AU2002300546B2 - Combinations of HMG-CoA Reductase Inhibitors and Nicotinic Acid and Methods for Treating Hyperlipidemia - Google Patents

Description

S&F Ref: 494109D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: Kos Pharmaceuticals, Inc.

Suite 2502 1001 South Bayshore Drive Miami Florida 33131 United States of America David J. Bova Josephine Dunne Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Combinations ofHMG-CoA Reductase Inhibitors and Nicotinic Acid and Methods for Treating Hyperlipidemia The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c COMBINAIONS OF HMG-COA REDUCTASE INHIBITORS AND NICOTIC ACID AND METHODS POR TREATING

HYPERLOPIDEMA

Field of rh Inlvention This invention generally rotates to pharmaceuical combinations for oral administration S comprising nicotinic acid or a nicotinic acid compound or mi xtures threo L'in an extended release form and 3-hydro\y-3-mcthylgluiaryl co-enzyme A (HIMG-CoA) reductase inhibitor in an immediate or extended release lbrm. which are usclful for altering serum lipid levels in subjects when given once per day as a single dose during the evening hours. without causing druginduced hepatroxicity, myopathy or rhabdomyolsis. The present invention also relates to methods of orally dosing subjects with such pharmaccutical combinations once per day as a single dose during the evening hours lfor altering their scrum lipid levels to treat. for example, byperlipidemiaand atherosclerosis without causing drug-induced hepatrtoxicity. myopathy or rhabdomyolysis.

Background Hyperlipidemid or an elevation in serum lipids is associated widi an increase incidence of cardiovascular disease and atherosclerosis. Specific forms of hyperlipidemia include, for example. hypercholcstermia.familial dyshetalipoprotei nemia.diabetiedyslipidemia. nephrotic dyslipidemniaand familial combined hyperlipidemia. Hlypercholesteremiais characterized by an elevation in serum low density lipoprotein-choleserolarid serum total cholesterol. Low density lipoprotein (LDL-cholesterol) transports cholesterol in the blood. Familial dysbetalipoproteinemia. also known as Type Ill hyperlipidemia. is characterized by an accumulation of very low density lipoprotein-cholesterol (VLDL-cholesterol) panicles called beta-VLDLs in the serum. Also associated with this condition, there is a replacement of normal apolipoprotein E3 with abnormal isolbrm apolipoprotein E2. Diabetic dyslipidemia is S characterized by multiple lipoprotein abnormalities, such as an overproduction of VLDLcholesterol. abnormal VLDL triglyceride lipolysis. reduced LDL-cholesterol receptor activity and. on occasion. Type Ill hyperlipidemia. Nephrotic dyslipidcmia is difficult to treat and frequently includes hypercholesteremia and hypertriglyceridemia. Familial combined hyperlipidemia is characterized by multiple phenotypes of hyperlipidemia.i.e.. Type Ila. lib, IV, V or hypcrapobctalipoproteinetnia.

It is well known that the likelihood of cardiovascular disease can be decreased, if the serum lipids. and in particular l.D.-cholcsterol, can be reduced. It is also well known that the progression of atherosclerosiscan be retarded or the regression of atherosclerosiscan be induced if serum lipids can be lowered. In such cases, individuals diagnosed with hyperlipidemia or I hypcrcholesteremia should consider lipid-lowering therapy to retard the progression or induce the regression of atherosclerosis for purposes of reducing their risk of cardiovasculardisease. and in particular coronary artery disease.

Hypenrtriglyceridemiais also an independent risk factor for cardiovascular disease. such as coronary artery disease. Many people with hypcrlipidemia or hypercholesteremia also have elevated triglyceride levels. It is known that a reduction in elevated triglycerides can result in the secondary lowering of cholesterol. These individuals should also consider lipid-lowering therapy to reduce their elevated triglycerides for purposes of' decreasing their incidence of atherosclerosis and coronary artery disease.

Cholesterol is transported in the blood by lipoprotein complexes. such as VLDL- 2 cholesterol. LDL-cholesteroland high density lipoprotein-cholesterol(HDL-cholesterol). LDL carries cholesterol in the blood to the subendothelial spaces of blood vessel walls. It is believed that peroxidation of LDL-cholesterol within the subendothelial space of blood vessel walls leads to atherosclerosisplaque formation. HDL-cholesterol. on the other hand. is believed to counter plaque formation and delay or prevent the onset of cardiovascular disease and atherosclerotic symptoms. Several subtypes of HDL-cholesterol. such as HDL,-cholesterol. HDL,-cholesterol and HDL.-cholesterol, have been identified to date.

-a in the past, thert; have been numerous methods proposed for reducing elevated cholesterol levels and for increasing VIDL31-cholesterol levels. Typically, these methods include diet and/or daily administration of lipid-altering or hypoiipidemnic agents. Another method proposed concerns periodic plasma dilapidation by a continuous flow filtration system. as in U.S. Patent No. 4,895.558. Scveral types of hypolipidemic agents have been dcveloped to treat hyperlipidetia or hvpercholestercmia or normolipidemics diagnosed with cardiovascular disease. In general. these agents act by reducing the production or the serum lipoproteins or lipids, or by enhancing their removal from the serum or plasma. Drugs that lower the concentration of' ser-um lipoprotcins or lipids include inhibitors of l-MG-CoA reductase, the rate controllingcenzyme in the biosqynthetic pathway of cholesterol. Examples of HMG-CoA reductase inhibitors include jnevatatin. U.S. Patent No. 3 .983,1 40. lovastatin also referred to as mevinolin. U.S. Patent No 4.231 .938. pruvastatin. U.S. Patent Nos, 4,146.227 and 4.4 10.629. lactones of' pravastatin. U.S. Patent No. 4.448.979. velostatin. also referred to as synvinolin. SimnvaStatin. 11.S. Pau=n Nos. 4.448.784 and 4.450.171. rivastatin. fluvaStatin, atorvastatin and cerivastatin. For other examples ol l-IMG-CoA reductase Inhibitors. see U.S.

Patent Nos. 5.217,992:. 5.196.440. -5.189.180. 5.lr66364: 5.157.134, 5.1 10.940; 5.106.992; 5.099.035: 5.081.136. -3,049.696. 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 Application Nos. 0142146A2 and 0221025A 1, and PCT Application Nos. WO 96/03418X and WO 86/07054.

Oilier drugs which lower serum cho lestLerol i nc I tide. ibr exam ple, nicotinic acid, bile acid sequestrants. cho lestyramine. coiestipol OFA .Sc phudex I Secholex® and Polidexide®XD) probucol and related compounds as disclosed in U.S. Patent No. 3.674,836, lipostabil (Rhone- Poulanc). Fisal ESO50 (an N-substituted ctlianolarnine derivative). imanixil (FlOE-402) cetrahydrolipstatin (TIMI). isitigmastanylpliosphiory Icholiine (SPC. Roche). amninocyclodextrin 2a (Tanabe Seiyoku). Ajinomoro AJ-8 14 (azulene derivative). inelinarrilde (Sumitomo)- Sandoz 58- 035. American Cyanirnid CL-277.082 and CL-283.546 (disubstituted urea derivatives). ronitol (which has an alcohol which corresponds to nicotinic acid), neomycin, p-aminosalicylic acid, aspirin. quartemuary amine puly(diaiiyldlintiiylaiimrium chloride) and ionences such as disclosed in U.S. Patent No. 4.027.009, poly(diollylmethylamine) derivatives such as disclosed in U.S. Patent No. 4.759.923. omnega-3-faitty acids found in various fish oil supploments. fibric acid derivatives. gemfibrozil. clofibrate. hezaibrate. tbnofibrate. ciprofibrato and clinofibrate. and other known serum cholesterol lowering agents such as those described in U.S.

Patent No: 5.200.424: European Patent Application No. 0065835AI. European Patent No. 164- 698-A. G.B. Patent No. 1.586.152 and G.B. Patent Application No. 2162-I79-A.

Nicotinic acid. also known as niacin. has been used for many years in ihe treatment of hyperlipidemia or hypercholesteremia. This compound has long been known to exhibit the beneficial effects of reducing total cholesterol. VLDL-cholesterol and VLDL-cholesterol remnants. LDL-cholesterol. triglyceridcsand apolipoprotein a. known as in the human body. while increasing desirable I-IDL-cholesterol.

Nicotinic acid has normally been administered three times per day after meals. This dosing regimen is known to provide a very beneficial effect on blood lipids as discussed in Knopp ct al: "'Contrasting Effectis of Unmodified and Time-Release Forms of Niacin on Lipoproteins in Ilyperlipidemic Subjects: Clues to Mechanism of Action of Niacin": Metabolism (34)7:642-647(1985). The chiefadvantage of this profile is the ability ofnicotinic acid to decrease total cholesterol. LDL-cholesterol. triglycerides and Lp(a) while increasing I 5 HDL-cholesterol particles. While such a regimen does produce beneficial effects. cutaneous flushing and the like still often occurs in the hypcrlipidemics to whom the nicotinic acid is administered.

In order to avoid or reduce the cutaneous flushing resulting from nicotinic acid therapy.

a number of agents have been suggested for administration with an effective antihyprlipidemic amount of nicotinic acid. such as guar gum us reported in U.S. Patent No. 4.965.252. mineral salts as disclosed in U.S. Patent No. 5.023,245. inorganic magnesium salts as reported in U.S.

Patent No. 4.911.917.and non-steroidal anii-inflammauories.such as aspirin, as disclosed in PCT Application No. 96/32942, These agents have been reported to avoid or reduce the cutaneous flushing side effect commonly associated with nicotinic acid dividend dose treatment.

7 5 Another method of avoiding or reducing the side effects associated with immediate release niacin is the use of extended or sustained release formulations. Extetided or sustained release formulations are designed to slowly release the active ingredient from the tablet or capsule. which allows a reduction in dosing fecquency as compared to the typical dosing frequency associated with conventional or immediate dosage forms. The slow drug release o0 reduces and prolongs blood levels of the drug and. thus. minimizes or lessens the cutaneous flushing side effects that are associated with conventional or immediate release niacin products.

Extended or sustained release fonnulations of niacin have been developed, such as Nicobid® capsules (Rhone-Poulenc Rorer). Endur-acin (Innovite Corporation), and the formulations described in U.S. Patent. Nos. 5.126.145 and 5.268,1 81 which describe a sustained release niacin formulation containing two different types of hydroxy propyl methylcclluloses and a hydrophobic component.

Studies in hypcriipidemic patients have been conducted with a number of extended or sustained release niacin products. These studies have demonstrated that the extended or sustained release products do not have the same advantageouslipid-altering effects as immediate release niacin. and in fact have a worse side effect profile compared to the immediate release IO product. The major disadvantage of the sustained release formulations, as reported in Knopp et al.: Metabolism. 34(7):642-647( 1985 is the significantly lower reduction in triglyccrides(-2% for the sustained release versus 38% tbr the immediate release) and lower increase in HDLcholesterol for the sustained release versus -22% for the immediate release) and HDL,cholesterol particles, which are known by the art to be most beneficial for the sustained fI release versus +37% lor the immediate release) Additionally. extended or sustained release niacin formulations are known to cause greater incidencesof liver toxicity. as described in Henkcnet al.: Am Med. 91:1991 (1991)and Dalton ct al.: Am I Med, 93: 102 (1992). There is also great concern regarding the potential of these formulations in disrupting glucose metabolism and uric acid levels.

In a previous edition of the Journal of the American Medical Association (JAMA), an article appeared which presented research results investigating the liver toxicity problems associated with a sustained release form of nicotinic acid. "A Comparison of the Efficacy and Toxic Effects of Sustained- vs. Immediate-Release Niacin in Hypercholesterolemic Patients".

McKenney et al..AMA. 271( 672 (March 2. 1994). The article presented a study of twentythree patients. Of that number, 18 or 78 percent were forced to withdraw because liver function tests (LFTs) increased indicating potential liver damage. The conclusion of the authors of that article was that the sustained release form of niacin "should be restricted from use." A similar conclusion was reached in an article by representatives of the Food and Drug Administration and entitled "Hepatic Toxicity of Unmodified and Time-Release Preparations of Niacin". Rader et al.: Am J Med, 92:77 (January, 1992). Because of these studies and similar conclusions drawn by other health care professionals, the sustained release forms of niacin have experienced limited utilization.

HMG-CoA rcductase inhibitors have ulso been used for many years to treat hyperlipidemia. These compounds are known to exhibit beneficial effects of reducing total cholesterol and LDL-cholesierol in the human body, and elevating HDL-cholesterol levels in some individuals. Grundy SM: En J Md. 319(1):24-32.at 25-26 and 31 (July 7, 1988). The conversion of HMG-CoA to mevalonale is an early step in the biosynthesis of cholesterol.

Inhibition of HMG-CoA reductase. which interferes with the production of mevalonate. is the basis by which the HMG-CoA reductase inhibitors exert their total cholesterol-lowering and LDL-cholesterol-loweringcffects. Grundy SM: N Enl J Mcd. 319(1):24-32. at 25 and 26 (July 7. 1988).

HMG-CoA rcductase inhibitors arc not without drawback, however. HMG-CoA reductase inhibitors arc known to induce hepatotoxicity. myopathy and rhabdomyolysis. as reported in. for example. Garnet WR: Am J Cardiol, 78(Suppl 6A):20-25 (Sept. 26. 1996); The Lovastatin PravastatinStudy Group: Am J Cardiol. 71:810-815 (April 1. 1993): Dujovne CA ct al.: Am J Med. 91(Suppl 1B):25S-30S (July 31. 1991): and Mantell GM et al.: Am J Cardiol.

66:11B-15B (Set. 18. 1990).

Moreover. on Page 1700. in column 3. of the Physicians' Desk Reference (PDR) Ed., 1996. it reports that lovastatin. an HMG-CoA rcductase inhibitor should be used with caution in patients who have a past history of liver disease, and that lovastatin therapy is contraindicated for those individuals with active liver disease or unexplained persistent elevations of serum transaminases. The 1996 PDR further reports on Page 1701. in column 1.

that rhabdomyolysis has been associated with lovastatin therapy alone and when combined with lipid-lowering doses I g/day) of nicotinic acid. and that physicians contemplating combined 2- therapy with lovastatin and lipid-lowering doses of nicotinic acid should carefully weigh the potential benefits and risks and should carefully monitor individuals for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. The 1996 PDR further reports on page 1701. in column I. that cases of myopathy have been associated with patients taking lovastatin concomitantly with lipid-loweringdoses of niotinic acid. The 1996 PDR also reports similar contraindications( I) for fluvastatin on page 2267, column 3. and on page 2268, column 1. for pravastatin on page 767. column I. und for simvastatin on page 1777. column 2.

Still further, the PDR recommendson page 768. column 3. that concomitant therapy with HMG- CoA reductase inhibitors and these agents [lipid lowering doses of nicotinic acidj is generally not recommended.

Notwithstanding the recommendations in the 1996 PDR. Cirundy SM: N Enu J Med, 319(1):24-33 (July 7. 1988). reports that HMG-CoA reduclase inhibitors when used alone (at pages 29-30) and nicotinic acid when used alone (at page 24) are effective in reducing elevated cholesterol plasma levels. Grundy further reports on page 24. in column 2 at lines 10-25. that "[b]ecause of their efficacy...bile acid scquestrants (cholestyramine and colestipol) and niacin )0 are probably the drugs of first choice tor hypcrcholesicremia...Although these drugs can be highly effctive and are satisfactory for use in many patients with high cholesterol levels, they unfortunately are not well tolerated by all patients. Therefore. in spite of their proved usefulness, bile acid sequestrantsand niacin are not ideal cholestcrol-loweringagents." Still further. Grundy reports on page 30. in column I at lines 13-17. that the "...administration of [HMG-CoA] I1 reductase inhibitors twice a day is somewhat more effective than administration once a day, at the same total dosage." Grundy also reports on page 29. in column I at lines 7-11. "...that the combination oflovastatinand cyclosporinc. gemfibruzi or nicotinicacid may predispose patients to myopathy and occasionally even to rhabdomyolysis." Still further. Urundy reports on page in column I at lines 54-59. that "-lthe combination of lovastatin and niacin has not been shown to be sale in a controlled clinical trial: furthermore, a manifestation of an adverse interaction between the agents, such as mytpathy. could occur." But see Gardner SF et al.; Pharmacntheranv. 16(3):421-423(1996); Pasternak RC et al.: AnnI ntem Med. 125(7):529-540 (Oct. 1. 1996); O'Keefe JH et al.; Am J Cardiol. 76:480-484 (Sept. 1. 1995); and Davignon J et al.: Am J Cardiol 73:339-345 (Feb. 15. 1994).

