KR20110132171A - Combination sustained-release formulation containing nicain - Google Patents

Abstract

PURPOSE: A complex controlled release formulation containing niacin is provided to stably preserve drugs and to maximize pharmacological effect of cholesterol reduction. CONSTITUTION: A complex controlled release formulation contains: niacin, HMG-CoA reduction inhibitor, pH-independent polymer base, pH-dependent polymer base, additive, disintegrant, lubricant, and selective containing binder. The formulation is formed in bilayered tablet comprising a first layer containing niacin and a second layer containing HMG-CoA reduction inhibitor. The HMG-CoA reduction inhibitor is rosuvastatin, atorvastatin, lovastatin, fluvastatin, pitavastatin, or pravastatin. The pH-dependent polymer base is water soluble salt or carboxyvinyl polymer.

Description

Combination sustained-release formulation containing nicain

The present invention relates to a controlled release oral formulation containing niacin and a statin drug. More specifically, the controlled release formulations of the present invention include niacin and statin drugs useful as therapeutic agents for hyperlipidemia; pH-independent polymer bases; pH-dependent polymer bases; Excipients; As a two-layered, double- or multi-layered tablet containing antioxidants, the statin-based drug is rapidly released upon oral administration, and the niacin is a water-soluble matrix system in which a pH-independent polymer base absorbs water. Controlled release and pH-dependent polymer bases allow controlled release of the drug in a pH-dependent manner, resulting in precise controlled release of the drug from the stomach to the intestine, especially in controlled release of the drug in the gut. As a result, the present invention relates to a controlled-release oral preparation containing niacin and a statin-based drug, in which a decrease in flushing, which is a side effect of niacin, and a decrease in LDL-cholesterol and an increase in HDL-cholesterol are significantly improved.

Elevated hyperlipidemia or serum lipids is associated with an increased frequency of cardiovascular disease and atherosclerosis. Specific types of hyperlipidemia include, for example, hypercholesterolemia, familial abnormal betalipoproteinemia, diabetic dyslipidemia, nephrotic dyslipidemia, and familial complex hyperlipidemia. Hypercholesterolemia is characterized by elevation of low density lipoprotein-cholesterol in serum and total cholesterol in serum. Low density lipoprotein (LDL-cholesterol) carries cholesterol in the blood. Familial aberrant betalipoproteinemia, also known as type III hyperlipidemia, is characterized by the accumulation of beta VLDL, called ultralow density lipoprotein cholesterol (VLDL-cholesterol) particles, in serum. This symptom is also associated with the replacement of normal apolipoprotein E3 with abnormal heterozygous apolipoprotein E2. Diabetic dyslipidemia is characterized by a number of lipoprotein abnormalities, such as overproduction of VLDL-cholesterol, abnormal lipolysis of VLDL triglycerides, decreased LDL-cholesterol receptor activity, and frequent type III hyperlipidemia. Nephrotic dyslipidemia is difficult to treat, of which frequently occur are hypercholesterolemia and hypertriglyceridemia. Familial complex hyperlipidemia is characterized by multiple phenotypes of hyperlipidemia, type IIa, IIb, IV, V or hyperapobetalipoprotein.

When serum lipids, especially LDL-cholesterol, are lowered, the likelihood of developing cardiovascular disease may be lowered. It is also known that when lipids in serum are lowered, the progression of atherosclerosis can be delayed or the regression of atherosclerosis can be induced. In such cases, individuals diagnosed with hyperlipidemia or hypercholesterolemia may be treated with lipid lowering therapies that delay the progression of atherosclerosis or induce degeneration of atherosclerosis for the purpose of reducing the risk of cardiovascular disease, particularly coronary artery disease. Should be taken into account.

Hypertriglyceridemia is also an independent risk factor for cardiovascular disease (eg coronary artery disease). Most people with hyperlipidemia or hypercholesterolemia have high levels of triglycerides. It is known that lowering high levels of triglycerides can indirectly lower cholesterol. In addition, they should consider lipid lowering therapies that lower high levels of triglycerides for the purpose of reducing the incidence of atherosclerosis and coronary artery disease. Cholesterol is carried in the blood by lipoprotein complexes such as VLDL-cholesterol, LDL-cholesterol and high density lipoprotein-cholesterol (HDL-cholesterol). LDL carries cholesterol in the blood into the subdermal space of the vessel wall. Peroxidation of LDL-cholesterol in the subcutaneous endothelial space of blood vessel walls is thought to form thrombus of atherosclerosis. HDL-cholesterol, on the other hand, is thought to have an inhibitory effect on thrombus formation and delay or prevent the onset of cardiovascular disease and atherosclerosis symptoms. Several subtypes of HDL-cholesterol have recently been identified, such as HDL1-cholesterol, HDL2-cholesterol, HDL3-cholesterol.

In the past, several methods have been proposed for lowering high cholesterol and raising HDL-cholesterol levels. Typically, these methods include the daily administration and / or diet of lipid modifying agents or hypolipidemic agents. Another proposed method relates to the cyclic plasma destruction method by a continuous flow filtration system as described in US Pat. No. 4,895,558. Several hypolipidemic agents have been developed to treat hyperlipidemia or hypercholesterolemia or normal lipidemia diagnosed with cardiovascular disease. Typically, these drugs act to (1) reduce the production of serum lipoproteins or lipids, or (2) enhance the removal of lipoproteins or lipids from serum or plasma. Drugs that lower serum lipoprotein or lipid concentrations include inhibitors of HMG-CoA reductase, a rate controlling enzyme in the biosynthetic pathway of cholesterol. Examples of HMG-CoA reductase inhibitors include mevastatin (US Pat. No. 3,983,140), lovastatin (US Pat. No. 4,231,938), also known as mevinolin, pravastatin (US Pat. Nos. 4,346,227 and 4,410,629), and lactones of pravastatin (US Patent No. 4,448,979), velostatin and rosuvastatin, rivastatin, fluvastatin, atorvastatin and cerivastatin, called mysterolin. Still other examples of HMG-CoA reductase inhibitors include U.S. Patents 5,217,992, 5,196,440, 5,189,180, 5,166,364, 5,157,134, 5,110,940, 5,106,992, 5,099,035, 5,081,136, 5,049,696, 5,049,577, 5,025,017, 5,011,947, 5,010,105, 4,970,221, 4,940,800, 4,866,058, 4,686,237, 4,647,576, European Patent Application Nos. 0142146A25A2A And PCT applications WO86 / 03488 and WO 86/07054.

Examples of other drugs that lower cholesterol in serum include nicotinic acid, bile acid blockers such as cholestyramine, cholestipol DEAE Sephadex [Secholex ^® and Polidexide ^® ], pros as disclosed in US Pat. No. 3,674,836. Bucol and related compounds, lipostavill (long-furan), Eisai E5050 (N-substituted ethanolamine derivatives), imanisyl (HOE-402), tetrahydrorifstatin (THL), isitigmastanylphosphate Porylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seyoku), Ajinomoto AJ-814 (Azlene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamide ) CL-277,082 and CL-283,546 (double substituted urea derivatives), ronitol (containing alcohols corresponding to nicotinic acid), neomycin, p-aminosalicylic acid, aspirin, quaternary amines such as those disclosed in US Pat. No. 4,027,009 Poly (diallyldi Ammonium methyl chloride) and ionene, poly (diallylmethylamine) derivatives such as those disclosed in US Pat. No. 4,759,923, omega-3-fatty acids, fibric acid derivatives (e.g. gemfibrozil, chlorine, etc.) contained in various fish oil supplements Fibrate bezafibrate, fenofibrate, cipropibrate and clinofibrate) and US Patent 5,200,424, European Patent Application 0065835A1, European Patent 164-698-A, British Patent 1,586,152 and British Patent Application There are other known serum cholesterol lowering agents, such as those described in heading 22162-179-A.

More effective therapies for treating hyperlipidemia include the administration of the two drugs listed above in combination. Among them, research on a combination of statin-based drugs, which are HMG-CoA reductase inhibitors that effectively inhibit the synthesis of niacin and cholesterol, effectively inhibits the synthesis of LDL, has been widely conducted. It is clinically observed that patients who had difficulty in treating complex lipid-related diseases with a single therapy of either niacin or statin drugs can increase HDL, a healthy cholesterol, and lower LDL and TG (triglyceride), a bad cholesterol. Proved to be. Based on a study involving more than 640 patients with both hyperlipidemia and type 2 hyperlipidemia, patients taking combinations in clinical trials had an additional LDL of 12 compared to a single dose of statins. % Decreased, HDL increased 21%. On the other hand, LDL decreased by 7% and HDL increased by 8%. Triglyceride (TG) reduction was only 15% with a single dose, but 27% with a combination (Approval of FDA administration, February 15, 2008, Abbott ^® Lab.)

Nicotinic acid, known as niacin, has been used for decades in the treatment of hyperlipidemia or hypercholesterolemia. This compound lowers total HDL-cholesterol in the human body while lowering total cholesterol, VLDL-cholesterol and VLDL-cholesterol residues, LDL-cholesterol, triglycerides and apolipoproteins (known as "Lp (a)"). It has long been known to exhibit beneficial effects of increasing.

Nicotinic acid is usually administered three times / day after a meal. Such administration regimens are described in Knopp et al., "Contrasting Effects of unmodified and Time-Release Forms of Niacin on Lipoproteins in Hyperlipidemic Subjects: Clues to Mechanism of Action of Niacin"; Metabolism (34) 7: 642-647 (1985), which is known to provide a very beneficial effect on blood lipids. Although such a regimen has a beneficial effect, flushing and skin fever symptoms often occur in patients with hyperlipidemia administered with nicotinic acid.

The most common reason for patients' long-term rejection when taking niacin depends on the site of action of GPR109A, a nicotinic acid receptor. GPR109A activity in adipocytes (adipocytes) decreases cAMP, decreases very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and increases high-density lipoprotein (HDL). However, when G-protiein of macrophage binds to GPR109A and is active in dermal dendritic cells of the subcutaneous tissue, it is converted into arachidonic acid and selectively binds to cyclooxygenase inhibitors (COX-1). Prostaglandin D2 and Prostaglandin E2 produce prostaglandin E2, which bind to cells of smooth muscle to develop redness (Niacin use and cutaneous flushing.The American journal of cardiology, Vol 101, 2008). .

Guar gum (US Pat. No. 4,965,252), inorganic salt (US Pat. No. 5,023,245), inorganic magnesium salt (US Pat. No. 4,911,917), with an effective amount of nicotinic acid, in order to prevent or alleviate the symptoms of skin fever caused by nicotinic acid treatment, A formulation for the simultaneous administration of a nonsteroidal anti-inflammatory agent (PCT Application No. 96/32942) such as aspirin has been proposed. These drugs are reported to prevent or alleviate the skin fever side effects associated with nicotinic acid split administration.

Another way to prevent or alleviate the side effects associated with immediate release niacin is to use sustained release formulations. Sustained release formulations are designed to release the active ingredient slowly from tablets or capsules, thereby reducing the frequency of administration compared to the usual frequency of administration associated with conventional or immediate release dosage forms. Such sustained release of the drug lowers and prolongs drug levels in the blood, thereby lowering or reducing skin fever side effects associated with conventional niacin products or immediate release niacin products.

Sustained release preparations of niacin are abbreviated, for example, Nicobid ^TM capsules (Long-Furn Lauler), Endur-acin ^™ (Inophyte Corporation) and two types of hydroxyl-propylmethyl-cellulose (hereinafter HPMC). ) And slow release niacin preparations containing hydrophobic components (US Pat. Nos. 5,126,145 and 5,268,181) have been developed. There are also commercially available Niaspan ^® (KOSpharmaceutinals, Inc.) Containing the representative niacin-containing swelling agents, binders and lubricants in addition to the drug as a sustained-release tablet formulation. However, existing sustained-release preparations are simply sustained-release preparations that delay the release of the drug by swelling agents such as HPMC to absorb water to form a water-soluble matrix. Sophisticated controlled release in the intestines cannot be achieved.

In recent years, another side effect of niacin, hepatotoxicity, has emerged, requiring more sophisticated drug release control. Hepatotoxicity, another side effect of niacin, promotes the production of a liver enzyme called aminotransferase as niacin is metabolized to nicotinamide when taken, and aminotransferase has been reported to cause severe hepatotoxicity (The role of nicotinic acid metabolites in flushing and hepatotoxicity.Journal of clinical lipidology, Vol 1, 2007). However, such hepatotoxicity is rarely expressed when taking niacin immediate-release tablets and extended-release tablets, and when taking sustained-release tablets. The reason why hepatotoxicity is expressed only in the sustained-release tablet is reported to be caused by the metabolic processes of the respective formulations, ie, immediate-release tablets, sustained-release tablets, and sustained-release tablets. Flushing, a side effect of niacin immediate release, is quickly absorbed by the gastrointestinal tract, causing niacin to metabolize with low-affinity and high-capacity for liver metabolism. In addition, hepatotoxicity is slowly absorbed by the gastrointestinal liver, and thus, when unconjugated with high-affinity and low-capacity for metabolites, hepatotoxicity increases. Details of this are described in "Safety of niacin and simvastatin combination therapy" (The American journal of cardiology, Vol 101, 2008).

