WO2001037831A1 - PHARMACEUTICAL COMBINATION COMPRISING SEPARATE DOSAGE FORMS IN A COMPLIANCE PACKAGE OF AN INHIBITOR OF HMG CoA REDUCTASE AND FIBRIC ACID DERIVATIVE - Google Patents

PHARMACEUTICAL COMBINATION COMPRISING SEPARATE DOSAGE FORMS IN A COMPLIANCE PACKAGE OF AN INHIBITOR OF HMG CoA REDUCTASE AND FIBRIC ACID DERIVATIVE Download PDF

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WO2001037831A1
WO2001037831A1 PCT/GR2000/000032 GR0000032W WO0137831A1 WO 2001037831 A1 WO2001037831 A1 WO 2001037831A1 GR 0000032 W GR0000032 W GR 0000032W WO 0137831 A1 WO0137831 A1 WO 0137831A1
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diabetics
combination
treatment
inhibitor
dosage forms
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PCT/GR2000/000032
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French (fr)
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Demetrius Spyriounis
Alexandros Alexidis
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Demetrius Spyriounis
Alexandros Alexidis
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Priority to AU11661/01A priority Critical patent/AU1166101A/en
Publication of WO2001037831A1 publication Critical patent/WO2001037831A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/405Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics

Definitions

  • the present invention relates to a pharmaceutical combination comprising an inhibitor of the enzyme 3-hydroxy-3-methyl- glutaryl coenzyme A (HMG CoA) reductase (statin) and a fibric acid derivative (fibrate), and to a method of administering these medicaments for the treatment of dyslipidemia (especially mixed hyperlipidemia and familial combined hyperlipidemia) in diabetics and non-diabetics.
  • HMG CoA 3-hydroxy-3-methyl- glutaryl coenzyme A
  • statin ase
  • fibric acid derivative fibric acid derivative
  • LDL low density lipoprotein
  • Hypertriglyceridemia changes the composition of lipoproteins, enriches them with triglycerides and makes them better substrates for hepatic lipase. This leads not only to decreased levels of HDL but also to small, dense LDL particles (K. R.
  • Inhibitors of the hepatic enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase like lovastatin (disclosed in US Pat. No 4,231 ,938) simvastatin (disclosed in US Pat. No 4,478,784 and 4,450, 171 ) and pravastatin (disclosed in US Pat. No 4,346,227) substantially reduce total and LDL cholesterol, and their safety and efficacy in reducing coronary artery disease morbidity and mortality are established in primary (J. Shepherd et al, N Engl J Med 1995, 333, 1301 -1307) and secondary (The Scandinavian Simvastatin Survival Group, Lancet 1994, 344, 1383-1389, F.M. Sacks et al, N Engl J Med 1996, 335, 1001 - 1009, The Long-Term Intervention with Pravastatin in Ischaemic
  • HMG CoA 3-hydroxy-3-methyl-glutaryl coenzyme A
  • Fibric acid derivatives like fenofibrate (disclosed in US Pat. No 4,058, 552), ciprofibrate (disclosed in US Pat. No
  • Fenofibrate (D. R. P. Guay, Ann Pharmacother 1993, 33, 1083- 1 103), ciprofibrate and bezafibrate induces beneficial changes in the plasma levels of triglycerides, total cholesterol, VLDL cholesterol, HDL cholesterol, and in the metabolism of LDL particles.
  • Statins reduce LDL cholesterol levels effectively, but have limited effect on plasma fibrinogen, TG and HDL, as well as a minor or even an adverse effect on LDL particle distribution and structure in diabetics or non-diabetics with mixed hyperlipidemia.
  • fibrates reduce TGs and fibrinogen, increase H DL and LDL particle size, but have diverse effects in LDL levels. Fibrates change the small, dense LDL particle pattern to a more buoyant one, mainly through enhancement of the metabolism of the VLDL subpopulation. VLDL particles, despite their large size, are converted paradoxically to small, dense LDL particles in patients with untreated mixed hyperlipidemia.
  • an effective approach to diabetic or non-diabetic patients with mixed hyperlipidemia best fit a statin-fibrate combination, which might have a global beneficial effect; the shift in LDL particle subtractions to a less dense pattern, the absolute reduction in LDL mass, the increase in HDL, and the reduction in plasma fibrinogen levels induce an additive beneficial metabolic improvement in these patients, which should translate into clinical benefit.
  • statin-fibrate combinations a study in the United Kingdom, namely the Lipids in Diabetes Study (LDS) (S.M.
  • statins and fibrates have been linked individually to myopathy [Statins: 0,08% in 6.582 patients receiving lovastatin (C.A. Dujovne et al, Am J Cardiol, 1991 , 91 (1 B), 25-30), 0,08% in 2.361 patients on simvastatin therapy (S.J. Boccuzzi et al, Am J Cardiol, 1991 , 68, 1 127-31 ) and 0,09% in 15.300 subjects wordlwide on pravastatin therapy (J. Shepherd, Eur Heart J 1995, 16, 5-13 (reference 20). Fibrates: R.M.
  • Chichmanian et al Ann Med Interne 1991 , 142, 587-91 ]. In combination they may carry the potential of accentuating this adverse event. Aggregate experience of combination fibrate-statin treatment in 1.506 hyperlipidemic subjects who participated in these studies indicated that CK elevation was usually asymptomatic and transient, and did not require withdrawal of therapy. No life threatening rhabdomyolysis or myoglobinuria was reported. Nevertheless, it should be noted that drug-induced myopathy is a very rare phenomenon and probably is inappropriately represented in a 1 .506 patient sample.
  • H.Y. Pan in, "Combination of pravastatin and a fibrate, and a method for treating dyslipidemia using such combination” (EP0455042) and “Pravastatin alone or in combination with a fibrate for preventing onset of or treating type III hyperlipoproteinemia” (EP0475148) describes a method which comprises fixed combinations of pravastatin and fibrates for the everyday treatment of dyslipidemia in diabetics and non- diabetics.
  • the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances.
  • Fixed combinations of pravastatin and fibrates are more convenient and are preffered, especially in tablet or capsule form for oral administration”.
