KR101072600B1 - Stable pharmaceutical composition comprising fluvastatin and method for preparing the same - Google Patents

Abstract

The present invention relates to pharmaceutical compositions of fluvastatin with increased stability.

Preferably, the pharmaceutical composition of fluvastatin for the prevention and treatment of hyperlipidemia or hepatitis C, including fluvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof having improved stability upon long-term storage, and a method of preparing the same. It is about.

HMG-CoA reductase inhibitor, fluvastatin, stability, stabilizer, poloxamer

Description

Stable pharmaceutical composition comprising fluvastatin and method for preparing the same

The present invention relates to a two-component complex preparation of fluvastatin of a lipid lowering agent statin and a bile acid-based ursodeoxycholic acid. The present invention is also an invention for fluvastatin mono-component single agent.

Fluvastatin and ursodeoxycholic acid bicomponent combinations are intended to be used as a hepatitis C treatment or as a hyperlipidemia treatment, and fluvastatin monotherapy can also be used as a hepatitis C treatment or as a hyperlipidemia treatment .

The present invention relates to a pharmaceutical composition which ensures the stability of fluvastatin which is poor in long-term storage, and a method for preparing the same.

The treatment of hyperlipidemia with fluvastatin has been widely known and proven for a long time, and hepatitis C treatment is also known. (Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Ikeda M, Abe K, Yamada M, Dansako H, Naka K, Kato N. Hepatology. 2006 Jul; 44 (1): 117-25.)

Ursodeoxycholic acid is also a drug that has long been known for improving liver function, treating hyperlipidemia, and treating hepatitis C.

The present invention not only devised a formulation technology to increase the efficacy and reduce side effects when oral administration of each component in combination or oral administration of fluvastatin as a single formulation, as well as to ensure stability in storage and patient And made it easy for the prescriber to use.

Statin-based drugs, such as fluvastatin, are easily decomposed by acid, which may cause stability problems such as decreased content in tablets and prolonged softening during long-term storage. This is a problem that must be solved when preparing a statin-based drug such as fluvastatin. This problem is solved by using an alkalizing agent in the pharmaceutical composition in the prior art. However, these alkalizing agents have a problem that their effects are insufficient and can cause side effects.

Korean Patent No. 10-0253824 discloses a stabilized pharmaceutical composition comprising an HMG-CoA reductase inhibitor compound. Since the HMG-CoA reductase inhibitor compound is acid labile, a general stabilization method for improving the storage stability of the HMG-CoA reductase inhibitor using an inorganic salt type alkalizing agent is described. It is described as an alkaline medium which can impart the above, and more specifically, carbonate is used to improve stability.

As in the prior art, in general, an alkalizing agent is used to improve the stability of statin-based drugs, but the alkalizing agent has various side effects. In general, the intragastric pH is around 2, but the intragastric pH may be increased by the administration of an alkalizing agent. This prevents proper gastric function, and co-administration of pH-sensitive drugs in the gastrointestinal tract may affect the absorption of the drug, resulting in no expected efficacy or side effects.

Ursodeoxycholic acid is approved in Korea for cholelithiasis, chronic hepatitis, bile secretion failure, but not for hyperlipidemia and hepatitis C. Ursodeoxycholic acid inhibits bile cholesterol but is known to have no effect on blood cholesterol. (The effects of ursodeoxycholic acid on serum and biliary noncholesterol sterols in patients with gallstones.Miettinen TE, Tarpila S, Gylling H. Hepatology. 1997 Mar; 25 (3): 514-8.) Also, ursodeoxycholic acid is directly C A number of literatures have been published that do not inhibit hepatitis virus (Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'.Lazaridis KN, Gores GJ, Lindor KD. J Hepatol. 2001 Jul; 35 (1): 134- 46.). This suggests that ursodeoxycholic acid monotherapy for the treatment of hyperlipidemia or hepatitis C is not sufficient.

Although the present invention contains fluvastatin but does not use an alkalizing agent to reduce side effects, and in order to solve the problem of fluvastatin, which is poor in long-term storage, the temperature condition of 40 ± 2 ℃, 75 ± 5% relative It is an object of the present invention to provide a pharmaceutical composition of fluvastatin comprising fluvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof having improved storage stability at humidity conditions, and a method of preparing the same.

In addition, the present invention includes fluvastatin and improves storage stability, and is prepared in various forms such as rapid release, sustained release, and nucleated tablets, which is convenient for patients and doctors, and prevents hyperlipidemia, cardiovascular disease, arteriosclerosis, or hepatitis C. It is an object to provide a pharmaceutical composition for treatment.

In addition, the present invention provides a prevention or treatment of hyperlipidemia, cardiovascular disease, arteriosclerosis, or hepatitis C with fluvastatin, including ursodeoxycholic acid or hydrochlorothiazide, preferably ursodeoxycholic acid and improved storage stability. It is an object to provide a pharmaceutical composition for.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising fluvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof through poloxamer, unlike the method of imparting basicity to the pharmaceutical composition of the prior art. Storage stability was secured.

Specific embodiments of the present invention,

(1) Fluvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof and a pharmaceutical composition for lowering cholesterol comprising poloxamer,

(2) The pharmaceutical composition according to the above (1), wherein the pharmaceutically acceptable salt of fluvastatin is fluvastatin sodium salt,

(3) The pharmaceutical composition according to (1) or (2), wherein the poloxamer is poloxamer 407 or poloxamer 188,

(4) The pharmaceutical composition according to the above (1) to (3), wherein the poloxamer is contained in an amount of 1 to 500 parts by weight based on 100 parts by weight of fluvastatin,

(5) The pharmaceutical composition according to the above (4), wherein the poloxamer is contained in an amount of 10 to 100 parts by weight based on 100 parts by weight of fluvastatin,

(6) The pharmaceutical composition according to the above (1) to (5), wherein the pharmaceutical composition further comprises ursodeoxycholic acid or hydrochloric acid as an active ingredient.

(7) The pharmaceutical composition according to the above (6), which is a compounding agent further comprising ursodeoxycholic acid as an active ingredient,

(8) The pharmaceutical composition according to the above (1) to (7), further comprising at least one release controlling substance selected from the group consisting of an enteric polymer, a water insoluble polymer, a hydrophobic compound and a hydrophilic polymer,

(9) The pharmaceutical composition according to the above (8), wherein the content of the release controlling substance is 10 to 500 parts by weight based on 100 parts by weight of fluvastatin,

(10) a pharmaceutical composition for the prevention or treatment of hyperlipidemia, cardiovascular disease or atherosclerosis, comprising fluvastatin, a pharmaceutically acceptable salt thereof or isomers thereof and poloxamer,

(11) The pharmaceutical composition for the prevention or treatment of (10), wherein the hyperlipidemia is hypercholesterolemia, familial abnormal betaproteinemia, dyslipidemia, familial complex hyperlipidemia,

(12) a pharmaceutical composition for the prevention or treatment of hepatitis C, comprising fluvastatin, a pharmaceutically acceptable salt thereof, or isomers thereof and poloxamer, and

(13) The pharmaceutical composition according to the above (10) to (12), which is a compounding agent further comprising ursodeoxycholic acid as an active ingredient.

