WO2008068217A2

WO2008068217A2 - Pharmaceutical composition comprising a coated hmg-coa reductase inhibitor and an inhibitor of the renin-angiotensin system

Info

Publication number: WO2008068217A2
Application number: PCT/EP2007/063138
Authority: WO
Inventors: Andrea Staab; Amar Lulla; Geena Malhotra
Original assignee: Boehringer Ingelheim International Gmbh; Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2006-12-04
Filing date: 2007-12-03
Publication date: 2008-06-12
Also published as: WO2008068217A3

Abstract

The invention describes a pharmaceutical composition comprising a cholesterol lowering agent in combination with an inhibitor of the renin angiotensin system (RAS) and a process of preparation thereof.

Description

Pharmaceutical composition

Technical field:

The present invention relates to a pharmaceutical composition comprising a cholesterol lowering agent in combination with an inhibitor of the renin angiotensin system (RAS) and a process of preparation thereof.

Background:

Cholesterol can both benefit and harm the body. On the one hand cholesterol plays important roles in the structure of cells and in the production of hormones. On the other hand too high cholesterol levels in the blood favour the development of heart and blood vessel disease. One type of cholesterol called high-density lipoprotein (HDL) cholesterol, or "good cholesterol", actually lowers the risk of these problems but the other type, low density lipoprotein (LDL) cholesterol, or "bad cholesterol", is the type that threatens people's health.

Many factors may contribute to the fact that some people have higher cholesterol levels than others. And some people have inherited disorders that prevent their body from properly using and eliminating fats. This allows cholesterol amounts to increase in the blood.

Treatment for high cholesterol levels usually begins with changing daily habits. However, some patients need to use cholesterol-reducing drugs to reduce their risk of health problems efficiently. Cholesterol-reducing drugs are medicines that lower the amount of cholesterol in the blood.

There are different types of cholesterol reducing agents that can be used. One such type are HMG-CoA reductase inhibitors, also called "statins", which block the enzyme "3-hydroxy-3-methyl-glutaryl-coenzyme A reductase" thus blocking one of the metabolic steps in converting fat to cholesterol. Statins are the most effective cholesterol lowering agents available and in recent years have received increased attention for their benefits beyond helping patients with high cholesterol. Drugs in this group include: atorvastatin, cehvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and rosuvastatin.

Frequently patients which require treatment with cholesterol reducing drugs are also indicated for the treatment of another condition such as elevated blood pressure, diabetes or obesity, and it would be convenient for those patients to have available fixed dose combinations of the relevant active agents. Though formulations of various statins are available in the market, most of them in the form of tablets, a drawback of these formulations is that as the strength of the tablet increases so does the size of the tablet, e.g. a formulation comprising 80 mg of a statin can result in a tablet weight of 800 mg and a formulation comprising 80 mg of atorvastatin in a tablet weight of 1200 mg. Such large tablet sizes are problematic from the patient compliance point of view since they are difficult to swallow, and it has been observed that reducing the tablet weight by simply reducing the amount of excipients often results in tablets with a poor biopharmaceutical performance in vitro and in vivo (see WO 2007/072060).

Additionally, the formulations available normally pose serious technical problems for the development of fixed dose combinations with other active principles such as blood pressure lowering agents. For example regulatory requirements actually necessitate the development of multiple fixed dose combinations with biopharmaceutical properties that can be reasonably compared and which represent the various therapeutically relevant dose strengths of the active agents combined. Existing formulations of the angiotensin Il receptor antagonist telmisartan for example and also existing formulations of the HMG-CoA reductase inhibitor simvastatin rely on the concept of dose proportionality. This means that, if a tablet comprising 80 mg simvastatin as active ingredient has a weight of 800 mg, a tablet comprising 40 mg is manufactured by compressing only half the amount of the final blend comprising the active ingredient and the suitable excipients, thus resulting in a tablet weight of 400 mg. As a consequence, a tablet comprising 20 mg of simvastatin has a tablet weight of 200 mg, and a tablet comprising 10 mg of simvastatin has a tablet weight of 100 mg. Following this same concept of dose proportionality the weight of a tablet comprising 40 mg telmisartan is 240 mg, while a tablet comprising 80 mg of telmisartan has a weight of 480 mg. Applying this concept to a fixed dose combination comprising 40 mg of simvastatin and 80 mg of telmisartan would result in a tablet of 880 mg, a size which is not acceptable to many patients. Thus, when developing fixed dose combinations such as combinations of statins with inhibitors of the renin-angiotensin system, there is the need to provide tablets with a size acceptable from the patient compliance point of view while not affecting the performance of the drug product. The present invention provides a novel technical solution to this problem.

