WO1998001119A2

WO1998001119A2 - Pharmaceutical compositions comprising simvastatin

Info

Publication number: WO1998001119A2
Application number: PCT/US1997/010867
Authority: WO
Inventors: Yale B. Mitchel; Jonathan A. Tobert
Original assignee: Merck & Co., Inc.
Priority date: 1996-07-09
Filing date: 1997-07-03
Publication date: 1998-01-15
Also published as: WO1998001100A3; AU4228997A; AU3667297A; AU4326197A; WO1998001100A2; WO1998001116A1

Abstract

The instant invention provides pharmaceutical compositions comprised of 80 mg or more of simvastatin which are useful for treating homozygous familial hypercholesterolemia, combined hyperlipidemia and for lowering elevated levels of very low density lipoprotein cholesterol in mammals.

Description

TITLE OF THE INVENTION PHARMACEUTICAL COMPOSITIONS

RELATED APPLICATIONS This application is a continuing application and claims priority to U.S. provisional application number 60/021 ,420, filed July 9, 1996, and to U.S. provisional application number 60/029,351 , filed October 31 , 1996.

FIELD OF THE INVENTION

The instant invention involves a pharmaceutical composition comprised of at least 80 mg per day of simvastatin, which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, or a pharmaceutically acceptable salt or ester thereof, which is useful for treating homozygous familial hypercholesterolemia. The instant invention further involves a pharmaceutical composition comprised of at least 160 mg per day of simvastatin, or a pharmaceutically acceptable salt or ester thereof, which is useful for treating combined hyperlipidemia and for lowering the level of very low density lipoprotein (VLDL) in mammals, especially humans.

BACKGROUND OF THE INVENTION

I. Homozygous familial hypercholesterolemia

Homozygous familial hypercholesterolemia (HFH) is a rare disorder characterized by the presence of two abnormal low density lipoprotein (LDL) receptor genes which results in the patient having dysfunctional LDL receptors. This results in severe hypercholesterolemia, particularly extreme elevations in LDL levels, and rapid development of coronary atherosclerosis and coronary heart disease in those who suffer with HFH. Most patients develop coronary disease in adolescence and usually do not survive beyond their teen-age years.

HMG-CoA reductase inhibitors such as compactin, lovastatin, simvastatin, pravastatin, etc., are believed to work by upregulating LDL receptor activity and increasing LDL removal from the blood. Since FH homozygotes do not have functional LDL receptors, this class of drugs was generally believed to be ineffective in these patients. Previous experience with HMG-CoA reductase inhibitors in FH homozygote children bore this out. For example, in J. Thiery, et al., European Journal of Pediatrics, (1990) 149: 716-721 , it is noted that compactin, at dosages as high as 200 mg per day, and lovastatin caused only marginal lowering of LDL cholesterol levels in HFH patients and therefore were not considered to be useful therapies for this condition. The treatment options available to those suffering with HFH have been limited to liver transplantation or LDL aphaeresis therapy. LDL aphaeresis is a technique where plasma is removed from patients and run over columns either with an antibody to apo B or reagents to precipitate LDL. It is usually performed once every two weeks in this population with about a 70% reduction in LDL cholesterol immediately after the procedure, with levels returning to baseline at one week post- treatment. Both treatment options are associated with considerable morbidity and are in limited supply. More recently, a second- generation HMG-CoA reductase inhibitor, atorvastatin, has been shown to be useful for treating HFH.

Contrary to what was previously believed due to the nature of HFH and the mechanism of action understood to be associated with HMG-CoA reductase inhibitors as well as the available published studies in this field, it has been discovered that simvastatin (marketed in the U.S. under the trademark ZOCOR®) in doses of at least 80 mg per day can be used to treat patients suffering with HFH.

II. Combined hyperlipidemia/Lowering VLDL

Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. There are five classifications of lipoproteins based on their degree of density: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), intermediate density lipoproteins (IDL), and high density lipoproteins (HDL). Triglycerides are the major lipids transported in the blood; between 70 and 150 gm enter and leave the plasma daily compared to 1 to 2 gm of cholesterol or phospholipid.

