KR20010022508A - COMBINATIONS OF HMG-CoA REDUCTASE INHIBITORS AND NICOTINIC ACID COMPOUNDS AND METHODS FOR TREATING HYPERLIPIDEMIA ONCE A DAY AT NIGHT - Google Patents

Abstract

The present invention relates to a solid pharmaceutical composition for oral administration comprising a nicotinic acid or nicotinic acid compound or a mixture of nicotinic acid compounds in a sustained release form and an HMG-CoA reductase inhibitor, wherein the composition is hepatotoxic by a drug, It is useful for altering lipid levels in patients with hyperlipidemia and atherosclerosis, without causing rhabdomyolysis. In addition, the present invention provides a single dosage for evening hours without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis, or without causing hepatotoxicity, myopathy, or rhabdomyolysis by at least a significant number of individual drugs. By administering the oral solid pharmaceutical composition once a day to a level that requires the discontinuation of the treatment of the disease, for example, hyperlipidemia in hyperlipidemia, normal lipidemia diagnosed or likely to be cardiovascular disease. A method for altering serum lipids in a patient to be treated for lipidemia and atherosclerosis. More specifically, the present invention provides, for example, (1) immediate or sustained release HMG-CoA reductase inhibitors, (2) a mixture of nicotinic acid or nicotinic acid compounds or nicotinic acid compounds and (3) the nicotinic acid or nicotinic acid compounds or nicotinic acid It consists of a swelling agent that forms a sustained release composition for the slow release of a mixture of compounds, and relates to an oral solid pharmaceutical composition administered at night or evening to reduce serum lipids and increase HDL-cholesterol. According to the present invention, at night to alter the night-release sustained-release serum lipid composed of nicotinic acid and hydroxypropyl methylcellulose in a formulation of a sustained-release tablet or caplet coated with a coating of an HMG-CoA reductase inhibitor in immediate release form Serum lipid modifying compositions for oral administration are illustrated. In addition, in the present invention, the pharmaceutical composition may include a nonsteroidal anti-inflammatory agent for reducing the ability of the nicotinic acid or nicotinic acid compound to generate an exothermic reaction in the subject.

Description

Composition of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and nicotinic acid compound and method of treating hyperlipidemia by administering once daily at night {COMBINATIONS OF HMG-CoA REDUCTASE INHIBITORS AND NICOTINIC ACID COMPOUNDS AND METHODS FOR TREATING HYPERLIPIDEMIA ONCE A DAY AT NIGHT}

Elevated hyperglycemia or elevated serum lipids is associated with an increased incidence of cardiovascular disease and atherosclerosis. Specific types of hyperlipidemia include, for example, hypercholesterolemia, familial abnormal betalipoproteinemia, diabetic abnormal lipidemia, 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, lowering of 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, namely type IIa, IIb, IV, V or hyperapobetalipoproteinemia.

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

Hypertriglyceridemia is also an independent risk factor for cardiovascular disease (eg, coronary artery disease). Most people with hyperlipidemia or hypercholesterolemia have high levels of triglycerides. It is known that lowering high levels of triglycerides can indirectly lower cholesterol. In addition, they should consider lipid lowering therapies that lower high levels of triglycerides for the purpose of reducing the incidence of atherosclerosis and coronary artery disease.

Cholesterol is carried in the blood by lipoprotein complexes such as VLDL-cholesterol, LDL-cholesterol and high density lipoprotein-cholesterol (HDL-cholesterol). LDL carries cholesterol in the blood into the subdermal space of the vessel wall. Thrombus formation of atherosclerosis is thought to occur when LDL-cholesterol in the subcutaneous space of the vessel wall is peroxidated. 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. Until recently several subtypes of HDL-cholesterol have been identified, such as HDL ₁ -cholesterol, HDL ₂ -cholesterol, HDL ₃ -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, and cerivastatin. Still other examples of HMG-CoA reductase inhibitors include U.S. Pat. 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 alcohol 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 other known serum cholesterol lowering agents, such as those described in US Patent Application No. 2216-179-A.

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

Nicotinic acid has usually been 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 Lipoproteins in Hyperlipidemic Subjects: Clues to Mechanism of Action of Niacin"; Metabolism (34) 7: 642-647 (1985) is known to provide a very beneficial effect on blood lipids as discussed in. A major advantage of this profile is the ability of nicotinic acid to lower total cholesterol, LDL-cholesterol, triglycerides and Lp (a) while increasing HDL-cholesterol particles. Although such a regimen has a beneficial effect, skin fever symptoms still occur in patients with hyperlipidemia administered with nicotinic acid.

To prevent or alleviate the symptoms of skin fever caused by nicotinic acid treatment, guar gum reported in US Pat. No. 4,965,252, inorganic salts disclosed in US Pat. No. 5,023,245, inorganic magnesium salt reported in US Pat. No. 4,911,917, PCT application A formulation for administration with an antihyperlipidemic effective amount of nicotinic acid, such as a nonsteroidal anti-inflammatory agent such as aspirin disclosed in US96 / 32942, has been proposed. These drugs are reported to prevent or alleviate skin fever side effects that are commonly associated with nicotinic acid split dose treatment.

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. This slow drug release lowers and prolongs drug levels in the blood, thus reducing or reducing the 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-Furn Lauler), Endur-acin® (Innobyte Corporation) and two other types of hydroxypropyl methylcelluloses and hydrophobic components Such as those described in US Pat. Nos. 5,126,145 and 5,268,181, which describe sustained release niacin preparations.

Studies using multiple sustained release niacin products have been made for patients with hyperlipidemia. These studies have shown that sustained release products do not have the same beneficial lipid altering effects as immediate release niacin and actually produce a more severe profile of side effects than immediate release products. As reported in Knob et al., Metabolism, 34 (7): 642-647 (1985), the major drawback of sustained release formulations is that significantly lower triglyceride reduction rates (-2 for sustained release formulations). %, But -38% for immediate release formulations, lower HDL-cholesterol growth rate (+ 8% for sustained release formulations, but + 22% for immediate release formulations) and more Low growth rate of HDL ₂ -cholesterol particles (+ 5% for sustained release formulations, but + 37% for immediate release formulations).

In addition, sustained-release niacin preparations further increase the incidence of hepatotoxicity, as described by Henken et al. (Am J Med, 91: 1991 (1991)) and Dalton et al. (Am J Med, 93: 102 (1992)). It is known to make. There is also a significant association with regard to the potential for disrupting glucose metabolism and uric acid levels of these agents.

In the previous edition of the Journal of American Medical Association (JAMA), a paper describing the results of a study of hepatotoxicity associated with sustained-release formulations of nicotinic acid, ie ["A Comparison of the Efficacy and Toxic Effects of Sustained-" vs. Immediate-Release Niacin in Hypercholesterolemic Patients ", McKenny et al., JAMA, 271 (9), 672 (1994.3.2). The paper published a study of 23 patients. Eighteen or 78% of these patients were forcibly evicted because of an increased rate of indication of potential liver damage by liver function tests (LFT). The authors concluded that the sustained release formulation of niacin should "restrict its use."

A paper by representatives of the Food and Drug Administration (FDA) [“Hepatic Toxicity of Unmodified and Time-Release Preparations of Niacin”, Rader et al .; Am J Med, 92:77 (1992.1). Due to these studies and similar conclusions drawn by other health care professionals, sustained release formulations of niacin have been used only in limited quantities.

In addition, HMG-CoA reductase inhibitors have been used to treat hyperlipidemia for decades. These compounds are known to have a beneficial effect of lowering total cholesterol and LDL-cholesterol in the human body and raising HDL-cholesterol levels in some individuals. See Grundi S.M, N Engl J Med, 319 (1): 24-32, 25-26 and 31 (1988.7.7). The conversion of HMG-CoA to mevalonate is an early stage of cholesterol biosynthesis. Inhibition of HMG-CoA reductase that interferes with the production of mevalonate is made in accordance with the HMG-CoA reductase inhibitor exhibiting their total cholesterol lowering effect and LDL-cholesterol lowering effect. See Grundi S.M. N Engl J Med, 319 (1): 24-32, 25-26 (1988.7.7).

However, HMG-CoA reductase inhibitors have drawbacks. HMG-CoA reductase inhibitors are described, for example, in Garnet 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), are known to cause hepatotoxicity, myopathy or rhabdomyolysis.

In addition, in column 1, page 3 of the 50th edition of the Physics Desk Reference (PDR) (1996), lovastatin, an HMG-CoA reductase inhibitor, should be used carefully in patients with a history of liver disease. It is reported that lovastatin therapy should be contraindicated in individuals with unexplained persistent ascension or active liver disease. In addition, the 1996 edition of the PDR, in column 1701, page 1701, shows that rhabdomyolysis occurs in lovastatin alone treatment and in parallel treatment with nicotinic acid at a lipid lowering dose (≥1 g / day). Physicians considering co-administration with nicotinic acid should carefully assess the potential effects and risks, and especially any signs of myalgia, tenderness or weakness in the subject during the first few months of treatment and during titer of doses of the two drugs and It is reported that the symptoms should be monitored carefully. In addition, the 1996 edition of PDR reported that a case of muscle disease in a column 1701 page 1 correlates with a patient taking a combination of nicotinic acid and lovastatin at a lipid-lowering dose. In addition, the 1996 edition of the PDR contained similar contraindications for (1) fluvastatin in column 3, page 2267 and column 1, page 2268, (2) pravastatin in column 1, page 767 and (3) simvastatin, column 2, page 1777. Reported. In addition, PDR reports, on page 768, column 3, that the combination therapy of HMG-CoA reductase inhibitors with these drugs (lipophilic doses of nicotinic acid) is not normally recommended.

Despite these recommendations in the 1996 edition of the PDR, Grundi SM, N Engl J Med, 319 (1): 24-33 (1988.7.7), provided that HMG-CoA reductase inhibitors were administered alone (page 29-30) and nicotinic acid alone (page 24) are reported to be effective in lowering high cholesterol levels in plasma. In addition, Grundi, in lines 10-25 of column 2 on page 24, said, "Bile acid blockers (cholestiramine and cholestipol) and niacin are considered to be the most suitable drugs for hypercholesterolemia due to their efficacy." These drugs are very effective and satisfactory when used in many patients with high cholesterol, but unfortunately not all patients have good resistance to these drugs, so bile acid blockers and niacin may It is not an ideal cholesterol lowering agent though. " In addition, Grundi, page 30, column 13-17, states that "administering a [HMG-CoA] reductase inhibitor twice a day is somewhat more effective than administering it once a day at the same total dose." It is reported. In addition, Grundi, in column 1 on page 29, column 7-11, states that "administering a combination of lovastatin and cyclosporine, gemfibrozil or nicotinic acid may result in patients having predisposition to muscle disease and, in some cases, even rhabdomyolysis. Is there. " In addition, Grundi, page 30, column 1, lines 54-59, stated that "combined administration of lovastatin and niacin has not been found to be safe in controlled clinical trials, and adverse reactions between the drugs (e.g. myopathy) may occur. You can. " However, Gardner S.F. Et al. (Pharmacotherapy, 16 (3): 421-423 (1996)), S. H. of Pasternak R.C. et al. [Ann Intern Med, 125 (7): 529-540 (1996.10.1)], O'Keefe J.H. See Am J Cardiol, 76: 480-484 (1995.9.1), and Davignon J. et al. Am J Cardiol, 73: 339-345 (1994.2.15).

In page 183 of Bassek JL et al., Am J Cardiol, 76: 182-184 (1995.7.15), “A drug of this formulation is currently known as lovastatin because the risk of hepatotoxicity associated with sustained release formulations of nicotinic acid is known. Should not be used in future trials or clinical care. "

Bassek J.L. As reported by the 1996 and PDR editions, Jacobson T.A. And page 28D-29D of Amorossa LF (Am J Cardiol, 73: 25D-29D (1994.5.26)), “Aberrant and abrupt liver failure of liver enzyme profiles correlates with the use of niacin, especially sustained release preparations. … (Omitted)… According to this study, the combination use of fluvastatin and sustained release niacin preparations cannot normally be recommended, only for crystalline or immediate release niacin. ”

Thus, methods of delivering lipid altering agents or anti-lipidemia agents and those agents to provide a "balanced lipid alteration" to a patient, in particular on hepatotoxicity, effects on glucose metabolism or uric acid levels, on muscle disease and rhabdomyolysis It is foreseen by the aforementioned scientific literature that there is a need for a method of increasing HDL particles as well as lowering total cholesterol, LDL-cholesterol, triglycerides and Lp (a) with an acceptable safety profile.

The present invention generally relates to nicotinic acid or nicotinic acid compounds or mixtures thereof in a sustained release form and 3-hydroxy-3-methylglutaryl coenzyme A (in a sustained release or sustained release form). A pharmaceutical composition for oral administration comprising a HMG-CoA) reductase inhibitor, wherein the combination causes hepatotoxicity, myopathy, or rhabdomyolysis by the drug when administered once daily as a single dose during the evening. This is useful for altering serum lipid levels in an individual without this. In addition, the present invention, oral administration of the pharmaceutical composition to the subject once a day as a single dose during the evening to change the lipid level in the serum, for example, to cause hepatotoxicity, myopathy or rhabdomyolysis by drugs A method of treating hyperlipidemia and atherosclerosis without.

Summary of the Invention

In summary, the present invention relates to a novel pharmaceutical composition for oral administration of HMG-CoA reductase / nicotinic acid and methods of treatment using such pharmaceutical compositions, the existing tactics in connection with HMG-CoA reductase inhibitor therapy and nicotinic acid therapy. One alleviates and overcomes certain problems and drawbacks.

According to the present invention, the present invention provides oral administration for altering serum lipid levels in an individual, for example, to alleviate hyperlipidemia and to suppress atherosclerosis without causing hepatotoxicity, rhabdomyolysis or muscle disease by drugs. It provides a pharmaceutical composition. Typically, the pharmaceutical compositions of the present invention comprise nicotinic acid, a derivative of nicotinic acid, a compound that is metabolized in the body to form nicotinic acid or any mixture thereof, and a HMG-CoA reductase inhibitor. The pharmaceutical composition is administered in an amount effective to alter or decrease serum lipid levels such as total cholesterol, VLDL-cholesterol, LDL-cholesterol, Lp (a) and triglyceride levels, and to enhance or increase HDL-cholesterol levels. do. This results in no drug-induced hepatotoxicity, rhabdomyolysis, or muscle disease, or a deleterious effect on glucose metabolism or uric acid levels, or at least to the level at which the discontinuation of the treatment is required in the least evaluable population. This is achieved without causing the above side effects.