According to the present invention, storage stability of a pharmaceutical composition comprising fluvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof may be ensured for long term storage through poloxamer.

In addition, the pharmaceutical composition according to the present invention has a prophylactic or therapeutic effect of hyperlipidemia, cardiovascular disease, arteriosclerosis, or hepatitis C, and preferably, the effect is increased by further combining ursodeoxycholic acid or hydrochlorothiazide.

In addition, the pharmaceutical composition of the present invention can be prepared by the wet granulation method, which is a conventional manufacturing method in the pharmaceutical field, does not require a special device, and has the advantage of producing tablets at a low production cost.

In addition, the pharmaceutical composition of the present invention can be prepared in various forms such as tablets, capsules, granules as well as multi-layered tablets, nucleated tablets.

In addition, the pharmaceutical composition of the present invention has the advantage of being able to prepare not only the immediate release formulation but also a sustained release formulation to be taken once a day to increase medication compliance.

Hereinafter, a pharmaceutical composition of fluvastatin containing fluvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof having improved storage stability upon long-term storage containing poloxamer will be described in detail.

The active ingredient of the pharmaceutical composition of the present invention may be selected from fluvastatin, or a pharmaceutically acceptable salt thereof, or an isomer thereof, but is not limited thereto, and a compound having fluvastatin nucleus may be used. Fluvastatin sodium salt can be used. Fluvastatin is used 5 to 160 mg, preferably 10 to 100 mg, more preferably 20 to 85 mg per day for adults (65-75 kg adult male).

Poloxamer is suitable as a material contributing to the stabilization of fluvastatin in the present invention.

Poloxamer is a compound consisting of a unit polymer of polyoxyethylene and polyoxypropylene and has a pH of 5.0 to 7.5 when dissolved in water. According to the molecular weight of the hydrophobic polyoxypropylene and the content of polyoxyethylene, which is hydrophilic, more than 30 poloxamers exist, and poloxamer 188 and poloxamer 407 are the most used. According to the nomenclature, poloxamer 188 is characterized in that the average molecular weight of hydrophobic polyoxypropylene is 1800 and the hydrophilic polyoxyethylene is 80%, and poloxamer 407 has an average molecular weight of 4000 hydrophilic and hydrophilic. Polyoxyethylene is characterized in that 70% ratio. Poloxamers are generally used for the purpose of thickeners or gel formers in the preparation of gel preparations and as dissolution aids or co-emulsifiers in cream or liquid preparations. In addition, when applied to solid preparations as a substance to help wetting and improve the solubility and increase the bioavailability, it is used as a stabilizer to prevent the sedimentation of the main ingredient or excipient when the suspension is stored in the decomposition of the main ingredient of the present invention. Poloxamer is now marketed under the trade name Lutrol by BASF.

As the poloxamer used in the present invention, poloxamer 407 or poloxamer 188 is preferable, and poloxamer 407 is particularly preferable. In addition, the poloxamer is used 1 to 500 parts by weight based on 100 parts by weight of fluvastatin, more preferably 10 to 100 parts by weight, the amount of poloxamer is less than 1 part by weight based on 100 parts by weight of fluvastatin. If the effective stabilization effect can not be expected, if more than 500 parts by weight has a high poloxamer ratio in the pharmaceutical composition is difficult to manufacture and difficult to control the dissolution of the formulation.

The preparation of the pharmaceutical composition of the present invention may include additives such as pharmaceutically acceptable diluents, binders, disintegrants, stabilizers, lubricants, pH adjusting agents, dissolution aids, etc. without departing from the effects of the present invention. Its content is preferably 1 to 10,000 parts by weight based on 100 parts by weight of fluvastatin.

The diluent may be starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.

The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin Or mixtures thereof.

The disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

The lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate , Glyceryl palmitostearate, or a mixture thereof can be used.

The pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and a basicizing agent such as precipitated calcium carbonate, aqueous ammonia, meglumine and the like.

The dissolution aid can be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium and the like.

In addition, a pharmaceutically acceptable additive may be selected and used in the preparation of the present invention as various additives selected from colorants and fragrances.

The additives usable in the present invention are not limited to the additives exemplified above, and the additives described above may be formulated to contain a range of doses in a usual range by selection.

The formulation may be filled with capsules as necessary, and the material of the capsule may be one or a mixture of two or more selected from gelatin, succinate gelatin, hydroxypropylmethylcellulose.

The pharmaceutical composition of the present invention may be prepared in various forms such as an immediate release tablet, an immediate release capsule, a controlled release tablet, a controlled release capsule, and the like, but the pharmaceutical composition of the present invention is not limited thereto. .

The controlled release compartment in the pharmaceutical composition of the present invention comprises an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, as well as a release control material selected from the group consisting of a combination of an osmotic pressure control agent and a semipermeable membrane coating base and mixtures thereof. .

The release controlling substance may be used in an amount of 10 to 500 parts by weight based on 100 parts by weight of fluvastatin, and when the amount of the release controlling substance is less than 10 parts by weight based on 100 parts by weight of fluvastatin, sufficient controlled release property may not be obtained. Exceeding the parts by weight delays drug release and no significant effect can be obtained.

The enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher. The enteric polymer that can be used in the present invention is selected from the group consisting of enteric cellulose derivatives, enteric acrylic acid copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof, wherein the enteric cellulose derivative is hydroxypropylmethylcellulose. Acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl At least one selected from cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose, and mixtures thereof; The enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylates (e.g., acrylics), butyl-styrene acrylate-acrylic acid copolymers, methacrylic acid-methacrylates Methyl acid copolymer (e.g. Eudragit L 100, Eudragit S, Evonik, Germany), methacrylic acid ethyl acrylate copolymer (e.g. Eudragit L 100-55, Evonik, Germany), acrylic acid At least one selected from methyl-methacrylic acid-octyl acrylate copolymer and mixtures thereof; The enteric maleic acid-based copolymer may be a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride copolymer, a styrene-maleic acid monoester copolymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, or a vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, butyl styrene-maleic-maleic anhydride copolymer and mixtures thereof; The enteric polyvinyl derivative may be used at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, polyvinyl acetal phthalate, and mixtures thereof.

