KR20070063350A - Pharmaceutical composition with extended release layer and fast release layer for treatment of hyperlipidemia and arteriosclerosis - Google Patents

Abstract

A pharmaceutical composition for treatment of hyperlipidemia and arteriosclerosis comprising an extended release layer and a fast release layer is provided to minimize influence on absorption of HMG-CoA(3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor caused by nicotinic acid, so that the HMG-CoA reductase inhibitor is rapidly released and absorbed into the human body. The pharmaceutical composition for treatment of hyperlipidemia and arteriosclerosis comprises the extended release layer containing an active compound mixed with an extended release polymer and the fast release layer surrounding or being separated from the extended release layer and containing an active compound mixed with a film-forming agent or a layer-forming agent, and a plasticizer, wherein the extended release layer continuously releases the active compound in water or medium having physiological pH for at least 12 hours, and the fast releasing layer releases 80% or more of the active compound in water or medium having physiological pH within 30 minutes; the active compound of the extended release layer is nicotinic acid, and the active compound of the fast release layer is the HMG-CoA reductase inhibitor such as simvastatin or atovastatin; and the fast release layer contains a recrystallization inhibitor such as polyvinylpyrrolidone.

Description

Pharmaceutical composition with extended release layer and fast release layer for treatment of hyperlipidemia and arteriosclerosis}

1 is a schematic diagram of the dissolution pattern of nicotinic acid from nicotinic acid sustained-release tablet containing the slow-release polymers of Examples 2, 3, and 4,

Figure 2 shows the dissolution pattern of simvastatin released from the simvastatin immediate release film or a separate layer of Examples 6, 13, 15, 17, 19,

Figure 3 shows the dissolution pattern of simvastatin released from the nicotinic acid sustained release layer and simvastatin immediate release layer composite of Example 27 and Comparative Example 1,

Figure 4 shows the dissolution pattern of simvastatin released from the nicotinic acid sustained release layer and simvastatin immediate release layer composite of Examples 41, 43 and Comparative Example 2,

5 shows the dissolution patterns of nicotinic acid and simvastatin released from the nicotinic acid sustained release layer and simvastatin immediate release layer composite of Examples 44 and 45;

Figure 6 shows the elution pattern of atorvastatin released from the nicotinic acid sustained release layer and the atorvastatin immediate release layer composite of Examples 50, 51 and Comparative Example 3.

The present invention is a tablet form consisting of HMG-CoA reductase inhibitor in a sustained release coating or a separate layer in the sustained release layer of nicotinic acid and nicotinic acid compound or mixtures thereof, thereby suppressing drug interaction as much as possible in hyperlipidemia and atherosclerosis. It relates to a pharmaceutical composition exhibiting an optimal therapeutic effect.

Hyperlipidemia is a disease characterized by elevated levels of low-density lipoprotein-cholesterol and serum total cholesterol in blood and is closely associated with the incidence of atherosclerosis and cardiovascular disease. It is known that the reduction of serum lipids, especially low-density lipoprotein-cholesterol, may lower the likelihood of developing cardiovascular diseases and lower serum lipids, which may delay the progression of atherosclerosis or lead to the degeneration of atherosclerosis. . Therefore, hypolipidemic therapy is needed to reduce the risk of cardiovascular disease in individuals with hyperlipidemia. People with hyperlipidemia have high triglyceride levels, so lowering triglyceride levels is known to indirectly lower cholesterol. Therefore, there is a need for a treatment that lowers triglycerides to reduce the incidence of atherosclerosis and coronary artery disease.

Low-density lipoproteins carry blood cholesterol into the vascular endothelial wall, where the low-density lipoprotein-cholesterol is peroxidized under the vascular endothelial to form a thrombus of atherosclerosis. On the other hand, high density lipoprotein-cholesterol is known to inhibit thrombus formation and delay or prevent cardiovascular disease and atherosclerosis symptoms.

These studies have suggested methods for lowering cholesterol and raising high-density lipoprotein-cholesterol levels to treat hyperlipidemia, arteriosclerosis, or cardiovascular disease.

Representative drugs for treating hyperlipidemia or hypercholesterolemia include HMG-CoA reductase inhibitors that inhibit the biosynthesis of lipoproteins or lipids in serum or plasma. Examples of HMG-CoA reductase inhibitors are mevastatin, lovastatin, pyrastatin, velostatin, simvastatin, rivastatin, fluvastatin, atorvastatin and cerivastatin. Other drugs that lower cholesterol in the serum include nicotinic acid, bile acid blockers such as cholestyramine, cholestipol DEAE cefadex, probucol and related compounds, lipostavill, esai E5050, imanicil, tetrahydrolipsatin, ishi Tigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814, melinamide, Sandoz 58-035, american cinnamid CL-277,082 and CL-283,546, ronitol, neomycin, p-aminosalicylic acid, aspirin And quaternary amine poly (diallyldimethylammonium chloride) and ionone, poly (diarylmethylamine) derivatives, omega-3-fatty acid and fibric acid derivatives contained in various fish oil supplements.

Nicotinic acid is a substance that has been used for a long time in the treatment of hyperlipidemia or hypercholesterolemia. Nicotinic acid is shown to have an effect of increasing total cholesterol, ultra low density lipoprotein-cholesterol and ultra low density lipoprotein-cholesterol residues, low density lipoprotein-cholesterol, triglycerides and apolipoproteins, while increasing high density lipoprotein-cholesterol. Known.

Conventionally, nicotinic acid was administered three times a day for immediate release formulations, but skin fever symptoms and the like often occurred in hyperlipidemic patients to which immediate release formulations were administered. Sustained release formulations have been required to prevent or alleviate the side effects of such immediate release nicotinic acid formulations. Sustained release formulations can be designed to release the active ingredient slowly, thereby reducing the usual frequency of administration of conventional dosage forms or immediate release formulations. Nicotinic acid sustained release formulations can solve the problems of conventional immediate release nicotinic acid formulations by lowering and prolonging drug levels in the blood.

Meanwhile, HMG-CoA reductase inhibitors have long been used as drugs for treating hyperlipidemia. These compounds have the effect of inhibiting the biosynthesis of lipoproteins or lipids in serum or plasma and elevating high density lipoprotein-cholesterol levels in some individuals.

The two drugs, which have long been used for the treatment of hyperlipidemia, have been developed in some combinations.