In Vacek JL et al.: Am Cardiol, 76:182-184 (July. 15. 1995). they report on page 183 that "...because of the present state of knowledge of the risks of hepatotoxicily with slow-release forms of nicotinic acid, this form of the drug should probably not be used [in combination with lovastatinj in future trials or clinical practice." Consistent with the reports by Vacek JL ct al. and the 1996 PDR. the article by Jacobson TA and Amorosa LF: Am J Cardiol, 73:25D-29D(May 26. 1994), reports. on pages 28D-29D.

that because "[aJbnormalities in liver enzyme profiles and fulminant hepatic failure have also FEB. 2006 15:01 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 14 8 N been associated with the use of niacin, particularly sustained-release preparations the o use of fluvastatin in combination with a sustained release niacin preparation cannot generally be recommended based upon this study, which only examined crystalline or [4 immediate release niacin." Therefore, it can be seen from the scientific literature that there is a need for development of lipid-altering or hypolipidemic pharmaceuticals and methods of delivering u said pharmaceuticals which would provide patients with "balanced lipid alteration," i.e., t reductions in total cholesterol, LDL-cholestero], triglycerides and Lp(a), as well as increases in HDL particles, with an acceptable safety profile, especially as to liver toxicity, effects on glucose metabolism, uric acid levels, myopathy and rhabdomyolysis.

Therefore, it can be seen from the scientific literature that there is a need for development of lipid-altering or hypolipidemic pharmaceuticals and methods of delivering said pharmaceuticals which would provide patients with "balanced lipid alteration," i.e., reductions in total cholesterol, LDL-cholesterol, triglycerides and Lp(a), as well as increases in HDL particles, with an acceptable safety profile, especially as to liver toxicity, effects on glucose metabolism, uric acid levels, myopathy and rhabdomyolysis.

Summary of the Invention In brief, the present invention alleviates and overcomes certain of the aboveidentified problems and shortcomings of the present state of HMG-CoA reductase inhibitor therapy and nicotinic acid therapy through the discovery of novel HMG-CoA reductase/nicotinic acid pharmaceutical combinations for oral administration and methods of treatment with such pharmaceutical combinations.

Thus, herein disclosed is a pharmaceutical combination for oral administration is provided to alter serum lipid levels in individuals, reducing hyperlipidemia and inhibiting atherosclerosis, without causing drug-induced hepatotoxicity, rhabdomyolysis, or myopathy. Generally speaking, the pharmaceutical combinations of the present invention comprise nicotinic acid, a derivative of nicotinic acid, a compound which is metabolized by the body to form nicotinic acid or any mixtures thereof in an extended release form, and an HMG-CoA reductase inhibitor. The pharmaceutical combinations are administered in amounts which are effective to alter or A4 I9 llpiDCei COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:01 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 8a N0 reduce serum lipids levels such as total cholesterol, VLDL-cholesterol, LDL-cholesterol,

O

0 Lp(a) and triglyccrides levels, and to enhance or increase HDL-cholesterol levels. This is accomplished without causing drug-induced hepatotoxicity, rhabdomyolysis or myopathy Sor adversely effecting glucose metabolism or uric acid levels, or at least without causing such side effects in at least an appreciable number of individuals to such a level that discontinuation of such therapy would be required.

According to an embodiment of the invention, there is provided a pharmaceutical I\ composition for once per day administration to alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis, said pharmaceutical O 10 composition comprising an effective lipid altering amount of nicotinic acid in an extended Ce release form, an effective lipid altering amount of an HMG-CoA reductase inhibitor, and a Sflush inhibiting agent to reduce the capacity of the nicotinic acid to provoke a flushing o reaction in the individual.

According to another embodiment of the invention, there is provided a coated tablet for oral administration to alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis, wherein said coated tablet comprises an effective lipid-altering amount of nicotinic acid in an extended release form, and a coating containing an effective lipid-altering amount of an HMG-CoA reductase inhibitor in an immediate release form.

Processes for the preparation of pharmaceutical compositions and/or coated tablets of the invention, and pharmaceutical compositions and/or coated tablets prepared by such processes are also provided.

According to another embodiment of the invention, there is provided a method for altering lipids in an individual without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis, said method comprising administering to the individual once per day as a single dose a pharmaceutical combination comprising an effective lipid-altering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an HMG-CoA reductase inhibitor. According to related aspects of this embodiment, there is also provided: use of nicotinic acid in an extended release form and an HMG-CoA reductase inhibitor for the manufacture of a medicament for once per day administration for altering lipids in an individual without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis; and a pharmaceutical composition comprising an effective lipidaltering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an HMG-CoA reductase inhibitor, when administered once per day to an individual to alter lipids in said individual without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis.

A494I(wn)ptci COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 In accordance with the present invention, the pharmaceutical combinations are administered once a day as a single oral dose, Preferably. and for those individuals on a typical day time schedule, the single oral dose is administered during evening hours, such as with or after their evening meals or at their bedtimes. to achieve in those individuals during the night effective in vivo levels for reducing total cholesterol. VLDL-cholesterol.LDL-cholesterol Lp(a) and triglycerideslevels and for enhancing or increasing HDL-cholesterol levels, some of which lipid components are biosynthesized predominantly at night in such individuals. For those individuals with typical night time. as opposed to day time. schedules, those individualswho work through the night and sleep during the day. it may be preferable to administer the )0 pharmaceutical combinations of the present invention as a single oral dose at or near their day time bedtimes.

It also has been found that. when a pharmaceutical combination of the present invention is administered once a day as a single oral dose. the single dose provides additional total cholesterol LDL-cholesterol.and triglyceride reduction effects over that which is obtained using the nicotinic acid alone. In fact. it has been found that the pharmaceutical combinations of the present invention, when administered as a single oral dose. reduces total cholesterol, LDLcholesterol and triglycerides levels to a substantially greater extent than when either lipidlowering drug is administeredalone as a single oral dose in an equal dosage amount. Moreover, it has been found that the pharmaceutical combinations of the present invention, when administered as a single oral dose. increases HDI.-cholesterol levels to a substantially greater extent than when the HMG-CuA reductase inhibitor is administered alone as a single oral dose in an equal dosage amount. It is also believed that when the pharmaceutical combinationsof the present invention are administered once a day as a single dose, the single oral dose is at least as effective as the combination of an equal or higher daily dosage of nicotinic acid administered 2 in divided oral doses and an equal daily oral dosage of HMG-CoA reductase inhibitor administered separate from the divided doses of nicotinic acid. and it has less capacity to provoke hepatotoxicity than the divided dose therapy.

Quite surprisingly, the pharmaceutical combinations of the present invention can be used to effectively treat. for instance, hyperlipidemial(.g., cholesterol-relatedcardiovascular disease) and atherosclerosisof multiple etiology, and normolipidemicsdiagnosed with or predisposed to cardiovascular disease, without causing drug-induced liver damage. rhabdomyolysis or myopathy. or adversely effecting glucose metabolism or uric acid levels.

While the pharmaceutical combinations of the present invention contemplate the combination of an HMG-CoA reductase inhibitor, and nicotinic acid, as well as S derivativesof nicotinic acid. compounds which the body metabolizes to nicotinic acid and any combinations thereof in an extended release form. the preferred pharmaceutical combinations in accordance with the present invention are pharmaceutical combinations for oral administration which are comprised of an HMG-CoA reductase inhibitor in an immediate release form, and nicotinic acid in an extended release form. Preferred IHMG-CoA reductase inhibitors include IO atorvastatin. ccrvastatin. fluvastatin. lovastatin. pravastatin and simvastatin.

In carrying out a method of the present invention. the pharmaceuticalcombinationsofthe present invention can be administered to humans and other animal species, such as bovines.

canines. fc ines. porcines. equines. sheep. rabbits. mice. rats. rodents, monkeys. etc. and. as such.

may be incorporated into conventional systemic dosage forms. such as tablets, capsules, caplets.

I( granules. beads. etc. Other lipid-altering or hypolipidemic agents as well as agents known to reduce or prevent cutaneous flushing may be included in the pharmaceutical combinations or administered concomitantly with the pharmaccuticalcombinationsin appropriate regimenswhich complement the beneficial effects of the pharmaceutical combinations of the present invention, so long as such additives do not defeat the objectives ol'the present invention.

The present invention also contemplates pretreating subjects with a nonsteroidal antiinflammatory drug (NSAID) prior to the start of nicotinic acid therapy to reduce or eliminate nicotinic acid induced flushing which limits patient compliance. Prctreatment with low dosages of an NSAID. such as aspirin, when used according to a prcdosing schedule. cumulatively suppresses prostaglandin D, (PGD:) production. making administration of nicotinic acid more 2. tolerable. In accordance with the present invention. predosing a subject with an NSAID involves administering a low dose NSAID. such as aspirin, one to four times a day for at least about 7 days. and preferably for at least about 14 days. prior to nicotinic acid administration.

The doses administered should be carefully adjusted according to age. weight and condition of the patient, as well as the route of administration.dosage form and regimen and the 'lon desired result.

11 Thus, for oral administration a satisfactory result may be obtained employing an HMG- CoA reductase inhibitor in dosages as indicated in. for example, the 1996 Physician's Desk Reference or package inserts for those products, such as in an amount within the range of from about 0.05mg to about 160mg. and preferably from about 0.05 to 80mg. and more preferably from about 0.2mg to about 40mg. in combination with nicotinic acid in dosages normally employed, as indicated in the 1996 Physician's Desk Reference, for nicotinic acid, such as in an amount within the range of from about 250mg to about 3000mg. and preferably from about 500mg to about 2500mg, and most preferably from about 1000mg to about 2000mg, with the HMG-CoA reductase inhibitor and nicotinic acid being employed together in the same oral \0 dosage form or in separate oral dosage forms taken at the same or about the same time. The nicotinic acid. therefore. may he daily dosed in increments of. for example. 250mg. 500mg, 750mg. 1000mg. 1500mg. 2000mg. 2500mi and 3000mg. Thus. the oral dosage forms of the present invention may include nicotinic acid in dosage amounts of. for example, 250mg. 375mg, 500mg. 750mg and 1000mg.

I 1 It should be understood to those versed in this an that the exact dosing for an HMG-CoA reductase inhibitor will depend upon the particular HMG-CoA reductase inhibitor selected.

Therefore, and in accordance with the present invention. the oral dosage forms may include lovastatin,atorvastatinor pravastatin in dosage amounts of. (or example, between about and about 80mg or more. such as 10mg. 20mg. 40mg or 80mg. simvastatin in dosage amounts of. for example. between about 5mu and about 80mg or more. such as 5mg, 10mg. 20mg, or 80mg. iluvastatin in dosage amounts of, oIr example, between about 20mg and 80mg or more, such as 20mg, 40mg or 80mg. and cerivastatin in dosage amounts of. for example. between about 0.05mg and about 0.3mg or more, such as 0.5mg. 0. 1 mg. 0.2mg and 03mg, to achieve a desired daily dosage.

Thus, and in accordance with the present invention, an oral solid dosage form, such as tablets, may contain the HMG-CoA reductase inhibitor in an amount of from about 0.05mg to about 40mg. and preferably from about 0.1mg to about 20mg. and nicotinic acid in an amount of from about 250mg to about 1 000mg. and preferably from 500mg to about 1000mg. Examples of oral solid dosage forms in accordance with the present invention include: nicotinic acid/atorvastatin. fluvastatin. lovastatin, pravastatin. or simvastatin tablets in dosage strengths of. for instance. 250mg/5mg. 500mg/5mg. 750mg/5mg,. 00Omg/Smng, 250mg/7.5mg, 12 500mg/7.5mg. 750mg/7.5mg. 1000mg/7.Smg. 250mg/10mg. 500mg/10mg 7 50mg/10mg, 1000mg/10mg. 25 Omg/20mgm. OOmg/20mg. 750mg/20mg. I 1000mg/20mgtablets.250mg/40mg, 500mg/4Omg. 750mg/40mg.and I 000mg/40mg and nicoti nic acidicerivasatintablcts in dosage strengths of. for instance. 250mg/0.05mg. 500mg/0.05mg. 750mg/0.05m. I mgg/0.05mg, 250mg/0.1mg.500mg 1 mg. 750mg/0.t mg. 1000mg/0. 1mg. 250mg/0.15mg. 500mg/0.15mg, 750mg/0.15mg. 1000mg/0.15mg tablets. 250mg/0.2mg. 500g/0.2mg., 750mg/0.2mg, I 000m.2mg tablets. 250mg/0. 3mg. SOO5mg/0.3 mg. 750mg/0.3mg and 1000mg/.3mg tablets.

It is therefore an object ofthe present invention to provide a pharmaceutical combination for oral administration comprising(a) an HIMG-CoA reductase inhibitor. and nicotinic acid, 0 derivatives of nicotinic acid. compounds which are metabolized by the body to form nicotinic acid and combinations thereof in a sustained release form for altering serum lipids to treat subjects. subjects diagnosed ih hyperlipidemia. atherosclerosis and lipidemia in normolipidemics.

It is another object aof' the present invention to provide an oral solid pharmaceutical combination having extended release cliaracteristics for the nicotinic acid, a derivative of nicotinic acid. a compound metabolized to nicotinic acid by the body or mixtures thereof, and having extended or immediate release characteristics for the HMG-CA reductase inhibitor.

It is yet another object of the present invention to provide a method for employing a composition as above. for treating hyperlipidemics or normnolipidemics diagnosed with or 2o predisposed to cardiovascular disease. which results in little or no liver damage. myopathy or rhabdomyolysis.

At least one or more of the foregoing objects. together with the advantages thereof over the known art relating to the ireatinentofhypcrlipidemia.which shall become apparent from the specification which follows. are accomplished by the invention as hereinafter described and 24 claimed.

In general. the present invention provides an improved lipid-altering or antihyperlipidemia pharmaceutical combination or the oral type employing an effective lipidaltering or antihyperlipidemic amount of an HMG-CoA reductase inhibitor and nicotinic acid, wherein the pharmaceutical combination comprises compounding the nicotinic acid with, for go example. from about 5% to about 50% parts by weight of hydroxy propyl methyl cellulose per 13 hundred pans by weight of the tablet or formulation and coating the tablet with an HMG-CoA reductase inhibitor from about 0.01% to about 30%/ pans by weight of the tablet or formula.

The present invention also provides an orally administered lipid altering or antihyperlipidemia composition which comprises from about 0.01% to about 30% parts by weight of an HMG-CoA reductase inhibitor; from about 30% to about 90% parts by weight of nicotinic acid: and. from about 5% to about 50% parts by weight of hydroxy propyl methyl cellulose.

The present invention also includes a method of altering lipid levels in subjects- such as treating hyperlipidcmiain a hyperlipidemicor lipidemia in a normolipidemic diagnosed with or i 0 predisposed to cardiovasculardiscase. The method comprises the steps of forming a composition which comprises effective lipid-altering amounts of an HMG-CoA reductase inhibitor and nicotinic acid. and an amount of excipients to provide immediate or extended release of the HMG-CoA reductase inhibitor and extended release of the nicotinic acid. The method also includes the step of orally administering the composition to the hyperlipidemic or IS normolipidemic nocturnally.

A method of treating hyperlipidemia in a hyperlipidemic or lipidemia in a normolipidemic according to the present invention, comprises dosing the hyperlipidemic or nonnolipidemic with an effective lipid-alteringamount of an HMG-CoA reductase inhibitorand nicotinic acid. a derivative of nicotinic acid. a compound metabolized to nicotinic acid by the body or mixtures thereof The dose is given once per day. preferably in the evening or at night.

combined with a pharmaceutically acceptable carrier to produce a significant reduction in total cholesterol and LDL-cholesterolas well as a significant reduction in triglyceridesand Lp(a). with a significant increase in HDL cholesterol.

The above features and advantages of the present invention will be better understood with the reference to the following detailed description and examples. It should also be understood that the particular methods and formulations illustrating the present invention arc exemplary only and not to be regarded as limitations of the present invention.