The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. The water insoluble polymers usable in the present invention include polyvinyl acetate, polymethacrylate copolymers, poly (ethylacrylate-methyl methacrylate) copolymers, poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate Copolymers (e.g. Eudragit RS30D), ethylcellulose, cellulose esters, cellulose ethers, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and these At least one selected from the group consisting of mixtures of may be used.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. The hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, glycerol. One or more selected from among reel stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, threaric acid and mixtures thereof; The fatty acid alcohol may be at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; The waxes are at least one selected from carnauba wax, beeswax, microcrystalline wax and mixtures thereof; And the inorganic material may be used at least one selected from talc, precipitated calcium carbonate, calcium monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bigum and mixtures thereof.

The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. The hydrophilic polymer usable in the present invention may be used at least one selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. Can be. The sugars here are dextrins, polydextrins, dextran, pectin and pectin derivatives, alginates, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactans, starches, hydroxypropylstarches, amylose, amylopectin and At least one selected from a mixture thereof; The cellulose derivative is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose and their One or more selected from mixtures; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum and mixtures thereof; The protein is at least one selected from gelatin, casein, zein and mixtures thereof; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate and mixtures thereof; The polymethacrylate copolymer is a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, a poly (methacrylate-methylmethacrylate) copolymer, a poly ( At least one selected from methacrylic acid-ethylacrylate) copolymers and mixtures thereof; The polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide and mixtures thereof; And the carboxyvinyl polymer is carbomer.

The combination of the osmotic pressure regulator and the semipermeable membrane coating base may include a compartment including the osmotic pressure regulator in the controlled release compartment and coated with a semipermeable membrane coating base.

The semi-permeable membrane coating base is a pharmaceutically usable coating base, which is a substance used in the coating layer of the pharmaceutical formulation to form a membrane which allows some components to pass but does not pass other components, and refers to the above-mentioned water-insoluble polymer. Can also be used. The semipermeable membrane coating base in the present invention is, for example, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate 1) selected from the group consisting of copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose diacetate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof More than one species can be used.

The osmotic pressure control agent refers to a component used to control the release rate of the drug by using the principle of osmotic pressure, the osmotic pressure control agent usable in the present invention is magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, Sodium sulfate, and mixtures thereof. Preferably sodium chloride and sodium sulfate are used.

The formulation may form a film-like coating layer on the outer surface of the tablet, if necessary. That is, the fluvastatin formulation of the present invention can be used in the form of uncoated tablets without a coating layer by shading through an aluminum package, and when the coating layer is formed on the surface of the tablet containing the active ingredient to form a coated tablet, the active ingredient There is an advantage that can further secure the stability.

The coating layer may be a coating agent, a coating aid or a mixture thereof. Specifically, the coating layer may be a coating agent such as cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, and fats. And gelatin, and the like, and may be used one or two or more selected from polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, and ethyl phthalate as the coating aid. In this case, when formulated as a coated tablet, the coating layer is preferably 0.5 to 15 parts by weight based on 100 parts by weight of the tablet in an untreated state.

The method of forming the coating layer may be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer using the above-described components, and may be applied to methods such as a fluidized bed coating method and a fan coating method. Can be. It is preferable to use a pan coating method.

In the embodiment of the present invention as such additives are used microcrystalline cellulose, poloxamer, copovidone, hydroxypropyl methyl cellulose, ethyl cellulose, magnesium stearate, polyethylene glycol, titanium oxide and the like, but the scope of the present invention uses the additive It is not limited to this, and the above-mentioned additives may contain a conventional range of doses by the choice of those skilled in the art.

The pharmaceutical composition of the present invention can be prepared in the form of a combination containing other active ingredients together. By preparing a pharmaceutical composition of the present invention in the form of a combination, there is an advantage that patients can take the convenience to increase medication compliance.

Fluvastatin of the present invention or a pharmaceutically acceptable salt thereof or a substance thereof can be used in combination with other drugs for the purpose of treating or preventing coronary heart disease. To prepare a combination drug for the treatment and prevention of coronary heart disease together with a dihydropyridine-based drug such as amlodipine and a zigzag-based drug such as hydrochlorziat, a lipid-lowering agent such as ezematic, and a thrombolytic agent such as aspirin Can be. In addition, the combination with ursodeoxycholic acid can prepare a complex for the purpose of preventing and treating blood lipid lowering and liver disease.

The pharmaceutical composition of the present invention can be prepared in various forms such as fast-release tablets, fast-release capsules, fast-release granules, sustained-release tablets, sustained-release capsules, sustained-release pellets, etc. in consideration of the release pattern of fluvastatin and other active ingredients, multi-layered tablets, nucleated tablets, It can be prepared in various forms such as biphasic matrix tablets, biphasic capsules, coated tablets, and the like, but the pharmaceutical composition of the present invention is not limited thereto.

In the pharmaceutical composition of the present invention, a granule composed of a fluvastatin compartment and a compartment containing other active ingredients is mixed with pharmaceutical additives, and then compressed into double or triple tablets in which each layer is parallel using a multi-layer tablet tablet machine. It is possible to obtain a tablet for oral administration capable of releasing the active ingredient along the layer.

In addition, the granules constituting the compartment containing fluvastatin or other active ingredients are mixed with a pharmaceutical additive and tableted to form a nucleus tablet, or after the pharmaceutical coating is applied to exhibit controlled release properties. Tablets for oral administration in a form in which the granules constituting the compartment containing the non-active ingredient are mixed with pharmaceutical additives and compressed into an outer layer, which is controlled to be released into the nucleated tablet and the surface of the nucleated tablet is surrounded by an immediate release layer. You can get it.

In addition, the present invention can obtain a tablet in the form of a two-phase matrix prepared by tableting a compartment containing fluvastatin and a compartment containing another active ingredient into a single tablet as follows.

In addition, each of fluvastatin or other active ingredients may be mixed with pharmaceutical additives as necessary to prepare a rapid-release granule, pellet, tablet, or sustained-release granule, pellet, tablet, and filling each capsule into a capsule. A formulation for oral administration in the form can be obtained.

In addition, the granules constituting the compartment containing fluvastatin or other active ingredients are mixed and tableted with pharmaceutical additives to form tablets, and the active ingredients not used in the manufacture of the tablets are coated on the film coating layer to be used for coating the tablets. After dissolving and dispersing, a tablet for oral administration can be obtained by coating the outer layer of the tablet.

In addition, the present invention is prepared in the form of pellets or tablets by mixing each of the fluvastatin or other active ingredients as needed in the form of pellets or tablets to prepare a kit that can be taken at the same time by filling together, such as foil, blisters, bottles, etc. It is possible.