European Patent No. 373,507 discloses a simple combination for the treatment of hyperlipidemia and arteriosclerosis by a combination of an HMG-CoA reductase inhibitor and an HMG-CoA reductase biosynthesis inhibitor, and US Patent No. 5,260,305 also discloses HMG-CoA. It is a combination of revastatin inhibitors pravastatin and nicotinic acid or nicotinic acid derivatives acipimox, acifran, nicotinic acid-N-oxide-2-t-butyl-4-cyclohexylphenyl ester International Patent No. 5817 describes a combination of an HMG-CoA reductase inhibitor with an inducer, inhibitor or substrate of p450 isoenzyme 3A4, which is simply a derivative, inhibitor or substrate of p450 isoenzyme 3A4. It's just a combination that contains niacin among the many substances in it.

US Patent No. 6,090,830 discloses HMG-CoA reductase inhibitors and nicotinic acid microsphere compositions. HMG-CoA reductase inhibitor microspheres were characterized by the use of a solubilizer in the preparation, and to achieve controlled release by coating separately for nicotinic acid.

International Publication No. 3,103,640 is characterized by the production of nanoparticles by miniaturization of the particle size of the HMG-CoA reductase inhibitor and the application of the HMG-CoA reductase inhibitor by particle control. These patents have a problem that the preparation process for improving the slow and low dissolution rate of the HMG-CoA reductase inhibitor, or the manufacturing process, such as forming a micro or nano-particle particles and coating a controlled release membrane again, and low productivity.

The invention disclosed in U.S. Patent No. 6,469,035 is characterized by the use of a fever inhibitor to suppress skin fever symptoms caused by nicotinic acid administration of hyperlipidemia and atherosclerosis. However, the patent is a technique for administering a nonsteroidal anti-inflammatory agent as a skin pyrogen inhibitor only when the nicotinic acid agent and the HMG-CoA reductase inhibitor are administered through different formulations.

U.S. Patent No. 4,053,975 and International Publication No. 9906035 disclose the administration of a HMG-CoA reductase inhibitor and nicotinic acid complex once daily at night, but the U.S. Kospharm commercialized by the above patent (KOS pharm) According to the clinical pharmacology and biopharmaceutics review submission to the FDA of Nicostatin ^® , the bioavailability of Mevacor ^® , a lovastatin monotherapy, and Nicostatin ^® , a combination of nicotinic acid and lovastatin In the comparative test, the combination showed only about 75% lovastatin Cmax and about 88% AUC compared to lovastatin alone administration.

The present inventors from the above comparative test results show that the lovastatin single agent shows the form of immediate dissolution rate, whereas in the nicotinic acid and lovastatin combination formulations, the lovastatin component is eluted over about 1 hour, thereby affecting the absorption and metabolism of lovastatin and thus bioavailability It is found that there is a problem that indicates the difference between.

In order to solve the above problems, the present inventors have studied that the HMG-CoA reductase inhibitor statin-type drugs can be released immediately, and thus HMG-CoA induced by nicotinic acid is administered even when the HMG-CoA reductase inhibitor and nicotinic acid complexes are administered. The present invention has been completed by developing an agent that minimizes the effect on the absorption of the reductase inhibitor so that the HMG-CoA reductase inhibitor is rapidly eluted and absorbed.

The present invention provides an agent which allows the HMG-CoA reductase inhibitor to be rapidly eluted and absorbed by minimizing the effect of the absorption of the HMG-CoA reductase inhibitor by nicotinic acid even when the HMG-CoA reductase inhibitor and the nicotinic acid complex preparation are administered. It aims to do it.

In order to achieve the above object, the present invention surrounds the sustained release layer with a sustained release layer, and an outer layer in which an effective amount of the nicotinic acid and nicotinic acid compound or a mixture thereof is present as a mixture with the sustained release polymer, or a separate layer. In the form of a layered tablet, an immediate release layer is essentially a pharmaceutical product in the form of a tablet comprising an immediate release layer in which an effective drug amount of the HMG-CoA reductase inhibitor is present as a mixture with a film-forming or layer-forming agent and a plasticizer. It provides a pharmaceutical composition for the treatment and prevention of hyperlipidemia and atherosclerosis, characterized by the use of anti-recrystallization agent in the interior.

In addition, the present invention is a sustained release layer of the composite formulation containing the pharmaceutical composition is continuously released for at least 12 hours in a medium of water or physiological pH, the immediate release layer is in a medium of water or physiological pH Provided is a composite formulation that exhibits an elution pattern of at least 80% within 30 minutes.

Hereinafter, the present invention will be described in detail.

The present invention is a pharmaceutical composition for the treatment and prevention of hyperlipidemia and arteriosclerosis,

The sustained release layer contains a) an effective amount of nicotinic acid and a nicotinic acid compound or a mixture thereof, b) one or more sustained release polymers,

The immediate release layer comprises a coating or a separate layer, c) an effective drug amount of at least one HMG-CoA reductase inhibitor, d) at least one filming or layering agent, and e) at least one plasticizer. ,

f) Sustained release nicotinic acid and nicotinic acid compounds or mixtures thereof, containing essentially one or more anti-recrystallization agents, have the property of sustained release for at least 12 hours in a medium of water or physiological pH, and immediate release HMG- CoA reductase inhibitors are directed to pharmaceutical compositions characterized by an elution pattern of at least 80% within 30 minutes in a medium of water or physiological pH.

It is an object of the present invention to provide oral administration for the treatment of hyperlipidemia and atherosclerosis, including sustained release nicotinic acid, nicotinic acid derivatives, compounds metabolized in the body to form nicotinic acid, and mixtures thereof and immediate release HMG-CoA reductase inhibitors. To provide a pharmaceutical composition for oral solid pharmaceutical compositions that can exhibit the optimal therapeutic effect by minimizing the inappropriate interaction of the two drugs.

The pharmaceutical composition is administered in an amount effective to alter or decrease serum lipid levels such as total cholesterol, VLDL-cholesterol, LDL-cholesterol, apolipoprotein and triglyceride levels, and to enhance or increase HDL-cholesterol levels.

An example of an effective dose of an HMG-CoA reductase inhibitor that alters lipids is from about 0.05 mg to about 160 mg. Preferably in the range of about 0.05 mg to 80 mg, more preferably in the range of about 0.2 mg to about 40 mg and for nicotinic acid about 250 mg to about 3000 mg, preferably about 500 mg to about 2500 mg, most preferably Was satisfactory when used in combination with a dose of nicotinic acid used in the range of about 1000 mg to about 2000 mg, wherein the HMG-CoA reductase inhibitor and nicotinic acid were in the same oral formulation, or at the same time or nearly Used together in separate oral dosage forms administered simultaneously. This amount depends on a number of variables, including the physiological needs of the patient to be treated. Therefore nicotinic acid can be administered daily in increments of, for example, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg and HMG-CoA reductase inhibitors are for example 2.5 mg, 5 mg, 10 mg. , 20 mg, 40 mg.