According to the invention, the pharmaceutical composition is administered once daily as a single oral dose. For individuals with a typical weekly schedule, a single oral dose may be administered in the evening, for example during or after dinner, or at bedtime, such as total cholesterol, VLDL-cholesterol, LDL-cholesterol, Lp (a) -In vivo, it is desirable to achieve in vivo levels in the individual that are effective in lowering cholesterol, Lp (a) and triglyceride levels and improving or increasing HDL-cholesterol levels, with some of the lipid components in the individual It is mainly biosynthesized at night. Unlike weekly schedules, for individuals with typical nighttime schedules, such as those who work at night and sleep during the day, it may be desirable to administer the pharmaceutical compositions of the present invention as a single oral dose at or near daytime bedtime. have.

In addition, when the pharmaceutical composition of the present invention is administered once daily as a single oral dose, the single dose was found to be higher than that obtained using only nicotinic acid in terms of reducing total cholesterol, LDL-cholesterol and triglycerides. lost. Indeed, the pharmaceutical compositions of the present invention, when administered at a single oral dose, result in substantially higher levels of total cholesterol, LDL-cholesterol and triglyceride levels than at the same dose of lipid-lowering drug alone as a single dose. It was found to lower. In addition, the pharmaceutical compositions of the present invention, when administered as a single oral dose, increase HDL-cholesterol levels to substantially greater levels than when administered only the same dose of HMG-CoA reductase inhibitor as a single dose. It turned out. In addition, when the pharmaceutical composition of the present invention is administered once a day in a single dosage form, the single dose is (1) an amount equal to or greater than the daily dose of nicotinic acid administered at least in part, and the division of the nicotinic acid It has been found to be as effective as a combination of the same daily oral dose of HMG-CoA reductase inhibitor administered separately from the dose, and (2) has a lower performance in producing hepatotoxicity than the split dose therapy.

The pharmaceutical compositions of the present invention, for example, do not cause liver damage, rhabdomyolysis or muscle disease caused by drugs, or without adversely affecting glucose metabolism or uric acid levels, and hyperlipidemia (eg, cholesterol-related cardiovascular system). Disease) and various etiologies and atherosclerosis diagnosed with or prone to cardiovascular disease, and predisposed normal lipidemia.

The pharmaceutical compositions of the present invention are considered as combinations of (a) HMG-CoA reductase inhibitors, and (b) nicotinic acid derivatives as well as nicotinic acid derivatives in the sustained release form, compounds metabolized to nicotinic acid in the body, and any mixtures thereof, Preferred pharmaceutical compositions according to the invention are pharmaceutical compositions for oral administration consisting of HMG-CoA reductase inhibitors in immediate release form and nicotinic acid in sustained release form. Preferred HMG-CoA reductase inhibitors include atorvastatin, cervastatin, fluvastatin, lovastatin, pravastatin and simvastatin.

In carrying out the methods of the invention, the pharmaceutical compositions of the invention may be administered to humans and other animal species, such as cattle, dogs, cats, pigs, horses, sheep, rabbits, mice, rats, rodents, monkeys, and the like. Or, as such, may be incorporated into conventional systemic dosage forms (eg, tablets, capsules, caplets, granules, beads, etc.). Drugs known to reduce or prevent skin fever symptoms, as well as other lipid modifiers or hypolipidemic agents, can be incorporated into the pharmaceutical compositions so long as these drug additives do not interfere with the object of the present invention. It may also be administered in parallel with the pharmaceutical composition in a suitable regimen that reinforces the beneficial effects of the pharmaceutical composition of the present invention.

The present invention also relates to a method of reducing or eliminating the symptoms of fever caused by nicotinic acid, which limits patient compliance by pretreatment of the subject with a non-steroidal anti-inflammatory agent (NSAID) prior to initiating nicotinic acid therapy. Pretreatment with low doses of NSAIDs (eg, aspirin), when used according to a predose regimen, progressively inhibits production of prostaglandin D ₂ (PGD ₂ ) and increases resistance to nicotinic acid administration. . The method of pre-administering NSAIDs to a subject in accordance with the present invention comprises administering a small dose of NSAID (e.g. aspirin) at least about 7 days, preferably at least about 14 days once to four times prior to administering nicotinic acid. The process of administration.

Dosages to be administered should be carefully adjusted according to the age, body weight and symptoms of the patient, as well as the route of administration, dosage form and regimen, and the desired outcome.

Thus, for oral administration, for example, the HMG-CoA reductase inhibitor is administered in a 1996 edition PDR as described above in the 1996 edition or in the package insert of the product, such as about 0.05 mg to about 160 mg, preferably Is an amount present in the range of from about 0.05 mg to 80 mg, more preferably from about 0.2 mg to about 40 mg, as indicated in the PDR above, from about 250 mg to about 3000 mg, preferably about about nicotinic acid. Satisfactory results could be obtained when used in combination with a commonly used dosage of nicotinic acid as an amount present in the range of 500 mg to about 2500 mg, most preferably from about 1000 mg to about 2000 mg. The HMG-CoA reductase inhibitor and nicotinic acid are used together in the same oral dosage form or in separate oral dosage forms administered simultaneously or nearly simultaneously. Therefore, nicotinic acid can be administered daily in increments of, for example, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg and 3000 mg. Thus, oral dosage forms of the invention may contain nicotinic acid at dosages of, for example, 250 mg, 375 mg, 500 mg, 750 mg and 1000 mg.

Those skilled in the art should naturally appreciate that the exact dosage of the HMG-CoA reductase inhibitor depends on the specific HMG-CoA reductase inhibitor chosen. Therefore, according to the present invention, oral dosage forms for achieving the desired daily dosage amount comprise lovastatin, atorvastatin or pravastatin, such as from about 10 mg to about 80 mg or more, such as 10 mg, 20 mg, 40 As a dosage of mg or 80 mg simvastatin, for example fluvastatin, in an amount of about 5 mg to about 80 mg or more, for example 5 mg, 10 mg, 20 mg, 40 mg or 80 mg, Such as about 20 mg to 80 mg or more, for example 20 mg, 40 mg or 80 mg, and cerivastatin, such as about 0.05 mg to about 0,3 mg or more, for example As dosages of 0,5 mg, 0.1 mg, 0.2 mg and 0.3 mg.

Thus, in accordance with the present invention, solid oral dosage forms, such as tablets, contain an HMG-CoA reductase inhibitor in an amount of about 0.05 mg to about 40 mg, preferably about 0.1 mg to about 20 mg, and about 250 mg to nicotinic acid. It may be contained in an amount of about 1000 mg, preferably 500 mg to about 1000 mg. Examples of solid oral dosage forms according to the invention include, for example, 250 mg / 5 mg, 500 mg / 5 mg, 750 mg / 5 mg, 1000 mg / 5 mg, 250 mg / 7.5 mg, 500 mg / 7.5 mg, 750 mg / 7.5 mg, 1000 mg / 7.5 mg, 250 mg / 10 mg, 500 mg / 10 mg, 750 mg / 10 mg, 1000 mg / 10 mg, 250 mg / 20 mg, 500 mg / 20 mg, 750 mg / Nicotinic acid / atorvastatin, fluvastatin, lovastatin, pravastatin or at 20 mg, 1000 mg / 20 mg, 250 mg / 40 mg, 500 mg / 40 mg, 750 mg / 40 mg, and 1000 mg / 40 mg dosage concentrations Simvastatin tablets and such as 250 mg / 0.05 mg, 500 mg / 0.05 mg, 750 mg / 0.05 mg, 1000 mg / 0.05 mg, 250 mg / 0.1 mg, 500 mg / 0.1 mg, 750 mg / 0.1 mg, 1000 mg / 0.1 mg, 250 mg / 0.15 mg, 500 mg / 0.15 mg, 750 mg / 0.15 mg, 1000 mg / 0.15 mg, 250 mg / 0.2 mg, 500 mg / 0.2 mg, 750 mg / 0.2 mg, 1000 mg / 0.2 mg , Nicotinic acid / cerivastatin tablets at 250 mg / 0.3 mg, 500 mg / 0.3 mg, 750 mg / 0.3 mg and 1000 mg / 0.3 mg dosage concentrations.

Therefore, a first object of the present invention is to include (a) HMG-CoA reductase inhibitors, (b) nicotinic acid, nicotinic acid derivatives in sustained release form, compounds metabolized in the body to form nicotinic acid, and mixtures thereof, It is to provide a pharmaceutical composition for oral administration for altering lipids to treat an individual, such as an individual diagnosed with lipidosis in a patient with hyperlipidemia, atherosclerosis and normal lipidemia.

A second object of the present invention is to provide an oral solid pharmaceutical composition having sustained-release nicotinic acid, a derivative of nicotinic acid, a compound metabolized into nicotinic acid in the body or a mixture thereof, and a sustained-release and immediate-release HMG-CoA reductase inhibitor. It is.

A third object of the present invention is to use the above-described composition for treating normal lipidemia diagnosed or susceptible to hyperlipidemia or cardiovascular disease, with little or no occurrence of liver damage, muscle disease or rhabdomyolysis. To provide a way.

At least one or more of the above-mentioned objects, together with the known techniques related to the treatment of hyperlipidemia, which will become apparent from the following description, are achieved by the invention described below and in the claims.

In general, the present invention provides an improved lipid-modifying or anti-hyperlipidemic oral pharmaceutical composition using an effective amount of HMG-CoA reductase inhibitor and nicotinic acid that alters lipids or inhibits hyperlipidemia. The composition mixes nicotinic acid with, for example, about 5% to about 50% by weight of hydroxy propyl methyl cellulose relative to 100 parts by weight of the tablet or formulation, and mixes the tablet with about 0.01% to about 30% by weight of the tablet or formulation. Coating with a negative HMG-CoA reductase inhibitor.

In addition, the present invention provides about 0.01% to about 30% by weight of HMG-CoA reductase inhibitor, about 30% to about 90% by weight of nicotinic acid, and about 5% to about 50 hydroxy propyl methyl cellulose. It provides a lipid-modified or antihyperlipidemic oral composition comprising% by weight.

The invention also includes a method of altering lipid levels in a subject, such as treating hyperlipidemia in a patient with hyperlipidemia, or lipidemia in a normal lipidemia patient diagnosed or susceptible to cardiovascular disease. The method comprises the steps of preparing a composition comprising an effective amount of an HMG-CoA reductase inhibitor and nicotinic acid that alters lipids and an excipient in an amount to provide such a rapid or sustained release HMG-CoA reductase inhibitor and a sustained release nicotinic acid. It includes. The method also includes orally administering the composition to a hyperlipidemic patient or a patient with normal lipidemia at night time.

The method for treating hyperlipidemia or hyperlipidemia in hyperlipidemia patients or hyperlipidemia patients according to the present invention is an HMG-CoA reductase inhibitor and nicotinic acid in an effective amount that effectively alters lipids in hyperlipidemia patients or normal lipidemia patients. Administering nicotinic acid derivatives, compounds metabolized to nicotinic acid in the body, or mixtures thereof. The dosage is administered once daily, preferably in the evening or at night, with pharmaceutically acceptable carriers, as well as a significant decrease in triglycerides and Lp (a) with a significant increase in HDL cholesterol, as well as total cholesterol and Produces significant degradation of LDL-cholesterol.

The above features and advantages of the present invention will be more readily understood by reference to the following detailed description and examples. It is to be understood that the specific methods and formulations illustrating the invention are for purposes of illustration only and should not be regarded as limiting the invention.

details

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following detailed description and examples are provided below in connection with novel methods and medicaments by providing a more complete understanding and a number of advantages that accompany the present invention.

The present invention exhibits the same effect as described herein using HMG-CoA reductase inhibitors, nicotinic acid, nicotinic acid derivatives or compounds dashed into nicotinic acid in the body (except nicotinic acid itself) and mixtures thereof. Specific examples of nicotinic acid derivatives and other compounds include nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH- Nicotinic acid, nicotinic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl Esters of -2-pyridone-5-carboxylic acid, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and nicotinic acid, such as methyl ester, Lower alcohol esters such as ethyl esters, propyl esters or butyl esters, but are not limited to these. These optional derivatives or compounds are each referred to as "nicotinic acid compounds" as described above.

Examples of specific HMG-CoA reductase inhibitors include lovastatin and related compounds disclosed in US Pat. No. 4,231,938, pravastatin and related compounds reported in US Pat. Nos. 4,346,227 and 4,448,979, and mevastatin disclosed in US Pat. No. 3,983,140. Compounds, velostatin and simvastatin and related compounds disclosed in US Pat. Nos. 4,448,784 and 4,450,171, fluvastatin, atorvastatin, rivastatin and fluindostatin (acidos XU-62-320), preferably fluvasu Tannins, lovastatin, pravastatin, atorvastatin, simvastatin and cerivastatin, but are not limited to these. Other HMG-CoA reductase inhibitors that can be used in the present invention include pyrazole analogues of mevalonolactone derivatives disclosed in US Pat. No. 4,613,610, indentation analogues of mevalonolactone derivatives disclosed in PCT Application WO 86/03488. 6- [2- (substituted-pyrrole-1-yl) alkyl] pyran-2-one and derivatives thereof disclosed in US Pat. No. 4,647,576, Seale SC-45355 (3-substituted pentanedione) Acid derivatives) dichloroacetate, imidazole analogue of mevalonolactone disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphate derivative disclosed in French Patent No. 2,596,393, European Patent Application No. 2,3-di-substituted pyrrole, furan and thiophene derivatives disclosed in 0221025 A14, naphthyl analogs of mevalonolactone disclosed in US Pat. No. 4,686,237, octahydronaphthelene disclosed in US Pat. No. 4,499,289, European Patent Lovastatin disclosed in Application No. 0142146 A2 As well as keto analogs of U.S. Patents 2,205,837 and 2,205,838, and U.S. Patents 5,217,992, 5,196,440, 5,189,180, 5,166,364, 5,157,134, 5,110,940, 5,106,992, 5,099,035 5,081,136, 5,049,696, 5,049,577, 5,025,017, 5,011,947, 5,010,105, 4,970,221, 4,940,800, 4,866,058, 4,686,237 CoA reductase inhibitors, but are not limited to these.

As mentioned above, in the past, HMG-CoA reductase inhibitors and nicotinic acid have been used to treat hyperlipidemia, a symptom characterized by the presence of excess fats such as cholesterol and triglycerides in the bloodstream. According to one aspect of the invention, a sustained or sustained release composition of nicotinic acid is prepared which is coated with a rapid release coating of an HMG-CoA reductase inhibitor. "Extended release or sustained release" is a composition in which an active ingredient, such as an HMG-CoA reductase inhibitor, nicotinic acid, nicotinic acid compound, or mixtures thereof, is released to be absorbed into the bloodstream over a period of time when administered orally to a patient to be treated. It means. For example, at a dose of about 1500 milligrams of nicotinic acid (hereinafter referred to as mg), approximately 100% nicotinic acid is preferably released into the bloodstream within about 4 hours to about 8 hours after ingestion, preferably within about 6 hours.