Object:

The object of the present invention is to provide a statin formulation allowing the manufacture of reasonably sized fixed dose combination tablets with renin angiotensin system inhibitors (blood pressure lowering agents) in all the therapeutically used dosage strengths of the active agents. Another object of the present invention is to provide enhanced technological and economic advantage to the state of the art through an improved therapeutic product.

Summary:

It is provided by the present invention a pharmaceutical composition comprising a coated HMG-CoA reductase inhibitor with an optional antioxidant, an inhibitor of the renin angiotensin system, and optionally further pharmaceutically acceptable excipients.

It is further described by the present invention a method to manufacture a pharmaceutical composition according to the invention and a pharmaceutical composition for use in the combined treatment of a condition requiring the reduction of cholesterol and blood pressure.

Description:

Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. According to the present invention the various statins (HMG-CoA reductase inhibitors) that can be used comprise lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, cehvastatin, pitavastatin, rosuvastatin and atorvastatin. The preferred HMG-CoA reductase inhibitor is simvastatin. Additionally various available salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, or polymorphs of the various HMG-CoA reductase inhibitors mentioned above may be used.

The terms HMG-CoA reductase inhibitor and statin are referred to in the description and the claims in a broad sense to include not only HMG-CoA reductase inhibitors or statins per se but also their salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, or polymorphs.

A problem with the development of fixed dose combinations of existing dosage forms of statins such as simvastatin and renin angiotensin system inhibitors such as telmisartan is that they are of larger unit dose weight, especially for the unit dosages with higher strengths of the drug, which leads to an undesirable size of fixed dose combination products from the patient compliance point of view. Thus, there is a need to provide fixed dose combination products with reasonable weight and size. However, if the unit dose weight such as the tablet weight of a prior art tablet is reduced, it results in a tablet with delayed disintegration delaying dissolution and eventually delaying availability of the medicament to the patient in need. Thus, there is need of a pharmaceutical composition that is of smaller size, but does not delay the availability of the medicament to the patient in need.

To simplify manufacturing of dosage forms and to reduce the efforts needed in packaging development for different dosage strengths of a fixed dose combination, the concept of dose proportionality often cannot be applied to the formulations of both active ingredients. Thus, the components of a pharmaceutical composition of at least one active ingredient such as simvastatin should allow to formulate various dosage strengths of the active ingredient in a dose similar manner, i.e. in single entities with identical weight. In this case, the concept of dose proportionality can be confined to the other active ingredient of the fixed dose combination. For example, if the formulation comprising the inhibitor of the renin angiotensin system is chosen to be dose proportional, the formulation comprising the statin should be dose similar, i.e. the weight of said formulation should be identical for all dose strengths of the statin. If this can be achieved , the resulting fixed dose combination dosage forms such as bilayer tablets are sufficiently similar in parameters such as size and weight, which considerably reduces the amount of equipment required for manufacturing and the number of packaging configurations required for packaging of the different strengths. To enable such an approach, a dose similar formulation of one of the components (e.g. a statin) does not only have to allow for a drug load higher than in the existing formulations for the high strengths, but also for a drug load lower than in the existing formulations for the low strengths.

Simvastatin tablets, for example, should exhibit dissolution of not less than 75% (Q) in 30 minutes according to the USP, preferably 80%, but it has been observed that prior art tablets with reduced tablet weight fail the dissolution test according to the USP. Surprisingly the inventors of the present invention have observed that smaller tablets and tablet layers manufactured according to the present invention show a dissolution profile comparable to and complying with the USP standard and thus overcome a technical problem associated with the technical teaching of the prior art. Additionally it was surprisingly found, that the high and low dose strengths of the same compound manufactured in a dose similar formulation with identical tablet weight show comparable dissolution profiles despite the difference in drug load.