  • Non-compliance with the elderly population is generally higher than other groups. This can be attributed to a variety of factors such as declining mental functioning, increasing numbers of medication prescribed and the increase in side effects and/or drug interactions associated with these multiple drug regimens.
  • non-compliance among the elderly is associated with taking more than five prescription medications concurrently, an inability to read prescription labels and difficulty opening flip-off type medication container lids.
  • M. D. Murray et al. DICP 1986, 20, 146.
  • Multiple medication administration, complex treatment regimens, frequent dose regimens and the physical characteristics of the dosage form can contribute to non-compliance (S.A. Eisen et al, Arch Intern Med 1990, 150, p.p. 1881 ).
  • Medication compliance aids have been developed, to enhance patient's compliance.
  • a compliance package is defined as "a prepackaged unit that provides one treatment cycle of the medication to the patient in a ready-to-use package.” Remington's Pharmaceutical Sciences
  • Ovcon ® (Bristol-Meyers Squibb), Ortho-Novum ® Dialpak (Ortho Pharmaceutical Corp.), Loestrin ® (Parke-Davis), etc. are oral contraceptives packaged in blister cards. These packages are generally a single blister card, with 21 or 28 day regimens. Each tablet is labeled with a particular day of the week so that the patient can tell if any doses have been missed. Written patient information, which informs the patient of risks and benefits of therapy, is a mandatory requirement for oral-contraceptive packaging. Additional examples of compliance packaging include Rheumatrex ® Dose Packs (Lederle Laboratories), for therapy of methotrexate.
  • Medrol ® Dosepak (Upjohn Company), is a packaging designed for the administration of methylprednisolone.
  • the present invention relates to a pharmaceutical combination comprising an inhibitor of the enzyme 3-hydroxy-3-methyl- glutaryl coenzyme A (HMG CoA) reductase (statin) and a fibric acid derivative (fibrate), and to a method of administering these medicaments for the treatment of dyslipidemia (especially mixed hyperlipidemia and familial combined hyperlipidemia) in diabetics and non-diabetics.
  • HMG CoA 3-hydroxy-3-methyl- glutaryl coenzyme A
  • statin 3-hydroxy-3-methyl- glutaryl coenzyme A reductase
  • fibric acid derivative fibric acid derivative
  • statin and the fibrate for combination should depend on respective pharmacokinetics or the formulation characteristics (controlled or modified or extended release forms, micronised forms, etc.) of each drug.
  • a statin with short half life as is the case with most statins currently in use
  • a fibrate with short half life too
  • one tablet (or capsule) of statin for the first day of treatment and one tablet (or capsule) of fibrate for the following should be administered.
  • extended release forms of the statin and the fibrate could also be employed, in order to prolong the anti-hyperlipidemic action of each drug during the day of treatment.
  • statin with a long half-life e.g. atorvastatin
  • fibrate with a short one e.g. bezafibrate
  • a fibrate with a long half-life e.g. ciprofibrate
  • a statin with a short one e.g. simvastatin
  • the compliance package of the present invention comprises either of at least one blister card comprising tablets of both statin and fibrate or a dispenser supplying the patient with one tablet per day.
  • each of the components of the combination should be incorporated in separate dosage forms in tablets or capsules for oral administration.
  • the blister card is divided into sections, preferably perforated sections, separating each dosage form. Each section comprises an indicia denoting each separate day of treatment (For example, “Day 1 ", “Day 2", “Day 3", or “Monday”, “Tuesday”, “Wednesday”, etc.).
  • the blister card can also comprise arrows indicating the order of administration of each dosage form. Further information, guiding the patient to the proper administration of the medicaments, can also be printed on the blister card: “Follow the arrows", “Lunch”, “Dinner”, “Breakfast”, “Bedtime”, etc.
  • a dispenser supplying the patient with one-per-day of the tablets (or capsules) of the combination could also be manufactured in order to improve patient's compliance to treatment.
  • One preferred embodiment for the tablet release is through the press of a button, connected to an internal mechanism, that drives the tablet to be administered on the surface of the dispenser.
  • Another embodiment for the tablet release is by dragging a blister strip coiled inside the dispenser, comprising separate dosage forms of the medicaments.
  • the blister strip should be perforated, as to allow easy separation of the part containing the tablet to be used.
  • Also preferred embodiment for the tablet release is through the aid of a spiral, placed in the bottom of the dispenser, which force on the surface the tablet to be used.
  • the dispenser is preferably made of plastic material such as polypropylene, polypropylene copolymere or high density polyethylene.
  • dispenser could be manufactured from a clear plastic material so that the patient can readily see the separate dosage forms of the medicaments and the printed information in the packaging material (for example, a blister strip). This is necessary when patient has to administer the medicaments at different times during each day of treatment. For example: statin on “Day 1 " "Bedtime” and fibrate on "Day 2" "Lunch”.
  • statin for the combination is one that effectively lowers LDL-cholesterol but also lowers triglycerides, to a certain degree.
  • a rather short half-life is a desirable characteristic.
  • Most suitable fibrate for the combination is one that effectively lowers triglycerides and raises HDL-cholesterol but also lowers LDL-cholesterol to a certain degree (e.g.
  • micronized fenofibrate, ciprofibrate Also preffered characteristic of the fibrate, is to eliminate during the day of treatment. A fibrate eliminating during the day of treatment will not interact with the statin administered the other day. Furthermore, hepatotoxicity of the statin maybe reduced by administering the medicaments at different days, as compared either to everyday administration of a statin-fibrate combination or with monotherapy with higher doses of a statin.
  • Hepatotoxicity of the fibrate may also be reduced by administering the medicaments at different days, as compared either to everyday administration of a statin-fibrate combination or with monotherapy with higher doses of a fibrate.
  • the incidence of ALT or AST elevations to at least three times the upper limit of normal was
  • statins suitable for use herein include, but are not limited to, simvastatin, fluvastatin, atorvastatin, cerivastatin and the like.
  • Fibrates suitable for use herein include, but are not limited to, fenofibrate, micronized fenofibrate, ciprofibrate, bezafibrate, extended release bezafibrate, and the like.
  • the dosage forms of the present invention will also include the necessary carrier material, excipient, buffer, bulking agent (such as mannitol), anti-oxidants (such as ascorbic acid or sodium bisufite) or the like.