Statins are inhibitors of hydroxymethylglutaryl-CoA reductase, a key enzyme in the synthesis of cholesterol, and directly lower cholesterol levels. These compounds are known to be safe and effective hypocholesterolemic agents and have been shown to make a significant therapeutic contribution to the treatment of coronary heart disease and to the reduction of morbidity and mortality caused by these severe cardiovascular pathologies.

Statins commonly used in medicine are rosuvastatin (USP RE 37314), atorvastatin (USP 5273995), cerivastatin (USP5177080), fluvastatin (USP 4739073), Lovastatin (USP 4231938), pravastatin (USP 4346227) and rosuvastatin (USP Patent Publication 10-2006-0118579-4 -4444784). They may be used in free form, generally in the form of pharmaceutically acceptable salts in anhydrous or hydrated form of alkalis or alkaline earths, with sodium or calcium salts being generally preferred.

For example, in clinical practice, atorvastatin is used as sodium (2: 1) salt trihydrate, cerivastadine, fluvastatin and pravastadine are used as sodium salts, rosuvastatin is used as sodium salts, Lovastatin and simvastatin are used in free form. A more recent compound, pitavastatin (EP 304063), is currently in development III in Europe.

Rosuvastatin (7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)- Dihydroxy- (E) -6-heptenic acid) calcium, HMG-CoA reductase inhibitors can lower LDL-cholesterol and triglyceride levels more effectively than first generation statin drugs. Rosuvastatin calcium has the formula

Rosuvastatin calcium is marketed under the trade name CRESTOR for the treatment of mammals such as humans. According to the CRESTOR manufacturer, it should be administered in a daily dose of about 5 to about 40 mg to reduce LDL cholesterol.

When used in combination with drugs metabolized by cytochrome P450 2C9 enzyme, rosuvastatin may inhibit liver metabolism of rosuvastatin and increase blood levels. That is, when rosuvastatin is simultaneously administered to patients receiving cyclosporin, the initial starting dose is 5 mg per day, and should not exceed 10 mg per day. If rosuvastatin is administered simultaneously to a patient receiving amiodarone or verapamil, the dose of THIS DRUG should not exceed 20 mg per day. If rosuvastatin is used in combination with hypolipidemic doses of niacin, it may cause myopathy / rhabdomyolysis and is not excreted in the kidneys. do.

Atorvastatin is administered once daily in 10 mg patients with primary hypercholesterolemia and complex dyslipidemia, with a therapeutic response within 2 weeks, with a maximum effect achieved within 4 weeks. Atorvastatin is generally well tolerated, but adverse reactions such as muscle pain and dyspepsia or general weakness occurred in 2% of patients in the control trial.

HMG-CoA reductase inhibitors have drawbacks. HMG-CoA reductase inhibitors can cause several myopathy / rhabdomyopathy. Myopathy is mainly caused by muscle pain and tenderness or muscle weakness and is accompanied by an increase in creatinine kinase. In addition, clinical trials show that transaminase levels rise in 1% of patients receiving statin drugs. This phenomenon has been described in Garnett WR (Am J Cardiol, 78 (Suppl 6A): 20-25 (1996.9.26)), by the Lovastatin Pravastatin Study Group (Am J Cardiol, 71: 810-). 815 (1993.4.1)], Duzovne CA et al., Am J Med, 91 (suppl 1B): 25S-30S (1991.7.31)] and Mantel GM Et al., Am J Cardiol, 66: 11B-15B (1990.9.18).

The present invention has been made to solve the problems of the prior art, and the HMG-CoA reductase inhibitors and HDL-cholesterol, which is excellent in lowering LDL-cholesterol, which is the same as the conventional hyperlipidemia therapeutics, and elevates HDL-cholesterol, in particular, It is an object of the present invention to provide a niacin-containing oral complex having excellent controlled release. That is, the present invention preserves the drug in a stable form and at the same time maximizes the pharmacological effect of cholesterol lowering by using the HMG-CoA reductase inhibitor as an immediate release layer, and flushes by finely controlling the release of niacin in the stomach and intestine as the western layer. And to provide a drug delivery system for oral administration to minimize the niacin side effects of hepatotoxicity.

In order to achieve the above object, the present invention is HMG-CoA reductase inhibitors and niacin; pH-independent polymer bases; pH-dependent polymer bases; Excipients; Provided is a double-layered tablet containing antioxidant and coated tablets for oral administration, which may include a lubricant and optionally further include a binder.

According to a suitable embodiment of the present invention, niacin; HMG-CoA reduction inhibitors; pH-independent polymer bases; pH-dependent polymer bases; additive; Disintegrants; Glidants; Provided are niacin-containing complex controlled release formulations, which optionally contain a binder.

According to another suitable embodiment of the present invention, the preparation consists of a first layer containing niacin and a second layer containing HMG-CoA reduction inhibitor Provided are niacin-containing complex controlled release formulations which are bilayer tablets.

According to another suitable embodiment of the present invention, the niacin-containing complex controlled-release preparation is provided, wherein the niacin-containing layer is coated with an HMG-CoA reduction inhibitor layer.

According to another suitable embodiment of the present invention, the HMG-CoA reduction inhibitor is preferably one selected from the group consisting of rosuvastatin, atorvastatin, lovastatin, fluvastatin, pitavastatin, pravastatin.

According to another suitable embodiment of the present invention, the pH-independent polymer base is hydroxypropylmethylcellulose (Hydroxyproxylmethylcellulose), ethyl cellulose (Ethylcellulose), hydroxypropylcellulose (Hydroxypropylcellulose), hydroxypropylmethylcellulose phthalate (Hydroxypropylmethylcellulose At least one selected from cellulose derivatives consisting of phthalate, hydroxypropylmethylcellulose acetylsuccinate, and sodium carboxymethylcellulose.

According to another suitable embodiment of the present invention, the pH-dependent polymer base is preferably at least one selected from water-soluble salts of alginic acid or carboxyvinyl polymer.

According to another suitable embodiment of the present invention, the disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone, other commercially available polyvinylpolydone, low substituted hydride It is preferred that they are single or mixtures thereof selected from the group consisting of oxypropyl cellulose, alginic acid, carboxymethyl cellulose calcium and sodium salts, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methyl cellulose, powdered cellulose, starch and sodium alginate. .

According to another suitable embodiment of the present invention, it is preferable that the binder is a polymer having a repeating unit of 1-ethenyl-2-pyrrolidinone.

According to another suitable embodiment of the present invention, it is preferred that the lubricant is one selected from the group consisting of magnesium stearate, silica oxide, colloidal silicon dioxide, talc and mixtures thereof.

According to another suitable embodiment of the present invention, 300 to 1000 parts by weight of niacin relative to the total weight of the formulation; 2 to 80 parts by weight of HMG-CoA reduction inhibitor; 5 to 300 parts by weight of hydroxypropylmethylcellulose or hydroxypropyl cellulose as a pH-independent polymer base; 5 to 100 parts by weight of sodium alginate and carboxyvinyl polymer as a pH-dependent polymer base; 5 to 200 parts by weight of sodium starch glycolate or crospovidone as a disintegrant; 0.1 to 20 parts by weight of magnesium stearate as a lubricant; 1 to 500 parts by weight of microcrystalline cellulose and lactose as additives; And optionally 1 to 20 parts by weight of the binder povidone is provided.

According to another suitable embodiment of the present invention, 300 to 1000 parts by weight of niacin relative to the total weight of the formulation; 100 to 200 parts by weight of a coating comprising 2 to 80 parts by weight of a HMG-CoA reduction inhibitor as a coating agent; 5 to 300 parts by weight of hydroxypropylmethylcellulose or hydroxypropyl cellulose as a pH-independent polymer base; 5 to 100 parts by weight of sodium alginate and carboxyvinyl polymer as pH-dependent polymer bases; 5 to 200 parts by weight of sodium starch glycolate or crospovidone as a disintegrant; 0.1 to 20 parts by weight of magnesium stearate as a lubricant; 1 to 500 parts by weight of microcrystalline cellulose and lactose as additives; 0.01 to 5 parts by weight of butylhydroxyanisole or ascorbic acid as antioxidant; And optionally a niacin-containing complex controlled release formulation containing 1 to 20 parts by weight of the binder povidone.

According to another suitable embodiment of the present invention, the drug is niacin; pH-independent polymer bases and pH-dependent polymer bases; A first step of uniformly mixing the additives and the disintegrant and adding a liquid solvent to prepare wet granules, drying and pulverizing them; HMG-CoA inhibitors; additive; A second step of preparing the wet granules by mixing an antioxidant and adding a liquid solvent, drying and pulverizing the wet granules; And final mixing and lubricating the lubricating agent in the wet granules obtained in the first and second steps, respectively, to provide a method for preparing a niacin-containing complex controlled release formulation.

According to another suitable embodiment of the present invention, the drug is niacin; pH-independent polymer bases and pH-dependent polymer bases; Uniformly mixing the additives and the disintegrant and adding a liquid solvent to prepare wet granules, drying and pulverizing; Preparing a niacin-containing tablet by mixing the lubricant with the wet granules; Provided is a method for preparing a niacin-containing complex controlled release formulation comprising coating the tablet with a coating agent in which an HMG-CoA inhibitor is mixed. According to another suitable embodiment of the present invention, there is provided a method for producing a niacin-containing complex controlled release formulation, characterized in that it further comprises a binder in preparing the wet granules.

According to another suitable embodiment of the present invention, the liquid solvent is preferably one or a mixed solvent selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol, polyethylene glycol.

According to another suitable embodiment of the present invention, the liquid solvent is water or a mixed solvent of water and ethanol, the amount is preferably 10 to 23% by weight of the main drug.

Oral formulations containing immediate release HMG-CoA reduction inhibitors and sustained release niacin according to the present invention, unlike commercial formulations, are capable of separate controlled release in the stomach and intestine, and the controlled release of drugs is significantly improved compared to each single agent. Side effects such as skin fever and flushing, which are side effects of niacin, can be minimized. The rapid release of HMG-CoA reductant suppressor can maximize the effect of hyperlipidemia.

1 is a graph showing the dissolution rate test results of niacin-containing tablets and commercially available tablets of Examples 46 to 49 of the present invention.
2 is a graph showing the dissolution rate test results of niacin-containing tablets and commercially available tablets of Examples 71 to 74 of the present invention.
Figure 3 is a graph showing the dissolution rate test results of the rosuvastatin-containing tablets and commercial tablets of Examples 76 to 82 of the present invention.
Figure 4 is a graph showing the dissolution rate test results of rosuvastatin in the niacin-containing double layer tablets of Examples 83 to 88 of the present invention.
5 is a graph showing the dissolution rate test results of rosuvastatin in the niacin-containing double layer tablets of Examples 109 to 114 of the present invention.
6 is a graph showing the dissolution rate test results of niacin in the niacin-containing double layer tablets of Examples 83 to 88 of the present invention.
7 is a graph showing the dissolution rate test results of rosuvastatin in the niacin-containing coating agent of Examples 115 to 118 of the present invention.
8 is a graph showing the dissolution rate test results of niacin in the niacin-containing coating agent of Examples 115 to 118 of the present invention.
9 is a graph showing the dissolution rate test results of rosuvastatin in the niacin-containing coating agent of Examples 119 to 122 of the present invention.
10 is a graph showing the dissolution rate test results of niacin in the niacin-containing coating agent of Examples 119 to 122 of the present invention.
11 is a graph showing the dissolution rate test results of atorvastatin in tablets and commercially available tablets of Examples 123 to 126 of the present invention.
FIG. 12 is a graph showing the dissolution rate test results of atorvastatin in the niacin-containing coating agent of Examples 128 to 129 of the present invention.
12 is a graph showing the dissolution rate test results of niacin in niacin-containing bilayer tablets of Examples 127 to 130 of the present invention.

The present invention provides HMG-CoA reductase inhibitors and niacin; pH-independent polymer bases; pH-dependent polymer bases; Excipients; Provided is a double-layered tablet containing antioxidant and coated tablets for oral administration, which may include a lubricant and optionally further include a binder.

In the present invention, the term "niacin" is a concept including nicotinic acid and derivatives thereof, for example, nicotinic acid, nicotinamide, nicotyl alcohol tartrate, D-glucinitol hexanicotinate ( d-glucitol hexanicotinate) and all compounds metabolized in vivo and convertible to nicotinic acid.

Oral dose of niacin according to the present invention can generally be administered daily in increments of 250 mg, 500 mg, 750 mg, 1000 mg, in the case of rosuvastatin, which is an HMG-CoA reductase inhibitor, generally from 5 mg to 80 mg, lovastatin, atto Vastatin or pravastatin may contain from 10 mg to 80 mg or more, and fluvastatin or pitavastatin from 20 mg to 100 mg or more as dosage.

The term "pH-independent polymer base" used in the oral preparation of the present invention means a substance capable of controlling and delaying the release of the drug by absorbing moisture regardless of a change in pH. Thus, the use of pH-independent polymer bases in oral formulations containing niacin of the present invention can control and delay the release of the drug. As the pH-independent polymer base, any pharmaceutically acceptable pH-independent polymer may be used. Examples thereof include HPMC, ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose phthalate. Cellulose derivatives composed of (Hydroxypropylmethylcellulose phthalate), hydroxypropylmethylcellulose acetylsuccinate, and sodium carboxymethylcellulose; Polyethylene oxide and its derivatives; Polyvinylpyrrolidone (commercially known as kollidons); Polyethylene glycol (commercially carbo waxes) and polyvinyl alcohols: polyvinylacetate, polyvinylacetate phthalglycerol monostearate and poloxamer, guar gum One selected from the group consisting of leucine, chitosan, sodium pectinate, gelatin and gum tragacanth, or mixtures thereof.