Hyperlipidemia is generally subdivided into the conditions of hypercholesterolemia and hypertriglyceridemia. The existence of elevated LDL chholesterol levels along with hypertriglyceridemia is known as combined hyperlipidemia. The initial treatment for both conditions is often to modify the diet to one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when lipid-lowering goals are not met by diet and exercise alone.

Prior to 1987, cholesterol lowering drugs were limited essentially to the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), probucol, and the fibrates such as clofibrate, fenofibrate, and gemfibrizol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. Substantial reductions in LDL cholesterol accompanied by increases in HDL cholesterol could be achieved by the combination of a lipid-lowering diet and a bile acid sequestrant, with or without the addition of nicotinic acid. However, this therapy is not easy to administer or tolerate and was therefore often unsuccessful except in specialist lipid clinics. The fibrates produce a moderate reduction in LDL cholesterol accompanied by increased HDL cholesterol and a substantial reduction in triglycerides, and because they are well tolerated these drugs have been more widely used particularly for the treatment of hypertriglyceridemia. Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable. With the introduction of lovastatin (MEVACOR®), the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol levels with very few adverse effects. Additional HMG-CoA reductase inhibitors have since followed, such as simvastatin (ZOCOR®), pravastatin (PRAVACHOL®) and fluvastatin (LESCOL®). However, at the currently approved dosage amounts, these HMG-CoA reductase inhibitors are not indicated for the treatment of hypertriglyceridemia. Recent studies have unequivocally demonstrated that lovastatin and simvastatin, both members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries. Simvastatin has also been shown to reduce the risk of coronary heart disease events, and a highly significant reduction in the risk of coronary death and total mortality has been shown by the Scandinavian Simvastatin Survival Study. This study also provided some evidence for a reduction in cerebrovascular events.

Hypertriglyceridemia is a condition in which there is an excessive amount of triglyceride (generally greater than about 300mg/dl) in the plasma. Triglyceride lowering is recognized as a desirable therapeutic goal since elevated triglyceride levels may play a role in atherogenesis and the development of coronary heart disease. In addition, severe hypertriglyceridemia ( > lOOOmg/dl) is associated with chylomicronemia and causes acute pancreatitis. Severe elevations in chylomicrons directly induce pancreatitis, which can be prevented by triglyceride reduction. Elevated triglyceride levels are commonly seen in Type IV and Type V hyperlipoproteinemic patients and are associated with obesity, diabetes, beta -blocker therapy and chronic renal failure. It is therefore desirable to provide a method for reducing plasma triglycerides in patients with combined hyperlipidemia.

In addition to providing pharmaceutical compositions which are useful for treating HFH, the present invention also provides pharmaceutical compositions comprised of at least 160 mg of simvastatin which are useful for treating combined hyperlipidemia and lowering VLDL. It has been dicovered that a daily dosage of 160 mg of simvastatin reduces triglyceride and VLDL levels to a surprisingly greater degree than would have been expected based on the reductions previously seen with lower daily dosage amounts of the drug, as well as effectively reducing elevated LDL cholesterol levels. SUMMARY OF THE INVENTION

One object of the instant invention is to provide a pharmaceutical composition comprised of at least 80 mg of simvastatin and a pharmaceutically acceptable carrier, and in particular a composition comprised of either 80 mg or 160 mg of simvastatin. Such compositions are useful for treating homozygous familial hypercholesterolemia.

A second object of the instant invention is to provide a pharmaceutical composition comprised of at least 160 mg of simvastatin and a pharmaceutically acceptable carrier, and in particular a composition comprised of 160 mg of simvastatin. Such compositions are useful for treating hypertriglyceridemia and for lowering very low density lipoprotein cholesterol levels in mammals having combined hyperlipidemia. The term simvastatin as used herein is intended to encompass the chemical compound simvastatin and all pharmaceutically acceptable salt or ester forms thereof.