HMG-CoA reductase inhibitors can also be formulated to be immediate or sustained release after ingestion while nicotinic acid is released from the pharmaceutical composition in a sustained release manner. By "immediate release" is meant that when administered orally to a patient to be treated, the HMG-CoA reductase inhibitor is completely released from the composition to be absorbed into the bloodstream within about 30 minutes after ingestion.

Specific sustained release compositions according to the present invention utilize an effective amount of nicotinic acid to alter lipids coated with an effective amount of HMG-CoA reductase inhibitor to alter lipids. "Effective amount that alters lipids" or "effective amount that inhibits hyperlipidemia" means an amount that has a beneficial effect on the physiology of a patient when orally administered to a patient to be treated, and total cholesterol, LDL in the blood flow of the patient At least partially lowering one or more of cholesterol, triglycerides and Lp (a), increasing at least a portion of HDL-cholesterol, and more specifically, for example, increasing HDL ₂ -cholesterol and / or HDL ₃ -cholesterol . The beneficial effect also includes some reduction in the ratio of total cholesterol to HDL-cholesterol and the ratio of LDL-cholesterol to HDL-cholesterol in the bloodstream of the patient. In some patients, the beneficial effect may also include a decrease in apolipoprotein B, a decrease in apolipoprotein E, and / or an increase in apolipoprotein AI. Examples of effective amounts of altering the lipids of nicotinic acid are from about 250 mg to about 3000 mg of nicotinic acid to be administered according to the present invention, which is described in more detail below. An example of an effective amount of an HMG-CoA reductase inhibitor that alters lipids is from about 0.1 mg to about 80 mg. These amounts, of course, depend on a number of variables, including the physiological needs of the patient to be treated.

In addition, the sustained release composition according to the present invention includes a swelling agent or a sustained release drug mixed with nicotinic acid and / or nicotinic acid compound, and when the composition is orally administered to a patient, the swelling agent expands over time in the patient's gastrointestinal tract. And to release the active nicotinic acid and / or nicotinic acid compound over time. As known in the art, such swelling agents and amounts thereof may be preselected to control the release time of the active nicotinic acid component. Examples of such swelling agents include, but are not limited to, polymers such as sodium carboxymethylcellulose and ethylcellulose, waxes such as beeswax, and natural substances such as gums and gelatin, or mixtures thereof. Since the amount of the swelling agent depends on its nature, the release time requirement of the patient, and the like, it is preferable to use the amount of the swelling agent which will achieve the object of the present invention.

Examples of preferred swelling agents are hydroxy propylmethylcellulose in amounts ranging from about 5% to about 50% by weight relative to 100 parts by weight of the tablet or formulation. Preferred examples of this ensure a sustained release time over about 4 to 8 hours.

Binders can also be used in the compositions of the present invention. Although all known binders are useful in the present invention, it is preferable to use at least one substance such as a polymer whose repeating unit is 1-ethenyl-2-pyrrolidinone. Such polyvinyl pyrrolidinone polymers generally have a molecular weight ranging from about 10,000 to 700,000, also known as "povidone or PVP".

Of course, the amount of binder depends on the nature of the binder and the amount of other components in the composition. Exemplary amounts of povidone in the compositions of the present invention range from about 1% to about 5% by weight povidone, relative to 100 parts by weight of the total formulation.

In addition, processing aids, such as glidants, including stearic acid, magnesium stearate, glyceryl behenate, talc, and colloidal silicon dioxide, may be used as is well known in the art. Exemplary amounts of glidants, such as stearic acid, in the compositions of the present invention are from about 0.5% to about 2.0% by weight based on 100 parts by weight of the tablet or formulation.

In addition, according to the present invention, it is preferable that the sustained release composition containing nicotinic acid and / or nicotinic acid compound is coated with an immediate release HMG-CoA reductase inhibitor after oral administration. Exemplary coatings according to the present invention include HMG-CoA reductase inhibitors, plasticizers, film formers and / or coatings and coloring agents. Specific examples of plasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin, mineral oils and lanolin alcohols, petroleum and lanolin alcohols, polyethylene glycols, propylene glycol, sorbitol, triacetin and triethyl citrate But it is not limited to these. Exemplary amounts of plasticizers used in the coatings of the present invention are from about 0.01% to about 5% by weight of the tablet.

Specific examples of film formers and / or coating agents include carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, refined sugar, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl Methyl cellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, polymethacrylate, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide and zein, but are not limited to these. Exemplary amounts of film formers / coating agents in the coatings of the present invention are from about 0.01% to about 5% by weight of the tablet. Generally, to prepare a coating according to the present invention, an HMG-CoA reductase inhibitor is suspended or dissolved in an aqueous solution of polyethylene glycol and hydroxy propyl methyl cellulose, and then contains an effective amount of an HMG-CoA reductase inhibitor that inhibits hyperemia. 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 according to the present invention range from about 0.1 mm to about 2.0 mm or more.

Coated sustained-release tablets of various sizes contain the two active substances within this range, with the remainder being a physiologically acceptable carrier according to accepted pharmaceutical practice, for example, having a total weight of about 265 mg to about 1650 mg. It can be made into a tablet. Of course, these coated tablets can be labeled to provide divided doses. Similarly, gelatin capsules can be formulated.

In accordance with the present invention, such dosage forms are to be administered once daily to the patient, preferably during the evening hours.

To more closely adjust the dosing regimen, the active substances may be administered separately or as separate dosage units at the same time or at carefully adjusted times. Since blood levels are controlled and maintained by the dosing schedule, the same results are achieved by the simultaneous coexistence of the two substances. Each substance may be formulated separately in separate unit dosage forms in a manner similar to that described above.

Since the composition of the HMG-CoA reductase inhibitor and the nicotinic acid and / or nicotinic acid compound is more convenient in the same medicament, it is particularly preferable in the case of coated tablets or caplets for oral administration. However, the pharmaceutical compositions of the present invention may comprise two separate oral dosage forms which can be administered simultaneously, one of which is formulated in nicotinic acid or nicotinic acid compounds or sustained release or delayed form thereof, and the other is HMG. It is formulated to be sustained or immediate release of a -CoA reductase inhibitor.

Oral pharmaceutical compositions of the invention may optionally include other active ingredients. In addition, the present invention also encompasses the possibility of administering the other active ingredient simultaneously with the pharmaceutical composition of the present invention. Examples of other active ingredients include antilipidemia agents and antipyretic agents. Specific examples of antilipidemia agents include bile acid blockers, such as cholestyramine, cholestipol, DEAE Sephadex (Secholex® and Polidexide®), probucol and related compounds disclosed in US Pat. No. 3,674,836. , Lipostabil (Long-Franck), Esai E5050 (N-Substituted Ethanolamine Derivatives), Imanicil (HOE-402), Tetrahydroleafstatin (THL), Icyig as disclosed in US Pat. No. 4,027,009 Mastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seyoku), Ajinomoto AJ-814 (Azlene derivative), melinamide (Sumitomo), Sandoz 58-035, American cinnamid CL- 277,082 and CL-283,546 (di-substituted urea derivatives), neomycin, p-aminosalicylic acid, aspirin, quaternary amine poly (diallyldimethylammonium chloride) and polyene (dione such as those disclosed in US Pat. No. 4,759,923) Allylmethylamine) induction , Various fish oils such as those disclosed in U.S. Patent 5,200,424, European Patent Application 0065835A1, European Patent 164-698-A, British Patent 1,586,152 and British Patent Application 2216-179-A. Enhancers, fibric acid derivatives such as, but not limited to, gemfibrozil, colofibrate, bezafibrate, fenofibrate, cipropibrate and clinfibrate, and other known serum cholesterol lowering agents.

Specific examples of antipyretic agents include nonsteroidal anti-inflammatory agents such as aspirin and salicylates, propionic acids such as ibuprofen, flurbiprofen, phenopropene, ketoprofen, naproxen, sodium naproxen, caprophen and suprofen, Indoleacetic acid derivatives, such as indomethacin, etodolak and sulindac, benzeneacetic acid such as aclofenac, diclofenac and fenclofenac, pyrroleacetic acid such as jomepilac and tolmectin, pyrazole such as phenylbuta Zones and oxyfenbutazone, oxycams such as pyroxicam, and anthranilic acids such as meclofenamate and mefenamic acid, but are not limited to these.

In formulating the compositions of the present invention, the active ingredients in the amounts described above are in units of the prescribed format, in admixture with physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavoring agents and the like in accordance with accepted pharmaceutical practice. In dosage form.

Further examples of auxiliaries that may be incorporated into tablets include binders such as gum tragacanth, acacia, corn starch, potato starch, alginic acid and the like, sweetening agents such as sucrose, aspartase, lactose or saccharin, flavoring agents such as oranges, mints And oils of winter greens and cherries. When the dosage unit dosage form is a capsule, it may contain a liquid carrier such as fatty acid oil in addition to the materials of the aforementioned kind. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets or capsules may be coated with shellac, sugar or both.

As mentioned above, some active drugs usually form known pharmaceutically acceptable salts such as alkali metals and other common basic or acid addition salts and the like. Therefore, reference to the base drug includes those conventional salts known to be substantially equivalent to the parent compound.

In carrying out the objectives of the present invention, nicotinic acid, nicotinic acid compounds and / or HMG-CoA reductase inhibitors are suitable for oral use in various oral dosage forms, such as tablets, eg, rapid disintegrating tablets, compressed skin tablets, enteric Sustained release tasks, sustained release granules, sustained release coating granules or sustained release according to any method known in the art for the preparation of pharmaceutical compositions for incorporation into tablets, capsules, caplets, sachets for spray administration. It may be formulated as a sex bead or pellet. In addition, HMG-CoA reductase inhibitors may be formulated as immediate release granules or immediate release coatings for incorporation into the oral dosage forms of the present invention.

A preferred nicotinic acid sustained release dosage form is Niaspan (registered trademark). It is a tablet. Niaspan tablets are modified to include HMG-CoA reductase inhibitors during the formation of niapan granules or during the formation of a niaspane tablet mixture prior to compaction into niapan tablets according to the present invention so that the nicotinic acid and HMG-CoA reductase inhibitors are A pharmaceutical composition of the invention may be formulated in a sustained release formulation. On the other hand, Niaspan tablets are coated with a coating agent containing an HMG-CoA reductase inhibitor in an immediate release formulation to prepare a pharmaceutical composition of the present invention in which nicotinic acid is sustained release and an HMG-CoA reductase inhibitor is present in an immediate release form. It may be.

The present invention also provides other combination dosage forms containing HMG-CoA reductase inhibitors and nicotinic acid, nicotinic acid compounds or mixtures thereof. For example, such complex dosage forms include bilayer tablets or multi-layer tablets, capsules or sachets, which contain, for example, immediate release or sustained release granules of HMG-CoA reductase inhibitors and sustained release granules of nicotinic acid, nicotinic acid compounds or mixtures thereof. do. Bilayer tablets or multi-layer tablets utilize techniques well known in the art, such as, for example, lightly pre-launching the nicotinic acid layer containing sustained release nicotinic acid granules, and with or without a sustained release agent or swelling agent. It can be prepared by adding a layer containing an enzyme inhibitor and compressing the mixed powder to form a bilayer tablet. The HMG-CoA reductase layer may further contain other agents, such as antipyretics such as aspirin.

In another embodiment, the pharmaceutical composition of the present invention may be enteric skin to delay the degradation and absorption in the gastrointestinal tract. For example, (1) sustained release nicotinic acid granules or immediate release or sustained release HMG-CoA reductase inhibitor granules are individually enteric avoided and compressed to form tablets or bilayer tablet layers, or (2) enteric tablets themselves or layers thereof. It can coat with a coating agent.

Enteric skin dosage forms are not necessarily dissolved or absorbed by humans until they pass through the low pH environment in the stomach and into the small intestine at a relatively higher pH. Representative materials commonly used as enteric coatings include, but are not limited to, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, and methacrylic acid-methyl methacrylate copolymers. Such materials can be used individually or as mixtures. Additional formulation agents such as plasticizers (such as one or more polyethylene glycols or propylene glycols) can be added to obtain physical strength and processability and to prevent cracking due to, for example, stress, low humidity or other factors.

Enteric skin nicotinic acid or HMG-CoA reductase inhibitor granules may be prepared by coating or agglomerating niacin powder with one or more enteric skin materials to form microspheres or small particles of enteric skin nicotinic acid in a fluid bed granulator. On the other hand, the whole tablet or capsule containing HMG-CoA reductase inhibitor and / or nicotinic acid can be coated with an enteric coating material.

Typically, the enteric coating process is preferably one or two layers of enteric coating material, such as methacrylate polymers such as Eudragit S-100, which can be obtained from multiple layers, such as Rohm. Preferably a coating step of dipping the weight tablets or capsules in the readily prepared material solution for 5 seconds. A solution of enteric skin material can be prepared by dissolving a suitable amount of material, for example in 100 ml of a 4: 6 mixture of acetone and isopropyl alcohol. After each soaking step, the coating is dried in air, such as 30 minutes, and then soaked for 5 seconds. A single coating is usually sufficient to prevent the capsule or tablet from dissolving in the stomach. Alternatively, the granules, tablets or capsules may be coated or spray dried in standard coaters such as those commonly used in the pharmaceutical industry.

In addition, the present invention provides a nonsteroidal anti-inflammatory agent (NSAID) in an amount effective to inhibit or reduce prostaglandin PGD ₂ synthesis prior to initiation of nicotinic acid or nicotinic acid combination therapy so that any exothermic reaction by nicotinic acid therapy is reduced or prevented. Provide a method of preliminary treatment. In carrying out this embodiment of the invention, the preliminary treatment should be initiated at least about 7 days prior to nicotinic acid administration, preferably for at least about 14 days. Pretreatment for a shorter period of time may not sufficiently prevent the patient's fever, and some protective effects can be observed, so such a shorter period of pretreatment can be implemented within the scope of the present invention.

During pretreatment of patients with NSAIDs, this selected NSAID is administered orally at a frequency of once to four or more times per day. However, although a small frequency of administration three times or less per day is preferred, once or twice daily administration is preferred for convenience and better reception of the patient. NSAIDs can be administered orally as immediate or sustained release dosage forms. Of course, when a sustained release dosage form is selected, NSAIDs can be administered in fewer times per day, then a significant immediate release dosage form can be administered while providing similar preventive action against the nicotinic acid induced fever.