  • the amount of statin or fibrate incorporated in each tablet or capsule may be varying accordingly.
  • simvastatin is selected as the statin of the combination, an amount of 0.1 to about 1 00mg, preferably from about 5 to 80mg, and more preferably from about 10 to 40mg, may be employed. If fluvastatin is selected as the statin of the combination, an amount of 0.1 to about 240mg, preferably from about 5 to 160mg, and more preferably from about 40 to 80mg, may be employed. If atorvastatin is selected as the statin of the combination, an amount of 0.1 to about 160mg, preferably from about 5 to 80mg, and more preferably from about 10 to 40mg, may be employed. If cerivastatin is selected as the statin of the combination, an amount of 0.1 to about 1 .6mg, preferably from about 0.1 to O. ⁇ mg, and more preferably from about 0.2 to 0.4mg may be employed.
  • fenofibrate is selected as the fibrate of the combination, an amount of 2 to about 500mg, preferably from about 100 to 250mg, may be employed. If ciprofibrate is selected as the fibrate of the combination, an amount of 2 to about 200mg, preferably an amount of about 100 may be employed.
  • bezafibrate is selected as the fibrate of the combination, an amount of from 2 to about 800mg, preferably from about 200 to 400mg may be employed.
  • Tablets of various sizes can be prepared, e.g. of about 0.1 to 2000mg in total weight, containing each of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice.
  • the following examples are intended to describe the best mode and preferred embodiments of the present invention and are not intended to limit the claims.
  • Simvastatin tablets are prepared, employing conventional pharmaceutical techniques, comprising simvastatin and inert ingredients like cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, lactose, magnesium stearate, starch, talc, titanium oxide and other ingredients.
  • Butylated hydroxyanisole, as described in the 2000 PDR, is added as a preservative.
  • Fenofibrate capsules are prepared employing conventional pharmaceutical procedures and containing micronized fenofibrate and the following additional ingredients: lactose, pregelatinized starch, sodium lauryl sulfate, crospovidone and magnesium stearate, as described in the 2000 PDR.
  • Simvastatin tablets and micronised fenofibrate capsules may be employed in a blister with a sequence of one tablet of simvastatin every one capsule of fenofibrate.
  • Blister card may have arrows or indications like "Day 1 ", "Day 2", “Lunch”, "Bedtime”, "Follow the Arrows” etc. guiding the patient in receiving one tablet of simvastatin on day one, then one capsule of fenofibrate on the following, and so forth. (Scheme 1, Scheme 2, Scheme 3 ).
  • Flouvastatin tablets are prepared, employing conventional pharmaceutical techniques, containing flouvastatin and inert ingredients like gelatin, magnesium stearate, microcrystalline cellulose, pregeletatinized starch, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide as described in the 2000 PDR.
  • Bezafibrate extended release tablets are prepared, employing conventional pharmaceutical procedures, comprising bezafibrate and inactive ingredients like those described above.
  • Flouvastatin and bezafibrate tablets may be employed in a blister with a sequence of one tablet of flouvastatin every one tablet of bezafibrate.
  • Blister card may have arrows or indications like “Day 1 ", "Day 2", “Lunch”, “Bedtime”, “Follow the Arrows” etc. guiding the patient in receiving one tablet per day (Scheme
  • Atorvastatin tablets are prepared employing conventional pharmaceutical techniques containing atorvastatin and inert ingredients, namely calcium carbonate, USP; candelilla wax FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hydroxypropyl methylcellulose, USP; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1 -7040 polysorbate 80, NF; simethicone emulsion, as described in the 1 999 PDR.
  • atorvastatin and inert ingredients namely calcium carbonate, USP; candelilla wax FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hydroxypropyl methylcellulose, USP; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1 -7040 polysorbate 80, NF; simethicone
  • Bezafibrate tablets are prepared employing conventional pharmaceutical procedures and containing extended release bezafibrate and inactive ingredients.
  • Statin and fibrate tablets may be employed in a blister with a sequence of one tablet of atorvastatin every two tablets of bezafibrate.
  • Blister card may have arrows or indications like “Day 1 ", “Day 2", “Lunch”, “Bedtime” "Follow the Arrows” etc. guiding the patient in receiving one one tablet per day (Scheme
  • EXAMPLE 4 Simvastatin tablets are prepared employing conventional pharmaceutical techniques containing simvastatin and inert ingredients, as described in Example 1 .
  • Fenofibrate tablets are prepared employing conventional pharmaceutical procedures containing micronized fenofibrate and additional ingredients, as described in Example 1 .
  • Both medicaments are blistered in a mode alternating one tablet (or capsule) of simvastatin with one tablet (or capsule) of fenofibrate and employed in a dispenser releasing one tablet per day.
  • Each tablet (or capsule) could be blistered separately and released through the press of a button. Alternately, tablet release could be effected through the aid of a spiral, placed in the bottom of the dispenser, which force on the surface the tablet to be administered (Scheme 5). Tablets (or capsules) could be incorporated in a perforated blister, coiled inside the dispenser. In order to be administered, tablets (or capsules) are dragged out of the dispenser. (Scheme 6).

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Abstract

The present invention relates to a pharmaceutical combination comprising an inhibitor of the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase (statin), which is simvastatin, fluvastatin, atorvastatin or cerivastatin and a fibric acid derivative (fibrate), which is fenofibrate, ciprofibrate or bezafibrate, and to a method of administering these medicaments for the treatment of dyslipidemia (especially mixed hyperlipidemia and familial combined hyperlipidemia) in diabetics and non-diabetics.