In the present invention, preferably, a cellulose derivative is used as the pH-independent polymer base, and among them, the most ideal effect can be obtained when using HPMC. In the embodiment of the present invention, the amount of HPMC used as the pH-independent polymer base is preferably 5 to 300 parts by weight, more preferably 100 to 200 parts by weight based on the total weight of the preparation.

In addition, the pH-dependent polymer base used in the oral preparation of the present invention is a pH-dependent system in which the system is released under acidic conditions (above) to operate to form a hydrogel (gel) to surround the drug to release the drug To control. PH-dependent polymer bases that can be used in the formulations of the present invention include water-soluble salts of alginic acid such as sodium alginate, polyacrylic and derivatives thereof (typically carbomers). Preferably, carboxyvinyl polymer is used. The amount of the pH-dependent polymer base used in the embodiment of the present invention is preferably 5 to 100 parts by weight, more preferably 10 to 70 parts by weight based on the total weight of the formulation.

The HPMC and carbomers are known to have a wide variety of purposes for pharmaceutical use according to their molecular weight. (Handbook of Pharmaceutical Excipients, Edited by Raymond C Rowe, Paul J sheskey and Paul weller, 2003, fourth edition, APhA)

In the oral preparation of the present invention, a binder may be used as necessary. Any known binder can be used, but it is preferable to select and use from polymers having repeating units of 1-ethenyl-2-prrrolidinone. Such polymers generally have a molecular weight of 10,000 to 700,000 and are known as “povidones”. The amount of the binder used in the embodiment of the present invention is preferably 1 to 20 parts by weight, more preferably 10 to 20 parts by weight based on the total weight of the formulation.

Disintegrants are used to absorb the water to promote disintegration of the formulation to promote the dissolution of niacin and HMG-CoA reductase inhibitors, an example of a disintegrant that can be used in the formulation of the present invention is croscarmellose sodium (Croscamellose) sodium), sodium starch glycolate (sodium starch glycolate), pre-gelatinized starch (pregelatinized starch) [starch 1500 ^{® ®} or Prejel], microcrystalline cellulose in o tm (microcrystalline cellulose), crospovidone (crospovidone, cross- linked povidone and other commercially available polyvinylpyrrolidone (PVP, Povidone ^® ), low substituted hydroxypropylcellulose (low substituted), alginic acid, carboxymethylcellulose calcium salt and Sodium salt, colloidal silica dioxide (guar gum), guar gum, magnesium aluminum silicate um silicate, methylcellulose, powdered cellulose, starch and sodium alginate, or a mixture thereof may be used.

In the present invention, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone and commercially available polyvinylpyrrolidone are preferably used as the disintegrant. Most preferably, as the disintegrant, crospovidone, sodium starch glycolate, or microcrystalline cellulose is used, and is particularly effective when two or more disintegrants are mixed and used. The disintegrant may be added to the oral solid preparation in addition to the pharmaceutically acceptable method, and a second disintegrant may be further used for the faster release of the preparation. Disintegrant is preferably 5 to 200 parts by weight based on the total weight of the formulation, most preferably 10 to 100 parts by weight.

In addition, the lubricant used in the oral preparation of the present invention is used to improve the moldability of the oral preparation, for example, magnesium stearate (magnesium state), silica oxide (SiO ₂ ) or colloidal silicon dioxide (collidal silica, Cabo-SIL ^® ) or talc, but are not limited to these. The use range of the lubricant is preferably 0.1 to 20 parts by weight based on the total weight of the formulation.

Sustained release oral preparations of the present invention may include additives commonly used in pharmacy, and such additives may include lactose, sugar, mannitol, lactose, sorbitol, and the like. It may include.

In addition, the antioxidants used in the oral preparations of the present invention include antioxidants widely used in pharmaceuticals, and these antioxidants are water-soluble vitamin C, vitamin E, tocopherol (Tocopherol) and sesamol (Sesamol) which are radical inhibitors. , Gingeron, Capsaicin, Quercetin, Garlic acid and little antioxidant, but co-existing with a radical inhibitor, citric acid, ascorbic acid and the like.

In the case of niacin sustained-release tablets using HPMC and carbomer, the dissolution rate was controlled using a pH-dependent polymer and a pH-independent polymer. It is difficult to precisely control the dissolution of niacin in the stomach under acidic conditions only by using the HPMC which maintains the carbomer controlling the dissolution of niacin in the alkaline solution and the matrix form of the tablet. Therefore, when the elution of niacin from above shows an immunologic release (IR) pattern, side effects such as flushing are expressed. In the present invention, gelation is performed in an acidic condition of early dissolution to control and sustain elution of niacin. In order to minimize the sodium alginate (sodium alginate) was used as an additive. To minimize hepatotoxicity, another side effect of niacin, late elution was controlled. Carbomer was used to slow the late elution of niacin sustained-release tablets under alkaline conditions. Sodium alginate gels under acidic conditions to control dissolution rates, and under alkaline conditions carbomers gelizes to regulate drug release.

The present invention includes a combination of a niacin derivative, a compound metabolized to nicotinic acid in the body, and any mixture thereof, as well as a sustained-release form of niacin and an immediate release form of HMG-CoA reductase inhibitor, to provide a pharmaceutical composition. Provided are methods for the preparation of tablet and coated tablet oral formulations.

Specifically, the oral preparation of the present invention uniformly mixes niacin, a polymer base, and an additive, and then adds a small amount of liquid solvent and mixes again to prepare wet and dried wet granules, and the wet granules and the HMG-CoA reductase inhibitor The lubricant may be mixed with each of the mixtures containing the mixture, and then mixed with a tablet press.

The first layer tablet according to the invention comprises rosuvastatin dispersed in a tablet matrix having immediate release. The first layer tablet composition generally comprises 3 to 50%, preferably 5 to 35%, of the active ingredient. The active ingredient is not limited to rosuvastatin but may include an HMG-CoA reductase inhibitor.

The second layer tablet according to the invention comprises niacin dispersed in a tablet matrix having sustained release. The second layer tablet composition generally comprises 10 to 80%, preferably 30 to 70% of the active ingredient. The active ingredient may include niacin derivatives and salts.

The solvent added to the mixed powder when preparing the wet granules of the present invention may be used one or a mixed solvent selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol and polyethylene glycol. Preferably the liquid solvent uses ethanol or a mixed solvent of water and ethanol. In this case, when the solvent is water alone or a mixed solvent of water and ethanol, 5 to 40% of the total weight of the drug is used, more preferably 10 to 23%.

According to the present invention, it is also preferred that the sustained release composition containing niacin is coated with a rapid release HMG-CoA reductase inhibitor after tableting. Exemplary coatings according to the present invention include HMG-CoA reductase inhibitors, plasticizers, film formers and coatings and coloring agents.

Common solvents used for coating include water, alcohols, esters, ketones, chlorinated hydrocarbons, and bases include celluloses, vinyls, glycols, acrylics, polyhydric alcohols, acetate esters, phthalate esters, Glycerides and oils can be used.

Exemplary amounts of film formers and coatings in the coatings above are from about 0.01% to about 5% by weight of the total weight of the tablet. In general, to prepare a coating according to the present invention, the film is coated to a thickness containing an effective amount of the HMG-CoA reductase inhibitor after the HMG-CoA reductase inhibitor is suspended or dissolved in an aqueous solution of polyethylene glycol and hydroxy propyl methylcellulose. Sprayed to the sustained release tablet surface by the process. Examples of suitable coating thicknesses in accordance with the present invention range from about 0.1 mm to about 2.0 mm or more.

The amount of niacin included in the oral preparation may be appropriately selected in consideration of drug economics and stability, and is usually 300 to 1000 mg (daily sustained release daily), preferably 500 to 1000 mg.

The amount of the statin-based drug which is an HMG-CoA reductase inhibitor included in the oral preparation may be appropriately selected in consideration of the economics and stability of the drug, and usually 2 to 80 mg (once a day), preferably 10 to 20 mg.

Oral preparations containing the sustained release niacin and the immediate release HMG-CoA reductase inhibitor of the present invention is 300 to 1000 drug niacin relative to the total weight of the preparation; 2 to 80 parts by weight of HMG-CoA reductase inhibitor; 10 to 70 parts by weight of the pH-dependent polymer base; Additives 1 to 300 parts by weight; 10 to 100 parts by weight of disintegrant; 5 to 20 parts by weight of lubricant; Optionally containing 10 to 20 parts by weight of the binder.

In practicing the present invention, niacin, niacin compounds, and HMG-CoA reductase inhibitors can be formulated in a variety of oral dosage forms suitable for oral use, such as rapid disintegrating tablets, compressed tablets, enteric coatings, capsules, caplets. According to any method known in the pharmaceutical art for the preparation of a pharmaceutical composition for incorporation, it may be formulated into a sustained release task, sustained release granules, sustained release coated granules, sustained-release beads or pellets. In addition, HMG-CoA reductase inhibitors may be formulated into immediate release granules or immediate release coatings for incorporation into the oral dosage forms of the present invention.

For the oral preparations according to the present invention, when elution of the commercially available Niaspan ^® and Zocor ^® drugs in water, pH 1.2, pH 4.0, and pH 6.8 eluents showed different elution patterns than the conventional commercially available agents. . Niacin showed a dissolution profile similar to that of commercial tablets at pH 1.2, which was gastric fluid condition, but showed a different dissolution profile than commercial tablets with increasing pH. In the case of rosuvastatin, the dissolution control of oral preparations according to the present invention in all eluates It can be seen that it is significantly superior to the commercial tablets.

In addition, when the carboxyvinyl polymer is used as a pH-dependent polymer base in the oral preparations according to the present invention, it is shown that as the pH is increased, it has an excellent effect on the control of the dissolution rate. It seems to be able to significantly improve side effects such as skin fever and flushing.

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

Example 1 Preparation of Tablets Containing Niacin

500.0 mg of drug niacin, 128.5 mg of excipient lactose and 128.5 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above, 17.0 mg of HPMC was added to a powder mixer as a polymer base, and then uniformly mixed, and then sprayed with ethanol to prepare wet granules.

Typically, 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then crushed evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 2>

A tablet containing niacin was prepared in the same manner as in Example 1, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 1.

<Example 3>

Carried out for example, as a base polymer in the composition of the first embodiment in the same manner as in Example 1 except that an additional Carbopol (Carbopol ^®) 60.0mg was prepared appointed to other tablets containing niacin.

<Example 4>

A tablet containing niacin was prepared in the same manner as in Example 1, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 1 and 17.0 mg of povidone were used.

Example 5

A tablet containing niacin was prepared in the same manner as in Example 1, except that 15.0 mg of sodium starch glycolate was added as a disintegrant in the composition of Example 1, and then, tablets containing niacin were prepared.

<Example 6>

500.0 mg of drug niacin, 120.0 mg of excipient lactose and 120.0 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 34.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then crushed evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

Example 7

A tablet containing niacin was prepared in the same manner as in Example 6, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 6.

<Example 8>

A tablet containing niacin was prepared in the same manner as in Example 6, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 6.

Example 9

A tablet containing niacin was prepared in the same manner as in Example 6, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 6 and 17.0 mg of povidone was used as a binder. .

<Example 10>

A tablet containing niacin was prepared in the same manner as in Example 6, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 6.

<Example 11>

500.0 mg of drug niacin, 111.5 mg of excipient lactose and 111.5 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 51.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then crushed evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 12>

A tablet containing niacin was prepared in the same manner as in Example 11, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 11.

Example 13

A tablet containing niacin was prepared in the same manner as in Example 11, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 11.

<Example 14>

A tablet containing niacin was prepared in the same manner as in Example 6, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 11 and 17.0 mg of povidone was used as a binder. .

<Example 15>

A tablet containing niacin was prepared in the same manner as in Example 6, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 11.

<Example 16>

500.0 mg of drug niacin, 103.0 mg of excipient lactose and 103.0 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 68.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then crushed evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 17>

A tablet containing niacin was prepared in the same manner as in Example 16, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 16.

&Lt; Example 18 >

A tablet containing niacin was prepared in the same manner as in Example 16, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 16.

&Lt; Example 19 >

A tablet containing niacin was prepared in the same manner as in Example 16, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 16 and 17.0 mg of povidone was used as a binder. .

Example 20

A tablet containing niacin was prepared in the same manner as in Example 16, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 16.

&Lt; Example 21 >

500.0 mg of drug niacin, 94.5 mg of excipient lactose and 94.5 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 85.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at a temperature of 60 ° C., then evenly pulverized, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 22>

A tablet containing niacin was prepared in the same manner as in Example 21, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 21.

<Example 23>

A tablet containing niacin was prepared in the same manner as in Example 21, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 21.

<Example 24>

A tablet containing niacin was prepared in the same manner as in Example 21, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 21 and 17.0 mg of povidone was used as a binder. .

<Example 25>

A tablet containing niacin was prepared in the same manner as in Example 21, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 21.

