AU732465B2 - Combination therapy for reducing the risks associated with cardiovascular disease - Google Patents

Description

I I I- I r I WO 97/38694 PCT/US97/06127 TITLE OF THE INVENTION COMBINATION THERAPY FOR REDUCING THE RISKS ASSOCIATED WITH CARDIOVASCULAR

DISEASE

BACKGROUND OF THE INVENTION The instant invention involves a combination therapy comprising the administration of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) and folic acid or a pharmaceutically acceptable salt or ester thereof for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events.

There is increasing evidence that high blood levels of homocysteine are associated with an increased risk of coronary heart disease (CHD) and stroke. The mechanism of the association is unknown, but it is well established that folic acid (a B complex vitamin) lowers plasma homocysteine by increasing its catabolism.

It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease, and many studies have shown that the risk of CHD events can be reduced by lipidlowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol). nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability. or both. Substantial reductions in LDL (low density lipoproteiin) cholesterol accompanied by increases in HDL (high density lipoprotein) 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. Probucol produces only a small reduction in LDI. cholesterol and also reduces I I

I

WO 97/38694 PCT/US97/06127 -2- 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, 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 with very few adverse effects.

Recent studies have unequivocally demonstrated that lovastatin, simvastatin and pravastatin, all members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries. Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events, and in the case of simvastatin a highly significai.. 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.

Despite the substantial reduction in the risk of coronary morbidity and rortality achieved by simvastatin, the risk is still substantial in the treated patients. For example, in the Scandinavian Simvastatin Survival Study, the 42% reduction in the risk of coronary death still left 5% of the treated patients to die of their disease over the course of this 5 year study. Further reduction of risk is clearly needed.

The use of folic acid to reduce the risk of cardiovascular disease by reducing homocysteine levels is attractive as this therapy is believed to be almost risk-free (folic acid is a vitamin) and relatively inexpensive. In addition, as the dose of folic acid required to reduce homocysteine is small (typically 1-5 mg daily) and, like HMG-CoA reductase inhibitors, may be given once daily, the active agents can be readily combined in a single tablet, capsule or other dosage form having the same or similar size as the inhibitor of HMG-CoA reductase alone.

This would provide patient convenience, an important consideration especially in patients who already have coronary heart disease, as such patients generally have several different drugs to take.

Summary of the Invention The instant invention provides a novel combination therapy comprised of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof.

Accordingly, in a first aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of an HMG-CoA reductase inhibitor, a therapeutically effective amount of folic acid or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

According to a second aspect of the invention there is provided a process for preparing the composition of the first aspect comprising admixing an HMG-CoA reductase inhibitor and folic acid or a pharmaceutically acceptable salt or ester thereof S with a pharmaceutically acceptable carrier.

5 According to a third aspect of this invention there is provided a pharmaceutical process prepared by the process of the second aspect.

According to a fourth aspect of the invention there is provided a method for preventing or reducing the risk of developing atherosclerotic disease comprising the administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor 2 in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person at risk of developing atherosclerotic disease.

According to a fifth aspect of the invention there is provided an HMG-CoA reductase inhibitor in combination with a pharmaceutical dosage of folic acid or a pharmaceutically acceptable salt or ester thereof when used bor preventing or reducing the risk of developing atherosclerotic disease.

According to a sixth aspect of the invention there is provided the use of an HIMG- CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for preventing or reducing the risk of developing atherosclerotic disease.

Sii According to a seventh aspect of the invention there is provided a method for halting or slowing the progression of atherosclerotic disease comprising the administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person who has atherosclerotic disease.

I R:\l.lHM102544.doc:aak 3a According to an eighth aspect of the invention there is provided an HMG-CoA reductase inhibitor in combination with a pharmaceutical dosage of folic acid or a pharmaceutically acceptable salt or ester thereof when used for halting or slowing the progression of atherosclerotic disease.

According to a ninth aspect of the invention there is provided the use of an HMG- CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for halting or slowing the progression of atherosclerotic disease.

According to a tenth aspect of the invention there is provided a method for I( preventing or reducing the risk of occurrence, or recurrence where the potential exists, of io an atherosclerotic disease event comprising the administration of a therapeutically l'ffective amount of an HMG-CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person at risk of having an atherosclerotic disease event.