Thus, the present invention provides a pharmaceutical composition comprising a coated HMG-CoA reductase inhibitor with an optional antioxidant, an inhibitor of the renin angiotensin system, and further pharmaceutically acceptable excipients. The coated HMG-CoA reductase inhibitor and the antioxidant are preferably comprised in a single tablet layer of a size smaller than known from the prior art for high doses and of larger size than known from the prior art for low doses. It does not delay the dissolution of the inhibitor, while the renin angiotensin system inhibitor is comprised in a different tablet layer.

Simvastatin is the common medicinal name of the chemical compound butanoic acid 2.2-dimethyl-, 1 ,2,3,7,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oso- 2H-pyran-2-yl)ethyl]-1 -naphthalenyl ester, [1 S-[13,38,70,80(2 S^*, 4 S^*)8ab]]. It is disclosed in EP-A-33538 as a long-acting HMG-CoA reductase inhibitor with the Chemical name (1 S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxo-tetrahydro-2H- pyran-2-yl]ethyl]-3,7-dimethyl-1 ,2,3,7,8,8a-hexahydronaphtahlene-1 -yl-2,2- dimethylbutanoate or alternatively (βR,δR,1 S)-8β-(2,2-dimethylbutyryloxy)- 1 ,2,6,7,8,8aα-hexahydro-β,δ-dihydroxy-2α,6β-dimethyl-1α-naphthalene-heptanoic acid δ-lactone having the following structure:

Lovastatin is the common medicinal name of the chemical compound [S [1a(R*).3a,7b,8b(2S*_J 4S*) 8ab]]-1 ,2,3,7, 8,8a-hexahydro-3,7-dimethyl-8-[2- tetrahydro-4-hydroxy-6-oxo-2yl)ethyl]-|.baphthylenyl 2-tretylbulanoate Pravastatin sodium is the common medicinal name of the chemical compound 1-Naphthalene- heptanoie acid 1 ,2,6,7,8,8a-hexahydro-b.d, 6-teihydroxy-2-methyl-8-(2-methyl-|- oxobutoxy)-, monosodium salt [1 S-[a(hS^*, dS^*), 2a, 6a, 8b(R^*, 8aa]].

Rosuvastatin is the common medicinal name of the chemical compound bis(E)-7-[4- (4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfony)amino] pyrimindin-5-yl](3R,5S)- 3,5-dihydroxyhept-6-enoic acid].

Cerivastatin is the common medicinal name of the chemical compound [S-[R^*. S^*- (E)]-7-[4-(4-b fluorophenyl)-5-methoxymethyl)- 2,6bis(|methylethyl) 3-pyridinyl[-3,5- dihydroxy heptenoate. Mevastatin is the common medicinal name of the chemical compound [1 S-[Ia(R^*) 7β, 8β (2 S^*, 4 S^*) 8 α β[ -2-Methylbutanoic acid 1 ,2,3,7,8,8 α - hexahydro-7-methyl- 8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H-pyram-2-yl)ethyl]-1 -naphthalenyl ester.

An "inhibitor of the renin-angiotensin system (RAS)" means any compound which in itself or upon administration blocks the negative effects of angiotensin Il on the vasculature either by reducing the synthesis of angiotensin Il or blocking its effect at the receptor. It includes pharmaceutically acceptable derivatives or salts of said compounds. Inhibitors of the renin-angiotensin system (RAS) known from the prior art include angiotensin converting enzyme (ACE) inhibitors, angiotensin Il antagonists, also known as angiotensin receptor blockers (ARBs), renin inhibitors, and vasopeptidase inhibitors (VPIs).

Examples of ACE inhibitors which can be used in a fixed dose combination with statins are benazepril, benazeprilhydrochloride, benazephlat, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, perindopril, quinapril, ramipril, ramiprilat and trandolapril.