<Example 26>

500.0 mg of drug niacin, 86.0 mg of excipient lactose and 86.0 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 102.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

Example 27

A tablet containing niacin was prepared in the same manner as in Example 26, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 26.

<Example 28>

A tablet containing niacin was prepared in the same manner as in Example 26, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 26.

&Lt; Example 29 >

A tablet containing niacin was prepared in the same manner as in Example 26, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 26 and 17.0 mg of povidone was used as a binder. .

<Example 30>

A tablet containing niacin was prepared in the same manner as in Example 26, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 26.

<Example 31>

500.0 mg of drug niacin, 77.5 mg of excipient lactose, and 77.5 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above, as a polymer base, 119.0 mg of HPMC was put in a powder mixer, mixed uniformly, and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 32>

A tablet containing niacin was prepared in the same manner as in Example 31, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 31.

&Lt; Example 33 >

A tablet containing niacin was prepared in the same manner as in Example 31, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 31.

&Lt; Example 34 >

A tablet containing niacin was prepared in the same manner as in Example 31, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 31 and 17.0 mg of povidone was used as a binder. .

<Example 35>

A tablet containing niacin was prepared in the same manner as in Example 31, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 31.

<Example 36>

500.0 mg of drug niacin, 69.0 mg of excipient lactose and 69.0 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 136.0mg into a powder mixer was mixed uniformly and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

&Lt; Example 37 >

A tablet containing niacin was prepared in the same manner as in Example 36, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 36.

<Example 38>

A tablet containing niacin was prepared in the same manner as in Example 36, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 36.

<Example 39>

Tablets containing niacin were prepared in the same manner as in Example 36, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 36 and 17.0 mg of povidone was used as a binder. .

<Example 40>

A tablet containing niacin was prepared in the same manner as in Example 36, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 36.

<Example 41>

500.0 mg of drug niacin, 60.5 mg of excipient lactose and 60.5 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 153.0mg into a powder mixer was mixed uniformly and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 42>

A tablet containing niacin was prepared in the same manner as in Example 41, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 41.

<Example 43>

A tablet containing niacin was prepared in the same manner as in Example 41, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 41.

<Example 44>

A tablet containing niacin was prepared in the same manner as in Example 41, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 41 and 17.0 mg of povidone was used as a binder. .

<Example 45>

A tablet containing niacin was prepared in the same manner as in Example 41, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 41.

<Example 46>

500.0 mg of drug niacin, 52.0 mg of excipient lactose and 52.0 mg of microcrystalline cellulose were mixed well to increase the fluidity of the drug. In addition to the above as a polymer base, HPMC 170.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 47>

A tablet containing niacin was prepared in the same manner as in Example 46, except that 60.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 46.

<Example 48>

A tablet containing niacin was prepared in the same manner as in Example 46, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 46.

<Example 49>

A tablet containing niacin was prepared in the same manner as in Example 46, except that 60.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 46 and 17.0 mg of povidone was used as a binder. .

<Example 50>

A tablet containing niacin was prepared in the same manner as in Example 46, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 46.

The composition for the oral preparation containing niacin according to the above embodiment is summarized in Table 1 below.

Experimental Example 1 Hardness Test and Drug Content Experiment

Ten tablets of the conventional tablets (Niaspanor ^® ) and oral tablets containing niacin prepared in the Examples of the present invention were each taken, and hardness was measured using an ERWEKA hardness tester.

In addition, 20 tablets of the conventional commercially available tablets and tablets prepared in Examples of the present invention were taken from powders to mortars. The prepared powder was weighed in an amount corresponding to 500.0 mg as niacin, and placed in a 100 ml volumetric flask, and 50 ml of water was warmed for 30 minutes, followed by ultrasonic extraction, followed by 100 ml of water. Accurately take 1 ml of the above solution into a 100 ml volumetric flask, add 100 ml of water, and filter the resulting solution with 0.45 μm membrane filter. Was measured. The average hardness and content of conventional commercially available tablets and tablets prepared in Examples of the present invention are shown in Table 2 below.

As described in Table 2, the tablets prepared in the Examples of the present invention tended to have a similar or higher hardness than conventional commercially available tablets as the content of the polymer-based HPMC, carbomer or sodium alginate was higher. In addition, as shown in Table 2, oral tablets prepared in Examples of the present invention contained more than 95% of niacin on average, it was confirmed that the results show significant results compared to conventional commercial preparations.

Experimental Example 2

For the tablets prepared in the Examples of the present invention and the conventional commercially available tablets, the elution rate of the water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) was determined as follows. Tested.

A tablet containing a certain amount of niacin was tested for dissolution according to the pharmacopeia eighth tablet dissolution test method. Specifically, after precisely weighing the tablets prepared in Examples of the present invention and conventional commercial tablets in 900 ml of water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) eluent Paddle method (paddle method) (100rpm) was used, the dissolution test was carried out for 24 hours at 37 ± 1 ℃ dissolution temperature. After dissolution test was started, 15 ml, 30 minutes, 60 minutes, 90 minutes, and 2 hours, 1 ml of each eluate was taken up to 24 hours at 1 hour intervals, and the same amount of the dissolution solution was supplemented at the same time. The collected eluate was filtered through a 0.45 ㎛ membrane filter and then tested as the test solution under the following conditions.

<Experimental conditions>

Column: Kromasil KR100-5C18 (250 × 4.6 mm)

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: Methanol (4: 1) is 1L, and 1.1g of 1-octane sulfonate is added to make a mobile phase.

Wavelength: 262 nm

Flow rate: 1.0 ml / min

The concentration of drug was first calculated from the standard calibration curve and converted into percent dissolution. As a result of comparing the dissolution rate of the commercially available tablets with the above examples in each liquid environment, in some embodiments, dissolution rates similar to those of commercially available tablets (Examples 46 to 47) or more sustained release rates (Examples 48 to 48) 49). Among the results, the dissolution rate in water is shown in Table 3 below.

Dissolution Rate in Water (%) time Commercially available tablets Example 46 Example 47 Example 48 Example 49 15 minutes 7.1 14.6 9.5 6.1 4.2 30 minutes 12.5 20.5 15.4 10.5 8.2 60 minutes 17.1 30.4 15.2 15.2 13.2 90 minutes 21.4 35.0 31.3 20.2 18.3 2 hours 26.2 45.3 39.5 25.4 23.2 3 hours 33.4 53.0 48.4 30.3 28.1 5 hours 47.0 70.0 65.4 40.1 38.1 6 hours 52.5 80.5 75.6 45.3 43.1 8 hours 65.3 95.3 90.3 55.5 53.2 10 hours 76.4 100.3 95.3 69.3 63.1 12 hours 86.1 100.2 83.1 73.3 15 hours 100.0 98.3 88.1 16 hours 100.3 93.1 20 hours 100.3

<Example 51>

The fluidity of the drug was increased by thoroughly mixing 1000.0 mg of the drug niacin, 63.0 mg of the excipient lactose and 63.0 mg of the microcrystalline cellulose. In addition to the above as a polymer base, HPMC 24.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 20 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 52>

A tablet containing niacin was prepared in the same manner as in Example 51, except that 30.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 51.

<Example 53>

A tablet containing niacin was prepared in the same manner as in Example 51, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 51.

<Example 54>

A tablet containing niacin was prepared in the same manner as in Example 51, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 51 and 17.0 mg of povidone was used as a binder. .

<Example 55>

A tablet containing niacin was prepared in the same manner as in Example 51, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 51.

<Example 56>

The fluidity of the drug was increased by thoroughly mixing the drug niacin 1000.0mg, excipient 51.0mg lactose and microcrystalline cellulose 51.0mg. In addition to the above as a polymer base, HPMC 48.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 20 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 57>

A tablet containing niacin was prepared in the same manner as in Example 56, except that 30.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 56.

<Example 58>

A tablet containing niacin was prepared in the same manner as in Example 56, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 56.

<Example 59>

A tablet containing niacin was prepared in the same manner as in Example 56, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 56 and 17.0 mg of povidone was used as a binder. .

<Example 60>

A tablet containing niacin was prepared in the same manner as in Example 56, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 56.

<Example 61>

The fluidity of the drug was increased by thoroughly mixing 1000.0 mg of the drug niacin, 39.0 mg of the excipient lactose, and 39.0 mg of the microcrystalline cellulose. In addition to the above as a polymer base, HPMC 72.0mg into a powder mixer was mixed uniformly and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 20 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 62>

A tablet containing niacin was prepared in the same manner as in Example 61, except that 30.0 mg of sodium alginate was further used as the polymer base in the composition of Example 61.

<Example 63>

A tablet containing niacin was prepared in the same manner as in Example 61, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 61.

<Example 64>

A tablet containing niacin was prepared in the same manner as in Example 61, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 61 and 17.0 mg of povidone was used as a binder. .

<Example 65>

A tablet containing niacin was prepared in the same manner as in Example 61, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 61.

Example 66

The fluidity of the drug was increased by thoroughly mixing 1000.0 mg of the drug niacin, 27.0 mg of the excipient lactose, and 27.0 mg of the microcrystalline cellulose. In addition to the above as a polymer base, HPMC 96.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 20 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 67>

A tablet containing niacin was prepared in the same manner as in Example 66, except that 30.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 66.

<Example 68>

A tablet containing niacin was prepared in the same manner as in Example 66, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 66.

<Example 69>

A tablet containing niacin was prepared in the same manner as in Example 66, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 66 and 17.0 mg of povidone was used as a binder. .

<Example 70>

A tablet containing niacin was prepared in the same manner as in Example 66, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 66.

<Example 71>

The fluidity of the drug was increased by thoroughly mixing 1000.0 mg of the drug niacin, 15.0 mg of the excipient lactose, and 15.0 mg of the microcrystalline cellulose. In addition to the above as a polymer base, HPMC 120.0mg into a powder mixer was uniformly mixed and then sprayed with ethanol to prepare wet granules.

Typically 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base in the formulation can be dissolved in a mixed solvent of water or alcohol and used to granulate the powder.

The granules thus prepared were prepared by sufficiently drying in an oven at 60 ° C. and then pulverizing evenly, further mixing 20 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary purifier.

<Example 72>

A tablet containing niacin was prepared in the same manner as in Example 71, except that 30.0 mg of sodium alginate was additionally used as a polymer base in the composition of Example 71.

<Example 73>

A tablet containing niacin was prepared in the same manner as in Example 71, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 71.

<Example 74>

A tablet containing niacin was prepared in the same manner as in Example 71, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 71 and 17.0 mg of povidone was used as a binder. .

<Example 75>

A tablet containing niacin was prepared in the same manner as in Example 71, except that 15.0 mg of sodium starch glycolate was used as a disintegrant in the composition of Example 71.

The composition for the oral preparation containing niacin according to the above embodiment is summarized in Table 4 below.

Example
Niacin Microcrystalline cellulose Lactose HPMC Sodium alginate Carbopol® Povidone® Sodium Starch Grill Cholate Magnesium stearate Example 51 1000.0 63.0 63.0 24.0 - - - - 20.0 Example 52 1000.0 63.0 63.0 24.0 30.0 - - - 20.0 Example 53 1000.0 63.0 63.0 24.0 - 30.0 - - 20.0 Example 54 1000.0 63.0 63.0 24.0 - 30.0 17.0 - 20.0 Example 55 1000.0 63.0 63.0 24.0 - - - 15.0 20.0 Example 56 1000.0 51.0 51.0 48.0 - - - - 20.0 Example 57 1000.0 51.0 51.0 48.0 30.0 - - - 20.0 Example 58 1000.0 51.0 51.0 48.0 - 30.0 - - 20.0 Example 59 1000.0 51.0 51.0 48.0 - 30.0 17.0 - 20.0 Example 60 1000.0 51.0 51.0 48.0 - - - 15.0 20.0 Example 61 1000.0 39.0 39.0 72.0 - - - - 20.0 Example 62 1000.0 39.0 39.0 72.0 30.0 - - - 20.0 Example 63 1000.0 39.0 39.0 72.0 - 30.0 - - 20.0 Example 64 1000.0 39.0 39.0 72.0 - 30.0 17.0 - 20.0 Example 65 1000.0 39.0 39.0 72.0 - - - - 20.0 Example 66 1000.0 27.0 27.0 96.0 - - - - 20.0 Example 67 1000.0 27.0 27.0 96.0 30.0 - - - 20.0 Example 68 1000.0 27.0 27.0 96.0 - 30.0 - - 20.0 Example 69 1000.0 27.0 27.0 96.0 - 30.0 17.0 15.0 20.0 Example 70 1000.0 27.0 27.0 96.0 - - - - 20.0 Example 71 1000.0 15.0 15.0 120.0 - - - - 20.0 Example 72 1000.0 15.0 15.0 120.0 30.0 - - - 20.0 Example 73 1000.0 15.0 15.0 120.0 - 30.0 - - 20.0 Example 74 1000.0 15.0 15.0 120.0 - 30.0 17.0 - 20.0 Example 75 1000.0 15.0 15.0 120.0 - - - 15.0 20.0

Experimental Example 3

Ten tablets of the conventional commercially available tablets Niaspanor ^® and oral tablets containing niacin prepared in the Examples of the present invention were each taken, and hardness was measured using an ERWEKA hardness tester.