Pharmaceutical compositions prepared according to the present invention as in the following examples can be used for the prevention and treatment of hyperlipidemia, cardiovascular disease, arteriosclerosis, more preferably hypercholesterolemia, familial dysbetalipoproteinemia, dyslipidemia, It can be used for the prevention and treatment of familial complex hyperlipidemia. The pharmaceutical composition of the present invention can lower the lipid in serum to reduce the incidence of cardiovascular disease and can induce delay or regression of atherosclerosis progression.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the following Examples.

Example 1 Preparation of Fluvastatin Rapid Release Tablet

Next, fluvastatin sodium salt, microcrystalline cellulose, and poloxamer 407 were apples in No. 20 according to the ingredients and contents of Table 1, and then mixed in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Magnesium stearate was added to Apple No. 35 and mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) and then formed using a high coater (SFC-30N, Sejong Machinery, Korea) to form a film coating layer.

Example 2 Preparation of Fluvastatin Immediate-release Capsule

Next, fluvastatin sodium salt, microcrystalline cellulose, and poloxamer 407 were apples in No. 16 according to the ingredients and contents of Table 1, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, it was dried until the moisture content was less than 2% when LOD was measured at 90 ° C using a hot water gun at 45 ° C. It was established using a sizing machine. Magnesium stearate was added to apple No. 35 and mixed with a double cone mixer. The final mixed mixture was put into a powder feeder and filled into No. 2 gelatin hard capsules using a capsule charger.

Example 3 Preparation of Fluvastatin Immediate Granules

Next, fluvastatin sodium salt, microcrystalline cellulose, and poloxamer 407 were apples in No. 16 according to the ingredients and contents of Table 1, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, followed by 3 minutes of coalescence, and then dried until the water content was less than 2% when measuring LOD at 90 ° C using a 45 ° C hot water dryer. It was established using the machine. Granules were prepared by forming a film coating layer through the granules coating the granules using a fluidized bed granulator.

Example 4: Preparation of fluvastatin sustained-release tablet

Next, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, and povidone were apples in No. 20 according to the ingredients and contents of Table 1, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Hydroxypropylmethylcellulose was added to Apple No. 35 with apples and mixed with a double cone mixer. Finally, magnesium stearate was added to Apple No. 35 with apples and mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) and then formed using a high coater (SFC-30N, Sejong Machinery, Korea) to form a film coating layer.

Example 5 Preparation of Fluvastatin Sustained-release Capsule

Next, fluvastatin sodium salt and microcrystalline cellulose, poloxamer 407, povidone, and hydroxypropylmethylcellulose were appled in No. 16 according to the ingredients and contents of Table 1, and then mixed in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, followed by 3 minutes of coalescence, and then dried until the water content was less than 2% when measuring LOD at 90 ° C using a 45 ° C hot water dryer. It was established using the machine. Magnesium stearate was added to Apple No. 35 and mixed with a double cone mixer. The final mixed mixture was put into a powder feeder and filled into No. 1 gelatin hard capsules using a capsule charger.

Example 6 Preparation of Fluvastatin Sustained Release Pellets

Next, povidone was dissolved in ethanol according to the ingredients and contents of Table 1 to obtain a binding solution. Separately, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, hydroxypropylmethyl cellulose, and ethyl cellulose were appled in No. 16, and then mixed in a double cone mixer for 30 minutes to prepare a mixed powder. Pellet was prepared by spraying the mixed powder while spraying the binding liquid to the crystalline sugar seed in the CF granulator. The obtained pellets were dried at 50 ° C. until the water content was 2% or less, and then a film coating layer was formed on the pellets to complete the pellets.

Example 7 Preparation of a Pharmaceutical Composition in the Form of a Multi-Layered Tablet Comprising Fluvastatin and Ursodeoxycholic Acid

1) Preparation of fluvastitin sustained release granule composition

Next, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, and povidone were appled in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Hydroxypropylmethylcellulose was added to Apple No. 35 with apples and mixed with a double cone mixer. Finally, magnesium stearate was added with Apple No. 35 with apples and mixed with a double cone mixer.

2) Preparation of Ursodeoxycholic Acid Granules Composition

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, apples of ursodeoxycholic acid and lactose in No. 20 sieve were placed in a high speed mixer and mixed for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture, and then fed for 3 minutes, and then apologized using an oscillator equipped with a No. 20 sieve. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less, and then stipulated using a sizer equipped with a No. 20 sieve. Sodium starch glycolate was added to No. 35 apples and mixed with a double cone mixer. Finally, magnesium stearate was added to No. 35 apples and mixed.

3) tableting and coating

Tablet using a multi-layer tablet press (MRC-37T: Sejong). The fluvastatin sustained-release layer composition was placed in a primary powder feeder, a composition containing ursodeoxycholic acid was placed in a secondary powder feeder, tableted under conditions that can minimize the incorporation between layers, and a high coater (SFC-30N, Sejong, Korea). Machine, Korea) to form a film coating layer to prepare a sustained-release tablet in the form of a multi-layered tablet.

Example 8 Preparation of a Pharmaceutical Composition in Capsule Form Comprising Fluvastatin and Ursodeoxycholic Acid

1) Preparation of Fluvastitin Granule Composition

Next, fluvastatin sodium salt, microcrystalline cellulose, and poloxamer 407 were apples in No. 16 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, followed by 3 minutes of coalescence, and then dried until the water content was less than 2% when measuring LOD at 90 ° C using a 45 ° C hot water dryer. It was established using the machine.

2) Preparation of Ursodeoxycholic Acid Granules Composition

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, ursodeoxycholic acid, lactose and sodium starch glycolate were appled in No. 16, and then mixed in a high speed mixer for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture and fed together for 3 minutes, followed by apology using an oscillator equipped with a No. 16 body. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less.

3) Mixing and Capsule Filling

The final compositions of steps 1) and 2) were mixed in a double cone mixer, and magnesium stearate was apologized to No. 35 body, and finally mixed. The final mixed mixture was put into a powder feeder and filled into 00 gel gelatin hard capsules using a capsule charger.

Example 9 Preparation of a Pharmaceutical Composition in Capsule Form Containing Fluvastatin Tablet and Ursodeoxycholic Acid Granules

1) Preparation of Fluvastitin Sustained-Release Tablet

Next, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, and povidone were appled in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Hydroxypropylmethylcellulose was added to Apple No. 35 with apples and mixed with a double cone mixer. Finally, magnesium stearate was added with Apple No. 35 with apples and mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) and then formed using a high coater (SFC-30N, Sejong Machinery, Korea) to form a film coating layer.

2) Preparation of Ursodeoxycholic Acid Granules Composition

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, ursodeoxycholic acid, lactose and sodium starch glycolate were appled in No. 16, and then mixed in a high speed mixer for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture and fed together for 3 minutes. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less. Magnesium stearate was added to Apple No. 35 and mixed with a double cone mixer.

