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WO1998015290A1 - COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES INHIBITEURS DE REDUCTASE HMG-CoA, EN PARTICULIER DE LA FLUVASTATINE - Google Patents

COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES INHIBITEURS DE REDUCTASE HMG-CoA, EN PARTICULIER DE LA FLUVASTATINE

Info

Publication number
WO1998015290A1
WO1998015290A1 PCT/SE1997/001605 SE9701605W WO9815290A1 WO 1998015290 A1 WO1998015290 A1 WO 1998015290A1 SE 9701605 W SE9701605 W SE 9701605W WO 9815290 A1 WO9815290 A1 WO 9815290A1
Authority
WO
WIPO (PCT)
Prior art keywords
hmg
coa reductase
reductase inhibitor
significantly reduced
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE1997/001605
Other languages
English (en)
Inventor
Bertil Abrahamsson
Gunnar Fager
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
Astra AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astra AB filed Critical Astra AB
Priority to AU45781/97A priority Critical patent/AU4578197A/en
Publication of WO1998015290A1 publication Critical patent/WO1998015290A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic 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
    • A61K31/403—Heterocyclic 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
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the present invention relates to pharmaceutical compositions for sustained release of HMG-CoA reductase inhibitors.
  • the said compositions are useful for the treatment of hypercholesterolemia.
  • Hypercholesterolemia is related to an increased risk of coronary heart diseases.
  • a possible way to reduce blood cholesterol levels in a patient is to inhibit the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis.
  • HMG-CoA reductase inhibitors also referred to as "statins" constitute a well known group of therapeutic agents for the treatment of hypercholesterolemia, which group comprises fermentation products such as lovastatin and pravastatin, as well as semi-synthetic analogs such as simvastatin. More recently have completely synthetic drugs, e.g. fiuvastatin, been developed.
  • Fiuvastatin (R*, S*-(E)-(+)-7-[3-(4-fluorophenyl)-l-(l-methyl-ethyl)-lH-indol-2-yl]- 3,5-dihydroxy-6-heptenoic acid) is known from EP-A-0 114 027.
  • Hypercholesterolemic treatment is often life-long and patients do not usually perceive any direct symptoms caused by the elevated cholesterol levels. In the case of life-long treatment of asymptomatic diseases, it is very important to have a well tolerated drug treatment. Also mild forms of undesired effects will decrease compliance with treatment regimen and thereby endanger desired prevention of coronary heart diseases.
  • Common tolerability problems with HMG-CoA reductase inhibitors when administered as dosage forms such as capsules or tablets releasing the drug rapidly (i.e. within 2 hours), are mild gastro-intestinal symptoms, e.g. nausea, dyspepsia, flatulence and/ or constipation.
  • transaminases such as aspartate aminotransferase (AS AT) and alanine aminotransferase (ALAT), which indicates damages on liver cells caused by the HMG-CoA reductase inhibitor treatment.
  • AS AT aspartate aminotransferase
  • ALAT alanine aminotransferase
  • total blockade of cholesterol biosynthesis leads to a compensatory up-regulation of HMG-CoA reductase activity and thereby endogenous cholesterol synthesis.
  • This up-regulation counteracts the desired clinical effect and higher doses are needed, which increase the risk for adverse events of both presystemic and systemic nature.
  • Such undesirable up-regulation is obtained with conventional rapid release formulations, e.g. tablets, capsules and solutions of HMG-CoA reductase inhibitors, including fiuvastatin.
  • HMG-CoA reductase inhibitors in the form of natural fermentation products such as lovastatin and pravastatin, and semisynthetic analogs such as simvastatin, is disclosed in EP-B-0 375 156.
  • time-controlled administration was suggested as a means for reducing the amount of HMG-CoA reductase inhibitor circulating in the bloodstream of the subject. Consequently, sustained-release administration was used as a means for lowering systemic drug exposure and thereby achieving potential reduction of side effects associated with systemically circulating drug.
  • sustained release compositions comprising a HMG-CoA reductase inhibitor decreases the incidence of (i) undesirable gastro-intestinal side-effects, and (ii) undesirable increases of serum transaminase levels. Furthermore, undesirable up-regulation of HMG-CoA reductase levels is significantly reduced by administration of the said sustained release compositions.
  • the sustained-release compositions for which the said advantageous effects occur comprise HMG-CoA reductase inhibitors with pharmacokinetic, pharmadynamic and pharmacologic effects such that the specified presystemic adverse events (increased transaminase levels and increased incidence of mild gastro-intestinal tolerability problems) and up-regulation of HMG-CoA reductase appear after administration of formulations providing rapid availability of the complete dose, e.g. conventional tablets, capsules and solutions.