In addition, 20 tablets of the conventional commercially available tablets and tablets prepared in Examples of the present invention were taken from powders to mortars. The prepared powder was weighed in an amount corresponding to 1000.0 mg as niacin, and placed in a 100 ml volumetric flask, and 50 ml of water was warmed for 30 minutes, followed by ultrasonic extraction, followed by 100 ml of water. Accurately take 1 ml of the above solution into a 100 ml volumetric flask, add 100 ml of water, and filter the resulting solution with 0.45 μm membrane filter. Was measured. The average hardness and content of conventional commercially available tablets and tablets prepared in Examples of the present invention are shown in Table 5 below.

Example Hardness (kg) content(%) Example 51 12.1 100.3 Example 52 11.5 99.6 Example 53 13.4 99.1 Example 54 11.6 99.3 Example 55 14.5 98.5 Example 56 11.8 99.6 Example 57 11.9 100.1 Example 58 12.0 99.2 Example 59 13.4 99.3 Example 60 12.5 98.1 Example 61 11.4 99.2 Example 62 12.2 99.5 Example 63 10.2 98.6 Example 64 12.4 100.1 Example 65 13.6 100.2 Example 66 14.7 100.1 Example 67 12.5 99.5 Example 68 13.6 99.3 Example 69 12.5 99.2 Example 70 11.6 99.3 Example 71 13.7 100.3 Example 72 13.5 100.1 Example 73 14.8 99.1 Example 74 13.9 98.5 Example 75 12.8 100.2 Commercially available tablets 10.2 99.7

As shown in Table 5, the tablets prepared in the examples of the present invention tended to exhibit similar or higher hardness than conventional commercially available tablets as the content of the polymer-based HPMC, carbomer or sodium alginate is higher. In addition, as shown in Table 5, the oral tablet prepared in Examples of the present invention contained an average of 95% or more of niacin, and compared with conventional commercial preparations, it was confirmed that the results showed significant results.

Experimental Example 4

For the tablets prepared in the Examples of the present invention and the conventional commercially available tablets, the elution rate of the water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) was determined as follows. Tested.

A tablet containing a certain amount of niacin was tested for dissolution according to the pharmacopeia eighth tablet dissolution test method. Specifically, after precisely weighing the tablets prepared in Examples of the present invention and conventional commercial tablets in 900 ml of water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) eluent Paddle method (paddle method) (100rpm) was used, the dissolution test was carried out for 24 hours at 37 ± 1 ℃ dissolution temperature. After dissolution test was started, 15 ml, 30 minutes, 60 minutes, 90 minutes, and 2 hours, 1 ml of each eluate was taken up to 24 hours at 1 hour intervals, and the same amount of the dissolution solution was supplemented at the same time. The collected eluate was filtered with 0.45um membrane filter and then tested as the test solution under the following conditions.

<Experimental conditions>

Column: Kromasil KR100-5C18 (250 × 4.6 mm)

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: Methanol (4: 1) is 1L, and 1.1g of 1-octane sulfonate is added to make a mobile phase.

Wavelength: 262 nm

Flow rate: 1.0 ml / min

The concentration of drug was first calculated from the standard calibration curve and converted into percent dissolution. As a result of comparing the dissolution rate of commercially available tablets with the above examples in water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8), in some embodiments, (Examples 71-72) The more extended dissolution rate (Examples 73-74) was shown. Among the results, the dissolution rate in water is shown in Table 6 below.

Dissolution Rate in Water (%) time Commercially available tablets Example 71 Example 72 Example 73 Example 74 15 minutes 7.2 13.6 9.5 5.4 3.8 30 minutes 12.4 18.4 15.2 8.7 7.6 60 minutes 16.2 28.4 25.4 13.6 12.7 90 minutes 21.4 34.5 32.3 18.6 16.5 2 hours 25.2 44.5 35.5 24.3 20.4 3 hours 30.1 52.3 45.8 28.9 26.7 5 hours 45.2 69.4 63.8 39.5 35.6 6 hours 50.2 79.4 72.5 43.5 42.3 8 hours 63.8 87.6 88.3 54.2 50.2 10 hours 75.2 97.5 90.2 65.7 60.4 12 hours 84.5 99.3 98.4 82.4 72.3 14 hours 98.0 100.2 99.8 95.6 82.5 15 hours 99.3 100.3 97.6 86.5 17 hours 100.0 99.7 94.7 18 hours 100.3 95.8 22 hours 100.4

<Example 76>

20 mg of rosuvastatin, 80.0 mg of excipient, 80.0 mg of microcrystalline cellulose, and 2.5 mg of citric acid were sufficiently mixed to increase the fluidity of the drug. In addition, 5 mg of ascorbic acid and 0.1 mg of butylhydroxyanisole were mixed in a powder mixer as an antioxidant, and then sprayed with ethanol in which 20 mg of gelatinized starch was dissolved to prepare wet granules.

Typically, 5 ml of ethanol was used to prepare 100 tablets, and the granules prepared were sufficiently dried in an oven at 60 ° C. and then pulverized evenly. It was prepared by tableting a tablet containing rosuvastatin.

<Example 77>

A tablet containing rosuvastatin was prepared in the same manner as in Example 76, except that 100.0 mg of lactose and 60.0 mg of microcrystalline cellulose were used in the composition of Example 76.

<Example 78>

A tablet containing rosuvastatin was prepared in the same manner as in Example 76, except that 120.0 mg of lactose and 40.0 mg of microcrystalline cellulose were used in the composition of Example 76.

<Example 79>

A tablet containing rosuvastatin was prepared in the same manner as in Example 76, except that 140.0 mg of lactose and 20.0 mg of microcrystalline cellulose were used in the composition of Example 76.

<Example 80>

A tablet containing rosuvastatin was prepared in the same manner as in Example 76, except that 60.0 mg of lactose and 100.0 mg of microcrystalline cellulose were used in the composition of Example 76.

<Example 81>

A tablet containing rosuvastatin was prepared in the same manner as in Example 76, except that 40.0 mg of lactose and 120.0 mg of microcrystalline cellulose were used in the composition of Example 76.

<Example 82>

A tablet containing rosuvastatin was prepared in the same manner as in Example 76, except that 20.0 mg of lactose and 140.0 mg of microcrystalline cellulose were used in the composition of Example 76.

The composition for the oral preparation containing rosuvastatin according to the above embodiment is summarized in Table 7 below.

Prescription of oral preparation containing rosuvastatin (mg) Example Rosuvastatin Lactose Microcrystalline cellulose Ascorbic acid Butylhydroxyanisole Gelatinized starch Citric acid Example 76 20 80 80 5 0.1 20 2.5 Example 77 20 100 60 5 0.1 20 2.5 Example 78 20 120 40 5 0.1 20 2.5 Example 79 20 140 20 5 0.1 20 2.5 Example 80 20 60 100 5 0.1 20 2.5 Example 81 20 40 120 5 0.1 20 2.5 Example 82 20 20 140 5 0.1 20 2.5

Experimental Example 5

Taking each of 10 tablets with respect to oral tablets for containing rosuvastatin is manufactured by an embodiment of the present commercially available tablet of the prior information Crestor ^® invention to measure the hardness using a hardness tester ERWEKA.

In addition, take 10 tablets each of the conventional tablets and tablets prepared in the Examples of the present invention, each into a 500mL volumetric flask and add 300mL of water, and ultrasonically shake for about 30 minutes. 125 mL of acetonitrile was added thereto, followed by ultrasonic shaking for about 15 minutes. Cool this solution to room temperature, mix with water to the mark, and filter. 6 mL of this filtrate was added to a 50 mL volumetric flask, a 25v / v% acetonitrile solution was added to the mark, mixed, and the mixture was prepared as a sample solution. The content was measured. The average hardness and content of conventional commercially available tablets and tablets prepared in Examples of the present invention are shown in Table 8 below.

Example Hardness (kg) content(%) Example 76 6.8 100.1 Example 77 7.1 100.2 Example 78 7.3 100.8 Example 79 7.8 100.4 Example 80 6.5 99.8 Example 81 6.1 99.6 Example 82 5.5 100.1 Commercially available tablets 7.1 100.3

As shown in Table 8, the tablets prepared in the examples of the present invention tended to have a similar or higher hardness than conventional commercially available tablets as the content of lactose as an excipient is higher. In addition, as shown in Table 7, the oral tablets prepared in Examples of the present invention contained rosuvastatin on an average of 95% or more and showed significant results with conventional commercial preparations.

<Experimental Example 6>

Pharmacopeia 8 According to Revised Dissolution Test No. 2, the test is carried out at 37 ± 1 ° C for 50 revolutions per minute. Five minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes after the dissolution test was started, about 10 ml of the eluate was taken, centrifuged at 4000 rpm for about 2 minutes, the supernatant was taken, and the dissolution rate was tested under the following conditions.

<Test conditions>

Column: Spherisorb ODS-2 (5 cm × 4.6 mm, 5 μm) or corresponding column

Mobile phase: water: acetonitrile: phosphoric acid = 600: 400: 1

-Flow rate: 1.0 mL / min

Injection volume: 20µl

Detector wavelength: 242nm

-Column temperature: room temperature

-Run time: 5 minutes

The concentration of drug was first calculated from the standard calibration curve and compared in terms of dissolution rate (%). The results showed a dissolution pattern that was nearly similar or more solubilized than commercial tablets (Example 79). Table 9 shows the results of comparing the tablets prepared in Examples with commercially available tablets in the eluate.

Dissolution rate in the eluate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 76 85.4 89.9 95.5 98.1 99.1 Example 77 84.9 90.1 92.0 99.8 100 Example 78 84.7 91.8 94.9 99.2 98.7 Example 79 88.4 94.9 99.3 99.2 100 Example 80 83.2 88.1 94.4 97.4 99.1 Example 81 85.7 89.9 95.1 98.1 100 Example 82 86.8 91.1 95.8 97.4 99.8 Commercially available tablets 86.2 90.8 95.7 98.1 99.1

<Example 83>

The granules containing rosuvastatin prepared in the composition of Example 79 and the granules containing niacin prepared in the composition of Example 46 were compressed into bilayer tablets with the components of each layer.

<Example 84>

The granules containing rosuvastatin prepared in the composition of Example 79 and the granules containing niacin prepared in the composition of Example 47 were compressed into bilayer tablets with the components of each layer.

<Example 85>

Granules containing rosuvastatin prepared in the composition of Example 79 and granules containing niacin prepared in the composition of Example 48 were compressed into bilayer tablets using the components of each layer.

<Example 86>

The granules containing rosuvastatin prepared in the composition of Example 79 and the granules containing niacin prepared in the composition of Example 49 were compressed into bilayer tablets using the components of each layer.

<Example 87>

Granules containing rosuvastatin prepared in the composition of Example 80 and granules containing niacin prepared in the composition of Example 46 were compressed into bilayer tablets using the components of each layer.

<Example 88>

Granules containing rosuvastatin prepared in the composition of Example 80 and granules containing niacin prepared in the composition of Example 47 were compressed into bilayer tablets using the components of each layer.

<Example 89>

Granules containing rosuvastatin prepared in the composition of Example 80 and granules containing niacin prepared in the composition of Example 48 were compressed into bilayer tablets using the components of each layer.

<Example 90>

Granules containing rosuvastatin prepared in the composition of Example 80 and granules containing niacin prepared in the composition of Example 49 were compressed into bilayer tablets with the components of each layer.

<Example 91>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 46 were compressed into bilayer tablets using the components of each layer.

<Example 92>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 47 were compressed into bilayer tablets using the components of each layer.

<Example 93>

The granules containing rosuvastatin prepared in the composition of Example 81 and the granules containing niacin prepared in the composition of Example 48 were compressed into bilayer tablets with the components of each layer.

<Example 94>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 49 were compressed into bilayer tablets using the components of each layer.

<Example 95>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 46 were compressed into bilayer tablets using the components of each layer.

<Example 96>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 47 were compressed into bilayer tablets using the components of each layer.

<Example 97>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 48 were compressed into bilayer tablets using the components of each layer.

<Example 98>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 49 were compressed into bilayer tablets using the components of each layer.

<Example 99>

The granules containing rosuvastatin prepared in the composition of Example 79 and the granules containing niacin prepared in the composition of Example 71 were compressed into bilayer tablets with the components of each layer.

<Example 100>

The granules containing rosuvastatin prepared in the composition of Example 80 and the granules containing niacin prepared in the composition of Example 71 were compressed into bilayer tablets with the components of each layer.

<Example 101>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 71 were compressed into bilayer tablets with the components of each layer.

<Example 102>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 71 were compressed into bilayer tablets using the components of each layer.

<Example 103>

Granules containing rosuvastatin prepared in the composition of Example 79 and granules containing niacin prepared in the composition of Example 72 were compressed into bilayer tablets with the components of each layer.

<Example 104>

The granules containing rosuvastatin prepared in the composition of Example 80 and the granules containing niacin prepared in the composition of Example 72 were compressed into bilayer tablets with the components of each layer.

<Example 105>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 72 were compressed into bilayer tablets using the components of each layer.

<Example 106>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 72 were compressed into bilayer tablets with the components of each layer.

<Example 107>

Granules containing rosuvastatin prepared in the composition of Example 79 and granules containing niacin prepared in the composition of Example 73 were compressed into bilayer tablets using the components of each layer.

<Example 108>

Granules containing rosuvastatin prepared in the composition of Example 80 and granules containing niacin prepared in the composition of Example 73 were compressed into bilayer tablets with the components of each layer.

