WO1998015290A1

WO1998015290A1 - PHARMACEUTICAL COMPOSITIONS COMPRISING HMG-CoA REDUCTASE INHIBITORS, IN PARTICULAR FLUVASTATIN

Info

Publication number: WO1998015290A1
Application number: PCT/SE1997/001605
Authority: WO
Inventors: Bertil Abrahamsson; Gunnar Fager
Original assignee: Astra AB
Current assignee: AstraZeneca AB
Priority date: 1996-10-08
Filing date: 1997-09-24
Publication date: 1998-04-16
Anticipated expiration: 1999-04-08
Also published as: SE9603668D0; AU4578197A

Abstract

The present invention relates to pharmaceutical compositions for sustained release of HMG-CoA reductase inhibitors, in particular fluvastatin. The said compositions are useful for the treatment of hypercholesterolemia, and have the further advantages of (i) decreasing the incidence of undesirable gastro-intestinal side-effects, and (ii) avoiding 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.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING HMG-CoA REDUCTASE INHIBITORS, IN PARTICULAR FLU-

VASTATIN

TECHNICAL FIELD

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.

BACKGROUND ART

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. The 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.

fiuvastatin

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.

Another frequently occurring undesired effect for rapid release dosage forms of HMG-CoA reductase inhibitors is elevated blood levels of 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. Transaminase levels are checked on a routine basis in clinical practice and if too high levels are maintained, treatment has to be terminated.

Furthermore, 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.

Consequently, there is a need for new pharmaceutical formulations which can effectively reduce plasma cholesterol levels, but at the same time avoid the above mentioned undesired effects.

Sustained-release administration of 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. In that publication, 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.

However, since the above described gastro-intestinal side-effects and liver transaminase elevations represent presystemic actions of the drug, since these organs are reached before the drug enters the systemic circulation, there is also a need for pharmaceutical preparations which can reduce such presystemic actions.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1:

HMG-CoA reductase mRNA levels in lymphocytes of healthy volunteers after administration of fiuvastatin by conventional rapid-release administration (a single dose of 40 mg of fiuvastatin) (-□-); or sustained-release-mimicking administration (four rapid releases of 10 mg of fiuvastatin each, given with an interval of two hours) (-■-)■

DISCLOSURE OF THE INVENTION

It has surprisingly been found that administration of 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.

In general, 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.

In a first aspect, 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:

(i) has a rapid absorption; and

(ii) has a high degree of first pass liver extraction.

In the present context, the term "rapid 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.

The term "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.

In a preferred form of the invention, the said HMG-CoA reductase inhibitor is a fully synthetic HMG-CoA reductase inhibitor, most preferably fiuvastatin. In the present context, the term "fiuvastatin" comprises both of the pure enantiomers, as well as racemic mixtures.

In a further aspect, the invention provides a pharmaceutical composition as described above, for use in the treatment of hypercholesterolemia. Such use is in particular characterized in that 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.

Pharmaceutically acceptable salts of fiuvastatin to be used in the 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. In general, 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.

Consequently, 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. Such a use is in particular characterized in that 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.

In yet a further aspect 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. Such a method is in particular characterized in that 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. EXAMPLES

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.

(a) Gastro-intestinal symptoms

No gastro-intestinal symptoms were found for fiuvastatin ER, whereas 4 cases (nausea 1 case, loose stools 3 cases) were obtained for fiuvastatin IR.

(b) Transaminase levels

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.

TABLE 1

ER IR μkat/L

ASAT 0.03 0.24

ALAT 0.01 0.14

It is thus concluded that extended release-administration of the pharmaceutical compositions according to the invention provides therapeutically important advantages, more specifically reduced incidence of gastrointestinal side-effects and lower effects on transaminases, compared to other HMG-CoA reductase inhibitor treatments.

EXAMPLE 2: Compensatory up-regulation of HMG-CoA reductase activity is avoided with fiuvastatin ER

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.

EXAMPLE 3: Manufacture of pharmaceutical formulations

3.1. 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.

3.2.

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.

3.3.

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. Sodium stearyl fumarate (0.8 g) is mixed with the granulation for 2 minutes. Then, extended release round 11 mm tablets are prepared by compressing with a 25 kN compression force. This fiuvastatin tablet comprises 20 mg of fiuvastatin sodium.

3.5.

After the initial forming of beads containing 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.

Fiuvastatin sodium 300 g

Methylene chloride 2000 g

Ethanol 99.5% 1000 g

Si0 (0.15-0.25) 100 g Polymeric layer

Ethyl cellulose 10 cps 65.0 g

Hydroxypropyl methyl cellulose 15.0 g

Acetyltributyl citrate 9.0 g Methylene chloride 1500 g

Isopropylic alcohol 350 g

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.

Claims

1. A pharmaceutical composition comprising a HMG-CoA reductase inhibitor as an active ingredient, said composition characterized in that it is adapted for sustained release and in that the said HMG-CoA reductase inhibitor has a rapid absorption and has a high degree of first pass liver extraction.

2. A pharmaceutical composition according to any one of claim 1 for use in the treatment of hypercholesterolemia.

3. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of hypercholesterolemia, said use characterized in that gastro- intestinal side-effects, e.g. nausea, dyspepsia, flatulence and/ or constipation are significantly reduced.

4. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of hypercholesterolemia, said use characterized in that elevation of plasma transaminase levels is significantly reduced.

5. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of hypercholesterolemia, said use characterized in that upregulation of HMG-CoA reductase levels is significantly reduced.

6. A pharmaceutical composition according to any one of claims 1 to 5 wherein the said HMG-CoA reductase inhibitor is of fully synthetic origin.

7. A pharmaceutical composition according to claim 6 wherein the said HMG- CoA reductase inhibitor is fiuvastatin.

8. Use of a HMG-CoA reductase inhibitor for the manufacture of a pharmaceutical composition for sustained release, for the treatment of hypercholesterolemia, said use characterized in that the said HMG-CoA reductase inhibitor has a rapid absorption and has a high degree of first pass liver extraction.

9. The use according to claim 8 wherein the said HMG-CoA reductase inhibitor is of fully synthetic origin.

10. The use according to claim 8 or 9 wherein the said HMG-CoA reductase inhibitor is fiuvastatin.

11. The use according to any one of claims 8 to 10, characterized in that gastro- intestinal side-effects, e.g. nausea, dyspepsia, flatulence and/ or constipation are significantly reduced.

12. The use according to any one of claims 8 to 10, characterized in that elevation of plasma transaminase levels is significantly reduced.

13. The use according to any one of claims 8 to 10, characterized in that upregulation of HMG-CoA reductase levels is significantly reduced.

14. 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 which has a rapid absorption; and has a high degree of first pass liver extraction.

15. A method according to claim 14 wherein the said HMG-CoA reductase inhibitor is of fully synthetic origin.

16. A method according to claim 14 or 15 wherein the said HMG-CoA reductase inhibitor is fiuvastatin.

17. A method according to any one of claims 14 to 16, characterized in that gastro- intestinal side-effects, e.g. nausea, dyspepsia, flatulence and/ or constipation are significantly reduced.

18. A method according to any one of claims 14 to 16, characterized in that elevation of plasma transaminase levels is significantly reduced.

19. A method according to any one of claims 14 to 16, characterized in that upregulation of HMG-CoA reductase levels is significantly reduced.