5 According to an eleventh aspect of the invention there is provided an HMG-CoA reductase inhibitor in combination with a pharmaceutical dosage of folic acid or a pharmaceutically acceptable salt or ester thereof when used for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease cven.

1 According to a twelfth aspect of the invention there is provided the use of an HMG- CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease event.

One object of the instant invention is to administer the above-described combination therapy to people who do not yet sho\v clinical signs of atherosclerosis, but who are at risk of developing atherosclerosis and associated diseases. Clinical manifestations of atherosclerosis include atherosclerotic cardiovascular disease such as coronary heart disease (also know as ischemic heart disease), cerebrovascular disease, and peripheral vessel disease. Toward this end, the instant invention provides methods for preventing or reducing the risk of developing atherosclerotic cardiovascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, Sby administering the above-described combination therapy to said at-risk persons.

I R:\IRI H1-102544.( c:mik 3b A second object of the instant invention is to provide the above-described combination therapy to people who have clinical signs of atherosclerosis. Toward this end, the instant invention provides methods for halting or slowing the progression of atherosclerotic cardiovascular disease, coronary heart disease, ischemic heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the abovedescribed combination therapy to said persons who have clinically manifest atherosclerotic disease.

.9 9 9 *94* 9 99 IR:\LI I-1102544.doc:aak WO 97/38694 PCT/US97/06127 -4- A third object of the instant invention involves the abovedescribed methods further comprising the administration of one or more additional active agents, for example, a bile acid sequestrant, cholesterol absorption inhibitor, squalene synthase inhibitor, and/or niacin, either in separate or combined dosage formulations. A fourth object is to provide pharmaceutical compositions which can be used in the above-described methods. Additional objects will be evident from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION The instant invention provides methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a therapeutically effective amount of an HMG-CoA RI in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person who is at risk of developing atherosclerosis or who already has atherosclerotic disease.

Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis" and "atherosclerotic disease." The combination comprised of an ilMG-CoA RI and folic acid or folate may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular WO 97/38694 PCT/US97/06127 accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. The term "atherosclerotic disease event" as used herein is intended to encompasses coronary heart disease events, ccrebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease event are those for whom the potential for recurrence of such an event exists.

Accordingly, the instant invention also provides a method for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease event comprising the administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with folic acid or folate to a person at risk of developing atherosclerotic disease. The instant combination therapy can also be administered to a person who already has atherosclerotic disease for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease event.

Persons to be treated with the instant combination therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event. Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include hut are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein (HDL) cholesterol, and a family history of atherosclerotic cardiovascular disease. Published guidelines for determining those who are at risk of developing atherosclerotic disease can he found in: National Cholesterol Education Program. Second report of the Expert Panel on Derection. Evaluation. and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), National Institute of Health, National Heart Lung and Blood Institute. NIH Publication No.

93-3095, September 1993: abbreviated :ersion: Expert Panel on Detection. Evaluation, and Treatment of High B1lood Cholesterol in Adults, Summary of the second report of the national cholesterol education program (NCEP) Expert Panel on Detection. Evaluation. and WO 97/38694 PC/US97/06127 -6- Treatment of Hligh Blood Cholesterol in Adults (Adult Treatment Panel II), JAMA, 1993, 269, pp. 3015-23. People who are identified as having one or more of the above-noted risk factors are intended to be included in the group of people considered at risk for developing atherosclerotic disease. People identified as having one or more of the above-noted risk factors, as well as people who already have atherosclerosis, are intended to be included within the group of people considered to be at risk for having an atherosclerotic disease event.

A compound which inhibits HMG-CoA reductase is used in combination with folic acid or folate to practice the instant invention.

Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®), simvastatin (ZOCOR®). pravastatin (PRAVACHOL®). fluvastatin (LESCOL®), atorvastatin and rivastatin (also known as cerivastatin). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M.

Yalpani, "Cholesterol Lowering Drugs", Chemistry Industry, pp. 89 (5 February 1996). The term HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts and esters is included within the scope of this invention.

Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example. see the assays described or cited in U.S. Patent 4,231,938 at col. 6. and WO 84/02131 at pp. 30-33. Preferably, the HMG-CoA RI is selected from lovastatin and simvastatin.

