WO2009148245A2 - Novel niacin and hmg-coa reductase inhibitor combination formulation - Google Patents

Abstract

The present invention relates to a controlled release formulation containing niacin. More specifically, the present invention relates to a controlled release-niacin formulation and a preparation method thereof, wherein the controlled release-niacin formulation comprises niacin, hydroxypropyl methylcellulose, carboxyvinyl polymers, additives, disintegrants, and lubricants, wherein the carboxyvinyl polymer and hydroxypropyl methylcellulose are included so that the weight ratio of the carboxyvinyl polymer: HPMC is 1:1 - 1:100. In addition, the present invention provides a combination formulation further containing an HMG-CoA reductase inhibitor in the controlled release-niacin formulation and a preparation method thereof.

Description

[Correction 23.10.2009 by Rule 26] New niacin and HMV-COA Reductase Inhibitor Complex

The present invention relates to controlled release formulations containing niacin, and methods for their preparation.

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 elevated serum low density lipoprotein-cholesterol and serum total cholesterol. 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 heteromorphic 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.

 It is known that when serum lipids, in particular 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 should consider a lipid lowering therapy that delays the progression of atherosclerosis or induces the degeneration of atherosclerosis for the purpose of reducing the risk of cardiovascular disease, particularly coronary artery disease. do.

 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. Thrombus formation of atherosclerosis is thought to be caused by peroxidation of LDL-cholesterol in the subendothelium of the vessel wall. 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 and 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 called mevinolin, pravastatin (US Pat. Nos. 4,346,227 and 4,410,629), and lactones of pravastatin (US Patent 4,448,979), velostatin and simvastatin (US Pat. Nos. 4,448,784 and 4,450,171), called mysterolin, rivastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin. Still other examples of HMG-CoA reductase inhibitors include U.S. Pat.Nos. 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, and 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®), US Pat. No. 3,674,836 Probucol and related compounds as disclosed in the present invention, lipostavill (long-furan), Eisai E5050 (N-substituted ethanolamine derivatives), imanisyl (HOE-402), tetrahydrorifstatin (THL) Isitigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seyoku), Ajinomoto AJ-814 (Azlene derivative), melinamide (Sumitomo), Sandoz 58-035, American 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, US Pat. No. 4,027,009 Quaternary amines as disclosed Poly (diallylmethylamine) derivatives such as li (diallyldimethylammonium chloride) and ionone, as disclosed in US Pat. No. 4,759,923, omega-3-fatty acids, fibric acid derivatives (e.g. gempies) contained in various fish oil supplements Brozil, clofibrate bezafibrate, fenofibrate, cipropibrate and clinofibrate) and US Pat. No. 5,200,424 European Patent Application No. 0065835A1, European Patent No. 164-698-A, British Patent No. 1,586,152 and There are other known serum cholesterol lowering agents, such as those described in British Patent Application No. 2216-179-A.

Nicotinic acid, known as niacin, has been used for decades to treat hyperlipidemia or hypercholesterolemia. This compound lowers total cholesterol, VLDL-cholesterol and VLDL-cholesterol residues, LDL-cholesterol, triglycerides and apolipoproteins known as "Lp (a)" while increasing the desired HDL-cholesterol in the human body. It has been known to exhibit an advantageous effect.

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

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 and the like 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 include, for example, Nicobid ^™ capsules (Long-Furan Laura), Endur-acin ^™ (Innobyte Corporation) and two types of hydroxypropylmethylcellulose (abbreviated as 'HPMC') and Sustained release niacin preparations containing hydrophobic components have been developed (US Pat. Nos. 5,126,145 and 5,268,181). In addition, Niaspan is a representative niacin-containing sustained release formulation that includes a swelling agent, a binder, and a lubricant in addition to the drug.  (MERCK) is commercially available.

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.

However, existing sustained-release preparations are simply sustained-release preparations in which swelling agents, such as HPMC, delay water release by absorbing moisture to form a water-soluble matrix, and do not provide a separate control mechanism for coping with changes in pH in the gastrointestinal tract. It has the disadvantage of not being able to achieve separate controlled release in the stomach and intestine.

In contrast, statin drugs, HMG-CoA reductase inhibitors, have been used to treat hyperlipidemia for decades. As a representative example simvastatin is known to have the beneficial effect of raising HDL-cholesterol levels in some individuals (Grundi SM, N Engl J Med, 319 (1): 24-32, 25-26 and 31 (1988.7). ) Reference). The conversion of HMG-CoA to mevalonate is an early stage of cholesterol biosynthesis. Inhibition of HMG-CoA reductase, which interferes with the production of mevalonate, is achieved in response to HMG-CoA reductase inhibitors exerting their total cholesterol lowering effect and LDL-cholesterol lowering effect (Grundi SM et al. Engl J Med, 319 (1): 24-32, 25-26 (1988.7.7)].

Simvastatin is administered once daily in patients with homozygous familial hypercholesterolemia (40 mg / d) in the evening or 80 mg / day (20 mg / 20 mg / 40 mg / d) in three doses. Simultaneously with other lipid lowering therapies, or other lipid lowering therapies, simvastatin is administered. In elderly patients, a daily dose of 20 mg can achieve a maximum reduction in cholesterol levels. If simvastatin is simultaneously administered to a patient receiving cyclosporine, the initial starting dose is 5 mg per day and should not exceed 10 mg per day. If simvastatin is administered simultaneously to patients receiving amiodarone or verapamil, the dose of THIS DRUG should not exceed 20 mg per day. If simvastatin is used in combination with hypolipidemic doses of niacin, it can cause myopathy / rhabdomyopathy and is not excreted in the kidneys. Therefore, dose adjustment is not necessary for mild renal injuries, but should be monitored carefully for severe renal insufficiency.

Atorvastatin is administered once daily in 10 mg patients with primary hypercholesterolemia and combined 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 an increase in transaminase levels in 1% of patients receiving simvastatin. This phenomenon has been described by 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).

Therefore, for the treatment of hyperlipidemia or atherosclerosis, there is a strong demand for the development of a therapeutic agent that can effectively treat the disease while alleviating side effects of niacin and HMG-CoA reductase inhibitors.

On the other hand, sophisticated and constant controlled release of niacin for side effects reduction and effective treatment is not only achieved by simply adjusting the dissolution rate of the formulation within the desired dissolution range, but also the dissolution pattern does not change rapidly until the dissolution of the formulation is complete. It is also very important to keep the desired dissolution pattern consistently. In particular, since niacin preparations are used to treat diseases such as hyperlipidemia that require long-term administration of drugs, the development of niacin controlled-release preparations that maintain the effective blood concentration of drugs and maintain higher drug stability This is a very important prerequisite for the production of niacin.

Theoretically, the matrix form should provide a very consistent pattern of initial release and overall release control of the drug in such a way that the polymer can be distributed evenly in the formulation to control the release of the drug, thus enabling safer drug intake. However, the conventional water-soluble matrix of the niacin sustained release formulation of the active niacin eluted by an irregular erosion mechanism that does not maintain a constant form, such a mechanism by the mechanism does not maintain a constant form Dissolution patterns are very uneven because of very irregular erosion, which can lead to a sudden increase in dissolution due to unexpected conditions in vivo (e.g. dose-dumping), resulting in unwanted side effects of niacin. In addition, the dissolution of the active ingredient can be completed earlier than the desired time and it is difficult to expect a constant bioavailability for each time, each formulation, each individual. Despite these problems, until now, for the development of sustained-release preparations of niacin, the release of the drug in a sustained-release form by using a polymer such as HPMC and / or carboxyvinyl polymer alone or in combination to produce a water-soluble matrix form Only known techniques are known, and there are no known problems and solutions to such problems of maintaining such a matrix for substantially the desired time.