3) Capsule filling

The fluvastatin tablet of step 1) and the ursodeoxycholine acid granule composition of step 2) were filled into hydroxypropyl methylcellulose hard capsules of 00 using a capsule charger.

Example 10 Preparation of a Pharmaceutical Composition in the Form of Two-Phase Matrix Including Fluvastatin and Ursodeoxycholic Acid

1) Preparation of Fluvastitin Granule Composition

Next, fluvastatin sodium salt, microcrystalline cellulose, and poloxamer 407 were apples in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of coalescing, the resultant was dried until the water content was less than 2% when measuring LOD at 90 ° C using a 45 ° C hot water dryer. It was established using the machine.

2) Preparation of Ursodeoxycholic Acid Granules Composition

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, ursodeoxycholic acid, lactose, and sodium starch glycolate were appled in No. 20, and then mixed in a high-speed mixer for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture, and then fed for 3 minutes, and then apologized using an oscillator equipped with a No. 20 sieve. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less, and then stipulated using a sizer equipped with a No. 20 sieve.

3) Mixing and Capsule Filling

The final compositions of steps 1) and 2) were mixed in a double cone mixer, and magnesium stearate was apologized to No. 35 body, and finally mixed. The final mixed mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong), followed by forming a film coating layer using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare a two-phase matrix tablet.

Example 11 Preparation of Pharmaceutical Composition in Nucleated Tablet Form Comprising Fluvastatin and Ursodeoxycholic Acid

1) Preparation of Fluvastitin Nuclear Tablet

Next, fluvastatin sodium salt, microcrystalline cellulose, and poloxamer 407 were apples in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Magnesium stearate was added to apple No. 35 and mixed with a double cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) to make a core tablet.

2) Preparation of Ursodeoxycholic Acid Granules Composition

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, apples of ursodeoxycholic acid and lactose in No. 20 sieve were placed in a high speed mixer and mixed for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture, and then fed for 3 minutes, and then apologized using an oscillator equipped with a No. 20 sieve. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less, and then stipulated using a sizer equipped with a No. 20 sieve. Sodium starch glycolate was added to No. 35 apples and mixed with a double cone mixer. Finally, magnesium stearate was added to No. 35 apples and mixed.

3) tableting and coating

A tablet using a nucleated tablet tableting machine (RUD-1: Kilian) as the inner core of fluvastatin immediate-release core tablets and the outer layer of a composition containing ursodeoxycholic acid is tableted. Nucleated tablets were prepared by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example 12 Preparation of a Nucleated Tablet Form Pharmaceutical Composition Comprising Fluvastatin and Ursodeoxycholic Acid

1) Preparation of Fluvastitin Sustained Release Nuclear Tablet

Next, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, and povidone were appled in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Hydroxypropylmethylcellulose was added to Apple No. 35 with apples and mixed with a double cone mixer. Finally, magnesium stearate was added with Apple No. 35 with apples and mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) to give a nuclear tablet.

2) Preparation of Ursodeoxycholic Acid Granules Composition

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, apples of ursodeoxycholic acid and lactose in No. 20 sieve were placed in a high speed mixer and mixed for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture, and then fed for 3 minutes, and then apologized using an oscillator equipped with a No. 20 sieve. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less, and then stipulated using a sizer equipped with a No. 20 sieve. Sodium starch glycolate was added to No. 35 apples and mixed with a double cone mixer. Finally, magnesium stearate was added to No. 35 apples and mixed.

3) tableting and coating

A tablet using a nucleated tablet tablet machine (RUD-1: Kilian) as a inner layer of fluvastatin sustained-release core tablets and a composition containing ursodeoxycholic acid as an outer layer is tableted. Sucrose tablets in the form of nucleated tablets were prepared by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example 13 Fluvastatin-Ursodeoxycholine Acid Blister Packaging Kit

1) Preparation of Fluvastitin Tablets

It prepared according to the method for preparing fluvastatin sustained-release tablet of Example 4.

2) Preparation of Ursodeoxycholic Acid Tablets

Next, hydroxypropyl cellulose was dissolved in purified water according to the ingredients and contents of Table 2 to obtain a binding solution. Separately, apples of ursodeoxycholic acid and lactose in No. 20 sieve were placed in a high speed mixer and mixed for 3 minutes. The binding solution was added to a high speed mixer containing the main component mixture, and then fed for 3 minutes, and then apologized using an oscillator equipped with a No. 20 sieve. When the LOD was measured at 90 ° C. in a fluidized bed dryer, it was dried up to 2% or less, and then stipulated using a sizer equipped with a No. 20 sieve. Sodium starch glycolate was added to No. 35 apples and mixed with a double cone mixer. Finally, magnesium stearate was added to No. 35 apples and mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) to prepare tablets.

3) Packing

The tablets of steps 1) and 2) are packaged in blister packaging containers for simultaneous use.

Example 14 Preparation of a Pharmaceutical Composition in the Form of a Multi-Layered Tablet Comprising Fluvastatin and Hydrochlorazite

1) Preparation of fluvastitin sustained release granule composition

Next, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, and povidone were appled in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Hydroxypropylmethylcellulose was added to Apple No. 35 with apples and mixed with a double cone mixer. Finally, magnesium stearate was added with Apple No. 35 with apples and mixed with a double cone mixer.

2) Preparation of Hydrochloricazite Granule Composition

Next, according to the ingredients and contents of Table 2, hydrochloric acid and microcrystalline cellulose, pregelatinized starch, povidone, and silicon dioxide were placed in a No. 20 sieve, and then mixed in a double cone mixer for 10 minutes. Finally, magnesium stearate was poured into a No. 35 sieve and placed in a double cone mixer for final mixing.

3) tableting and coating

Tablet using a multi-layer tablet press (MRC-37T: Sejong). The fluvastatin sustained-release granule composition was placed in the primary powder feeder, and the granule composition including hydrochloricitate was placed in the secondary powder feeder, which was compressed to a condition that minimizes the incorporation between layers, and a high coater (SFC-30N). , Sejong Machine, Korea) to form a film coating layer to prepare a sustained-release tablet in the form of a multi-layered tablet.

Example 15 Preparation of Fluvastatin-Hydrochlorzigit Coated Tablets

1) Preparation of Fluvastitin Tablets

Next, fluvastatin sodium salt, microcrystalline cellulose, poloxamer 407, and povidone were appled in No. 20 according to the ingredients and contents of Table 2, followed by mixing in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Hydroxypropylmethylcellulose was added to Apple No. 35 with apples and mixed with a double cone mixer. Finally, magnesium stearate was added with Apple No. 35 with apples and mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-3: Sejong) and then formed using a high coater (SFC-30N, Sejong Machinery, Korea) to form a film coating layer.

