HK1216079B - Complex formulation containing sustained release metformin and immediate release hmg-coa reductase inhibitor - Google Patents

Abstract

The present invention relates to a complex formulation containing metformin used in the treatment of non-insulin dependent diabetes and an HMG-CoA reductase inhibitor used in the treatment of dyslipidemia. The present invention provides a complex formulation and a method for preparing the complex formulation, wherein the complex formulation contains metformin and an HMG-CoA reductase inhibitor, and has effectively improved stability by securing the stable release of respective active ingredients and blocking physical and chemical reactions between the active ingredients.

Description

Complex formulation containing extended release metformin and immediate release HMG-CoA reductase inhibitor

Technical Field

The present invention relates to a complex formulation comprising metformin for the treatment of non-insulin dependent diabetes mellitus and the like and an HMG-CoA reductase inhibitor for the treatment of dyslipidemia, and a preparation method thereof.

Background

Diabetes, a chronic disease characterized by high blood glucose levels, can be divided into two types, type I diabetes, which causes the pancreas to stop producing insulin, and type II diabetes, which simultaneously causes increased insulin resistance and degeneration of pancreatic β -cell function.

Particularly, type II diabetes is a high risk disease due to insulin resistance and high blood glucose level, and is very closely related to cardiovascular diseases representing healthy states such as obesity, hypertension, dyslipidemia, excessive blood coagulation, and the like. Therefore, it is known that it is necessary in its treatment to appropriately control the accompanying metabolic diseases while actively controlling the blood glucose level.

Cardiovascular disease is a very common and serious disease in diabetics. In fact, macrovascular complications such as coronary artery disease, cerebrovascular disease, and peripheral artery disease account for about 75% of the causes of death in diabetic patients. Generally, diabetic patients are at a risk of cardiovascular disease about 2-to 4-fold higher than normal. Since cardiovascular diseases occur in a relatively young age and spread throughout the body, the mortality rate caused by the disease is known to be high. Furthermore, because published research reports disclose that diabetic patients with a history of cardiovascular disease may have the same level of cardiovascular disease development or their subsequent risk of mortality as patients without diabetes but with a history of cardiovascular disease, the american National Cholesterol Education Program (NCEP) Adult Treatment group 3 rd edition of guidelines (adolt Treatment panel III (ATP III)) has treated diabetes itself as equivalent to cardiovascular disease (CVD) risk and recommended that diabetic patients strictly follow the same level of preventive guidelines as patients with a history of cardiovascular disease.

Examples of therapeutic approaches to reduce the risk of cardiovascular disease in diabetic patients may include the regulation of blood pressure, blood glucose levels and lipid levels, of which lipid regulation is known to be most effective. According to the treatment guidelines at home and abroad, dyslipidemia of diabetic patients should be actively treated, and HMG-CoA reductase inhibitors, statins, are recommended as an initial treatment. Thus, metformin, an insulin-independent treatment of diabetes due to the effect of lowering blood glucose levels, and HMG-CoA reductase inhibitors, which treat dyslipidemia, are specified as the most effective methods for treating dyslipidemia in diabetic patients. However, when diabetic patients who were administered an HMG-CoA reductase inhibitor and an oral hypoglycemic agent simultaneously checked their drug compliance over two years, at least 80% of the patients administered these drugs showed 52% of drug compliance with the HMG-CoA reductase inhibitor and 63% of drug compliance with the oral hypoglycemic agent, thereby confirming that the drugs for treating dyslipidemia showed comparatively low drug compliance (p < 0.001). Therefore, there is a need to improve the medication compliance.

In view of this, the present invention provides a complex formulation comprising as active ingredients an oral hypoglycemic agent metformin and an HMG-CoA reductase inhibitor, in order to improve the above-mentioned drug compliance.

Metformin is an effective oral hypoglycemic agent, and is widely used for the prevention and treatment of the occurrence and progression of diabetic complications (e.g., cardiovascular diseases and the like). However, metformin is highly water-soluble, so that it is necessary to prepare metformin in a form of a formulation capable of controlling its effective sustained release, and this may cause problems in developing complex formulations containing metformin and other active ingredients having different properties. That is, due to its highly water-soluble nature, metformin, when formulated into conventional tablets, can be rapidly released causing excessive drop in blood glucose levels and may also cause gastrointestinal disturbances. In addition, metformin is conventionally administered as an immediate release tablet up to 500mg to 850mg, two or three times per day (maximum 2,550mg daily), and thus a drastic change in blood glucose levels due to its rapid release may cause adverse reactions and resistance to metformin.

In order to prepare the sustained-release metformin formulation, korean patent No.10-0774774 discloses a method for controlling the release of metformin using a fatty acid ester derivative, which is a water-insoluble carrier for sustained release, while international publication No. wo 09/117130 discloses a method for controlling the release of a water-soluble drug containing metformin using up to 40% of wax. However, in constructing the sustained release of a highly water-soluble drug, if the drug is impregnated in a polymer matrix or coated with a polymer film using a water-insoluble agent, it is likely that the drug is rapidly released at an initial stage due to a slow hydration rate of the polymer used therein, and then a sharp change in blood concentration thereof may cause adverse reactions and metformin resistance due to a sharp change in blood glucose level. In addition, it may have the disadvantage of requiring very large amounts of polymer to build up sustained release.