While it is preferred to ingest NSAIDs during pretreatment, the present invention also provides for continuous administration of NSAIDs during nicotinic acid or nicotinic acid compound treatment. This can be accomplished by ingesting the NSAID in a separate dosage form on a daily basis or by ingesting a pharmaceutical component of the invention comprising the NSAID.

Particularly preferred NSAIDs include indomethacin, ibuprofen, naproxen, aspirin, ketoprofen, flurbiprofen, phenylbutazone and pyroxicam. These NSAIDs can be administered at their usual dosages for the treatment of inflammation. Aspirin is particularly preferred. Aspirin may be administered in a daily dosage of at least about 60 mg to about 1000 mg, more preferably at least about 80 mg to 650 mg, most preferably about 80 mg to 325 mg. Aspirin may be consumed in higher daily doses to suppress the symptoms of fever according to the present invention, but higher doses as well as higher doses present a risk of causing gastrointestinal upset and ulcer formation.

While sustained release formulations for some NSAIDs are commercially available, other sustained release formulations may be mixed with nicotinic acid by conventional methods by those skilled in the art, or during granulation or powder mixing, according to the methods described herein. It can be prepared by producing a sustained release pharmaceutical composition consisting of nicotinic acid and NSAID. NSAIDs, on the other hand, can be mixed with HMG-CoA reductase inhibitors in immediate release coatings of NSAIDs. As another alternative contemplated by the present invention, sustained-release nicotinic acid tablets such as Niaspan® may be enteric coated for delayed release, so that they are coated with a coating consisting of HMG-CoA reductase and NSAID for immediate release. Can be covered.

In another aspect of the present invention, the pharmaceutical composition for solid oral administration may be formulated in various shapes. For example, tablets may be round / flat, round / convex, ovoid / flat, ovoid / convex, or capsules (caplets), while capsules may be round or elongated. If the tablets are oval / convex in shape, it is believed that the coating can be improved when the tablets are coated according to the invention. For example, by formulating sustained release nicotinic acid tablets, such as niaspan tablets, in the oval / convex form, coatings containing HMG-CoA reductase inhibitors have been improved, for example, compared to similar coatings on tablets with capsule (caplet) shapes. I think.

The aforementioned agents are administered for an extended period of time, ie as long as elevated serum cholesterol and atherosclerosis remain or symptoms persist. A dosing period of about 4 weeks or more may be required to achieve the desired therapeutic benefit.

The disclosures of US patents and patent applications mentioned and cited herein are hereby incorporated by reference in their entirety.

Examples of various embodiments of the present invention will be further described with reference to the following embodiments.

In order to demonstrate that the compositions and methods of the present invention are potent over the antihyperlipidemic compositions and methods known in the art, a number of substantially identical compositions were prepared as described below. The components and contents of the composition are as described in Table 1A below.

Test tablet composition ingredient 375 mg 500 mg 750 mg Nicotinic acid 375.0 500.0 750.0 Hydroxypropyl methyl cellulose 188.7 203.0 204.7 Povidone 12.9 17.2 25.9 Stearic acid 5.8 7.3 9.9 sum 582.4 mg 727.5 mg 990.5 mg

All of these ingredients were mixed to make a tablet. In particular, once daily tablets of niaspane according to the present invention use a hydrophilic matrix controlled drug delivery system. This is a kinetic system consisting of polymer wetting, polymer hydration and polymer degradation / dissolution. The mechanisms controlling drug release are determined, for example, by initial polymer wetting, gel layer expansion, tablet erosion, and niacin solubility. After the initial wetting, the hydrophilic polymer partially begins to hydrate and form a gel layer. As water penetrates into the tablet, the thickness of the gel layer increases, causing the drug to diffuse out of the gel layer. The tablet erodes when the outer layer of the tablet is fully hydrated. This erosion is thought to result in further drug release. The controlled release from the matrix delivery system can vary depending on the type and molecular weight of the hydrophilic polymer used.

Niaspan formulations consist of niacin, the trademarked methocel E10M premium, povidone (povidone) K90, and Hysrene 5016 (stearic acid). Methocel E10M Premium is used as a controlled release agent in Niaspan formulations. Methocel is a partially O-methylated and O- (2-hydroxypropylated) cellulose, which is commercially available in several grades with different viscosities and degrees of substitution. Methocel is manufactured by Dow Chemical.

Povidone K90 is used as granulation / binding agent in niaspane formulations. Povidone is a synthetic polymer composed of 1-vinyl-2-pyrrolidone groups, and by this degree of polymerization, polymers having various molecular weights are produced or as described above. This is characterized by the fact that the viscosity in the aqueous solution is 10 to 120 rather than the viscosity in water when expressed by the K value. Povidone K90 has a molecular weight of about 1,000,000. Povidone is a water-soluble substance with hygroscopicity. Povidone K90 present in niaspane formulations is manufactured by International Specialty Products (ISP). Hysrene 5016 is used as an external lubricant in Niaspan formulations. Hysrene 5016 is a mixture of stearic acid and palmitic acid. The content of stearic acid is at least about 40.0%, and the sum of these two acids is at least about 90.0%. Heisten 5016 is manufactured by Witco. See Table IB below for details on niaspane formulations.

The four formulations of the following strengths are quantitatively identical. The main component of each formulation is a processed mixture of granules of niacin, methocel E10M and povidone K90. The granulation process improves the compression properties.

Niaspan tablet formulation Niaspan products 375 mg tablets 500 mg tablets 750 mg tablets 1000 mg tablets Formulation (%) Niacin 64.4 70.5 77.4 83.1 Methocel E10M Premium (within granules) 7.4 8.1 8.9 9.5 Povidone K90 2.2 2.4 2.7 2.9 Methocel E10M Premium (out of granule) 25.0 18.0 10.0 3.5 Hysrene 5016 (stearic acid) 1.0 1.0 1.0 1.0 Tablet weight (mg) 582.5 709.5 968.6 1203.6

Niaspan formulations take the form of white caplet-shaped tablets. The size of the caplet depends on the strength of the product. 375 mg and 500 mg tablets of Niaspan were compressed using an instrument to a size of about 0.687 "long by 0.281" wide. Tablets of 750 mg and 1000 mg were compressed to a length of about 0.750 "x 0.320" using an instrument. The weight and hardness of the desired tablets define the thickness of the four Niaspan products. Hereinafter, a method of preparing the niaspane tablet will be described.

Niaspan Granulation Process Flowchart Raw material Process flow Device used Niacinpovidone K90Methocell E10M (within granules) Granulation High shear granulator (Littleford FM130) ↓ dry Fluid Bed Dryer (Glatt Fluid Bed Dryer) ↓ Reduced to small package size Kemutec Betagrind

Description of Granulation Process of Niaspan

The granulation raw material of Niaspan is dispersed and granulated with a high shear granulator. The wet granules are sieved through a fluid bed drier and dried. After the drying process is completed, the granules are ground. The crushing process makes the particle size distribution of the particles which have undergone granulation of the Niaspan become uniform.

Niaspan Purification Process Flowchart Raw material Process flow device Methocel E10M (out of granule) hysrene 5016 (stearic acid) Mixing of Niaspan Tablets Mixing crushed Niaspan with Methocel E10M (out of granules) and Hysrene 5016 Mixer (Patterson-KelleyV-Blender) ↓ Niaspan tablet manufacturing squeezed niaspan tablet mixture Rotary tablet press

Description of Niaspan Purification Process

Niaspan tablet mixtures were prepared by mixing Niaspan granulated, Methocel E10M (extragranular) and Hysrene 5016 (Stearic acid). The content of each of the components of the Niaspan purification mixture is determined according to the specific Niaspan dose prepared (see Table IB). The niaspan tablet mixture is compressed to form a niaspan tablet. The physical properties of niaspan tablets depend on the dose of the particular niaspan produced.

Hereinafter, the manufacturing method of niase plate will be discussed in detail. The initial manufacturing steps are the same for all four tablet strengths of niaspane (375, 500, 750 and 1000 mg). One batch of niaspan granulate consists of four units of 40.0 kg each of the granulate separately treated under similar conditions. Four samples of each granulate are taken, each tested and then discharged for mixing. The strength of the reference granulate is not specified and can be used to prepare Niaspan tablets of all strengths.

The components of the reference granulate are as described in Table IC below.

ingredient function Content per kg of granulated product (kg) % Per kg of granulate Content per kg of ash (kg) Niacin, USP Drug composition 0.87 87.00 139.20 Povidone, USP Binder 0.03 3.00 4.80 Methocel E10M Premium CR Grade, USP Controlled release 0.10 10.00 16.00 Purified Water, USP ^* Granulating agent 0.00 ^* 0.00 ^* 48.00 sum 160.00 ^* Purified water, USP is used as granulating agents does not appear in the final granulation.

The raw material is quantitatively dispensed using the calibration scale in a properly labeled double polyethylene lined container. The purified water, USP, is dispensed into a suitable container and taken out from this container later using a pump during the wet massing process.

In a Littleford FM130 granulator, approximately half (~ 17.4 kg) of niacin, USP required for the process unit, add about 4.00 kg of metocell, USP E10M Premium CR grade, povidone, USP about 1.20 kg, and the rest of niacin , SP (˜17.40 kg) was added. The powder layer is dry mixed for about 1 minute using a chopper in a Littleford FM130 granulator. Complete a 1 minute premix cycle and spray about 12.00 ± 0.05 kg purified water, USP, at a rate of about 2.40 ± 0.24 kg per minute to the powder bed. Immediately after addition of purified water, USP, the unit is granulated for about 5 minutes.

The granulated unit is discharged into a double polyethylene-lined vessel and then manually placed in a Glat bowl while passing through a screen of # 4 mesh. The bowl was placed in a GlatO-60 fluid bed dryer with the inlet air temperature set at about 70 ° C ± 5 ° C. The unit is dried until a moisture concentration of 1.0% or less is obtained when measured using the Computrac Moisture Analyzer, Model MA5A. The dried granulation is adjusted by draining into a properly labeled double polyethylene lined drum.

The dried and adjusted granulation is passed through a Kemutec BetaGrind mill equipped with a 1.5 mm screen and driven at about 1500 RPM. The milled granulate is adjusted by discharge into a properly labeled double polyethylene lined drum. Samples of the milled granulate are taken and tested and discharged by quality control before further processing.

The discharged granulation unit is fed to a Patterson-Kelly 20 ft ³ V-mixer, which is then mixed together for 10 ± 1 minutes and discharged into a properly labeled double polyethylene lining vessel.

As described above, Niaspan tablets were prepared from conventional granulations and mixed with an appropriate amount of methocel, USP E10M Premium CR Grade and Stearic Acid, NF to prepare the final dosage formulation. Tables 1A and 1B show the composition of each of the strengths of 375 mg, 500 mg, 750 mg and 1000 mg of Niaspan tablets, respectively.

Two groups of study consisted of seven patients and 14 patients. Blood samples were taken from patients and total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol were tested to establish baseline concentrations that can be compared to variations in these lipid concentrations. Patients were then given the regimen of the tablets described above, with 1500 mg of nicotinic acid once daily before sleep. After eight weeks of this regimen, the lipid concentrations of the patients were retested. The results of the tests performed at week 8 are reported in the table below, indicating the change in lipid concentration as a percentage change from baseline concentration. In the following table, the positive number represents the increase rate and the negative number represents the decrease rate.

Lipid Concentration Study in Patients Patient number Gun-C LDL-C Apo b Trigs HDL-C HDL₂-C Lp (a) Group A One -8.2 -12.0 NA -17.3 22.0 NA NA 2 -5.9 -27.0 NA -28.7 65.0 NA NA 3 -15.1 -13.0 NA -22.0 -9.1 NA NA 4 -3.3 -10.0 NA 61.6 3.8 NA NA 5 -16.5 -17.7 NA -28.8 11.1 NA NA 6 -12.4 -25.9 NA -42.0 51.6 NA NA 7 -24.2 -31.4 NA -39.4 12.5 NA NA 8 -6.7 -7.4 NA -42.4 18.8 NA NA 9 4.5 1.1 NA 7.2 9.2 NA NA 10 2.8 -0.2 NA -2.7 22.9 NA NA 11 -13.0 -9.4 NA -54.0 44.3 NA NA Average -8.9 -13.9 NA -18.9 23.0 NA NA p value 0.0004 0.0001 0.0371 0.0068 Group B One -19.2 -27.1 -24.4 -33.4 20.0 22.3 -81.9 2 -32.2 -35.7 -28.0 -60.4 4.3 3.2 -25.3 3 -21.4 -33.6 -35.6 -33.4 30.4 38.6 -17.4 4 -19.9 -24.6 -15.1 -20.8 9.6 16.1 -27.0 5 -3.3 -2.1 -29.4 -41.1 5.8 2.4 -22.4 6 Patient left during the study 7 23.1 -32.6 -42.6 -58.6 49.2 68.9 -14.3 8 24.8 34.0 -28.4 5.5 6.5 -6.8 NA 9 10.1 12.0 -16.8 -11.6 20.7 -12.3 40.6 10 -2.9 -7.7 -28.0 -59.0 53.1 70.5 -41.2 11 -10.5 -18.8 -25.3 -53.4 31.8 39.7 NA 12 -20.0 -30.8 -30.4 11.7 21.1 25.0 -28.4 13 17.4 16.8 -17.5 -17.5 51.3 51.9 38.5 14 -9.4 -16.6 -32.0 -46.9 52.3 67.6 17.6 Average -8.7 -12.8 -32.2 -27.2 25.3 30.1 -17.9 p-value 0.0002 <0.0001 0.0001 <0.0001 <0.0002 0.0002 〈0.0188 Sum -8.7 -13.3 GpB -26.1 25.3 GpB GpB p-value 0.0002 <0.0001 Barely measurable 〈.0001 <0.0001 Barely measurable Barely measurable

The data reported in Table 2 indicate that the mean reduction in LDL values of group A patients is -13.9% and the reduction in triglycerides is -18.9%. HDL cholesterol concentration, a useful cholesterol, improved by 23.0% in this group. Similar results were obtained in the group of patients in group B. The study found that sustained-release preparations during the morning or night hours resulted in the same reduction in LDL cholesterol as immediate release niacin in mg / mg. However, a better reduction of triglycerides in mg / mg compared to sustained release preparations was obtained when administered weekly. In addition, the increase in HDL cholesterol obtained when the sustained release formulation was administered in the morning or at night was + 23.0% in one group and + 25.3% in the other group. Thus, once daily administration at night results in a significant reduction in LDL cholesterol and a marked decrease in triglycerides and an increase in HDL cholesterol.

