase inhibitor; and

[0055] formulating the first sustained-release composition and the second immediate-release composition into a unit formulation.

[0056] Additionally, the method of the present invention may further include forming a film layer on the external surface of the combination formulation.

[0057] As used herein, the terms first sustained-release composition, metformin, swellable polymer, water-insoluble polymer, a second immediate-release composition, HMG-CoA, a pharmaceutically acceptable salt, and film layer are the same as described above.

DETAILED DESCRIPTION OF THE INVENTION

[0058] Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.

EXAMPLE 1

[0059] 1) Preparation of Sustained-Release Metformin Hydrochloride Granules

[0060] Sustained-release metformin hydrochloride granules were prepared according to the composition and the content shown in Table 1. Specifically, metformin hydrochloride and colloidal silicon dioxide were passed through a 20-mesh sieve and mixed with polyethylene oxide (Polyox WSR301). Then, the resultant was sprayed with a binder solution in which a solvent mixture containing isopropyl alcohol, acetone, and purified water mixed in a ratio of 6:3:1 was dissolved at a concentration of 10 w/v % with addition of a methacrylic acid copolymer (Eudragit RS PO), then dried in a fluidized bed granulator for granulation, and the resultant was passed through a 20-mesh sieve. The thus-obtained granulated product was treated with magnesium stearate and mixed to prepare sustained-release metformin hydrochloride granules.

TABLE-US-00001 TABLE 1 Active Ingredient metformin hydrochloride 500 mg Lubricant colloidal silicon dioxide 5 mg Water-insoluble Agent methacrylic acid 50 mg copolymer (Eudragit RS PO) Swelling agent polyethylene oxide 150 mg (Polyox WSR301) Lubricant magnesium stearate 5 mg Total Weight 710 mg

[0061] 2) Preparation of Immediate-Release Atorvastatin Granules

[0062] Immediate-release atorvastatin granules were prepared according to the composition and the content shown in Table 2. Specifically, atorvastatin calcium salt, precipitated calcium carbonate, microcrystalline cellulose, lactose hydrate, and croscarmellose sodium were mixed, treated with hydroxypropylcellulose dissolved in 20% ethanol to obtain granules, and the resulting granules were dried in a fluidized bed dryer and then passed through a 20-mesh sieve. The thus-obtained granulated product was treated with croscarmellose sodium and magnesium stearate, and mixed to prepare immediate-release atorvastatin granules.

TABLE-US-00002 TABLE 2 Active Ingredient Atorvastatin Calcium Salt 10.85 mg Diluent precipitated calcium carbonate 20 mg Diluent microcrystalline cellulose 58 mg Diluent lactose hydrate 42.8 mg Surfactant Polysorbate 80 0.6 mg Binder hydroxypropylcellulose 3 mg Disintegrant croscarmellose sodium 14 mg Lubricant magnesium stearate 0.75 mg Total Weight 150 mg

[0063] 3) Tableting of Double-Layer Tablets

[0064] The metformin hydrochloride and atorvastatin granules prepared in 1) and 2) above were tableted into double-layer tablets in the amounts of 710 mg and 150 mg, respectively, thereby preparing white tablets having a unit weight of 860 mg per tablet.

[0065] 4) Preparation of Coating Solution and Coating

[0066] A coating pan (Hi-coater, Freund) was filled with the tablets prepared in 3) above and the exhaust air temperature was maintained at about 30 C. to 40 C. 10 g of an Opadry 03B64650 (62.5% hydroxypropyl methylcellulose 2910, 30.79% titanium oxide, 6.25% polyethylene glycol 400, 0.27% yellow iron oxide, 0.18% red iron oxide, and 0.01% indigo carmine aluminum lake) coating agent was dissolved in 90 g of water to prepare a coating solution, which was sprayed on dried tablets using a sprayer operated under air pressure, and dried by further providing inlet air flow for about 10 minutes, thereby affording 885 mg of unit tablets of the present invention, in which the amount of coating per tablet was 25 mg.