  • the invention thus provides a pharmaceutical composition for sustained release comprising a HMG-CoA reductase inhibitor as an active ingredient, said composition characterized in that the said HMG-CoA reductase inhibitor:
  • rapidly absorption should be understood as an absorption such that the peak plasma drug concentration level is generally reached within approximately 3 hours after oral administration of a formulation, not providing modified release properties, under fasting conditions in humans.
  • high degree of first pass liver extraction should be understood as indicating that more than 50% of the dose is extracted by the liver during the first pass (E > 50%) after oral administration of a formulation, not providing modified release properties, under fasting conditions in humans.
  • E is be determined from the equation 1-(F/Fa) where F is the absolute bioavailability and Fa is the fraction of drug absorbed from the gastro-intestinal tract.
  • the said HMG-CoA reductase inhibitor is a fully synthetic HMG-CoA reductase inhibitor, most preferably fiuvastatin.
  • fiuvastatin comprises both of the pure enantiomers, as well as racemic mixtures.
  • the invention provides a pharmaceutical composition as described above, for use in the treatment of hypercholesterolemia.
  • gastro-intestinal side-effects e.g. nausea, dyspepsia, flatulence and/ or constipation are significantly reduced; in that elevation of plasma transaminase levels is significantly reduced; and in that upregulation of HMG-CoA reductase levels is significantly reduced.
  • compositions according to the invention comprise e.g. the sodium, potassium, ammonium salts.
  • the sodium salt is preferred.
  • the pharmaceutical formulations according to the invention can be prepared by use of well known pharmaceutical processing techniques such as blending, granulation, milling, spray drying, compaction, or coating.
  • the typical daily dose of the HMG-CoA reductase inhibitor varies within a wide range and will depend on various factors such as for example the individual requirement of each patient and the disease.
  • sustained-release dosages will be in the range of 1 to 1000 mg per day per day of the HMG-CoA reductase inhibitor, preferably 2 to 200 mg/day.
  • the pharmaceutical formulations according to the invention are useful for lowering the blood cholesterol level in mammals, in particular humans. They are therefore useful as hypercholesterolemic and anti-atherosclerotic agents.
  • an other aspect of the invention is the use of a HMG-CoA reductase inhibitor as specified above, preferably fiuvastatin, for the manufacture of a pharmaceutical composition for sustained release, for the treatment of hypercholesterolemia.
  • a HMG-CoA reductase inhibitor as specified above, preferably fiuvastatin
  • gastro- intestinal side-effects e.g. nausea, dyspepsia, flatulence and/ or constipation are significantly reduced; in that an elevation of plasma transaminase levels is significantly reduced; and in that an upregulation of HMG-CoA reductase levels is significantly reduced.
  • the invention provides a method for the treatment of hypercholesterolemia comprising administering to a mammal, including man, a therapeutically effective amount of a pharmaceutical composition for sustained release, said pharmaceutical composition comprising a HMG-CoA reductase inhibitor as specified above, preferably fiuvastatin.
  • a pharmaceutical composition for sustained release said pharmaceutical composition comprising a HMG-CoA reductase inhibitor as specified above, preferably fiuvastatin.
  • gastro-intestinal side-effects e.g. nausea, dyspepsia, flatulence and/ or constipation are significantly reduced; in that an elevation of plasma transaminase levels is significantly reduced; and in that an upregulation of HMG-CoA reductase levels is significantly reduced.
  • EXAMPLE 1 Gastrointestinal side-effects and increase in transaminase levels are avoided with fiuvastatin ER
  • Fiuvastatin extended release (ER) and fiuvastatin immediate release (IR) dosage forms were administered to 20 male subjects for 4 weeks in a randomized 2 way cross-over designed study (i.e. the same subject takes both drugs at separate occasions). The same daily dose (40 mg) of the two treatments were given.
  • fiuvastatin ER No gastro-intestinal symptoms were found for fiuvastatin ER, whereas 4 cases (nausea 1 case, loose stools 3 cases) were obtained for fiuvastatin IR.
  • Serum transaminase levels were determined according to accredited laboratory methods. The mean difference between transaminase serum levels after 4 weeks treatment with fiuvastatin ER and IR are shown in Table 1.
  • HMG-CoA reductase mRNA was measured in lymphocytes using RT-PCR in 4 healthy volunteers in a double-blind, cross-over study.
  • Fiuvastatin was given either as a 40 mg capsule or as a sustained release-mimicking administration regimen obtained by administering 4 capsules of 10 mg at four separate occasions separated by 2 hours. Lymphocytes were recovered from venous blood samples at indicated times. There was a two-fold increase in mRNA levels after the 40 mg capsule thus showing an undesired up-regulation, whereas no significant change was seen after the sustained release administration regimen (Fig. 1). Consequently, a sustained release administration of fiuvastatin avoids or leads to less compensatory up-regulation of HMG-CoA reductase than the conventional capsule.