Groups A and B were tested for liver enzymes (AST, ALT and alkaline phosphatase), uric acid and fasting glucose concentrations at the beginning of the above study (to establish baseline concentrations) and at weeks 2, 4 and 8. The test results are summarized in Tables III-VII below.

Effect of Niaspan Therapy on AST (SGPT) Concentration (U / L) (1500 mg once daily at night) (n = 28) Patient number Reference concentration 2 weeks 4 Weeks 8 Weeks Reference range Group A One 28 29 25 25 0-50 2 24 25 24 26 0-50 3 17 18 22 21 0-50 4 14 16 15 17 0-50 5 22 NA 32 52 0-50 6 21 17 17 14 0-50 7 17 17 14 18 0-50 8 20 21 22 22 0-50 9 16 16 17 20 0-50 10 18 21 21 25 0-50 11 21 21 22 21 0-50 Group B One 23 25 38 33 0-50 2 20 20 21 21 0-50 3 15 20 18 19 0-50 4 25 22 25 26 0-50 5 23 21 17 18 0-50 6 Patient left due to fever 7 21 18 18 19 0-50 8 18 19 18 19 0-50 9 15 16 18 15 0-50 10 16 15 19 28 0-50 11 20 22 24 28 0-50 12 23 25 28 22 0-50 13 20 15 20 19 0-50 14 18 25 20 18 0-50 Total average 19.8 20.4 20.8 21.1 Rate of change from reference concentration + 3.0% + 5.1% + 6.6% Level of significance: p = 0.4141

Effect of Niaspan Therapy on ALT (SGPT) Concentration (U / L) (1500 mg once daily at night) (n = 28) Patient number Reference concentration 2 weeks 4 Weeks 8 Weeks Reference range Group A One 32 28 39 30 0-55 2 24 25 23 26 0-55 3 18 23 30 30 0-55 4 7 13 14 14 0-55 5 14 NA 43 46 0-55 6 22 11 14 10 0-55 7 9 7 11 7 0-55 8 16 18 23 21 0-55 9 14 17 20 14 0-55 10 14 15 17 19 0-55 11 18 18 20 16 0-55 Group B One 16 17 27 29 0-55 2 16 14 15 22 0-55 3 13 21 13 16 0-55 4 23 20 26 17 0-55 5 21 23 17 15 0-55 6 Patient left due to fever 7 21 16 18 21 0-55 8 18 20 17 18 0-55 9 11 5 11 8 0-55 10 8 10 14 17 0-55 11 17 12 18 16 0-55 12 14 18 20 16 0-55 13 14 NA 11 10 0-55 14 23 23 19 19 0-55 Total average 17.7 17.5 19.3 18.2 Rate of change from reference concentration -1.1% 9.0% + 2.8% Significance level p = 0.3424

Effect of Niaspan Therapy on Alkaline Phosphate Concentration (U / L) (1500 mg once daily at night) (n = 28) Patient number Reference concentration 2 weeks 4 Weeks 8 Weeks Reference range Group A One 52 56 57 55 20-140 2 103 100 89 102 20-140 3 54 45 53 51 20-140 4 70 68 71 91 20-140 5 77 NA 74 81 20-140 6 55 48 49 51 20-140 7 72 71 79 75 20-140 8 55 49 47 50 20-140 9 53 55 56 45 20-140 10 74 73 75 75 20-140 11 18 18 20 16 20-140 Group B One 73 67 89 95 20-140 2 82 64 72 71 20-140 3 73 69 72 82 20-140 4 37 36 37 38 20-140 5 65 53 54 61 20-140 6 Patient left due to fever 7 64 58 58 58 20-140 8 79 78 65 73 20-140 9 94 92 103 93 20-140 10 69 67 70 65 20-140 11 59 67 63 72 20-140 12 65 59 59 63 20-140 13 64 68 66 64 20-140 14 72 61 59 64 20-140 Total average 66.5 61.5 63.3 65.8 Rate of change from reference concentration -6.1% -3.4% + 0.005% Significance level p = 0.0236

Effect of Niaspan Therapy on Uric Acid Concentration (U / L) (1500 mg once daily at night) (n = 28) Patient number Reference concentration 2 weeks 4 Weeks 8 Weeks Reference range Group A One 5.2 5.0 4.8 4.3 4.0-8.5 2 4.0 4.6 4.5 6.2 2.5-7.5 3 6.3 7.0 6.5 6.2 4.0-8.5 4 3.1 4.6 4.2 3.8 2.5-7.5 5 3.4 NA 3.3 4.2 2.5-7.5 6 6.6 5.5 5.6 4.7 4.0-8.5 7 3.8 4.5 4.3 4.9 2.5-7.5 8 4.4 3.8 5.1 4.5 2.5-7.5 9 3.9 4.5 4.6 3.5 2.5-7.5 10 2.6 2.9 2.8 2.7 2.5-7.5 11 4.7 5.5 5.2 5.3 2.5-7.5 Group B One 3.7 4.2 4.7 3.5 2.5-7.5 2 2.8 3.5 3.6 2.3 4.0-8.5 3 4.2 5.3 5.5 5.3 2.5-7.5 4 4.7 3.9 5.1 3.6 4.0-8.5 5 3.7 4.1 4.1 3.8 2.5-7.5 6 Patient arrives due to fever 7 5.8 6.6 6.6 6.8 2.5-7.5 8 4.7 4.3 5.4 5.6 2.5-7.5 9 3.7 4.6 5.1 3.8 2.5-7.5 10 4.2 5.0 4.4 8.5 2.5-7.5 11 1.9 3.0 2.8 5.0 2.5-7.5 12 5.6 5.4 6.2 5.6 4.0-8.5 13 4.2 4.6 4.6 5.3 2.5-7.5 14 5.5 5.4 6.1 5.3 2.5-7.5 Total average 4.54 4.82 4.92 4.86 * p = 0.3450 Rate of change from reference concentration + 6.2% + 8.4% + 7.0% Significance level p = 0.3450

Effect of Niaspan Therapy on Fasting Glucose Concentration (U / L) (1500 mg administered once daily at night time) (n = 28) Patient number Reference concentration 2 weeks 4 Weeks 8 Weeks Reference range Group A One 114 122 123 110 70-115 2 101 105 107 101 80-125 3 99 98 109 103 70-115 4 100 118 94 94 80-125 5 89 NA 82 103 80-125 6 97 103 94 107 70-115 7 85 107 100 94 80-125 8 98 107 103 101 80-125 9 97 97 100 110 80-125 10 94 101 111 97 70-115 11 102 103 95 95 80-125 Group B One 101 97 83 99 70-115 2 90 95 96 89 80-125 3 96 98 95 97 70-125 4 116 139 113 125 80-125 5 88 92 91 95 70-115 6 Patient left due to fever 7 106 114 118 117 70-115 8 95 106 106 108 70-115 9 81 92 84 92 70-115 10 108 117 122 105 70-115 11 85 106 106 108 70-115 12 92 89 101 86 80-125 13 99 105 94 100 70-125 14 100 108 84 107 70-125 Total average 98.4 105.8 101.6 102.3 Rate of change from reference concentration + 7.5% + 3.3% + 4.0% Significance level p = 0.0021

Other studies were conducted to compare the state of the art prior to the present invention and to evaluate the degree of improvement provided by the present invention over prior art. This study was performed on 240 patients administered in accordance with the present invention as described above. The comparison group for this group was the patient group studied by McKenney et al. As previously reported. The results of this study are summarized in Table VIII below.

Comparison of Changes in Liver Function Tests 0 500 1000 1500 2000 2500 3000 Sum McKenley SR ^b Niacin AST 23.8 27.9 40.4 36.6 56.5 na 97.0 % - 117 170 154 237 na 408 Invention Dosage Form ^c AST 24.3 na 23.7 27.5 26.6 27.6 27.8 % - na 98 113 109 114 114 McKenley SR Niacin AST 25.6 29.5 36.3 39.0 59.1 na 100.0 % - 115 142 152 231 na 391 Dosage Forms of the Invention ALT 21.4 na 18.7 22.6 21.3 22.4 21.8 % - na 87 106 100 105 102 McKenley SR Niacin ALK 95 95 106 105 136 na 135 % - 100 112 111 143 na 142 Dosage Forms of the Invention ALK 74.7 na 73.9 76.1 73.4 76.7 78.0 % - na 99 102 98 103 104 McKenley SR Niacin Drop - 0 2 2 7 na 7 18 n - - - - - - - 23 % - 0 9 9 30 na 30 78 Dosage Forms of the Invention Drop - - 0 0 0 0 0 0 n - - 26 67 97 35 15 240 % - - 0 0 0 0 0 0 1 year - - 15 47 77 31 15 184 1 year - - 58 69 79 89 100 77 A Comparison of the Efficacy and Effects of Sustained- vs. Immediate-Release Niasin in Hypercholesterolemic Patients ″ by McKenney et al. Journal of the American Medical Association, March 2, 1994; Vol. 271, No. 9, pp. 672 to 677, twice daily. ^b SR stands for ″ sustained release ″. ^c administered once daily at night.

The results of the comparative study summarized in Table VIII show that the control group (McKenney group) lost 18 of the 23 patients, or 78%, due to enhancement in each liver function test. Patients were withdrawn as directed by the investigator. In contrast, the 240 patient groups treated according to the present invention did not have any patients deviating even with the same standard of withdrawal instructions. From the test results reported earlier, this sustained release dosage form showed no enhancement (i.e. liver damage) and no increase in uric acid in the liver function test, but only a small amount, an increase in the fasting glucose concentration of 7.5%. In fact it decreased during the duration of treatment.

Therefore, the compositions and methods of the present invention have been found to be quite effective in controlling hyperlipidemia by reducing the concentrations of LDL cholesterol, triglycerides and LP (a) while increasing the concentration of HDL cholesterol. In addition, the present invention has been demonstrated not to result in enhancement in liver function tests, increase in uric acid or glucose concentrations, evidence of hyperlipidemia.

Example II

In order to demonstrate efficacy as antihyperlipidemic compounds and methods of the pharmaceutical preparations and methods of the present invention, nicotinic acid sustained release compositions coated with other HMG-CoA reductase inhibitors were prepared according to the methods described above and below. The components and contents of the composition are summarized in Tables IXA and IXB below and the test results are summarized in Tables X and XI below.

Coating tablet composition ingredient 500 mg 750 mg 1000 mg Core tablets --- --- ---- Nicotinic acid 500 750 1000 Hydroxypropyl Methyl Cellulose (Methocell E10) 203 183.1 157 Povidone 17.2 25.8 34.5 Stearic acid 7.3 9.7 12.1 Core tablet weight 727.5 mg 990.5mg 1203.6 Lovastatin 10mg 10mg 10mg Polyethylene glycol 0.9mg 0.9mg 0.9mg Hydroxypropyl Methyl Cellulose (Methocell E5) 29.1mg 29.1mg 29.1mg Sheath weight 40mg 40mg 40mg Seed gross weight 767.5 1030.5 1243.6

Ash composition Niacin 750 mg lovastatin 10 mg Niacin 100 mg lovastatin 10 mg matter Mg / tablet per unit Per ash, g Mg / tablet per unit Per ash, g Lovastatin 10.0 80.54 10.0 64.74 Methocel E5 Premium, LV 29.1 234.35 19.4 125.60 Pluracol E1450 0.9 7.25 0.6 3.88 Purified water na 2899.26 na 1942.20 Cloth suspension total amount na 3221.4 na 2136.42 Niacin 750 mg core tablet 968.5 6000.0 1203.6 6000.0 Total amount 1008.5 9221.4 1233.6 8136.42

The core tablet components are mixed together to prepare a sustained release tablet, as in Example 1. The sustained release tablet is then coated as follows. Rovastatin, Methocel E5 and Pulacol E1450 are premixed in a polyethylene bag for about 2-3 minutes. The mixture is passed through a 710 mm sieve. The low shear propeller blade mixer is mounted in a stainless steel beaker containing purified water, USP. The mixer speed is adjusted until a vortex is formed. The mixture in the polyethylene bag is slowly added to purified water. If necessary, the mixer speed should be adjusted to maintain the vortex while adding the dry mixture. Continue mixing until the mixed material is completely dispersed.

Place a stainless steel beaker on the balance to determine the gross weight. The net weight of the coating suspension is calculated as follows.

Net weight of coating suspension = total weight of coating suspension-beaker weight

After preparation of the coating suspension, the sustained release tablet is coated as follows. The high coater HCT 48/60 tablet coater is first suitably cleaned according to the SOP FM 700-procedure for cleaning the high coater HCT 48/60 tablet coater. The high coater HCT 48/60 tablet coater should be equipped with a 9-liter pan, a 0.6 cc gear propeller, a single gun spray bar, a 2.5 mm lid and a 1.5 mm nozzle opening.

According to the manual SOP FM 500-procedure for the operation of the high coater HCT 48/60 tablet coater, the spray air pressure is set to 150 l / min and the pattern air pressure to 100 l / min. Once the spray and pattern air pressures have been established, the coating suspension is placed on the balance and the suspension supply line is placed in the coating suspension. The suspension recovery line is then placed in another vessel. The low shear mixer is then placed in the coating suspension to begin mixing. Allow approximately 60 minutes before performing the next step.

After about 60 minutes, the suspension pump and cleaning line are turned on (“ON”). Once the line is filled with the coating suspension, the suspension recovery line is relocated to the coating suspension container. The solution passed through the gun should be set to about 40 g / min in accordance with SOP FM500.

Next, the ash of nicotinic acid sustained-release tablet is charged to a coating machine. Close the glass door of the coater. Start the air inlet and exhaust blowers. Adjust the air inlet and exhaust blowers until the air flow rate is 170 (± 20) cfm and the negative pressure of the fan is -1/2 inch to 1 inch.

The tablets are coated as follows. Set the fan to 3.3 rpm on the JOG to run for 5 seconds and stop for 30 seconds. Adjust to 60 ° C. by operating the inlet air heater. It proceeds onto the film coating in which the exhaust air temperature reaches 40 ° C. Set the fan run to cover more. Increase fan speed to 15 rpm and start spray treatment. The coating endpoint or target coated tablet weight is calculated as follows.

Coating endpoint (750 mg) = starting tablet weight (mg) x 1.0413 (750 mg tablets)

Coating endpoint (1000 mg) = starting tablet weight (mg) x 1.0249 (1000 mg tablets)

Coating endpoint (500 mg) = starting tablet weight (mg) × 1.0643 (500 mg tablet)

The coating end point should be approximately ± 10% of the target coated tablet weight range.

Continue spraying the coating suspension until the end point is reached. When the end point is reached, proceed to the next step to cool.