Thus, according to the present invention, solid oral dosage forms such as tablets are effective amounts of nicotinic acid and nicotinic acid compounds or mixtures thereof and HMG-CoA reductase inhibitors of 250 mg / 2.5 mg, 500 mg / 2.5 mg, 750 mg / 2.5 mg, 1000 mg / 2.5 mg, 2000 mg / 2.5 mg, 250 mg / 5 mg, 500 mg / 5 mg, 750 mg / 5 mg, 1000 mg / 5 mg, 2000 mg / 5 mg, 250 mg / 7.5 mg, 500 mg / 7.5 mg, 750 mg / 7.5 mg, 1000 mg / 7.5 mg, 2000 mg / 7.5 mg, 250 mg / 10 mg, 500 mg / 10 mg, 750 mg / 10 mg, 1000 mg / 10 mg, 2000 mg / 10 mg, 250 mg / 20 mg, 500 mg / 20 mg, 750 mg / 20 mg, 1000 mg / 20 mg, 2000 mg / 20 mg, 250 mg / 40 mg, 500 mg / 40 mg, 750 mg / 40 mg and 1000 mg / 40 mg, 2000 mg / 40 mg dosage units.

Specific examples of nicotinic acid and nicotinic acid compounds or mixtures thereof in the present invention include nicotinic acid, nicotinyl alcohol tartrate, D-glucinitol hexanicotinate, aluminum nicotinate, niceritrol, DL-alpha-tocopheryl nicotine. Tinate, 6-OH-nicotinic acid, nicotinic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl- Of nicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradilian, sorbinate, hexanisite, ronitol and nicotinic acid Esters such as, but not limited to, lower alcohol esters such as methyl esters, ethyl esters, propyl esters or butyl esters. Such derivatives or compounds are referred to as nicotinic acid compounds.

The sustained release layer of the nicotinic acid and nicotinic acid compound or mixture thereof in the present invention is sustained release through formulation immediately after mixing the main component and the sustained release release polymer without association or association using a binder and a binder solution. The castle can be secured. The composition can be administered orally to a patient to release the active ingredient nicotinic acid or nicotinic acid compound or mixtures thereof over time by the sustained release polymer.

The sustained release polymer according to the present invention enables release control of at least 6 hours or more, preferably 12 hours or more, so as to reduce side effects due to rapid blood concentration increase in immediate release and to extend the drug duration. . That is, it is possible to keep the release rate of the nicotinic acid or nicotinic acid compound or a mixture thereof as a main component constant until release of about 80% or more is achieved. Sustained release polymers suitable for the present invention include hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, and hydroxy derivatives of cellulose. Hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, alkyl hydroxypropyl methyl cellulose, polysaccharide-based corn starch, potato starch and gelatinized starch and its derivatives hydroxyethyl starch, dextrin and its derivatives dextran , Maltodextrin, polydextrose, alginic acid alkali metal salts of alginic acid series, guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum, casein, tara gum, tamarind gum, traga Gacan gum, Gatti gum, Peptides, Gelatin, Collagen, Prota , Zein, acrylic acid, carbomer, polyacrylamide, other polyvinyl acetal diethan amino acetate, glucomannan, glucosamine, arabinogalatan, percelanan, furan, polyurethane, chitosan, chitin, agar, pectin, Carrageenan, etc., but not limited to these. Sustained release polymers may be used in an amount of about 1% to about 70% by weight, preferably about 10% to about 50% by weight, based on 100 parts by weight of the tablet or formulation. To ensure a sustained release time.

In addition, the sustained release layer of the nicotinic acid and nicotinic acid compound or a mixture thereof of the present invention may further use one or more kinds of pharmaceutically acceptable diluents, binders, disintegrants, pigments, preservatives, foaming agents, lubricants and the like. It is also possible to use excipients which have a combination of functions.

The diluent that can be used in the present invention may be used at least one selected from lactose, dextrose, microcrystalline cellulose, starch and the like, and at least one selected from hydroxypropyl cellulose (low molecule), povidone and the like may be used as the binder. In the disintegrant, at least one selected from sodium croscamelloose, sodium starch glycolic acid, crosslinked polyvinylpyrrolidone, gelatinized starch, low-substituted hydroxypropyl cellulose, and the like are selected from water-soluble and tar dyes. At least one selected from benzoic acid, methyl paraben, ethyl paraben, propyl paraben, and the like as the preservative, at least one selected from calcium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium glycerine, and the like; Magnesium stearate, talc, light silicic anhydride, sucrose fatty acid ester, glycerol At least one selected from reel behenate and the like may be used, but is not limited thereto.

Sustained release compositions containing the nicotinic acid and nicotinic acid compounds or mixtures thereof of the present invention are coated with immediate release HMG-CoA reductase inhibitors or formed in separate layers. However, the immediate release layer may be a direct coating layer, and may be composed of a separate layer and may have an additional one or more protective layers containing no drug, and the immediate release layer is formed by a conventional method inside or outside. do.

Examples of HMG-CoA reductase inhibitors of the present invention include, but are not limited to, mevastatin, lovastatin, pyrastatin, belostatin, simvastatin, rivastatin, fluvastatin, atorvastatin, cerivastatin, and the like. .

In the present invention, a film forming agent or a layer forming agent is used to form the HMG-CoA reductase inhibitor immediate release coating or a separate layer in the sustained release layer of nicotinic acid and nicotinic acid compound or mixtures thereof. The film-forming agent or layer-forming agent contains an HMG-CoA reductase inhibitor to attach to the nicotinic acid or nicotinic acid compound or a mixture of sustained release release layers to form a coating or a separate layer to enable the composition of the two components.

Specific examples of the film-forming or layer-forming agent include microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxyethyl methyl as cellulose series. Cellulose, hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, alkyl hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate, cellulose acetate phthalate, polysaccharide Corn starch, potato starch, gelatinized starch and its derivatives, hydroxyethyl starch, dextrin and its derivatives dextran, maltodextrin, polydextrose, guar gum, locust bean gum, xanthan gum, seaweed Clodextrin, gum arabic, gellan gum, karaya gum, casein, tara gum, tamarind gum, tragacanth gum, gati gum, gelatin as peptide series, collagen, protamine, zein, acrylic acid carbomer, polyacrylamide, Examples of waxes include carnauba wax, non-wax, sucrose, liquid sucrose, lactose, polyvinyl acetal diethamino acetate, other polyurethanes, chitosan, chitin, agar, pectin, carrageenan, shellac, and the like. It is not limited to. Exemplary amounts of the film former or layering agent of the present invention range from about 0.01% to about 50% by weight of the tablet and preferably range from 0.5% to about 10% by weight.