When the inventors use HPMC as a pH-independent polymer and carboxy vinyl polymer as a pH-dependent polymer in a constant ratio, the inventors surprisingly control the niacin formulation to maintain a constant matrix until the elution of the niacin formulation is completed to achieve excellent performance. It was confirmed that niacin preparations in release form can be prepared. In addition, the present inventors have further added that such niacin controlled release formulations with immediate release of HMG-CoA reductase inhibitors to produce a single combination formulation, reducing the side effects of niacin due to the precise controlled release of niacin and excellent hyperlipidemia and The present invention has been accomplished by discovering that it may have a therapeutic effect on atherosclerosis.

The present invention has been made to solve the problems of the prior art, and while having the advantages of the water-soluble matrix, the niacin formulation maintains a constant matrix form until the elution of the niacin formulation is completed, so the release control of niacin is very sophisticated. There is provided a new niacin controlled release formulation. In addition, the present invention further comprises a HMG-CoA reductase inhibitor preparation in the preparation for the controlled release of niacin to provide a complex preparation having a very excellent hyperlipidemia and atherosclerosis treatment effect, and a method for producing the same.

Unlike commercially available niacin controlled release formulations according to the present invention, the form of the matrix is maintained until the completion of dissolution of the formulation to maintain a constant dissolution pattern for a time required for dissolution of the drug to treat diseases such as hyperlipidemia Maintain high drug stability and have useful value. In addition, the complex preparation of the present invention inhibits HMG-CoA reductase, a rate determining step for cholesterol biosynthesis, and elutes the inhibitor of HMG-CoA reductase which lowers total cholesterol, LDL-cholesterol, VLDL-cholesterol, and triglyceride levels. While increasing the amount of HDL-cholesterol, the form of the matrix of the niacin controlled release formulation having a synergistic effect is maintained until the dissolution of the formulation is completed, so that the dissolution pattern does not change drastically for the time required for dissolution of the drug, and the desired dissolution pattern is constantly It is maintained at, which has the effect of effectively treating hyperlipidemia or atherosclerosis, and significantly alleviating side effects caused by niacin to allow long-term treatment.

1 and 2 are photographs showing the results after the swelling test for 24 hours for the niaspano controlled release formulations included in the conventional formulations Niaspano ^TM and the composite formulation of the present invention.

Figure 3 is a graph showing the time-phase whether or not to maintain a constant matrix form after preparing the niacin preparation by varying the ratio of carboxyvinyl polymer to HPMC.

Figure 4 is a graph showing the dissolution profile after preparing a niacin tablet by varying the viscosity of HPMC put into water and the dissolution test.

5 is a graph showing the dissolution profile of the niacin tablet prepared by varying the content of HPMC, put into water, and subjected to a dissolution test.

Figure 6 is a graph showing the dissolution profile after preparing a niacin tablet by varying the content of the carboxyvinyl polymer, put it in an artificial intestinal fluid and the dissolution test.

Figure 7 is a graph showing the dissolution profile after the dissolution test for a variety of drugs having the composition ratio of the same carboxyvinyl polymer and HPMC.

In one embodiment, the present invention provides niacin; Hydroxypropylmethyl cellulose; Carboxyvinyl polymers; additive; Carboxyvinylpolymers and hydroxypropylmethylcellulose, including disintegrants and glidants, are directed to niacin controlled release formulations comprising carboxyvinylpolymers: hydroxypropylmethylcellulose in a weight ratio of 1: 1 to 1: 100.

In the present invention, "niacin" is a concept including nicotinic acid and its derivatives, for example nicotinic acid, nicotinamide, nicotyl alcohol tartrate and d-glucinol hexanicotinate (d- glucitol hexanicotinate), and all compounds metabolized in vivo and convertible to nicotinic acid. The amount of niacin included in the controlled release formulation of the present invention may be appropriately selected in consideration of the economics and stability of the drug, but is usually 300 to 1000 mg (once daily sustained release), preferably 500 to 1000 mg. In a preferred embodiment, the niacin of the invention is formulated in a characteristic controlled release form.

In addition, the carboxyvinyl polymers used as pH-dependent polymer bases in the controlled release formulations of the invention are also known as "carbomers" or carboxypolymethylenes, which are sources such as Noveon, Inc. (Cleveland, Ohio). (Available under the trade name Carbopol ^® ). Carbopol polymer is a crosslinked, acrylic acid-based polymer that is crosslinked with allyl sucrose or allyl pentaerythritol. Carbopol copolymer is a polymer of acrylic acid modified with C _10-80 alkyl atrylate and crosslinked with allylpentaerythritol.

Examples of the carboxyvinyl polymer include carbomer 910, 934, 934P, 940, 971P, 974P, 1342, and the like. The present invention is not limited to this example, and any kind of carboxyvinyl polymer can be used. Preferably it is a carboxyvinyl polymer selected from the group consisting of carbomer 934P, 971P and 974P. In one specific embodiment, we used Carbopol 934P NF, Carbopol 971NF, Carbopol 974P NF and Carbopol 71G NF. The proportion of carboxyvinyl polymer used in the present invention is 0.3% to 10% of the total weight.

The "hydroxypropylmethylcellulose" used in the controlled release formulations of the present invention is also called HPMC and is generally commercially available from Dow Chemical Company under the brand name Methocel. HPMC is available in various grades. All commercially available HPMCs can be used in the compositions of the present invention and include all materials mentioned in the prior art, for example EP 375156, US 4,369,172, US 4,357,469, US 4,226,846 and US 4,389,393. Methods of making such HPMCs are well known in the art. HPMC used in the present invention preferably has a viscosity of 80,000 to 120,000 cps, more preferably the viscosity of the HPMC is 100,000 cps.

The HPMC and carboxyvinyl polymer used in the present invention can control the dissolution of niacin by maintaining the form of the matrix that can maintain a constant dissolution rate and pattern for the time that the niacin preparation wants to maintain the drug efficacy. To make it possible, it is included in the niacin controlled release formulation of the present invention in a constant ratio. Preferably, the carboxyvinyl polymer and HPMC used in the present invention are included in the niacin controlled release formulation of the present invention in a weight ratio of carboxyvinyl polymer: HPMC of 1: 1 to 1: 100.

In the controlled release formulation of the present invention, a binder may be used as necessary, and any known binder may be used without limitation, but 1-ethenyl-2-pyrrolidinone (1-ethenyl-2- It is preferable to select and use from polymers having a repeating unit of pyrrolidinone). 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.

In the present invention, the disintegrant is used to absorb the moisture to promote the dissolution of niacin, and one example of the disintegrant which can be used in the formulation of the present invention is croscarmellose sodium, sodium starch glycolate (Sodium) starch glycolate) Pregelatinized Starch [Starch 1500 ^® or Prejel ^® ], microcrystalline cellulose, crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidones (Polyvinylpyrrolidone, PVP, Povidone ^® ), hydroxypropylcellulose (low substituted), alginic acid, carboxymethylcellulose, calcium and sodium salts, colloidal silicon dioxide (fumed silica, colloidal sillica, guar gum, magnesium aluminum silicate, methylcellulose cellulose), powdered cellulose, starch and sodium alginate, or a mixture thereof.

Preferably, as the disintegrant, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose or crospovidone and commercially available polyvinylpyrrolidone can be used.

More preferably, crospovidone, sodium starch glycolate, or microcrystalline cellulose may be used as the disintegrant, and most preferably, two or more disintegrants are mixed and used. At this time, the disintegrant is preferably used 5 to 200 parts by weight, more preferably 10 to 100 parts by weight.

In addition, the lubricant used in the niacin controlled release formulation of the present invention is used to improve the moldability of the oral formulation, for example magnesium stearate (Magnesium stearate), silica oxide (SiO2) or colloidal dioxide Silicon (colloidal silica, Cab-O-SIL®) or talc (talc) and the like, but is not limited thereto. The lubricant is preferably used at 0.1 to 20 parts by weight.

The niacin controlled release formulation of the present invention may include additives commonly used in pharmaceuticals, and as such additives, lactose, sugar, mannitol, lactose and sorbitol may be used, and preservatives, stabilizers, etc. may be used as necessary. It may further include.