<Example 109>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 73 were compressed into bilayer tablets with the components of each layer.

<Example 110>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 73 were compressed into bilayer tablets with the components of each layer.

<Example 111>

The granules containing rosuvastatin prepared in the composition of Example 79 and the granules containing niacin prepared in the composition of Example 74 were compressed into bilayer tablets with the components of each layer.

<Example 112>

The granules containing rosuvastatin prepared in the composition of Example 80 and the granules containing niacin prepared in the composition of Example 74 were compressed into bilayer tablets with the components of each layer.

<Example 113>

Granules containing rosuvastatin prepared in the composition of Example 81 and granules containing niacin prepared in the composition of Example 74 were compressed into bilayer tablets with the components of each layer.

<Example 114>

Granules containing rosuvastatin prepared in the composition of Example 82 and granules containing niacin prepared in the composition of Example 74 were compressed into bilayer tablets with the components of each layer.

Experimental Example 7

Ten tablets of oral tablets containing niacin and rosuvastatin prepared as bilayer tablets in the Examples of the present invention were measured for hardness using an ERWEKA hardness tester.

In an embodiment of the present invention, 20 tablets containing oral tablets containing niacin and rosuvastatin prepared as bilayer tablets were ground from induction to powder. The powders prepared above were weighed into 500mg and 1000.0mg, respectively, as niacin, and placed in a 100ml volumetric flask, and 50ml of water was warmed for 30 minutes, followed by ultrasonic extraction, followed by 100ml of water. Accurately take 1 ml of the above solution into a 100 ml volumetric flask, add 100 ml of water, and filter the resulting solution with 0.45 μm membrane filter using a reversed-phase column chromatography (C18) at a wavelength of 262 nm. Was measured. The average hardness and content of conventional commercially available tablets and tablets prepared in Examples of the present invention are shown in Table 10 below.

In addition, the powder prepared above was accurately weighed in an amount corresponding to 20.0 mg as rosuvastatin, placed in a volumetric flask, and 300 mL of water was added thereto, followed by ultrasonic shaking for about 30 minutes. 125 mL of acetonitrile was added thereto, followed by ultrasonic shaking for about 15 minutes. Cool this solution to room temperature, mix with water to the mark, and filter. 6 mL of this filtrate was added to a 50 mL volumetric flask, a 25v / v% acetonitrile solution was added to the mark, mixed, and the mixture was prepared as a sample solution. The content was measured. The hardness average values and contents of conventional commercially available tablets and tablets prepared in Examples of the present invention are shown in Table 10 below.

Example Hardness (kg) Rosuvastatin Content (%) Niacin content (%) Example 83 11.3 99.5 99.8 Example 84 11.2 99.4 99.2 Example 85 12.4 99.2 99.6 Example 86 12.8 100.4 100.1 Example 87 11.9 100.7 100.2 Example 88 11.4 100.8 100.6 Example 89 11.8 101.1 101.0 Example 90 10.7 99.4 99.7 Example 91 11.8 99.4 99.2 Example 92 11.3 99.3 99.5 Example 93 10.9 100.1 100.0 Example 94 10.8 100.5 100.2 Example 95 10.2 100.7 100.4 Example 96 11.4 100.8 100.1 Example 97 11.5 100.4 100.2 Example 98 12.8 100.3 100.6 Example 99 12.6 99.5 99.8 Example 100 11.3 99.4 99.8 Example 101 11.7 99.1 99.4 Example 102 12.1 100.8 100.1 Example 103 11.2 100.1 100.9 Example 104 11.8 101.0 101.1 Example 105 12.6 100.1 100.4 Example 106 11.4 99.5 99.4 Example 107 11.4 100.9 101.1 Example 108 12.4 99.8. 100.9 Example 109 11.1 99.1 99.8 Example 110 11.6 99.7 99.5 Example 111 12.9 101.1 100.1 Example 112 11.7 100.8 100.3 Example 113 11.9 100.9 100.1 Example 114 12.2 99.8 99.9

As shown in Table 10, the bilayer tablet prepared in Examples of the present invention tended to have a higher hardness as the content of the lactose as an excipient was higher. In addition, as shown in Table 10, the oral tablet prepared in the embodiment of the present invention contains an average of 95% or more of rosuvastatin and niacin, and can be confirmed the significance of hardness compared to each single tablet.

<Experimental Example 8>

In the bilayer tablets prepared in the above examples, the elution rate of the sustained-release niacin in water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) was tested as follows. .

A tablet containing a certain amount of niacin was tested for dissolution according to the pharmacopeia eighth tablet dissolution test method. Specifically, after precisely weighing the tablets prepared in Examples of the present invention and conventional commercial tablets in 900 ml of water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) eluent Paddle method (paddle method) (100rpm) was used, the dissolution test was carried out for 24 hours at 37 ± 1 ℃ dissolution temperature. After dissolution test was started, 15 ml, 30 minutes, 60 minutes, 90 minutes, and 2 hours, 1 ml of each eluate was taken up to 24 hours at 1 hour intervals, and the same amount of the dissolution solution was supplemented at the same time. The collected eluate was filtered through a 0.45 ㎛ membrane filter and then tested as the test solution under the following conditions.

<Experimental conditions>

Column: Kromasil KR100-5C18 (250 × 4.6 mm)

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: Methanol (4: 1) is 1L, and 1.1g of 1-octane sulfonate is added to make a mobile phase.

Wavelength: 262 nm

Flow rate: 1.0 ml / min

Rosuvastatin, which is immediate release in the bilayer tablet prepared in the above Example, is tested at a rate of 50 revolutions at 37 ± 1 ° C. per minute according to Method 8 of the pharmacopeia 8th amendment using the dissolution test solution 900ml. 5, 10, 15, 30 and 45 minutes after the dissolution test was started, about 10 ml of the eluate was taken and centrifuged at 4000 rpm for about 2 minutes. After filtration with a 0.45㎛ membrane filter was tested as a sample solution under the following conditions.

<Experimental conditions>

Column: Spherisorb ODS-2 (5 cm × 4.6 mm, 5 μm) or corresponding column

Mobile phase: water: acetonitrile: phosphoric acid = 600: 400: 1

-Flow rate: 1.0 mL / min

Injection volume: 20µl

Detector wavelength: 242nm

-Column temperature: room temperature

-Run time: 5 minutes

The concentration of drug was first calculated from the standard calibration curve and converted into percent dissolution. First, the most suitable examples were selected into two groups according to the content of niacin (Examples 83-88 and Examples 109-114), and dissolution tests were performed on the tablets prepared in each Example and conventional commercial tablets. And the dissolution rate in the eluate is shown in Tables 11 and 12. Tables 13 and 14 show the results of elution of niacin in water in bilayer tablets.

Dissolution rate of rosuvastatin in bilayer tablets containing 500 mg of niacin in the eluate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 83 88.9 91.8 99.5 99.4 100 Example 84 89.1 93.5 98.7 98.9 100 Example 85 89.1 94.6 98.9 99.7 100 Example 86 90.5 95.5 99.9 97.1 100 Example 87 90.4 94.4 99.1 99.0 100 Example 88 87.9 95.1 99.3 99.4 100 Commercial single tablet 86.2 93.4 97.7 97.6 100

Dissolution Rate of Rosuvastatin in Bilayer Tablets Containing 1000mg of Niacin in Eluate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 109 90.8 95.8 98.1 97.1 100 Example 110 90.1 94.1 99.3 98.6 100 Example 111 92.5 95.8 98.8 99.1 100 Example 112 91.4 93.8 98.4 98.1 100 Example 113 90.9 93.1 99.7 97.9 100 Example 114 91.1 94.5 98.9 98.5 100 Commercial single tablet 86.2 92.8 97.7 99.5 100

Dissolution Rate of Niacin 500mg in Water in Double Layer Tablets (%) time Commercial Schedule Example 83 Example 84 Example 85 Example 86 Example 87 Example 88 15 minutes 7.1 10.1 8.2 4.1 2.4 5.9 7.8 30 minutes 12.5 18.4 16.7 5.9 6.8 6.5 18.4 60 minutes 17.1 27.6 24.9 12.1 10.8 13.4 23.8 90 minutes 21.4 32.1 29.8 17.8 15.9 19.7 30.1 2 hours 26.2 41.9 40.9 21.6 19.2 22.1 41.9 3 hours 33.4 52.8 47.1 29.7 25.7 30.8 50.7 5 hours 47.0 69.7 60.8 38.1 35.4 39.6 59.1 6 hours 52.5 79.5 71.3 45.1 40.4 48.7 70.8 8 hours 65.3 92.8 90.3 53.8 50.7 54.9 88.1 10 hours 76.4 100.0 94.2 65.9 61.6 66.7 92.4 12 hours 86.1 100.0 71.8 69.9 74.2 98.9 14 hours 96.4 78.4 75.6 80.1 100 15 hours 100.0 83.9 81.4 85.9 17 hours 91.7 88.1 92.8 18 hours 98.9 92.7 99.1 22 hours 100 98.7 100 24 hours 100

Dissolution Rate of Niacin 1000mg in Water in Double Layer Tablets (%) time Commercial Schedule Example 109 Example 110 Example 111 Example 112 Example 113 Example 114 15 minutes 7.1 6.9 4.8 3.1 5.1 4.0 4.2 30 minutes 12.5 12.1 8.1 6.8 7.1 7.1 7.5 60 minutes 17.1 18.4 11.5 12.2 13.5 13.0 13.1 90 minutes 21.4 22.4 17.8 14.7 16.8 15.9 15.7 2 hours 26.2 25.9 28.1 19.8 24.3 20.1 21.0 3 hours 33.4 32.8 38.4 25.1 36.9 28.4 27.3 5 hours 47.0 46.1 41.3 33.8 40.9 35.2 36.1 6 hours 52.5 50.9 49.2 40.3 47.2 42.8 41.7 8 hours 65.3 64.3 55.7 48.7 57.7 50.4 51.7 10 hours 76.4 77.1 64.1 58.4 65.8 60.8 59.4 12 hours 86.1 85.4 78.6 68.1 77.3 67.1 66.8 14 hours 96.4 95.7 86.4 71.8 84.7 73.4 74.4 15 hours 100.0 100 91.8 81.7 92.6 80.8 81.4 17 hours 98.1 88.4 97.8 91.8 91.5 18 hours 100 91.3 100 97.2 97.1 22 hours 98.6 100 100 24 hours 100

As shown in Tables 11 and 12 above, the rosuvastatin in the bilayer tablet prepared in the Examples of the present invention has similar results to those prepared in a single tablet without interaction between drugs or additives. In the case of rosuvastatin, dissolution rates similar to those of commercially available tablets have been shown to be effective in treating early hyperlipidemia. In addition, in Tables 13 and 14 niacin can account for the microscopic controlled release pattern in the stomach by suggesting a dissolution rate similar to that of commercially available tablets or more sustained release at initial time.

<Example 115>

The niacin sustained-release composition of Example 49 described above was prepared in a sustained-release tablet coated with a coating consisting of the HMG-CoA reductase inhibitor rosuvastatin in immediate release form. Tablets containing niacin were prepared using a rotary tablet machine in the composition prepared in Example 49.

The prepared niacin-containing sustained-release tablets were coated using a high coater HCT 48/60 as follows. 20 mg of rosuvastatin, 1.65 mg of hydroxypropylmethylcellulose, 1.65 mg of hydroxypropylcellulose and 1.5 mg of titanium oxide, 0.60 mg of purified talc are premixed for about 5 minutes. After passing the mixture through a 100mesh sieve, the mixture is slowly added to a previously weighed container with purified water, and mixing is continued until the mixed material is completely dispersed and suspended. After preparation of the coating suspension, the sustained release tablet is coated as follows. The tablet coater should be equipped with a single dry spray bar, a 2.5mm cap and a 1.5mm nozzle opening. The mechanical conditions are set at a fan speed of 15 rpm, an inlet air temperature of 60 ° C. and an exhaust air temperature of 40 ° C., cooling of the fan at a speed of 3.3 rpm, inlet air heating is stopped, and the temperature of the coated tablet is 35 ° C. or lower. Cool to.

The coated tablets contain immediate release rosuvastatin, sustained release niacin and should be approximately ± 10% of the coated tablet weight range.

<Example 116>

In the composition of Example 115, except that 0.02 mg of butylhydroxyanisole and 2.5 mg of ascorbic acid were additionally used as antioxidants, the preparation was carried out in the same manner as in Example 115, and immediate release rosuvastatin and sustained release niacin. A coated tablet containing was prepared.

<Example 117>

Except for the addition of 0.092 mg of yellow iron oxide and 0.023 mg of red iron oxide as the colorant in the composition of Example 115, the preparation was carried out in the same manner as in Example 115 and coated with immediate release rosuvastatin and sustained release niacin. Tablets were prepared.

<Example 118>

In the composition of Example 115 in the same manner as in Example 115, except that 0.02 mg of butylhydroxyanisole, 2.5 mg of ascorbic acid, 0.092 mg of yellow iron oxide, and 0.023 mg of red iron oxide were used as coloring agents. The preparation was made to prepare coated tablets containing immediate release rosuvastatin, sustained release niacin.

Experimental Example 9

In the embodiment of the present invention 10 tablets containing oral tablets containing immediate release rosuvastatin were taken to measure the content and hardness in the same manner as in Experiment 7.