Examples of angiotensin Il antagonists which can be used in a fixed dose combination with statins are candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan. A particularly preferred angiotensin Il antagonist is telmisartan or a pharmaceutically acceptable derivative or salt thereof. Telmisartan is an angiotensin Il receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP-A-502314. Its chemical name is 4'-[2-n-propyl-4-methyl-6-(1 -methylbenzimidazol- 2-yl)-benzimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid having the following structure:

Telmisartan is manufactured and supplied in the free acid form. It is characterized by its very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7. As disclosed in WO 00/43370, crystalline telmisartan can exist in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.

An example of a renin-inhibitor is the compound known as aliskiren.

Tablet layers comprising the renin angiotensin system inhibitor are generally composed and manufactured as described for the commercially available medication comprising the inhibitor as the only active agent. For example a tablet layer of the angiotensin Il receptor antagonist telmisartan will use telmisartan in a dissolving tablet matrix comprising a basic agent, a water-soluble diluent and, optionally, other excipients and adjuvants.

The basic agent can be selected from alkali metal hydroxides, basic amino acids and meglumine; the water-soluble diluent from monosaccharides like glucose; oligosaccharides like sucrose and lactose; and sugar alcohols like sorbitol, mannitol, and xylitol; and the other excipients and adjuvants from binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, coloring agents, pH control agents, surfactants and emulsifiers. Preferably a tablet layer of telmisartan is produced by spray-drying an aqueous solution comprising telmisartan and a basic agent to obtain a spray-dried granulate, mixing said spray-dried granulate with a water-soluble diluent to obtain a premix, mixing said premix with a lubricant to obtain a final blend and compressing the final blend to form the tablet layer with 10-160 mg, and preferably 20-80 mg or 40-80 mg telmisartan.

The term "lactose" is used to refer equally to lactose anhydrous, lactose mono- hydrate and mixtures thereof. The terms is also used to refer equally to [alpha]- lactose, [beta]- lactose and mixtures thereof. Further information about the grades of lactose is available in "Handbook of Pharmaceutical Excipients", Ed R..C. Rowe, 4th Edition, pages 323 to 332.

Tablets or tablet layers comprising statins are generally made by mixing statins with excipients (inactive ingredients) and compressing the mixture into tablets on a tablet press. Among ingredients most commonly used as fillers and binders in pharmaceutical tablets are lactose (which may be either anhydrous lactose or lactose monohydrate) and cellulose. They are considered to be binders as well as fillers, because they usually enable compression into hard tablets, if they are the predominant ingredients.

According to the present invention there is provided a formulation comprising a coated HMG-CoA reductase inhibitor and optionally a coated antioxidant. The coated granules so obtained are then further mixed with other pharmaceutically acceptable excipients. Alternatively, there is provided a formulation comprising a coated HMG- CoA reductase inhibitor and an antioxidant added by dry mixing. The formulation is such that its final unit dose weight in a tablet or tablet layer is preferably less than 400 mg, more preferably 100 - 400 mg and most preferred between 150 and 250 mg. In a preferred embodiment the final unit dose weight in the tablet or tablet layer is identical for all dose strengths such as between 150-250 mg. The dosage units so manufactured do not exhibit problems with dissolution.

In one aspect of the present invention HMG-CoA reductase inhibitor, and optionally antioxidants, are coated with a suitable coating comprising one or more polymers. The coated granules so obtained may further be mixed with suitable pharmaceutically acceptable excipients. For example a plurality of particles comprising a core of the HMG-CoA reductase inhibitor is coated with a film, said particle core containing less than 10 wt% filler, binder and/or diluent, and said particles being dispersed in a pharmaceutically acceptable carrier. Preferably, said particle core contains less than 5 wt% filler, binder and/or diluent, and most preferably said particle core contains substantially no filler, binder and/or diluent.

In a preferred embodiment, the particle core contains substantially no other material except the active material, i.e. the HMG-CoA inhibitor such as simvastatin. However, the core may include at least one other excipient such as a lucricant and/or glidant and/or preferably an antioxidant.