To solve these problems, international publication nos. WO 98/055107, WO 99/047125, WO 99/047128, WO 02/036100 and WO 03/028704, and korean patent nos.10-0772980, 10-0791844 and 10-1043816 disclose sustained release metformin formulations using a hydrophilic swellable polymer. In these sustained release metformin formulations using a hydrophilic swellable polymer, a stable drug release pattern can be constructed by allowing the hydrophilic polymer to immediately hydrate in an aqueous solution. However, the use of such swellable polymers as a slow release carrier for metformin causes a significant problem in the development of complex formulations, since those agents having high viscosity and high molecular weight are present on the outer surface of the granule and delay the release of the drug which should be released immediately. Therefore, techniques need to be developed to overcome this problem.

Meanwhile, HMG-CoA reductase inhibitors have excellent effects of lowering LDL-cholesterol levels, lowering triglyceride levels and increasing HDL-cholesterol levels, while exhibiting stability and drug resistance with few side effects, and thus are widely used for the treatment of dyslipidemia. HMG-CoA reductase inhibitors have a long half-life of 20 to 30 hours, but their bioavailability is not high. Because it can be absorbed throughout the gastrointestinal tract, it is beneficial when the active ingredient can be rapidly released from a given formulation.

HMG-CoA reductase inhibitors are reported to be susceptible to decomposition and/or oxidation when exposed to adverse physical and/or chemical conditions. Therefore, a great deal of research has long been focused on improving stability. For example, UK patent application publication No.2262229 discloses pharmaceutical formulations of the sodium salt of 7-substituted-3, 5-dihydroxy-6-heptenoic acid, which is an inhibitor of HMG-CoA reductase, and describes that the formulations require a basic medium (e.g., carbonate, bicarbonate) capable of providing an aqueous solution or dispersion of the composition with a pH of at least 8.

In addition, according to previous reports in Journal papers (Determination of Rosuvastatin in the Presence of its Degradation Products by the LC Method Indicating Stability of Rosuvastatin by a Stability-Indicating LC Method) (Journal of AOACInternational Vol.88, No.4, 2005)), calcium salt of Rosuvastatin is readily decomposable under acidic conditions below pH 5 and by oxidation, sunlight or high temperature, as for the formulation, the granular product having a larger area exposed to the environment is not stabilized by uncoated tablets, whereas film-coated tablets are more stabilized than uncoated tablets. In addition, in another journal article (the Stability of cholesterol lowering statin drugs in aqueous samples (Stability study in aqueous HPLC and LC-MS) using HPLC and LC-MS) (Environ ChemLett (2010) 8; 185)), the degree of Stability according to the pH of simvastatin, lovastatin, and pravastatin, and sunlight or solvents is disclosed.

In this regard, international publication No. wo 00/35425 discloses an attempt to stabilize statin mixtures using a buffer capable of providing a pH of 7 to 11, korean patent No.10-0388713 discloses a ternary phosphate salt, and korean patent No.10-0698333 discloses a method of stabilizing rosuvastatin using a pharmaceutical composition in which a counter anion is an inorganic salt instead of a phosphate salt. In addition, U.S. patent nos.5686104 and 6126971 disclose stabilizing atorvastatin by the addition of pharmaceutically acceptable alkaline earth metals.

In this respect, in order to manufacture a complex formulation containing metformin and an HMG-CoA reductase inhibitor, it is necessary to appropriately control the in vivo release of each active ingredient while ensuring that no side effects (e.g., deterioration in stability, etc.) due to complex constitution of two different compounds can occur between the two ingredients. Specifically, the complex formulation should be designed in such a way that: providing metformin with a stable sustained release profile of the active ingredient, while providing HMG-CoA reductase inhibitors with stability towards decomposition and oxidation while enabling the active ingredient to be in an immediate release profile.

However, as described above, the sustained release agent of metformin can inhibit the immediate release of HMG-CoA reductase inhibitor, thus making it difficult to design a formulation that can satisfy the desired release rate of both components. Stabilizers used for the stability of HMG-CoA reductase inhibitors may have a negative effect on the release rate of metformin and the like. That is, there is a high risk that a sustained-release agent, a stabilizer, or the like included in the complex formulation may exert a negative influence on the stability of the drug and its release rate, and thus it is not easy to design a complex formulation capable of securing optimal stability and release rate.

In order to control the sustained release of metformin, a great deal of research has been conducted on the type of formulation which can prevent rapid release of a drug by constructing a matrix-type formulation containing a certain amount of a swellable sustained-release agent having a high molecular weight and a high viscosity.

In general, swellable agents for sustained release are hydrophilic polymers having a three-dimensional network structure in which they are physically or chemically densely bonded, and thus become swollen and form hydrated gels in a short period of time when they come into contact with an aqueous solution, thereby preventing rapid drug release. However, when a complex formulation having both a gastric retention type sustained release using a swellable agent and an immediate release for rapidly releasing a drug at the initial release is developed, there is a problem in that the release of the drug for immediate release is delayed due to the high viscosity of the swellable agent for sustained release.