A further object of the instant invention involves the above- described pharmaceutical compositions further comprising one or more additional active agents, for example, a bile acid sequestrant, cholesterol absorption inhibitor, squalene synthase inhibitor, folic acid, and/or niacin. Additional objects will be evident from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Simvastatin, shown below, is currently marketed worldwide under a variety of trademark names in unit dosage amounts of up to 40 mg. The current maximal recommended dose of simvastatin is 40 mg daily.

Simvastatin

I. Homozygous Familial Hypercholesterolemia

It has been found that simvastatin in daily dosages above 40 mg are useful for the treatment of HFH. Preferably, the daily dosage is at least 80 mg, and more preferably, at least 160 mg. The compound may be administered in a single daily dose, or divided doses, for example two, three or four times daily. The instant invention includes the use of both oral rapid-release and time-controlled release pharmaceutical formulations. For example, simvastatin may be administered in a sustained release formulation, for example employing the formulation described in U.S. Patent No. 5,366,738. Sustained release and/or daily divided dose administration is preferred for the treatment of HFH.

The following study results demonstrate the usefulness of simvastatin in the treatment of HFH.

A. Study Design

Design: double blinded, randomized, parallel, dose-escalation, controlled, 18 week study

Patients: 12 patients with well-characterized HFH Treatment: After a 4 week placebo diet run in period, the 12 patients were randomized to simvastatin (S) 80 mg/day (group 1 , n=8) or 40 mg/day (group 2, n=4). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day and treatment continued for an additional 9 weeks. Simvastatin was administered orally. The simvastatin treatment information is summarized in the table, below.

Period 1 (9 weeks) Period 2 (9 weeks)

Group 1 (n=8): 80 mg/day in 3 divided 160 mg/day in 3 divided] doses doses Group 2 (n=4): 40 mg/day once a day 40 mg/day in 3 divided doses

Endpoint: Change in low density lipoprotein cholesterol

B. Study Results

The results of the study are as follows. For T-C, LDL-C and HDL-C, mean baseline and mean % change from baseline are shown; for TRIG, median baseline and median % change from baseline are shown:

GROUP 1 GROUP 2

(n=8) (n=4)

BL 80 160 BL 40 40

(mg/dl) mg/day mg/day (mg/dl) mg/day mg/day tid dosing tid dosing hs tid dosing

% change % change % change % change

T-C 627 -23 -29 562 -12 -13

LDL-C 570 -25 -31 519 -14 -15

TRIG 136 -9 -15 72 7 -1 1

HDL-C 32 12 6 28 1 1 17

BL = baseline; T-C = total cholesterol; LDL-C = low density lipoprotein cholesterol; TRIG = triglyceride level; HDL-C = high density lipoprotein cholesterol. All 12 patients completed the trial and there were no serious or unexpected adverse events. No patients sustained significant hepatic transaminase or creatine kinase elevations.

As can be seen from the above study results, simvastatin at therapeutical ly effective doses of 80 mg/day and higher is surprisingly effective in lowering LDL-C in patients suffering with homozygous familial hypercholesterolemia.

As such, a pharmaceutical composition comprised of simvastatin may be administered as monotherapy to a patient suffering with HFH, or the composition may be comprised of additional active agents which are suitable for the treatment of HFH. For example, simvastatin may be co-adminstered with one or more additional drugs which are effective in lowering LDL cholesterol such as HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; and bile acid sequestrants. Agents such as aspirin and beta-blockers may also be co- administered with simvastatin. Simvastatin may also be administered in conjunction with therapies such as LDL aphaeresis.