According to one embodiment of the invention the core of the HMG-CoA reductase inhibitor containing less than 10 wt% lactose, microcrystalline cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose may be coated with a film. Preferably, the core contains less than 5 wt% lactose, microcrystalline cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose and most preferably the core contains substantially no lactose, microcrystalline cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose.

According to another embodiment of the invention a pharmaceutical composition comprises a plurality of particles comprising a core of a HMG-CoA reductase inhibitor such as simvastatin coated with a film, the core containing at least 50% of the HMG- CoA reductase inhibitor, and the particles being dispersed in a pharmaceutically acceptable carrier. Preferably, the core contains at least 60 wt% of the HMG-CoA reductase inhibitor, more preferably from 60 to 70 wt%, and most preferably from 65 to 70wt% of the HMG-CoA reductase inhibitor.

Another pharmaceutical composition can also contain at least 15 wt% of said HMG- CoA reductase inhibitor, more preferably at least 20 wt%, and more preferably at least 30 wt% of said HMG-CoA reductase inhibitor. Still more preferably the pharmaceutical composition can contain from 30 to 50 wt% of HMG-CoA reductase inhibitor, for example from 35 to 45 wt% of HMG- CoA reductase inhibitor, 40 wt% being especially preferred.

In another aspect of the present invention the coating may optionally comprise one or more antioxidants and chelating agents. For example, the pharmaceutical composition comprises a plurality of particles consisting of a core of a HMG-CoA reductase inhibitor in combination with one or more antioxidants, and, optionally one or more lubricants and/or glidants, said core being coated with a film, and said particles being dispersed in a pharmaceutically acceptable carrier. Thus, in this aspect of the invention, the film coated particles contain a core of the active material, in combination with the antioxidant(s) and the optional lubricant(s)/glidant(s). If desired, the lubricant and/or glidant may be the same material.

The pharmaceutical compositions according to the invention are obtainable by mixing the ingredients to form particles; coating the particles; and mixing the coated particles with the carrier.

In a further aspect of the present invention the HMG-CoA formulation may be formulated as various dosage forms such as tablets, capsules, or dry syrup for suspension sachet, but preferably as a tablet or tablet layer.

In a preferred embodiment of the present invention there is provided a dosage unit or tablet layer preferably comprising from 5 mg to 80 mg of simvastatin or any suitable HMG-CoA reductase inhibitor and preferably a dosage amount selected from 10 mg, 20 mg and 40 mg of simvastatin. Further the total weight of the single dosage unit of statin is identical for all strengths such as 150-250 mg.

According to the present invention suitable antioxidants may comprise one or more of but not limited to butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, malic acid, ascorbyl palmitate, sodium ascorbate, sodium metabisulphite. The preferred antioxidants are BHA and ascorbic acid. According to the present invention suitable polymers may comprise one or more of but not limited to hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and other cellulose derivatives, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVA), or gelatine. Suitably the polymers may be present in a range of 1 to 15% w/w as per the amount of active ingredient. The preferred polymer is HPMC.

A tablet layer comprising the HMG-CoA reductase inhibitor (statin) according to the present invention may further comprise one or more of pharmaceutically acceptable excipients such as a diluent, binder, disintegrant, lubhcant/glidant, chelating agent and coloring agent. The resulting tablet layer composition then comprises

1 -15% w/w polymer relative to the total weight of statin;

15-90% w/w diluent relative to the total weight of the statin layer;

0.1 -15% w/w binder relative to the total weight of the statin layer;

1 -20% w/w disintegrant relative to the total weight of the statin layer;

0.5-5% w/w lubricant/glidant relative to the total weight of the statin layer; and

0.001 -5% w/w chelating agent relative to the total weight of the statin layer.

Suitable diluents may include one or more of but not limited to calcium phosphate- dibasic, calcium sulphate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectiomers and equivalents thereof. Suitably the diluents may be present in a quantity ranging from 15 to 90% w/w relative to the total weight of the statin layer. The preferred diluent is microcrystalline cellulose.