EXAMPLE 2

[0067] Suspended-release metformin hydrochloride granules were prepared according to the composition and the content shown in Table 3. Specifically, metformin hydrochloride and colloidal silicon dioxide were passed through a 20-mesh sieve and mixed with hypromellose (Metolose 90SH-100,000 cps). Then, the resultant was sprayed with a binder solution in which a solvent mixture containing isopropyl alcohol, acetone, and purified water mixed in a ratio of 6:3:1 was dissolved at a concentration of 10 w/v % with addition of a methacrylic acid copolymer (Eudragit RS P0), then dried in a fluidized bed granulator for granulation, and the resultant was passed through a 20-mesh sieve. The thus-obtained granulated product was mixed with magnesium stearate to prepare final sustained-release metformin hydrochloride granules. The processes of preparing immediate-release atorvastatin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 1.

TABLE-US-00003 TABLE 3 Active Ingredient metformin hydrochloride 500 mg Lubricant colloidal silicon dioxide 5 mg Water-insoluble methacrylic acid copolymer 50 mg Agent (Eudragit RS PO) Swelling Agent hypromellose (Metolose 150 mg 90SH-100,000 cps) Lubricant magnesium stearate 5 mg Total Weight 710 mg

EXAMPLE 3

[0068] Immediate-release rosuvastatin granules were prepared according to the composition and the content shown in Table 4. Specifically, anhydrous calcium hydrogen phosphate was used as a stabilizing agent, and specifically, rosuvastatin calcium salt, microcrystalline cellulose, lactose hydrate, crospovidone, and magnesium stearate were mixed with anhydrous calcium hydrogen phosphate to prepare immediate-release rosuvastatin granules. The processes of preparing suspended-release metformin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 1.

TABLE-US-00004 TABLE 4 Active Ingredient rosuvastatin calcium salt 10.4 mg Diluent anhydrous calcium 20.9 mg hydrogen phosphate Diluent microcrystalline cellulose 30.3 mg Diluent lactose hydrate 78.4 mg Disintegrant crospovidone 8.0 mg Lubricant magnesium stearate 2.0 mg Total Weight 150 mg

EXAMPLE 4

[0069] Immediate-release rosuvastatin granules were prepared in the same manner as in Example 3, and the processes of preparing suspended-release metformin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 2.

COMPARATIVE EXAMPLE 1

[0070] Immediate-release atorvastatin granules were prepared in the same manner as in Example 1 and then tableted into single tablets. The amount of coating per tablet was 5 mg, and 155 mg of unit tablets were obtained therefrom.

COMPARATIVE EXAMPLE 2

[0071] Immediate-release rosuvastatin granules were prepared in the same manner as in Example 3 and then tableted into single tablets. The amount of coating per tablet was 5 mg, and 155 mg of unit tablets were obtained therefrom.

COMPARATIVE EXAMPLES 3 and 4

[0072] Suspended-release metformin hydrochloride granules were prepared according to the composition and the content shown in Table 5. Specifically, metformin hydrochloride and colloidal silicon dioxide were passed through a 20-mesh sieve, mixed with microcrystalline cellulose, and treated with polyvinylpyrrolidone (K-30) dissolved in distilled water for granulation. The resultant was dried in a fluidized bed dryer and passed through a 20-mesh sieve. The thus-obtained granulated product was mixed with polyethylene oxide (Polyox WSR301) and magnesium stearate, and mixed to prepare final sustained-release metformin hydrochloride granules.

TABLE-US-00005 TABLE 5 Active Ingredient metformin hydrochloride 500 mg Lubricant colloidal silicon dioxide 5 mg Excipient microcrystalline cellulose 50 mg Binder polyvinylpyrrolidone 10 mg (K-30) Swelling Agent polyethylene oxide 200 mg (Polyox WSR301) Lubricant magnesium stearate 5 mg Total Weight 770 mg

[0073] The processes of preparing immediate-release atorvastatin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 1, and the amount of the tablets finally obtained was 945 mg (Comparative Example 3).

[0074] The processes of preparing immediate-release rosuvastatin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 3, and the amount of the tablets finally obtained was 945 mg (Comparative Example 4).

COMPARATIVE EXAMPLES 5 and 6

[0075] Suspended-release metformin hydrochloride granules were prepared according to the composition and the content shown in Table 6. Specifically, metformin hydrochloride and colloidal silicon dioxide were passed through a 20-mesh sieve, mixed with microcrystalline cellulose, and treated with polyvinylpyrrolidone (K-30) dissolved in distilled water for granulation. The resultant was dried in a fluidized bed dryer and passed through a 20-mesh sieve. The thus-obtained granulated product was mixed with hypromellose (Metolose 90SH-100,000 cps) and magnesium stearate, and mixed to prepare final sustained-release metformin hydrochloride granules.

