OA17601A - Oral formulation for the treatment of cardiovascular diseases. - Google Patents

Abstract

The present invention relates to a pharmaceutical composition which includes a HMG-CoA reductase inhibitor, in particular, a statin and acetylsalicylic acid in a manner to minimize interaction of acetylsalicylic acid with the statin, for use in the prevention or treatment of cardiovascular diseases.

Description

The présent invention relates to a pharmaceutical composition which includes a HMG-CoA reductase inhibitor, in particular, a statin and acetylsalicylic acid in a manner to minimize interaction of acetylsalicylic acid with the statin, for use in the prévention or treatment of cardiovascular diseases.

BACKGROUND OF THE INVENTION

Cardiovascular diseases are one of the leading causes of death in the world and one of the most significant factors for these diseases is total/high density lipoprotein (HDL) cholestérol level. However, recent developments hâve indicated that only taking the cholestérol level under control is not sufficient for cardiovascular treatment. In line with this need, researchers hâve found that the use of some active agents in combination provides a more effective treatment method.

The use of acetylsalicylic acid for reducing the risk of myocardial infarction and the use of statins for lowering cholestérol and preventing or treating cardiovascular disease and cerebrovascular disease are well documented. In fact, it is not uncommon that patients having elevated cholestérol levels who are at high risk for a myocardial infarction take both a statin and acetylsalicylic acid. However, use of both a statin and acetylsalicylic acid may require spécial care to insure that drug interaction, including physical and chemical incompatibility, and side effects, are kept to a minimum while achieving maximum benefit from these drugs.

HMG-CoA reductase inhibitors can be divided into two groups: those administered as a prodrug, i.e., the lactone form and those administered in the active form, i.e., the acid form or salts of the acid form (e.g. pravastatin sodium, atorvastatin calcium and rosuvastatin calcium). These compounds are unstable since they are susceptible to heat, moisture, low pH environment and light. Both atorvastatin and rosuvastatin and salts thereof, including calcium and magnésium salts, are particularly unstable when compared to other statins. In particular, atorvastatin is transformed into the lactone as a resuit of the intramolecular estérification reaction. Major dégradation products (3R, 5S) produced as a resuit of disintegration of statins are lactones and oxidation products. This fact reduces the stability of atorvastatin and therefore shortens its shelf life.

It is known from the prior art that HMG-CoA reductase inhibitors dégradé in the presence of acetylsalicylic acid during storage.

Document WO9738694 discloses pharmaceutical compositions comprising aspirin and a statin. However, the problem of statin-aspirin interaction is not addressed. Document EP1071403 addresses the problem of said interaction and describes a formulation in the form of a bilayered tablet. Aspirin, in the form of granules, is présent in the first layer while the statin is présent in the second layer. However, combination products produced in bilayer dosage forms can fail to prevent interaction of the active agents with each other. In this case, the product may be degraded during its shelf life. This may resuit in serious complications to the patient and insufficient dose intake.

Document EP 1581194 relates to multilayer tablet dosage form comprising pravastatin and aspirin as active agents. The layers comprising the active agents are separated by a barrier layer in order to impede their interaction. However, it is quite inconvénient to produce this type of tablet formulations and it is not certainly known if the barrier layer would maintain its effect during the shelf life.

Document WO2011096665 describes that the détérioration in the stability of HMG-CoA reductase can be prevented by coating aspirin with a barrier containing a hydrophobie additive. According to said document, when aspirin is coated with conventional coatings, HMG-CoA reductase inhibitors are degraded. When a hydrophobie additive is added to the coating layer, the dégradation of HMG-CoA reductase inhibitors is reduced.

In view of the above, it is seen that there is a need in patients required to take both a statin and acetylsalicylic acid for a statin-acetylsalicylic acid formulation which provides for maximum effect in cardiovascular diseases prévention and treatment without the undesirable side effects and drug interaction normally associated with use of such combination.