Stop spraying process to cool. Set the fan to 3.3 rpm on the JOG. The inlet air heating is stopped and the coated tablet is cooled to approximately 35 ° C. Stop the fan and stop the inlet and exhaust blowers.

Turn the pan using the JOG button on the front of the machine to release the trap until the trap door is above the product bed surface. A double polyethylene lining vessel weighing the vessel, with the desiccant present in the outer bag, is placed under the drain chute. Open the trap door. Rotate the JOG button until the coated tablets begin to release. Rotate the pan until all product is released from the pan. Stop the pan and remove the container. The coated sustained release tablets are then weighed.

Example 3

A study group of 382 patients was formed. Blood samples were taken from the patients and tested for total cholesterol, LDL-cholesterol, triglycerides, and HDL-cholesterol to establish baseline values that could constitute these lipid fluctuations. Then, the patients were given a diet as follows. As shown in Table X, 258 of 382 patients had approximately 2000 mg of Niaspan (registered trademark) before bedtime once a day. ), 122 of 124 patients had approximately 2000 mg of Niaspan (registered trademark) once a day before bedtime. (2 definition Niaspan (registered trademark) 1000 mg tablets) and 1 definition HMG-CoA reductase inhibitor tablets at the same time. More specifically, four patients had two tablets of Niaspan (registered trademark) at bedtime once a day. 1000 mg tablets and one fluvastatin 20 mg tablet were taken at the same time. Twelve patients received two tablets of Niaspan® once per night before bedtime. One dose of 1000 mg tablets and one lovastatin 20 mg tablet was taken at the same time, and 69 patients received two tablets of Niaspan (registered trademark) once a day before bedtime. 1000 mg tablets and 1 tablet of pravastatin 20 mg tablets were taken at the same time. 27 patients received 2 tablets of Niaspan (registered trademark) once a day before bedtime. 1000 mg tablets and one simvastatin 10 mg tablet were taken at the same time, and 10 patients received 2 tablets of Niaspan (registered trademark) once a day before bedtime. 1000 mg tablets and one HMG-CoA reductase tablet were taken simultaneously. However, during the study, these 10 patients varied between different HMG-CoA reductase inhibitors. Nevertheless, the specific HMG-CoA reductase inhibitors taken by these 10 patients are those listed in Table X.

After treatment for an average treatment period of approximately 43 weeks, the patient's lipid profile was tested again. The results of the tests performed, showing lipid profile changes as percent change from baseline, are shown in Tables X and XI below. The results of the tests performed, showing clinical chemistry profile changes as a percentage change from baseline, are shown in Table XII below, and the number and study of patients who recorded a rise above the upper limit of normal (ULN) for selected clinical chemistry parameters. Results representing the total percentage of patients in the subjects are shown in Tables XIII and XIV below.

The incidence or signs of myopathy or rhabdomyolysis was not seen or observed in 122 individuals who received the combination treatment according to Example 3.

Niaspan (registered trademark) And Niaspan (registered trademark) / HMG-CoA Reductase Inhibitor Long Term Study Efficacy Data: Average Duration of Treatment—About 43 Weeks % Change from baseline Median dose (mg) N TC LDL-C HDL-C TG Niaspan (registered trademark) Statins Niaspan (registered trademark) 258 -12.4 -19.1 +26.0 -25.5 2000 - Niaspan (registered trademark) + Statin total 122 -23.8 -31.8 +27.7 -32.5 2000 - Fluvastatin 4 -22.1 -31.8 +29.3 -30.3 2000 20 Lovastatin 12 -20.9 -28.2 +23.5 -23.8 2000 20 Pravastatin 69 -23.7 -31.4 +26.5 -34.5 2000 20 Simvastatin 27 -24.9 -33.0 +33.9 -36.4 2000 10 multiple 10 -25.3 -35.1 +23.7 -19.8 2000 -

Table XI also shows the results of the tests performed. More specifically, Table XI shows Niaspan (registered trademark) once a day before bedtime, as described above in Example 3. Full efficacy data (geological results) for 53 of 124 patients who were concurrently taking HMG-CoA reductase inhibitors. In addition, Table XI shows Niaspan (registered trademark) once a night before bedtime. Full efficacy data (lipid results) for 16 patients taking BAS (bile acid blockers, namely cholestyramine or cholestipol) simultaneously. In addition, Table XI shows Niaspan (registered trademark) once a night before bedtime. Also shown are full efficacy data (lipid results) for 15 patients simultaneously taking BAS (bile acid blockers, ie cholestyramine or cholestipol) and HMG-CoA reductase inhibitors.

Average percent change from lipid outcome baseline Long term population n subgroup total Niaspan (registered trademark) Exclusive Niaspan (registered trademark) + HMGCoA Niaspan (registered trademark) + BAS Niaspan (registered trademark) + 2 ingredients The total number of patients 269 185 53 16 15 LDL (mg / dL) Baseline 269 201.0 ± 1.9 185 198.2 ± 2/1 53 208.0 ± 4.7 16 207.1 ± 11.1 15 203.7 ± 8.8 12 Weeks 234 (-10.7 ± 0.84) ** 150 (-11.4 ± 1.03) ** 53 (-8.6 ± 1.85) ** 16 (-11.2 ± 3.42) ** 15 (-10.3 ± 3.32) ** 24 Weeks 208 (-14.5 ± 0.98) ** 126 (-13.4 ± 1.16) ** 52 (-16.0 ± 2.43) ** 16 (-14.8 ± 3.24) ** 14 (-18.2 ± 2.53) ** 48 Weeks 174 (-21.5 ± 1.10) ** 101 (-17.7 ± 1.28) ** 45 (-31.7 ± 2.12) ** 15 (-19.5 ± 3.73) ** 13 (-18.6 ± 3.50) ** 72 Weeks 140 (-23.2 ± 1.19) ** 79 (-18.1 ± 1.52) ** 39 (-31.6 ± 1.73) ** 9 (-30.9 ± 3.83) ** 13 (-24.0 ± 4.12) ** 96 Weeks 130 (-23.8 ± 1.37) ** 73 (-17.5 ± 1.65) ** 37 (-32.2 ± 2.32) ** 7 (-27.8 ± 4.19) ** 13 (-33.0 ± 4.18) ** HDL (mg / dL) Baseline 269 43.4 ± 0.6 185 43.6 ± 0.7 53 42.7 ± 1.4 16 42.5 ± 2.3 15 44.0 ± 2.2 12 Weeks 234 (19.6 ± 1.09) ** 150 (20.2 ± 1.36) ** 53 (15.1 ± 2.16) ** 16 (31.1 ± 4.40) ** 15 (17.3 ± 3.83) ** 24 Weeks 208 (24.9 ± 1.31) ** 126 (25.1 ± 1.74) ** 52 (22.5 ± 2.37) ** 16 (38.7 ± 3.02) ** 14 (16.4 ± 5.09) ** 48 Weeks 174 (27.9 ± 1.56) ** 101 (29.0 ± 2.05) ** 45 (22.8 ± 3.07) ** 15 (36.2 ± 5.25) ** 13 (17.6 ± 4.74) ** 72 Weeks 140 (25.8 ± 1.54) ** 79 (27.8 ± 2.15) ** 39 (22.2 ± 2.57) ** 9 (37.4 ± 6.31) 13 (16.5 ± 3.44) ** 96 Weeks 130 (29.1 ± 1.68) ** 73 (32.1 ± 2.46) ** 37 (24.7 ± 2.36) ** 7 (31.2 ± 9.44) ** 13 (23.2 ± 4.00) ** Total Cholesterol (mg / dL) Baseline 269 276.0 ± 2.1 185 273.0 ± 2.4 53 285.2 ± 4.9 16 282 ± 10.6 15 272.8 ± 9.1 12 Weeks 234 (-7.2 ± 0.63) ** 150 (-7.4 ± 0.76) ** 53 (-6.9 ± 1.50) ** 16 (-6.3 ± 2.23) ** 15 (-7.0 ± 2.47) * 24 Weeks 208 (-9.2 ± 0.6) ** 126 (-7.8 ± 0.88) ** 52 (-11.8 ± 1.92) ** 16 (-8.2 ± 2.20) ** 14 (-13.7 ± 1.96) ** 48 Weeks 174 (-14.0 ± 0.87) ** 101 (-10.5 ± 0.94) ** 45 (-23.1 ± 1.77) ** 15 (-11.3 ± 2.82) ** 13 (-13.4 ± 2.42) ** 72 Weeks 140 (-15.7 ± 0.97) ** 79 (-11.4 ± 1.15) ** 39 (-24.1 ± 1.41) ** 9 (-13.9 ± 4.51) 13 (-18.2 ± 2.99) ** 96 Weeks 130 (-15.5 ± 1.10) ** 73 (-10.0 ± 1.15) ** 37 (-23.8 ± 2.05) ** 7 (-15.1 ± 2.62) ** 13 (-23.1 ± 3.45) **

Average percent change from lipid outcome baseline Long term population n subgroup total Niaspan (registered trademark) Exclusive Niaspan (registered trademark) + HMGCoA Niaspan (registered trademark) + BAS Niaspan (registered trademark) + 2 ingredients The total number of patients 269 185 53 16 65 Triglycerides (mg / dL) Baseline 269 157.7 ± 4.1 185 155.9 ± 5.0 53 172.2 ± 9.3 16 161.5 ± 17.7 15 124.8 ± 11.0 12 Weeks 234 (-21.1 ± 1.80) ** 150 (-20.8 ± 2.32) ** 53 (-23.4 ± 3.78) ** 16 (-19.3 ± 6.32) ** 15 (-18.9 ± 6.24) ** 24 Weeks 208 (-21.7 ± 2.13) ** 126 (-20.9 ± 2.65) ** 52 (-23.5 ± 4.34) ** 16 (-20.3 ± 7.98) ** 14 (-23.8 ± 10.4) * 48 Weeks 174 (-24.2 ± 2.50) ** 101 (-23.5 ± 2.91) ** 45 (-30.4 ± 6.05) ** 15 (-12.7 ± 9.78) ** 13 (-22.2 ± 6.27) ** 72 Weeks 140 (-28.1 ± 2.75) ** 79 (-26.5 ± 3.67) ** 39 (-37.4 ± 3.53) ** 9 (-1.6 ± 20.7) ** 13 (-28.7 ± 5.71) ** 96 Weeks 130 (-25.8 ± 2.86) ** 73 (-26.4 ± 3.80) ** 37 (32.2 ± 4.10) ** 7 (-5.13 ± 21.4) ** 13 (-20.5 ± 8.32) * VLDL (mg / dL) Baseline 269 31.6 ± 0.8 185 31.2 ± 1.0 53 34.4 ± 1.9 16 32.4 ± 3.5 15 25.0 ± 2.2 12 Weeks 234 (-21.2 ± 1.80) ** 150 (-20.6 ± 2.35) ** 53 (-23.8 ± 3.61) ** 16 (-20.0 ± 6.23) ** 15 (-18.7 ± 6.31) ** 24 Weeks 208 (-21.7 ± 1.80) ** 126 (-20.9 ± 2.69) ** 52 (-23.7 ± 4.30) ** 16 (-20.4 ± 7.98) * 14 (-23.9 ± 10.4) * 48 Weeks 174 (-24.0 ± 2.58) ** 101 (-23.4 ± 2.91) ** 45 (-29.4 ± 6.57) ** 15 (-13.3 ± 9.80) 13 (-22.5 ± 6.35) ** 72 Weeks 140 (-27.2 ± 3.14) ** 79 (-26.2 ± 3.65) ** 39 (-37.4 ± 3.53) ** 9 (10.5 ± 31.0) 13 (-28.6 ± 5.70) ** 96 Weeks 130 (-25.8 ± 2.86) ** 73 (-25.8 ± 3.85) ** 37 (32.0 ± 4.12) ** 7 (-1.7 ± 22.4) 13 (-20.6 ± 8.09) * TC to HDL ratio Baseline 269 6.63 ± 0.09 185 6.52 ± 0.10 53 6.99 ± 0.23 16 6.96 ± 0.51 15 6.40 ± 0.34 12 Weeks 234 (-21.0 ± 0.88) ** 150 (-21.6 ± 1.08) ** 53 (-18.0 ± 1.81) ** 16 (-27.1 ± 3.26) ** 15 (-19.4 ± 3.87) ** 24 Weeks 208 (-25.9 ± 0.99) ** 126 (-24.8 ± 1.21) ** 52 (-26.7 ± 2.25) ** 16 (-33.4 ± 2.48) ** 14 (-24.0 ± 4.03) ** 48 Weeks 174 (-31.3 ± 1.15) ** 101 (-29.1 ± 1.32) ** 45 (-37.5 ± 2.37) ** 15 (-33.0 ± 4.18) ** 13 (-24.5 ± 4.61 ** 72 Weeks 140 (-31.8 ± 1.15) ** 79 (-29.4 ± 1.51) ** 39 (-36.9 ± 1.87) ** 9 (-36.0 ± 5.32) ** 13 (-28.7 ± 4.21) ** 96 Weeks 130 (-33.4 ± 1.16) ** 73 (-30.1 ± 1.64) ** 37 (-38.4 ± 1.82) ** 7 (-33.5 ± 3.85) ** 13 (-37.2 ± 3.10) **

Note: Actual value ± S.E. (% Change)

* significant at p <0.05, ** significant at p <0.01; Matched pair t test.