TABLE-US-00006 TABLE 6 Active Ingredient metformin hydrochloride 500 mg Lubricant colloidal silicon dioxide 5 mg Excipient microcrystalline cellulose 50 mg Binder polyvinylpyrrolidone (K-30) 10 mg Swelling Agent hypromellose (Metolose 200 mg 90SH-100,000 cps) Lubricant magnesium stearate 5 mg Total Weight 770 mg

[0076] The processes of preparing immediate-release atorvastatin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 1, and the amount of the tablets finally obtained was 945 mg (Comparative Example 5).

[0077] The processes of preparing immediate-release rosuvastatin granules, tableting of double-layer tablets, and coating were performed in the same manner as in Example 3, and the amount of the tablets finally obtained was 945 mg (Comparative Example 6).

EXAMPLES 5 to 8

[0078] Sustained-release metformin hydrochloride granules were prepared according to the composition and the content shown in Table 7. Specifically, sustained-release metformin hydrochloride granules were prepared in the same manner as in Example 1, except that they were prepared using the ingredients of Eudragit S100, Ethocel Std 14, cetyl alcohol, and Kollicoat SR 30D, respectively (See Table 7), instead of a methacrylic acid copolymer (Eudragit RS PO). The amount of each tablet obtained after tableting into double-layer tablets and completing the coating process was 885 mg.

TABLE-US-00007 TABLE 7 Example 5 Example 6 Example 7 Example 8 Metformin hydrochloride 500 mg 500 mg 500 mg 500 mg Colloidal silicon dioxide 5 mg 5 mg 5 mg 5 mg Polyethylene oxide 150 mg 150 mg 150 mg 150 mg (Polyox WSR301) Methacrylic acid 50 mg copolymer (Eudragit S100) Ethylcellulose 50 mg (Ethocel Std 14) Waxes (cetyl alcohol) 50 mg Polyvinyl acetate 50 mg (Kollicoat SR 30D) Magnesium stearate 5 mg 5 mg 5 mg 5 mg Total 710 mg 710 mg 710 mg 710 mg

EXPERIMENTAL EXAMPLE 1

Release Test of Metformin

[0079] In order to confirm whether the combination formulation according to the present invention can exhibit a release rate equivalent to that of a Glucophage XR 500 mg tablet, a reference drug, a release test was performed for the combination formulations prepared above.

[0080] Specifically, the sustained-release formulations prepared in Examples 1 and 2 and Comparative Examples 3 and 5, and the Glucophage XR 500 mg tablet as in commercial sale, which was used as a reference, were tested at 37 C. in 900 mL of dissolution media of phosphate buffer (pH 6.8) at 50 rpm according to the dissolution method (Method II) in USP. The samples were collected at scheduled times and analyzed via HPLC to calculate the release rates. The results are shown in Table 8 and FIG. 1.

[0081] The conditions used for HPLC are as follows.

[0082] Column: Waters XBridge (C18, 150 mm4.6 mm, 5 m)

[0083] Detector: spectrophotometric detector (218 nm)

[0084] Mobile phase: solution prepared by dissolving 17 g of NH.sub.4H.sub.2PO.sub.4 in 1 L of water and adjusting pH thereof to 3.0 with phosphoric acid

[0085] Flow rate: 1.0 mL/min

[0086] Column temperature: 40 C.

[0087] Time of analysis: 4 min

TABLE-US-00008 TABLE 8 Release Rate of Metformin Hydrochloride (%) Compar- Compar- Glucophage Release Example Example ative ative XR 500 Time (min) 1 2 Example 3 Example 5 mg Tablet 30 17.3 1.6 18.6 0.1 16.2 0.1 17.6 0.5 15.8 3.2 60 25.3 1.3 26.4 1.1 25.7 0.2 26.5 0.5 24.9 3.1 90 32.4 2.2 34.1 1.2 33.6 0.5 34.8 0.7 31.6 3.2 120 39.0 2.4 40.7 1.5 40.1 0.3 41.1 0.9 37.1 3.4 180 48.8 3.4 50.8 2.0 51.6 0.7 52.0 1.2 47.1 2.8 240 58.4 3.9 60.7 2.0 60.9 1.0 61.2 1.5 55.2 3.0 360 72.1 4.6 74.6 1.9 75.4 1.0 76.1 1.8 67.3 3.1 480 80.4 3.9 82.4 1.4 85.6 0.7 86.3 1.6 76.8 2.4 600 87.2 2.1 89.4 0.7 90.7 0.1 92.1 1.4 83.9 2.3 720 92.0 1.3 94.2 0.1 94.6 0.1 96.7 0.6 88.9 2.3