In the present invention, a recrystallization inhibitor is used to secure the immediate release of the HMG-CoA reductase inhibitor. Since all HMG-CoA reductase inhibitors are poorly soluble drugs that are difficult to dissolve in water, it is highly recommended that the HMG-CoA reductase inhibitor inhibit the recrystallization that may be involved in the manufacturing process or product storage together with the dispersion of the drug through the film-forming or layer-forming agent. It is important. The change or precipitation of the poorly soluble drug into the crystalline form is continuously carried out over a long period of time, and the crystallization of the produced drug does not show a rapid dissolution due to a very slow dissolution rate in water and causes a dissolution rate itself.

In addition, even if it does not suppress the change to the crystalline form and known in the art to add a conventional surfactant to form a coating or a separate layer, the dissolution rate as well as the dissolution rate of the HMG-CoA reductase inhibitor has an obvious limitation. In other words, the poorly soluble drug is dissolved in an organic solvent having good solubility, and then volatilized to crystallize again to show poor solubility. After dissolving the HMG-CoA reductase inhibitor in the film-forming or layer-forming agent and the organic solvent, forming a film or separate layer and volatilizing the solvent, the drug is precipitated again in the film or the separate layer to show poor solubility. There is a big problem in reducing the speed to achieve immediate release. Recrystallization of the drug reduces the thermodynamic activity, reducing the solubility of the drug, and may present problems with the stability of the composition for long term storage.

In the present invention, in order to suppress such a recrystallization phenomenon, by mixing or dissolving a recrystallization agent homogeneously with the drug and forming it in a film or a separate layer, rapid HMG-CoA cannot be achieved by the composition of a conventional film or a separate layer. Elution of reductase inhibitors has proved possible.

HMG-CoA reductase inhibitors are present in the coating or in separate layers by the film-forming or layer-forming agents, but the solubility between drug particles acts to form crystal nuclei which gradually recrystallize and decrease solubility. The dissolution rate of is reduced. Recrystallization inhibitors act on HMG-CoA reductase inhibitor particles in the coating or in separate layers to prevent drug particles from forming nuclei, thereby inhibiting recrystallization to secure drug dissolution rates in the coating or in separate layers. To be achieved.

Specific examples of the anti-recrystallization agent in the present invention include polyvinylpyrrolidone-based polyvinylpyrrolidone, crospovidone, polyvinylpyrrolidone vinyl acetate copolymer, dextrin derivatives, and cyclodextrin, dimethylcyclodextrin, and hydroxyethyl. Cyclodextrins, hydroxypropyl cyclodextrins, trimethyl cyclodextrins, alkylene oxide-based poloxamers and polyethylene glycols, polyethylene oxides, acrylate-based polymethacrylates and derivatives thereof (trade name: Eudragit series), poly Saccharide-based alginic acid and its alkali metal salts, polyvinyl acetate, but are not limited to these. Exemplary amounts of anti-recrystallization agents of the present invention range from about 0.01% to about 30% by weight of the tablet and preferably range from 0.5% to about 10% by weight.

In the present invention, a plasticizer is used to secure the film or separate layer formation and immediate release of the HMG-CoA reductase inhibitor. In the present invention, the plasticizer is a component that affects the plasticity, tension, and adhesion of the immediate release film or a separate layer to help the film forming force and impart flexibility to the film. Film-forming agents or layer-forming agents tend to aggregate into three-dimensional shapes when forming films or separate layers, but plasticizers are more preferably formed by providing plasticity by removing the firmness of film-forming agents or layer-forming agents. Or to allow a separate layer to be formed. The role of this plasticizer also allows HMG-CoA reductase inhibitors, which are present as membrane formers or layer formers, to be more homogeneously arranged in the coating or in separate layers, and the coating or separate layers can be dissolved or dissolved in a short time. By allowing it to be separated, it serves to help immediate release of the present invention.

Specific examples of the plasticizer in the present invention include polyglyceryl fatty acid esters, polyoxyethylene glyceryl fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyethylene glycol and polyethylene glycol fatty acid esters, polyoxyethylene Castor oils, polyoxyethylene alkyl ethers, polyoxyethylene phytosterols, polyoxyethylene alkyl phenyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene lanolin, polyoxyethylene alkyl ether phosphates, Propylene Glycol and Propylene Glycol Fatty Acids, Glycerol Fatty Acid Ester, Fatty Acid Matrogol Glyceride, Glyceryl Monolinoleate, Glyceryl Monooleate, Diethylene Glycol Monoethyl Ether, Benzylbenzoate, Chlorobutanol, Dibu Sugars such as sebacate, diethyl phthalate, glycerin, mineral oils and lanolin alcohols, petroleum and lanolin alcohols, triacetin and triethyl citrate, sodium lauryl sulfate, docuate sodium, sorbitol, mannitol, and the like. It doesn't happen.

In addition, the HMG-CoA reductase inhibitor immediate release coating or a separate layer of the present invention may be used by additionally selecting one or more from pharmaceutically acceptable disintegration accelerators, antioxidants, dusting agents, light agents, light-shielding agents, colorants, and the like. And excipients having the above functions in combination.

The disintegration accelerator that can be used in the present invention is at least one selected from primogel, Avicel and the like, and the antioxidant is at least one selected from ascorbic acid, butylated hydroxy anisole, citric acid, tocopherol and derivatives and compounds thereof, At least one selected from talc, precipitated calcium carbonate, magnesium stearate, calcium sulfate, powdered sugar, particulate silicic anhydride, calcium phosphate, starch, etc. for the spreading agent, at least one selected from carnauba wax, beeswax, etc. One or more selected from titanium, zinc oxide, water soluble and tar pigments may be used, but is not limited thereto.

The pharmaceutical composition is prepared by the following process, but is not limited thereto.

First, the nicotinic acid and nicotinic acid compound or mixtures thereof and the sustained release polymer are mixed and then sieved with a standard mesh of 30 mesh or more as necessary to homogenize the mixture. The mixture is combined to produce wet granules or compression molded using a tableting machine without the wet granulation process. If necessary, one or more kinds of diluents, disintegrants, colorants, coloring agents, preservatives, foaming agents, lubricants, and the like may be added.