Folic acid or a pharmaceutically acceptable salt or ester thereof is administered in combination with the HMG-CoA reductase inhibitor. Pharmaceutically acceptable salts of folic acid are well known to those skilled in the art and include, for example, the sodium salt and the methylglucamine salt. The acid moiety also lends itself to the preparation of pharmaceutically acceptable esters, and such esters are likewise included in the scope of the invention. The term "folate" is WO 97/38694 PCT/US97/06127 -7used herein to refer to the pharmaceutically acceptable salts and esters of folic acid.

Herein, the term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base.

Ester derivatives of the described compounds may act as prodrugs which, when absorbed into the bloodstream of a warmblooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.

The >:stant method involves the administration of an HMG- CoA reductase n-,itor in combination with folic acid or a folate. This combination therapy includes administration of a single pharmaceutical dosage formulation which contains both the HMG-CoA reductase inhibitor and the folic acid or folate, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.

Where separate dosage formulations are used, the HMG-CoA reductase inhibitor and the folic acid or folate can be administered at essentially the same time, concurrently, or at separately staggered times, i.e, sequentially. It is preferred that the HMG-CoA reductase inhibitor and the folic acid or folate be co-administered concurrently on a once-a-day dosing schedule. A single dosage formulation comprised of both an HMG-CoA reductase inhibitor and the folic acid or folate is preferred.

A single dosage formulation will provide convenience for the patient, which is an important consideration especially for patients who already have coronary heart disease and may be in need of multiple medications.

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 a tissue, a system. animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Thk dosage regimen utilizing an HMG-CoA RI in combination with folic acid or folate 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 Ybl I I WO 97/38694 PCT/US97/06127 -8route 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 combination therapy. Dosage information for HMG-CoA Rl's and for folic acid is well known in the art, since several IIMG-CoA RI's and nutritional supplements containing folic acid are marketed in the U.S.

In particular, the dai!y dosage amounts of the HMG-CoA reductase inhibitor are intended to be the same or similar to those amounts which are employed for anti-hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR). For example, see the 50 th Ed. of the PDR, 1996 (Medical Economics Co); in particular, see at page 216 the heading "Hypoiipidemics." sub-heading "HMG-CoA Reductase Inhibitors," and the reference pages cited therein.

Preferably, the oral dosage amount of HMG-CoA RI is from about I to 200 mg/day, and more preferably from about 5 to 160 mg/day.

However, dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors as noted above. An HMG-CoA RI which has sufficiently greater potencymay be given in sub-milligram daily dosages.

As examples, the daily dosage amount for simvastatin may be selected from 5 mg, 10 mg, 20 rmg, 40 mg, 80 mg and 160 mg: for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg: for fluvastatin sodium, mg. 40 mg and 80 mg: and for pravastatin sodium. 10 mg. 20 mg. and mg.

The therapeutically effective amount of folic acid to be used in the instant method is intended to be a dosage amount sufficient to reduce the plasma level of homocysteine below the pretreatment plasma level of homocysteine in the person receiving the combination therapy. Examples of dosage amounts of folic acid are described in the PDR. For example, see at page 119 of the 1996 PDR the heading "Folic Acid" and the reference pages cited therein.

3L, I- WO 97/38694 PCT/US97/06127 -9- For example, the daily dosage amount of folic acid or folate employed in the instant combination therapy can be from about 0.1 to 20 mg/day. In particular, the dosage is from about 0.1 to mg/day, more particularly from about 0.1 to 5 mg/day, and most particularly from about I to 5 mg/day, based on the free acid weight.

For example, the daily dosage amount of folic acid or folate may be selected from 1 mg, 2 mg and 5 mg. based on the free acid weight.

Additional active agents may be combined with the HMG-CoA RI and folic acid or folate in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration. One or more additional active agents may be administered with the HMG-CoA RI and folic acid or folate. The additional active agent or agents can be 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 a. the HCI salt; vitamin B 2 (also known as cyanocobalamin); aspirin: 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 411 703.

The squalene synthetase inhibitors suitable for use herein include, but are not limited to. those disclosed by Biller ct al., J. Med. Chem., 1988 Vol. 31, No. 10. pp. 1869-1871, including isoprenoid (phosphinylmethyl)-phosphonates such as those of the formula WO 97/38694 WO 9738694PCT/US97/061 27 o 0 0 0 RI P-HI P0

'-P-CF

2 -P-0- 0 0I I 0- 0-0- 0wherein R 1 is: a b

C

d includingt. the triacids thereof, triesters thereof and tripotassium and trisodiurn salts thereof as well as other squalene synthctase inhibitors disclosed in pending U.S. Patent No. 4,971,721 and 4,924.024 and in Biller et at., Mcd.Chcm., 1999, Vol. 31, No. 10. pp. 1969 to 1871.