Description

TITLE
PHARMACEUTICAL COMBINATION COMPRISING SEPARATE DOSAGE FORMS IN A COMPLIANCE PACKAGE OF AN INHIBITOR OF HMG COA REDUCTASE AND FIBRIC ACID DERIVATIVE
DESCRIPTION 1. Field of the Invention
The present invention relates to a pharmaceutical combination comprising an inhibitor of the enzyme 3-hydroxy-3-methyl- glutaryl coenzyme A (HMG CoA) reductase (statin) and a fibric acid derivative (fibrate), and to a method of administering these medicaments for the treatment of dyslipidemia (especially mixed hyperlipidemia and familial combined hyperlipidemia) in diabetics and non-diabetics. 2. Description of the Related Art Mixed hyperlipidemia is the most common lipid disorder among survivors of myocardial infarction (A. Mooney, Curr Med Res Opin 1999, 1 5, 65-77) A cluster of various lipid disorders and thrombogenic or antifibrinolytic abnormalities increase the risk for coronary artery disease significantly in patients with mixed hyperlipidemia (M. de Oya et al, Molecular Cell Biology of Cardiovascular Diseases. Madrid: Mosby/Doyma Libros, 1995, 149-79): high low density lipoprotein (LDL) levels consist of a well-established coronary artery disease risk factor, and their reduction has a beneficial effect on coronary artery disease morbidity and mortality (The Scandinavian Simvastatin Survival Group, Lancet 1994, 344, 1 383-1389, J. Shepherd et al, N Engl J Med 1995, 333, 1301 -1307, F.M. Sacks et al, N Engl J Med 1996, 335, 1001 -1009, The Long-Term Intervention with Pravastatin in Ischemic Heart Disease (LIPID) Study Group, N Engl J Med 1998, 339, 1349-1357). Furthermore, the predominence of small, dense LDL particles in patients with mixed hyperlipidemia, along with low high density lipoprotein (HDL), has been reported to be positively related to a threefold increase in coronary artery disease incidence (M.A. Austin et al, JAMA, 1988, 260, 1917-1921 ) and to the global severity of atherosclerotic lesions in coronary arteries (P. Tornvall et al, Circulation, 1993, 88, 2180-2189) irrespective of LDL levels. These adverse effects have been attributed to high atherogenicity of small, dense LDL particles, probably due to their increased susceptibility to oxidative modification, in contrast to light-buoyant LDL particles (A. Chait et al, Am J Med 1993, 94, 350-356). Moreover, in prospective studies, plasma fibrinogen, strongly associated with triglyceride (TG) levels, was found to be an independent predictor of myocardial infarction in both sexes (J. Heinrich et al, J Cardiovasc Risk 1995, 2, 197- 205).
Diabetes mellitus and insulin resistance affect virtually every lipid and lipoprotein (E. L. Bierman, Arterioscler Thromb Vase Biol 1992, 12, 647-656, M. Syvanne et al, Lancet 1997, 350 (Suppl I), 20-23). Chylomicron and very low density lipoprotein (VLDL) remnants accumulate, leading to high levels of potentially atherogenic particles; in addition, there is triglyceride enrichment of both HDL and LDL. Triglyceride enrichment of these particles leads to decreased levels of HDL and small, dense LDL particles. When hyperglycemia occurs, there may be further impairment in removal of triglyceride-rich lipoproteins. The combination of increased production and decreased catabolism of triglyceride-rich lipoproteins accentuates hypertriglyceridemia.
Hypertriglyceridemia changes the composition of lipoproteins, enriches them with triglycerides and makes them better substrates for hepatic lipase. This leads not only to decreased levels of HDL but also to small, dense LDL particles (K. R.
Feingold et al, Atrerioscler Thromb Vase Biol 1992, 12, 1496-
1502). As triglycerides increase within the "normal range", abnormalities in HDL and LDL become more apparent. When triglyceride levels are >200mg/dL, LDL particles will be small and dense in approximately 90% of patients (M.J . Stamfer et al, JAMA 1996, 276, 882-889). High levels of apoprotein B, total cholesterol, TGs, and plasma fibrinogen, heterogeneous LDL particles hyperlipidemia (M. de Oya et al, Molecular Cell Biology of Cardiovascular Diseases. Madrid: Mosby/Doyma Libros, 1995, 149-179) and HDL cholesterol (G. Franceschini et al, Arterioscler Thromb 1994, 14, 1569-1575) are an assembly of abnormalities which usually require drug treatment.
Inhibitors of the hepatic enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase like lovastatin (disclosed in US Pat. No 4,231 ,938) simvastatin (disclosed in US Pat. No 4,478,784 and 4,450, 171 ) and pravastatin (disclosed in US Pat. No 4,346,227) substantially reduce total and LDL cholesterol, and their safety and efficacy in reducing coronary artery disease morbidity and mortality are established in primary (J. Shepherd et al, N Engl J Med 1995, 333, 1301 -1307) and secondary (The Scandinavian Simvastatin Survival Group, Lancet 1994, 344, 1383-1389, F.M. Sacks et al, N Engl J Med 1996, 335, 1001 - 1009, The Long-Term Intervention with Pravastatin in Ischaemic
Disease (LIPID) Study Group, N Engl J Med 1998, 339, 1349-
1357) prevention studies.
Fibric acid derivatives (fibrates) like fenofibrate (disclosed in US Pat. No 4,058, 552), ciprofibrate (disclosed in US Pat. No
3,948,973) bezafibrate (disclosed in US Pat. No 3,781 ,328) and gemfibrozil (disclosed in US Pat. No 3,674,836) act by activating lipoprotein lipase and are especially effective in reducing high blood levels of triglycerides. Gemfibrozil has been proven very effective in reducing coronary artery disease events in patients with combined hyperlipidemia in the Helsinski Heart Stydy (V. Manninen et al, Circulation 1992,
85, 37-45).
Fenofibrate (D. R. P. Guay, Ann Pharmacother 1993, 33, 1083- 1 103), ciprofibrate and bezafibrate induces beneficial changes in the plasma levels of triglycerides, total cholesterol, VLDL cholesterol, HDL cholesterol, and in the metabolism of LDL particles.
However, monotherapy with either of the above mentioned anti- hyperlipidemic agents is usually not adequate to control all the above lipid disorders, and a combination therapy may be required.
Statins reduce LDL cholesterol levels effectively, but have limited effect on plasma fibrinogen, TG and HDL, as well as a minor or even an adverse effect on LDL particle distribution and structure in diabetics or non-diabetics with mixed hyperlipidemia.
Most fibrates reduce TGs and fibrinogen, increase H DL and LDL particle size, but have diverse effects in LDL levels. Fibrates change the small, dense LDL particle pattern to a more buoyant one, mainly through enhancement of the metabolism of the VLDL subpopulation. VLDL particles, despite their large size, are converted paradoxically to small, dense LDL particles in patients with untreated mixed hyperlipidemia.