As another aspect, the present invention provides a method for preparing a controlled release formulation of niacin. Specifically, the composition for oral administration may be prepared according to a conventional method using the composition of the present invention. For example, the formulation composition of the present invention may be prepared by a wet or dry method, but is not limited thereto. The wet or dry method is divided by the granulation method of raw materials, and the dry method is a slug or sheet-like material made by dry granulation by using a device such as a slug machine or a roller compactor. It is a method of crushing and sizing to mix and compress the lubricant. In addition, the wet method is a method of compressing the wet granules made by adding the main medicine and is a general formulation method applied to many drugs. Wet granules are wet granulated by extrusion granulation and crushing granulation. The granules are dried and granulated, and then compressed by adding a lubricant and, if necessary, a disintegrant. Such wet or dry methods are well known to those skilled in the art.

In one preferred aspect, the present invention

(a) niacin; Hydroxypropylmethyl cellulose; Carboxyvinyl polymers; Mixing the additive and the disintegrant;

(b) adding liquid solvent to produce wet granules; And

(c) mixing and tableting the lubricant;

At this time, the carboxyvinyl polymer and hydroxypropylmethylcellulose relates to a method for producing a niacin controlled release formulation in which carboxyvinyl polymer: HPMC is mixed in a weight ratio of 1: 1 to 1: 100.

In the preparation of the niacin controlled release formulation of the present invention, the solvent added to the mixed powder does not affect the activity of niacin, which is an active ingredient, and in general, all solvents used for preparing granules may be used, and these solvents may be used in the art. Very well known. For example, but not limited to, one or a mixed solvent thereof selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol and polyethylene glycol may be used. Preferably, the liquid solvent uses ethanol or a mixed solvent of water and ethanol. At this time, when the solvent is water alone or a mixed solvent of water and ethanol, 5 to 40% is used for the drug weight ratio, more preferably 10 to 23%. In addition, in a preferred embodiment, the production method of the present invention may further include mixing the binder in step (a).

In one specific embodiment, the inventors uniformly mix niacin, HPMC, carbomer, additives and disintegrant, and then add a small amount of liquid solvent and mix again to prepare wet and dried wet granules and after drying the wet granules It was prepared by milling and postmixing the lubricant and / or binder directly into a tablet using a general tablet machine.

As can be seen in the following examples, the inventors prepared a niacin preparation by varying the ratio of the carboxyvinyl polymer and HPMC, and then observed whether these preparations kept the matrix form constant. In the case of including carboxyvinyl polymer and HPMC in a weight ratio of vinyl polymer: HPMC in a ratio of 1: 1 to 1: 100, unlike the conventional commercially available formulations, it was unexpectedly confirmed that the matrix form of the formulation remained constant for more than 24 hours. It was. Therefore, the niacin controlled release formulation according to the present invention appears to have an excellent dissolution control action compared to conventional commercial formulations, and it is possible to significantly improve side effects such as skin fever and redness due to excessive niacin release.

As another aspect, the present invention relates to a complex formulation comprising a HMG-CoA reductase inhibitor in addition to the niacin controlled release formulation, specifically comprising niacin, carboxyvinyl polymer and hydroxypropylmethylcellulose Niacin controlled release formulations; And an HMG-CoA reductase inhibitor, wherein the carboxyvinyl polymer and hydroxypropylmethylcellulose have a carboxyvinyl polymer: hydroxypropylmethylcellulose 1: 1 to 1: 100, preferably 1: 1.5 to 1:50, The most preferred is a controlled-release complex preparation for treating hyperlipidemia or atherosclerosis, which is included in a weight ratio of 1: 1.5 to 1:20.

As used herein, the term "HMG-CoA reductase inhibitor" is an enzyme that plays an important role in regulating the synthesis of coenzyme Q10 or the synthesis of cholesterol in vivo, in particular HMG-CoA to mevalonate during the synthesis of cholesterol. Inhibit the action of HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase) that serves to convert, in the present invention can be used without limitation, a substance known as HMG-CoA reductase inhibitors, Without limitation, simvastatin, atorvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin, pravastatin and the like can be used.

Niacin, carboxyvinyl polymer and hydroxypropylmethylcellulose included in the composite formulation of the present invention are as described above.

Specifically, the amount of niacin included in the controlled release complex preparation of the present invention may be appropriately selected in consideration of the economics and stability of the drug, but usually from 300 to 1000 mg (once daily sustained release), preferably 500 to 1000 mg to be. In a preferred embodiment, the niacin of the invention is formulated in a characteristic controlled release form.

The "hydroxypropylmethylcellulose" used in the composite formulations of the present invention is also called HPMC and is generally commercially available from Dow Chemical Company under the brand name Methocel. HPMC is available in various grades. All commercially available HPMCs can be used in the compositions of the present invention and include all materials mentioned in the prior art, for example EP 375156, US 4,369,172, US 4,357,469, US 4,226,846 and US 4,389,393. Methods of making such HPMCs are well known in the art. HPMC used in the present invention preferably has a viscosity of 80,000 to 120,000 cps, more preferably the viscosity of the HPMC is 100,000 cps.

In addition, the carboxyvinyl polymers used in the composite formulations of the present invention are also known as "carbomers" or carboxypolymethylenes, which are sourced from, for example, Noveon, Inc. (Cleveland, Ohio) under the trade name Carbopol ^® Commercially available). Carbopol polymer is a crosslinked, acrylic acid-based polymer that is crosslinked with allyl sucrose or allyl pentaerythritol. Carbopol copolymer is a polymer of acrylic acid modified with C _10-80 alkyl atrylate and crosslinked with allylpentaerythritol.

Examples of the carboxyvinyl polymer include carbomer 910, 934, 934P, 940, 971P, 974P, 1342, and the like. The present invention is not limited to this example, and any kind of carboxyvinyl polymer can be used. Preferably it is a carboxyvinyl polymer selected from the group consisting of carbomer 934P, 971P and 974P. In one specific embodiment, we used Carbopol 934P NF, Carbopol 971NF, Carbopol 974P NF and Carbopol 71G NF. The proportion of carboxyvinyl polymer used in the present invention is 0.3% to 10% of the total weight.

The HPMC and carboxyvinyl polymer used in the present invention can control the dissolution of niacin by maintaining the form of the matrix that can maintain a constant dissolution rate and pattern for the time that the niacin preparation wants to maintain the drug efficacy. To make it possible, it is included in the combination formulation of the present invention at a constant ratio. Carboxyvinyl polymer and HPMC used in the present invention is a carboxyvinyl polymer: HPMC is preferably, 1: 1 to 1: 100, more preferably 1: 1.5 to 1:50, most preferably 1: 1.5 to 1 It is included in the complex formulation of the present invention in a weight ratio of: 20.

In one preferred embodiment, the combination formulation of the present invention may further comprise an antioxidant.

Antioxidants used in the present invention can be used without limitation the pharmaceutically widely used antioxidants are examples of such antioxidants are water-soluble vitamin C, vitamin E, radical inhibitors Tocopherol (Tocopherol), Sesamol (Sesamol), Gingeron, Capsaicin, Quercetin, and Garlic acid have little antioxidant activity, but there are synergistic effects of citric acid and ascorbic acid when co-existed with radical inhibitors.

In a preferred embodiment, the co-formulations of the invention further comprise one or more components selected from the group consisting of additives, disintegrants, lubricants, binders and mixtures thereof. Additives, disintegrants, lubricants and binders included in the composite formulation of the present invention are as described above.

In carrying out the objectives of the present invention, the complex preparations according to the invention may be formulated into a variety of suitable oral dosage forms. In another preferred embodiment, the combination formulations of the present invention may be formulated in bilayer or coated tablets for the optimization of hyperlipidemia or atherosclerosis treatment effects and for efficient reduction of side effects.