In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed hy P.

Ortiz de Monte Ilano et al.. J. Med. Chemp., 1977. 20, 243-249, the famesyl diphosphate analog A and presqualene pyrophosphate (PSQ- PP) analogs as disclosed by Corey and Volanite, J. Am. Chemn. Soc.

1976. 98, 1291-1293, phosphinylphosphonate reported by McClard, R. W. et 1987, 109, 5544 and cyclopropanes reported by Capson, PhD dissertation, June, 1997, i)t. Med. Chemn. U.

WO 97/3694 PCT/US97/06127 11of 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 Takcda Chemical Industries, and the quinuclidinyl squalene synthase inhibitors described in PCT publications WO 94/03451, WO 93/09115, WO 93/21183, WO 93/21184, WO 93/24486, and U.S. 5,135,935, may be coadministered 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, mav 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 disc!osed 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 polyImethyl-(3-trimethylaminopropyl)imino-trimethylene dihalidej and those disclosed in WQ95/34585 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.

WO 97/38694 PCT/US97/06127 12 The additional active agents described above which may be employed along with the HMG-CoA RI and folic acid or folate combination therapy 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 both HMG-CoA RI's and for folic acid or folates are well-kno-.n to those skilled in the art, as evidenced by the information provided in the 1996 PDR. Methods for preparing various pharmaceutical compositions comprising the combination of an HMG-CoA RI and folic acid or folate are likewise well known to those skilled in the art. 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. The instant invention includes the use of both oral rapid-release and time-controlled release pharmaceutical formulations. Oral formulations are preferred.

In the methods of the present invention, the HMG-CoA RI and the folic acid or folate may be formulated together with or without an additional active agent, and are typically administered in admixture with suitable pharmaceutical diluent:;, 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 he combined with a nontoxic, pharmaceutically acceptable, inert carrier such a: lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, diralcium phosphate, calcium sulfate. mannitol.

sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid. sodium stearyl fumarate, glyceryl behenate. calcium WO 97/38694 97/38694 ~PC I *.J'atI I A; srearatte and tile Iikc. [or (oral -ldiinstrato n hI jih Ir1. the urnq components canl I)c co[ilnd with 1101-lox ic. 1 ha;icuial acceptable imi carrier sticli as et I an ol I. vee rot. water and Ow i like.

M'oreove 1 vvhen (lest red or neessa:ry. >ui hie h nirs. lubricarn.

7~(fisitlte,-ratnL gt.et't andl~ c~)lrim!~ andi flav rmn aniwt call zd- he a~dded( to stbilize tde dosa pe trnis. (Jilii sutable conop lnt ii: lJ4.

tgehlti. SwveeirS. natiurAl arnd SVIitliiC -IW N~1l' tLIJ AN atcIAeA.

tramicanthi or aIifivates, irov~tllcl ~4\ti!re~ "axes and Whe Il~e.

Aldhonewh the Ictive aC-entS OftWp~ lik rCfltl Io01d HIA"i be admr1inistered iill diVided dose., for exml w 4' he ime> dab Sill (lailV LI(Oe of eachi of1 On I INK-05* 141 arnd the folic aid or t',aI!i 157 is preferred. with a irllCdatI\ dose i'1111 t' inl J ir pharmaceutical compo',it ion !)oing most prcfe-rred.

AS such. a thlerapeutically e;Icci\'e armount ti' in I CoA' RI andI fuhe,, ;acid a pharmaceuticall- vac-eptable)I salt tr eder thereof call be used to!,:ether for the preparation 4)1 a 'u~iediaPILer a e fill for p revepmtiti or reducilg, thle risk of' dce CI p n at hen~cr c rot iL dise:ise. haltinn Ski4wifl the progresi4r1i'!*Jlillr,'!Cjr4tLc L~iSL.a On1ce At has becOme t cinilcally' m~anitet.st anJ pvent,1l ,t ret (ificirie the.