Suitable binders may include one or more of but not limited to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatine, gum arabic, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof. Suitably the binders may be present in a quantity ranging from 0.1 to 15% w/w relative to the total weight of the statin layer, preferably 1 -15 % w/w. The preferred binders are hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone. Suitable disintegrants may include one or more of but not limited to hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, starch crystalline cellulose, sodium starch glycolate, hydroxypropyl starch, partly pregelatinized starch, crospovidone and equivalents thereof. Suitably the disintegrants may be present in a quantity ranging from 1 to 20% w/w relative to the total weight of the statin layer, preferably 5 to 20% w/w. The preferred disintegrant is Croscarmellose sodium.

Suitable lubricants/glidants may include one or more of but not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, colloidal silicon dioxide and equivalents thereof. Suitably the lubricants may be present in a quantity ranging from 0.5 to 5% w/w relative to the total weight of the statin layer. The preferred lubricants/glidants are magnesium stearate and colloidal silicon dioxide.

Suitable chelating agents may include one or more of but not limited to citric acid, sodium citrate and propyl gallate. Suitably the chelating agents may be present in a quantity ranging from 0.001 to 5% w/w relative to the total weight of the statin layer.

Optionally suitable coloring agents may be added.

According to the present invention there are also provided alternative methods to manufacture a pharmaceutical composition according to the present invention, wherein the antioxidant can be introduced at a combination of more than one of the process steps. Thus, the present invention provides processes for the preparation of a pharmaceutical composition wherein the inhibitor of the renin angiotensin system and the HMG-CoA reductase inhibitor are comprised in different tablet layers comprising (a1 ) coating an HMG-CoA reductase inhibitor with a solution of polymer and subsequently adding antioxidant and suitable excipients to form a premix; or (a2) coating an HMG-CoA reductase inhibitor with a solution of polymer and antioxidant and subsequently adding suitable excipients to form a premix; or (a3) coating a mixture of HMG-CoA reductase inhibitor and antioxidant with a solution of polymer and subsequently adding suitable excipients to form a premix;

(b) forming a final blend by mixing the premix with lubricant and optionally an antioxidant;

(c) compressing the final blend to form a first tablet layer; and

(d) compressing the first tablet layer with a second tablet layer comprising a renin angiotensin system inhibitor.

In one embodiment of such a method HMG-CoA reductase inhibitor is coated with a solution of one or more polymers in water using suitable coating techniques known in the art. The granules so coated are mixed with one or more antioxidants and one or more suitable excipients using a suitable blender. This premix is subsequently mixed with a lubricant and optionally with an antioxidant using a suitable blender to yield the final blend.

In an alternative embodiment of such a method HMG-CoA reductase inhibitor is coated with a solution of polymer and one or more antioxidants in water using suitable coating techniques known in the art. The granules so coated are then mixed with one or more suitable excipients using a suitable blender. This premix is subsequently mixed with lubricant, and optionally with antioxidant, using a suitable blender, to yield the final blend.

In yet another alternative embodiment of such a method HMG-CoA reductase inhibitor is mixed with antioxidant and subsequently coated with a solution of polymer in water using suitable coating techniques known in the art. The granules so coated are mixed with one or more suitable excipients using a suitable blender. This premix is subsequently mixed with lubricant, and optionally with antioxidant, using a suitable blender, to yield the final blend.

The final blend obtained according to the methods above can be compressed to form tablet layers but may also be filled in capsules or sachets if desired. For preparing a bilayer tablet according to the present invention, a first and second tablet layer composition may be compressed in the usual manner in a bilayer tablet press, e.g. a high-speed rotary press in a bilayer tabletting mode. However, care should be taken not to employ an excessive compression force for the first tablet layer. Preferably, the ratio of the compression force applied during compression of the first tablet layer to the compression force applied during compression of both the first and second tablet layers is in the range of from 1 : 10 to 1 :2. For instance, the first tablet layer may be compressed at moderate force of 2 to 8 kN, whereas the main compression of first plus second layer is performed at a force of 10 to 20 kN. During bilayer tablet compression adequate bond formation between the two layers is achieved by virtue of distance attraction forces (intermolecular forces) and mechanical interlocking between the particles.