2) Preparation of Hydrochloric Acid Coating Liquid

Hydrochloricazite coating solution was prepared by dissolving and dispersing hydrochloricitate, hydroxypropylmethylcellulose, polyethylene glycol, and titanium oxide in an ethanol-methylene chloride mixture according to the ingredients and contents of Table 2 below.

3) coating

Fluvastatin tablets prepared in step 1) were added to a high coater (SFC-30N, Sejong Machinery, Korea) and coated with the hydrochloric acid coating solution prepared in step 2).

[Experimental Example]

The inventors of the present invention confirmed through experiments that poloxamer improves the storage stability of tablets containing fluvastatin. The evaluation of storage stability is conducted in accordance with the Stability Test Standards of the Korea Food and Drug Administration Notification No. 2007-14, which is a test for evaluating the stability of quality according to changes over time, in order to establish the storage method and the period of use of drugs. Can be evaluated. In general, KFDA conducts accelerated stability tests to evaluate the shelf life and stability of drugs, and recognizes long-term stability based on the results of the short-term accelerated stability test. The inventors of the present invention confirmed that the poloxamer improves the stability of fluvastatin through the accelerated test in the test criteria.

The following comparative experiments confirmed that poloxamer improves the storage stability of fluvastatin.

Comparative Example 1: Preparation of fluvastatin granules

Next, fluvastatin sodium salt and microcrystalline cellulose were apologized to No. 20 sieve according to the ingredients and contents of Table 3, and then mixed in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Magnesium stearate was added to No. 35 apples and mixed with a double cone mixer to prepare granules.

Comparative Example 2: Preparation of fluvastatin granules containing sodium bicarbonate as a stabilizer

Next, according to the ingredients and contents of Table 3, fluvastatin sodium salt, microcrystalline cellulose, and sodium bicarbonate as a stabilizer were apologized to No. 20, and then mixed in a high speed mixer for 3 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Magnesium stearate was added to No. 35 apples and mixed with a double cone mixer to prepare granules.

Comparative Example 3 Preparation of Fluvastatin Granules Containing Magnesium Oxide as Stabilizer

To prepare according to the components and contents of the following Table 3, except that it comprises magnesium oxide instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 4: Preparation of fluvastatin granules containing butylated hydroxytoluene as stabilizer

Prepared according to the ingredients and contents of the following Table 3, except that it contains butylated hydroxytoluene instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 5: Preparation of fluvastatin granules containing butylated hydroxyanisole as stabilizer

Prepared according to the components and contents of the following Table 3, except that it contains a butylated hydroxyanisole instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 6: Preparation of fluvastatin granules containing ascorbic acid as stabilizer

Prepared according to the ingredients and the contents of the following Table 3, except that ascorbic acid instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 7: Preparation of fluvastatin granules containing tocopherol as stabilizer

Prepared according to the ingredients and the contents of the following Table 3, but as in Comparative Example 2 except that tocopherol instead of sodium bicarbonate as a stabilizer.

Comparative Example 8: Preparation of fluvastatin granules containing ascorbic acid and tocopherol as stabilizers

Prepared according to the ingredients and contents of the following Table 3, except that ascorbic acid and tocopherol instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 9 Preparation of Fluvastatin Granules Containing Citric Acid as Stabilizer

Prepared according to the ingredients and the contents of the following Table 4, except that it contains citric acid instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 10 Preparation of Fluvastatin Granules Containing Malic Acid as Stabilizer

Prepared according to the ingredients and the contents of the following Table 4, but as in Comparative Example 2 except that it contains maleic acid instead of sodium bicarbonate as a stabilizer.

Comparative Example 11 Preparation of Fluvastatin Granules Containing Castor Oil as Stabilizer

Next, fluvastatin sodium salt and microcrystalline cellulose were apologized to No. 20 sieve according to the ingredients and contents of Table 4, mixed in a high speed mixer for 3 minutes, and mixed with castor oil for 5 minutes. Purified water was added to a high-speed mixer containing the main ingredient mixture, and after 3 minutes of association, the resultant was dried until the moisture content was less than 2% when the LOD was measured at 90 ° C by using a fluidized bed dryer having a suction air temperature of 45 ° C. It was established using a sizing machine installed No. 20 body. Magnesium stearate was added to No. 35 apples and mixed with a double cone mixer to prepare granules.

Comparative Example 12 Preparation of Fluvastatin Granules Containing Mineral Oil as Stabilizer

It is prepared according to the ingredients and the contents of Table 4, except that it contains mineral oil instead of castor oil as a stabilizer is the same as Comparative Example 12.

Comparative Example 13: Preparation of fluvastatin granules containing glyceryl monostearic acid as a stabilizer

Prepared according to the ingredients and the contents of the following Table 4, except that glyceryl monostearic acid instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 14 Preparation of Fluvastatin Granules Containing Sorbitan Sesquistearic Acid as Stabilizer

Prepared according to the ingredients and the contents of the following Table 4, except that sorbitan sesquistearic acid instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 15 Preparation of Fluvastatin Granules Containing Lecithin as Stabilizer

Prepared according to the ingredients and the contents of the following Table 4, except that it contains a lecithin instead of sodium bicarbonate as a stabilizer is the same as Comparative Example 2.

Comparative Example 16: Preparation of fluvastatin granules containing ethylenediaminetetraacetic acid as a stabilizer

Prepared according to the ingredients and the contents of the following Table 4, but as in Comparative Example 2 except that it contains ethylenediaminetetraacetic acid instead of sodium bicarbonate as a stabilizer.

Experimental Example 1 Content Test of Fluvastatin Granules Containing Stabilizer

Accelerated tests in the stability test criteria of the fluvastatin granules prepared according to Example 2, but not filled in capsules and fluvavastatin granules prepared according to Comparative Examples 1 to 16 according to the 2007 Food and Drug Safety Notice No. 2007-14 It is stored under the conditions of 40 ± 2 ℃ and 75 ± 5% relative humidity, and is packaged in a high-density polyethylene, including silica gel, in an air-free shading flask to create more harsh conditions. The reaction was induced. After 15 days, granules were taken and tested for content according to the assay section of USP31 Fluvastatin capsule. The results are shown in Table 5 below.

Experimental Example 1 evaluated the stabilizing effect of alkaline agents, antioxidants, fatty acids and polymers, chelating solvents to fluvastatin as candidates to improve the storage stability of fluvastatin. More specifically, sodium bicarbonate and magnesium oxide as the alkalizing agent, butylated hydroxytoluene as the antioxidant, butylated hydroxyanisole, ascorbic acid, tocopherol, citric acid and malic acid, castor oil as a fatty acid and mineral oil, and poloxamer as a polymer The stabilizing effect of fluvastatin of sorbitan sesquistearic acid and glyceryl monostearic acid, phospholipid lecithin, and chelating solvent ethylenediaminetetraacetic acid as a nonionic surfactant was confirmed through the content test. Among the stabilizers, butylated hydroxyanisole and butylated hydroxytoluene were limited to 1 mg per pharmaceutical composition in consideration of acceptance criteria as pharmaceuticals.