  • a dosage form adapted, designed and shaped for the oral delivery of fiuvastatin sodium to a patient in need of fiuvastatin therapy is manufactured as follows: first 30.0 g of fiuvastatin sodium, 90.0 g of paraffin, 50.0 g calcium carbonate and 20.0 g sorbitol are screened through a 1.0 mm screen. The screened material are mixed in a planetary mixer for 10 minutes to produce a homogenous blend. Then, a granulation solution is prepared by dissolving 2.0 g ethyl cellulose (10 cps) in 150.0 g 95% ethanol during constant stirring for 6 hours. The granulation solution is slowly added to the dry mixture during agitation, to yield a wet granulation.
  • the granulation is dried at +50°C for 12 hours. After drying, the granulation is passed through a screen of 1.5 mm. Magnesium stearate (2.0 g) is mixed in to the granulate for 3 minutes. Then, 8 mm round tablets, each comprising 30 mg of fiuvastatin sodium are compressed in a Korsch® press under a pressure of 25 kN.
  • Fiuvastatin sodium (20.0 g), 150.0 g of hydroxypropyl methyl cellulose (molecular weight 30,000), 30.0 g of sorbitol, 30.0 g of sodium aluminium silicate are dry mixed in a planetary mixer for 5 minutes. Then, a granulation solution is prepared by dissolving 10.0 g of polyvinyl pyrrolidone (molecular weight 360,000) in 200 g of 99.5% ethanol. The granulation solution is slowly added to the dry mixture during agitation, to yield a wetted mass. The granulation is dried overnight at +60°C. Next, the granulation is milled in a oscillating granulator through a screen of 0.7 mm.
  • Magnesium stearate (2.0 g) is mixed with the granulation for 2 minutes. Then, extended release round 10 mm tablets are prepared by compressing the composition with a 30 kN compression force. This fiuvastatin tablet comprises 20 mg of fiuvastatin sodium.
  • Fiuvastatin sodium (10 g), 50 g of 8,000,000 molecular weight polyethylene oxide, 50 g lactose are dry mixed. Then, 60 g of 99.5% ethanol and the dry mixture are slowly mixed together in a planetary mixer for 5 minutes. The granulate is dried for 12 hours in +45°C Next, the granulation is passed through a 1.0 mm screen. 1.0 g of magnesium stearate is mixed with the granulation for 2 minutes. Then, extended release round 8 mm tablets are prepared by compressing with a 20 kN compression force. This fiuvastatin tablet comprises 10 mg of fiuvastatin sodium. 3.4.
  • Fiuvastatin tablets is manufactured as follows: first, 3 g of fiuvastatin sodium, 20 g of 30,000 molecular weight hydroxypropyl methyl cellulose, 10 g of sodium aluminium silicate and 0.2 g carboxypolymethylene are dry mixed. Then, a granulation solution is prepared by dissolving 2.0 g ethyl cellulose (10 cps) in 20.0 g 99.5% ethanol. The granulation solution is slowly added to the dry mixture during agitation, to yield a wet granulation. The granulate is dried for 12 hours in 45°C. Next, the granulation is passed through a 1.0 mm screen.
  • This fiuvastatin tablet comprises 20 mg of fiuvastatin sodium.
  • the beads obtained are coated with the polymeric layer controlling the release from the pellet, example of this coating is described below.
  • the polymeric mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and/ or methylene chloride.
  • the spraying can be carried out in a coating pan, but is preferably carried out in a fluidized bed.
  • a solution is prepared by dissolving fiuvastatin sodium in 99.5% ethanol and methylene chloride, the solution is then sprayed onto the cores of silicon dioxide in a fluidized bed.
  • 100 g of the beads (fraction 0.4-0.65 mm) are covered with the polymeric layer containing ethyl cellulose 10 cps, hydroxypropyl methyl cellulose and acetyltributyl citrate by spraying a solution of the mentioned substances in methylene chloride and isopropylic alcohol.
  • the coated beads are then filled into hard gelatin capsules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques pour la libération prolongée d'inhibiteurs de la réductase HMG-CoA, en particulier de la fluvastatine. Lesdites compositions sont utiles pour le traitement de l'hypercholestéromie, et présentent l'avantage (i) de réduire l'incidence d'effets secondaires gastro-intestinaux secondaires et (ii) d'empêcher l'augmentation indésirable des taux de transaminase sérique. De plus, la régulation positive indésirable des taux de réductase HMG-CoA est sensiblement réduite par l'administration desdites compositions de libération prolongée.
PCT/SE1997/001605 1996-10-08 1997-09-24 COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES INHIBITEURS DE REDUCTASE HMG-CoA, EN PARTICULIER DE LA FLUVASTATINE Ceased WO1998015290A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45781/97A AU4578197A (en) 1996-10-08 1997-09-24 Pharmaceutical compositions comprising hmg-coa reductase inhibitors, in particular fluvastatin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9603668-6 1996-10-08
SE9603668A SE9603668D0 (sv) 1996-10-08 1996-10-08 Pharmaceutical compositions