Specifically, when the complex formulation of the present invention is formulated as a bilayer tablet, the first layer according to the present invention may comprise an HMG-CoA reductase inhibitor dispersed in a tablet matrix. The first layer composition generally comprises 3 to 50%, preferably 5 to 35%, of the active ingredient. In addition, the second layer comprises a niacin controlled release formulation in which the carboxyvinyl polymer and HPMC are included in a specific composition ratio, and generally contains 10 to 80% by weight of active ingredient, preferably 30 to 70% by weight.

In addition, when the complex formulation of the present invention is formulated as coated tablets, it is preferable that the controlled release formulation containing niacin is made into a nucleus and coated with a HMG-CoA reductase inhibitor. Exemplary coatings according to the present invention include HMG-CoA reductase inhibitors, plasticizers, surfactants, film formers and coatings and coloring agents.

Common solvents used for coating include water, alcohols, esters, ketones and chlorinated hydrocarbons, and bases include celluloses, vinyls and glycols, and plasticizers such as polyhydric alcohols, acetate esters, phthalate esters and glycerides. And oils can be used.

Exemplary amounts of film former and coating agent in the coating are from about 0.01% to about 5% by weight of the tablet. In general, to prepare a coating according to the present invention, an HMG-CoA reductase inhibitor is suspended or dissolved in a solution of polyvinylpyrrolidone, polyethylene glycol and hydroxy propyl methyl cellulose, followed by containing an effective amount of the HMG-CoA reductase inhibitor. Sprayed to the surface of a sustained release tablet by the film coating process so that it may become thick. Examples of suitable coating thicknesses in accordance with the present invention are preferably in the range of about 0.1 mm to about 2.0 mm or more.

The amount of niacin included in the co-formulation according to the present invention may be appropriately selected in consideration of the economics and stability of the drug, but is usually 300 to 1000 mg (for one-time sex use), preferably 500 to 1000 mg. In addition, the amount of the HMG-CoA reductase inhibitor included in the complex preparation according to the present invention may be appropriately selected in consideration of the economics and stability of the drug, but is usually 2 to 80 mg (once a day), preferably 10 to 20 mg. .

As another aspect, the present invention provides a method for the preparation of the combination formulation. Specifically, the composition for oral administration may be prepared according to a conventional method using the composition of the present invention. For example, the formulation composition of the present invention may be prepared by a wet or dry method, but is not limited thereto. The wet or dry method is divided by the granulation method of raw materials, and the dry method is a slug or sheet-like material made by dry granulation by using a device such as a slug machine or a roller compactor. It is a method of crushing and sizing to mix and compress the lubricant. In addition, the wet method is a method of compressing the wet granules made by adding the main medicine and is a general formulation method applied to many drugs. Wet granules are wet granulated by extrusion granulation and crushing granulation. The granules are dried and granulated, and then compressed by adding a lubricant and, if necessary, a disintegrant. Such wet or dry methods are well known to those skilled in the art.

In one preferred aspect, the present invention

(a) niacin; Hydroxypropylmethyl cellulose; Carboxyvinyl polymers; Mixing the additive and the disintegrant;

(b) HMG-CoA reductase inhibitors; additive; Disintegrants; And mixing antioxidants;

(c) preparing granules by adding a liquid solvent to each of the mixtures prepared in steps (a) and (b); And

(c) mixing and tableting the lubricant;

At this time, the carboxyvinyl polymer and hydroxypropylmethyl cellulose are related to the method for producing a niacin controlled release formulation in which carboxyvinyl polymer: HPMC is mixed in a specific weight ratio.

The weight ratio of the carboxyvinyl polymer to HPMC is preferably 1: 1 to 1: 100, more preferably 1: 1.5 to 1:50, and most preferably 1: 1.5 to 1:20.

In the preparation of the niacin controlled release formulation of the present invention, the solvent added to the mixed powder does not affect the activity of niacin, which is an active ingredient, and in general, all solvents used for preparing granules may be used, and these solvents may be used in the art. Very well known. For example, but not limited to, one or a mixed solvent thereof selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol and polyethylene glycol may be used. Preferably, the liquid solvent uses ethanol or a mixed solvent of water and ethanol. At this time, when the solvent is water alone or a mixed solvent of water and ethanol, 5 to 40% is used for the drug weight ratio, more preferably 10 to 23%. In addition, in a preferred embodiment, the production method of the present invention may further include mixing the binder in step (a).

In one specific embodiment, the inventors uniformly mix niacin, HPMC, carbomer, additives and disintegrant, and then add a small amount of liquid solvent and mix again to prepare wet and dried wet granules and after drying the wet granules It was prepared by milling and postmixing the lubricant and / or binder directly into a tablet using a general tablet machine.

As another preferred aspect, the present invention

(a) preparing a nucleus comprising a niacin controlled release formulation; And

(b) coating a composition comprising an HMG-CoA reductase inhibitor to the nucleus prepared in (a),

In this case, the carboxyvinyl polymer and the hydroxypropylmethylcellulose have a weight ratio of carboxyvinyl polymer: HPMC of 1: 1 to 1: 100, preferably 1: 1.5 to 1:50, and most preferably 1: 1.5 to 1:20. It relates to a method for producing a controlled release complex preparation for treating hyperlipidemia or arteriosclerosis according to claim 1 to be mixed with. The composite formulation prepared according to this production method will have the form of a coated tablet.

As can be seen in the following examples, the inventors prepared a niacin preparation by varying the ratio of the carboxyvinyl polymer and HPMC, and then observed whether these preparations kept the matrix form constant. Unexpectedly when carboxyvinyl polymer and HPMC are included in a weight ratio of vinyl polymer: HPMC 1: 1 to 1: 100, preferably 1: 1.5 to 1:50, most preferably 1: 1.5 to 1:20 Unlike the conventional commercially available formulations, it was confirmed that the matrix form of the formulations remained constant for more than 24 hours. Therefore, the combination preparation according to the present invention is shown to have a superior dissolution control action compared to conventional commercial formulations by the novel niacin controlled release formulations contained therein, thereby significantly reducing side effects such as skin fever and flushing due to excessive niacin release. In addition to these improvements, the side effects of the combination of niacin and HMG-CoA reductase inhibitors, which are low in efficacy due to the complex formulation, can be used to increase the therapeutic effect of hyperlipidemia and atherosclerosis.

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

<Example 1>

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 milling evenly, further mixing 16 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary tablet machine.

<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>

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.

<Example 4>

Tablets containing niacin were 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 was used as a binder. .

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

Table 1

 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 500.0mg 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. Take exactly 1ml of the above solution, put it into a 100ml volumetric flask and add 100ml of water to filter the medicinal solution with 0.45㎛ membrane filter.The content of niacin is measured using a reversed phase column (C18) at a wavelength of 262nm using high-performance liquid chromatography. 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.

TABLE 2

As shown in Table 2, 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 was higher. In addition, oral tablets prepared in Examples of the present invention, as shown in Table 2, it was confirmed that the average contains more than 95% of niacin and shows significant results with 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), acetic acid 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 8th tablet dissolution test method. Specifically, after accurately weighing the tablet prepared in the embodiment of the present invention and a conventional commercial tablet, 900 ml of the elution solution from water, gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestine (pH 6.8) In the 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.

<Condition>

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

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: 1 L of methanol (4: 1) is added and 1.1 g of 1-octane sulfonate is added to the 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. First, the formulation of the most appropriate example was selected and the tablets prepared in the embodiments of the present invention in water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestinal fluid (pH 6.8) and conventional commercial tablets according to the selected prescription. A dissolution test was performed for. And the dissolution rate in water compared to commercially available tablets are shown in Table 3 below.

TABLE 3

Example 5

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 milling evenly, further mixing 20 mg of magnesium stearate for molding of the formulation by post-mixing and tableting tablets containing niacin using a rotary tablet machine.

<Example 6>

A tablet containing niacin was prepared in the same manner as in Example 5, except that 30.0 mg of sodium alginate was further used as a polymer base in the composition of Example 5.

<Example 7>

A tablet containing niacin was prepared in the same manner as in Example 5, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 5.