14- Detailed Descrintion By way of illustrating and providing a more complete appreciation of the present invention and many of the attendant advantages thereof, the following detailed description and examples are given concerning the novel methods and pharmaceuticals.

The present invention employs an HMG-CoA reductase inhibitor and nicotinic acid, a derivative of nicotinic acid or a compound other than nicotinic acid itself which the body metabolizes into nicotinicacid and mixtures thereof, thus producing the same etfect as described herein. The nicotinic acid derivatives and other compounds specifically include, but are not limited to the following: nicotinyl alcohol tartrate. d-glucitol hexanicotinate. aluminum (0 nicotinate, niceritrol, d.l-alpha-tocopheryl nicotinate. 6-OH-nicotinic acid. nicotinaria acid, nicotinamide. nicotinamide-N-oxide. 6-OH-nicotinamidc. NAD. N-methyl-2-pyrridine-8carboxamide. N-methyl-nicotinamide.N-ribosyl-2-pyridonc-5-carboxidcN-methyl-4-pyridonebradilian. sorbinicaie. hcxanicite. ronitol. and esters of nicotinic acid such as lower alcohol esters like methyl. ethyl. propyl or butyl esters. Each an any such derivative or compound will be collectively referred to hereinabove by "nicotinic acid compound." The speci ic HMG-CoA reductase inhibitors include. but are not limited to, lovastatinand related compounds as disclosed in U.S. Patent No. 4,231.938. pravastatin and related compounds as reported in U.S. Patent Nos. 4.346.227 and 4.448.979. mcvastatin and related compounds as disclosed in U.S. Patent No. 3.983.140. velostatin and simvastatin and related compounds as discussed in U.S. Patent Nos. 4.448.784 and 4.450.171. I'luvastatin. aorvastatin. rivastatin and fluindostatin (Sandoz XU-62-320). with fluvastatin. lovastatin, pravastatin. atorvastatin.

simvastatinand cerivastatin being preferred. Other HMG-CoA reductive inhibitors which may be employed herein include, but are not limited to. pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Patent No. 4.613.610. indent analogs of mevalonolactone derivatives as disclosed in PC I application WO 86/03488. 6-L2-(substituted-pyrrol-lyl)alkyl]pyran-2-ones and derivatives thereofas disclosed in U.S. Patent No. 4,647.576, Searlc's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloraccate. imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054. 3-carboxy-2-hydroxy-propanephosphoric acid derivatives as disclosed in French Patent No, 2,596.393, 2.3-di-substituted pyrrole, furan and thiophene derivatives as disclosed, in European Patent Application No.

0221025 Al 4. naphthyl analogs of mevalonolactone as disclosed in U.S. Patent No. 4.686.237, octahydro-naphthelenes such as disclosed in U.S. Patent No. 4.499.289. keto analogs of lovastatin as disclosed in European Patent Application No. 0142146 A2. as well as other known HMG-CoA reduciase inhibitors, such as those disclosed in GB Patent Nos. 2.205.837 and 2,205.838: and in U.S. Patent Nos. 5.217.992: 5.196.440: 5.189,180: 5,166.364: 5.157,134; 5.110,940: 5.106.992: 5.099.035 5.081.136: 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.

As stated hereinabove. l-IMG-CoA reductase inhibitors and nicotinic acid have been employed in the past for the treatment of hyperlipidemia. which condition is characterizedby the presence of excess fats such as cholesterol and triglycerides, in the blood stream. According to .1 one aspect of the present invention, an extended or sustained release composition of nicotinic acid coated with an immediate release coaing of an HMG-CoA reductase inhibitor is prepared as an example. By -extended release" or "sustained release" it is understood to mean a composition which when orally administered to a patient to be treated, the active ingredient like an HMG-CoA reductase inhibitor. nicotinic acid, a nicotinic acid compound or mixtures thereof I c will be released for absorption into the blood stream over a period of time. For example, it is preferred that in a dosage of about 1500 milligrams (hereinafter "mgs") of nicotinic acid, approximately 100 percent of the nicotinic acid will he released to Ihe blood stream in about 4 to about 8 hours and preferably within about 6 hours following ingestion.

While the nicotinic acid is released from the pharmaceutical combination in a sustained release manner, the HMG-CoA reductase inhibitorscan be formulated for immediate or extended release following ingestion. By "immediate release." it is understood to mean that the HMG- CoA reductase inhibitor, which when orally administered to a patient to be treated, will be completely released from the composition for absorption into the blood stream within about minutes following ingestion.

2 c A specific sustained release composition according to the present invention employs an effective lipid-altering amount of nicotinic acid coated with an effective lipid-altering amount of an HMG-CoA reductase inhibitor. By "effective lipid-altering amount" or "effective antihyperlipidemic amount" it is understood to mean an amount which when orally administered to a patient to be treated, will have a beneficial effect upon the physiology of the patient, to 3o include at least some lowering of. one or more of the following, total cholesterol, LDLcholesterol, triglycerides and Lp(a) and at least some increase in HDL-cholesterol. and more -16particularly an increase in. HDL-cholesterol and/or HDL.-cholesterol. in the patient's blood stream. The beneficial effect will also include some decreases in the total cholesterol to HDLcholesterol ratio and in the LDL-cholesterol-HDL-cholesterolratio in the patient's blood stream.

In some individuals, the beneficial effect may also include reduction in apolipoprotein B, reduction in apolipoprotein E and/or an increase in apolipoprotein A-L. An exemplary effective lipid-altering amount of nicotinic acid would be from about 250mg to about 3000mg of nicotinic acid to be administered according to the present invention, as will be more fully describe hereinbelow. An exemplary effective lipid-alteringamount of an HMG-CoA reductase inhibitor would be from about 0. mg to about 80 mg. These amounts will of course vary, dependent upon a number of variables, including the psychological needs of the patient to be treated.

Preferably. there is also included in a sustained release composition according to the present invention, a swelling or sustained release agent which is compounded with the nicotinic acid. and/or nicotinic acid compounds, such that when the composition is orally administered to the patient, the swelling agent will swell over time in the patient's gastrointestinal tract, and release the active nicotinic acid. and/or nicotinic acid compound over a period of time. As is known in the an. such swelling agents and amounts thereof, may be preselected in order to control the time release of the active nicotinic acid ingredient. Such swelling agents include, but are not limited to. polymers such as sodium carboxymethylcellulose and ethylcellulose and waxes such as bees wax and natural materials such as ums and gelatins or mixtures of any of the above. Because the amount of the swelling agent ill vary dcpending upon the nature of the agent, the time release needs of the patient and the like. it is preferred to employ amounts of the agent which will accomplish the objects of the invention.

An exemplary and preferred swelling agent is hydroxy propyl methyl cellulose, in an amount ranging from about 5% to about 50% pans by weight per 100 pans by weight of tablet or formulation. A preferred example will ensure a sustained time release over a period of approximately 4-8 hours.

A binder may also be employed in the present compositions. While any known binding material is useful in the present invention, it is preferred to employ a material such as one or more of a group of polymers having the repeating unit of ethenyl-2-pyrrolidinone. These .polyvinyl pyrrolidinonepolymers generally have moleoular weightsof between about 10.000 and 700,000. and are also known as "povidone or PVP." 17- Amounts of the binder material will of course, vary depending upon the nature of the binder and the amount of other ingredients of the composition. An exemplary amount of povidone in the present compositions would be from about 1% to about 5% by weight of povidone per 100 parts by weight of the total formulation.

Processing aids such as lubricants. including stearic acid. magnesium stearate. glyceryl behenatc. talc and colloidal silicon dioxide, may also be employed, as is known in the an. An exemplary amount of a lubricant, such as stearic acid, in the present compositions would be from about 0.5% to about 2.0% by weight per 100 parts by weight of tablet or formulation.

Also in accordance with the present invention, the sustained release compositions containing the nicotinic acid and/or nicotinic acid compounds are preferably coated with an HMG-CoA reductase inhibitor for immediate release following oral administration. An exemplary coating in accordance with the present invention comprises an HMG-CoA reductase inhibitor, a plasticizer. Iilm forming and/or coating agent and a coloring agent. Specific examples of plasticizers include. hut arc not limited to. benzyl benzoase. chlorobutanol. diburyl I 4 sebacate. diethyl phthalate. glycerin, mineral oil and lanolin alcohols, petrolatum and lanolin alcohols, polyethylene glycol. propylene glycol. sorhitol. triacetin and triethyl citrate. An exemplary amount ofa plasticizer utilized in the coatings of the present invention would be from about 0.01% to about 5% by weight of the tablet, Specific examples of film forming and/or coating agents include, but are not limited to, carboxymethylcellulose sodium. carnauha wax. cellulose acetate phthalatc. celyl alcohol, confectioner's sugar. ethylcellulose, gelatin. hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, liquid glucose, maltodextrin. methyl cellulose, microcrystalline wax, polymethacrylates.polyvinyl alcohol. shellac, sucrose. talc. titanium dioxide and zein. An exemplary amount of a film forming/coatingagent in the present coatings would be from about 0.01% to about 5% by weight of the tablet. Generally speaking to prepare a coating in accordance with the present invention, an HMG-CoA reducase inhibitor is suspended or dissolved in an aqueous-solutionof polyethlene glycol and hydroxy propyl methyl cellulose and then sprayed on the sustained release tablets by a film-coating process to a thickness containing an effective antihyperlipidemic amount of an HMG-CoA reductase inhibitor. Examples of suitable coating thicknesses in accordance with the present invention are from about 0.1mm to about 2.0mm or more.

-18- Coated sustained release tablets of various sizes can be prepared, of about 265mg to 1650mg in total weight, containing both of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrierof other materials according to accepted pharmaceutical practice. These coated tablets can, of course, be scored to provide for fractional doses. Gelatin capsules can be similarly formulated.

Consistent with the present invention, such dosage forms should be administered to individuals on a regimen of one dose per day. preferably during the evening hours.

In order to more finely regulate the dosage schedule, the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances. The respective substances can be individually formulated in separate unit dosage forms in a manner similar to that described above.

Combinations of an HMG-CoA reductase inhibitor and nicotinic acid and/or nicotinic |I acid compounds in the same pharmaceutical are more convenient and are therefore preferred.

especially in the coated tablet or caplet form for oral administration. Alternatively. however, the pharmaceutical combinations of the present invention may comprise two distinct oral dosage forms which may be administered concomitantly, where one oral dosage form is formulated for extended or sustained release of nicotinic acid or a nicotinic acid compound or mixtures thereof.

and the other oral dosage form is formulated for extended or immediate release of an HMG-CoA reduciase inhibitor.

Optionally, the oral pharmaceutical combinations of the present invention may include other active ingredients. In addition, the present invention contemplates that other active ingredients may be administered concurrently with the pharmaceutical combinations of the present invention. Examples of other active ingredients include anti-lipidemic agents and flushinhibitingagents. Specific examples of anti-lipidemicagents include but are not limited to. bile acid sequestrants,e.g., cholestyraminc.colestipol DEAESephadex(Secholexoand Polidexide®), probucol and related compounds as disclosed in U.S. Patent No. 3.674.836, lipostabil (Rhone- Poulanc). Eisai E5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402) tetrahydrolipstatin (THL), isitigmastanylphosphorylcholine (SPC, Roche). aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-8 14 (azulene derivative),melinamide (Sumitomo). Sandoz 58- S19- 035, American Cyanimid CL-277.082 and CL-283,546 (disubstituted urea derivatives), neomycin, p-aminosalicylic acid. aspirin. quarternary amine puly(diallyldimcthylammonium chloride) and ionenes such as disclosed in U.S. Patent No. 4.027.009. poly(diallylmethylamine) derivatives such as disclosed in U.S. Patent No. 4.759.923. omega-3-fatty acids found in various fish oil supplements, ibric acid derivatives.e.g.. gemfibrozil,clofibratc. bezafibrate, fenofibrate, ciprofibrateand clinofibrale. and other known serum cholesterol lowering agents such as those described in U.S. Patent No. 5.200.424: European Patent Application No. 0065835AI. European Patent No. 164-698-A. G.B. Patent No. 1.586,152 and G.B. Patent Application No. 2162-179-A.

Specific examples of flush-inhibitingagents include. but are not limited to. nonsteroidal (O anti-inflammatorydrugs such as aspirin and salicylate salts: propionic acids such as ibuprofen, flurbiprofen. fenoprofen. ketoprofene naproxn. sodium naproxen, carprofen and suprofen: indoleacetic acid derivatives such as indomcrhacin. etodolac and sulindac: benzeneacctic acids such as acloflnac. diclofenac and tinclofenac: pyrroleacetic acids such as zomepirac and tolmectin: pyrazoles such as phenylbutazoncand oxyphenbutazone;oxicams such as piroxicam; and anthranilic acids such as mcclolenamate and metenamic acid.

In formulating the compositions, the active substances, in the amounts described above, are compounded accordingto occupted pharmaceutical practice with a physiologicallyacceptable vehicle, carrier, excipient. binder, preservative, stabilizer, l1avor. etc.. in.the particular type of unit dosage form.

Additional illustrations of adjuvants which may be incorporated in the tablets are the following: a binder such as gum tragacanth. acacia, corn starch, potato starch, alginic acid or the like; a sweetening agent such as sucrose, aspanase. lactose or saccharin: a flavoring such as orange, peppermint, oil of wintergreenor cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both.

Some of the active agents described above form commonly known pharmaceutically acceptable sals, such as alkali metal and other common basic salts or acid addition salts, etc.

References to the base agents are therefore intended to include those common salts known to be substantially equivalent to the parent compound.

20 In carrying out the objective of the present invention, the nicotinic acid. nicotinic acid compounds and/or HIMG-CoA reductase inhibitors may be formulated into sustained release granules, sustained release particles, sustained release coated particles or sustained release beads or pellets according to any method known to the art for the manufacture of pharmaceutical compositions for incorporation into a variety io oral dosage forms suitable for oral use, such as tablets,such as rapidly disintcgrating tablets. compression coated tablets. enteric coated tablets, capsules. caplets. sachets for sprinkle administration, and the like. In addition, the HMG-CoA inhibitors may be formulated into immediate release granules or immediate release coated raw materials for incorporation into the oral dosage forms of the present invention.

(0 A preferred nicotinic acid sustained release dosage form is the Niaspan" tablets. The Niaspan" tablets can he modilied consistent with the present invention to include an HMG-Co reductasc inhibitor during the ormnation of the Niaspan" granules or during the manufacture of the Niaspan" tablet blend prior to compression into the Niaspan' tablets to formulate a pharmaceuticalcombinuaion ol' the present invention in which the nicotinic acid and HMG-CoA I S reductase inhibitor are in a susained release form. Alternauvely. the Niaspanr tablets may be coated with a coating containing an H-MG-CoA rcductasc inhibitor in immediate release form to formulate a pharmaceutical combination ol the prescn invention in which the nicotinic acid is in an extended release form and the HMG-CoA reductase inhibitor is in an immediate release form.

o The present invention also contemplates other combined dosage forms containing an HMG-CoA reductas inhibitorand nicotinic acid. a nictinic acid compound or mixtures thereof.

For instance, such combined dosage forms include bilayer or multilayer tablets, capsules or sachets containing, for example, immediate or sustained release granules of an I MG-CoA reductase inhibitor and sustained release granules of nicotinic acid, a nicotinic acid compound or mixtures thereof. Bi layer or multilayer tablets may be manufactured utilizing techniques well known in this art, such as by lightly prestamping a nicotinic acid layer containing sustained release nicotinic acid granules. adding a layer containing an HMCi-CoA reductase inhibitor.either deficient in or containing a sustained release or swelling acnlt. and compressing the combined powder to form the bilayer tablet. Optionally. the HMG-CoA reductase layer may further RC, contain other agents, such as a flush inhibiting agent, like as aspirin.

-21 In a further embodiment, the pharmaceutical combination of the present invention may he enterically coated to delay disintegration and absorption in the gastrointestinal tract. For example. sustained release nicotinic acid granules or immediate or sustained release HMG- CoA reductase inhibitor granules may be individually entrically coated and compressed to form a tablet or a layer of a bilayer tablet, or the tablet itsclf or a layer thereof may be coated with an enteric coating.

Enterically coated dosage forms do not necessarily dissolve or become absorbed by humans until they pass through the low pH environment of the stomach and pass into the relatively higher pH of the small intestine. Typical materials conventionally used as enteric coatings include. but are not limited to. cellulose acetate phthalatc. polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate and methacrylic acid-methyl methacrylate copolymers.