risk of occurree or recurrericti wlete- theC potential e its 441ar atheroscle!rotic diseause event. For cxauic. Owe niic';Mler ria he comprised o4 tolic acid or Ma~ie in Leorlhitiai4' v, Ult jhout I nmu it; ingi of all I-IN1-CA\ Ill. or iwl'.rc paI-60icnlarlV about1 3 Inn 1;1 I(A) inn (it' the I NI(0co\R. NiI.)re Specific aniiilIHN it' I I( i-(io.\A RI which 11,1 he used in tWe riedicj~iret prcpaiimti)t include I me. M tu.It ine mge. 40 mg, SO "in. andl 16 111.s walI Nt unr-mill icpi a :uimi 'not ho II(-Co.\ IZF which haveL \UfJil Inekva \11ci Aevk a\ limiler .,-xample. tile tlI'ediecullit tIlay be Ci ni 1n Ii IINI( kI inl combhination %vith about to 20) rlo foli. acid l lae In 1particular. the ameult of t')IiC: Acid M' l4ik-t' sd inl thL preparatinl 44! the ruledicameint mlay 1101) about it in" (ir, m~ort part iLnrlv WO 97/38694 PCT/US97/06127 14from about 0.1 !o 5 mg, and most particularly from about I to 5 mg, based on the free acid weight. For example, the medicament may be comprised of 1 mg, 2 mg or 5 mg of folic acid or folate, based on the free acid weight.

The above-described medicament may also be prepared with one or more additional active agents such as an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol. niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B6 and the pharmaceutically acceptable salts thereof, vitamin B12. aspirin, beta-blockers, vitamin C, vitamin E and beta carotene.

An example of an oral dosage formulation comprising both an HMG-CoA RI and folic acid which is suitable for use in practicing the instant method invention is as follows: Ingredient Amount simvastatin I 200 mg.

folic acid or folic acid equivalent 0.05 20 mg.

diluent binder disintegrant excipients qs. 200 400 mg.

lubricant More specific examples of oral dosage formulations are as follows.

WO 97/32694 PCT/US97/06127 15 EXAMPLE 1 Ingredient Simvastatin

BHA

Ascorbic acid Citric acid Microcrystalline cellulose Pregel starch Magnesium stearate Lactose Folic acid Amount 5.0 0.02mg 2.50 mg 1.25 mg 5.0 mg 10.0 mg 0.5 mg 74.73 mg 1.0 mg All the ingredients except magnesium stearate are blended together in a suitable mixer. The powder mixture is then granulated with adequate quantities of granulating solvent(s). The wet granulated mass is dried in a suitable dryer. The dried granulation is sized through a suitable screen. The sized granulation is mixed with magnesium stearate before tableting. The tablets may be coated if deemed necessary. Additional ingredients that may be added to the above include suitable color and mixtures of colors.

EXAMPLE 2 r~ Ingredient Simvastatin

BHA

Citric acid Microcrystalline cellulose Pregel starch Magnesium stearate Lactose Folic acid Hydrolized gelatin Amount 5.0 mg 0.04 mg 2.5 mg 10.0 mg 20.0 mg 1.0 mg 148.46 mg 5.0 mg 8.0 mg The process of manufacture is essentially the same as in Example 1, above.

WO 97/38694 PCTIUS97/06127 16- EXAMPLE 3 Ingredient Amount Simvastatin 80.0 mg BHA 0.16 mg Ascorbic acid 20.0 mg Citric acid 10.0 mg Microcrystalline cellulose 40.0 mg Pregel starch 80.0 mg Lactose 550.0 mg Folic acid 10.0 mg Colorant 5.0 mg Magnesium stearate 4.8 mg The process of manufacture is essentially the same as in Example 1. above.

While the invention has been described and illustrated with reference to certain 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, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the active agents used in the instant invention as indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well ;s 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 (65)

1. A pharmaceutical composition comprising a therapeutically effective amount of an HMG-CoA reductase inhibitor, a therapeutically effective amount of folic acid or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

2. The composition of claim 1 wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof.

3. The composition of claim 2 wherein the HMG-CoA reductase inhibitor is rI selected from lovastatin and simvastatin.

4. The composition of any one of claims 1 to 3 wherein the pharmaceutically acceptable salt of folic acid is selected from the sodium salt and the methylglucamine salt.