To solve these problems, international application No. pct/EP 2003/004472 discloses a multilayer tablet in which each drug is contained in a different layer and an inert layer is provided therebetween; korean patent application No.10-2012 0120519 also discloses a multilayer tablet in which each drug is contained in a different layer and an intermediate layer containing no drug is provided therebetween.

The above disclosed technology attempts to minimize physical and chemical reactions between drugs using a multilayer tablet system, thereby allowing for improved stability and effective release of each drug. However, the disadvantage of multilayer tablets is that manufacturing a multilayer tablet consisting of at least three layers results in significant loss of ingredients during processing, increases working time, and further increases tablet mass due to the additional intermediate layer, making it difficult to apply such techniques to high dose sustained release metformin formulations.

Meanwhile, international publication No. wo 03/026637 discloses a composite formulation manufactured by coating a water-insoluble polymer on a controlled-release formulation as an intermediate layer while coating an immediate-release formulation on an outer layer, and korean patent No.10-0705210 discloses a composite formulation in which a water-soluble polymer is coated on a sustained-release formulation as an intermediate layer while coating an immediate-release formulation on an outer layer. These techniques disclose coating an intermediate layer located between two different drugs and thereby facilitating minimization of physical and chemical reactions, improving stability and reducing tablet quality.

However, since the immediate release drug should be coated on the sustained release preparation, the crystal form of the active ingredient may be changed during the process of dissolving or dispersing the immediate release drug, and there is a commercial problem that it is difficult to secure content uniformity through a coating process in mass production. In addition, it may be desirable to apply the techniques to those components that are included in trace amounts as active ingredients in the formulations of the above-mentioned patents. However, these techniques are limited in their application to relatively high doses of the drug, and thus it is not desirable to apply these techniques to atorvastatin calcium salt preparations in unit dosage amounts of 10mg to 80 mg.

Under these circumstances, the present inventors have made intensive efforts to develop a formulation capable of securing optimal stability and release rate, and as a result, have found that by constituting a complex formulation from a first sustained-release composition consisting of particles containing metformin or a pharmaceutically acceptable salt thereof and a swellable polymer and a water-soluble polymer film surrounding the particles and a second sustained-release composition containing an HMG-CoA reductase inhibitor, the complex formulation having effectively improved stability can be provided by preventing physical and chemical reactions between active ingredients while securing stable release of each active ingredient contained therein, thereby completing the present invention.

Disclosure of Invention

[ problem ] to

The present invention aims to provide a complex formulation having effectively improved stability by preventing physical and chemical reactions between active ingredients while ensuring stable release of each active ingredient contained therein, and a method for preparing the same.

[ technical solution ]

The object of the present invention is to provide a pharmaceutical composition containing metformin for the treatment of non-insulin dependent diabetes mellitus and the like and a statin for the treatment of dyslipidemia and the like. In detail, the present invention relates to a composition having a biphasic system, which is capable of controlling an initial burst of a sustained-release drug in an initial stage while rapidly releasing an immediate-release drug without being affected by a high-viscosity swellable agent and improving drug stability, by preparing particles coated with a water-insoluble polymer, the particles containing metformin or a pharmaceutically acceptable salt thereof and a swellable polymer.

[ advantageous effects of the invention ]

The drug release control system according to the present invention provides improved convenience and compliance in administration by suppressing initial burst release through dual release control even with a small amount of polymer by using a swellable polymer and a water-insoluble polymer together. In addition, the system of the present invention can control the delay of immediate release by using a water-insoluble polymer film on the sustained release particles. The drug release control system according to the present invention thus provides an effective sustained and immediate release biphasic system.

Drawings

FIG. 1 shows the combination preparations prepared in examples 1 and 2 of the present invention with GlucophageRelease test results for 500mg tablets.

Fig. 2 shows the results of the release test of the composite formulations prepared in examples 1 and 2 of the present invention with a Lipitor 10mg tablet.

Fig. 3 shows the results of the release test of the complex formulation prepared in examples 3 and 4 of the present invention with a Crestor 10mg tablet.

Detailed Description

Preferred embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. This invention may, however, be embodied in many 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 invention to those skilled in the art.

In order to solve the above problems, the present invention provides a complex formulation comprising a first sustained-release composition comprising particles containing metformin or a pharmaceutically acceptable salt thereof and a swellable polymer and a water-insoluble polymer film coating the particles,

and a second release composition comprising an HMG-CoA reductase inhibitor.

As used herein, the term "first sustained release composition" refers to a composition containing metformin or a pharmaceutically acceptable salt thereof, which is capable of releasing it for a long period of time by preventing its rapid release. For sustained release, metformin or a pharmaceutically acceptable salt thereof is formed into particles with a swellable polymer and each individual particle is coated with a water-insoluble polymer membrane.

As used herein, the term "metformin" refers to a compound having the chemical name of N, N-dimethyl imidodicarbonimidine diamine (formula 1 below), which is used as a therapeutic agent for preventing or treating non-insulin dependent diabetes mellitus.