In accordance with the présent invention, a pharmaceutical composition is provided which includes a HMG-CoA reductase inhibitor selected from atorvastatin and rosuvastatin and salts thereof, and acetylsalicylic acid, which provides for maximum patient benefits with minimal physical and chemical incompatibility and reduced side effects normally associated with use of such drugs.

SUMMARY OF THE INVENTION

The authors of the présent invention hâve found that when acetylsalicylic acid is provided in an oral formulation and the amount of coating for acetylsalicylic acid units is above 6 mg/cm² and said coating contains a water-soluble polymer, the détérioration in the stability of atorvastatin and rosuvastatin can be surprisingly prevented.

Thus, the présent invention refers to an orally administrable pharmaceutical dosage form for use in the prévention and/or treatment of a cardiovascular disease comprising:

(a) acetylsalicylic acid as a first active agent; and (b) HMG-CoA reductase inhibitor as a second active agent, wherein said HMG-CoA reductase inhibitor is selected from atorvastatin and rosuvastatin and salts thereof, and wherein (a) are two or more single separate coated dosage units comprising one or more water-soluble polymer in said coating and being said coating substantially free from a water-insoluble polymer or an enteric polymer; and wherein the amount of coating is above 6 mg/cm2; and showing a non-modified release profile; and (b) is one or more single separate coated dosage units; and the dosage units are selected from the group consisting of tablets, particles, granules, pellets and capsules.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 represents the dissolution profiles of 100 mg and 50 mg ASA strength formulations (4.3 mg/cm² coating).

Figure 2 shows the dissolution profile of acetylsalicylic acid 100 mg tablets containing different amounts of film coating agent per cm² (2.17, 4.3 and 8.7).

Figure 3 shows the dissolution profile of 50 mg versus 100 mg ASA tablets containing 4.3 and

8.7 mg/cm² of film coating agent.

Figure 4 shows the dissolution profile of AAR capsules containing ASA 50 mg x 2 film-coated tablets with 8.7 mg/cm² at pH 4.5.

Figure 5 shows the dissolution profile of AAR capsules containing ASA 50 mg x 2 film-coated tablets with 8.7 mg/cm² at pH 6.8.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical dosage form of the présent invention exhibits improved storage stability of HMG-CoA reductase inhibitors atorvastatin and rosuvastatin (and salts thereof) in the presence of acetylsalicylic acid, thereby providing useful combinations for the prévention and treatment of cardiovascular diseases.

The authors of the présent invention hâve developed a new formulation. This new formulation consists of an oral dosage form containing separate coated dosage units for each drug substance, being said units tablets, particles, granules or pellets and being the amount of coating for acetylsalicylic acid units above standard levels. In fact, the authors of the présent invention hâve found that when the amount of coating for acetylsalicylic acid units is above 6 mg/cm² and said coating contains a water-soluble polymer, the détérioration in the stability of atorvastatin or rosuvastatin can be surprisingly prevented. As it is shown in the examples below, the production of lactone H, which is the major dégradation product of atorvastatin, is significantly lower in the formulation of the invention when compared to a formulation containing a standard coating.

Thus, in a first aspect, the présent invention refers to an orally administrable pharmaceutical dosage form for use in the prévention and/or treatment of a cardiovascular disease comprising:

(a) acetylsalicylic acid as a first active agent; and (b) HMG-CoA reductase inhibitor as a second active agent, wherein said HMG-CoA reductase inhibitor is selected from atorvastatin and rosuvastatin and salts thereof, and wherein (a) are two or more single separate coated dosage units comprising one or more water-soluble polymer in said coating and being said coating substantially free from a water-insoluble polymer or an enteric polymer; and wherein the amount of coating is above 6 mg/cm2; and showing a non-modified release profile; and (b) is one or more single separate coated dosage units; and the dosage units are selected from the group consisting of tablets, particles, granules, pellets and capsules.

As used herein the term “dosage units” refers to dosage forms containing a single dose or a part of a dose of drug substance in each unit. According to the présent invention, said dosage units can be in the form of tablets, particles, granules, pellets or capsules.