5. The composition of any one of claims 1 to 4 further comprising a therapeutically effective amount of an active agent selected from an HMG-CoA synthase 5 is inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B( and the pharmaceutically acceptable salts thereof, vitamin Bi 2 aspirin, a P-blocker, vitamin C, vitamin E and P-carotene.

6. A pharmaceutical composition substantially as hereinbefore described with 20 reference to any one of the examples.

7. A process for preparing the pharmaceutical composition as claimed in any one of claims I to 6 comprising admixing an HMG-CoA reductase inhibitor and folic acid or a pharmaceutically acceptable salt or ester thereof with a pharmaceutically acceptable carrier.

8. A process for preparing the pharmaceutical composition as claimed in claim 7 comprising admixing an HMG-CoA reductase inhibitor, folic acid or a pharmaceutically acceptable salt or ester thereof, and one or more additional active agents selected from an IHMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B, and the pharmaceutically acceptable salts thereof, vitamin B 1 2 aspirin, a 1[-blocker, vitamin C, RAL vitamin E and 13 carotene, with a pharmaceutically acceptable carrier.

9. A process for preparing the pharmaceutical composition substantially as hereinbefore described with reference to any one of the examples. IR:\LI nI-102544.doc:aak A pharmaceutical composition prepared by the process of any one of claims 7 to 9.

11. A method for preventing or reducing the risk of developing atherosclerotic disease comprising the administration of a therapeutically effective amount of an HMG- CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person at risk of developing atherosclerotic disease.

12. The method of claim 11, wherein the atherosclerotic disease is selected from cardiovascular disease, cerebrovascular disease and peripheral vessel disease.

13. The method of claim 12, wherein the cardiovascular disease is coronary heart disease.

14. The method of any one of claims I1 to 13, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof.

15. The method of claim 14, wherein the HMG-CoA reductase inhibitor is 15 selected from lovastatin and simvastatin.

16. The method of any one of claims 1 1 to 15, wherein the pharmaceutically acceptable salt of folic acid is selected from the sodium salt and the methylglucamine salt.

17. The method of any one of claims 11 to 16 further comprising the administration of a therapeutically effective amount of an active agent selected from an I-IMG-CoA syntltase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate. a cholesterol absorption inhibitor. a bile acid sequestrant, an LDL receptor inducer, vitamin B,6 and the )harmaceutically acceptable salts thereof, vitamin B12, aspirin, a [3-blocker, vitamin C, vitamin E and p carotene.

18. An H-MG-CoA reductase inhibitor in combination with a pharmaceutical dosage of folic acid or a pharmaceutically acceptable salt or ester thereof when used for preventing or reducing the risk of developing atherosclerotic disease. I9. The combination of claim 18, wherein the atherosclerotic disease is selected Irom cardiovascular disease, cerebrovascular disease and peripheral vessel disease. •n 20. The combination of claim 19, wherein the cardiovascular disease is coronary heart disease.

21. The combination of any one of claims 18 to 20, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof. I R:\L1131I2544.doc:aak 19

22. The combination of claim 21, wherein the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

23. The combination of any one of claims 18 to 22, wherein the pharmaceutically acceptable salt of folic acid is selected from the sodium salt and the methylglucamine salt.

24. The combination of any one of claims 18 to 23 further comprising the administration of a therapeutically effective amount of an active agent selected from an H-/IMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequestrant, an LDL receptor inducer, vitamin B, and the I pharmaceutically acceptable salts thereof, vitamin B 12 aspirin, a p-blocker, vitamin C, vitamin E and p carotene.

25. Use of an HMG-CoA reductase inhibitor in combination with folic acid or a *pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for preventing or reducing the risk of developing atherosclerotic disease.

26. The use of claim 25, wherein the atherosclerotic disease is selected from carciovascular disease, cerebrovascular disease and peripheral vessel disease.

27. The use of claim 26, wherein the cardiovascular disease is coronary heart Sdisease.

28. The use of any one of claims 25 to 27, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof.

29. The use of claim 28, wherein the HMG-CoA reductase inhibitor is selected Irom lovastatin and simvastatin. The use of any one of claims 25 to 29, wherein the pharmaceutically Sacceptable salt offolic acid is selected from the sodium salt and the methylglucamine salt.

31. The use of any one of claims 25 to 30 further comprising the administration of a therapeutically effective amount of an active agent selected liom an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor; probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequestrant, an LDL receptor inducer, vitamin B13 and the pharmaceutically acceptable salts thereof, vitamin B 1 2 aspirin, a p-blocker, vitamin C. vitamin E and p carotene.