[ formula 1]

Metformin can be utilized by isolation from natural resources, production by chemical modification after obtaining it from natural resources, or chemical synthesis easily by those skilled in the art according to known methods. Alternatively, commercially available metformin can be purchased for use.

Preferably, metformin or a pharmaceutically acceptable salt thereof may be included in the complex formulation of the present invention in an amount of 250mg to 1000 mg.

As used herein, the term "swellable polymer" refers to a pharmaceutically acceptable polymer that becomes swollen in aqueous solution, thereby allowing for controlled drug release. In the present invention, the swellable polymer forms a particle with metformin or a pharmaceutically acceptable salt thereof and exhibits the same sustained release characteristics. The swellable polymer useful in the present invention may include at least one selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene oxide, carrageenan, natural gum, guar gum, tragacanth gum, acacia gum, locust bean gum, xanthan gum, polyvinyl alcohol and polyvinylpyrrolidone, and is preferably hydroxypropylmethyl cellulose or polyethylene oxide, but is not limited thereto, as long as it is a pharmaceutically acceptable swellable polymer capable of controlled release according to the object of the present invention. Preferably, the swellable polymer has a viscosity of 100cps or greater.

Preferably, the swellable polymer may be included in the complex formulation in an amount of 10 wt% to 40 wt%, based on the total weight of the first sustained-release composition. When less than 10 wt% of the swellable polymer is contained, it becomes difficult to achieve effective control of drug release, and when more than 40 wt% of the swellable polymer is contained, the size of the tablet becomes too large to be taken, and thus is not appropriate.

The particles of the present invention comprising metformin or a pharmaceutically acceptable salt thereof and the swellable polymer are formed by coating the outer surface with a water-insoluble polymer.

As used herein, the term "water-insoluble polymer" refers to a pharmaceutically acceptable polymer capable of controlling drug release, which is water-insoluble or nearly water-insoluble. In addition, the purpose of the water-insoluble polymer of the present invention includes not only preventing the release of metformin or a pharmaceutically acceptable salt thereof but also preventing the HMG-CoA reductase inhibitor contained in the second rate-release composition from coming into contact with the swellable polymer. That is, the complex formulation according to the present invention is formed such that the swellable polymer can be prevented from physically contacting and chemically reacting with the HMG-CoA reductase inhibitor by the water-insoluble polymer film coating.

The present invention relates to a complex formulation comprising an HMG-CoA reductase inhibitor in addition to metformin, while a swellable polymer for 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. Thus, the type of formulation comprising a swellable polymer for the sustained release of metformin without affecting the HMG-CoA reductase inhibitor should be considered. For this purpose, in the present invention, the outer surface of the particles containing metformin or a pharmaceutically acceptable salt and a swellable polymer is coated with a water-insoluble polymer, thereby preventing contact between the swellable polymer and an HMG-CoA reductase inhibitor.

In an exemplary embodiment of the invention, the swellable polymer exhibits an effect on the HMG-CoA reductase inhibitor in the absence of the water-insoluble polymer, thereby reducing the release rate of the HMG-CoA reductase inhibitor and increasing impurity formation. In contrast, in the case of the composite formulation of the present invention using a water-insoluble polymer film, the first sustained-release composition and the second sustained-release composition each show a release pattern similar to that of a single formulation type without increasing the formation of impurities. Since the first sustained-release composition according to the present invention does not cause the high viscosity problem caused by the swellable polymer while effectively controlling the sustained release of metformin, these results suggest that the metformin sustained-release agent does not affect the immediate release of the second sustained-release composition.

The water-insoluble polymer useful in the present invention may include at least one selected from the group consisting of methacrylic acid copolymer, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, fatty acid ester, fatty alcohol and wax, and preferably methacrylic acid copolymer or ethyl cellulose, but the water-insoluble polymer is not limited thereto as long as it is a pharmaceutically acceptable water-insoluble polymer capable of controlled release in accordance with the object of the present invention.

Preferably, the water-insoluble polymer according to the present invention may be included in an amount of 1 wt% to 20 wt%, based on the total weight of the first sustained-release composition. When the polymer content exceeds 20 wt%, the film thickness will be increased and the hydration of the swellable polymer will be slowed down, and thus it is not suitable for controlling the initial release of the drug.

As used herein, the term "second-rate release composition" refers to a composition containing an HMG-CoA reductase inhibitor that disintegrates completely within 5 minutes in distilled water at 37 ℃.

As used herein, the term "HMG-CoA", as an acronym for "3-hydroxy-3-methylglutaryl-coenzyme a", refers to a precursor for the biosynthesis of sterols including cholesterol. As used herein, the term "HMG-CoA reductase inhibitor" refers to a compound that provides a lowering effect on total cholesterol and LDL-cholesterol levels in the body by inhibiting HMG-CoA reductase activity, which is involved in the early stage of the conversion of HMG-CoA to mevalonate during the cholesterol biosynthesis process. For example, the HMG-CoA reductase inhibitor may be at least one selected from the group consisting of rosuvastatin, atorvastatin, pitavastatin, lovastatin, simvastatin, pravastatin and fluvastatin, or a pharmaceutically acceptable salt, but it is not limited thereto. In addition, the formulation of the present invention may further comprise a pharmaceutically acceptable basifying agent. The HMG-CoA reductase inhibitor according to the invention is preferably atorvastatin or rosuvastatin. Preferably, the HMG-CoA reductase inhibitor may be included in the complex formulation of the present invention in an amount of 5mg to 160 mg. In addition, in the case of rosuvastatin, it may be included in the composite preparation of the present invention in an amount of 5mg to 40 mg.