Separately, HMG-CoA reductase inhibitor is dissolved in a suitable organic solvent to completely dissolve, and a film forming agent, a layer forming agent or a recrystallization inhibitor is added to dissolve or disperse homogeneously. If necessary, it may be prepared by adding one or more of a plasticizer, a disintegration accelerator, an antioxidant, a dusting agent, a light shielding agent, a light shielding agent, and a colorant. As described above, after the preparation of the coating solution, a sustained-release tablet containing nicotinic acid and the nicotinic acid compound or a mixture thereof is sprayed with a coating solution at a constant rate to volatilize the solvent to contain a prescribed amount of HMG-CoA reductase inhibitor per tablet. The coating may be carried out to obtain a pharmaceutical composition according to the present invention. However, the immediate release layer prepared as described above may have an additional one or more protective layers containing no drug inside or outside.

Sustained-release nicotinic acid and nicotinic acid compounds or mixtures thereof of the pharmaceutical compositions completed in the present invention have the property of sustained release for at least 6 hours, preferably 12 hours, in a medium of water or physiological pH. Sexual HMG-CoA reductase inhibitors have the property of rapidly releasing within 30 minutes and preferably within 15 minutes in water or physiological pH media. By achieving these opposing release properties, the HMG-CoA reductase inhibitor released in the pharmaceutical composition of the present invention can minimize the interaction of nicotinic acid or nicotinic acid compounds and mixtures thereof in the gastrointestinal tract and reduce bioavailability. Can improve the problem.

In contrast to the above release rate, the release rate is 12 times or more, preferably 24 times or more, more preferably, until 80% of the active material of the immediate release layer and the sustained release layer is released in comparison with the rate. The pharmaceutical composition should be at least 36 times different.

Hereinafter, the present invention will be described in detail through examples. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited to these.

<Examples 1 to 4>

Examples 1-4 prepared a number of sustained release tablets of nicotinic acid and nicotinic acid compounds or mixtures thereof. The components and contents of the composition are as described in Table 1 below.

Pharmaceutical Compositions of Examples 1-4 (Unit: mg) Example 1 Example 2 Example 3 Example 4 Nicotinic acid 375 500 750 1000 HPMC 2208 97.5 130 130 130 Polyethylene oxide 30 40 40 40 Silicone dioxide 15 20 20 20 Sodium Bicarbonate 11.25 15 15 15 Stearic acid 11.25 15 15 15 Total 540 720 970 1220

All components except stearic acid were mixed as a lubricant, sieved through a 30 mesh standard mesh, and mixed with a lubricant to prepare a tablet.

<Examples 5 to 19>

For Examples 5 to 19, first, simvastatin, hydroxypropylmethylcellulose 2910 as a film forming agent or a layer forming agent, and polyethylene glycol 6000 as a plasticizer, ethanol and dichloromethane as solvents, as shown in Tables 2, 3, and 4 below. And dissolved in povidone, copovidone, poloxamer, Eudragit, HP-beta-cyclodextrin, respectively, and 5 mL of the prepared solution was taken in 4 cm diameter petri dishes, and the solvent was evaporated under reduced pressure at 60 ° C. Was prepared.

Pharmaceutical Compositions of Examples 5-90 (Unit: mg) Example 5 Example 6 Example 7 Example 8 Example 9 Simvastatin 20 20 20 20 20 HPMC 2910 40 40 40 40 40 PEG 6000 4 4 4 4 4 Povodone 5 - - - - Copovidone - 5 - - - Poloxamer 407 - - 5 - - Eudragit EPO - - - 5 - HP-β-Cyclodextrin - - - - 5 Ethanol 4 4 4 4 4 Methylene Chloride One One One One One

Pharmaceutical Compositions of Examples 10-14 (Unit: mg) Example 10 Example 11 Example 12 Example 13 Example 14 Simvastatin 20 20 20 20 20 HPMC 2910 40 40 40 40 40 PEG 6000 4 4 4 4 4 Povodone 10 - - - - Copovidone - 10 - - - Poloxamer 407 - - 10 - - Eudragit EPO - - - 10 - HP-β-Cyclodextrin - - - - 10 Ethanol 4 4 4 4 4 Methylene Chloride One One One One One

Pharmaceutical Compositions of Examples 15-19 (Unit: mg) Example 15 Example 16 Example 17 Example 18 Example 19 Simvastatin 20 20 20 20 20 HPMC 40 40 40 40 40 PEG 6000 4 4 4 4 4 Povodone 20 - - - - Copovidone - 20 - - - Poloxamer 407 - - 20 - - Eudragit EPO - - - 20 - HP-β-Cyclodextrin - - - - 20 Ethanol 4 4 4 4 4 Methylene Chloride One One One One One

  * However, organic solvent is volume unit (mL).

<Example 20 to Example 25>

For Examples 20 to 25, simvastatin and hydroxypropylmethylcellulose 2910 as a film-forming or layer-forming agent, copovidone, povidone, Eudragit EPO, polyethylene glycol 6000 as a plasticizer, A coating solution (I) was prepared by using citric acid triethyl, polysorbate 80, sorbitol, and using ethanol and dichloromethane as a solvent. The prepared coating solution (I) was sieved through a 100 mesh standard network, and the core tablet prepared in Example 2 was coated with a coater.

Pharmaceutical Compositions of Examples 20-25 (Unit: mg) Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Nuclear Example 2 720 720 720 720 720 720 I Simvastatin 20 20 20 20 20 20 HPMC 2910 40 10 30 20 20 20 Copovidone 5 20 30 30 - - Eudragit EPO - - - - 30 - Povidone - - - - - 30 PEG 6000 4 4 - - - - TEC - - 7.5 10 10 10 Polysorbate 80 - 6 7.5 10 10 10 Sorbitol - - 10 20 20 20 Total 789 780 825 830 830 830

<Example 26 to Example 31>

For Examples 26 to 31, hydroxypropylmethylcellulose 2910 as a film forming agent or a layer forming agent, polyethylene glycol 6000 as a plasticizer, titanium oxide as a colorant, and ethanol and dichloromethane as solvents, as shown in Table 6 below. To prepare a coating solution (I) for a protective film containing no drug. Separately, simvastatin, hydroxypropylmethylcellulose 2910 as a film-forming or layer-forming agent, copovidone, eudragit EPO as recrystallization agent, polyethylene glycol 6000 as plasticizer, triethyl citrate, talc as other excipients, and ethanol as solvent. And coating solution (II) was prepared using dichloromethane. The prepared coating liquids (I) and (II) were sieved through a standard mesh of 100 mesh, and the core tablets prepared in Example 3 were first coated with the coating liquid (I), and subsequently coated with the coating liquid (II).