32. A method for halting or slowing the progression of atherosclerotic. disease RAM comprising the administration of a therapeutically effective amount of an HMG-CoA p reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or -3 ester thereof to a person who has atherosclerotic disease. I R:\LI 131-02544.doc:aak

33. The method of claim 32, wherein the atherosclerotic disease is selected from cardiovascular disease, cerebrovascular disease and peripheral vessel disease.

34. The method of claim 33, wherein the cardiovascular disease is coronary heart disease. The method of any one of claims 32 to 34, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof.

36. The method of claim 35, wherein the HMG-CoA reductase inhibitor is :elected from lovastatin and simvastatin. i 37. The method of any one of claims 32 to 36, wherein the pharmaceutically acceptable salt of folic acid is selected from the sodium salt and the methylglucarnine salt.

38. The method of any one of claims 32 to 37 further comprising the ;idministration of a therapeutically effective amount of an active agent selected from an MG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B 6 and the pharmaceutically acceptable salts thereof, vitamin B 1 2 aspirin, a P-blocker, vitamin C, vitamin B and p carotene.

39. An HMG-CoA reductase inhibitor in combination with a pharmaceutical o dosage of folic acid or a pharmaceutically acceptable salt or ester thereof when used for halting or slowing the progression of atherosclerotic disease.

40. The combination of claim 39, wherein the atherosclerotic disease is selected lrom card iovascular disease, cerebrovascular disease and peripheral vessel disease.

41. The combination of claim 40. wherein the cardiovascular disease is coronary heart disease.

42. The combination of any one of claims 39 to 41. wherein the HMG-CoA ;cductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, alorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof.

43. The combination of claim 42, wherein the HMG-CoA reductase inhibitor is selected flom lovastatin and simvastatin.

44. The combination of any one of claims 39 to 43, wherein the pharmaceutically -Lacceptable salt offolic acid is selected from the sodium salt and the methylglucamine salt.

45. The combination of any one of claims 39 to 44 ifurther comprising the 3 administration of a therapeutically effective amount of an active agent selected from an S.Ii. H M G-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase I R:\I III I 102544.doc:aak inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B 6 and the pharmaceutically acceptable salts thereof, vitamin Bi2, aspirin, a P-blocker, vitamin C, vitamin B and P carotene.

46. Use of an HMG-CoA reductase inhibitor in combination with folic acid or a HiMarmaceutically acceptable salt or ester thereof in the manufacture of a medicament for haltin or slowing the progression of atherosclerotic disease.

47. The use of claim 46, wherein the atherosclerotic disease is selected from cardiovascular disease, cerebrovascular disease and peripheral vessel disease. n 48. The use of claim 47, wherein the cardiovascular disease is coronary heart disease. S 49 The use of any one of claims 46 to 48. wherein the l-IMG-CoA reductase inhibitor is selected from lovastatin, simvastatin. pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereol.

50. The use of claim 49, wherein the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

51. The use of any one of claims 46 to 50, wherein the pharmaceutically acceptable salt of folic acid is selected from the sodium salt and the methylglucamine salt.

52. The use of any one of claims 46 to 51 ifurther comprising the administration of therapeutically effective amount of an active agent selected from an HIMG-CoA svinthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid o o. S: seluesterant, an LDL receptor inducer, vitamin B 6 and the pharmaceutically acceptable salts thereof, vitamin B 1 2 aspirin, a P-blocker, vitamin C. vitamin B and 1 carotene.

53. A method for preventing or reducing the risk of occurrence. or recurrence where the potential exists, of an atherosclerotic disease event comprising the iumiiinistration of a therapeutically effective amount of an HI-IMG-CoAI- reductase inhibitor m cmiiibination with folic acid or a pharmaceutically acceptable salt or ester thereof to a Ipeson at risk of having an atherosclerotic disease event. S54. The method of claim 53, wherein the )person receiving the administration has atherosclerotic disease. SThe method of claim 53. wherein the person receiving the administration is at olvrisk f Ce\velopinig atherosclerotic disease. I R:\1-1131-102S4.doc:aak 22

56. The method of any one of claims 53 to 55, wherein the atherosclerotic disease event is selected from a coronary heart disease event, a cerebrovascular event and intermittent claudication.