II. Combined hyperlipidemia/Lowering VLDL

To evaluate the effectiveness of extending the dosage range of simvastatin up to 80 mg and 160 mg once daily, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80 and 160 mg once daily in a 26 week, double-blind, three period, complete block cross-over study. Each active treatment period was 6 weeks in duration with intervening 2 week wash-out periods. Median reductions from baseline in LDL cholesterol were 41 %, 47%, and 53% in the 40, 80 and 160 mg groups, respectively. The corresponding reductions in plasma triglycerides were 21 , 23 and 33%. HDL cholesterol increased by 6-8% in each group. No patient taking 80 mg and 1 (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg and 3 (2.1 %) taking 160 mg had transaminase elevations > 3X the upper limit of normal. No new or unexpected adverse effects were observed. The methods employed in this study were as follows:

Subjects: Men, post-menopausal women, and women highly unlikely to conceive, aged 21 to 70 with an LDL cholesterol of 160 to 250 mg/dl and fasting triglycerides £ 350 mg/dl were eligible. Major exclusion criteria were myocardial infarction or a coronary revascularization procedure within the past 6 months, acute coronary insufficiency, uncontrolled systemic hypertension, secondary hypercholesterolemia, diabetes mellitus, serum creatinine >1.6 mg/dl, underlying hepatic disease (or elevations of liver transaminases above the normal limit), creatine kinase > 1.5 times the upper normal limit, history of alcohol abuse, body weight > 50% above ideal, or previously demonstrated intolerance to hydroxymethylglutaryl coenzyme A reductase inhibitors. The protocol was approved by the institutional review board at each site and written informed consent was obtained from all patients.

Study design: This was a 26-week, multicenter, double-blind, three- period crossover study in 7 US lipid clinics. Patients not currently complying with a National Cholesterol Education Program Step 1 diet or better were provided with detailed instruction with reinforcement throughout the study. Patients already on lipid lowering agents underwent at least a 6- week washout before randomization. Those patients meeting the eligibility requirements after a 4-week placebo and diet treatment period were assigned to simvastatin 40 mg, 80 mg, or 160 mg daily in random sequence each for 6 weeks, with a 2-week placebo washout period between treatments. There were 1 1 study visits at weeks -4, - 1 , 1 , 3, 6, 8, 1 1 , 14, 16, 19, and 22.

Study Therapy: Simvastatin (ZOCOR®, Merck & Co, Inc, New Jersey) 40, 80 and 160 mg once daily were administered as a combination of 20 and 40 mg tablets. Patients were given 3 bottles containing active drug or matching placebo, with instructions to take 2 tablets from each bottle every evening. The study was thus double- blind.

Study procedures: A physical examination was performed at randomization and at the conclusion of the study. Vital signs, blood count and routine serum chemistry and urinalysis were obtained at each visit. Morning blood samples after a 12 hour fast were drawn for lipoproteins and cortisol, and in men only testosterone, follicle stimulating hormone, and leutinizing hormone, at the start of the study (week 1) and at the end of each 6-week treatment period (weeks 6, 14 and 22). Adverse events, defined as new symptoms or signs or a worsening of a previous condition, were noted at each visit.

Laboratory methods: All assays except for plasma drug concentrations were performed at the central laboratory (Medical Research Laboratories, Cincinnati, Ohio). The laboratory participated in and remained certified by the National Heart Lung and Blood Institute- Center for Disease Control Part III program throughout the study (see Myers G. et al., "The Centers for Disease Control-National Heart,