Such materials can be used individually or in combination. Additional formulating agents, such as plasticizers one or more polyethylene glycols or propylene glycol) may be added to ensure physical strength and proccssability.c.g.. to prevent cracking due to stress. tow humidity or other factors.

Enterically coated nicotinic acid or HMO-CoA reductase inhibitors granules can be prepared in a fluid bed granulator by coating or agglomerating niacin powder with one or more enteric coating materials, such that micr0spheres or small particles ol'entericallycoated nicotinic acid are formed. Alternatively. a whole tablet or capsule comprising an HMG-CoA reductase inhibitor and/or nicotinic acid can be coated with enteric coating materials.

Typically, the enteric coating process comprises coating the dosage form with a plurality of layers. one or two layers or more. of enteric coaling material, like a methacrylate polymer such as EUDRAGIT S-100. available from Rohm. preferably by dipping the weight tablet or capsule into a freshly prepared solution of the material for five seconds. The solution of enteric coating material(s) may be prepared by dissolvingan appropriate amount of material in. 100 ml of a 4:6 mixture of acetone and isopropyi alcohol. After each immersion, the coating is allowed to dry in air, for 30 minutes, prior to the next five-second immersion. A single coating is usually adequate to prevent the capsule or table from dissolving in the stomach.

Alternatively.the granules. tablets or capsules may be coated or spray-dried in standard coating machines such as those typically employed in the pharmaceutical industry.

The present invention also contemplates methods for pretreating subjects, prior to the start of nicotinic acid or nicotinic acid combination therapy, with a nonsteroidal antiinflammatory drug (NSAID) in an amount effective to inhibit or reduce prostaglandin PGD; synthesis, so that any flush reaction induced by the nicotinic acid therapy is lessened or .c prevented. In carrying out this aspect of the present invention, the pretreatment should stan at least about 7 days prior to administration of the nicotinic acid, and preferably for at least about 14 days. While pretreatment for a shorter duration may not provide a subject with adequate protection against flushing. some protective effect may be observed and. thus. such shorter pretreatment periods may be practiced within the scope of the present invention.

to During pretreatment of subjects with an NSAID, the NSAID selected is orally administered in at least one to four or more doses daily- However, while three or fewer doses per day is preferred. one or two doses per day are preferential for the convenience and improved compliance of the subjects. The N SAID may be administeredorally as an immediate or extended release dosage form. Of course. i 'an extended release dosage form is selected, the NSAID can \s be administered fewer times daily then a comparable immediate release dosage form, while providing similar protection against nicotinic acid-induced flushing.

While it is preferable to take an NSAID during pretreatment. the present invention also contemplates continued administration of the NSA[I during the nicotinic acid or nicotinic acid compound treatment. This can be accomplished by taking the NSAIDas a separate dosage form on a daily basis. or by taking a pharmaceutical component of the present invention which includes an NSAID.

Particularly preferred NSAIDs include indomcthacin. ibuprofen. naproxen, aspirin.

ketoprofen, flurbiprofen. phenylbutazonc.and piroxicam. These NSAIDs may be administered in their usual doses for treatment of inflammation. Aspirin is especially preferred. Aspirin may 2 ,5 be administered in daily dosages of at least between about 60mg and about 1000mg. and more preferably at least between about 80mg and 650mg. and most preferably between about and 325mg. Even though higher daily dosages of aspirin may be consumed to suppress flushing in accordance with the present invention, there is risk that these higher dosages, as well as the high end of the preferred dosages, could induce gastrointestinal upset and ulceration.

3o While extended release forms are commercially available for some NSAIDs, other extended release formulations may be prepared by conventional methods from those versed in 23 the art. or by blending the NSAID with the nicotinic acid during granules or during the powder blending stage pursuant to the methods described herein to generate a pharmaceutical combination comprised of nicotinic acid and an NSAID in extended release form. Alternatively, the NSAID could be blended with an HMCi-CoA rcductse inhibitor in a coating for immediate release of the NSAID. As a furthr alternative contemplated by the present invention, extended release nicotinic acid tablets, such as Niaspan'. can be cnterically coated for delayed release, which then may be coated with a coat comprised of an HMG-CoA rcductase and an NSAID for immediate release.

In a furtheraspect ofthe present invention.the solid pharmaccuticalcombinations for oral (O administrationmay be formulated into various shapes. For example, tablets may be round/flat, round/convex, oval/flat, oval/convex. or capsule (caplet) in shape, whereas capsules may be round or elongated in shape. It is presently believed that when tablets arc coated in accordance with the present invention, the coatings cn he improved if the tablets are in an oval/convex shape. For instance, it is believed that by lHrmulating the sustained release nicotinic acid tablets, such as Niaspana tablets, into oval/convex shapes, the coatings containing an HMG-CoA reductase inhibitorare improved, as compared to simi tar coatings on tablets having, for example, a capsule (caplet) shape- The formulations as described above will be udministered for a prolonged period, that is, for as long as the potential for elevated serum cholcstcrol and atherosclerosis remains or the symptoms continue. A dosing period of at least about weeks maybe required to achieve a desired therapeutic benefit.

The disclosures of the U.S. patents and patent applications mentioned and cited herein are incorporated herein by reference in their entireties.

Examples of various rnbodimentsof the present invention will now be funher illustrated 2 5 with reference to the following examples.

Examnle I In order to demonstrate the effectiveness of the compositions and method of the present invention over known antihyperlipidemiacomposiionsand methods heretoforeknown in the art.

-24a number of substantially identical composition wercprepared according to the disclosure hereinabove. The composition ingredients and amounts are listed in TABLE IA hereinbelow.

TABLE IA Test Tablet Composition lredient 327mg e ZSmg Nicotinic Acid 375.0 500.0 750.0 Hydroxy propyl 188.7 203.0 204.7 methyl cellulose Povidone 12.9 17.2 25.9 Stearic Acid 5,8 7.3 9.9 TOTAL 582.4mg 727.5mg 990.5mg The ingredients were compoundcdiogether to form a tablet. More specifically.Niaspan@ once-daily tablets in accordance ith he present invention utilize a hydrophilic matrix controlled drug delivery system. This is a dnamic system composed of polymer wetting, polymer hydration and polymer disintegration/dissolution. The mechanism by which drug release is controlled depends on. for example, initial polymer wctting. expansion ofthe gel layer, tablet Io erosion and niacin solubility. After initial wetting. the hydrophilic polymer starts to partially hydrate. forming a gel layer. As water permeates into the tablet increasing the thickness of the gel layer, drug diffuses out of the gel layer. As the outer layer of the tablet becomes fully hydrated it erodes. It is believed that this erosion results in additional drug release. The controlled release from this matrix delivery system can be modified depending on the type and molecular weight of hydrophilic polymer used.

A Niaspan® formulation consists of Niacin. Methocel@ El OM Premium. Povidone and.Hystrene 5016 (stcaric acid). Methocel® E10M Premium is utilized as a controlled-release agent in the Niaspan® formulation. Methocel is a partly O-methylated and 0-(2hydroxypropylated)cellulose and is available in several grades which vary in terms of viscosity a O and degree of substitution. Methocel is manufactured by Dow Chemical.

Povidone K90 is employed as a granulating/binding agent in a Niaspan® formulation.

Povidone is a synthetic polymer consisting of linear 1 -vinyf-2-pyrrolidonegroups, the degree of polymerization of which results in polymers of various molecularweights. or as indicated above.

It is characterized by its viscosity in aqueous solution, relative to that of water. expressed as a K-value. ranging from 10-120. Povidone K90 has an approximate molecular weight of 1.000.000. Povidone is a hygroscopic, water soluble material. Povidone K90 present in a Niaspan@ formulation is manufactured by ISP (Intemational Speciality Products). Hystene 5016 is utilized as an external lubricant in the Niaspan® formulation. Hystrene 5016 is a mixture of stearic acid and palmirric acid. The content of stcaric acid is not less than about 40.0% and the sum of the two acids is not less than about 90.0%. Hystrene 5016 is manufactured by Witco.

Refer to Table IB for Niaspan® formulation details.

Qualitativelythe four tablet strength Ibrmulations are identical. The major component of each formulation is a granulated mixture f Niacin. Methocel E OM and Povidone K90. The granulation process improves compression properties.

-26 TABLE IB NiaspanS Tablet Formulations Niaspan®D 375mg Tablets 500mg Tablcts 750mg Tablets 1000mg Tablets Product EormUWinL- Niacin 64.4 70.5 77.4 83.1 Meihocel E1lOM 7.4 8.1 5.9 Premium (Intragranular) Povidone K90 2.2 2.4 2.7 2.9 Methocel FEl OM Premium 25.0 18.0 10.0 (Exuragranular) Hystrene 501 6 (Steauic Acid) 1 1.0 1 1.0 Tablet weight. 582.5 709.5 968.6 1203.6 mg Niaspan® formulations are presented in white capler shape tablets. Capiet dimensions differ with respect to product strength. The 375mg, and 500mg Niaspawk ablets are compressed with tooling measuring approximately 0.68 7' in length 0.2 1I" by width. The length and width of the 750mg and I1000mg tooling measures approximately 0.750" x. 0.320". Target tablet weight and hardness dictate thickness across the four Niaspan®, products. The production of the NiaspanI® tablets will now be described generally as set fonth below.

27 Niaspan® Granulation Process Flow Chart Raw Niaterials Niacin Povidone K90 Mexhocel E IOM ntragrinular) Purified Water Process Flow Granulate Hi1gh shear granulator (Littleford FM 130) Fluid bed drier (Glatt fluid bed drier) Mill. (Kemnutec Betagrind) Parcel size reduction Niaspn® Granulation Process Description NisspanO grariula~iof rawv materials are: dispensed and granulated in a bigh shear granulator. The Wet granules% are sieved into a fluid bed drier Und are dried, When the drying process is complete. the granules are milled. Milling ensures unitbrm particle size distribution throughout the Niaspan®S granulation.

Nisnan® Tablet Process f low Chart Methocel SIOM (Exiragranular) Hystrene 5016 (Stearic Acid) l'rocess Hown\ Niasnan(O TaLhktj likuIll B lend Milled Niaspamfi granules with extravtranular Merhocel E IOM and Hystrene 5016 kgjinm=n Blender (Patterson-Kelley V-B lender) Niaspan©D TableT Manufaciture Compress Niaspan& Tablet Blend Rotary tablet press -28- Niaspan® Tablet Process Descrintion A Niaspan® tablet blend is manufactured by blending the Niaspan® granulation, extragranular Methocel E I OM and Hystrene 5016. The quantities of each Niaspan® tablet blend component will depend on the particular Niaspan® dose being manufactured (refer to Table IB).

S A Niaspan, tablet blend is compressed to form Niaspan' tablets. Niaspan® tablet physical properties will vary depending on the particular NiaspanO® dose being manufactured.

ProductionotNiaspan tablets will now be discussed in greater detail. The initial stage of manufacturing is the same for all four tablet strengths of Niaspan@ (375. 500. 750. and 100mg). One batch of Niaspano granulation is comprised of four individual 40.0kg units of granulation which arc processed separately, but under like conditions. The four individual granulations are sampled and tested individually and subsequently released for blending. The base granulation is not strength spccific and may be used to manufacture any tablet strength of Niaspant.

The ingredients in the base granulation are set forth in Table IC below: TABLE IC Component Function Quantity per per Quantity per kilogram kilogram 160.00 kg batch granulation granulation (kg) (kg) Niacin. USP Drug Substance 0.87 87.00 139.20 Povidone. USP Binder 0.03 3.00 4.80 Methocel USP. Controlled- 0.10 10.00 16.00 Premium Release Agent CR Grade Purified Water, Granulation 0.00* 0.00* 48.00 USP* Reagent Total 160.00 *Purified Water. USP is used as a granulation reagent and does not appear in the finished granulation.

Raw materials are quantatively dispensed into appropriately labeled double polyethylenelined containers using calibrated scales. Purified Watqr. USP is dispensed into an appropriate vessel from which it is later pumped during the wet-massing operation.

t0 29 A Littleford FM 130 granulator is charged with approximatelyone halfof the Niacin, USP required for the process unit 17.4kg) followed by about 4.00kg of Methocel, USP EIOM Premium CR Grade: about 1.20kg of Povidone. USP, and the balance of the Niacin, SP (-17,40kg). The powder bed is dry mixed in the Liuleford FM 130 granulator. with choppers on.

for approximately I minute. At the completion of the I-minute pre-mix cycle, about 12.0*0.05kg of Purified Water. USP are sprayed onto the powder bed at a rate of about 2.40+0.24kg/minute. Immediately following the addition of the Purified Water. USP, the unit is granulated for about 5 minutes.

The granulated unit is discharged into double polyethylene-lined containers and then t0 manually loaded into a Glatt bowl while being passed through a #4 mesh screen. The Glatt bowl is loaded into a Glatt TFO-60 fluid-bed drier with an inlet air temperature setting of about 70C±5°C. The unit is dried until a moisture level of i 1.0% is obtained as determined using a Computrac® Moisture Analyzer. model MASA. The dried granulation is discharged inot appropriately labeled, double polyethylene-lined drums and reconciled.

4 The dried and reconciled granulation is passed through a Kemutec BetaGrind mill equipped with a 1.5mm screen and running at approximately 1500 RPM. The milled granulation is collected into appropriately labeled, double polyethylene-lined drums and reconciled. The milled granulation is sampled and tested by Quality Control and released prior to further processing.

2O The released granulation units are charged to a Patterson-Kelley 20 ftR V-blender after which they are blended together for about 10 ±1 minutes and then discharged to appropriately labeled, double polyethylene-lined containers.

As stated above. Niaspan® tablets are formulated from a common granulation which is blended with appropriate quantities of Methocel. USP E10M Premium CR Grade and Stearic 2 Acid, NF to achieve the final dosage formulation. Tables IA and IB describe the formulation for each Niaspan® tablet strength. 375mg, 500mg. 750mg, and 1000mg, respectively.

Two study groups consisting of eleven and fourteen patients each were formed. Blood samples were taken from the patients, and tested for total cholesterol. LDL cholesterol.

triglycerides and HDL cholesterol to establish baseline levels from which fluctuations in these lipids could be compared- The patients were then placed upon a regimen of the above discussed tables, totaling approximately 1500mg of nicotinic acid. once per day before going to bed. After eight weeks of this regimen. the patients were again tested for lipid profiles. The results of the tests conducted at eight weeks, showing the changes in the lipid profiles as a percentage change from the baseline. are reported in the table hereinbelow. Positive numbers reflect percentage increases and negative numbers reflect percentage decreases in this table.

TABLE I1 Patient Study Lipid Profile Data P. No. Tlal.C LDL-C Apo n I.[I gikC dm,. d all Group

A

1 -B.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 -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 2.8 -0.2 NA -2.7 22.9 NA NA 11 -13.0 -9.4 NA -54.0 44.3 NA NA Mean -8.9 -13.9 NA -18.9 23.0 NA NA p-Value 0.0004 0.0001 0.0371 0.0068 -31- Pt. No. Tal-C LDL-C A _por Trim HDL-C HDL.- Ltua Group B 1 -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 -3.3 2.1 -29.4 -41.1 5.8 2.4 -22.4 6 Patient Withdrew From Study 7 23.1 -32.6 -42.6 -58.6 49.2 68.9 -14.3 8 24.8 34.0 -284 5.5 6.5 -6.8 NA 9 10.1 12.0 -16.I -11.6 20.7 -12.3 40.6 -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 Mean -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 Combined -8.7 -13.3 (p 8 -26.1 25.3 Gp B Gp B p-Value 0.0002 <0.0001 only <.0001 <0.0001 only only The data reported in TABLE II shows that the LDL levels in the Group A patients had a mean decrease of -13.9% and triglyceride decrease of -18.9% HDL cholesterol levels, the beneficial cholesterol, were raised by 23.0% in this Group. Similar results were obtained with the Group B patients. These studies demonstrate that dosing the sustained release formulation during the evening hours or at night provides reductions in LDL cholesterol levels equal to immediate release niacin on a milligram per milligram basis, but superior reductions in triglyceride reductions when compared to sustained release fIrmulations dosed during daytime hours on a milligram per milligram basis. Additionally. the increases in HDL cholesterol obtained from dosing.the sustained release formulation during the evening or a night were 32 +23.0% for one group and +25.3% fobr the other group. Dosing during the evening therefore provides reduction in cholesterol plus significant decreases in triglycerides and increases in IHDL cholesterol with once-a-day dosing.