Pharmaceutical Compositions of Examples 26-31 (Unit: mg) Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Nuclear Example 3 970 970 970 970 970 970 I HPMC 2910 2 2 2 2 2 2 PEG 6000 0.4 0.4 0.4 0.4 0.4 0.4 TiO2 0.4 0.8 0.8 0.4 0.4 0.4    Ⅱ Simvastatin 20 20 20 20 20 20 HPMC 2910 10 10 25 10 10 10 Copovidone 40 40 25 30 - - Eudragit EPO - - - - 30 - Povidone - - - - - 30 PEG 6000 20 20 20 7.5 7.5 7.5 TEC - 10 10 7.5 7.5 7.5 Talc 20 20 20 10 10 10 Total 982.8 993.2 993.2 957.8 957.8 957.8

<Examples 32 to 34>

For Examples 32 to 34, hydroxypropylmethylcellulose 2910 as a film forming agent or a layer forming agent, polyethylene glycol 6000 as a plasticizer, titanium oxide as a colorant, ethanol and dichloromethane as a solvent were used. To prepare a protective coating (I) containing no drug. Separately, simvastatin, hydroxypropylmethylcellulose 2910 as a film-forming or layer-forming agent, copovidone, povidone, eudragit, citric acid triethyl as a plasticizer, sorbitol, butylated hydroxy anisole as an antioxidant, citric acid , Coating solution (II) was prepared using talc as another excipient and ethanol and dichloromethane as a solvent. The prepared coating liquids (I) and (II) were sieved through a standard mesh of 100 mesh, and the core tablets prepared in Example 2 were first coated with the coating liquid (I), and subsequently coated with the coating liquid (II). The tablets were dried for a period of time and then coated again to increase by 3 mg by using the coating solution (I).

Pharmaceutical Compositions of Examples 32-34 (Unit: mg) Example 32 Example 33 Example 34 Nuclear Example 2 720 720 720 I HPMC 2910 2 2 2 PEG 6000 0.4 0.4 0.4 TiO2 0.6 0.6 0.6     Ⅱ Simvastatin 20 20 20 HPMC 2910 10.46 10.46 10.46 Copovidone 30 - - Eudragit EPO - 30 - Povidone - - 30 TEC 5 5 5 Sorbitol 20 20 20 BHA 0.04 0.04 0.04 Citric acid 2.5 2.5 2.5 Talc 10 10 10 Ⅲ Coated with Ⅰ 3 3 3 Total 824 824 824

<Examples 35 to 40>

For Examples 35 to 40, simvastatin, hydroxypropylmethylcellulose 2910, hydroxyethylcellulose, copovidone, povidone, Eudragit EPO, plasticizer as a film forming agent or layer forming agent, as shown in Table 8 below. The coating solution (I) was prepared by using polyethylene glycol 6000, triethyl citric acid, butylated hydroxy anisole as citric acid, citric acid, talc, titanium oxide as other excipients, and ethanol and dichloromethane as solvents. The prepared coating solution (I) was sieved through a 100 mesh standard mesh and coated with the core tablet prepared in Example 2.

Pharmaceutical Compositions of Examples 35-40 (Unit: mg) Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 Nuclear Example 2 720 720 720 720 720 720 I Simvastatin 20 20 20 20 20 20 HPMC 2910 10.96 - 10.96 - - - HEC - 10.96 - 10.96 10.96 10.96 Copovidone 40 40 30 5 - - Eudragit EPO - - - - 30 - Povidone - - - - - 30 PEG 6000 30 30 20 10 20 20 TEC 20 20 10 5 10 10 BHA 0.04 0.04 0.04 0.04 0.04 0.04 Citric acid 2.5 2.5 - - - - TiO2 - - 5 2 5 5 Talc 20 20 - - - - Total 862 862 816 773 816 816

<Example 41 to Example 46>

For Examples 41 to 46, simvastatin and hydroxypropylmethylcellulose 2910, hydroxyethylcellulose, copovidone, povidone, Eudragit EPO, Polyethylene glycol 6000 as a plasticizer, triethyl citrate, sodium lauryl sulfate, docuate sodium, butylated hydroxy anisole as antioxidant, titanium oxide as colorant, ethanol and dichloromethane as solvent, coating liquid (I) Was prepared. The prepared coating solution (I) was sieved through a 100 mesh standard mesh and coated with the core tablet prepared in Example 3.

Pharmaceutical Compositions of Examples 41-46 (Unit: mg) Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Nuclear Example 3 970 970 970 970 970 970     I Simvastatin 20 20 20 20 20 20 HPMC 2910 - - 9.96 9.96 9.96 9.96 HEC 10.96 10.56 - - - - Copovidone 30 30 30 30 - - Eudragit EPO - - - - 30 - Povidone - - - - - 30 PEG 6000 20 20 20 20 20 20 TEC 10 10 10 10 10 10 SLS 15 7 15 10 10 10 Docusate sodium - 2.4 2.5 3 3 3 BHA 0.04 0.04 0.04 0.04 0.04 0.04 TiO2 5 5 5 5 5 5 Total 980 975 983 978 978 978

<Example 47 to Example 52>

For Examples 47-52, as shown in the following Table 10, atortostatin and hydroxypropylmethylcellulose 2910 as a film-forming or layer-forming agent, hydroxyethyl cellulose, copovidone, povidone, eudragit as recrystallization inhibitors. EPO, polyethylene glycol 6000 as a plasticizer, triethyl citrate, sodium lauryl sulfate, docuate sodium, butylated hydroxy anisole as antioxidant, titanium oxide as colorant and ethanol and dichloromethane as solvent I) was prepared. The prepared coating solution (I) was sieved through a 100 mesh standard mesh and coated with the core tablet prepared in Example 2.

Pharmaceutical Compositions of Examples 47-52 (Unit: mg) Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Nuclear Example 2 720 720 720 720 720 720     I Attorvastatin 10 10 10 10 10 10 HPMC 2910 - - 4.98 4.98 4.98 9.96 HEC 5.48 5.28 - - - - Copovidone 15 12.5 12.5 12.5 - - Eudragit EPO - - - - 12.5 - Povidone - - - - - 25 PEG 6000 10 10 10 10 10 20 TEC 5 5 5 5 5 10 SLS 7.5 3.5 7.5 5 5 10 Docusate sodium - 1.2 1.25 1.5 1.5 3 BHA 0.02 0.02 0.02 0.02 0.02 0.04 TiO2 2.5 2.5 2.5 2.5 2.5 5 Total 775 770 774 771.5 771.5 771.5

<Comparative Example 1 to Comparative Example 3>

For Comparative Examples 1 to 3, simvastatin and hydroxypropylmethylcellulose 2901 as a film-forming or layer-forming agent, polyethylene glycol 6000 as a plasticizer, sodium lauryl sulfate, docuate sodium, butyl-lay as antioxidant, as shown in Table 11 below. Tide hydroxy anisole, a coating solution (I) was prepared using titanium oxide as a colorant and ethanol and dichloromethane as a solvent. The prepared coating solution (I) was sieved through a 100 mesh standard network and the core tablet of Example 2 was coated.