[0088] The release tests were performed for metformin hydrochloride on the combination formulations prepared in Examples 1 and 2 and Comparative Examples 3 and 5, and the results were compared with that of the Glucophage XR 500 mg tablet, the reference drug. The results show that the combination formulations exhibited release rates similar to that of the Glucophage XR 500 mg tablet. From the results, it was confirmed the drug release was effectively controlled using the swellable polymer and the water-insoluble polymer. The release control is highly significant considering that the tablet mass of the Glucophage XR 500 mg tablet is 1,000 mg or higher whereas the tablet mass of combination formulations according to the present invention is 900 mg or less.

[0089] Additionally, the sustained-release tablets prepared in Examples 5, 6, 7, and 8 according to the kinds of water-insoluble polymers, and the commercial product, the Glucophage XR 500 mg tablet, which was used as a control drug, were analyzed under the same conditions as described above, and the results are shown in Table 9 below. As a result of the analysis, the sustained-release tablets prepared in Examples 5, 6, 7, and 8 were shown to have a release pattern similar to that of the Glucophage XR 500 mg tablet, a control drug. From this result, it was confirmed that the drug release was effectively controlled using the swellable polymer and the water-insoluble polymer.

TABLE-US-00009 TABLE 9 Release Rate of Metformin Hydrochloride (%) Glucophage Release Example Example Example Example XR 500 mg Time (min) 5 6 7 8 Tablet 30 21.2 2.9 23.8 3.1 24.4 2.8 23.9 2.9 15.8 3.2 60 28.0 2.1 30.6 2.8 33.4 2.6 33.2 1.8 24.9 3.1 90 36.0 1.5 41.7 2.1 43.8 2.5 42.4 1.8 31.6 3.2 120 42.7 1.2 50.0 1.9 52.9 2.1 49.8 1.0 37.1 3.4 180 53.8 1.1 63.2 1.8 66.9 2.0 61.0 1.1 47.1 2.8 240 65.1 0.9 73.9 1.9 76.4 2.1 69.5 0.9 55.2 3.0 360 78.9 0.9 85.4 1.5 89.0 1.8 81.9 0.8 67.3 3.1 480 87.2 0.6 91.4 1.3 92.2 1.2 87.8 0.8 76.8 2.4 600 92.3 0.5 92.6 0.9 99.4 0.8 92.7 0.5 83.9 2.3 720 94.4 0.4 97.1 0.8 99.5 0.8 93.6 0.2 88.9 2.3

EXPERIMENTAL EXAMPLE 2

Release Test of Atorvastatin

[0090] In order to confirm whether the combination formulations according to the present invention can constantly maintain concentration in the blood via immediate release of a fast-release drug, a .sup.Lipitor 10 mg tablet, i.e., a control drug of atorvastatin calcium salt, the formulations prepared in Comparative Examples 1, 3, and 5, and Examples 1 and 2 were tested at 37 C. in 900 mL of dissolution media of distilled water at 50 rpm according to the dissolution method (Method II) in USP. The samples were collected at scheduled times and analyzed via HPLC to calculate the release rates. The results are shown in Table 10 and FIG. 2.

[0091] The conditions used for HPLC are as follows.

[0092] Column: Phenomenex Luna (C18, 250 mm4.6 mm, 5 m)

[0093] Detector: spectrophotometric detector (244 nm)

[0094] Mobile phase: 0.05 mol/L ammonium citrate (pH 4.0):ACN:THF =2:2:1

[0095] Flow rate: 1.5 mL/min

[0096] Column temperature: 40 C.