Monotherapy with any of these agents often leaves the mixed hyperlipidemic patient with a "borderline hypertriglyceridemia" (J. Shepherd, Eur Heart J 1995, 1 5, 5-1 3).
Thus, an effective approach to diabetic or non-diabetic patients with mixed hyperlipidemia best fit a statin-fibrate combination, which might have a global beneficial effect; the shift in LDL particle subtractions to a less dense pattern, the absolute reduction in LDL mass, the increase in HDL, and the reduction in plasma fibrinogen levels induce an additive beneficial metabolic improvement in these patients, which should translate into clinical benefit. Currently, data are lacking from randomized clinical trials, substantiating the net benefit from statin-fibrate combinations on coronary artery disease morbidity and mortality of patients with mixed hyperlipidemia. However, a study in the United Kingdom, namely the Lipids in Diabetes Study (LDS) (S.M. Haffner, Am J Cardiol 1999, 83, 17F-21 F) will attempt to show that long-term treatment with a statin-fibrate combination results in reduction of morbidity and mortality in patients with type II diabetes melittus. LDS will employe a 2X2 factorial design using everyday treatment with fenofibrate and/or cerivastatin in about 4.000 subjects.
Analysis of a score of studies published on 1 .506 patients over the last 9 years shows consistent clinically useful gains in total cholesterol, triglyceride and LDL reduction, HDL elevation and plasma fibrinogen reduction, are achievable over monotherapy with either agent when fibrates and statins are used in combination [J . Shepherd, Europ Heart J 1995, 16, 5-13 (and references cited there in), J.W.A. Smit et al, Am J Cardiol 1995,
76, 126A-128A, R.C. Pasternak et al, Annals Intern Med 1996,
125, 529-40, V.G. Athyros et al, Am J Cardiol 1997, 80, 608-13, R. L.B. Ellen et al, Am J Cardiol 1998, 81 (4A), 60B-65B, E.A.
Iliadis et al, Clin Cardiol 1999, 22, 25-28, D.K. Murdock et al, Am
Heart J 1999, 138, 151 -55].
The crucial issue remaining to be addresed is whether these lipid lowering benefits offset the potential risks of therapy. Both, statins and fibrates, have been linked individually to myopathy [Statins: 0,08% in 6.582 patients receiving lovastatin (C.A. Dujovne et al, Am J Cardiol, 1991 , 91 (1 B), 25-30), 0,08% in 2.361 patients on simvastatin therapy (S.J. Boccuzzi et al, Am J Cardiol, 1991 , 68, 1 127-31 ) and 0,09% in 15.300 subjects wordlwide on pravastatin therapy (J. Shepherd, Eur Heart J 1995, 16, 5-13 (reference 20). Fibrates: R.M. Chichmanian et al, Ann Med Interne 1991 , 142, 587-91 ]. In combination they may carry the potential of accentuating this adverse event. Aggregate experience of combination fibrate-statin treatment in 1.506 hyperlipidemic subjects who participated in these studies indicated that CK elevation was usually asymptomatic and transient, and did not require withdrawal of therapy. No life threatening rhabdomyolysis or myoglobinuria was reported. Nevertheless, it should be noted that drug-induced myopathy is a very rare phenomenon and probably is inappropriately represented in a 1 .506 patient sample.
A different perspective on the magnitude of the problem may be obtained from post marketing surveillance and adverse drug reaction data. This approach, of course, suffers from the weakness of being unable to define the number of patients who require to be given continued statin-fibrate combination therapy in order to generate one case of myopathy. The following example relating to simvastatin may help to elucidate this issue.
Thirty months following the introduction of simvastatin into the U.K. market the Committee for the Safety of Medicines highlighted clinical experience with the drug in its newsletter,
Current Problems (Scrip 1992, 1696, 24): Within that time frame, approximately 257.000 prescriptions had been written for the drug and 738 adverse reaction reports received. The two most frequently reported reactions were abnormal hepatic function (36 reports) and myalgia (48 reports). Adverse reactions involving combined simvastatin-fibrate therapy were not recorded. However, FDA has cautioned against routine use of statin-fibrate combinations. The data one which these recommendations have been established come from a small (12 patient) published trial (D. R. Illingworth et al, Circulation 1989, 79, 590-6) and anecdotal reports (L. R. Pierce et al, JAMA 1990, 264, 71 -5, J.A. Tobert N Engl J Med 1988, 318, 48, D.J. Norman et al, N Engl J Med 1988, 318, 46-7). These recommendations has discouraged the everyday treatment of mixed dyslipidemia with statin-fibrate combinations.
H.Y. Pan in, "Combination of pravastatin and a fibrate, and a method for treating dyslipidemia using such combination" (EP0455042) and "Pravastatin alone or in combination with a fibrate for preventing onset of or treating type III hyperlipoproteinemia" (EP0475148) describes a method which comprises fixed combinations of pravastatin and fibrates for the everyday treatment of dyslipidemia in diabetics and non- diabetics. In a modification of the above method "in order to more finely regulate the dosage schedule, the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances. Fixed combinations of pravastatin and fibrates are more convenient and are preffered, especially in tablet or capsule form for oral administration".
Though combinations of pravastatin with fibrates are not claimed herein, it is evident that this approach refers to within the same day (everyday) treatment either with fixed pravastatin-fibrate combinations or with individual dosage units of each of the drugs, but in this last case it is presupposed that both pravastatin and the fibrate will coexist and will "built up and maintain blood levels". Fixed pravastatin-fibrate combinations are anticipated to improve patient's compliance. Patient compliance has been defined as "the extent to which an individual's behavior coincides with medical or health advise. Compliance with therapy implies a positive behavior in which the patient is motivated sufficiently to adhere to the prescribed treatment because of a perceived self- benefit and a positive outcome (e.g. enhanced daily functioning and well-being)" Remington's Pharmaceutical Sciences, 1995, 19th Edit., Chpt. 103, Vol. 1 1 , p.p. 1976. Most physicians assume that, when they do a diagnosis of a condition and select a therapeutic agent and a regimen for a patient to treat that condition, the patient will follow their recommendation and take the therapeutic agent according to instructions. However, patient compliance studies indicate otherwise. Studies indicate a high incidence of medication errors and non-compliance with respect to taking prescription drugs (R.B. Stewart et al, Clin Pharm Ther 1972, 13, 463-468).