<Example 8>

A tablet containing niacin was prepared in the same manner as in Example 5, except that 30.0 mg of Carbopol was additionally used as a polymer base in the composition of Example 5 and 17.0 mg of povidone was used as a binder. .

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

Table 4

Example	Niacin	Microcrystalline cellulose	Lactose	HPMC	Sodium alginate	Cabopol	Povidone	Sodium starch glycolate	Magnesium stearate
Example 5	1000.0	15.0	15.0	120.0	-	-	-	-	20.0
Example 6	1000.0	15.0	15.0	120.0	30.0	-	-	-	20.0
Example 7	1000.0	15.0	15.0	120.0	-	30.0	-	-	20.0
Example 8	1000.0	15.0	15.0	120.0	-	30.0	17.0	-	20.0

Experimental Example 3

Ten tablets of the conventional tablets (Niaspanor®) and oral tablets containing niacin prepared in the Examples of the present invention were each taken to measure hardness 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, placed in a 100 ml volumetric flask, heated to 50 ml, heated for 30 minutes, and then ultrasonically extracted to make 100 ml. 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) in the wavelength range 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 5 below.

Table 5

As shown in Table 5, 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 5, oral tablets prepared in Examples of the present invention contained an average of 95% or more of niacin, and it was confirmed to show significant results with conventional commercial preparations.

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 8th tablet dissolution test method. Specifically, after accurately weighing the tablet prepared in the embodiment of the present invention and a conventional commercial tablet, 900 ml of the elution solution from water, gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestine (pH 6.8) In the 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 simultaneously. The collected eluate was filtered through a 0.45 ㎛ membrane filter and then tested as the test solution under the following conditions.

<Condition>

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

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: 1 L of methanol (4: 1) is added and 1.1 g of 1-octane sulfonate is added to the 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. First, the formulation of the most appropriate example was selected and the tablets prepared in the embodiments of the present invention in water, artificial gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestinal fluid (pH 6.8) and conventional commercial tablets according to the selected prescription. A dissolution test was performed for. And dissolution rate in water compared to commercially available tablets are shown in Table 6.

Table 6

Example 9

20 mg of simvastatin, 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 were dried sufficiently in an oven at 60 ° C. and then milled evenly, followed by additional mixing of 2 mg of magnesium stearate for molding of the formulation, followed by a rotary purifier. It was prepared by tableting a tablet containing simvastatin.

<Example 10>

Tablets containing simvastatin were prepared in the same manner as in Example 9, except that 100.0 mg of lactose and 60.0 mg of microcrystalline cellulose were used in the composition of Example 9.

<Example 11>

Tablets containing simvastatin were prepared in the same manner as in Example 9, except that 120.0 mg of lactose and 40.0 mg of microcrystalline cellulose were used in the composition of Example 9.

<Example 12>

A tablet containing simvastatin was prepared in the same manner as in Example 9, except that 140.0 mg of lactose and 20.0 mg of microcrystalline cellulose were used in the composition of Example 9.

Example 13

Tablets containing simvastatin were prepared in the same manner as in Example 9, except that 60.0 mg of lactose and 100.0 mg of microcrystalline cellulose were used in the composition of Example 9.

<Example 14>

A tablet containing simvastatin was prepared in the same manner as in Example 9, except that 40.0 mg of lactose and 120.0 mg of microcrystalline cellulose were used in the composition of Example 9.

<Example 15>

Tablets containing simvastatin were prepared in the same manner as in Example 9 except that 20.0 mg of lactose and 140.0 mg of microcrystalline cellulose were used in the composition of Example 9.

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

TABLE 7

Experimental Example 5

Ten tablets of conventional commercial tablets (Zoko® tablets) and oral tablets containing simvastatin prepared in Examples of the present invention were each taken and measured for hardness 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. 20.0 mg of the powder prepared as simvastatin is accurately weighed, placed in a 100 ml volumetric flask, pH 4.0, acetonitrile: 0.01 M potassium dihydrogen phosphate solution (60:40), mixed with a sample solution, and prepared as a sample liquid. The content of simvastatin was measured by using a reversed phase column (C18) in the wavelength region of 238 nm by using the chromatography method. 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.

Table 8

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 8, the oral tablet prepared in Examples of the present invention contained more than 95% of simvastatin on average, and it was confirmed to show significant results with conventional commercial preparations.

Experimental Example 6

According to Method 8 of the Pharmacopoeia Eighth Amendment Test Method using 900 ml of the dissolution test solution (0.5% sodium lauryl sulfate, 0.01 M phosphate buffer, pH 7.0) with respect to the tablet prepared in the embodiment of the present invention, Test 50 turns at 37 ± 1 ° C per minute. After the elution test was started, 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 45 minutes, 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.

<Condition>

Column: Hypersil ODS C18 (250 × 4.6 mm)

Mobile phase: 0.025M sodium dihydrogen phosphate (pH 4.5): acetonitrile mixture (35:65)

Wavelength: 238nm

Flow rate: 1.5 ml / min

-Column temperature: 45 ℃

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 water compared to commercially available tablets are shown in Table 9.

Table 9

<Example 16>

The granules containing simvastatin prepared in the composition of Example 12 and the granules containing niacin prepared in the composition of Example 1 were compressed into two-layer tablets.

<Example 17>

The granules containing simvastatin prepared in the composition of Example 12 and the granules containing niacin prepared in the composition of Example 2 were compressed into two-layer tablets.

Example 18

The granules containing simvastatin prepared in the composition of Example 12 and the granules containing niacin prepared in the composition of Example 3 were compressed into two-layer tablets.

Example 19

The granules containing simvastatin prepared in the composition of Example 12 and the granules containing niacin prepared in the composition of Example 4 were compressed into two-layer tablets.

Experimental Example 7

Ten tablets of oral tablets containing niacin and simvastatin 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 simvastatin prepared as bilayer tablets were ground from induction to powder. The powder prepared above was weighed in an amount corresponding to 500 mg as niacin, respectively, placed in a 100 ml volumetric flask, and 50 ml of water was heated 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 using a reversed phase column chromatography (C18) in the wavelength range 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.

Also, the powder prepared above is weighed exactly 20.0 mg as simvastatin and placed in a 100 ml volumetric flask, and the pH is adjusted to 4.0 ml with acetonitrile: 0.01 M potassium dihydrogen phosphate solution (60:40). The content of simvastatin was measured by using a reverse phase column (C18) in the wavelength region of 238 nm by using liquid chromatography. 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.

Table 10

Example	Hardness (kg)	Simvastatin Content (%)	Niacin content (%)
Example 16	11.3	99.5	99.8
Example 17	11.2	99.4	99.2
Example 18	12.4	99.2	99.6
Example 19	12.8	100.4	100.1

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 lactose as an excipient was higher. In addition, as shown in Table 10, the oral tablet prepared in Examples of the present invention contains more than 95% of the average content of simvastatin 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 dissolution 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 in the following manner. .

A tablet containing a certain amount of niacin was tested for dissolution according to the pharmacopeia 8th tablet dissolution test method. Specifically, after accurately weighing the tablet prepared in the embodiment of the present invention and a conventional commercial tablet, 900 ml of the elution solution from water, gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestine (pH 6.8) In the 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.

<Condition>

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

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

Wavelength: 262 nm

Flow rate: 1.0 ml / min

Simbastatin, which is immediate release, in the bilayer tablet prepared in the above example, was used for 900 ml of the dissolution test solution (0.5% sodium lauryl sulfate, 0.01 M phosphate buffer, pH 7.0) according to the second method of the pharmacopeia 8th amendment dissolution test method, 37 ± per minute Test 50 revolutions at 1 ° C. 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes after the dissolution test, take about 10ml of the eluate, centrifuge at 4000rpm for about 2 minutes, add 1ml of supernatant to a 100ml volumetric flask, add acetonitrile to 100ml, and use the 0.45㎛ membrane filter. After filtration, the test solution was tested under the following conditions.