[0097] Time of analysis: 4 min

TABLE-US-00010 TABLE 10 Release Rate of Atorvastatin (%) Time for Example Example Comparative Comparative Comparative Lipitor 10 mg Release (min) 1 2 Example 1 Example 3 Example 5 Tablet 5 61.2 2.5 64.5 3.0 65.1 5.3 41.3 21.7 42.5 10.9 69.5 2.5 10 78.8 3.1 79.1 2.0 86.9 3.3 54.1 14.0 62.7 7.7 84.4 1.5 15 88.7 2.8 86.8 2.3 93.6 1.3 53.6 12.9 72.2 5.4 89.1 1.6 30 94.6 1.8 93.8 2.1 97.5 0.6 78.6 9.0 81.6 4.2 94.6 1.6 Disintegration 3 min 20 sec 3 min 10 sec 3 min 10 sec 10 min 50 sec 9 min 40 sec 3 min 10 sec Time

[0098] In the above experiment, the formulation of Comparative Example 1 (atorvastatin single tablets) showing a release rate similar to that of the Lipitor 10 mg tablet, a control drug, was prepared and its release rate was evaluated. When combination formulations were prepared using atorvastatin granules, which were prepared in the same manner as in Comparative Example 1, according to the methods in Comparative Example 3 and Comparative Example 5, there occurred a delay in disintegration of the immediate-release layer of atorvastatin granules due to a swellable polymer, thus lowering the release rate.

[0099] Meanwhile, in Examples 1 and 2, in which sustained-release metformin granules were prepared by coating a water-insoluble polymer on a swellable polymer and metformin hydrochloride, the disintegration time of atorvastatin was secured at a level the same as or similar to that of the atorvastatin single tablets. That is, it was confirmed that, by preventing the physical contact between two granules according to the present invention, the immediate-release atorvastatin hydrochloride granules were disintegrated and released in a similar manner to that of the single tablets, and this suggests that the same can be effectively applied to a combination formulation requiring a two-phase system consisting of a sustained-release formulation and a fast-release formulation requiring immediate release.

[0100] Additionally, the same experiment was performed for the formulations prepared in Examples 5 to 8. The formulations of Examples 5 to 8 were prepared by coating a different water-insoluble polymer on a swellable polymer and metformin hydrochloride, instead of a methacrylic acid copolymer (Eudragit RS PO), in which the atorvastatin granules prepared in the same manner as in Comparative Example 1 were tableted into double-layer tablets. The results of the release test are shown in Table 11 below.

TABLE-US-00011 TABLE 11 Release Rate of Atorvastatin (%) Lipitor Time for Example Example Example Example 10 mg Release (min) 5 6 7 8 Tablet 5 62.1 3.5 61.7 2.7 61.9 3.1 63.4 2.8 69.5 2.5 10 79.4 2.9 78.4 2.5 79.5 2.7 79.8 1.9 84.4 1.5 15 89.1 1.9 90.1 2.9 90.4 3.1 91.4 1.4 89.1 1.6 30 95.1 3.1 94.8 2.1 93.4 1.8 93.9 1.1 94.6 1.6 Disintegration 4 min 30 4 min 50 4 min 40 4 min 10 3 min Time sec sec sec sec 10 sec

[0101] The release rate of atorvastatin was shown to be similar to that of the formulation of Comparative Example 1, without being affected by the swellable polymer with high viscosity. Additionally, when a water-insoluble polymer other than the methacrylic acid copolymer (Eudragit RS PO) was used, the effect of preventing the physical contact between two granules was shown to be identical.

EXPERIMENTAL EXAMPLE 3

Release Test of Rosuvastatin

[0102] In order to confirm the release rate for the rosuvastatin calcium salt formulation, a Crestor 10 mg tablet, i.e., a control drug of rosuvastatin calcium salt, and the formulations prepared in Comparative Examples 2, 4, and 6 and Examples 3 and 4 were tested at 37 C. in 900 mL of a citrate buffer solution (pH 6.6) at 50 rpm according to the resolution method (Method II) in USP. The samples were collected at scheduled times and analyzed via HPLC to calculate the release rates. The results are shown in Table 12 and FIG. 3.

[0103] The conditions used for HPLC are as follows.