Lung, and Blood Institute Lipid Standardization Program: an approach to accurate and precise lipid measurements," Clin Lab Med. 1989, 9:105-135). Samples for lipoproteins were collected in ethylene diamine tetra-acaetate (1 mg/ml) and centrifuged within 30 minutes. The plasma was separated and shipped at 4°C to the central laboratory. Total cholesterol and triglycerides were analyzed by enzymatic methods on a Hitachi 737 analyzer as previously described (see Steiner P, et al., "Standardization of micromethods for plasma cholesterol, triglyceride and HDL-cholesterol with the lipid clinics' methodology," / Clin Chem. 1981 ;/ 9:850). HDL was isolated using heparin-2M manganese chloride. (see Warnick G, Albers J., "A comprehensive evaluation of the heparin manganese precipitation procedure for estimating high-density lipoprotein cholesterol," / Lipid Res. 1978; 79:65-76.) At randomization, weeks 6, 14 and 22 of therapy, LDL- and VLDL- cholesterol levels were determined by ultracentrifugation (see "Lipid RCP., Manual of Laboratory Operations: Lipid and Lipoprotein Analysis," Washington, DC: US Dept. of Health Education and Welfare, Publication NIH. 1982; 75:628.) LDL-cholesterol was obtained by subtracting HDL-cholesterol from the d> 1.006 g/ml fraction cholesterol. Very low density lipoprotein (VLDL)-cholesterol level was obtained by subtracting the d> 1.006 g/ml cholesterol from the total cholesterol. Apolipoproteins A-I and B analyses were performed using competitive enzyme-linked immunoabsorption assays (see Stein E, et al., "Effects of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia. Multicenter Group I," Arch Intern Med. 1990; 750(2):341-5; Stein E, et al., "Development and evaluation of a competitive ELISA for Lp(a)" (abstr), Clin Chem. 1992; 35: 1067; Miller J, et al., "Development of a competitive binding enzyme-linked immunoabsorbent assay (ELISA) for plasma apoprotein E using a monoclonal antibody (Mab)" (abstr), Clin Chem. 1990; 36:964; and Stein EA, et al., "Enzyme-linked immunoabsorbant assay of apo lipoprotein All in plasma, with use of a monoclonal antibody," Clin Chem. 1986; 32(6):967-71). Serum concentrations of follicle stimulating hormone and luteinizing hormone were assayed using a competitive binding assay with I radiolabelled hormone using an anti-hormone antibody (see Santer S, et al., "A model for validation of radioimmunoassay kit reagents: measurement of follitropin and lutropin in blood and urine," Clin Chem. 1981; 27: 1892-1895; and Kubasik N, et al., "Evaluation of direct solid phase radioimmunoassay for progesterone, useful for monitoring luteal function," Clin Chem. 1984; 30(2):284-286), and serum cortisol was measured by a fluorescence polarization immunoassay (see Tdx System Operator's Manual, Abbot Diagnostics, Abbot Park, IL 1993). Total serum testosterone was measured in a solid-phase radioimmunoassay using a competitive binding assay (see Newton WT, et al., "Radioimmunoassay of peptides lacking tyrosine," J Lab Clin Med. 1970; 75(5):886-892). Plasma drug levels were obtained by analyzing hydroxymethylglutaryl coenzyme A reductase inhibitory activity at the Department of Drug Metabolism, Merck Research Laboratories, West Point, PA (see Alberts A, et al., "Mevinolin. A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol lowering agent," Proc Natl Acad Sci. 1980; 77:3957-3961 ; and Stubbs RJ, et al., "Comparison of plasma profiles of lovastatin, simvastatin, and pravastatin in the dog," Drug Invest. 1990; 2 (Suppl. 2).T 8-28).

Statistical Analysis: The data were analyzed using the intention-to- treat approach, including all patients with data in at least 2 treatment periods. For variables with more than I measurement prior to randomization, the average of the last 2 values prior to starting active treatment (week 1) was used as the baseline value. The primary endpoint was the change in LDL cholesterol between groups. All tests were 2-sided at the a=0.05 level. Analysis of variance was used to compare change from baseline among treatment groups. Initially the model contained the following factors: study center, patient(center), period, center-by-period interaction, treatment, center-by -treatment interaction, and carryover. The factors for carryover, and the interactions, were tested for significance and if their F-statistics were less than 2, they were removed from the model. For the normality assumptions (i.e., that the residuals are normally distributed), the residuals were examined graphically. The F-max test was used to check the homogeneity of variance assumption. For serum enzymes and hormones, linear trend tests were done on the log-dose scale using contrasts from the analysis of variance model. McNemar's test (exact version) was used for the analysis of adverse experience counts.