Numerous factors determine the probability for compliance and explain why patients do not comply with prescribed drug therapy. One factor is the type of illness involved. For example, patients having chronic illness or illnesses that are not associated with significant symptomatology, such dyslipidemia, are likely to display higher medication non-compliance rates. It is somewhat understandable for patients to become discouraged with extended therapeutic drug regimens that do not eventually "cure" the disease. However, one can expect that compliance will increase where increased disability results from non-compliance. Another factor, related to non-compliance, is the age of the patient. Non-compliance with the elderly population is generally higher than other groups. This can be attributed to a variety of factors such as declining mental functioning, increasing numbers of medication prescribed and the increase in side effects and/or drug interactions associated with these multiple drug regimens. Also, improper dosing leading to side effects may also contribute to non-compliance. In addition non-compliance among the elderly is associated with taking more than five prescription medications concurrently, an inability to read prescription labels and difficulty opening flip-off type medication container lids. (M. D. Murray et al. , DICP 1986, 20, 146). Multiple medication administration, complex treatment regimens, frequent dose regimens and the physical characteristics of the dosage form (tablet vs. capsule vs. liquid), can contribute to non-compliance (S.A. Eisen et al, Arch Intern Med 1990, 150, p.p. 1881 ). Medication compliance aids have been developed, to enhance patient's compliance. One example is compliance package. A compliance package is defined as "a prepackaged unit that provides one treatment cycle of the medication to the patient in a ready-to-use package." Remington's Pharmaceutical Sciences
1995, 19th Edit., Chpt. 103, Vol. 1 1 , p.p. 1804. Packages for oral contraceptives were possibly the first packaging of this type to be introduced and continue to be used extensively for these agents. Specific examples of oral contraceptive compliance packaging are listed in the Physicians' Desk Reference, 1995, p.
306, 322, 323. For example, Ovcon® (Bristol-Meyers Squibb), Ortho-Novum® Dialpak (Ortho Pharmaceutical Corp.), Loestrin® (Parke-Davis), etc. are oral contraceptives packaged in blister cards. These packages are generally a single blister card, with 21 or 28 day regimens. Each tablet is labeled with a particular day of the week so that the patient can tell if any doses have been missed. Written patient information, which informs the patient of risks and benefits of therapy, is a mandatory requirement for oral-contraceptive packaging. Additional examples of compliance packaging include Rheumatrex® Dose Packs (Lederle Laboratories), for therapy of methotrexate. Medrol® Dosepak (Upjohn Company), is a packaging designed for the administration of methylprednisolone. Axid® Convenience Pak previously made by Eli Lilly & Company, which contained a 30-day supply of nizatidine in a singly medication blister card, is another example. This medication is to be taken once a day and is for the treatment of duodenal ulcers. 3. Unveiling of the invention
The present invention relates to a pharmaceutical combination comprising an inhibitor of the enzyme 3-hydroxy-3-methyl- glutaryl coenzyme A (HMG CoA) reductase (statin) and a fibric acid derivative (fibrate), and to a method of administering these medicaments for the treatment of dyslipidemia (especially mixed hyperlipidemia and familial combined hyperlipidemia) in diabetics and non-diabetics.
Justified selection of the components of the combination, administration in separate dosage forms and at different days, is the strategy claimed to surpass the possible statin-fibrate interaction and the potential of accentuating myopathy. Selection of the statin and the fibrate for combination should depend on respective pharmacokinetics or the formulation characteristics (controlled or modified or extended release forms, micronised forms, etc.) of each drug. In case of selecting as components of the combination, for example, a statin with short half life (as is the case with most statins currently in use) and a fibrate with short half life too, then one tablet (or capsule) of statin for the first day of treatment and one tablet (or capsule) of fibrate for the following, should be administered. Alternatively, extended release forms of the statin and the fibrate could also be employed, in order to prolong the anti-hyperlipidemic action of each drug during the day of treatment.
If a statin with a long half-life (e.g. atorvastatin) and a fibrate with a short one (e.g. bezafibrate) are selected, then one tablet (or capsule) of statin for one day of treatment every two (or more) tablets (or capsules) of fibrate, for the next two or more days (depending on elimination patern of statin) of treatment respectively, should be administered.
If a fibrate with a long half-life (e.g. ciprofibrate) and a statin with a short one (e.g. simvastatin) are selected, then one tablet (or capsule) of fibrate for the first day of treatment every two tablets (or capsules) of statin, for the second and third day of treatment respectively, should be administered.
What emerges from this strategy, ordered to surpass the possible statin-fibrate interaction, is a complicated regime of administration of the medicaments. A direct result of this complexity is an anticipated low patient's compliance to treatment, especially in the long term. However, administration of the medicaments at different days with the aid of a compliance package, should improve compliance. The compliance package of the present invention comprises either of at least one blister card comprising tablets of both statin and fibrate or a dispenser supplying the patient with one tablet per day. In carrying out the method of the present invention, each of the components of the combination should be incorporated in separate dosage forms in tablets or capsules for oral administration.
Consequently, tablets (or capsules) of both medicaments should properly placed in a blister card guiding the patient through each treatment cycle. The blister card is divided into sections, preferably perforated sections, separating each dosage form. Each section comprises an indicia denoting each separate day of treatment (For example, "Day 1 ", "Day 2", "Day 3", or "Monday", "Tuesday", "Wednesday", etc.). The blister card can also comprise arrows indicating the order of administration of each dosage form. Further information, guiding the patient to the proper administration of the medicaments, can also be printed on the blister card: "Follow the arrows", "Lunch", "Dinner", "Breakfast", "Bedtime", etc. Alternatively, a dispenser supplying the patient with one-per-day of the tablets (or capsules) of the combination could also be manufactured in order to improve patient's compliance to treatment. One preferred embodiment for the tablet release is through the press of a button, connected to an internal mechanism, that drives the tablet to be administered on the surface of the dispenser. Another embodiment for the tablet release is by dragging a blister strip coiled inside the dispenser, comprising separate dosage forms of the medicaments. The blister strip should be perforated, as to allow easy separation of the part containing the tablet to be used. Also preferred embodiment for the tablet release, is through the aid of a spiral, placed in the bottom of the dispenser, which force on the surface the tablet to be used.