Groups A and R were also tested for liver enzymes (AST. ALT and Alkaline Phosphatase). uric acid and thsting glucose levels at the startnof the study described hereinabove (to form a baseline)and at two. Ibur and cight week intervals. The resultsofI these tests are listed in TABLES III-VII hereinbelow.

TABLE III THE EFFECT OF NIASPAN® THERAPY ON AST (SGOT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n 28) Week' of lerapy With NIASPAN*.) PA D assdiNa I W kS T A Wks& Reference Group A 1 28 29 15 25 0-50 2 24 25 24 26 0-50 3 17 18 22 2 1 0-50 4 )4 16 15 17 0-50 22 NA 2 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 to 18 21 21 25 0-50 11 21 21 22 21 0-50 33 D_ aseline 2 Wks. 4 Wks, f iWks, I Reference Group B I23 25 3833 0-50 220 20 21 21 0-50 315 20 is 19 0-50 4 25 22 25 26 0-50 23 21 17 1S 0-50 6 PATIENT WITHDREW DUE TO FLUSHING 7 1I 819 0-50 S o191 19 0-50 9 51 s15 0-50 tO16151 28 0-50 11 22428 0-50 12 3252822 0-50 13 201 019 0-50 14 182 018 0-50 Combined 1989 20.4 20.8 21.1 Mean Change From +66 Baseline Level of Significance: p=0.4141 34- TABLE IV THE EFFECT OF NIASFANO THERAPY ON ALT (SGPT) LEVELS (tilL) (1500 mgs dosed Once-a-day at night) (ai 28) Weeks Of Therapy With Niaspan® Ek1Baseline J22&ka9. J4 ka Wks.U Reference Group A I 32 28 39 30 0-55 2 24 25 23 26 0-55 .3 18 2 3 30 30 0-55 4 7 13 14 14 0-55 4NA 43 46 0-55 6 211 14 10 0-55 797 11 7 0-55 8 618 23 21 0-55 9 417 20 14 0-55 14 15 17 19 0-55 I11 IS 18__ 20 16 0-55 ETAj Baseling 2 Wks 4 Wks Reference Group B 1 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 21 23 17 15 0-55 6 PATIENT WI1'THDREW DUE TO FLUSHING 7 21 16 18 21 0-55 8 18 201 17 18 0-55 9 11 5 11 8 0-55 8 10 14 17 0-55 11 17 12 18 16 0-55 12 14 18 20 16 0-55 13 14 NA II 10 0-55 14 23 23 I 19 0-55 Combincd 17.7 17.5 193 18.2 Mean Change From -11% 9.0% +2.8% Baseline I.evel of Signilicance p=0.3424 36 TABLE V THE EFFECT OF NIASPbAN® THERAPY ON ALKALINE PHOSPHATE LEVELS (U/L) 0 mgs dosed once-a-day at might) (n =28) Weeks OfrTherapy With Niaspan®D Baseline 2 ZWks. 14 Wks, Wa wk. ee __I__II__IEwag Group A I 52 56 57 55 20-140 2 103 100 89 102 20-140 3 54 45 15 51 20-140 4 70 68 71 91 20-14U 77 NA 74 81 20-140 6 55 48 49 51 20-140 7 72 71 79 75 20-140 S 55 49 47 so 20-140 9 531 55 56 45 20-140 74 73 75 75 20-140 1i 8 Is 20 16 20-140' IP-1lin [2 Wki j 8Wks. 1ej c Group B I 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 65 5354 61 20-140 6 PATIEN'r WITHDREW DUE TO FLUSHING 7 64 58 58 58 20-140 S 79 78 65 7 3 20-140 9 94 92 103 93 20-140 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 Combined 66.5 61.5 63.3 65.8 Mean Change From +0-005% Baseline Level of Signiicance. p=0.0236 TABLE VI THlE EFFECT OF NIASPAN® ON URIC ACID LEVELS (mgldL) (1500 mgs dosed once-a-day at night) (ni 28) Weeks Of Therapy With NIASPAN® Pt# 1Baselinc J2Wks, 4tWks, I8Wks, J Group A 1 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 70) 6.5 6.2 4.0-8.5 4 3.1 4.6 4.2 3.8 2.5-7.3 3.4 NA .34.2 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.S-7.5 9 3.9 4,5 4.6 3.5 2.5-7.5 216 2.9 2.8 2.7 2.5-7.5 II4.7 535 5.2 5.3 2.5-75 39.- Pt# Baseline I Wk. Wks, k, Reqc Group B I 3.74.4. 52.75 2 2.9 3 4.25. 4 4.73.51 64085 3.7 41.13.8 2.5-7.5 6 PATIENT WITHDREW DUE TO FLUSHING 7 5.8 6.6 6.6 6.8 1 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 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 6A1 5.3 2.5-7.5 Combined 4.54 4.82 4.92 4.86 *TwOJ.

4

SO

Mean Change From t8.4% Baseline *LeveI of Significance: pr- 0.3450 TABLE VII THE EFFECT OF NIASPAN® THERAPV ON FASTING GLUCOSE LEVELS (mg/dL) (1500 mgs dosed once-a-day at night) (n 28) Weeks Of Therapy With NIASPANM eR 21li0nl 2 Wks, 4 Wk ltW ks Reference Group A 1 114 122 123 110 70-115 2 101 105 107 101 80-125 3 99 98 109 103 70-115 4 100 118 94 94 80-125 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.

94 101 111 97 70-115 11 102 103 95 95 80-125 -41 Pt Biaseine 2 Wks. 4 Wks. 8 Wk. Reference Group B 1 101 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 88 92 91 95 70-115 6 PATI ENT WITI [DREW DUE TO FLUSHING 7 106 114 118 117 70-115 8 95 106 106 108 70-115 9 81 92 84 92 70-115 108 117 122 105 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 Combined 98.4 105.8 101.6 102.3 Mean Change From 17.5% Baseline Level of Significance; p 0,0021 In order to provide a comparison between the state of the art prior to the present invention, and in order to quantify the magnitudeof the improvement that the invention provides over the prior art. another study was conducted. This study included 240 patients dosed according to the present invention as described hereinabove. Compared to this group was.the group of patients studied by McKenney ci al.. as reported hercinabove. The results of this study are reported in TABLE VIII hereinbelow.

-42- 'FABLE VIlI A Comparison of Changes in Liver Function Tests 43 MeKcnney SR Niacin Drop 0 2 2 7 na 7 18 n 23 0 9 9 30 na 30 78 Invention Dosage Drop 0 0 0 0 0 0 n 26 67 97 35 15 240 0 0 0 0 0 0 Slyear 15 47 77 31 15 184 1 year 5 69 79 89 100 77 Dosed twice-per-day as described in "A Comparison of the Efficacy and Toxic Effects of Sustained- vs. Immediate- Release Niacin in Hypercholesterolemiic Paticnts" by McKenney et al. Journal of the American Medical Association, March 2. 1994; Vol. 271, No. 9. pages 672- 677.

bSR is 'sustained release" Dosed once-per-day at night The results of the comparison of the studies reportcd in TABLE VIll show that the control group (the McKenney group) had 18 of 23. or 78 percent of the patients therein drop out of the test because of an increase in their respective liver tunction tests. The patients withdrew at the direction ol'the investigator. In comparison. a group of 240 patients treated according to the present invention had zero patients drop out. based upon the same criteria for withdrawal.

The tests results reported above indicate that this sustained release dosage form caused no elevation in liver function tests no liver damage). no elevations in uric acid and only a small, increase in fasting glucose levels which in fact decreased during continued therapy.

Thus, it should be evident that the compositions and method of the present inventiop are highly effectivein controlling hyperlipidemia in hyperlipidemics by reducing the levels of LDL cholesterol, triglyceride and Lp(a) while increasing IDL cholesterol levels. The present invention is also demonstrated nor to cause elevations in liver function tests, uric acid or glucose levels for the hypcrlipidemics.

.44- Example 11 In order to demonstrate the effectiveness of the pharmaceutical combinations and methods of the present invention over an antihypcrlipidemia compound and method. nicotinic acid sustained release compositions coated with different HMG-CoA reductase inhibitors are prepared according to the disclosure hereinabove and hereinbelow. The composition ingredients and amounts are listed in Table IXA and IXB and the results of the study are recited in Tables X and XI hereinbelow.

TABLE IXA Coated Tablet Composition Ingredient .OOmn 750mg 100Qma Core Tablet Nicotinic Acid 500 750 1000 Hydroxypropyl 203 183.1 157 methylcellulose (Methocel Povidone 17.2 25,8 34.5 Stearic Acid 7,3 9.7 12.1 Core Tablet Weight 727.5mg 990.5mg 1203.6 Lovastatin 10-mg 10mg Polyethylene Glycol 0.9mg 0.9mng 0.9mg Hydroxypropyl 29.1 mg 29.1 g 29.1 mg methylcellulose (Methocel ES) Coating Weight 40mg 40mg Total Tablet Weight 767.5 1030.5 1243.6 TABLE IXB Batch Formulation Niacin 750mg Niacin OO1 mg Lovastatin 10mrg l.ovastatin Material Per Unit Per Batch. G Per Unit Per Batch. G MG/Tablet MG/Tablet Lovastatin 10.0 80.54 10.0 64.74 Methocel E5 29.1 234.35 19.4 125.60 Premium. LV Pluracol E1450 0.9 7.25 0.6 3.88 Purified Water na 2899.26 na 1942.20 /O Coating na 3221.4 Ia 2136.42 Suspension Total Niacin 750mg 968.5 6000.0 1203.6 6000.0 Core Tablet A Total 1008.5 9221.4 1233.6 8136.42 The core tablet ingredients are compounded together to form sustained release tablets, as described in Example I. The sustained release tablets are then coated as follows. The lovastatin. Methocel E5 and Pluracol 1450 are pre-blended in a polyethylenebag for about 2-3 minutes. The mixture is then passed through a 710mm sieve. A low sheer propeller blade mixer is positioned in a stainless steel beaker containing purified water. USP. The mixer speed is adjusted until a vortex forms. The blended mixture in the polyethylene bag is slowly added to the purified water If necessary, the mixer speed should be adjusted during the addition of the dry mixture so that the vortex conditions are maintained. Continue mixing until the blended material is completely dispersed.

Place the stainless steel beaker on a balance and record gross weight. Calculate net weight of coating suspension as follows: Net weight of coating suspension gross weight of cOating suspension beaker tare weight -46- Following manufacture of the coating suspension. the sustained release tablets are coated as follows. The Hicoater HCT 48/60 tablet coating machine is first cleaned appropriately pursuant to SOP FM700-Procedure for the cleaning of Hicoater HCT 48/60 tablet coating machine. The Hicoater HCT 48/60 tablet coating machine should be equipped with a 9 liter pan, 0.6cc gear prop. single gun spray bar. 2.5mm cup and 1.5mm nozzle porn Following SOP FM500 Procedure for the operators of the Hicoater HCT 48/60 tablet coating machine in manual mode. the atomization air pressure should be set to 150 liter/min and the pattern air pressure should be set to 100 liters/min. Once the atomization air pressure and the pattern air pressure are set. the coating suspension is placed on a balance and the suspension feed /0 line is placed in the coating suspension. The suspension return line is then placed in another container. The low sheer mixer is then placed in the coating suspension and the mixing is started. A period of about 60 minutes should be allowed before proceeding to the next step.

After about 60 minutes. the suspension pump and purge lines are switched on. When the lines are filled with coating suspension, relocate the suspension return line to the coating suspension container. The solution fiolloing through the guns should be set to about according to SOP FM500.

Next. the batch of nicotinic acid sustained release tablets are loaded into the coating machine. Close the glass door on the machine. Stan the inlet and exhaust air blowers. Adjust the inlet and exhaust air blower until air flow is 17)(±20)cfm and pan pressure negative is between 'A inch and I inch.

Coat the tablets as follows. Set the pan to .IOG at 3.3rpm. 5 seconds on and 30 seconds off. Switch on the inlet air heater and adjust to 60 0 C. Proceed to the film coating phase where the exhaust air temperature reaches 40°C. To further coat. set the pan to run. Increase the pan speed to 15rpm and stan the spray. Calculate the coating end point or target coated tablet weight as follows: -47- Coating Starting tablet weight. mg end point x 1.0413 for 750 mg (750mg) tablets Coating Starring tablet weight. mg Send point x 1.0249 for t000mg (1000mg) tablets Coating Starring tablet weight mg end point x 1.0643 for 500 mg (500mg) tablets to The coating end point should be approximately of the target coated tablet weight range.

Continue to apply coaling suspension until the end point is reached. Proceed to the next step. which is cooling upon reaching the end point.

1< To cool. stop the spray. Set the pan to JOG at 3.3rpm. Switch off the inlet air heat and allow the coated tablets to cool to approximately 35°C. Stop the pan and turn off the inlet and exhaust blowers.

To discharge. use the JOG button on the front of the machine to turn the pan until the trap door is above the surface of the product bed. Position a tared double polyethylene lined container 2 with desiccant present in the outer bag beneath the discharge chute. Open the trap door. Rotate the JOG button until coated tablets begin to discharge. Continye to rotate the pan until all the product is discharged from the pan. Stop the pan and remove the container. Then weigh the coated sustained release tablets.

Example II1 A study group consisting of 382 patients was formed. Blood samples were taken from the patients. and were tested for total cholesterol. LDL-cholcsterol. triglycerides and HDLcholesterol to establish baseline levels from which fluctuations in these lipids could be composed. The patients were then placed upon a regimen as follows: Of the 382 patients, 258 a0 patients took approximately 2000mg of Niaspan®. once per day before going to bed. and 122 of 124 patients took concomitantly, once per day at night before going to bed, approximately 2000mgof Niaspan®(twoNiaspan® 1000 mg tablets) and one HMG-CoA reductase inhibitor tablet. as reported in Table X. More specifically,4 patients took two Niaspan® 1000mg tablets -48and one fluvastatin 20mg tablet at the same time once per day at bedtime; 12 patients took two Niaspan® 1000mg tablets one lovasiatin 20mg tablet at the same time once per day at night before going to bed: 69 patients look two Niaspan 1000mg tablets and one pravastatin tablet at the same time once per day at night before going to bed: 27 patients took two Niaspan@ N 1000mg tablets and one simvastatin 1 Omg tablet at the same lime once per day at night before going to bed; and 10 patients took two Niaspan® 1000mg tablets and one HMG-CoA reductase tablet at the same time once per day at night before going to bed. However. during the study, these 10 patients changed between different HMG-CoA rcductase inhibitors. Nevertheless, the particular HMG-CoA reductase inhibitors taken by these 10 patients were those recited in Table

X.

After treatment, with a mean treatment duration of approximately 43 weeks, the lipid profiles of the patients were again tested. The results of the tests conducted. showing the change in the lipid profiles as percentage change from the baseline- are reported in Tables X and XI hereinbelow. The results of the tests conducted. showing the change in clinical chemistry profiles as percentage change from baseline. are reported in Table XII hereinbelow, and showing the number of patients and the of the total patients in the study that recorded elevations above upper limits of normal (ULN) for selected clinical chemistry parameters, are reported in Tables XIII and XIV hereinbelow.

No incidences or symptoms of myopathy or rhabdomyolysis were described by or observed in the 122 individuals receiving the combination therapy pursuant to this Example III.

-49- TABLE X, NIASPAN® AND NIASPAN® /HMG-CoA REDUCTASE INHIBITOR LONG-TERM STUDY EFFICACY DATA: MEAN TREATMENT DURATION ABOUT 43 WEEKS Change from Baseline Median Dose (mep N TC LDL-C HDL-C TG Niaspan Statin NiaspanQ 258 -12.4 -19.1 +26.0 -25.5 2000 Niaspan®+ 122 -23.8 -31.8 +27.7 -32.5 2000 Statin Total Fluvastatin 4 -22.1 -31.8 +29.3 -30.3 2000 Lovastatin 12 -20.9 -28.2 +23 5 -23.8 2000 Pravastatin 69 -23.7 -31.4 +26.5 -34.5 2000 Simvastatin 27 -24.9 -33.0 +33.9 -36.4 2000 Multiple 10 -25.3 -35.1 +23.7 -19.8 2000 Table XI also reports results of the tests conducted. More specifically, Table XI reports complete efficacy data (lipid results) for 53 of the 124 patients. who look concomitantly, once per day at night before going to bed. Niaspan® and an HMG-CoA reductase inhibitor, as indicated above in this Example III. Table XI further reports complete efficacy data (lipid results) for 16 patient, who rook concomitanly. once per day at night before going to bed.