<Condition>

Column: Hypersil ODS C18 (250 × 4.6 mm)

Mobile phase: 0.025M sodium dihydrogen phosphate (pH 4.5): acetonitrile mixture (35:65)

Wavelength: 238nm

Flow rate: 1.5 ml / min

-Column temperature: 45 ℃

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 11 and Table 12.

Table 11

Table 12

 Example 20

In the niacin sustained-release composition of Example 4 described above, a sustained-release tablet coated with a coating consisting of the HMG-CoA reductase inhibitor simvastatin in immediate release form was prepared.

Tablets containing niacin were prepared using a rotary tablet machine in the composition prepared in Example 4.

The prepared niacin-containing sustained-release tablets were coated using a high coater HCT 48/60 as follows. 20 mg of simvastatin, 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. The mixture is passed through a 100mesh sieve and purified water is added slowly to a pre-weighed container 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 fan speed of 15 rpm, inlet air temperature of 60 ° C and exhaust air temperature of 40 ° C. When cooling, fan speed of 3.3 rpm, inlet air heating is stopped, and the temperature of coated tablet is cooled to 35 ° C or lower. do.

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

Example 21

The composition of Example 20 was prepared in the same manner as in Example 20, except that 0.02 mg of butylhydroxyanisole and 2.5 mg of ascorbic acid were further used as antioxidants to contain immediate-release simvastatin and sustained-release niacin. Coated tablets were prepared.

<Example 22>

A coated tablet containing immediate release simvastatin and sustained release niacin was prepared in the same manner as in Example 20, except that 0.092 mg of yellow iron oxide and 0.023 mg of red iron oxide were additionally used as a colorant in the composition of Example 20. Prepared.

<Example 23>

In the same manner as in Example 20, 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 an antioxidant in the composition of Example 20. The run preparations prepared coated tablets containing immediate release simvastatin, sustained release niacin.

Experimental Example 8

In the embodiment of the present invention 10 tablets containing oral tablets containing immediate release simvastatin was taken to measure the content and hardness in the same manner as in Experimental Example 7.

Table 13

As shown in Table 13, the hardness of the tablet containing the sustained release niacin coated with the rapid release HMG-CoA reduction inhibitor prepared in the embodiment of the present invention did not show a significant difference in the composition of the coating. In addition, as shown in Table 10, the oral tablet prepared in the Examples of the present invention contains more than 95% of the average content of simvastatin and niacin, and can be confirmed the significance of hardness compared to each single tablet. .

<Example 24>

In the niacin sustained-release composition of Example 8 described above, a sustained-release tablet coated with a coating consisting of the HMG-CoA reductase inhibitor simvastatin in immediate release form was prepared.

Tablets containing niacin were prepared using a rotary tablet machine for the composition prepared in Example 8.

The prepared niacin-containing sustained-release tablets were coated using a high coater HCT 48/60 as follows. 20 mg of simvastatin, 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. The mixture is passed through a 100mesh sieve and purified water is added slowly to a pre-weighed container 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 fan speed of 15 rpm, inlet air temperature of 60 ° C and exhaust air temperature of 40 ° C. When cooling, fan speed of 3.3 rpm, inlet air heating is stopped, and the temperature of coated tablet is cooled to 35 ° C or lower. do.

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

<Example 25>

The composition of Example 24 was prepared by the same method as in Example 24, except that 0.02 mg of butylhydroxyanisole and 2.5 mg of ascorbic acid were used as antioxidants to contain immediate-release simvastatin and sustained-release niacin. Coated tablets were prepared.

Example 26

A coated tablet containing immediate release simvastatin and sustained release niacin was prepared and prepared in the same manner as in Example 24, except that 0.092 mg of iron oxide yellow and 0.023 mg of red iron oxide were additionally used as a colorant in the composition of Example 24. Prepared.

Example 27

In the same manner as in Example 24, 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 antioxidants in the composition of Example 24. The run preparations prepared coated tablets containing immediate release simvastatin, sustained release niacin.

Experimental Example 9

In the above Example, 10 tablets were taken for oral tablet containing niacin immediately coated with immediate release simvastatin, and the content and hardness were measured in the same manner as in Experimental Example 8.

Table 14

 As shown in Table 14, 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 in the composition of the coating. In addition, as shown in Table 10, the oral tablet prepared in Examples of the present invention contains more than 95% of the average content of simvastatin and niacin, and can be confirmed the significance of hardness compared to each single tablet. .

Experimental Example 10

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 8th tablet dissolution test method. Specifically, after accurately weighing the tablet prepared in the embodiment of the present invention and a conventional commercial tablet, 900 ml of the elution solution from water, gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestine (pH 6.8) In the 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.

<Condition>

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

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

Wavelength: 262 nm

Flow rate: 1.0 ml / min

The immediate release simvastatin in the coating prepared in the embodiment of the present invention using 900 ml of elution test solution (0.5% sodium lauryl sulfate, 0.01M phosphate buffer, pH 7.0) according to the second method of the pharmacopeia 8th amendment dissolution test method, 37 Test 50 turns at ± 1 ° C. 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes after the dissolution test, take about 10ml of the eluate, centrifuge at 4000rpm for about 2 minutes, add 1ml of supernatant to a 100ml volumetric flask, add acetonitrile to 100ml, and use the 0.45㎛ membrane filter. After filtration, the test solution was tested under the following conditions.

<Condition>

Column: Hypersil ODS C18 (250 × 4.6 mm)

Mobile phase: 0.025M sodium dihydrogen phosphate (pH 4.5): acetonitrile mixture (35:65)

Wavelength: 238nm

Flow rate: 1.5 ml / min

-Column temperature: 45 ℃

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 Tables 15 to 18 below.

Table 15

Table 16

Table 17

Table 18

<Example 28>

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. In addition, 0.6 mg of polysorbate 80 as granules and 9 mg of croscarmellose sodium as disintegrants were used.

The granules were wet granulated using 3.0 mg of hydroxypropyl cellulose as a binder, and the granules prepared were sufficiently dried in an oven at 60 ° C. and then milled evenly. Prepared by mixing and tableting tablets containing atorvastatin using a rotary tablet machine.

Subsequently, the granules containing the atorvastatin thus prepared and the niacin-containing granules prepared in the composition of Example 4 were compressed into two-layer tablets.

<Example 29>

The granules containing atorvastatin prepared in the composition of Example 28 and the granules containing niacin prepared in the composition of Example 8 were compressed into two-layer tablets.

<Example 30>

In the niacin sustained-release composition of Example 4 described above, a sustained-release tablet coated with a coating consisting of the HMG-CoA reductase inhibitor atorvastatin in immediate release form was prepared.

Tablets containing niacin were prepared using a rotary tablet machine in the composition prepared in Example 4.

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. The mixture is passed through a 100mesh sieve and purified water is added slowly to a pre-weighed container 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 fan speed of 15 rpm, inlet air temperature of 60 ° C and exhaust air temperature of 40 ° C. When cooling, fan speed of 3.3 rpm, inlet air heating is stopped, and the temperature of coated tablet is cooled to 35 ° C or lower. do.

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

<Example 31>

The sustained-release tablet coated with the coating consisting of the HMG-CoA reductase inhibitor atorvastatin in immediate release form was prepared in the niacin sustained-release composition of Example 8 described above.

Tablets containing niacin were prepared using a rotary tablet machine for the composition prepared in Example 8.

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. The mixture is passed through a 100mesh sieve and purified water is added slowly to a pre-weighed container 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 fan speed of 15 rpm, inlet air temperature of 60 ° C and exhaust air temperature of 40 ° C. When cooling, fan speed of 3.3 rpm, inlet air heating is stopped, and the temperature of coated tablet is cooled to 35 ° C or lower. do.

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

A drug coating solution was prepared by dissolving a corresponding amount of other polymer including a hydrophilic polymer and a pH-dependent hydrophilic polymer in an appropriate amount of methanol, and then adding and dissolving a drug (atorvastatin). (Atorvastatin / coating base = 1/9 weight ratio). The concentration of solid components (drug and coating base) in the solution was adjusted to 10% (w / v).