Example Hardness (kg) Rosuvastatin Content (%) Niacin content (%) Example 115 11.5 99.3 99.9 Example 116 11.9 99.4 99.1 Example 117 11.8 99.7 100.3 Example 118 12.1 99.8 100.1

As shown in Table 15, the hardness of the tablets containing the sustained release niacin coated with the rapid release HMG-CoA reduction inhibitor prepared in Examples of the present invention did not show a significant difference depending on the composition of the coating. In addition, as shown in Table 15, the oral tablet prepared in Examples of the present invention contained an average of 95% or more of rosuvastatin and niacin, and can be confirmed the significance of hardness compared to each single tablet.

<Example 119>

A sustained-release tablet coated with a coating consisting of the HMG-CoA reductase inhibitor rosuvastatin in immediate release form was prepared in the niacin sustained-release composition of Example 74 described above.

Tablets containing niacin were prepared using a rotary tablet machine in the composition prepared in Example 74. The prepared niacin-containing sustained-release tablets were coated using a high coater HCT 48/60 as follows. 20 mg of rosuvastatin, 1.65 mg of hydroxypropylmethylcellulose, 1.65 mg of hydroxypropylcellulose, 1.5 mg of titanium oxide and 0.60 mg of purified talc are premixed for about 5 minutes. After passing the mixture through a 100mesh sieve, the mixture is slowly added to a previously weighed container with purified water, and mixing is continued until the mixed material is completely dispersed and suspended. After preparation of the coating suspension, the sustained release tablet is coated as follows. The tablet coater should be equipped with a single dry spray bar, a 2.5mm cap and a 1.5mm nozzle opening. The mechanical conditions are set at a fan speed of 15 rpm, an inlet air temperature of 60 ° C. and an exhaust air temperature of 40 ° C., cooling of the fan at a speed of 3.3 rpm, inlet air heating is stopped, and the temperature of the coated tablet is 35 ° C. or lower. Cool to.

The coated tablets contain immediate release rosuvastatin, sustained release niacin and should be approximately ± 10% of the coated tablet weight range.

<Example 120>

Except for the addition of 0.02 mg of butylhydroxyanisole and 2.5 mg of ascorbic acid as antioxidants in the composition of Example 119, the preparation was carried out in the same manner as in Example 115, and immediate release rosuvastatin and sustained release niacin A coated tablet containing was prepared.

<Example 121>

Except for the addition of 0.092 mg of yellow iron oxide and 0.023 mg of red iron oxide as colorants in the composition of Example 119, the preparation was carried out in the same manner as in Example 115, and was coated with immediate release rosuvastatin and sustained-release niacin. Tablets were prepared.

<Example 122>

In the composition of Example 115 in the same manner as in Example 115, except that 0.02 mg of butylhydroxyanisole, 2.5 mg of ascorbic acid, 0.092 mg of yellow iron oxide, and 0.023 mg of red iron oxide were used as coloring agents. The preparation was made to prepare coated tablets containing immediate release rosuvastatin, sustained release niacin.

Experimental Example 10

In the above example, 10 tablets of the oral tablet containing niacin coated with immediate release rosuvastatin were measured, and the content and hardness were measured in the same manner as in Experimental Example 7.

Example Hardness (kg) Rosuvastatin Content (%) Niacin content (%) Example 119 11.5 99.8 99.7 Example 120 11.9 99.6 99.8 Example 121 11.8 99.9 100.1 Example 122 12.1 100.1 100.0

As shown in Table 16, the hardness of the tablets containing the sustained release niacin coated with the rapid release HMG-CoA reduction inhibitor prepared in Examples of the present invention did not show a significant difference depending on the composition of the coating. In addition, as shown in Table 16, the oral tablet prepared in Examples of the present invention contained more than 95% of the average content of rosuvastatin and niacin, and can be confirmed the significance of hardness compared to each single tablet.

Experimental Example 11

The dissolution rate of the tablets containing the sustained release niacin coated with the rapid release HMG-CoA reduction inhibitor prepared in the embodiment of the present invention was determined in water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8). Tested.

A tablet containing a certain amount of niacin was tested for dissolution according to the pharmacopeia eighth tablet dissolution test method. Specifically, the tablets prepared in Examples of the present invention and conventional commercial tablets are weighed correctly, and then eluate of water, gastric juice (pH 1.2), acetate buffer (pH4.0) and artificial intestinal fluid (pH 6.8,) Paddle method (100rpm) was used in 900ml, the dissolution test was carried out for 24 hours at 37 ± 1 ℃ dissolution temperature. After dissolution test was started, 15 ml, 30 minutes, 60 minutes, 90 minutes, and 2 hours, 1 ml of each eluate was taken up to 24 hours at 1 hour intervals, and the same amount of the dissolution solution was supplemented at the same time. The collected eluate was filtered through a 0.45㎛ membrane filter and then tested as the sample solution under the following conditions.

<Experimental conditions>

Column: Kromasil KR100-5C18 (250 × 4.6 mm)

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: Methanol (4: 1) is 1L, and 1.1g of 1-octane sulfonate is added to make a mobile phase.

Wavelength: 262 nm

Flow rate: 1.0 ml / min

The immediate release rosuvastatin of the coating prepared in the embodiment of the present invention using the dissolution test solution (solution made by dissolving 147 g of sodium citrate dihydrate in 2L of deionized water, 3.3L anhydrous citric acid and 10L added with water) According to Dissolution Test Method 2, the test is carried out at 37 ± 1 ° C for 50 revolutions per minute. 5, 10, 15, 30 and 45 minutes after the dissolution test was started, about 10 ml of the eluate was taken and centrifuged at 4000 rpm for about 2 minutes. After filtration with a 0.45㎛ membrane filter was tested as a sample solution under the following conditions.

<Experimental conditions>

Column: Spherisorb ODS-2 (5 cm × 4.6 mm, 5 μm) or corresponding column

Mobile phase: water: acetonitrile: phosphoric acid = 600: 400: 1

-Flow rate: 1.0 mL / min

Injection volume: 20µl

Detector wavelength: 242nm

-Column temperature: room temperature

-Run time: 5 minutes

The concentration of drug was first calculated from the standard calibration curve and converted into percent dissolution. Dissolution tests were performed on the tablets prepared in Examples of the present invention and conventional commercial tablets. And the dissolution rate in the eluate is shown in Tables 17 and 18. The dissolution rate of niacin is shown in Tables 19 and 20 in water.

Dissolution rate of rosuvastatin in the eluate of coated niacin 500 mg tablets (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 115 86.233 89.046 96.515 96.418 100 Example 116 86.427 90.695 95.739 95.933 100 Example 117 86.427 91.762 95.933 96.709 100 Example 118 87.785 92.635 96.903 94.187 100 Commercial Schedule 87.688 91.568 96.127 96.03 100

Dissolution rate of rosuvastatin in the eluate of coated niacin 1000 mg tablets (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 119 92.926 95.157 94.187 98.142 100 Example 120 91.277 96.321 95.642 99.224 100 Example 121 92.926 95.836 96.127 98.178 100 Example 122 90.986 95.448 95.157 99.962 100 Commercial Schedule 90.307 96.709 94.963 97.079 99.8

Niacin Dissolution Rate in Water of Coated Niacin 500mg Tablets (%) time Commercial Schedule Example 115 Example 116 Example 117 Example 118 15 minutes 7.1 2.8 2.6 2.7 2.5 30 minutes 12.5 6.9 7.0 7.1 6.8 60 minutes 17.1 11.0 11.1 10.9 10.7 90 minutes 21.4 16.0 16.1 15.8 15.9 2 hours 26.2 19.3 19.4 19.9 20.0 3 hours 33.4 26.1 26.3 26.0 25.8 5 hours 47.0 35.5 35.6 35.9 35.5 6 hours 52.5 40.8 41.2 40.9 41.6 8 hours 65.3 51.0 51.2 49.8 50.5 10 hours 76.4 60.6 61.1 62.0 60.9 12 hours 86.1 70.9 70.1 71.2 70.3 14 hours 96.4 76.6 76.9 76.3 75.9 15 hours 100.0 82.3 82.4 81.9 81.1 17 hours 89.1 89.3 88.9 88.7 18 hours 93.7 94.5 93.9 93.2 22 hours 98.9 99.1 99.2 98.9 24 hours 100 100 100 100

Niacin Dissolution Rate in Water of Coated Niacin 1000mg Tablets (%) time Commercial Schedule Example 119 Example 120 Example 121 Example 122 15 minutes 7.1 2.8 3.1 2.9 2.7 30 minutes 12.5 6.9 7.1 7.2 6.9 60 minutes 17.1 11.8 11.2 11.9 12.0 90 minutes 21.4 16.2 16.5 16.9 16.1 2 hours 26.2 20.2 20.1 20.5 19.9 3 hours 33.4 26.3 26.1 26.8 26.2 5 hours 47.0 36.4 37.1 37.2 35.8 6 hours 52.5 41.2 41.3 42.4 41.8 8 hours 65.3 50.9 51.2 51.1 50.7 10 hours 76.4 62.6 62.8 63.1 61.7 12 hours 86.1 70.1 70.8 69.1 70.2 14 hours 96.4 76.2 76.9 77.6 75.9 15 hours 100.0 82.1 82.3 81.9 81.2 17 hours 89.9 89.1 90.1 89.2 18 hours 93.7 93.1 93.8 93.5 22 hours 99.5 99.2 99.5 99.3 24 hours 100 100 100 100

As shown in Tables 17 and 18, rosuvastatin was prepared in a single tablet without interaction between drugs or additives in tablets containing sustained-release niacin coated with a rapid release HMG-CoA reductant prepared in the Examples of the present invention. Results similar to the examples shown. In addition, in Tables 19 and 20, niacin can account for the microscopic controlled release pattern in the stomach by suggesting a dissolution rate similar to that of commercially available tablets or more sustained release at initial time.

<Example 123>

10 mg of atorvastatin, 33.0 mg of excipient calcium carbonate, 60.0 mg of microcrystalline cellulose, and 32.5 mg of lactose were increased to increase the fluidity of the drug.

The granules were wet granulated using 3.0 mg of hydroxypropyl cellulose as a binder, and the granules thus prepared were sufficiently dried in an oven at 60 ° C. and then pulverized evenly, followed by further mixing with 1 mg of magnesium stearate for shaping the formulation by post mixing. Prepared by mixing and tableting tablets containing atorvastatin using a rotary purifier.

<Example 124>

A tablet containing atorvastatin was prepared in the same manner as in Example 123, except that 0.6 mg of polysorbate 80 was additionally used as a granule in the composition of Example 123.

<Example 125>

A tablet containing atorvastatin was prepared in the same manner as in Example 123 except that 9 mg of croscarmellose sodium was additionally used as a disintegrant in the composition of Example 123.

<Example 126>

A tablet containing atorvastatin was prepared in the same manner as in Example 123, except that 0.6 mg of polysorbate 80 as a granule in the composition of Example 123 and 9 mg of croscarmellose sodium as a disintegrant were further used. It was.

<Example 127>

Granules containing atorvastatin prepared in the composition of Example 126 and niacin containing niacin prepared in the composition of Example 49 were compressed into bilayer tablets using the components of each layer.

<Example 128>

Granules containing atorvastatin prepared in the composition of Example 126 and niacin containing niacin prepared in the composition of Example 74 were compressed into bilayer tablets using the components of each layer.

<Example 129>

A sustained-release tablet was prepared by coating the niacin sustained-release composition of Example 49 described above with a coating of HMG-CoA reductase inhibitor atorvastatin in immediate release form.

Tablets containing niacin were prepared using a rotary tablet machine in the composition prepared in Example 49. The prepared niacin-containing sustained-release tablets were coated using a high coater HCT 48/60 as follows. 10 mg of atorvastatin, 4.0 mg of hydroxypropylmethylcellulose, 0.4 mg of polyethylene glycol 6000 and 1.5 mg of titanium oxide are premixed for about 5 minutes. After passing the mixture through a 100mesh sieve, the mixture is slowly added to a previously weighed container with purified water, and mixing is continued until the mixed material is completely dispersed and suspended. After preparation of the coating suspension, the sustained release tablet is coated as follows. The tablet coater should be equipped with a single dry spray bar, a 2.5mm cap and a 1.5mm nozzle opening. The mechanical conditions are set at a fan speed of 15 rpm, an inlet air temperature of 60 ° C. and an exhaust air temperature of 40 ° C., cooling of the fan at a speed of 3.3 rpm, inlet air heating is stopped, and the temperature of the coated tablet is 35 ° C. or lower. Cool to.

The coated tablets contain immediate release atorvastatin, sustained release niacin and should be approximately ± 10% of the coated tablet weight range.

<Example 130>

A sustained-release tablet was prepared by coating the niacin sustained-release composition of Example 49 described above with a coating of HMG-CoA reductase inhibitor atorvastatin in immediate release form.