Of a total of 220 patients screened, 156 were randomized. The mean age of the cohort was 52 and 40% were women. Seven patients dropped out before the end of Period 1 and therefore contributed no efficacy data to the analysis. Individual patient percent changes showed a clearly skewed distribution for LDL cholesterol, especially at 80 and 160 mg. Therefore the median was used as the principal summary statistic for change from baseline. Table 1 summarizes the lipid and lipoprotein effects of simvastatin from the study outlined above. Table 1 shows median percent change from baseline in lipids and apolipoproteins, with p values for the difference between 40 and 80 mg and between 80 and 160 mg. Baseline values are mean (SD); percent changes are median (interquartile range). Abbreviations are as follows: Total-C is total cholesterol; LDL-C is low density lipoprotein cholesterol; Apo B is apolipopoprotein B; HDL-C is high density lipoprotein cholesterol; Apo Al is apolipoprotein Al; VLDL-C is very low density lipoprotein cholesterol; TG is triglycerides.

Table I

Baseline 40 mg — P — 80 mg 160 mg (N=147) (N=141) ^•(N=144) (N=140) mg/dl* % change % change % change

Total-C 282 (36) -30 <0.001 - 35 <0.001 -40

(-36 to -24) (-41 to -28) (-44 to -35)

LDL-C 199 (36) -41 0.001 -47 <0.00J -53

(-48 to -32) (-53 to -37) (-59 to -45)

Apo B 181 (24) -34 0.001 -40 <0.001 -45

(-41 to -26) (-44 to -31) (-50 to -39)

HDL-C 47 (12) 6 0.77 7 0.36 8

(0 tol3) (0 to 14) (O to 18)

Apo Al 143 (24) 7 0.65 8 0.38 7 (1 to 15) (2 to 16) (0 to 12)

VLDL-C 37 (24) -32 0.34 -33 0.03 -42 (-46 to -7) (-49 to -14) (-59 to -24)

TG 175 (84) -21 0.29 -23 0.001 -33

(-35 to 1) (-37 to -5) (-43 to -16)

*To convert to SI units, divide by 38.7 for cholesterol and 88.5 for triglycerides.

Doubling the dose of any inhibitor of 3-hydroxy-3- methylglutaryl coenzyme A reductase generally provides an additional absolute reduction in LDL cholesterol of about 6% relative to the original baseline, at least up to the currently maximal recommended doses (see Illingworth DR, Tobert JA, "A review of clinical trials comparing HMG-CoA reductase inhibitors," Clin Ther. 1994; ό(3):366-85; and Pedersen TR, Tobert JA, "Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal," Drug Safety. 1996; 7 :1 1-24). This continues to apply to simvastatin at least up to 160 mg. There is no evidence for departure from linearity in the log-dose response relationship for simvastatin with regard to LDL cholesterol, as can be seen from Table 1, which shows that at doses of 40, 80, and 160 mg/day, simvastatin produced median changes in LDL cholesterol of -41 %, -47%, and -53% respectively. Changes in total cholesterol and apolipopoprotein B were commensurate with those for LDL cholesterol. The changes in HDL cholesterol and apolipoprotein Al were essentially the same at all three doses.

In contrast to the results noted above, the 160 mg daily dose of simvastatin produced substantially greater reductions in VLDL cholesterol than what would have been expected from the VLDL cholesterol changes obtained with the 40 mg and 80 mg doses, as well as compared to the median percent changes seen at all doses for total cholesterol, LDL cholesterol, HDL cholesterol, apolipopoprotein B and apolipoprotein Al. The median change in VLDL cholesterol was virtually identical at the 40 mg (-32%) and 80 mg (-33%) doses, but dropped dramatically to -42% at the 160 mg dose.

Likewise, the 160 mg daily dose of simvastatin produced substantially greater reductions in triglycerides than what would have been expected from the triglyceride changes obtained with the 40 mg and 80 mg doses, as well as compared to the median percent changes seen at all doses for total cholesterol, LDL cholesterol, HDL cholesterol, apolipopoprotein B and apolipoprotein Al. Likewise, the median change in triglycerides was virtually identical at the 40 mg (-21 %) and 80 mg (-23%) doses, but dropped dramatically to -33% at the 160 mg dose.