Niaspan® and BAS. a bile acid sequestrant cholcstyramine or colestipol). Table XI also reports complete efficacy data (lipid results) for 15 patients. who look concomitantly, once per day at night before going to bed. NiaspanW, BAS (a bile acid sequestrant. cholestyramine or colestipol). and an HMG-CoA reductase inhibitor.

TABLE XI LIPID RESULTS Mean Percentage Change from Baseline LONG TERM POPULATION n Subgroup Niaspan' Only Niaspan* Niaspan' NiaspaiC Total firngCoA BAS Both Total of Patients 269 185 53 16 B~aseline' 269 201 -1*1.9 185 198.2*211 53 2418.0:t-.7 16 2017.1±11.1 15 203.7±8-8 (mg/dL) 12 weeks 234 150 1.4:L1.03' 53 (-86:l.85r'* 16 11.2±3.42)* 15 (-10.31.32)00 24 weeks 208 126 52 (-16.012.4310' 16 14 (-182±2.53)"* 48 weeks 174 (251.0" 101 (1 7.7:k1.28)1 45 15 13 72 weeks 140 79 (18.l+l.52)" 39 (-31.6±1.73r'* 9 13 96 weeks 130 (-21.8i1.37)** 73 37 (-32.2±2.32)4- 7 0-7.U*4.19)" 13 I IDL Baseline 269 43.4±0,6 185 43.6±0.7 53 42.7±1.I 4 16 42.5-±2.3 IS 44.042.2 (mg/dI.) 12 weeks 234 (19.6* 1.09)* 150 (20.2±1.361"* 53 16 (3 1. 15 (1 7.3*3.83)* 24%weeks 208 (24.911.3 1 126 52 16 (38.73.02)"* 14 (16.4*5.09)*" 48 weeks 174 (27.9k 1.56)* 101 (29.0t2.05)"* 45 (22.813.07)40 I5 (36.2*5.25)" 13 (17.6*4.74)** 72 weeks 140 (25.8tI1.54)"* 79 (27.8±2.15)* 39 9 (37-4:6031)0" 13 (16.5±3.44)** 96 weeks 130 (29.1*168)6* 73 37 7 13 (23.2*4.00)"* Taotal Cholesterol Baseline 269 276.0*2.1 185 273.0±2.4 53 285.2*4.9 16 282.0:L 10.6 15 272.8±9.1 (mg/dL) 12 weeks 234 150 53 16 15 24 weeks 208 126 52 16 14 (-13.7*1l.96)"* 48 wc 174 14.0±t.87)" 101 45 11.77)* 15 I1.3*±2.82j" 13 72 weeks 140 79 39 1± 1.4 9 13 96 weeks 130 1 5.5*h1 10) 73 37 7 15. 1*2.62W' 13 (-23.I*30.45r' TABLE X1 (continued) LIPID RESULTS Mean Percentage Change from Baseline LONG TERM POPULATION n Subgroup Niaspai* Only Niaspan' Niaspan, Niaspan Total HingCoA BAS Both Total of Patients 269 185 53 16 Triglycerides; Baseline 209 157.7±4.1 185 155.9;i5.0l 53 172.2i19.3 16 10 1.5±117.7 15 124.8±11.0 (ing/dL) 12 weeks 234 1-11±.50 S 53 0-3.40.78)"0 16 IS 24 weeks 208 (-21.7E1.13)** 126 (-20.912.65)** 52 c-23,5±4.34)** 16 14 (-23.8±10.4)' 48 weeks 174 l01 45 4±6 15 (-12.7±9.78) 13 72 weeks 140 79 (-2651367)"* 39 9 13 96 weeks 130 0-5.8±2.86)" 73 (-26.4±t3.80)* 37 (32.2±4. 10)* 7 (5.13*21.4) 13 (-20.5±8.32)' VLDL Baseline 269 31.61-0.8 185 31.2±1.0 53 34.4±1.9 16 32.4*3.5 15 25.0±2.2 (rng/dL) 12 weeks 234 1. 801" 150 (-20.6±2.351"* 53 (-23.-83.6 1) 16 15 (-18.71±6-31)" 24 weeks 208 126 52 16 14 (23.9*10.4)' 48 weeks 174 (-24.0±2.5W'0 101 45 15 13.309.80) 13 72 weeks 140 (-27.2±3.I41"* 79 (-26 39 9 (10.5±31.0) 13 (-28..6-5.701"* 96 weeks 130 (-25.8±2.861"* 73 (-25,80.85)" 37 7 13 (-20.6±8(19)' TC to IIDL Ratio Baseline 269 6.63±0.09 185 6.M±0. 10 53 6.99±0.23 16 6.96±0.5 1 15 6.40*0.34 12 weeks 234 150 (-21.6±1.081"0 53 16 15 24 weeks 208 126 52 16 14 (-24.0+E4.03)"* 48 weeks 174 101 1-29.1±1.32)"* 45 2.37)0* I5 13 (-24.50.61)** 72 weeks 140 79 39 9 13 (-28.7+4.21)" 96 weeks 130 73 37 7 13 LDL to I{DL Baseline 269 4.85±01.08 185 4.75±0.08 53 5.12±0.20 £6 5.16±0.47 15 4.804:0.31 Ratio 12 weeks 234 (-23.7±1.041"* 150 19)" 53 16 15 24 weeks 208 126 (-29.0*1l.42)1* 52 (-29.8+k2.593"* 16 14 48 weeks 173 100 45 1S 13 72 weeks 140 79 39 9 13 96 weeks 1130 73 37 7 13 Note: Observed Values S.E. (percentage change *Significant atp s 0.05, "significant atp s; 0.01; mnatched pair t-test TABLE XI (continued) LIPID RESULTS Mean Percentage Change from Baseline LONG TERM POPULATION Sugoup Niaspan Only Niaspan' Niaspan* Niaspan Total fImgCoA +BAS +Both T.otal or Patients 269 185 53 16 Apolipoprilcin 13 Baseline 244 148. 1I.23 165 145.7±1.41 48 155.8*285 16 149.36.03 15 149.2±4.53 (mc/dL) 12 weeks 138 76 I.5±l.38)4* 37 13 1.42.90)* 12 24 weeks 133 (-14.0±1.06I*0 71 36 14 (-13.72.28)" 12 (16.6±2.48)" 48 weeks 123 (-l8.7±1.14)0 70 (-15.4*1.33) 3U (-26.2±2.60) II 19.10,14) 12 (-18.5:3.44)" 72 weks 43 31 11 (-32.22.22)"0 0 1 (-19.3) 96 "eks 0 0 0 0 0 Lp(a) 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 (nigldI.) 12 weeks 139 78 J-2.882.69)"* 36 (-28.7*4.44W'* 13 12 (-14.9±10.9) 24 weeks 133 (-28.7±2.29)"0 72 (-30.412,70)** 35 (-28.0±5.3 1) 14 12 (-19.5±10.0) 48 weeks 131 74 (-36.312.731" 32 12 13 (-19.0±7.0I)* 72 weeks 44 (-33.03.84)" 29 -31.514.84)*1 12 0 3 (-24.7±12.6) 96weeks 0 0 0 0 0 Note: The indicates that no measurements have been collected for that visit. CObservd Values S.H. (percent change Individual data are provided on ZIP diskette.

Signiricant atp signilicant at p 0.0 1. matched-pair test 53 Table XII reports clinical chemistry parameters (liver function) for all 124 patients, who took concomitantly.once per day at night before going to bed. Niaspan® and an HMG-CoA rcductase inhibitor. Table XII further reports clinical chemistry parameters (liver function) for 22 patients, who took concomitantly. once per day at night before going to bed, Niaspan® and 4 BAS (a bile acid scquestrant, cholestyramine or colestipol). Table XII also repons clinical chemistry parameters (liver function) for 17 patients who took concomitantly, once per day at night before going to bed. Niaspan®. BAS (a bile acid sequestrant. cholestyramine or colcstipol). and an HMG-CoA reductasc inhibitor.

TABLE XII CHEMISTRY PARAMETERS MEAN PERCENT CHANGE FROM BASELINE LONG TERM POPULATION Niaspan 5~ NISSp3O a tim LNI*S~dU a nuui IS 'Total Niaspun Only IN i-pnA& Niaspan IIAS r4laspark dx DOW ING-CoA MeajntS.i. n NieaniSI:. n. Mean iSf.. n mcan S.E.

11 meati&S.E.

Total Patients AST(mIlrI)hi Ilusecline 12 weeks 48 '%tecks 96 weeks ALT (nilU/znL) Baseline 12 weeks 48 weeks 96 weceks Alk>Ph.

(mIU/ml.) Blaseline 12 weeks 48 weeks 96 weeks 18.9+0.22 (13.5±1.54)14 184.8±2. 18) (I 5.4±2.96)"* 23.540.39 1.8A 1.510 (5.7:t2,2 t) (5.7:3,50) 6939±0.10 jAJ.3 ±0.5 5) (0.8±0.79) (1.6±1.20) 14 7,90±0.92 (9.70.54)" (15.2±0.76)"* (17.9±1.04)4* 0.54±0.010 (1.6.+1.33) (9.3±1.81)' (15.1t±3.22) 454 18.71t) 20 352 0 13 6 1 1 .72)"l 240 (17,90.003" 76 (1 31±4189)" 454 23.4±0.48 353 (2.6±1.843 240 (3.92.82) 75 (1,0±5.4 1 .14 66.0*0 843 353 (-0.6±0.70) 239 (0.81-1.00) 75 454 147.3±1.024 353 240 (14.5±0.93)44 76 (17,1-t11.23)4 454 0.53*0.011 352 1.67) 240 (7.6±2.26)" 75 (6.0±'4.22) 124 22 17 224 l1eu1044 22 20.5±1.09 17 2(1,4±1.26 121 0113 f2.78), 22 (25.9±16).89) 17 011.4*4.351' I(M (21 51353)0 20 017,815.0))* 15 (16.619.14) 37 (18.2±336)" 7 13 (29.6t3.16)** 124 24.3±0.73 22 23.0±L2.08 17 14.4:k1 .66 121 (409±2.66) 22 (6.7:h11.47) 17 (-2.3±5.70) 101 20 f3.6:E5.74) I5 (16.8±12,50) 37 (10.9±5.09)' 7 13 (21.4-6.49) 124 67.0±1.56 22 59.2±2.30 17 63.6±3.29 221 22 (4.8±2.64) 17 (1.3*3.36) 101 19) 20 (2.9±5.28) IS (7.8±4.87) .37 7 (3,2±k4.19)) 13 (6.2±5.10) 124 149.4±1.96 22 15233±7.03 27 156.5±k6.80 121 0112±1.07)" 22 41 4,0±3.23)" 17 (10.8*k2.27)6* 101 (16.1±1,59)"0 20 I5 (12.8±2.40)"* 37 7 13 (16.1±2.97)"* 124 0.58±+0.022 22 0.65±0.069 17 0.53±0.039 121 (402Q2.46) 22 (2.3±4.84) 17 (1 7.1*7-03)' 101 (10.5±3.173" 20 (23.1*8.84) I5 (24.3± 12.55) 37 (25.5±&5.20)00 7 (26.3* 11.49) 13 (32.2±L12.31)' LDHI (NlU/M 1) Baseline 12 weeks 48 weeks 96 weeks Baseline 12 weeks 48 weeks 96 week Total Bili.(ngd.) TABLE XII (continued) CHEMISTRY PARAMETERS MEAN PERCENT CHANGE FROM BASELINE LONG TERM POPULATION LT Total Niaspan Only HMG-Coar& Niaspan BAS Niasp5na &naon HMG-CoA n _Men±S._E. n Mcan±S.E. is Mean ±S.E. a Mean 5.2. ns Mean S.E.

Di.ii m/l)Baseline 617 0.12*0.002 454 0.12*0.002 124 0. 12*0.004 22 0.13*0.013 17 0.1010.007 12 weeks 513 353 (9.1±1376)" 121 7*3.06) 22 (10.2*6.50) t17 (1S."*8.62) 48 weeks 376 240 (26.6*10.24)" 101 (24.4±4.23Jt* 20 (24.1±7.68)40 15 (40.1*12.24)40 96 weeks 132 75 (1 37 7 (16.7±7.66) 13 (49.0*14.36)" Ayae(gd)Baseline 617 51.2-+0.78 454 5 1.2*0.q2 124 52.2-t1.72 22 49.3*3.70 17 45.6:3.20 12 weeks 513 (6.4*0.84)1* 353 121 (4.9±l.59Y* 22 1*0.19) 17 (3.403.39) 48 weeks 376 240 (8.7*1.34)0" 101 20 (7.2*5.23) IS (10.1*7.06) 96 weeks 1 132 75 37 (6.6±5.23) 7 (3.1±3.582 13 (2.6*3.55) Note: Values are based upon two dilrerent central laboratories: thus, the Baseline: observed value is presented for de~scriptive purposes only.

*Significant atps 0.05 *4Significant atpsK 0.0 1 Matched-pair i-tst.

"*Observed Value fr Baseline (mean percent change lions Baseline SI.E. for Weeks 12. 48 and 96).

56- In Tables X-XII. positive numbers rellect percentage increases and negative numbers reflect percentage decreases.

Table XIll reports the number of patients and the of the total patients in the study that recorded elevations above upper limits of normal (ULN) for selected clinical chemistry parameters. More particularly. Table XIII reports the number ol patients and the of the 124 patients, who took concomitantlv. once per day at night before going to bed. Niaspani and an HMG-CoA reductase inhibitor, that recorded elevations above ULN for selected clinical chemistry parameters. Table XIII further reports the number of patients and the of the 22 patients, who took concomitantly.once per day at night before going to bed. Niaspan and BAS (a bile acid sequestrant. cholestyraminc or colestipol). that recorded elevations above ULN for selected clinical chemistry parameters. Table XIII Iurther reports the number of patients and the of the 17 patien.ts, who tonk cinuomnitantly. once per day at night before going to bed.

Niaspan,. BAS (a bile acid sequestrant. cholestyramine or colestipol). and an IMG-CoA reductase inhibitor, that recorded cl\lations above ULN obr selected clinical chemistry parameters.

57 TABLE Xl11 TREATMENT EMERGENT ABNORMALITIES IN SELECTED CHEMISTRY PARAMETERS LONG TERM POPULATION I'T Total' NiaspanIiJ N iaspanf Niaspan'* Niaspan® OnyKMG-CoA BAS Both Total Patients 617 454 124 22 17 AST 'Normal 70(11%1 44010%) 17(14%1/) 5(23%) 4(24%) (niiU/lL '.3,xULN 28( 17( 2(12%) ,2xULN 101%) 0 '3xULN 0 0 0 ALTr -Normal 441 23( 14011%) 20 5(291/) (mlU/mL) 'I .3xULN l5( 4(c 2( 4(24%/) ,2xUl.N 3(cl1%) Ij(l%) 21(2%) 0 0 )3xUL.N l10%) 0 0 0 ALL. Ples. 'Normal 17( 9( 31 2( 3018%) (mn[U/mI.) '1AxLLN 3( 1 0) 21 1( 0 LDII1 )Normal 94(150 N 143 23(19%/) 8036%) 3(18%) (mlUrml.) 'L3xIJLN (c 41c I3%) 10'1%) 0 1(60/) Fasting Glue 'Normal I11(180o) 67(15%) 30(28%) 4(18%) (24%) (mgldL) tl.3xU1.N 6(c 1Do) 3(cI%) 0 0 Uice Acid )Normal 89(144%-) 49(13%) 28423%) 7132%) N(29%) (mIU/ml.) l1.3xUJLN 301%) 016% Total Bili 'Normal 10( 413%) 016% jmgldL) '1x3.ULN 10'l%) 0 0 Amylase 'Normal 18( 11Ic2%) 71( 0 0 (mgldL) -l.3sULN 5( 16'1%) 0) 0 j2.JL.N 1 11%) 0)1)t Phosphorus (Normal 159(26%i 96(21%) 47(38%) 9(41%) 7(41%) (mg/l) (2.0mg/dl. 1903%) 14( 4( 11 0) Note: Percentages arc calculated From the total number of patients in each column.