Table 5 and Figure 1 shows the change in the content of fluvastatin by the stabilizer treatment after 15 days of accelerated test. Butylated hydroxyanisole is a drug of the HMG-CoA reductase inhibitor family such as fluvastatin and is used to stabilize simvastatin having a similar structure. It is easy to think that butylated hydroxyanisole will affect the stability of fluvastatin due to the similar structure, but there was no improvement effect in the content test result compared with Comparative Example 1 without using a stabilizer. Butylated hydroxytoluene, which is similar in structure to butylated hydroxyanisole, did not improve the stability of fluvastatin. Mineral oil, sorbitan sesquistearic acid, glyceryl monostearic acid, lecithin, and ethylenediaminetetraacetic acid content test results showed no improvement in stability of fluvastatin. Ascorbic acid, tocopherol, citric acid and malic acid, both organic acids and known as antioxidants, were found to decrease the content by inducing decomposition of unstable fluvastatin at low pH due to acidity. Sodium bicarbonate and magnesium oxide, which can impart basicity to pharmaceutical compositions with high molecular weight poloxamer, fatty acid castor oil, and alkalizing agent, have a smaller content drop compared to Comparative Example 1, which did not use a stabilizer. It was confirmed that the stability of the statin is improved. Among them, poloxamer was found to have the lowest stabilization effect with the least content decrease.

Experimental Example 2 Softening Test of Fluvastatin Granules Containing Stabilizer

Accelerated tests in the stability test criteria of the fluvastatin granules prepared according to Example 2, but not filled in capsules and fluvavastatin granules prepared according to Comparative Examples 1 to 16 according to the 2007 Food and Drug Safety Notice No. 2007-14 It is stored under the conditions of 40 ± 2 ℃ and 75 ± 5% relative humidity, and is packaged in a high-density polyethylene, including silica gel, in an air-free shading flask to create more harsh conditions. The reaction was induced. After 15 days, granules were taken and the soft substances were measured according to the impurity term of USP31 Fluvastatin capsule. The results are shown in Table 6 below.

Experimental Example 2 evaluated the stabilizing effect of alkaline agents, antioxidants, fatty acids and polymers, chelating solvents to fluvastatin as candidates to improve the storage stability of fluvastatin. More specifically, sodium bicarbonate and magnesium oxide as the alkalizing agent, butylated hydroxytoluene as the antioxidant, butylated hydroxyanisole, ascorbic acid, tocopherol, citric acid and malic acid, castor oil as a fatty acid and mineral oil, and poloxamer as a polymer The stabilizing effects of fluvastatin of sorbitan sesquistearic acid and glyceryl monostearic acid, phospholipid lecithin, and chelating solvent ethylenediaminetetraacetic acid as nonionic surfactants were confirmed through measurement of analogue. Among the stabilizers, butylated hydroxyanisole and butylated hydroxytoluene were limited to 1 mg per pharmaceutical composition in consideration of acceptance criteria as pharmaceuticals.

Table 6 and Figure 2 shows the amount of fluctuate produced by fluvastatin generated by the stabilizer treatment after 15 days of accelerated testing. Butylated hydroxyanisole is a drug of the HMG-CoA reductase inhibitor family such as fluvastatin and is used to stabilize simvastatin having a similar structure. It is easy to think that the butylated hydroxyanisole will affect the stability of fluvastatin due to the similar structure, but there was no improvement effect in comparison with Comparative Example 1, which did not use a stabilizer as a result of measuring the soft material. Butylated hydroxytoluene, which is similar in structure to butylated hydroxyanisole, did not improve the stability of fluvastatin. Mineral oil, sorbitan sesquistearic acid, glyceryl monostearic acid, lecithin, and ethylenediaminetetraacetic acid also showed no improvement in stability of fluvastatin. Ascorbic acid, tocopherol, citric acid, and malic acid, which are organic acids and known as antioxidants, induce degradation of fluvastatin, which is unstable at low pH due to acidity, thereby increasing the amount of analogues. Sodium bicarbonate and magnesium oxide, which can impart basicity to pharmaceutical compositions with high molecular weight poloxamer, fatty acid castor oil, and alkalizing agent, resulted in less fluctuation compared to Comparative Example 1 without using stabilizer. It was confirmed that the stability of the vastatin was improved. Among them, poloxamer was found to have the best stabilization effect because of the smallest amount of flexible substance.

Experimental Example 3 Content Test of Fluvastatin Granules Containing Stabilizer

Fluvastatin granules prepared according to Example 2 but not filled into capsules and fluvavastatin granules prepared according to Comparative Example 1, Comparative Example 2, and Comparative Example 11 were prepared by Food and Drug Safety Notification No. 2007-14. It is stored under 40 ± 2 ℃ 75 ± 5% moisture condition, which is accelerated test condition of stability test standard, and it is fast packaged by making a harsher condition by experimenting in air-free shading flask rather than packed in high density polyethylene including silica gel. Induced. After 50 days, granules were taken and tested for content according to the assay section of USP31 Fluvastatin capsule. The results are shown in Table 7 below.

Example 2, Comparative Example 2, Comparative Example 11 and the stabilization effect on the fluvastatin of Comparative Example 1 without using a stabilizer showed excellent stability as a result of the experiment through Experimental Example 3 content after standing in the accelerated condition for 50 days It was confirmed through the test. Compared with Comparative Example 1 without using the stabilizer, Example 2, Comparative Example 2, Comparative Example 11 all confirmed that the decrease in the content is improved stability. The least decrease in content was confirmed by Example 2 that poloxamer was most effective in stabilizing fluvastatin.

Experimental Example 4 Test of Flexible Material of Fluvastatin Granules Containing Stabilizer

Fluvastatin granules prepared according to Example 2 but not filled into capsules and fluvavastatin granules prepared according to Comparative Example 1, Comparative Example 2, and Comparative Example 11 were prepared by Food and Drug Safety Notification No. 2007-14. It is stored under 40 ± 2 ℃ 75 ± 5% moisture condition, which is accelerated test condition of stability test standard, and it is fast packaged by making a harsher condition by experimenting in air-free shading flask rather than packed in high density polyethylene including silica gel. Induced. After 50 days, granules were taken and the softening material was measured according to the impurity term of USP31 Fluvastatin capsule. The results are shown in Table 8 below.