Average percent change from lipid outcome baseline Long term population n subgroup total Niaspan (registered trademark) Exclusive Niaspan (registered trademark) + HMGCoA Niaspan (registered trademark) + BAS Niaspan (registered trademark) + 2 ingredients The total number of patients 269 185 53 16 65 LDL to HDL ratio Baseline 269 4.85 ± 0.08 185 4.75 ± 0.08 53 5.12 ± 0.20 16 5.16 ± 0.47 15 4.80 ± 0.31 12 Weeks 234 (-23.7 ± 1.04) ** 150 (-24.7 ± 1.29) ** 53 (-19.2 ± 2.12) ** 16 (-31.2 ± 3.94) ** 15 (-21.8 ± 4.50) ** 24 Weeks 208 (-29.9 ± 1.14) ** 126 (-29.0 ± 1.42) ** 52 (-29.8 ± 2.59) ** 16 (-38.2 ± 3.06) ** 14 (-28.0 ± 3.94) ** 48 Weeks 174 (-36.8 ± 1.30) ** 100 (-34.5 ± 1.58) ** 45 (-43.6 ± 2.54) ** 15 (-38.7 ± 4.61) ** 13 (-28.6 ± 5.44) ** 72 Weeks 140 (-37.6 ± 1.32) ** 79 (-34.3 ± 1.77) ** 39 (-42.9 ± 2.08) ** 9 (-49.4 ± 2.66) ** 13 (-33.5 ± 5.19) ** 96 Weeks 130 (-39.8 ± 1.37) ** 73 (-35.8 ± 1.92) ** 37 (45.0 ± 2.22) ** 7 (-44.3 ± 3.62) ** 13 (-45.3 ± 3.80) ** Apolipoprotein B (mg / dL) Baseline 244 148.1 ± 1.23 165 145.7 ± 1.41 48 155.8 ± 2.85 16 149.3 ± 6.03 15 149.2 ± 4.53 12 Weeks 138 (-9.8 ± 1.02) ** 76 (-11.5 ± 1.38) ** 37 (-6.2 ± 2.06) ** 13 (-11.4 ± 2.90) ** 12 (-8.0 ± 2.82) ** 24 Weeks 133 (-14.0 ± 1.06) ** 71 (-12.6 ± 1.37) ** 36 (-16.1 ± 2.56) ** 14 (-13.7 ± 2.28) ** 12 (-16.6 ± 2.48) ** 48 Weeks 123 (-18.7 ± 1.14) ** 70 (-15.4 ± 1.33) ** 30 (-26.2 ± 2.60) ** 11 (-19.2 ± 3.14) 12 (-18.5 ± 3.44) ** 72 Weeks 43 (-20.2 ± 1.85) ** 31 (-16.0 ± 1.95) ** 11 (-32.2 ± 2.22) ** 0 ··· 1 (-19.3) 96 Weeks 0 ··· 0 ··· 0 ··· 0 ··· 0 ··· Lp (a) (mg / dL) Baseline 244 36.7 ± 2.22 165 36.0 ± 2.64 48 34.4 ± 5.29 16 49.6 ± 8.95 15 38.5 ± 9.33 12 Weeks 139 (-27.5 ± 2.19) ** 78 (-28.8 ± 2.69) ** 36 (-28.7 ± 4.44) ** 13 (-28.2 ± 6.01) ** 12 (-14.9 ± 10.9) 24 Weeks 133 (-28.7 ± 2.29) ** 72 (-30.4 ± 2.70) ** 35 (-28.0 ± 5.31) ** 14 (-29.8 ± 5.99) ** 12 (-19.5 ± 10.0) 48 Weeks 131 (-29.3 ± 4.66) ** 74 (-36.3 ± 2.73) ** 32 (-19.2 ± 17.6) ** 12 (-24.0 ± 5.85) ** 13 (-19.0 ± 7.01) * 72 Weeks 44 (-33.0 ± 3.84) ** 29 (-31.5 ± 4.84) ** 12 (-38.4 ± 7.41) ** 0 ··· 3 (-24.7 ± 12.6) ** 96 Weeks 0 ··· 0 ··· 0 ··· 0 ··· 0 ···

Note: The symbol ... indicates that no measurements have been collected for the treatment.

Found ± S.E. (% Of change) ± S.E.Each data is provided on a ZIP diskette.

* significant at p <0.05, ** significant at p <0.01; Matched pair t test.

Table XII shows Niaspan (registered trademark) once a day before bedtime Clinical chemistry parameters (liver function) are shown for all 124 patients who simultaneously took and HMG-CoA reductase inhibitors. Table XII also shows Niaspan (registered trademark) once a night before bedtime. Clinical chemistry parameters (liver function) are shown for 22 patients who simultaneously and BAS (bile acid blockers, ie cholestyramine or cholestipol). Table XII also shows Niaspan (registered trademark) at night before bedtime once a day. Clinical clinical parameters (liver function) are also shown for 17 patients taking BAS (bile acid blockers, namely cholestyramine or cholestipol) and HMG-CoA reductase inhibitors simultaneously.

Average percentage change from chemical parameter baseline Long term population LT full Niaspan (registered trademark) alone Niaspan (registered trademark) and HMG-CoA Niaspan (registered trademark) and BAS Niaspan (registered trademark) and two components n Mean ± S.E. n Mean ± S.E. n Mean ± S.E. n Mean ± S.E. n Mean ± S.E. The total number of patients 617 454 124 22 17 AST (mlU / mL) Baseline 617 18.9 ± 0.22 454 18.7 ± 0.26 124 19.1 ± 0.44 22 20.5 ± 1.09 17 20.4 ± 1.26 12 Weeks 312 (13.5 ± 1.54) ** 352 (13.6 ± 1.72) ** 121 (11.3 ± 2.78) ** 22 (25.9 ± 16.89) 17 (11.4 ± 4.35) * 48 Weeks 376 18.8 ± 2.18) ** 240 (17.9 ± 3.00) ** 101 (21.5 ± 3.53) ** 20 (17.8 ± 5.07) ** 15 (16.6 ± 9.14) 96 Weeks 133 (15.4 ± 2.96) ** 76 (13.8 ± 4.89) ** 37 (18.2 ± 3.36) ** 7 (9.2 ± 3.67) ** 13 (19.6 ± 3.16) ** ALT (mlU / mL) Baseline 617 23.5 ± 0.39 454 23.4 ± 0.48 124 24.3 ± 0.73 22 23.0 ± 2.08 17 19.4 ± 1.66 12 Weeks 513 (1.8 ± 1.51) 353 (2.6 ± 1.84) 121 (-0.9 ± 2.66) 22 (6.7 ± 11.47) 17 (-1.3 ± 5.70) 48 Weeks 376 (5.7 ± 2.21) ** 240 (3.9 ± 2.82) 101 (-8.9 ± 4.26) * 20 (3.6 ± 5.74) 15 (16.8 ± 12.50) 96 Weeks 132 (5.7 ± 3.50) 75 (1.0 ± 5.41) 37 (10.9 ± 5.09) * 7 (-0.2 ± 8.19) 13 (21.4 ± 6.49) Alk〉 Ph (mlU / mL) Baseline 617 69.9 ± 0.70 454 66.0 ± 0.83 124 67.0 ± 1.56 22 59.2 ± 2.30 17 63.6 ± 3.29 12 Weeks 513 (-0.3 ± 0.55) 353 (-0.6 ± 0.70) 121 (-0.8 ± 0.93) 22 (4.8 ± 2.64) 17 (1.3 ± 3.36) 48 Weeks 375 (0.8 ± 0.79) 239 (0.8 ± 1.00) 101 (-0.4 ± 1.19) 20 (1.9 ± 5.28) 15 (7.8 ± 4.87) 96 Weeks 132 (1.6 ± 1.20) 75 (2.5 ± 1.71) 37 (-2.0 ± 1.43) 7 (3.2 ± 4.19) 13 (6.2 ± 5.10) LDH (mlU / mL) Baseline 617 147.90 ± 0.92 454 147.3 ± 1.04 124 148.4 ± 1.96 22 152.3 ± 7.03 17 156.5 ± 6.80 12 Weeks 513 (9.7 ± 0.54) ** 353 (9.9 ± 0.66) ** 121 (8.2 ± 1.07) ** 22 (14.0 ± 3.23) ** 17 (10.8 ± 2.27) ** 48 Weeks 326 (15.2 ± 0.76) ** 240 (14.5 ± 0.93) ** 101 (16.1 ± 1.59) ** 20 (21.6 ± 3.63) ** 15 (12.8 ± 2.40) ** 96 Weeks 133 (17.9 ± 1.04) ** 76 (17.1 ± 1.23) ** 37 (20.4 ± 2.51) ** 7 (16.8 ± 2.68) ** 13 (16.1 ± 2.97) **

Average percentage change from chemical parameter baseline Long term population LT full Niaspan (registered trademark) alone Niaspan (registered trademark) and HMG-CoA Niaspan (registered trademark) and BAS Niaspan (registered trademark) and two components n Mean ± S.E. n Mean ± S.E. n Mean ± S.E. n Mean ± S.E. n Mean ± S.E. The total number of patients 617 454 124 22 17 Total bile acid (mg / dL) Baseline 617 0.54 ± 0.010 454 0.53 ± 0.011 124 0.58 ± 0.022 22 0.65 ± 0.069 17 0.53 ± 0.039 12 Weeks 512 (1.6 ± 1.33) 352 (1.5 ± 1.67) 121 (-0.2 ± 2.46) 22 (1.3 ± 4.84) 17 (17.1 ± 7.03) * 48 Weeks 376 (9.3 ± 1.81) ** 240 (7.6 ± 2.26) ** 101 (10.5 ± 3.17) ** 20 (13.1 ± 8.84) 15 (24.3 ± 12.55) 96 Weeks 132 (15.1 ± 3.22) ** 75 (6.0 ± 4.22) 37 (25.5 ± 5.20) ** 7 (26.3 ± 11.49) 13 (32.2 ± 12.31) * Dir. Bile Acids (mg / dL) Baseline 617 0.12 ± 0.002 454 0.12 ± 0.002 124 0.12 ± 0.004 22 0.13 ± 0.013 17 0.10 ± 0.007 12 Weeks 513 (8.7 ± 1.47) ** 353 (8.1 ± 1.76) ** 121 (8.7 ± 3.06) ** 22 (10.2 ± 6.50) 17 (18.0 ± 8.62) 48 Weeks 376 (26.4 ± 6.66) ** 240 (26.6 ± 10.24) ** 101 (24.4 ± 4.23) ** 20 (24.1 ± 7.68) ** 15 (40.1 ± 12.24) ** 96 Weeks 132 (27.2 ± 3.52) ** 75 (17.8 ± 4.22) ** 37 (40.6 ± 6.77) ** 7 (16.7 ± 7.66) 13 (49.0 ± 14.36) ** Amylase (mg / dL) Baseline 617 51.2 ± 0.78 454 51.2 ± 0.92 124 52.2 ± 1.72 22 49.3 ± 3.70 17 45.6 ± 3.20 12 Weeks 513 (6.4 ± 0.84) ** 353 (7.2 ± 1.07) ** 121 (4.9 ± 1.59) ** 22 (4.1 ± 2.19) 17 (3.4 ± 3.39) 48 Weeks 376 (8.6 ± 1.07) ** 240 (8.7 ± 1.34) ** 101 (8.6 ± 1.90) ** 20 (7.2 ± 5.23) 15 (10.1 ± 7.06) 96 Weeks 132 (5.3 ± 2.00) ** 75 (5.4 ± 2.32) * 37 (6.6 ± 5.23) 7 (3.1 ± 3.58) 13 (2.6 ± 3.55)

Note: The figures are based on two different experimental values. Thus, Basra

These measurements are provided for illustration only.

* significant at p <0.05, ** significant at p <0.01; Matched pair t test.

** found ± S.E. For baseline (between 12, 48 and 96 weeks)

Mean percent change from Isline S.E.).

In Tables X-XII, positive numbers reflect the percentage increase and negative numbers reflect the percentage decrease.

Table XIII shows the number of patients who recorded a rise above the upper limit of normal (ULN) for selected clinical chemistry parameters and the total percentage of patients studied. More specifically, Table XIII shows Niaspan (registered trademark) at night before bedtime once a day. The number and percent of patients with elevated ULN or higher of selected clinical chemistry parameters among 124 patients who had concurrently treated with HMG-CoA reductase inhibitors. Table XIII also shows Niaspan (registered trademark) at night before bedtime once a day. The number and percentage of patients with elevated ULN or higher of selected clinical chemistry parameters among 22 patients who were concurrently treated with BAS (bile acid blockers, namely cholestyramine or cholestipol). Table XIII also shows Niaspan (registered trademark) once a day before bedtime. Of 17 patients who had concurrently taken BAS (bile acid blockers, ie cholestyramine or cholestipol) and HMG-CoA reductase inhibitors, had a rise in the normal upper limit (ULN) of selected clinical chemistry parameters And%.

Therapeutic emergency abnormalities of the selected chemical parameters LT gun Niaspan (registered trademark) Exclusive Niaspan (registered trademark) And HMG-CoA Niaspan (registered trademark) And BAS Niaspan (registered trademark) And two components The total number of patients 617 454 124 22 17 AST (mlU / mL) >normal 70 (11%) 44 (10%) 17 (14%) 5 (23%) 4 (24%) 〉 1.3 × ULN 28 (5%) 17 (4%) 6 (5%) 3 (14%) 2 (12%) 〉 × ULN 5 (1%) 3 (<1%) 1 (<1%) 1 (6%) 0 〉 3 × ULN 1 (<1%) 1 (<1%) 0 0 0 ALT (mlU / mL) normal 44 (7%) 23 (5%) 14 (11%) 2 (9%) 5 (29%) 〉 1.3 × ULN 15 (2%) 4 (<1%) 5 (4%) 2 (9%) 4 (24%) 〉 × ULN 3 (<1%) 1 (<1%) 2 (2%) 0 0 〉 3 × ULN 1 (<1%) 0 1 (<1%) 0 0 Alk.Phos (mlU / mL) >normal 17 (3%) 9 (2%) 3 (2%) 2 (9%) 3 (18%) 〉 × ULN 3 (1%) 0 2 (2%) 1 (5%) 0 LDH (mlU / mL) normal 94 (15%) 60 (13%) 23 (19%) 8 (36%) 3 (18%) 〉 1.3 × ULN 6 (<1%) 4 (<1%) 1 (<1%) 0 1 (6%) Single glue (mg / dL) normal 111 (18%) 67 (15%) 36 (28%) 4 (18%) 4 (24%) 〉 1.3 × ULN 6 (<1%) 3 (<1%) 3 (2%) 0 0 Uric acid (mlU / mL) >normal 89 (14%) 49 (11%) 28 (23%) 7 (32%) 5 (29%) 〉 × ULN 5 (<1%) 3 (<1%) 1 (<1%) 0 1 (6%) Total Bile Acid (mg / dL) >normal 10 (2%) 5 (1%) 4 (3%) 0 1 (6%) 〉 1.3 × ULN 2 (<1%) 1 (<1%) 1 (<1%) 0 0 Amylase (mg / dL) >normal 18 (3%) 11 (2%) 7 (6%) 0 0 〉 1.3 × ULN 6 (<1%) 5 (1%) 1 (<1%) 0 0 〉 2 × ULN 1 (<1%) 1 (<1%) 0 0 0 Phosphorus (mg / dL) <normal 159 (26%) 96 (21%) 47 (38%) 9 (41%) 7 (41%) 〈2.0mg / dL 19 (3%) 14 (3%) 4 (3%) 1 (5%) 0

Note: The percentage in each column is calculated from the total number of patients.

Abnormal liver testing of patient 3512 was not included in this table when data were collected at the local hospital [see earlier Safety Updates (Vol. 1, ¶.12-13, 37).