The second fast-release composition may further contain a pharmaceutically acceptable disintegrant and/or dissolution aid in order to completely disintegrate in distilled water at 37 ℃ within 5 minutes. The disintegrant and/or dissolution aid usable in the present invention may include at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, polysorbate, poloxamer and sodium lauryl sulfate, and preferably croscarmellose sodium or crospovidone may be used, but the disintegrant and/or dissolution aid is not limited thereto as long as they are pharmaceutically acceptable additives capable of controlling disintegration in accordance with the purpose of the present invention.

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

As used herein, the term "pharmaceutically acceptable salt" refers to a type of formulation that does not impair the biological activity and physical properties of the metformin or HMG-CoA reductase inhibitor to be administered. The pharmaceutically acceptable salts may include acid addition salts that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric, sulfuric, nitric, phosphoric, hydrobromic and hydroiodic 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; and so on. For example, the pharmaceutically acceptable salts may include metal or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, and the like; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like.

In addition, the composite pharmaceutical preparation of the present invention may further compriseA film layer on the outer surface. The film layer may be, for example, a protective film layer, a moisture-proof film layer, a glucose film layer, or the like. Preferably, the outer film layer is formed of a water-soluble material, which may include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate, ethyl cellulose, methyl cellulose, polymethacrylate, polyvinyl alcohol-polyethylene glycol graft copolymer ((r))BASF, Germany), polyvinyl alcohol (C: (A)Colorcon, usa), or a combination thereof, but is not limited thereto.

In addition, the complex pharmaceutical formulation of the present invention may be formulated further using additives conventionally used in the art, such as diluents, binders, lubricants, pH adjusters, antifoaming agents, dissolution aids, antioxidants, and the like, within a range that does not impair the effects of the present invention.

The complex pharmaceutical formulation of the present invention may be prepared into various formulation types, for example, tablets such as uncoated tablets, film-coated tablets, single-layered tablets, double-layered tablets, multi-layered tablets, or core tablets; powder; particles; capsules, and the like. Preferably, the complex pharmaceutical formulation of the present invention is prepared in the form of a bilayer tablet consisting of the first sustained-release composition and the second sustained-release composition.

The thus-prepared complex pharmaceutical formulation of the present invention can provide an appropriate release profile suitable for each pharmaceutically active ingredient by continuously releasing metformin and rapidly releasing HMG-CoA reductase inhibitor during in vivo administration. In addition, the convenience of administration is improved by reducing the content of the sustained-release agent necessary for sustained release of metformin, while the immediate-release drug is rapidly dissolved and the stability of the HMG-CoA reductase inhibitor is improved by including a stabilizer. Therefore, the complex pharmaceutical preparation of the present invention can be effectively used for the prevention and treatment of dyslipidemia, atherosclerosis, diabetes and diabetic complications.

In another exemplary embodiment, the present invention provides a method for preparing the complex formulation, the method comprising preparing the first sustained-release composition by preparing particles containing metformin or a pharmaceutically acceptable salt thereof and a swellable polymer, followed by forming a water-insoluble polymer film on the particles;

preparing the second release-rate composition comprising an HMG-CoA reductase inhibitor; and

the first sustained release composition and the second sustained release composition are formulated as a unit formulation.

In addition, the method of the present invention may further include forming a film layer on the outer surface of the complex formulation.

As used herein, the terms "first sustained release composition", "metformin", "swellable polymer", "water-insoluble polymer", "second rate release composition", "HMG-CoA", "pharmaceutically acceptable salt" and "film layer" are as described above.

[ examples ]

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 present invention is not intended to be limited by these examples.

Example 1

1) Preparation of sustained-release metformin hydrochloride particles

Sustained-release metformin hydrochloride particles were prepared according to the composition and content shown in table 1. Specifically, metformin hydrochloride and colloidal silica were passed through a 20-mesh sieve and mixed with polyethylene oxide: (WSR 301). Then, the resultant was sprayed with a binder solution containing a solvent mixture of isopropyl alcohol, acetone and purified water mixed at a ratio of 6:3:1 and added methacrylic acid copolymer(s) ((meth) acrylic acid copolymer (s))RS PO) was dissolved at a concentration of 10 w/v%, and then dried in a fluidized-bed granulator to prepare granules, and the resultant was passed through a 20-mesh sieve. The granulated product thus obtained is treated with magnesium stearate and mixed to prepare sustained-release metformin hydrochloride granules.

[ Table 1]

2) Preparation of quick-release atorvastatin granules

The immediate release atorvastatin granules were prepared according to the compositions and contents shown in table 2. Specifically, atorvastatin calcium salt, precipitated calcium carbonate, microcrystalline cellulose, hydrated lactose and croscarmellose sodium were mixed, treated with hydroxypropyl cellulose 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 granulated product thus obtained was treated with croscarmellose sodium and magnesium stearate and mixed to prepare an immediate release atorvastatin granule.