Experimental Example 11

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. Put the powder prepared above as 500mg 1000.0mg corresponding amount of niacin, respectively, put in a 100ml volumetric flask, add 50ml water for 30 minutes, and ultrasonically extract and add water to make 100ml. 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) in the wavelength range of 262 nm. 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, filter the Korean liquor with 0.45㎛ membrane filter, and then reverse-phase column using a high-performance liquid chromatography method. 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 19 below.

Table 19

As shown in Table 19, the atorvastatin single tablet prepared in Examples of the present invention exhibited higher hardness than commercial tablets. In addition, as shown in Table 19, the oral tablet prepared in Examples of the present invention contained an average of 95% or more of atorvastatin and niacin, and the hardness of the tablets can be compared with each single tablet.

Experimental Example 12

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 8th tablet dissolution test method. Specifically, after accurately weighing the tablet prepared in the embodiment of the present invention and a conventional commercial tablet, 900 ml of the elution solution from water, gastric juice (pH 1.2), acetate buffer (pH 4.0), artificial intestine (pH 6.8) In the 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.

<Condition>

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

-Mobile phase: pH 3.0, 0.05mol Sodium dihydrogen phosphate: 1 L of methanol (4: 1) is added and 1.1 g of 1-octane sulfonate is added to the 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 Example was prepared using the 900 ml of water as a test solution. 50 revolutions per minute at 37 ± 1 ° C. 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes after the start of the dissolution test, 20 ml of the eluate is taken and filtered with a 0.45 um membrane filter. Discard the first 5 ml of the filtrate and use the following filtrate as the sample solution. Take the test solution and calculate the elution rate 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.

Table 20

Table 21

Table 22

Experimental Example 13: Comparative Dissolution Test of Existing Commercial Formulations and Formulations of the Invention

Dissolution tests were conducted to determine whether the niacin controlled release formulations and the existing commercially available niacin sustained release formulations contained in the composite formulation of the present invention maintained the matrix form for a desired time (at least 24 hours). Niacin controlled release formulations (500 mg of niacin, 90 mg of microcrystalline cellulose, 90 mg of microcrystalline cellulose, HPMC 170 mg and 16 mg of magnesium stearate) and commercially available niacin sustained release formulations included in the composite formulation according to the present invention each containing 500 mg of niacin. Niaspano ^™ was subjected to a dissolution test for 24 hours at 900 rpm of water at 37 ° C. and 50 rpm. For dissolution test, the test was performed using PT4005956 of Pharma test (Germany), and the paddle method of dissolution test Ⅱ of the USP was used. The test specimens were then taken out to confirm each matrix form retention (FIGS. 1 to 2). As a result, niaspano ^TM , a commercially available formulation, was gradually eroded and completely disintegrated and dispersed after 24 hours, thereby failing to maintain a constant matrix form. It was found that the formulation swelled for 24 hours to maintain a constant matrix form.

Experimental Example 14 Confirmation of Matrix Form Retention of Niacin Preparation According to Composition Ratio of Carboxyvinyl Polymer and HPMC

According to the composition ratio of the carboxyvinyl polymer and HPMC, to determine whether the niacin preparation maintains a constant matrix form, the matrix form was observed after the dissolution test for each composition ratio. Specifically, 500 mg of niacin tablets containing carboxyvinyl polymer: HPMC in a ratio of 1: 1, 1:10, 1:50, 1: 100, 1: 150, 1: 200, 10: 1 and 50: 1, respectively. , 90 mg of lactose and 16 mg of magnesium stearate were prepared to include carboxyvinyl polymer and HPMC in each ratio, and these tablets were subjected to a dissolution test for 48 hours at 900 rpm of water and 50 rpm at 37 ° C. Dissolution test method is the same as Experimental Example 13. After elution at each time period, the maintenance of the matrix form was visually confirmed, and the maintenance of the matrix form was based on maintaining the original shape of the tablet. The result is shown in FIG.

As can be seen in Figure 3, when the ratio of carboxyvinyl polymer to HPMC included in the niacin formulation is in the range of 50: 1 to 1: 100, the matrix form of the niacin tablet is maintained constant for at least 24 hours, but the range is In case of deviation, the shape retention time of the matrix was reduced drastically. In addition, when the ratio of carboxyvinyl polymer to HPMC is 50: 1 or 10: 1, although the matrix form may be maintained, the elution pattern of niacin is remarkably different when the ratio is maintained, such as hyperlipidemia and the like. It was confirmed that no dissolution rate could be indicated for the treatment of niacin applied disease (data not shown). Thus, when the carboxyvinyl polymer: HPMC is included in the niacin composition in a ratio of 1: 1 to 1: 100, the niacin tablet may exhibit the matrix form retention and proper dissolution of the niacin tablet. In the manufacture of tablets, even if the matrix form cannot be maintained for the desired time or the form is maintained, it is difficult to obtain a dissolution rate suitable for the treatment of niacin applied disease.

Experimental Example 15: Change of Dissolution Rate According to HPMC Type and Content

The type of HPMC can be classified into various types by the type of substituent, viscosity, sustained release (SR), ratio of methoxyl to hydroxypropyl group (methoxyl: hydroxypropyl), and the like.

First, the inventors identified dissolution rate profiles according to the viscosity of HPMC among them. Specifically, each of the niacin tablets by varying the viscosity of HPMC to 100, 400, 1500, 4000, 15000 and 100000 with the composition of 500 mg of niacin, 50 mg of lactose, 5 mg of magnesium stearate (lubricant) and 200 mg of HPMC. Prepared. Then, the niacin preparation was placed in 900 ml of water, and the dissolution rate of the niacin preparation was measured at each time zone at 50 rpm at 37 ° C., and the results are shown in FIG. 4. Dissolution test method is the same as Experimental Example 13.

Secondly, the inventors confirmed the dissolution rate profile according to the content of HPMC. Specifically, niacin tablets were prepared with a composition containing HPMC having a viscosity of 500 mg of niacin, 50 mg of lactose, 10 mg of magnesium stearate, and 100000 cps, wherein the content of HPMC was different within the range of 100 to 300 mg (100, 150). , 200, 250 and 300 mg). Thereafter, the niacin preparation was placed in 900 ml of water, and the dissolution rate of the niacin preparation was measured for each time zone at 50 rpm at 37 ° C., and the results are shown in FIG. 5. Dissolution test method is the same as Experimental Example 13.

As can be seen in Figures 4 and 5, the dissolution rate of the niacin formulation does not depend greatly on the content of the HPMC, it can be seen that it changes depending on the viscosity of the HPMC, niacin formulation when the viscosity of the HPMC is 100000 cps In consideration of the effects and side effects, the most appropriate elution rate was obtained.

Experimental Example 16: Change of Dissolution Rate According to Content of Carboxyvinyl Polymer

The present inventors prepared a niacin tablet with a composition containing 500 mg of niacin, lactose 50 mg, 10 mg magnesium stearate and carbomer (carboxyvinyl polymer) to observe the change in dissolution rate according to the content of the carboxyvinyl polymer, wherein the carbomer The content varied from 10 to 100 mg each. Then, the niacin preparation was added to 900 ml of artificial intestinal fluid (pH 7.5), and the dissolution rate of the niacin preparation was measured at each time period at 50 ° C. at 37 ° C., and the results are shown in FIG. 6. The dissolution test method was performed in the same manner as Experimental Example 13 except that artificial intestinal fluid was used as the eluent.

As can be seen in Figure 6, the dissolution rate of the niacin formulation was found to show a difference depending on the carbomer content.

Experimental Example 17: Dissolution Profile According to Type of Drug

In order to confirm whether the composition ratio of the carboxyvinyl polymer and HPMC according to the present invention is applied to other drugs besides niacin, dissolution test was performed according to the type of drug. Specifically, a formulation comprising lactose 90 mg, microcrystalline cellulose 90 mg, HPMC 170 mg and magnesium stearate 16 mg as a basic composition, and containing niacin (500 mg), propranolol (50 mg) and theophylline (50 mg) as active ingredients Each was prepared. Thereafter, the niacin preparation was placed in 900 ml of water, and the dissolution rate of the niacin preparation was measured at each time zone at 50 rpm at 37 ° C., and the results are shown in FIG. 7. Dissolution test method is the same as Experimental Example 13.