57. The method of claim 56, wherein the coronary heart disease event is selected liom coronary heart disease death, myocardial infarction, and coronary revascularisation procedures.

58. The method of claim 56, wherein the cerebrovascular event is selected from a ccrebrovascular accident and a transient ischemic attack.

59. The method of any one of claims 53 to 58, wherein the H-MG-CoA reductase il inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof. '60. The method of claim 59, wherein the I-IMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

61. The method of any one of claims 53 to 60, wherein the pharmaceutically S I; acceptable salt of folic acid is selected from the sodium salt and the methyglucamine salt.

62. The method of any one of claims 53 to 61 further comprising the dministration of a therapeutically effective amount of an active agent selected from -IMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor. an ACAT inhibitor, probucol, niacin, a librate. a cholesterol absorption n inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B 6 and the pha-rmaceutically acceptable salts thereof vitamin B12. aspirin. a (3-blocker, vitamin C, 1 vitamin 13 and [3 carotene.

63. An IMG-CoA reductase inhibitor in combination with a pharmaceutical dosage of folic acid or a pharmaceutically acceptable salt or ester thereof when used for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of ;an atherosclerotic disease event.

64. The combination of claim 63, wherein the person receiving the administration has atherosclerotic disease. The combination of claim 63, wherein the person receiving the administration :0 is at risk of developing atherosclerotic disease.

66. The combination of any one of claims 63 to 65. wherein the atherosclerotic R disease event is selected from a coronary heart disease event, a cerebrovascular event and Intermittent claudication. I RAL 11\1- II 02544.doc:aak

67. The combination of claim 66, wherein the coronary heart disease event is selected from coronary heart disease death, myocardial infarction, and coronary revascularisation procedures.

68. The combination of claim 66, wherein the cerebrovascular event is selected iim a cerebrovascular accident and a transient ischemic attack.

69. The combination of any one of claims 63 to 68, wherein the HMG-CoA redluctase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and the pharmaceutically acceptable salts and esters thereof. The combination of claim 69, wherein the I-IMG-CoA reductase inhibitor is Io selected from lovastatin and simvastatin.

71. The combination of any one of claims 63 to 70 wherein the pharmaceutically icceptable salt of folic acid is selected from the sodium salt and the methyglucamine salt.

72. The combination of any one of claims 63 to 71 further comprising the S* ndministration of a therapeutically effective amount of an active agent selected from I-I*IMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase *inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption nn; inhibitor. a bile acid sequesterant, an LDL receptor inducer., vitamin B, and the har-maceutically acceptable salts thereof vitamin B2, aspirin, a 3-blocker, vitamin C, vitamin B13 and P carotene. 20 73. Use of an HMG-CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof in the manufacture of' a medicament for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of i antherosclerotic disease event.

74. The use of claim 73, wherein the person receiving the administration has iitherosclerotic disease. The use of claim 73, wherein the person receiving the adiministration is at risk al developing atherosclerotic disease.

76. The use of any), one of claims 73 to 75, wherein the atherosclerotic disease event is selected from a coronary heart disease event, a cerebrovascular event and II itermittent claudication.

77. The use of claim 76, wherein the coronary heart disease event is selected from ,nron ary heart disease death, myocardial infarction, and coronary revascularisation Z 'pro cedures. 7S. The use of claim 76, wherein the cerebrovascular event is selected from a Ap 4 Ccerebrovascular accident and a transient ischemic attack. I R :\LIHI i-102544.doc:aak 24

79. The use of any one of claims 73 to 78, wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, nvastatin and the pharmaceutically acceptable salts and esters thereof. The use of claim 79, wherein the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

81. The use of any one of claims 73 to 80, wherein the pharmaceutically acceptable salt of folic acid is selected from the sodium salt and the methyglucamine salt.

82. The use of any one of claims 73 to 81 further comprising the administration of a therapeutically effective amount of an active agent selected from HMG-CoA synthase In inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B 6 and the pharmaceutically acceptable salts thereof vitamin B 12 aspirin, a p-blocker, vitamin C, vitamin B and 3 carotene. Dated 20 February, 2001 5 Merck Co., Inc. S.. Patent Attorneys for the Applicant/Nominated Person "o SPRUSON FERGUSON *0. I K:\LI 131-1102544.tloc:aak