The dispenser is preferably made of plastic material such as polypropylene, polypropylene copolymere or high density polyethylene. Alternatively, dispenser could be manufactured from a clear plastic material so that the patient can readily see the separate dosage forms of the medicaments and the printed information in the packaging material (for example, a blister strip). This is necessary when patient has to administer the medicaments at different times during each day of treatment. For example: statin on "Day 1 " "Bedtime" and fibrate on "Day 2" "Lunch".
Most suitable statin for the combination is one that effectively lowers LDL-cholesterol but also lowers triglycerides, to a certain degree. A rather short half-life is a desirable characteristic. A statin with short half-life (e.g. simvastatin, T1/2=1 .9h (Goodman & Gilman's The Pharmacological Basis of Therapeutics 1996, 9th Edition, p.p. 1781 ) will eliminate during the day of treatment and will not interact with the fibrate administered the other day. Most suitable fibrate for the combination is one that effectively lowers triglycerides and raises HDL-cholesterol but also lowers LDL-cholesterol to a certain degree (e.g. micronized fenofibrate, ciprofibrate). Also preffered characteristic of the fibrate, is to eliminate during the day of treatment. A fibrate eliminating during the day of treatment will not interact with the statin administered the other day. Furthermore, hepatotoxicity of the statin maybe reduced by administering the medicaments at different days, as compared either to everyday administration of a statin-fibrate combination or with monotherapy with higher doses of a statin. Physicians Desk Reference 1999, 53rd Edition, , p.p 1924, reports that "In 2 controlled clinical studies in 1 .105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0,9% and 2, 1 % at the 40- and 80-mg dose, respectively". In adittion, on page 2295, also reports that "Persistent elevations (>3 times the upper limit of normal occuring on 2 or more occasions) in serum transaminases occurred in 0,7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0,2%, 0,2%, 0,6% and 2,3% for 10, 20, 40, and 80 mg, respectively". Hepatotoxicity of the fibrate may also be reduced by administering the medicaments at different days, as compared either to everyday administration of a statin-fibrate combination or with monotherapy with higher doses of a fibrate. Physicians Desk Reference 1999, 53rd Edition, p. p 478, reports that "fenofibrate hepatotoxicity appears to be dose-related. In an 8- week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was
13% in patients receiving dosages equivalent to 2 to 3 capsules of 67mg TRICOR® per day and was 0% in those receiving dosages equivalent to 1 or capsule per day, or placebo".
Should also be stressed the fact that following a conventional, for example, alternate day administration of the medicaments, by means of standard commercial packages of statins and fibrates, a patient has to bear in mind which of the drugs received the preceding day. Thus patient's coherence to treatment is hard to achieve. In contrast, administration of the medicaments at different days with the aid of a blister comprising tablets of both statin and fibrate or a dispenser supplying the patient with one tablet per day, should improve compliance. Finaly, by selecting the alternate day administration of the medicaments (e.g. by employing a statin and a fibrate eliminating during the day of treatment), among the different day treatment options, the cost of therapy could be reduced nearly 50% as the drug doses are reduced to half, compared to everyday treatment.
In a recently published trial (M. Kayikcioglu et al, Am J Cardiol (1999, 83, 1 135-1 137) it was compared a regimen of alternating simvastatin with fenofibrate every other day with the standard daily combination of the same drugs at the same doses. Commercial packages of both simvastatin and fenofibrate were used for the purposes of the trial. Authors report that "At the end of a 6-month follow up period, there was no significant difference between groups with regard to percent changes in serum lipids from baseline values. These observed changes in lipid values in alternate-day therapy were consistent with the results of recent studies on the administration of simvastatin and fenofibrate as standard combination therapy, especially in patients with mixed hyperlipidemia and familial combined hyperlipidemia. With alternate-day usage, as the drug doses were reduced to half, the cost of therapy was decreased nearly 50%. We observed fewer side effects in the alternate-day therapy group. For laboratory safety assessment, the mean hepatic alanine aminotransferase values and the increase in γ-glutamyltransferase levels was significantly higher in the everyday regimen than in the alternate-day therapy group at the 6-month evaluation". Results of this report support our claim that separate dosage forms of statin-fibrate combinations properly ordered in a blister or a dispenser releasing one-tablet-per-day could be an effective approach for the treatment at different days of dyslipidemia, providing for patient's compliance, efficacy in normalising lipid parameters, safety in terms of myopathy and lower cost, as compared to conventional every day treatment. Statins suitable for use herein include, but are not limited to, simvastatin, fluvastatin, atorvastatin, cerivastatin and the like. Fibrates suitable for use herein include, but are not limited to, fenofibrate, micronized fenofibrate, ciprofibrate, bezafibrate, extended release bezafibrate, and the like.
Preferred are combinations of simvastatin, fluvastatin, atorvastatin or cerivastatin with micronized fenofibrate, ciprofibrate, bezafibrate.
The dosage forms of the present invention will also include the necessary carrier material, excipient, buffer, bulking agent (such as mannitol), anti-oxidants (such as ascorbic acid or sodium bisufite) or the like. The amount of statin or fibrate incorporated in each tablet or capsule may be varying accordingly.
If simvastatin is selected as the statin of the combination, an amount of 0.1 to about 1 00mg, preferably from about 5 to 80mg, and more preferably from about 10 to 40mg, may be employed. If fluvastatin is selected as the statin of the combination, an amount of 0.1 to about 240mg, preferably from about 5 to 160mg, and more preferably from about 40 to 80mg, may be employed. If atorvastatin is selected as the statin of the combination, an amount of 0.1 to about 160mg, preferably from about 5 to 80mg, and more preferably from about 10 to 40mg, may be employed. If cerivastatin is selected as the statin of the combination, an amount of 0.1 to about 1 .6mg, preferably from about 0.1 to O.δmg, and more preferably from about 0.2 to 0.4mg may be employed.