As can be seen in Figure 7, even if HPMC and carboxyvinyl polymer is included in the same ratio, each has a very different dissolution pattern depending on the type of drug and only niacin dissolution rate required for proper drug expression and reduction of side effects of niacin It was confirmed that the range was shown. As a result, it can be seen that the composition ratio of the HPMC and the carboxyvinyl polymer according to the present invention designed to establish an elution profile that can minimize the side effects of niacin is specifically applied to niacin.

The complex preparation according to the present invention inhibits HMG-CoA reductase, a rate-determining step for cholesterol biosynthesis, and elutes HMG-CoA reductase inhibitors that significantly lower the concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, and triglycerides. While increasing the amount of HDL-cholesterol, the form of the matrix of the niacin controlled release formulation having a synergistic effect is maintained until the dissolution of the formulation is completed, so that the dissolution pattern does not change drastically for the time required for dissolution of the drug, and the desired dissolution pattern is constantly It is maintained at, which has the effect of effectively treating hyperlipidemia or atherosclerosis, and significantly alleviating side effects caused by niacin to allow long-term treatment.

Claims (30)

1. Niacin; Hydroxypropylmethyl cellulose; Carboxyvinyl polymers; additive; A niacin controlled release formulation comprising a disintegrant and a lubricant, wherein the carboxyvinyl polymer and hydroxypropylmethylcellulose are included in a weight ratio of carboxyvinyl polymer: hydroxypropylmethylcellulose 1: 1.5 to 1:20.
2. The niacin controlled release formulation of claim 1 further comprising a binder.
3. The method of claim 1, wherein the disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone and other commercially available polyvinylpyrrolidone, low substituted hydroxypropylcellulose, A niacin controlled release formulation selected from the group consisting of alginic acid, carboxymethylcellulose calcium and sodium salts, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch, sodium alginate and mixtures thereof.
4. The niacin controlled release formulation of claim 1, wherein the glidant is selected from the group consisting of magnesium stearate, silica oxide, colloidal silicon dioxide, talc, and mixtures thereof.
5. The niacin controlled release formulation according to any one of claims 1 to 4, wherein the viscosity of the hydroxypropylmethylcellulose is 80,000 to 120,000 cps.
6. (a) niacin; Hydroxypropylmethyl cellulose; Carboxyvinyl polymers; Mixing the additive and the disintegrant;

   (b) adding a liquid solvent to prepare granules; And

   (c) mixing and tableting the lubricant;

   At this time, the carboxyvinyl polymer and hydroxypropyl methyl cellulose is carboxyvinyl polymer: hydroxypropyl methyl cellulose is a method of producing a niacin controlled release formulation in which the weight ratio is 1: 1.5 to 1:20.
7. The method of claim 6, wherein the step of (a) additionally mixing the binder together to prepare a niacin controlled release formulation.
8. The method of claim 6, wherein the liquid solvent is selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol, polyethylene glycol, and mixed solvents thereof.
9. The method of claim 8, wherein the liquid solvent is water or a mixed solvent of water and ethanol, wherein the amount of the liquid solvent is 10 to 30% by weight of the niacin weight ratio.
10. Niacin controlled release formulations comprising niacin, carboxyvinyl polymer and hydroxypropylmethylcellulose; And a HMG-CoA reductase inhibitor, wherein the carboxyvinyl polymer and hydroxypropylmethylcellulose are carboxyvinyl polymers: hydroxypropylmethylcellulose, which is included in a weight ratio of 1: 1 to 1: 100, hyperlipidemia or atherosclerosis Controlled Release Combination Formulations.
11. The formulation of claim 10 further comprising an antioxidant.
12. The formulation of claim 11, wherein the antioxidant is selected from the group consisting of vitamin C, vitamin E, tocopherol, cesamomol, ginger, capsaicin, quercetin, gallic acid and citric acid.
13. The formulation of claim 10 comprising a material selected from the group consisting of additives, disintegrants, glidants, binders and mixtures thereof.
14. The method of claim 13 wherein the disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone and other commercially available polyvinylpyrrolidone, low substituted hydroxypropylcellulose, Alginic acid, carboxymethylcellulose calcium and sodium salts, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch, sodium alginate and mixtures thereof.
15. The formulation of claim 13, wherein the glidant is selected from the group consisting of magnesium stearate, silica oxide, colloidal silicon dioxide, talc and mixtures thereof.
16. The formulation according to any one of claims 10 to 15, wherein the viscosity of the hydroxypropylmethylceltulose is 80,000 to 120,000 cps.
17. The formulation of claim 10, wherein the formulation of the combination formulation is a bilayer tablet or a coated tablet.
18. 18. The formulation of claim 17, wherein said coated tablet additionally comprises a plasticizer, a film former, a coating agent, and a coloring agent.
19. The formulation according to claim 17 or 18, wherein the coated tablet is coated with a composition containing a HMG-CoA reductase inhibitor to the nucleus containing niacin.
20. 18. The formulation of claim 17, wherein the bilayer tablet comprises a first tablet layer comprising 3-50% by weight of an HMG-CoA reductase inhibitor and a second tablet layer containing 30-70% by weight of niacin.
21. (a) niacin; Hydroxypropylmethyl cellulose; Carboxyvinyl polymers; Mixing the additive and the disintegrant;

    (b) HMG-CoA reductase inhibitors; additive; Disintegrants; And mixing antioxidants;

    (c) preparing granules by adding a liquid solvent to each of the mixtures prepared in steps (a) and (b); And

    (c) mixing and tableting the lubricant;

    At this time, the carboxyvinyl polymer and hydroxypropylmethylcellulose is a carboxyvinyl polymer: HPMC is mixed in a weight ratio of 1: 1 to 1: 100 of the controlled release type composite formulation for treating hyperlipidemia or arteriosclerosis according to claim 1 Manufacturing method.
22. The method of claim 20, wherein the binder is further mixed together in steps (a) and (b).
23. The method of claim 20, wherein the liquid solvent is selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol, polyethylene glycol and mixed solvents thereof.
24. (a) preparing a nucleus comprising a niacin controlled release formulation; And

    (b) coating a composition comprising an HMG-CoA reductase inhibitor to the nucleus prepared in (a),

    At this time, the carboxyvinyl polymer and hydroxypropylmethylcellulose is a carboxyvinyl polymer: HPMC is mixed in a weight ratio of 1: 1 to 1: 100 of the controlled release type composite formulation for treating hyperlipidemia or arteriosclerosis according to claim 1 Manufacturing method.
25. The method of claim 10, wherein the carboxyvinyl polymer: hydroxypropyl methyl cellulose is 1: 1.5 to 1: 50 of the controlled release type composite formulation for treating hyperlipidemia or atherosclerosis, which comprises a weight ratio.
26. The method of claim 10, wherein the carboxyvinyl polymer: hydroxypropyl methyl cellulose is 1: 1.5 to 1: 20 of the controlled release type composite formulation for treating hyperlipidemia or atherosclerosis, which comprises a weight ratio.
27. The method of claim 21, wherein the carboxyvinyl polymer: hydroxypropylmethylcellulose is mixed in a weight ratio of 1: 1.5 to 1:50.
28. The method of claim 21, wherein the carboxyvinyl polymer: hydroxypropylmethylcellulose is mixed in a weight ratio of 1: 1.5 to 1:20.
29. The method of claim 24, wherein the carboxyvinyl polymer: hydroxypropylmethylcellulose is mixed in a weight ratio of 1: 1.5 to 1:50.
30. The method of claim 24, wherein the carboxyvinyl polymer: hydroxypropylmethylcellulose is mixed in a weight ratio of 1: 1.5 to 1:20.

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