Abnormal liver test results for Patient 3532 are not included in this table as the data werc collected at a local hospital. Rcer to the initial Safety Update (Vol. 1. 1.)12-13.37) Table XIV reports the number of patients and the of the total patients in the study that recorded elevations 2 or 3 times above upper limits of normal (ULN) for the AST and ALT clinical chemistry parameters. More particularly, Table XIV reports the number of patients and the of the 124 patients, who took concomitantly, once per day at night before going to bed, Niaspan®P and an HMG-CoA reductase inhibitor, that recorded elevations which were 2 or 3 times above ULN for the AST and ALT clinical chemistry parameters. Table XIV is consistent with that reported in Table X1II.

TABLE XIV LONG-TERM STUDY SAFETY DATA LIVER FUNCTION TESTS Niaspan NiaspanLv HMG-CoA Reductase Inhibitor N454* hN=?124** AST>2xULN 1 AST 3xULN I 0 ALT 2xULN I 2(1.6%) ALT 3xULN 0 1 *Mean follow-up approximately 52 weeks **Mean follow-up approximately 43 weeks The data repored in Tables XI-XIV evidences that a pharmaceutical combination of the present invention.e.g.. sustained release nicotinic acid and an immediate release HMG-CoA reductase inhibitor, given concomitantly. once per day at night before bedtime, is effective in reducing serum lipid levels, and in particular total cholesterol. VLDL-cholestcrol. LDLcholesterol, trilycriidcs.apolipoproteinB and Lp(a) levels, and is effiective in reducing the total cholesterol to HDL-cholestcolratio and the I,DL-cholesterolto HDL-cholesterolraio. Thedata relorted in Tables XI-XIV also evidences that a pharmaceutical combination of the present invention. sustained release nicotinic acid and an immediate release HMG-CoA reductase inhibitor, given concomitantly, once per day at night before bedtime, is effective in enhancing or increasing HDL-cholesterol levels. Also. it is believed that the data reported in Tables XI-XIV evidences that a pharmaceutical combination of the present invention. sustained release nicotinic acid and an immediate release HMG-CoA reductase inhibitor, given concomitantly, once per day at night before bedtime, is more effective in reducing LDL-cholesterol levels than when either sustained release nicotinic acid or an immediate release HMG-CoA reductase inhibitorare given in similar dosages once per day at night before going to bed. but alone. Still further, it is believed that the data reported in Tables XI-XIV evidences that a pharmaceutical combination of the present invention, sustained release nicotinic acid and an immediate release HMG-CoA reductase inhibitor, given concomitantly, once per day at night before bedtime, is more effective in increasing HDL-cholestcrol levels than when an immediate release -59- HMG-CoA reductasc inhibitor is given by itself in a similar dosage once per day at night before going to bed.

The data reported in Tables XI-XIV also evidences that such concomitant therapy, e.g., sustained release nicotinic acid and an immediate release HMG-CoA rcductase inhibitor, given once per day at night before bedtime can be administered and the benefits achieved without inducing hepatotoxicity, myopathy or rhabdomyolysis. or at least without inducing in an appreciable number of individuals hepaltooxicity, myopathy or rhabdomyolysis to such a level that would require discontinuation of such therapy. Moreover, the data reported in Table XII evidences that such concomitant therapy, sustained release nicotinic acid and an immediate release HMG-CoA reductase inhibitor, given once per day at night before bedtime can be administered and the benefits achieved without adversely effecting glucose metabolism or uric acid levels, or without adversely eflicting in at least an appreciable number of individuals glucose metabolism or uric acid Ievels to such an extent that discontinuation of such therapy would be requiredxample IV Additional nicotinic acid sustained release compositions coated with lovastatin are prepared according to the disclosure hereinabove, The composition ingredients and amounts are recited in Tables XV. XVI and XVII. and the methods such coated compositions are set forth hereinafter.

TABLE XV Coated Tablet Composition Ingrsdient Do=jg 5Q0mg 500mg Core Table Table 13 Table IB Table IS Nicotinic Acid 500.2 50012 500.2 Hydroxypropyl 185.2 185.2 185.2 methylcellulose (Methocci Povidone 17.0 17.0 17.0 Stearic Acid 7.1 7.1 7.1 Core Table Weight 709.5mg 709.5mg 709.5mg Material Per Unit, Per Unit, Per Unit MGfTablet MG/Tablet IG/Tabiet Lovastatin 5mg I0mrg Hydroxypropyl methyceliulcse (Methocel E5) 63.05mg 58.18mg Premium LV

NFIUSP

PluracoL E1450. 1.95mg

NF/USP

Polyethylene Glycol 1.78mg 1450. NFIUSP Purified Water, USP n/a n/a n/a

COATING

SUSPENSION A

TOTAL

Opadry Y-30-13642- 23.38mg 23.38mg 23.38mg A-Orange Purified Water n/a n/a -61 Color Coating Suspension B Total Opadry YS-lI-l19025- A 4.02mg 4.02mg 4.02mg C lear Purified Water n/a n/a n/a Polish Coat Suspension C Niacin 500mg Core 709.5mg 709.5mg Tublets Total Tablet Weight 806.84mg 806.86mg121.

-62- TABLE XVI Coated Tablet Batch Composition Per KG Table XV Table XV Table XV Niacin 300mg Niacin 500mg Niacin 500mg Lovastatin Smue Lovostatin tMrn Lovsttin 2Pm! Material Per Batch KG Per Batch, KG Per Batch, KG Lovasatin 0.137 0.275 0.550 Hydroxypropyl nerhylceulos (Methoccl ES) 1.734 1.601 1.334 Premirnum LV.

NF/USP

Polyethylene GlycolI 0.050 0.041 1450. NF/USP Pluracol E1450. 0.054

NF/USP

Purified Water, USP 14.117 14.124 14.117

COATING

SUSPENSION A 16.042* 16.050* 16.042*

TOTAL

Opadry Y-30-13642- 0.643 0.643 0.643 A-Orange Purified Water 2.572 2.572 2.572 Color Coating Suspension B 3.215* 3.125m 3.125* Total Opadry YS-I- 0.136 0.136 0.136 19025-A Clear Purified Water 1.677 1.677 1.677 Polish Coat Suspension C Niacin 500mg Core Tablets 63- 1.813 1.813 1.813* 15.000 15.000 15.000

I

Total Tablet Weight *Coating suspension theoretical yields includes a 30% excess to facilitate pump and line purging.

*Opadry clear suspension includes a 60% excess to facilitatc complet purging.

TABLE XVII Cotoed Tablet Batch Composition Ni mnosition Niacin 500mg cores Lovastatin Methocel ES Polyethyleneglycol Opadry II Orange Opadry II Clear Water mf/Tablet 709.50 (Table IB) (Table XV) 10.00 67.86 2.10 23.38 4.02 807.37 me/Tablet 709,50 able 1B) (Table XV) 20,00 48.50 1.5 23.38 4,02 73..33 mf/Tablet 968.60 (Table IB) 20.00 73.33 2.27 31.93 5.49 1002.89 20.00 95.84 2.96 39.67 S6.81 1246.05 mg/Tablet 1203.60 (Table IB) Total (Inl. Water) 1624.23 1541.23 2104.50566 2614.92824 (Total (ExcL Water) 816.86 806.90 1101.62 1368.88 The core tablet ingredients are compounded together to form sustained release tablets, as described in Example 1.

Coating Suspension A The sustained release tablets are then coated as follows. The lovastatin. Methocel and Pluracol E1450 are pre-blended in a polyethylene bag for about 2-3 minutes to form a blended mixture. The blended mixture is then passed through a 1.00 mm sieve. A low sheer propeller blade mixer is positioned in a stainless steel vessel containing the purified water. USP.

The mixer speed is adjusted until a vortex forms. The sieved blended mixture in the nnlvethvenebait is slowly added to the puri fled water. If necessary, the mixer speed should be -64adjusted during the addition of the dry mixture so that vorex conditions are maintained.

Continue mixing until the sieved blended material is completely dispersed.

Continue mixing Coating Suspension A until the blended material is completely dispersed (for example, about 30 minutes).

O Place the stainless steel beaker on a balance and record gross weight. Calculate net weight of coating suspension as follows: Net weight of Coating Suspension A gross weight of Coating Suspension A beaker tare weight The theoretical yield of Suspension A is about 16.042 Kg.

Coa ting Susnension B Position a low sheer propeller blade mixer in the stainless steel vessel containing the pre-weighted purified water. USP. The mixer speed is adjusted until a vortex forms. The Opadry /I Y-30-13642-A-Orange is slowly added to the purilied water. Record addition start and stop times. If necessary, the mixer speed should be adjusted so that the vortex conditions are maintained. Continue mixing until completely dispersed.

The theoretical yield of Suspension B is about 3.215 kg.

Coating Suspnesion C 2A Position a low sheer propeller blade mixer in the stainless steel vessel containing the pre-weighed purified water. USP. The mixer speed is adjusted until a vortex forms. The Opadry YS-1-19025-A-Clear is slowly added to the purified water. Record addition start and stop times.

If necessary, the mixer speed should be adjusted so that the vortex conditions are maintained.

Continue mixing until completely dispersed.

The theoretical yield of Suspension C is about .1813 kg.

Following manufactureof Coating Suspension A. Coating Suspension B and Coating Suspension C. the sustained release tablets are coated as follows. The Hicoater HCT 48/60 tablet coating machine is first cleaned appropriately pursuant to SOP FM700-Procedure for the cleaning of Hicoater HCT 48/60 tablet coating machine. The Hicoater HCT 48/60 tablet coating machine should be equipped with a 23 liter pan. 0.22cc gear pump. double gun spray bar. air cap and 1.5mm nozzle port.

Film Coati 1 Place Coating Suspension A oil a balance. Place the solution feed line in the suspension. Place the solution return line in another container. Position the low sheer mixer in Coating Suspension A and start mixing. Allow the Coating Suspension A to mix for at least minutes before proceeding to the next step. Switch on the solution pump and purge the lines.

When the lines are filled with Coating Suspension A relocate the solution return line in the coating suspension container.

Set the solution flow spray rate to 55g/min according to SOP FM500 Procedure.

Load the batch of the appropriate niacin weight 500mg core. 750mg core or /0 1000mg core) tablets into the coating machine. Close the glass door on the machine. Start the inlet and exhaust air blowers. Adjust the inlet and exhaust air blower until air flow is 170cfm±20 and pan pressure negative between -t/2 inch and -1 inch.

Coat Tablets as Follows To preheat the niacin tablets, set the pan to JOG at 3.3rpm. about 5 seconds on, about 30 seconds off. Switch on the inlet air heater and adjust to about 62.5 C±0.5C. Proceed to the film coating phase when the exhaust air temperature reaches about 40 C.

Set the pan to run and increase the speed to 12rpm. Start the spray. Immediately collect a ten (10) niacin core tablet sample. Weigh and record the starting core weight. Every minutes during coating remove 10 tablets and record the processing parameters. Continue AsL applying coating suspension until the end point is reached.

Proceed to the next step upon reaching end point. Stop spray. Set the pan to JOG at 3.3rpm. Switch off the inlet air heater. Allow the product to cool to approximately 35 C.

Color Costinr: Oadrv Orange Place Coating Suspension B on balance. Place the solution feed line in the suspension.

-9 Place the solution return line in another container. Position the low sheer mixer in Coating Suspension B and start mixing. Allow the suspension to mix for at least 45 minutes before proceeding to the next step. Switch on the solution pump and purge the lines. When the lines are filled with Coating Suspension B relocate the solution return line in the Coating Suspension B container. Record the start time for this step. Set the solution flow through the guns to u O80g/min. According to SOP FM 500 as indicated earlier herein. Record the pump speed and spray rate. Start the inlet and exhaust air blowers. Adjust the inlet and exhaust air blower until h. air flnw is about 170cfm±20 and pan pressure negative between 1/2 inch and -1 inch. Switch -66on the inlet air heater and adjust to about 70 C±0.5C. Proceed to the flm coating phase when the exhaust air temperature reaches about 40 C.

Set the pan to run and increase the speed to 12rpmn. Start the spray. Immediately collect a ten (10) niacin core tablet/Lovasratin sample. Weigh and record the sinnting tablet weight. Every 5 minutes during coating remove 10 tablets and record the processing parameters.

Continue applying coating suspension until the end point is reached.

Proceed to the next step upon reaching end point.

Stop the spray. Set the pan to JOG at 3.3rpm. Switch off the inlet air heater. Allow the product to cool to approximately 35 0.

tO PolisktCoatiung: Opandry Cihar Place Coating Suspension Con balance. Place the solution feed line in the suspension.

Place the solution return line in another container. Position the low sheer mixer in Coating Suspesnion C and start mixing. Allow the suspension to mix for at least 45 minutes before proceeding to the next step. Switch on the solution pump and purge the lines. When the lines ame filled with Coating Suspension C relocate the solution return line in the Coating Suspension C container. Record the stan time for this step. Set the solution flow through the guns to SOS/mtin. According to SOP FM 500 as indicated earlier herein- Record the pump speed and spray rate. Stant the inlet and exhaust air blowers. Adjust the inlet and exhaust air blower until the air flow is about I 70cfm±+20 and pan pressure negative between 112 inch and -1I inch. Switch on the inlet air heater and adjust to about 70 C±0.5 C. Proceed to the film coating phase when the exhaust air temperature reaches about 40 C.

Set the pan to run and increase the speed to 12rpm. Stan the spray. Immediately collect a ten (10) niacin core rabler/Lovastatin sample. Weigh and record the sinnting tablet weight. Every 5 minutes during coating remove 10 tablets and record the processing parameters.

Continue applying coating suspension until the end point is reached.

Proceed to the enxt step upon reaching end point.

Stop the spray. Set the pan to JOG at 3.3rpm. Switch off the inlet air heater. Allow the product to cool to approximately 35 C. Stop the pan and turn off the inlet and exhaust blowers.

Disharge Use the JOG button on the front of the machine to turn the pan until the trap door is above the surface of the product bed. Position a tared double polyethylene lined container with desiccant present in the outer bag beneath the discharge chute. Open the trap door. Rotate pan -67using the JOG button until product begins to discharge Stop the pan and remove the container.

Weigh the coated sustained release niacin/immediate release lovasiatin tablets.

Based upon the foregoing disclosure, it should now be apparent that the pharmaceutical combinations, formulations, compositions and methods and the use thereof 'I described herein will carry out the objectives set forth hereinabovc. It is. therefore, to be understood that any variations evident in the pharmaceutical combinations, formulations, compositions and methods fall within the scope of the claimed invention and. thus, the selection of specific component elements can be determined without departing from the spirit of the invention herein disclosed and described. For example, sustained release excipients. binders and processing aids according to the present invention are not necessarily limited to those exemplified hereinabove. Thus. the scope of the invention shall include all modifications and variations that may fall within the scope of thc attached claims.