If fenofibrate is selected as the fibrate of the combination, an amount of 2 to about 500mg, preferably from about 100 to 250mg, may be employed. If ciprofibrate is selected as the fibrate of the combination, an amount of 2 to about 200mg, preferably an amount of about 100 may be employed.
If bezafibrate is selected as the fibrate of the combination, an amount of from 2 to about 800mg, preferably from about 200 to 400mg may be employed.
Tablets (or capsules) of various sizes can be prepared, e.g. of about 0.1 to 2000mg in total weight, containing each of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. The following examples are intended to describe the best mode and preferred embodiments of the present invention and are not intended to limit the claims.
EXAMPLE 1
Simvastatin tablets are prepared, employing conventional pharmaceutical techniques, comprising simvastatin and inert ingredients like cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, lactose, magnesium stearate, starch, talc, titanium oxide and other ingredients. Butylated hydroxyanisole, as described in the 2000 PDR, is added as a preservative.
Fenofibrate capsules are prepared employing conventional pharmaceutical procedures and containing micronized fenofibrate and the following additional ingredients: lactose, pregelatinized starch, sodium lauryl sulfate, crospovidone and magnesium stearate, as described in the 2000 PDR. Simvastatin tablets and micronised fenofibrate capsules may be employed in a blister with a sequence of one tablet of simvastatin every one capsule of fenofibrate. Blister card may have arrows or indications like "Day 1 ", "Day 2", "Lunch", "Bedtime", "Follow the Arrows" etc. guiding the patient in receiving one tablet of simvastatin on day one, then one capsule of fenofibrate on the following, and so forth. (Scheme 1, Scheme 2, Scheme 3 ).
EXAMPLE 2
Flouvastatin tablets are prepared, employing conventional pharmaceutical techniques, containing flouvastatin and inert ingredients like gelatin, magnesium stearate, microcrystalline cellulose, pregeletatinized starch, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide as described in the 2000 PDR.
Bezafibrate extended release tablets are prepared, employing conventional pharmaceutical procedures, comprising bezafibrate and inactive ingredients like those described above.
Flouvastatin and bezafibrate tablets may be employed in a blister with a sequence of one tablet of flouvastatin every one tablet of bezafibrate. Blister card may have arrows or indications like "Day 1 ", "Day 2", "Lunch", "Bedtime", "Follow the Arrows" etc. guiding the patient in receiving one tablet per day (Scheme
4).
EXAMPLE 3 Atorvastatin tablets are prepared employing conventional pharmaceutical techniques containing atorvastatin and inert ingredients, namely calcium carbonate, USP; candelilla wax FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hydroxypropyl methylcellulose, USP; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1 -7040 polysorbate 80, NF; simethicone emulsion, as described in the 1 999 PDR.
Bezafibrate tablets are prepared employing conventional pharmaceutical procedures and containing extended release bezafibrate and inactive ingredients.
Statin and fibrate tablets may be employed in a blister with a sequence of one tablet of atorvastatin every two tablets of bezafibrate. Blister card may have arrows or indications like "Day 1 ", "Day 2", "Lunch", "Bedtime" "Follow the Arrows" etc. guiding the patient in receiving one one tablet per day (Scheme
4) .
EXAMPLE 4 Simvastatin tablets are prepared employing conventional pharmaceutical techniques containing simvastatin and inert ingredients, as described in Example 1 .
Fenofibrate tablets are prepared employing conventional pharmaceutical procedures containing micronized fenofibrate and additional ingredients, as described in Example 1 .
Both medicaments are blistered in a mode alternating one tablet (or capsule) of simvastatin with one tablet (or capsule) of fenofibrate and employed in a dispenser releasing one tablet per day. Each tablet (or capsule) could be blistered separately and released through the press of a button. Alternately, tablet release could be effected through the aid of a spiral, placed in the bottom of the dispenser, which force on the surface the tablet to be administered (Scheme 5). Tablets (or capsules) could be incorporated in a perforated blister, coiled inside the dispenser. In order to be administered, tablets (or capsules) are dragged out of the dispenser. (Scheme 6).

Claims

1 . A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is fluvastatin and a fibric acid derivative which is fenofibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
2. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is fluvastatin and a fibric acid derivative which is ciprofibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
3. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is fluvastatin and a fibric acid derivative which is bezafibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
4. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is atorvastatin and a fibric acid derivative which is fenofibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
5. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is atorvastatin and a fibric acid derivative which is ciprofibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
6. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is atorvastatin and a fibric acid derivative which is bezafibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
7. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is cerivastatin and a fibric acid derivative which is fenofibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
8. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is cerivastatin and a fibric acid derivative which is ciprofibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
9. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is cerivastatin and a fibric acid derivative which is bezafibrate useful in the treatment at different days of dyslipidemia of diabetics or non diabetics, with each of the components of the combination.
10. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is simvastatin and a fibric acid derivative which is fenofibrate, useful in the treatment at different days of dyslipidemia of diabetics or non diabetics with each of the components of the combination.
1 1 . A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is simvastatin and a fibric acid derivative which is ciprofibrate, useful in the treatment at different days of dyslipidemia of diabetics or non diabetics with each of the components of the combination.
12. A pharmaceutical combination comprising separate dosage forms in a common blister card of an inhibitor of the enzyme 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase which is simvastatin and a fibric acid derivative which is bezafibrate, useful in the treatment at different days of dyslipidemia of diabetics or non diabetics with each of the components of the combination.
13. A dispenser supplying one-per-day of separate dosage forms of a combination of an inhibitor of the enzyme 3-hydroxy-3- methyl-glutaryl coenzyme A (HMG CoA) reductase and a fibric acid derivative as defined in Claims 1 through 12, useful in the treatment at different days of dyslipidemia of diabetics or non diabetics with each of the components of the combination.
PCT/GR2000/000032 1999-11-09 2000-11-08 PHARMACEUTICAL COMBINATION COMPRISING SEPARATE DOSAGE FORMS IN A COMPLIANCE PACKAGE OF AN INHIBITOR OF HMG CoA REDUCTASE AND FIBRIC ACID DERIVATIVE WO2001037831A1 (en)

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