Tablets containing niacin were prepared using a rotary tablet machine in the composition prepared in Example 49. The prepared niacin-containing sustained-release tablets were coated using a high coater HCT 48/60 as follows. 10 mg of atorvastatin, 4.0 mg of hydroxypropylmethylcellulose, 0.4 mg of polyethylene glycol 6000 and 1.5 mg of titanium oxide are premixed for about 5 minutes. After passing the mixture through a 100mesh sieve, the mixture is slowly added to a previously weighed container with purified water, and mixing is continued until the mixed material is completely dispersed and suspended. After preparation of the coating suspension, the sustained release tablet is coated as follows. The tablet coater should be equipped with a single dry spray bar, a 2.5mm cap and a 1.5mm nozzle opening. The mechanical conditions are set at a fan speed of 15 rpm, an inlet air temperature of 60 ° C. and an exhaust air temperature of 40 ° C., cooling of the fan at a speed of 3.3 rpm, inlet air heating is stopped, and the temperature of the coated tablet is 35 ° C. or lower. Cool to.

The coated tablets contain immediate release atorvastatin, sustained release niacin and should be approximately ± 10% of the coated tablet weight range.

Experimental Example 12

In the embodiment of the present invention, 20 tablets of oral tablets containing niacin prepared with atorvastatin single tablet, bilayer tablet, and immediate release atorvastatin coating were measured by using an ERWEKA hardness tester, and the content thereof was determined in the following test method. Measured accordingly.

In an embodiment of the present invention, 20 tablets containing oral tablets containing niacin prepared with atorvastatin mono-, bilayer, immediate-release atorvastatin coatings were taken from induction to powder. The powders prepared above were weighed into 500mg and 1000.0mg, respectively, as niacin, and placed in a 100ml volumetric flask, and 50ml of water was warmed for 30 minutes, followed by ultrasonic extraction, followed by 100ml of water. Accurately take 1 ml of the above solution into a 100 ml volumetric flask, add 100 ml of water, and filter the resulting solution with 0.45 μm membrane filter. Was measured.

In addition, 10 tablets of oral tablets prepared above were put into a 500 ml flask, and 0.05M ammonium citrate (pH 7.4) / acetonitrile mixture (1: 1) was added to shake well, followed by marking. Take 25 ml of this solution and add ammonium citrate (pH7.4) / acetonitrile mixture (1: 1) to make 100 ml of the solution, filter it with a 0.45 µm membrane filter, and then reverse-phase column at a wavelength of 244 nm using high-performance liquid chromatography. C18) was used to determine the content of atorvastatin.

The average hardness and content of conventional commercially available tablets and tablets prepared in Examples of the present invention are shown in Table 21 below.

Example Hardness (kg) Atorvastatin content (%) Niacin content (%) Example 123 5.5 99.8 - Example 124 6.1 99.5 - Example 125 6.3 100.1 - Example 126 6.5 100.2 - Example 127 11.9 100.1 100.1 Example 128 11.8 99.6 100.2 Example 129 12.8 100.4 99.8 Example 130 12.5 99.8 100.1 Commercially available tablets 5.8 99.4 -

As shown in Table 21, the atorvastatin single tablet prepared in Examples of the present invention showed higher hardness than commercial tablets. In addition, oral tablets prepared in Examples of the present invention, as shown in Table 21, contain an average content of at least 95% of atorvastatin and niacin, and can be confirmed the significance of hardness compared to each single tablet.

Experimental Example 13

Oral tablet containing niacin prepared with bilayer tablet, immediate release atorvastatin coating in the above example, water of artificial release niacin, gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestinal fluid (pH 6.8) The dissolution rate was tested in the following manner at each eluate condition.

A tablet containing a certain amount of niacin was tested for dissolution according to the pharmacopeia eighth tablet dissolution test method. Specifically, after precisely weighing the tablets prepared in Examples of the present invention and conventional commercial tablets in 900 ml of water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0) and artificial intestinal fluid (pH 6.8) eluent Paddle method (paddle method) (100rpm) was used, the dissolution test was carried out for 24 hours at 37 ± 1 ℃ dissolution temperature. After dissolution test was started, 15 ml, 30 minutes, 60 minutes, 90 minutes, and 2 hours, 1 ml of each eluate was taken up to 24 hours at 1 hour intervals, and the same amount of the dissolution solution was supplemented at the same time. The collected eluate was filtered through a 0.45 ㎛ membrane filter and then tested as the test solution under the following conditions.

<Experimental conditions>

Column: Kromasil KR100-5C18 (250 × 4.6 mm)

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: Methanol (4: 1) is 1L, and 1.1g of 1-octane sulfonate is added to make a mobile phase.

Wavelength: 262 nm

Flow rate: 1.0 ml / min

The dissolution test for oral tablets containing niacin prepared with the atorvastatin single tablet, double-layered tablet, and immediate release atorvastatin coating prepared in the above-described examples was carried out using 900 ml of water as a test solution. 50 revolutions per minute at 37 ± 1 ° C. After 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes from the start of the dissolution test, 20 ml of the eluate is taken and filtered through a 0.45 μm membrane filter. Discard the first 5 ml of the filtrate and use the following filtrate as the sample solution. With the test solution, the dissolution rate is calculated by measuring the absorbance at 244 nm using water as the control according to the absorbance measurement method in the general test method of the Pharmacopoeia.

The concentration of drug was first calculated from the standard calibration curve and converted into percent dissolution. Dissolution tests were performed on the tablets prepared in Examples of the present invention and conventional commercial tablets. And only the dissolution rate in water is shown in Table 22, Table 23, Table 24, Table 25.

% Of atorvastatin dissolution in water 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 123 11.7 32.8 58.7 85.1 91.4 Example 124 10.4 28.8 56.1 81.1 90.8 Example 125 17.2 39.8 63.4 95.1 100 Example 126 19.4 41.8 65.2 97.6 100 Commercially available tablets 15.7 40.1 62.1 90.2 100

Dissolution rate of atorvastatin in double-layered tablets in water (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 127 17.3 43.1 68.1 98.7 100 Example 128 17.5 43.5 68.9 98.5 100 Commercial Schedule 15.7 40.1 62.1 90.2 100

% Atorvastatin dissolution in coated niacin tablets in water 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 129 20.1 45.8 70.8 100 100 Example 130 20.4 47.5 71.3 100 100 Commercial Schedule 15.7 40.1 62.1 90.2 100

Niacin Dissolution Rate in Bilayer and Coated Tablets in Water (%) time Commercial Schedule Example 127 Example 128 Example 129 Example 130 15 minutes 7.1 2.5 2.8 2.7 2.4 30 minutes 12.5 7.2 7.5 6.9 6.7 60 minutes 17.1 11.0 11.1 11.4 10.9 90 minutes 21.4 14.9 15.1 15.8 16.0 2 hours 26.2     21.2 20.8 21.5 19.2 3 hours 33.4 26.7 26.3 25.9 25.8 5 hours 47.0 36.4 36.8 35.9 35.4 6 hours 52.5 41.1 41.5 41.3 41.1 8 hours 65.3 51.2 51.3 50.9 51.7 10 hours 76.4 60.9 62.5 62.4 61.9 12 hours 86.1 70.0 71.1 71.3 70.1 14 hours 96.4 76.5 76.8 75.3 75.8 15 hours 100.0 82.4 82.3 82.0 81.5 17 hours 89.1 88.6 88.7 88.0 18 hours 92.4 92.8 92.9 92.5 22 hours 99.1 99.2 98.7 98.6 24 hours 100 100 100 100

As shown in Table 22, the atorvastatin single tablet prepared in Examples of the present invention showed a similar pattern to commercially available tablets. In Table 23 and Table 24, atorvastatin in tablets containing immediate release HMG-CoA repression inhibitors and Western release niacin tablets, or sustained release niacin coated with HMG-CoA repression inhibitors, interact with drugs or additives. Similar results are obtained with the examples prepared in a single tablet without. In addition, in Table 25, niacin can account for the microscopic controlled release pattern in the stomach by suggesting a dissolution rate similar to or more sustained release at the initial time.

With the description of the invention described above, it becomes clear that the pharmaceutical compositions, formulations, compositions and methods described herein and the methods of use thereof can serve the purposes described above. Therefore, any variation of the pharmaceutical mixtures, formulations, compositions and methods of the present invention is within the scope of the invention as claimed, and therefore the choice of specific ingredient elements can be determined without departing from the spirit of the invention disclosed and described herein. For example, HMG-CoA reduction inhibitors, sustained release excipients, binders, and auxiliaries according to the present invention are not limited to those exemplified above.

Claims (16)

Niacin; HMG-CoA reduction inhibitors; pH-independent polymer bases; pH-dependent polymer bases; additive; Disintegrants; Glidants; Niacin-containing controlled release formulation, characterized in that it optionally contains a binder.
2. The formulation of claim 1 wherein the formulation consists of a first layer containing niacin and a second layer containing an HMG-CoA reduction inhibitor. Niacin-containing complex controlled release formulation, characterized in that it is a bilayer tablet.
The niacin-containing composite controlled release formulation according to claim 1, wherein the niacin-containing layer is coated with a HMG-CoA reduction inhibitor layer.
The method of claim 1, wherein the HMG-CoA reduction inhibitor is a niacin-containing controlled release formulation, characterized in that one selected from the group consisting of rosuvastatin, atorvastatin, lovastatin, fluvastatin, pitavastatin, pravastatin.
The method of claim 1, wherein the pH-independent polymer base is hydroxypropylmethylcellulose (Hydroxyproxylmethylcellulose), ethyl cellulose (Ethylcellulose), hydroxypropyl cellulose (Hydroxypropylcellulose), hydroxypropylmethylcellulose phthalate (Hydroxypropylmethylcellulose phthalate), hydroxy Niacine-containing complex controlled release formulation, characterized in that at least one selected from cellulose derivatives consisting of hydroxymethylmethyl acetylsuccinate and sodium carboxymethylcellulose.
The niacin-containing controlled release formulation according to claim 1, wherein the pH-dependent polymer base is at least one selected from a water-soluble salt of alginic acid or a carboxyvinyl polymer.
The disintegrant of claim 1, wherein the disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone, other commercially available polyvinylpolydone, low substituted hydroxypropylcellulose, alginic acid , Carboxymethyl cellulose calcium salt and sodium salt, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methyl cellulose, powdered cellulose, starch and sodium alginate alone or a mixture thereof, characterized in that the mixed control Release formulations.
2. The niacin-containing controlled release formulation according to claim 1, wherein the binder is a polymer having a repeating unit of 1-ethenyl-2-pyrrolidinone.
The niacin-containing controlled release formulation according to claim 1, wherein the lubricant is one selected from the group consisting of magnesium stearate, silica oxide, colloidal silicon dioxide, talc, and mixtures thereof.
According to claim 2, The formulation is 300 to 1000 parts by weight of niacin relative to the total weight of the formulation; 2 to 80 parts by weight of HMG-CoA reduction inhibitor; 5 to 300 parts by weight of hydroxypropylmethylcellulose or hydroxypropyl cellulose as a pH-independent polymer base; 5 to 100 parts by weight of sodium alginate and carboxyvinyl polymer as a pH-dependent polymer base; 5 to 200 parts by weight of sodium starch glycolate or crospovidone as a disintegrant; 0.1 to 20 parts by weight of magnesium stearate as a lubricant; 1 to 500 parts by weight of microcrystalline cellulose and lactose as additives; And optionally 1 to 20 parts by weight of the binder povidone.
According to claim 3, The formulation is 300 to 1000 parts by weight of niacin relative to the total weight of the formulation; 100 to 200 parts by weight of a coating comprising 2 to 80 parts by weight of a HMG-CoA reduction inhibitor as a coating agent; 5 to 300 parts by weight of hydroxypropylmethylcellulose or hydroxypropyl cellulose as a pH-independent polymer base; 5 to 100 parts by weight of sodium alginate and carboxyvinyl polymer as pH-dependent polymer bases; 5 to 200 parts by weight of sodium starch glycolate or crospovidone as a disintegrant; 0.1 to 20 parts by weight of magnesium stearate as a lubricant; 1 to 500 parts by weight of microcrystalline cellulose and lactose as additives; 0.01 to 5 parts by weight of butylhydroxyanisole or ascorbic acid as antioxidant; And optionally 1 to 20 parts by weight of a povidone as a binder.
The drug niacin; pH-independent polymer bases and pH-dependent polymer bases; A first step of uniformly mixing the additives and the disintegrant and adding a liquid solvent to prepare wet granules, drying and pulverizing them;
HMG-CoA inhibitors; additive; A second step of preparing the wet granules by mixing an antioxidant and adding a liquid solvent, drying and pulverizing it; And
A method for producing a niacin-containing complex controlled release formulation comprising the step of final mixing and lubricating the lubricant in each of the wet granules obtained in the first and second steps. The drug niacin; pH-independent polymer bases and pH-dependent polymer bases; Uniformly mixing the additives and the disintegrant and adding a liquid solvent to prepare wet granules, drying and pulverizing;
Preparing a niacin-containing tablet by mixing the lubricant with the wet granules; And
A method for preparing a niacin-containing complex controlled release formulation comprising coating the tablet with a coating agent in which an HMG-CoA inhibitor is mixed.
The method for producing a niacin-containing complex controlled release formulation according to claim 12 or 13, further comprising a binder in preparing the wet granules.
The method according to claim 12 or 13, wherein the liquid solvent is one or a mixed solvent selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol and polyethylene glycol.
The method according to claim 12 or 13, wherein the liquid solvent is water or a mixed solvent of water and ethanol, and the amount of the liquid solvent is 10 to 23% by weight of the main drug.

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