The pharmaceutical compositions may be prescribed to lower triglyceride levels and/or VLDL cholesterol in patients with combined hyperlipidemia when such lowering is deemed advisable within the educated discretion of the prescribing physician or other clinician. The benefit of triglyceride and LDL reductions in these patients must be balanced against safety concerns when utilizing high doses of HMG CoA reductase inhibitors. This therapy would not be indicated in patients with severe hypertriglyceridemia (levels > 800 mg/dl) who are at risk of pancreatitis and in whom fibrates are appropriate therapy

Simvastatin and its pharmaceutically acceptable salts and esters are intended to be included within the scope of the instant invention. Salt and ester derivatives can be made from the lactone ring- opened form of simvastatin. Herein, the term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds employed in this invention which can be prepared by reacting the lactone or free acid with a suitable organic or inorganic base. Ester derivatives of simvastatin may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.

The term "therapeutically effective amount" is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of the mammal that is being sought by a researcher, veterinarian, medical doctor or other clinician. The term mammal includes humans. The dosage regimen utilizing simvastatin is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective dosage amounts to be given to a person in need of the instant therapy.

The pharmaceutical composition used to lower triglyceride levels and/or VLDL cholesterol in patients with combined hyperlipidemia is comprised of 160 mg. or more of simvastatin, and preferably the dosage amount is 160 mg. administered in an oral formualtion. Although simvastatin may be administered in divided doses, for example two, three or four times daily, a once per day dosing schedule is preferred. For once a day dosing, the dosage amount may be given in a single oral dosage unit or in multiple oral dosage units. For example, a daily dosage amount of 160 mg may be administered with a single 160 mg tablet or with multiples of 40 or 80 mg tablets co- adminstered concurrently. The instant invention includes the use of both oral rapid-release and time-controlled release pharmaceutical formulations. For example, the simvastatin may be administered in a sustained release formulation, for example employing the formulation described in U.S.Patent No. 5,366,738.

One or more additional active agents which are suitable for the treatment of patients with combined hyperlipidemia may be combined with simvastatin in a single dosage formulation, or may be administered to the patient in separate dosage formulations, which allows for concurrent administration (i.e., co-administration at essentially the same time) or sequential administration (i.e., co- administration at separately staggered times). The additional active agent or agents may be but are not limited to cholesterol lowering compounds. Examples of additional active agents which may be employed include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HC1 salt; vitamin B 12 (also known as cyanocobalamin); platelet aggregation inhibitors such as aspirin and fibrinogen receptor antagonists; beta-blockers; and anti-oxidant vitamins such as vitamin C and E and beta carotene.

Examples of HMG-CoA synthase inhibitors include: the beta-lactone derivatives disclosed in U.S. Patent No. 4,806,564, 4,816,477, 4,847,271 , and 4,751 ,237; the beta lactam derivatives disclosed in U.S. 4,983,597 and the substituted oxacyclopropane analogues disclosed in European Patent Publication EP O 41 1 703. The squalene synthetase inhibitors suitable for use herein include, but are not limited to, those disclosed by Biller et al., J. Med. Chem., 1988 Vol. 31 , No. 10, pp. 1869-1871 , including isoprenoid (phosphinylmethyl)-phosphonates such as those of the formula