Pharmaceutical Compositions of Comparative Examples 1 to 3 (Unit: mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Nuclear Example 2 720 - 720 Example 3 - 970 -    I Simvastatin 20 20 - Attorvastatin - - 10 HPMC 2910 40 9.96 4.98 PEG 6000 4 20 10 TEC - 10 5 SLS - 10 5 Docusate sodium - 3 1.5 BHA - 0.04 0.02 TiO2 - 5 2.5 Total 784 1048 759

Experimental Example 1

The dissolution test was performed for each tablet prepared through Examples 2 to 4 to confirm the dissolution pattern. To this end, in each of the six tablets were eluted at 50 rotations per minute at 37 ± 0.5 ° C. As the medium, 5 mL of the eluate was purged after 1, 2, 4, 6, 8, 10, 12, 14, 18 and 24 hours after the start of elution in 900 mL of water. 2 mL of the purified eluate was taken up to 10 mL, filtered through a pore size 0.45 μm membrane filter, and the filtrate was analyzed by the following HPLC analysis to calculate the elution rate.

HPLC Analysis of Nicotinic Acid

Column: Kromasil C18 (100 mm, 5 μm, 4.6 mm ø250 mm) or equivalent column

Column Temperature: 40 ℃

Mobile phase: 0.005 M sodium hexanes sulfonate buffer / methanol / acetonitrile = 50/33/17

Flow rate: 1 mL / min

Main volume: 10 μL

Detector: ultraviolet absorption photometer (wavelength 262 nm)

As a result, the dissolution rate of nicotinic acid showed a sustained release pattern for 24 hours, proving that the sustained-release layer of nicotinic acid and nicotinic acid compound or mixture thereof is achieved through the release control which the present invention intends to achieve.

Experimental Example 2

The dissolution test was performed on each of the coating films or the separate layers prepared in Examples 6, 13, 15, 17, and 19 to confirm the dissolution patterns. To this end, three films in each example were eluted at 50 rotations per minute at 37 ± 0.5 ° C. As a medium, 5 mL of the eluate was clarified after 5, 10, 15, and 30 minutes from the start of elution in 900 mL of pH 7.0 (0.5% sodium lauryl sulfate) test solution. The filtered eluate was filtered with a 0.45 탆 pore membrane filter and the filtrate was analyzed by the following HPLC analysis to calculate the elution rate.

HPLC Analysis of Simvastatin

Column: Capsule Pack C18 (3.0 mm ㅧ 50 mm, 3 ㎛)

Column Temperature: 45 ℃

Detector: Ultraviolet 238 nm

Flow rate: 1.0 mL / min

Injection volume: 10 μl

Mobile phase: A mixture of sodium dihydrogen phosphate buffer / acetonitrile (35/65) at pH 4.0

As a result, it was confirmed that the dissolution rate of simvastatin can be well accelerated by recrystallization inhibitors such as povidone, copovidone, poloxamer, eudragit, and HP-β-cyclodextrin.

Experimental Example 3

Dissolution test was carried out for each of the coated tablets prepared in Example 27 and Comparative Example 1 to confirm the dissolution pattern. To this end, six tablets were taken in each of the Examples and Comparative Examples in the same manner as in Experimental Example 2, and the experiment was performed.

As a result, it was confirmed that the pharmaceutical composition of the present invention having a film forming agent or a layer forming agent, a recrystallization inhibitor, and a plasticizer showed a rapid rapid release of simvastatin at 80% or more within 15 minutes.

Experimental Example 4

Dissolution test was carried out for each of the coating tablets prepared in Examples 41, 43, 44, 45 and Comparative Example 2 to confirm the dissolution pattern. To this end, the respective samples were treated in the same manner as in Experimental Example 1 and Experimental Example 3 to calculate the dissolution rate of nicotinic acid and simvastatin, and are shown in FIGS. 4 and 5.

In the comparative example without the recrystallization inhibitor as shown in the results of Figure 4, the dissolution rate of simvastatin is significantly low and the dissolution rate did not meet the immediate release desired in the present invention. It was confirmed that the pharmaceutical composition of the present invention having a film forming agent or a layer forming agent, a recrystallization inhibitor, and a plasticizer showed a rapid rapid release of simvastatin at 80% or more within 15 minutes.

When the elution of simvastatin and nicotinic acid was simultaneously measured and observed as shown in FIG. 5, the dissolution rate until simvastatin and nicotinic acid was eluted by 80% showed a difference of at least 36 times at the same temperature and the elution speed.

Experimental Example 5

Dissolution test was carried out for each of the coated tablets prepared in Examples 50, 51 and Comparative Example 3 to confirm the dissolution pattern. To this end, the test was carried out as in Experimental Example 3, and each sample was treated to calculate the dissolution rate and plotted as shown in FIG.

HPLC analysis of atorvastatin

Column: Luna C18 (4.6 mm × 250 mm, 5 μm)

Column temperature: room temperature

Detector: Ultraviolet 248 nm

Flow rate: 1.0 mL / min

Injection volume: 10 μl

Mobile phase: A mixture of acetonitrile / ammonium acetate buffer / tetrahydrofuran (25/70/5) at pH 4.0

As a result, it was confirmed that the pharmaceutical composition of the present invention having a film forming agent or a layer forming agent, a recrystallization inhibitor, and a plasticizer showed a rapid rapid release of atorvastatin to 80% or more within 15 minutes.

In the combination of HMG-CoA reductase inhibitors and nicotinic acid, the HMG-CoA reductase inhibitor is configured to be rapidly absorbed, thereby minimizing inappropriate drug interactions with the absorption of HMG-CoA reductase inhibitors by nicotinic acid, thereby preventing hyperlipidemia and arteries. Provided is a pharmaceutical composition capable of exhibiting an optimal effect in the treatment and prevention of sclerosis.

Compared to conventional HMG-CoA reductase inhibitor therapy and nicotinic acid therapy, the present invention not only lowers low-lipoprotein cholesterol but also increases high-density lipoprotein cholesterol, thereby providing a more optimal therapeutic effect, as well as simple HMG-CoA. The problem of treatment by the interaction of two drugs in a reductase inhibitor / nicotinic acid combination can be improved.