Having described our invention. we claim:

Claims (53)

1. 2. A pharmaceutical composition of claim 1, when said HMG-CoA reductase inhibitor is in an extended release form or in an immediate release form.
2. 3. A pharmaceutical composition of claim 1 or claim 2, wherein said HMG- SCoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, Cf flavastatin, lovastatin, pravastatin and simvastatin. O 4. A pharmaceutical composition of any one of claims 1 to 3, wherein said 0 pharmaceutical composition is in the form of a solid oral dosage form.
3. 5. A pharmaceutical composition of claim 4, wherein said solid oral dosage form is selected from the group consisting of a tablet, caplet, capsule, granules, beads particles and pellets.
4. 6. A pharmaceutical composition of claim 5, wherein said solid oral dosage form is coated with a coating.
5. 7. A pharmaceutical composition of claim 6, wherein said coating is an enteric coating.
6. 8. A pharmaceutical composition of claim 4, wherein said solid oral dosage form is a bilayer tablet having first and second layers, the first layer containing the nicotinic acid and the second layer containing the HMG-CoA reductase inhibitor.
7. 9. A pharmaceutical composition of claim 8, wherein said bilayer tablet is an enterically coated bilayer tablet. A pharmaceutical composition of claim 8, wherein one of said layers is enterically coated.
8. 11. A pharmaceutical composition of any one of claims 1 to 10, wherein said flush inhibiting agent is a nonsteroidal anti-inflammatory agent.
9. 12. A pharmaceutical composition of claim 11, wherein said nonsteroidal anti- inflammatory agent is present in an amount effective to inhibit or reduce prostaglandin PGD 2 synthesis.
10. 13. A pharmaceutical composition of clam 11 or claim 12, wherein said nonsteroidal anti-inflammatory agent is selected from the group consisting of indomethacin, sulindac, etodolac, aspirin, salicylate salts, ibuprofen, fluribprofen, fenoprophen, suprofen, benoxaprofen, ketoprofen, carprofen, naproxen, sodium naproxen aclofenac, diclofenac, fenclofenac, tolmectin, zomepirac, meclofenamate, mefanamic acid, oxyphenbutazone, phenylbutazone and piroxicam. A40410dldIsi COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:02 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 17 69 IO 14. A pharmaceutical composition of claim 6, wherein said coating contains the O SHMG-CoA reductase inhibitor. r
11. 15. A pharmaceutical composition of any one of claims 1 to 14, said Spharmaceutical composition further including a lipid-altering agent selected from the group consisting of a bile acid sequestrant, an N-substituted ethanolamine derivative, an azulene O derivative, a disubstituted urea derivative, an ionene, a poly(diallylmethylamine) derivative, an omega-3-fatty acid and a fibric acid.
12. 16. A pharmaceutical composition of any one of claims 1 to 14, said pharmaceutical composition further including a lipid-altering dug selected from the group t 10 consisting of cholestyramine, colestipol, DEAE-Sephadex, probucol, lipostabil, Eisai O E5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azulene 0 derivative), melinamide, neomycin, quartemary amine 0, poly(diallyldimethylammoniumchloride), gemfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate and clinofibrate.
13. 17. A pharmaceutical composition of any one of claims 1 to 14, said pharmaceutical composition further including cholestyramine in an effective lipid-altering amount.
14. 18. A pharmaceutical composition of any one of claims 1 to 14, said pharmaceutical composition further including colestipol in an effective lipid-altering amount.
15. 19. A coated tablet for oral administration to alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis, said coated tablet comprising an effective lipid-altering amount of nicotinic acid in an extended release form, and a coating containing an effective lipid-altering amount of an H1MG-CoA reductase inhibitor in an immediate release form. A coated tablet of claim 19, wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, flavastatin, lovastatin, pravastatin and simvastatin.
16. 21. A coated tablet of claim 19 or claim 20, wherein said coated tablet is oval, flat or oval, convexed in shape.
17. 22. A coated tablet of claim 19 or claim 20, wherein said coated tablet is round, flat or round, convexed in shape.
18. 23. A coated tablet of claim 19 or claim 20, wherein said coated tablet is capsule-shaped.
19. 24. A coated tablet of any one of claims 19 to 23, wherein said coated tablet is coated with an enteric coating. A4 1WOdImci COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:02 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 18 IN 25. A coated tablet of any one of claims 19 to 24, wherein said coated tablet Sincludes a flush inhibiting agent to reduce the capacity of the nicotinic acid to provoke a C flushling reaction in a subject.
20. 26. A coated tablet of claim 25, wherein said flush inhibiting agent is a nonsteroidal anti-inflammatory. O 27. A coated tablet of claim 26, wherein said nonsteroidal anti-inflammatory agent is present in an amount effective to inhibit or reduce prostaglandin PGD 2 synthesis.
21. 28. A coated tablet of claim 26 or claim 27, wherein said flush inhibiting agent is selected from the group consisting of indomethacin, sulindac, etodolac, aspirin, salicylate salts, ibuprofen, fluribprofen, fenoprophen, suprofen, benoxaprofen, ketoprofen, O carprofen, naproxen, sodium naproxen, aclofenac, diclofenac. fenclofenac, tolmectin, C zomepirac, meclofenamate, mefanamic acid, oxyphenbutazone, phenylbutazone and 0 piroxicam. C 29. A coated tablet of any one of claims 19 to 28, said coated tablet further including a lipid-altering agent selected from the group consisting of a bile acid sequestrant, an N-substituted ethanolaine derivative, an azulene derivative, a disubstituted urea derivative, an ionene, a poly(diallylmethylamine) derivative, an omega- 3-fatty acid and a fibric acid. A coated tablet of any one of claims 19 to 28, said coated tablet further including a lipid-altering agent selected from the group consisting of cholestyramine, colestipol, DEAE-Sephadex, probucol, lipostabil, Eisai E5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402) tetrahydrolipstatin (THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azulene derivative), melinamide, neomycin, quarternary amine poly(diallyldimethylammonium chloride), gcmfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate and clinofibrate.
22. 31. A coated tablet of any one of claims 19 to 28, said coated tablet further including cholestyraminc.
23. 32. A coated tablet of any one of claims 19 to 28, said coated tablet further including colestipol. 33. A method for altering lipids in an individual without causing drug induced hepatotoxicity, myopathy or rhabdomyolysis, said method comprising administering to the individual once per day as a single dose a pharmaceutical combination comprising an effective lipid-altering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an BMG-CoA reductase inhibitor.
24. 34. A method of claim 33, wherein said administration comprises administering the pharmaceutical combination once per day as a single dose during the evening hours or before or at bedtime. A method of claim 33 or claim 34, wherein the lipids are selected from the group consisting of VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, Lp(a), total cholesterol, triglycerides, apolipoprotein A-I, Apolipoprotein B and apolipoprotein E. AalOdJO] Ipelr l COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:03 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 19 71 I 36. A method of claim 33 or claim 34, wherein said method reduces inert lipids O Sin the serum of the subject selected from the group consisting of VLDL-cholesterol, LDL- C cholesterol, Lp(a), total cholesterol, triglycerides, apolipoprotein B and apolipoprotein E.
25. 37. A method of claim 33 or claim 34, wherein said method increases HDL- [T 5 cholesterol levels in the serum of the individual. O 38. A method of claim 33 or claim 34, wherein said method increases apolipoprotein A-1 levels in the serum of the individual.
26. 39. A method of claim 33 or claim 34, wherein said method decreases total IN cholesterol to HDL-cholesterol levels in the serum of the individual. o 10 40. A method of claim 33 or claim 34, wherein said method decreases LDL- O cholesterol to HDL-cholesterol ratios in the serum of the subject. C 41, A method of any one of claims 33 to 40, wherein the HMG-CoA reductase 0inhibitor is in an immediate or extended release form. Ci 42. A method of any one of claims 33 to 41, said method including the further step of administering to the individual a flush inhibiting agent for reducing the capacity of the nicotinic acid to provoke a flushing reaction in the individual.
27. 43. A method of claim 42, wherein the flush inhibiting agent is a nonsteroidal anti-inflammatory agent.
28. 44. A method of claim 42, wherein said nonsteroidal anti-inflammatory agent is present in an amount effective to inhibit or reduce prostaglandin PGD 2 synthesis. A method of claim 43 or claim 44, wherein the nonsteroidal anti- inflammatory agent is selected from the group consisting of indomethacin, sulindac, etodolac, aspirin, salicylate salts, ibuprofen, fluribprofen, fenoprophen, suprofen, benoxaprofen, ketoprofen, carprofen, naproxen, sodium naproxen, aclofenac, diclofenac, fenclofenac, tolmectin, zomepirac, meclofenamate, mefanamic acid, oxyphenbutazone, phenylbutazone and piroxicam.
29. 46. A method of any one of claims 33 to 45, said method including the further step of administering to the individual an effective lipid-altering amount of a lipid-altering agent selected from the group consisting of a bile acid sequestrant, an N-substituted ethanolamine derivative, an azulene derivative, a disubstituted urea derivative, an ionene, a poly(diallylmethylamine) derivative, an omega-3-fatty acid and a fibric acid.
30. 47. A method of any one of claim 33 to 45, said method including the further step of administering to the individual an effective lipid-altering amount of a lipid-altering agent selected from the group consisting of cholestyramine, colestipol, DEAE-Sephadex, probucol, lipostabil, Eisai E5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402) tetrahydrolipstatin (THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azulene derivative), melinamide, neomycin, quartemary amine poly(diallyldimethyl ammonium chloride), gemfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate and clinofibrate. A4'4)0oQdihpci COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:03 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 72 I 48. A method of any one of claim 33 to 45, said method including the further O step of administering to the individual an effective lipid-altering amount of cholestyramine.
31. 49. A method of claim 33 to 45, said method including the further step of administering to the individual an effective lipid-altering amount of colestipol. H 5 50- A method for altering lipids in an individual without causing drug-induced Shepatotoxicity, myopathy or rhabdomyolysis, said method comprising administering to the individual once per day as a single dose a pharmaceutical combination comprising an effective lipid-altering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an HMG-CoA reductase inhibitor, said method being substantially as hereinbefore described with reference to any one of the examples. S51. Use of nicotinic acid in an extended release form and an HMG-CoA C reductase inhibitor for the manufacture of a medicament for once per day administration Sfor altering lipids in an individual without causing drug-induced bepatotoxicity, myopathy or rhabdomyolysis.
32. 52. The use of claim 51, wherein said lipids are selected from the group consisting of VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, Lp(a), total cholesterol, triglycerides, apolipoprotein A-I, Apolipoprotein B and apolipoprotein E.
33. 53. The use of claim 51 or claim 52, wherein said lipid alteration comprises the reduction in levels of one or more inert lipids selected from the group consisting of VLDL- cholesterol, LDL-cholesterol, HDL-cholesterol, Lp(a), total cholesterol, triglycerides, apolipoprotein A-I, Apolipoprotein B and apolipoprotein E.
34. 54. The use of claim 51 or claim 52, wherein said lipid alteration comprises an increase in HDL-cholesterol levels in the serum of the individual. The use of claim 51 or claim 52, wherein said lipid alteration comprises an increase in apolipoprotein A-I levels in the serum of the individual.
35. 56. The use of claim 51 or claim 52, wherein said lipid alteration comprises a decrease in total cholesterol to HDL-cholesterol levels in the serum of the individual.
36. 57. The use of claim 51 or claim 52, wherein said lipid alteration comprises a decrease in LDL-cholesterol to HDL-cholesterol ratios in the serum of the individual.
37. 58. The use of any one of claims 51 to 57, wherein the HMG-CoA reductase inhibitor is in an immediate or extended release form.
38. 59. The use of any one of claims 51 to 58, which further comprises the use of a flush-inhibiting agent for the manufacture of said medicament, wherein said flush- inhibiting agent reduces the capacity of the nicotinic acid to provoke a flushing reaction in the individual. The use of claim 59, wherein the flush inhibiting agent is a nonsteroidal anti-inflammatory agent.
39. 61. The use of claim 60, wherein said nonsteroidal anti-inflammatory agent is present in an amount effective to inhibit or reduce prostaglandin PGD 2 synthesis. A494l0l').latll COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:03 SPRUSON AND FERGUSON 61292615486 NO, 0178 P. 21 73 I 62. The use of claim 60 or claim 61, wherein the nonsteroidal antiinflammatory o agent is selected from the group consisting of indomethacin, sulindac, etodolac, aspirin, Cl salicylate salts, ibuprofen, fluribprofen, fenoprophen, suprofen, benoxaprofen, ketoprofen, carprofen, naproxen, sodium naproxen, aclofenac, diclofenac, fenclofenac, tolmectin, zomepirac, meclofenamate, mefanamic acid, oxyphenbutazone, phenylbutazone and O piroxicam.
40. 63. The use of any one of claims 51 to 62, which further comprises the use of a lipid-altering agent for the manufacture of said medicament, wherein said lipid-altering agent is selected from the group consisting of a bile acid sequestrant, an N-substituted t Io ethanolamine derivative, an azulene derivative, a disubstituted urea derivative, an ionene, a O poly(diallylmethylamine) derivative, an omega-3-fatty acid and a fibric acid. Cl 64. The use of any one of claims 51 to 62, which further comprises the use of a Slipid-altering agent for the manufacture of said medicament, wherein said lipid-altering C- agent is selected from the group consisting of cholestyramine, colestipol, DEAE-Sephadex, probucol, lipostabil, Eisai E5050 (an N-substituted ethanolamine derivative), imanixil (HOE402) tetrahydrolipstatin (THL), isitigmastanylphosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azulene derivative), melinamide, neomycin, quaternary amine poly(diallyldimethylammonium chloride), gemfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate and clinofibrate.
41. 65. The use of any one of claims 51 to 64, which further comprises the use of a nicotinic acid compound for the manufacture of said medicament.
42. 66. The use of any one of claims 51 to 65, said method including the further step of administering to the individual an effective lipid-altering amount of cholestyramine.
43. 67. The use of any one of claims 51 to 66, said method including the further step of administering to the individual an effective lipid-altering amount of colestipol.
44. 68. The use of any one of claims 51 to 67, wherein said medicament is a solid oral dosage form.
45. 69. The use of claim 68, wherein said oral dosage form is selected from the group consisting of tablets, capsules, caplets, granules, particles, beads or pellets.
46. 70. Use of nicotinic acid in an extended release form and an HMG-CoA reductase inhibitor for the manufacture of a medicament for once per day administration for altering lipids in an individual without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis, said use being substantially as hereinbefore described with reference to any one of the examples.
47. 71. A process for the preparation of a pharmaceutical composition for once per day administration to alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis, wherein said pharmaceutical composition comprises an effective lipid-altering amount of nicotinic acid in an extended release form A94l 109s peCl COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:04 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 22 74 I and an effective lipid-altering amount of an HMG-CoA reductase inhibitor, said process 0 Sbeing substantially as hereinbefore described with reference to any one of the examples. l 72. A pharmaceutical composition prepared by the process of claim 71.
48. 73. A pharmaceutical composition for once per day administration to alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy, or O rhabdomyolysis, wherein said pharmaceutical composition comprises an effective lipid- altering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an HMG-CoA reductase inhibitor, substantially as hereinbefore described with reference to any one of the examples.
49. 74. A process for the preparation of a coated tablet for oral administration to o alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy, or Cf, rhabdomyolysis, wherein said coated tablet comprises an effective lipid-altering amount of O nicotinic acid in an extended release form, and a coating containing an effective lipid- CI altering amount of an HMG-CoA reductase inhibitor in an immediate release form, said process being substantially as hereinbefore described with reference to any one of the examples. A coated tablet prepared by the process of claim 74.
50. 76. A coated tablet for oral administration to alter lipids in an individual without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis, wherein said coated tablet comprises an effective lipid-altering amount of nicotinic acid in an extended release form, and a coating containing an effective lipid-altering amount of an HMG-CoA reductase inhibitor in an immediate release form, said process being substantially as hereinbefore described with reference to any one of the examples.
51. 77. The method of any one of claims 33 to 50, wherein said nicotinic acid and said HMG-CoA reductase inhibitor are administered to said individual as a pharmaceutical composition of any one of claims 1 to 18, 72 or 73 or as a coated tablet of any one of claims 19 to 32, 75 or 76.
52. 78. A pharmaceutical composition comprising an effective lipid-altering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an HMG-CoA reductase inhibitor, when administered once per day to an individual to alter lipids in said individual without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis.
53. 79. A pharmaceutical composition of any one of claims 1 to 18, 72 or 73 or as a coated tablet of any one of claims 19 to 32, 75 or 76, when used to alter lipids in said individual without causing drug-induced hepatotoxicity, myopathy, or rhabdomyolysis. A pharmaceutical composition comprising an effective lipid-altering amount of nicotinic acid in an extended release form and an effective lipid-altering amount of an HMG-CoA reductase inhibitor, when administered once per day to an individual to alter lipids in said individual without causing drug-induced hepatotoxicity, myopathy, or A94 IO'Mllspc:i COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10 FEB. 2006 15:04 SPRUSON AND FERGUSON 61292615486 NO. 0178 P. 23 IN rhabdomyolysis, substantially as hereinbefore described with reference to any one of the Sexamples. c- SDated 10 February, 2006 SKOS Life Sciences, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON VO ci ci AAJd J:s,;eo COMS ID No: SBMI-02639900 Received by IP Australia: Time 15:03 Date 2006-02-10