[0104] Column: Capcell Pak (C18, 75 mm4.6mm, 3 m)

[0105] Detector: spectrophotometric detector (242 nm)

[0106] Mobile phase: purified water:ACN:phosphoric acid=600:400:1

[0107] Flow rate: 1.0 mL/min

[0108] Column temperature: room temperature

[0109] Time of analysis: 5 min

TABLE-US-00012 TABLE 12 Time for Release Rate of Rosuvastatin (%) Release Example Example Comparative Comparative Comparative Crestor 10 (min) 3 4 Example 2 Example 4 Example 6 mg Tablet 5 78.3 5.1 78.1 3.7 76.8 4.8 58.4 7.1 63.4 8.1 75.3 7.0 10 92.4 3.8 91.9 2.3 91.4 2.7 84.1 6.1 86.1 3.7 91.6 3.4 15 95.2 2.2 94.7 0.9 94.4 1.1 87.4 3.1 88.4 3.4 94.2 1.8 30 96.1 1.7 95.1 0.8 95.1 0.8 89.1 2.7 89.4 3.2 95.6 1.7 Disintegration 2 min 40 sec 2 min 40 sec 2 min 50 sec 9 min 30 sec 8 min 50 sec 2 min 50 sec Time

[0110] In the above experiment, the formulation of Comparative Example 2 (rosuvastatin single tablets) showing a release rate similar to that of the Crestor 10 mg tablet, a control drug, was prepared and its release rate was evaluated. In the formulation of Comparative Examples 4 and 6 affected by a swellable polymer, there occurred a delay in disintegration of the immediate-release granule layer, thus lowering the release rate. This is the same as the result of the release test of atorvastatin evaluated previously, and it was confirmed that fast-release granules are immediately released by the effect of coating of a water-insoluble polymer in preparing combination formulations of sustained-release granules and immediate-release granules.

EXPERIMENTAL EXAMPLE 4

Stability TestInteraction Between Atorvastatin Calcium Salt and Excipients

[0111] In order to select the most appropriate excipient for the stability of atorvastatin calcium salts, a chemical stability test was performed between the atorvastatin calcium salts and excipients. Specifically, 1 g of atorvastatin calcium salt and 5 g each of the excipients were respectively mixed at room temperature, and packed into vials in a powdered state. The vials were stored for 4 weeks at stress conditions (60 C., 80% relative humidity), the impurity contents (%) were examined via HPLC, and the results are shown in Table 13 below.

[0112] The conditions used for HPLC are as follows.

[0113] Column: Gemini (C18, 250 mm4.6 mm, 5 m)

[0114] Detector: spectrophotometric detector (244 nm)

[0115] Mobile phase: 0.05 M ammonium citrate (pH 4.0):ACN:THF=53:27:20

[0116] Flow rate: 1.5 mL/min

TABLE-US-00013 TABLE 13 Initial 4 Sample Stage Weeks Atorvastatin calcium salt 0.02 0.13 Atorvastatin calcium salt/Eudragit RS PO 0.06 0.22 Atorvastatin calcium salt/Eudragit S100 0.06 0.27 Atorvastatin calcium salt/Kollicoat SR 30D 0.06 0.29 Atorvastatin calcium salt/cetyl alcohol 0.05 0.22 Atorvastatin calcium salt/Ethocel Std 14 0.05 0.23 Atorvastatin calcium salt/Polyox WSR301 0.10 0.53 Atorvastatin calcium salt/Metolose 905H-100,000 cps 0.08 0.37 Atorvastatin calcium salt/metformin hydrochloride 0.07 0.31

[0117] As can be seen in Table 13, atorvastatin calcium salts showed various values of total impurities depending on the excipients mixed therewith. The values of total impurities of other constituting components of the combination formulation, such as metformin hydrochloride, and swellable polymers, such as polyethylene oxide (Polyox WSR301) and hypromellose (Metolose 90SH-100,000 cps), showed relatively high total impurity values compared to those of water-insoluble polymers. Accordingly, it was confirmed that when these constituting components are directly brought into contact with atorvastatin calcium salt, it significantly decreases the stability of the combination formulations containing the same.

[0118] Among the water-insoluble polymers, the increases in the amount of impurities in the methacrylic acid copolymer (Eudragit RS PO), waxes (cetyl alcohol), and ethylcellulose (Ethocel Std 14) were shown to be lower than those when other water-insoluble polymers were used with a swellable polymer and metformin hydrochloride in preparing combination formulations, thus allowing more advantageous formulations to be secured than when the formulations were prepared using the existing methods of preparing suspended-release metformin formulation types known in the art, from the aspect of stability.

[0119] From the foregoing, those of ordinary skill in the art will recognize that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the present invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within the scope of the present invention.