Claims (16)

Sustained release layers, in which the active compound is present as a mixture with a slow release polymer, An immediate release layer surrounding the sustained release layer as an outer layer or consisting of separate layers, wherein the active compound is present as a mixture with a film-forming or layer-forming agent, a plasticizer, Wherein the sustained release layer is continuously released for at least 12 hours in a medium of water or physiological pH, and the immediate release layer exhibits an elution pattern of 80% or more within 30 minutes in a medium of water or physiological pH. In the form of a medicament, An effective drug amount of nicotinic acid and a nicotinic acid compound or a mixture thereof is used as the active compound in the sustained release layer, and an effective drug amount of an HMG-CoA reductase inhibitor is used as the active compound in the immediate release layer. A pharmaceutical composition for the treatment and prevention of hyperlipidemia and atherosclerosis, comprising using a recrystallization inhibitor in the release layer. The pharmaceutical composition of claim 1, wherein the HMG-CoA reductase inhibitor is simvastatin. The pharmaceutical composition of claim 1, wherein the HMG-CoA reductase inhibitor is atorvastatin. 4. The recrystallization inhibitor according to any one of claims 1 to 3, wherein the recrystallization agent is a vinylpyrrolidone-based polyvinylpyrrolidone, crospovidone, polyvinylpyrrolidone vinylacetate copolymer, a dextrin derivative, cyclodextrin, di Methylcyclodextrin, hydroxyethyl cyclodextrin, hydroxypropyl cyclodextrin, trimethyl cyclodextrin, alkylene oxide-based poloxamer and polyethylene glycol, polyethylene oxide, acrylate-based polymethacrylate and derivatives thereof, poly Pharmaceutical composition, characterized in that it comprises one or more selected from the group consisting of saccharide-based alginic acid and alkali metal salts thereof, polyvinyl acetate. The pharmaceutical according to any one of claims 1 to 3, wherein the anti-recrystallization agent comprises at least one selected from copovidone, povidone, poloxamer, eudragit, and HP-β-cyclodextrin. Composition. The anti-recrystallization agent according to any one of claims 1 to 3, wherein the anti-crystallization agent comprises at least one member selected from polyvinylpyrrolidone-based polyvinylpyrrolidone, crospovidone, and polyvinylpyrrolidone vinyl acetate copolymer. Pharmaceutical composition, characterized in that. The pharmaceutical composition according to any one of claims 1 to 3, wherein the recrystallization inhibitor is polyvinylpyrrolidone. The pharmaceutical composition according to any one of claims 1 to 3, wherein the recrystallization inhibitor is a polyvinylpyrrolidone vinyl acetate copolymer. The nicotinic acid and nicotinic acid compound or mixtures thereof according to any one of claims 1 to 3, wherein the nicotinic acid and nicotinic acid compound or mixtures thereof are nicotinic acid, nicotinyl alcohol tartrate, d-glucinitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8 -Carboxamide, N-methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradylian sorbinicate, hexa A pharmaceutical composition, characterized in that it is selected from the group consisting of lower alcohol esters of nicite, ronitol and nicotinic acid. The sustained release polymer of the sustained release layer is a cellulose-based hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, or hydroxy. Hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, alkyl hydroxypropyl methyl cellulose, polysaccharide-based corn starch, potato starch and gelatin starch, and derivatives thereof Roxyethyl starch, dextrin and its derivatives dextran, maltodextrin, polydextrose, alginic acid alginate metal salts, guar gum, locust bean gum, xanthan gum, cyclodextrin, gum arabic, gellan gum, cara Night Sword, Casein, Tara Gum, Tamarind Gum, Tragacanth Gum, Gati Gum, Peptide As gelatin, collagen, protamine, zein, acrylic acid series, carbomer, polyacrylamide, other polyvinyl acetal diethaminoacetate, glucomannan, glucosamine, arabinogalatan, percelanan, flulan, polyurethane, chitosan Pharmaceutical composition, characterized in that it comprises one or more of the group consisting of chitin, agar, pectin, carrageenan and the like. 4. The film forming agent or layer forming agent of the immediate release layer is a cellulose-based microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxide. Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, alkyl hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl Cellulose acetate succinate, cellulose acetate, cellulose acetate phthalate, polysaccharide, corn starch, potato starch and gelatinized starch and its derivatives, hydroxyethyl starch, dextrin and its derivatives dextran, maltodextrin, polydextrose, Guar gum, locust bean gum, xanthan gum, cyclodextrin, gum arabic, gellan gum, karaya gum, casein, tarac gum, tamarind gum, tragacanth gum, gati gum, as peptides, gelatin, collagen, protamine, Jane, carbomer, polyacrylamide as acrylic acid, carnauba wax as wax, sucrose as sugar, sucrose as liquid, liquid sucrose, lactose, polyvinyl acetal ethylamino acetate, other polyurethanes, chitosan, chitin, agar, Pharmaceutical composition, characterized in that it comprises one or more of the group consisting of pectin, carrageenan, shellac. The plasticizer of the immediate release layer is polyglyceryl fatty acid esters, polyoxyethylene glyceryl fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters according to any one of claims 1 to 3. , Polyethylene glycol and polyethylene glycol fatty acid esters, polyoxyethylene castor oils, polyoxyethylene alkyl ethers, polyoxyethylene phytosterols, polyoxyethylene alkyl phenyl ethers, polyoxyethylene polyoxypropylene alkyl ethers , Polyoxyethylene lanolin, polyoxyethylene alkyl ether phosphate, propylene glycol and propylene glycol fatty acids, glycerol fatty acid esters, fatty acid martrogol glycerides, glyceryl monolinoleate, glyceryl monooleate, diethylene Glycol monoethyl ether, benzyl Zoate, chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin, mineral oils and lanolin alcohols, petroleum and lanolin alcohols, triacetin and triethyl citrate, sodium lauryl sulfate, docuate sodium, sorbitol, mannitol Pharmaceutical composition, characterized in that it comprises one or more of the group consisting of sugars. The pharmaceutical composition according to any one of claims 1 to 3, further comprising an additional one or more protective layers containing no drug inside or outside the immediate release layer. 4. A pharmaceutical composition according to any one of claims 1 to 3, further comprising an antioxidant in the immediate release layer. The pharmaceutical composition according to claim 14, wherein the antioxidant is at least one selected from ascorbic acid, butylated hydroxy anisole, citric acid, tocopherol and derivatives and compounds thereof, and the like. The method according to any one of claims 1 to 3, further comprising at least one selected from diluents, binders, disintegrants, pigments, preservatives, foaming agents, lubricants commonly used in the sustained release layer, Pharmaceutical composition, characterized in that it further comprises one or more selected from disintegration accelerator, spraying agent, light-agent, light-shielding agent, colorant in the immediate release layer.

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