As discussed above the total weight of the pharmaceutical dosage unit comprising the HMG-CoA inhibitor can be varied as desired, but for reasons of practicability it is preferable for the total weight of a single layer of the oral dosage unit to be less than 400 mg, preferably 100 - 400 mg, and most preferred the total weight of a single layer is identical for all strengths such as 150-250 mg.

The HMG-CoA inhibitor formulation of the present invention exhibits dissolution of at least 75% and preferably at least 80% by weight of the pharmaceutical composition in about 30 minutes.

The present invention further comprises a method of treatment which method comprises administering a formulation according to the present invention to a person in need of reducing cholesterol and blood pressure.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.

In one embodiment described above, the particle core does not include a binder, diluent or filler, in particular lactose. It is preferred that the particle coating does not contain any of these materials either.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention.

Example 1 : Formulation comprising 80 mg or 40 mg telmisartan.

Constituents mg mg

Telmisartan 80.00 40.00

Sodium hydroxide 6.72 3.36

Povidone 24.00 12.00

Meglumine 24.00 12.00

Sorbitol 337.28 168.64

Magnesium stearate 8.00 4.00

Purified water ^* _* _*

Total weight 480.00 240.00

^* volatile ingredient, does not remain in final product

The formulation can be compressed to form a tablet layer or may be filled in capsules if desired.

Example 2: Formulation comprising 40 mg, 20 mg or 10 mg simvastatin. Constituents mg

Simvastatin 40.00

HPMC 2.50

Ascorbic acid 10.00

BHA 0.20

Citric acid monohydrate 5.00

Microcrystalline cellulose 116.30

Croscarmellose sodium 7.00

Colloidal silicon dioxide 4.00

Corn starch 10.00

Pigment blend (iron oxides) 1.00

Magnesium stearate 4.00

Purified water ^* _*

Total weight 200.000

^* volatile ingredient, does not remain in final product

This formulation can be compressed to form the second tablet layer of a bilayer tablet with the formulations of example 1 being compressed to form the first tablet layer.

Example 3: Formulation comprising 40 mg, 20 mg or 10 mg simvastatin.

Constituents mg mg mg

Simvastatin 40.00 20.00 10.00

HPMC 2.50 1.25 0.625

Ascorbic acid 10.00 10.00 10.00

BHA 0.20 0.20 0.20

Citric acid monohydrate 5.00 5.00 5.00

Microcrystalline cellulose 76.30 97.55 108.175

Croscarmellose sodium 11.00 1 1.00 1 1.00

Colloidal silicon dioxide 4.00 4.00 4.00

Corn starch 66.00 66.00 66.00

Pigment blend (iron oxides) 1.00 1.00 1.00

Magnesium stearate 4.00 4.00 4.00

Purified water ^* _* _* _*

Total weight 220.000 220.000 220.000

^* volatile ingredient, does not remain in final product This formulations can be compressed to form the second tablet layer of a bilayer tablet with the formulations of example 1 being compressed to form the first tablet layer.

Example 4: Formulation comprising 5 mg ramipril

Constituents mg

Ramipril 5.00

HPMC 0.88

MCC 123.62

Pregelatinized starch 15.00

Corn starch 50.00

Colloidal silicon dioxide 0.50

Pigment blend (e.g., iron oxides) 3.00

Sodium stearyl fumarate 2.00

Purified water ^* _*

Total weight 200.000

^* volatile ingredient, does not remain in final product

This formulation can be compressed to form the first tablet layer of a bilayer tablet with the formulation of example 2 being compressed to form the second tablet layer.

Example 5: Process for the preparation of a simvastatin formulation Simvastatin is coated in a suitable granulator with a solution of HPMC in water. The granules so formed are mixed in a suitable blender with ascorbic acid, citric acid, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, corn starch, and pigment blend to form the premix. The premix is mixed in a suitable blender with BHA and magnesium stearate to yield the final blend. The formulation can be compressed as a tablet or tablet layer. It may also be filled in capsules if desired.

Claims

We claim:

1. A pharmaceutical composition comprising a coated HMG-CoA reductase inhibitor, an inhibitor of the renin angiotensin system, and further pharmaceutically acceptable excipients.