O O O O II

R¹ -P-CH₂-P-O R¹-P-CF₂-P-O^' I I I I o^" o - o^" o-

wherein R¹ is:

including the triacids thereof, triesters thereof and tripotassium and trisodium salts thereof as well as other squalene synthetase inhibitors disclosed in pending U.S. Patent No. 4,871 ,721 and 4,924,024 and in Biller et al., J. Med.Chem., 1988, Vol. 31 , No. 10, pp. 1869 to 1871. In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ- PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-1293, phosphinylphosphonate reported by McClard, R. W. et al., J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T.L., PhD dissertation, June, 1987, Dept. Med. Chem. U. of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51 , Summary. Further, the benzodiazepine squalene synthase inhibitors described in EP O 567 026 to Takeda Chemical Industries, and the quinuclidinyl squalene synthase inhibitors described in PCT publications WO 94/03451 , WO 93/09115, WO 93/21 183, WO 93/21 184, WO 93/24486, and U.S. 5,135,935, may be co- administered with the HMG-CoA RI plus folic acid or folate combination of the present invention. In addition, the zaragozic acid type squalene synthase inhibitors as described in U.S. Patents 5,284,758; 5,283,256; 5,262,435; 5,260,332; 5,264,593; 5,260,215; 5,258,401; 5,254,727; 5,256,689; 5,132,320; 5,278,067, and PCT Publications WO 92/12156; WO 92/12157; WO 92/12158; WO 92/12159; WO 92/12160; WO 93/18040; WO 93/18039; WO 93/07151; and European Patent Publications EP O 512 865, EP O 568 946; EP O 524,677 and EP O 450 812, as well as the acyclic tricarboxylic acid compounds of U.S. patent 5,254,727, may be employed.

Illustrative examples of squalene epoxidase inhibitors are disclosed in European Patent Publication EP O 318 860 and in Japanese Patent Publication J02 169-571 A. LDL-receptor gene inducer molecules are disclosed in U.S. Patent No. 5,182,298. Examples of bile acid sequestrants which may be employed in the present method include cholestyramine, colestipol, and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide] and those disclosed in W095/34585 to Geltex Pharmaceuticals, Inc. and EP 0 622 078 assigned to Hisamitsu Pharmaceutical Co., Inc.

Examples of cholesterol absorption inhibitors which may be employed in the present method include those described in WO 95/18143 and WO 95/18144 both assigned to Pfizer Inc., and WO 94/17038, WO 95/08532 and WO 93/02048 each assigned to Schering Corp.

The additional active agents described above which may be employed along with simvastatin can be used, for example, in amounts as indicated in the PDR or in amounts as indicated in the reference disclosures, as appropriate.

Pharmaceutical formulations for simvastatin, and for HMG- CoA reductase inhibitors in general, are well-known to those skilled in the art, as evidenced by the information provided in the 1996 PDR. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

For example, the active agents employed in the instant combination therapy can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Oral formulations are preferred. The instant invention includes the use of oral rapid-release as well as time- controlled release pharmaceutical formulations, particularly as described in U.S. Patent No. 5,366,738.

In the compositions of the present invention, simvastatin may be formulated together with or without an additional active agent, and is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a non- toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like. For oral administration in liquid form, the drug component can be combined with non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture. Stabilizing agents such as antioxidants (BHA, BHT, propyl gal late, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms. Other suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like. While the invention has been described and illustrated with reference to particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, the specific pharmacological responses observed may vary according to and depending upon the particular salt, ester or lactone selected, or the pharmaceutical carriers which are used, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising at least 80 mg of simvastatin and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1 which is a time-controlled release formulation.

3. The pharmaceutical composition of claim 1 wherein the composition is comprised of 80 mg of simvastatin.

4. A pharmaceutical composition comprising at least 160 mg of simvastatin and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4 which is a time-controlled release formulation.

6. The pharmaceutical composition of claim 4 wherein the composition is comprised of 160 mg of simvastatin.

7. A process for preparing the pharmaceutical composition of claim 1 comprising combining the simvastatin with a pharmaceutically acceptable carrier.

8. The process of claim 7 wherein the amount of simvastatin employed is 80 mg.

9. The process of claim 7 wherein the amount of simvastatin employed is 160 mg.

10. A pharmaceutical composition made by combining at least 80 mg of simvastatin and a pharmaceutically acceptable carrier.

1 1. The pharmaceutical composition of claim 10 wherein 80 mg of simvastatin is employed.

12. The pharmaceutical composition of claim 10 wherein 160 mg of simvastatin is employed.