[ Table 2]

3) Compression of bilayer tablet

The metformin hydrochloride and atorvastatin granules prepared in 1) and 2) above were compressed into bilayer tablets in amounts of 710mg and 150mg, respectively, to prepare white tablets having a unit weight of 860mg per tablet.

4) Coating solution and preparation of coating

The tablets prepared in 3) above were loaded into a coating pan (Hi-coater, Freund) and the degassing temperature was maintained at about 30 to 40 ℃.10 g of03B64650 (62.5% hydroxypropylmethylcellulose 2910, 30.79% titanium oxide, 6.25% polyethylene glycol 400, 0.27% yellow iron oxide, 0.18% iron oxide red, and 0.01% indigo carmine aluminum lake) coating agent was dissolved in 90g of water to prepare a coating solution, which was sprayed on the dried tablets using a sprayer operating under air pressure and dried by further providing an intake air flow for about 10 minutes to obtain 885mg of the unit tablets of the present invention, wherein the coating amount per tablet was 25 mg.

Example 2

Sustained-release metformin hydrochloride particles were prepared according to the composition and content shown in table 3. Specifically, metformin hydrochloride and colloidal silicon dioxide are passed through a 20-mesh sieve and mixed with hypromellose (b) ((b))90SH-100,000 cps). Then, the resultant was sprayed with a binder solution containing a solvent mixture of isopropyl alcohol, acetone and purified water mixed at a ratio of 6:3:1 and added methacrylic acid copolymer(s) ((meth) acrylic acid copolymer (s))RS PO) was dissolved at a concentration of 10 w/v%, and then dried in a fluidized-bed granulator to prepare granules, and the resultant was passed through a 20-mesh sieve. The granulated product thus obtained is mixed with magnesium stearate to prepare final sustained-release metformin hydrochloride granules. The process for preparing the immediate release atorvastatin granules, the tableting of the bilayer tablet, and the coating was performed in the same manner as in example 1.

[ Table 3]

Example 3

Immediate release rosuvastatin particles are prepared according to the composition and content shown in table 4. Specifically, anhydrous dibasic calcium phosphate was used as a stabilizer, and specifically, rosuvastatin calcium salt, microcrystalline cellulose, hydrated lactose, crospovidone, and magnesium stearate were mixed with anhydrous dibasic calcium phosphate to prepare immediate release rosuvastatin particles. The processes for preparing the sustained-release metformin granules, tableting the bilayer tablets, and coating were performed in the same manner as in example 1.

[ Table 4]

Example 4

Immediate release rosuvastatin granules are prepared in the same manner as in example 3, and the process of preparing the sustained release metformin granules, tableting and coating of the bilayer tablet is performed in the same manner as in example 2.

Comparative example 1

Immediate release atorvastatin granules were prepared in the same manner as in example 1 and then tabletted into a single tablet. The coating amount per tablet was 5mg, and 155mg of unit tablets were obtained therefrom.

Comparative example 2

Immediate release rosuvastatin granules are prepared in the same manner as in example 3 and then tabletted into a single tablet. The coating amount per tablet was 5mg, and 155mg of unit tablets were obtained therefrom.

Comparative examples 3 and 4

The sustained release metformin hydrochloride was prepared according to the composition and 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 to prepare granulation. The resultant was dried in a fluid bed dryer and passed through a 20-mesh screen. The granulated product thus obtained is reacted with polyethylene oxide(s) (II)WSR301) and magnesium stearate, and mixing to produce the final sustained release metformin hydrochloride particles.

[ Table 5]

The process for preparing the immediate release atorvastatin granules, the tableting of the bilayer tablet, and the coating was performed in the same manner as in example 1, and the amount of the finally obtained tablet was 945mg (comparative example 3).

The process for preparing immediate release rosuvastatin granules, tableting the bilayer tablet, and coating is performed in the same manner as in example 3, and the amount of the finally obtained tablet is 945mg (comparative example 4).

Comparative examples 5 and 6

The sustained release metformin hydrochloride was prepared according to the composition and content shown in table 6. In particular toMetformin 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 fluid bed dryer and passed through a 20-mesh screen. The granulated product thus obtained is mixed with hypromellose (b) ((iii))90SH-100,000cps) and magnesium stearate, and mixing to prepare final sustained release metformin hydrochloride particles.

[ Table 6]

The process for preparing the immediate release atorvastatin granules, the tableting of the bilayer tablet, and the coating was performed in the same manner as in example 1, and the amount of the finally obtained tablet was 945mg (comparative example 5).

The process for preparing immediate release rosuvastatin granules, tableting the bilayer tablet, and coating is performed in the same manner as in example 3, and the amount of the finally obtained tablet is 945mg (comparative example 6).