Table XIV shows the number of patients and the percentage of total subjects who showed a two-fold or three-fold rise above the upper normal limit (ULN) for AST and ALT. More specifically, Table XIV shows Niaspan (registered trademark) at night before bedtime once a day. The number and percentage of 124 patients who took concurrently with and HMG-CoA reductase inhibitors showed a two-fold or three-fold increase in ULN of AST and ALT clinical chemistry parameters. Table XIV is consistent with the data shown in Table XIII.

Long-term study safety data Inter function test Niaspan (registered trademark) N = 454 * Niaspan (registered trademark) + HMG-CoA reductase inhibitor N = 124 ** AST〉 2 × ULN 3 (<1%) 1 (<1%) AST〉 3 × ULN 1 (<1%) 0 ALT〉 2 × ULN 1 (<1%) 2 (1.6%) ALT〉 3 × ULN 0 1 (<1%)

* About 52 weeks follow-up average

** Average of 43 weeks follow-up

From the data shown in Tables XI to XIV, the pharmaceutical compositions of the invention, e.g., sustained release nicotinic acid and immediate release HMG-CoA reductase inhibitors, taken simultaneously at night before bedtime, show serum lipid levels, in particular total cholesterol. Effective in reducing levels of VLDL-cholesterol, LDL-cholesterol, triglycerides, apolipoprotein B and Lp (a) It can be seen that. In addition, the data shown in Tables XI to XIV show that the pharmaceutical compositions of the present invention, such as sustained-release nicotinic acid and immediate-release HMG-CoA reductase inhibitors, taken simultaneously at night before bedtime, improve HDL-cholesterol levels. It can be seen that it is effective to increase or increase. In addition, according to the data shown in Tables XI to XIV, the sustained-release nicotinic acid and the immediate-release HMG-CoA reductase inhibitors, which are simultaneously taken at bedtime once a day, for example, It is believed that the immediate release HMG-CoA reductase inhibitor is more effective in reducing LDL-cholesterol levels than when taken alone in a similar amount on the night before bedtime, but alone. Furthermore, according to the data shown in Tables XI to XIV, the sustained-release nicotinic acid and immediate-release HMG-CoA reductase inhibitors, which are taken simultaneously at bedtime once a day, for example, are treated with sustained-release nicotinic acid. It is believed that the immediate release HMG-CoA reductase inhibitor is more effective in increasing HDL-cholesterol levels than when taken alone at similar doses at night before bedtime, but alone.

In addition, the data shown in Tables XI to XIV indicate that hepatotoxicity, myopathy, or hepatotoxicity may be achieved by administering such concurrent treatment regimens, such as sustained-release nicotinic acid and immediate-release HMG-CoA reductase inhibitors that are taken nightly before bedtime. It has been shown that the benefits of no rhabdomyolysis, or of at least some individuals, can be obtained without stopping hepatotoxicity, myopathy or rhabdomyolysis, to the point that such treatment should be stopped. Furthermore, according to the data shown in Table XII, adverse effects on glucose metabolism or uric acid levels by administering such simultaneous treatment regimens, such as sustained-release nicotinic acid and immediate-release HMG-CoA reductase inhibitors, taken at night before bedtime, once a day It has been shown that benefits can be obtained that do not adversely affect glucose metabolism or uric acid levels, or at a level such that at least some individuals have to stop such treatment regimens.

The foregoing description of the present invention makes it clear that the pharmaceutical compositions, formulations, compositions and methods described herein and methods of use thereof can serve the purposes described above. Therefore, any modification of the pharmaceutical mixtures, formulations, compositions and methods of the present invention is within the scope of the invention as claimed, and therefore the choice of specific ingredient elements can be determined without departing from the spirit of the invention disclosed and described herein. Of course. For example, sustained release excipients, binders and processing aids according to the invention are not limited to those exemplified above. Accordingly, the scope of the invention includes all modifications and variations that fall within the scope of the claims.

Claims (54)

A pharmaceutical composition for once-daily administration that alters lipids in an individual without causing hepatotoxicity, myopathy, or rhabdomyolysis by drugs, A pharmaceutical composition comprising an effective amount of a sustained release form of a nicotinic acid compound or a mixture of nicotinic acid compounds and an effective amount of an HMG-CoA reductase inhibitor that alters lipids. The pharmaceutical composition of claim 1, wherein the HMG-CoA reductase inhibitor is in a sustained or immediate release form. The pharmaceutical composition of claim 2, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, flavastatin, lovastatin, pravastatin, and simvastatin. The pharmaceutical composition of claim 2 in the form of a solid oral dosage form. The pharmaceutical composition according to claim 4, wherein the solid oral dosage form is selected from the group consisting of tablets, capsules, caplets, granules, granular beads or pellets. 6. The pharmaceutical composition of claim 5, wherein the solid oral dosage form is enteric skin. The pharmaceutical composition according to claim 4, wherein the solid oral dosage form is a bilayer tablet comprising a first layer containing a nicotinic acid compound or a mixture of nicotinic acid compounds and a second layer containing an HMG-CoA reductase inhibitor. Composition. 8. The pharmaceutical composition of claim 7, wherein the first or second layer contains an effective amount of nicotinic acid to alter lipids. 8. The pharmaceutical composition of claim 7, wherein the solid dosage form further comprises a third layer containing an effective amount of nicotinic acid to alter lipids. 8. The pharmaceutical composition of claim 7, wherein the two-layer tablet is a two-layer tablet with enteric skin. The pharmaceutical composition of claim 2, further comprising a coating. The pharmaceutical composition of claim 11, wherein the coating contains the HMG-CoA reductase inhibitor. The pharmaceutical composition of claim 2, further comprising an effective amount of nicotinic acid to alter lipids. The pharmaceutical composition according to claim 2, further comprising an antipyretic agent for lowering the efficacy of the nicotinic acid compound or a mixture of nicotinic acid compounds which generates an exothermic reaction in the individual. The pharmaceutical composition of claim 14, wherein the antipyretic agent is a nonsteroidal anti-inflammatory agent. 16. The nonsteroidal anti-inflammatory agent according to claim 15, wherein the nonsteroidal anti-inflammatory agent is indomethacin, sulindac, etodolak, aspirin, salicylate, ibuprofen, fluribpropene, phenopropene, suprofen, venoxapropene, ketopro Group consisting of pen, caprophene, naproxen, sodium naproxen, aclofenac, diclofenac, fenclofenac, tolmectin, jomepilac, meclofenamate, mepanamic acid, oxyfenbutazone, phenylbutazone and pyricampam The pharmaceutical composition is selected from. 3. Nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotine Ariaic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2- Nicotinic acid compounds selected from the group consisting of pyridone-5-carboxylic acid, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and lower alcohol esters of nicotinic acid The pharmaceutical composition that further comprises. The method of claim 13, wherein nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotine Ariaic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2- Nicotinic acid compounds selected from the group consisting of pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and lower alcohol esters of nicotinic acid The pharmaceutical composition that further comprises. The method of claim 14, wherein nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotine Ariaic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2- Nicotinic acid compounds selected from the group consisting of pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and lower alcohol esters of nicotinic acid The pharmaceutical composition that further comprises. 3. The group of claim 2 wherein the bile acid blockers, N-substituted ethanolamine derivatives, azlene derivatives, di-substituted urea derivatives, ionene, poly (diallylmethylamine) derivatives, omega-3-fatty acids and fibric acid The pharmaceutical composition of claim 11, further comprising an effective amount of lipid modifying agent selected from among. The method of claim 2. Cholestyramine, cholestipol, DEAE Sephadex, probucol, lipostavill, Eisai E5050 (N-substituted ethanolamine derivatives), imanicsyl (HOE-402) tetrahydrorifstatin ( THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azlen derivative), melinamide, neomycin, quaternary amine poly (diallyldimethylammonium chloride), gemfibrozil, A pharmaceutical composition comprising a lipid modifier selected from the group consisting of clofibrate, bezafibrate, fenofibrate, cipropibrate and clinfibrate in an effective amount to alter lipids. A coated tablet for oral administration that alters lipids in an individual without causing hepatotoxicity, muscle disease, or rhabdomyolysis by drugs, A mixture of nicotinic acid compounds or nicotinic acid compounds in an effective amount of a sustained release form that alters lipids, Film containing HMG-CoA reductase inhibitor, an effective amount of immediate release form that alters lipids Coating tablet for oral administration comprising a. The coated tablet of claim 22, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, flavastatin, lovastatin, pravastatin, and simvastatin. The coated tablet of claim 22, wherein the coated tablet is oval, flat or elliptical in shape. The coated tablet of claim 22, wherein the coated tablet is spherical, flaky, or spherical in shape. The coated tablet of claim 22, wherein the coated tablet is in capsule form. The coated tablet of claim 22, wherein the coated tablet is coated with enteric skin. The coated tablet of claim 22 further comprising an effective amount of nicotinic acid to alter lipids. 23. The coated tablet of claim 22, further comprising an antipyretic agent that lowers the efficacy of the nicotinic acid compound or a mixture of nicotinic acid compounds causing an exothermic reaction in the subject. 30. The coated tablet of claim 29 wherein the antipyretic agent is a nonsteroidal anti-inflammatory agent. The non-steroidal anti-inflammatory agent according to claim 30, wherein the nonsteroidal anti-inflammatory agent is indomethacin, sullindac, etodolak, aspirin, salicylate, ibuprofen, fluribpropene, phenopropene, suprofen, venoxapropene, ketopro Group consisting of pen, caprophene, naproxen, sodium naproxen, aclofenac, diclofenac, fenclofenac, tolmectin, jomepilac, meclofenamate, mepanamic acid, oxyfenbutazone, phenylbutazone and pyricampam Coating tablets selected from. 30. The coated tablet of claim 29 further comprising an effective amount of nicotinic acid to alter lipids. The method of claim 22, wherein the nicotinic acid compound is nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH Nicotinic acid, nicotinic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ri Group consisting of lower alcohol esters of bovine-2-pyridone-5-carboxylic acid, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and nicotinic acid Coating tablets selected from. The method of claim 28, wherein nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotine Ariaic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2- Nicotinic acid compounds selected from the group consisting of pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and lower alcohol esters of nicotinic acid The coated tablet further comprising. The method of claim 29, wherein nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotine Ariaic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2- Nicotinic acid compounds selected from the group consisting of pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and lower alcohol esters of nicotinic acid The coated tablet further comprising. 23. The method of claim 22, wherein the bile acid blocker, N-substituted ethanolamine derivatives, azlene derivatives, di-substituted urea derivatives, ionene, poly (diallylmethylamine) derivatives, omega-3-fatty acids and fibric acid The coated tablet, further comprising the selected lipid modifier in an effective amount to alter lipid. The method of claim 22. Cholestyramine, cholestipol, DEAE Sephadex, probucol, lipostavill, Eisai E5050 (N-substituted ethanolamine derivatives), imanicsyl (HOE-402) tetrahydrorifstatin ( THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azlen derivative), melinamide, neomycin, quaternary amine poly (diallyldimethylammonium chloride), gemfibrozil, A coated tablet further comprising a lipid modifier selected from the group consisting of clofibrate, bezafibrate, fenofibrate, cipropibrate and clinofibrate in an effective amount to alter lipids. A method of altering lipids in an individual without causing hepatotoxicity, muscle disease or rhabdomyolysis by drugs, A pharmaceutical composition comprising a mixture of nicotinic acid compounds or nicotinic acid compounds in an effective sustained release form that alters lipids and an effective amount of an HMG-CoA reductase inhibitor that alters lipids is administered to a subject once daily Method comprising the steps. The method of claim 36, wherein the administering step comprises administering the pharmaceutical composition once daily as a single dosage form during the evening. The method of claim 36, wherein the administering step comprises administering the pharmaceutical composition once a day prior to or at bedtime as a single dosage form. 40. The method according to claim 39, wherein the VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, L _P (a), total cholesterol, triglycerides, apolipoprotein AI, apolipoprotein B and apolipoprotein E How to reduce the abnormal lipids. The method of claim 39, wherein the serum HDL-cholesterol level of the subject is increased. 40. The method of claim 39, wherein the serum DPTJ apolipoprotein A-I level is increased. The method of claim 39, wherein the serum total cholesterol level in the subject is lowered to HDL-cholesterol level. The method of claim 39, wherein the serum LDL-cholesterol ratio of the subject is lowered to the HDL-cholesterol ratio. The method of claim 39, wherein the HMG-CoA reductase inhibitor is in immediate or sustained release form. 40. The method of claim 39, further comprising administering to the subject an antipyretic agent that reduces the efficacy of the nicotinic acid compound or a mixture of nicotinic acid compounds in generating an exothermic reaction in the subject. 48. The method of claim 47, wherein the antipyretic agent is a nonsteroidal anti-inflammatory agent. 49. The nonsteroidal anti-inflammatory agent according to claim 48, wherein the nonsteroidal anti-inflammatory agent is indomethacin, sulindac, etodolak, aspirin, salicylate, ibuprofen, fluribpropene, phenopropene, suprofen, venoxapropene, ketopro Group consisting of pen, caprophene, naproxen, sodium naproxen, aclofenac, diclofenac, fenclofenac, tolmectin, jomepilac, meclofenamate, mepanamic acid, oxyfenbutazone, phenylbutazone and pyricampam Which is selected from. 40. The method of claim 39, wherein the nicotinic acid compound is nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH Nicotinic acid, nicotinic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ri Group consisting of lower alcohol esters of bovine-2-pyridone-5-carboxylic acid, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and nicotinic acid Which is selected from. 48. The method of claim 47, wherein the nicotinic acid compound is nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-alpha-tocopheryl nicotinate, 6-OH Nicotinic acid, nicotinic acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ri Group consisting of lower alcohol esters of bovine-2-pyridone-5-carboxylic acid, N-methyl-4-pyridone-5-carboxamide, bradyliane, sorbinate, hexanisite, ronitol and nicotinic acid Which is selected from. 40. The method of claim 39, wherein the bile acid blocker, N-substituted ethanolamine derivatives, azlene derivatives, di-substituted urea derivatives, ionones, poly (diallylmethylamine) derivatives, omega-3-fatty acids and fibric acid And administering the selected lipid modifier to the subject in an effective amount that alters the lipid. The method of claim 39. Cholestyramine, cholestipol, DEAE Sephadex, probucol, lipostavill, Eisai E5050 (N-substituted ethanolamine derivatives), imanicsyl (HOE-402) tetrahydrorifstatin ( THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azlen derivative), melinamide, neomycin, quaternary amine poly (diallyldimethylammonium chloride), gemfibrozil, And administering to the subject an effective amount of lipid modifying lipid, wherein the lipid modifying agent is selected from the group consisting of clofibrate, bezafibrate, fenofibrate, cipropibrate, and clinofibrate. 51. The method of claim 50, further comprising administering to the subject an effective amount of nicotinic acid to alter lipids.