Experimental Example 4 results in excellent stabilization of the fluvastatin of Example 2, Comparative Example 2, Comparative Example 11 and Comparative Example 1 without using a stabilizer showed excellent stability after leaving it to accelerated conditions for 50 days Confirmation through material measurement. Compared with Comparative Example 1 without using a stabilizer, all of Example 2, Comparative Example 2, and Comparative Example 11 were confirmed that the generation of the flexible material is less and the stability is improved. The least occurrence of analogues was confirmed in Example 2 that poloxamer was most effective in stabilizing fluvastatin.

Experimental Example 3 to 4 it can be seen that the castor oil of Comparative Example 12 also contributes to the stabilization of fluvastatin. However, it should be taken into account that castor oil is difficult to prepare into tablets easily. In general, during the preparation of granules for tableting, mixing, coalescence, granulation, drying, formulation, and post-mixing are performed. Castor oil is in a liquid state at room temperature, so it is not easy to apply to the mixing step, and when the amount of castor oil that can contribute to the stability of the formulation is used, the granules are wet and cannot be evaporated through drying. It is impossible to secure flowability as an element. In addition, in Experimental Examples 3 to 4, poloxamer is more suitable for stabilizing fluvastatin because the content decreases and the generation of the soft substance is more than when poloxamer is used.

As a result of Experimental Examples 1 to 4, it was confirmed that poloxamer showed an excellent effect on improving long-term stability of fluvastatin. The pharmaceutical composition comprising fluvastatin of the present invention consists of fluvastatin and poloxamer and can be embodied by adding one or two or more excipients commonly used in the pharmaceutical art.

The inventors of the present invention also found that fluvastatin is effective in suppressing hepatitis C virus.

Experimental Example 5 Comparison of Inhibitory Effects on Hepatitis C Virus by Drugs

1) Preparation of test solution

Interferon α-2b, fluvastatin, ursodeoxycholic acid, interferon + fluvastatin, interferon + fluvastatin + ursodeoxycholic acid are diluted to have a final concentration as shown in Table 9.

2) Cell division

end. 50 μL of the test solution was added to the wells, and blank, normal and vehicle wells were put in 50 μL of the test medium and left in a CO ₂ incubator for 30 minutes.

I. A549 cells having a doubling time of 22 hours were suspended in experimental media and prepared 20 ml at a concentration of 4 × 10 5 / ml.

All. 50 μL of the test solution was added to the remaining wells except the blank well on the 'A' plate, and the blank well was placed in a CO ₂ incubator for 24 hours after adding 50 μL of the test medium.

3) Hepatitis C virus infection

end. EMC virus stock was diluted to 5 x 10-3 (prepared)

I. 50 μL of the diluted solution was treated in the corresponding wells of all test groups except Blank and Normal, and the blank and Normal wells were placed in a CO ₂ incubator for 24 hours after 50 μL of the test medium.

4) MTT assay

end. 15 μL of reagent for MTT label was added.

I. Incubated for 4 hours in a CO ₂ incubator.

All. Solubilization solution was added to 150 μL for each well.

la. Incubated overnight (12 hours to 18 hours) in a 37 ℃ CO ₂ incubator for Virus.

hemp. Purple formazan confirms the solubility and measures absorbance at wavelengths between 550 nm and 600 nm using a microplate reader.

The inhibitory effect on hepatitis C virus measured by Experimental Example 5 is shown in Table 10.

The concentration of the test solution used in Experimental Example 5 was one tenth or one hundredth of the level compared with the conventional amount, but the antiviral effect was observed in all the test groups. In the test group using interferon α-2b and fluvastatin, hepatitis C virus inhibitory effect was 1.4 times higher than the test group using only interferon. The use of fluvastatin and ursodeoxycholic acid of the present invention together with interferon showed hepatitis C inhibitory effect about 1.7 times higher than the experimental group using only interferon, and the test using interferon and fluvastatin in combination Compared with the group, it could be seen that the additional inhibitory effect was unexpected. Considering the above results, the pharmaceutical composition of the present invention containing fluvastatin or the pharmaceutical composition of the present invention containing fluvastatin and ursodeoxycholic acid can be used for the prevention and treatment of hepatitis C. Confirmed.

1 is a graph showing the content after 15 days of the accelerated test of fluvastatin test formulation containing a stabilizer evaluated according to Experimental Example 1.

Figure 2 is a graph showing the amount of lead substances generated after 15 days of accelerated test of fluvastatin test formulation containing a stabilizer evaluated according to Experimental Example 2.

Figure 3 is a graph showing the content after 50 days of accelerated test of fluvastatin test formulation containing a stabilizer evaluated according to Experimental Example 3.

Figure 4 is a graph showing the amount of lead substances generated after 50 days of accelerated testing of fluvastatin test formulation containing a stabilizer evaluated according to Experimental Example 4.

5 is an experimental configuration diagram of the 96 plate of Experimental Example 1. FIG.

Figure 6 is a graph showing the inhibitory effect on hepatitis C virus of interferon α-2b, fluvastatin, interferon + fluvastatin, interferon + fluvastatin + ursodeoxycholic acid evaluated according to Experimental Example 1.

Claims (13)

A pharmaceutical composition with improved storage stability of fluvastatin comprising fluvastatin or a pharmaceutically acceptable salt thereof, and poloxamer as a stabilizer. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of fluvastatin is fluvastatin sodium salt. The pharmaceutical composition of claim 1, wherein the poloxamer is poloxamer 407 or poloxamer 188. The pharmaceutical composition according to any one of claims 1 to 3, wherein the poloxamer is contained in an amount of 1 to 500 parts by weight based on 100 parts by weight of fluvastatin. The pharmaceutical composition according to claim 4, wherein the poloxamer is included in an amount of 10 to 100 parts by weight based on 100 parts by weight of fluvastatin. The pharmaceutical composition according to any one of claims 1 to 3, which is a compounding agent further comprising ursodeoxycholic acid or hydrochloriazit as an active ingredient. The pharmaceutical composition according to claim 6, which is a compounding agent further comprising ursodeoxycholic acid as an active ingredient. The pharmaceutical composition of any one of claims 1 to 3, further comprising at least one release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds and hydrophilic polymers. The pharmaceutical composition according to claim 8, wherein the content of the release controlling substance is 10 to 500 parts by weight based on 100 parts by weight of fluvastatin. The pharmaceutical composition according to claim 1, which is for preventing or treating hyperlipidemia, cardiovascular disease or atherosclerosis. 11. The pharmaceutical composition of claim 10, wherein the hyperlipidemia is hypercholesterolemia, familial dysbetalipoproteinemia, dyslipidemia, or familial hyperlipidemia. The pharmaceutical composition according to claim 1, which is for preventing or treating hepatitis C. delete

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