Examples 5 to 8

Sustained-release metformin hydrochloride particles were prepared according to the composition and content shown in table 7. Specifically, sustained-release metformin hydrochloride particles were prepared in the same manner as in example 1, except that they were separately utilizedS100、Std 14, cetyl alcohol andSR 30D ingredient (Ginseng radix)See Table 7) in place of methacrylic acid copolymer (CRS PO) preparation. The amount of each tablet obtained after compression into a bilayer tablet and completion of the coating process was 885 mg.

[ Table 7]

Test example 1: release test for metformin

To confirm whether or not the complex formulation according to the present invention can exhibit the Glucophage-a reference drugThe release rate equivalent to 500mg tablets was tested for the release of the composite formulation prepared above.

Specifically, sustained-release preparations prepared in examples 1 and 2 and comparative examples 3 and 5, and commercially available Glucophage used as a reference500mg tablets, tested according to the dissolution method in USP (method II) in 900mL phosphate buffer dissolution medium (pH 6.8) at 37 ℃ and 50 rpm. Samples were collected at predetermined times and analyzed by HPLC to calculate release rates. The results are shown in table 8 and fig. 1.

The conditions for HPLC are as follows.

Column: waters Xbridge (C18, 150 mm. times.4.6 mm, 5 μm)

A detector: spectrophotometric detector (218nm)

Mobile phase: by mixing 17g of NH₄H₂PO₄Solution prepared by dissolving in 1L of water and adjusting its pH to 3.0 with phosphoric acid

Flow rate: 1.0mL/min

Column temperature: 40 deg.C

Analysis time: 4 minutes

[ Table 8]

The metformin hydrochloride release test was performed on the complex formulations prepared in examples 1 and 2 and comparative examples 3 and 5, and the results were compared with the reference drug Glucophage500mg tablets. The results show that the complex formulation appears similar to GlucophageRelease rate of 500mg tablet. From the results, it was confirmed that drug release was effectively controlled using the swellable polymer and the water-insoluble polymer. Considering GlucophageThe tablet mass of the 500mg tablet is 1,000mg or more, whereas the tablet mass of the composite preparation of the present invention is 900mg or less, the release control is highly significant.

In addition, sustained-release tablets prepared according to the kind of the water-insoluble polymer in examples 5, 6, 7 and 8, and commercial Glucophage used as a control drug500mg tablets, 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 Glucophage similar to the control drugRelease pattern of 500mg tablet. From the results, it was confirmed that drug release was effectively controlled using the swellable polymer and the water-insoluble polymer.

[ Table 9]

Test example 2: atorvastatin release test

To confirm whether the complex formulation according to the present invention can maintain a constant concentration in blood by immediate release of a rapid-release drug, according to the dissolution method in USP (method II), it was tested in 900mL of distilled water dissolution medium at 37 ℃ and 50rpm10mg tablets, a control of atorvastatin calcium salt, and the formulations prepared in comparative examples 1, 3 and 5 and examples 1 and 2. Samples were collected at predetermined times and analyzed by HPLC to calculate release rates. The results are shown in table 10 and fig. 2.

The conditions for HPLC are as follows.

Column: phenomenex Luna (C18, 250 mm. times.4.6 mm, 5 μm)

A detector: spectrophotometric detector (244nm)

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

Flow rate: 1.5mL/min

Column temperature: 40 deg.C

Analysis time: 4 minutes

[ Table 10]

In the above test, a drug showing a release rate similar to that of the control drug was preparedThe preparation of comparative example 1 (atorvastatin mono-tablet) was tableted at 10mg, and its release rate was evaluated. When a complex formulation was prepared using atorvastatin granules prepared in the same manner as in comparative example 1 according to the methods of comparative examples 3 and 5, a delay in disintegration of the immediate release layer of the atorvastatin granules due to the swellable polymer occurred, thereby decreasing the release rate.

Meanwhile, in examples 1 and 2, in which the sustained-release metformin granules were prepared by coating the water-insoluble polymer on the swellable polymer and metformin hydrochloride, the disintegration time of atorvastatin was fixed at the same or similar level as that of atorvastatin mono-tablet. That is, it was confirmed that the immediate release atorvastatin hydrochloride granules were disintegrated and released in a similar manner to the monolithic agent by preventing physical contact between the two granules according to the present invention, which suggests that it can be effectively applied to complex formulations requiring a biphasic system consisting of a sustained release formulation and a rapid release formulation requiring immediate release.

In addition, the same tests were carried out on the formulations prepared in examples 5 to 8. The formulations of examples 5 to 8 replaced the methacrylic acid copolymer by coating different water-insoluble polymers on the swellable polymer and metformin hydrochloride salt (II) ((III))RS PO), wherein the prepared atorvastatin granules were tableted into a bilayer tablet in the same manner as in comparative example 1. The results of the release test are shown in table 11 below.

[ Table 11]

Delivery of atorvastatinThe ratio showed a similar formulation to comparative example 1, unaffected by the high viscosity swellable polymer. In addition, when methacrylic acid copolymer(s) (b) is usedRS PO), the same effect is exhibited to prevent physical contact between the two particles.