2. The composition of claim 1 comprising a coated HMG-CoA reductase inhibitor with an optionally coated antioxidant.

3. The composition of claims 1 and 2, wherein the HMG-CoA reductase inhibitor and the antioxidant are coated with one or more polymers optionally comprising a further antioxidant.

4. The composition of claim 3, wherein the coating comprises relative to the total weight of statin 1 -15% w/w polymer selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), hydroxpropyl cellulose (HPC), and other cellulose derivatives, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVA), and gelatine.

5. The composition of claim 1 , wherein the HMG-CoA reductase inhibitor and the antioxidant are comprised in a single tablet layer.

6. The composition of claim 5, wherein the HMG-CoA reductase inhibitor exhibits a dissolution of at least 75% in 30 minutes.

7. The composition of claim 5, wherein the layer comprising the HMG-CoA reductase inhibitor has a weight of less than 400 mg.

8. The composition of claim 1 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, cehvastatin, pitavastatin, rosuvastatin, atorvastatin and enantiomers, polymorphs, and salts thereof.

9. The composition of claim 8 comprising 5 mg to 40 mg of simvastatin.

10. The composition of claim 1 , wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, malic acid, sodium ascorbate and sodium metabisulphite.

11. The composition of claim 1 , wherein the inhibitor of the renin angiotensin system is selected from the group consisting of benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolaphl; candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan.

12. The composition of claim 5, wherein the inhibitor of the renin angiotensin system is comprised in a different tablet layer.

13. The composition of claim 12, wherein further pharmaceutically acceptable excipients of the layer comprising the HMG-CoA reductase inhibitor are coating polymers such as HPMC, diluents, binders, disintegrants, lubricants, chelating agents or coloring agents.

14. The composition of claim 13, comprising in the layer comprising the HMG-CoA reductase inhibitor relative to the total weight of the layer 15-90% w/w of diluent selected from the group consisting of calcium phosphate-dibasic, calcium sulphate, cellulose-microcrystalline, cellulose powdered, dextrates dexthns, dextrose excipients, fructose, lacitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents.

15. The composition of claim 13, comprising in the layer comprising the HMG-CoA reductase inhibitor relative to the total weight of the layer 0.1-15% w/w binder selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatine, gum arabic, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents.

16. The composition of claim 13, comprising in the layer comprising the HMG-CoA reductase inhibitor relative to the total weight of the layer 1 -20 %w/w disintegrant selected from the group consisting of hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethyl-cellulose, sodium carboxymethylcellulose, croscarmellose sodium, starch crystalline cellulose, sodium starch glycollate, hydroxypropyl starch, partly pregelatinized starch, crospovidore and equivalents thereof.

17. The composition of claim 13, comprising relative to the total weight of the layer 0.5-5% w/w lubricant and/or glidant selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, talc, hydropgenated caster oil, sucrose esters of fatty acid, microcrystalline wax, colloidal silicon dioxide and equivalents thereof.

18. The composition of claim 13, comprising in the layer comprising the HMG-CoA reductase inhibitor 0.001 -5% w/w chelating agent selected from citric acid, sodium citrate, and propyl gallate.

19. The composition of claim 12, wherein the layer comprising the inhibitor of the renin angiotensin system comprises

(a) a basic agent selected from alkali metal hydroxides, basic amino acids and meglumine;

(b) a water-soluble diluent selected from monosaccharides like glucose; oligosaccharides like sucrose and lactose; and sugar alcohols like sorbitol, mannitol, and xylitol; and

(c) other excipients and adjuvants from binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, coloring agents, pH control agents, surfactants and emulsifiers.

20. A process for the preparation of a pharmaceutical composition according to claim 14 comprising (a1 ) coating an HMG-CoA reductase inhibitor with a solution of polymer and subsequently adding antioxidant and suitable excipients to form a premix; or (a2) coating an HMG-CoA reductase inhibitor with a solution of polymer and an antioxidant and subsequently adding suitable excipients to form a premix; or (a3) coating a mixture of HMG-CoA reductase inhibitor and antioxidant with a solution of polymer and subsequently adding suitable excipients to form a premix;

(c) compressing the final blend to form a first tablet layer; and