Publications (1)

Publication Number Publication Date
WO1998015290A1 true WO1998015290A1 (fr) 1998-04-16

Family

ID=20404166

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1997/001605 Ceased WO1998015290A1 (fr) 1996-10-08 1997-09-24 COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES INHIBITEURS DE REDUCTASE HMG-CoA, EN PARTICULIER DE LA FLUVASTATINE

Country Status (3)

Country Link
AU (1) AU4578197A (fr)
SE (1) SE9603668D0 (fr)
WO (1) WO1998015290A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242003B1 (en) 2000-04-13 2001-06-05 Novartis Ag Organic compounds
WO2009000286A1 (fr) * 2007-06-25 2008-12-31 Parmatheen S.A. Formulation pharmaceutique améliorée contenant un inhibiteur de la hmg-coa réductase et son procédé de préparation
EP1940391A4 (fr) * 2005-08-05 2010-01-20 Orbus Pharma Inc Compositions pharmaceutiques a liberation prolongee, stabilisees, comprenant un inhibiteur de l'hmg-coa reductase
US8303987B2 (en) 2001-04-11 2012-11-06 Novartis Ag Pharmaceutical compositions comprising fluvastatin

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465096A1 (fr) * 1990-06-26 1992-01-08 Merck & Co. Inc. Composition pour baisser le niveau du cholésterol du sang
US5356896A (en) * 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465096A1 (fr) * 1990-06-26 1992-01-08 Merck & Co. Inc. Composition pour baisser le niveau du cholésterol du sang
US5356896A (en) * 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DIALOG INFORMATION SERVICE, File 155, Medline, Dialog Accession No. 07180040, Medline Accession No. 92348718, TSE F.L. et al., "Pharmacokinetics of Fluvastatin After Single and Multiple Doses in Normal Volunteers"; & J. CLIN. PHARMACOL., (UNITED STATES), Jul. 1992, 32 (7), pages 630-8. *
DIALOG INFORMATION SERVICE, File 73, Embase, Dialog Accession No. 10146658, Embase Accession No. 96335132, DESAGER J.P. et al., "Clinical Pharmacokinetics of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors"; & CLINICAL PHARMACOKINETICS (NEW ZEALAND), 1996, 31/5, (348-371). *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242003B1 (en) 2000-04-13 2001-06-05 Novartis Ag Organic compounds
WO2001078680A3 (fr) * 2000-04-13 2002-04-11 Novartis Ag Compositions pharmaceutiques
US6432447B2 (en) 2000-04-13 2002-08-13 Novartis Ag Organic compounds
AU2001262196B2 (en) * 2000-04-13 2005-08-11 Novartis Ag Pharmaceutical compositions comprising fluvastatin
AU2001262196B8 (en) * 2000-04-13 2005-12-01 Novartis Ag Pharmaceutical compositions comprising fluvastatin
RU2297223C2 (ru) * 2000-04-13 2007-04-20 Новартис Аг Содержащие флувастатин фармацевтические композиции
JP2007131647A (ja) * 2000-04-13 2007-05-31 Novartis Ag 医薬組成物
CN100457102C (zh) * 2000-04-13 2009-02-04 诺瓦提斯公司 药物组合物
US8303987B2 (en) 2001-04-11 2012-11-06 Novartis Ag Pharmaceutical compositions comprising fluvastatin
EP1940391A4 (fr) * 2005-08-05 2010-01-20 Orbus Pharma Inc Compositions pharmaceutiques a liberation prolongee, stabilisees, comprenant un inhibiteur de l'hmg-coa reductase
WO2009000286A1 (fr) * 2007-06-25 2008-12-31 Parmatheen S.A. Formulation pharmaceutique améliorée contenant un inhibiteur de la hmg-coa réductase et son procédé de préparation
AU2007355452B2 (en) * 2007-06-25 2011-12-15 Pharmathen S.A. Improved pharmaceutical formulation containing an HMG-CoA reductase inhibitor and method for the preparation thereof

Also Published As

Publication number Publication date
SE9603668D0 (sv) 1996-10-08
AU4578197A (en) 1998-05-05

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