Test example 3: rosuvastatin release test

To confirm the release rate of the rosuvastatin calcium salt formulation, according to the dissolution method in USP (method II), the test was performed in 900mL citrate buffer (pH 6.6) at 37 ℃ and 50rpm10mg tablets, a control of rosuvastatin calcium salt, and the formulations prepared in comparative examples 2, 4 and 6 and examples 3 and 4. Samples were collected at predetermined times and analyzed by HPLC to calculate release rates. The results are shown in table 12 and fig. 3.

The conditions for HPLC are as follows.

Column: capcell Pak (C18, 75 mm. times.4.6 mm, 3 μm)

A detector: spectrophotometric detector (242nm)

Mobile phase: purified water ACN phosphoric acid 600:400:1

Flow rate: 1.0mL/min

Column temperature: at room temperature

Analysis time: 5 minutes

[ Table 12]

In the above test, a drug showing a release rate similar to that of the control drug was preparedThe formulation of comparative example 2 (rosuvastatin single tablet) was tableted at 10mg and its release rate was evaluated. In the formulations of comparative examples 4 and 6 affected by the swellable polymer, a delay in disintegration of the immediate release particle layer occurred, thereby decreasing the release rate. This is the same as the results of the previously evaluated atorvastatin release test, and confirms that the immediate release granules are immediately released by the effect of coating the water-insoluble polymer in preparing the complex formulation of the sustained release granules and the immediate release granules.

Test example 4: stability test-interaction between atorvastatin calcium salt and excipients

In order to select the most appropriate excipient for atorvastatin calcium salt stability, a chemical stability test was performed between atorvastatin calcium salt and excipient. Specifically, 1g of atorvastatin calcium salt and 5g of each excipient were mixed at room temperature, respectively, and filled into a vial in a powder state. The vials were stored under stress conditions (60 ℃, 80% relative humidity) for 4 weeks, checked for impurity content (%) by HPLC, and the results are shown in table 13 below.

The conditions for HPLC are as follows.

Column: gemini (C18, 250mm X4.6 mm, 5 μm)

A detector: spectrophotometric detector (244nm)

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

Flow rate: 1.5mL/min

[ Table 13]

As can be seen from table 13, atorvastatin calcium salt showed various total impurity values depending on the excipient mixed therewith.Other constituent components of the complex formulation, such as metformin hydrochloride and swellable polymers such as polyethylene oxide(s) ((s))WSR301) and hypromellose: (90SH-100,000cps), exhibits a relatively high total impurity value compared to the water-insoluble polymer. Thus, it was demonstrated that when these constituents were directly contacted with atorvastatin calcium salt, it significantly reduced the stability of the complex formulation containing it.

Among the water-insoluble polymers, methacrylic acid copolymers (A), (B), (C), (RS PO, wax (cetyl alcohol) and ethylcellulose: (The increase in the amount of impurities in Std 14) is lower than when other water-insoluble polymers are used together with the swellable polymer and metformin hydrochloride in the preparation of a composite formulation, thereby allowing the securing of a formulation more advantageous in terms of stability than would be the case if the formulation were prepared using existing methods known in the art for preparing the type of sustained release metformin formulation.

From the foregoing, those skilled 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 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 their scope.

Claims (15)

1. A composite formulation comprising:

a first sustained release composition comprising particles comprising metformin or a pharmaceutically acceptable salt thereof and a swellable polymer, and a water-insoluble polymer membrane for coating the particles; and

a second release composition comprising an HMG-CoA reductase inhibitor,

wherein the water-insoluble polymer is at least one selected from the group consisting of methacrylic acid copolymer, ethyl cellulose, polyvinyl acetate, cellulose acetate succinate, cellulose acetate phthalate, fatty acid ester, fatty alcohol and wax.

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

3. The complex formulation according to claim 1, wherein the swellable polymer has a viscosity of 100cps or more.

4. The complex formulation of claim 1, 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 mixtures thereof;

the fatty alcohol is at least one selected from the group consisting of cetearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; and is

The wax is at least one selected from the group consisting of carnauba wax, beeswax, microcrystalline wax, and mixtures thereof.

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

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

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

8. The complex 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.

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

10. The complex formulation of claim 1, wherein the second rate-release composition completely disintegrates within 5 minutes in distilled water at 37 ℃.

11. The complex formulation of claim 1, which is formulated such 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.

12. The composite formulation of claim 1, wherein the composite formulation is an uncoated tablet, a film-coated tablet, a bilayer tablet, a multilayer tablet, or a core tablet.

13. The composite formulation of claim 1, wherein the first sustained-release composition and the second sustained-release composition are in the form of a bilayer tablet.

14. A method of preparing the complex formulation of claim 1, the method comprising:

preparing the first sustained release composition by preparing particles comprising metformin or a pharmaceutically acceptable salt thereof and a swellable polymer, followed by forming a water-insoluble polymer film on the particles;

preparing the second release-rate composition comprising an HMG-CoA reductase inhibitor; and

formulating the first sustained release composition and the second sustained release composition into a unit formulation,

wherein the water-insoluble polymer is at least one selected from the group consisting of methacrylic acid copolymer, ethyl cellulose, polyvinyl acetate, cellulose acetate succinate, cellulose acetate phthalate, fatty acid ester, fatty alcohol and wax.

15. The method of claim 14, further comprising forming a film layer on an outer surface of the composite formulation.