Multiple dosage forms of the présent invention can be prepared by combining one or more dosage units in an oral formulation. These dosage units can be tablets, granules, pellets, capsules or particles or combinations thereof. As it can be understood by the skilled person in the pharmaceutical industry, the term “granulation” refers to the act or process in which primary powder particles are made to adhéré to form larger, multiparticle entities called granules. Thus, it is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in the manufacturing of tablets and pellets (or spheroids).

As used herein the term “tablet” includes tablets, mini tablets or micro tablets. Similarly, the term “capsule” also can refer to micro capsules. Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, gelatin capsules being preferred. Two-piece hard gelatin capsules are preferably sealed by gelatin bands or the like. In a preferred embodiment, said orally administrable pharmaceutical dosage form according to the invention is in the form of a capsule. In another preferred embodiment, wherein (a) and/or (b) dosage units are in the form of tablets.

The term cardiovascular disease as used herein refers to a disease such as hypercholesterolemia, atherosclerosis, coronary and cérébral diseases, for instance myocardial infarction, secondary myocardial infarction, myocardial ischemia, angina pectoris, congestive heart diseases, cérébral infarction, cérébral thrombosis, cérébral ischemia and temporary ischémie attacks.

The compositions of the présent invention may be used as treatment for acute cardiovascular events, as well as for chronic therapy for prévention or réduction of risk of occurrence of cardiovascular events.

The terms treating and treatment as used herein refer to réduction in severity and/or frequency of symptoms, élimination of symptoms and/or underlying cause, prévention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage. Thus, for example, treating a patient involves prévention of a particular disorder or adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual.

As used herein, the terms “aspirin” or “acetylsalicylic acid (ASA)” are used interchangeably.

This invention employs effective cholesterol-lowering agents that are HMG CoA reductase inhibitors. HMG-CoA reductase inhibitors can be divided into two groups: those administered as the prodrug, i.e., the lactone form and those administered in the active form, i.e., the acid form (e.g. atorvastatin and rosuvastatin).

Compounds which hâve inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat.

No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.

The HMG-CoA reductase inhibitor for use in the formulation of the invention is selected from atorvastatin and rosuvastatin and salts thereof, in particular calcium and magnésium salts.

The term “HMG-CoA reductase inhibitor” is intended to include ail pharmaceutically acceptable sait or ester of the compounds having HMG-CoA reductase inhibitory activity according to the invention, and therefore the use of such salts or esters is included within the scope of this invention.

The expression pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The expression pharmaceutically-acceptable cationic salts is intended to define but is not limited to such salts as the alkali métal salts, (e.g. sodium and potassium), alkaline earth métal salts (e.g. calcium and magnésium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (Ν,Ν'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The expression pharmaceutically-acceptable acid addition salts is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. It will also be recognized that it is possible to administer amorphous forms of the statins.

The pharmaceutically-acceptable cationic salts of statins containing free carboxylic acids may be readily prepared by reacting the free acid form of the statin with an appropriate base, usually one équivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnésium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine. The sait is isolated by concentration to dryness or by addition of a non-solvent. In many cases, salts are preferably prepared by mixing a solution of the acid with a solution of a different sait of the cation (sodium or potassium ethylhexanoate, magnésium oleate), employing a solvent (e.g., ethyl acetate) from which the desired cationic sait précipitâtes, or can be otherwise isolated by concentration and/or addition of a non-solvent.

The pharmaceutically acceptable acid addition salts of statins containing free amine groups may be readily prepared by reacting the free base form of the statin with the appropriate acid. When the sait is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the ptoluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar équivalent and usually a molar excess of the acid is employed. However when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate or the phosphate are desired, the appropriate and exact chemical équivalents of acid will generally be used. The free base and the acid are usually combined in a co-solvent from which the desired sait précipitâtes, or can be otherwise isolated by concentration and/or addition of a non-solvent.

A number of mechanisms are likely responsible for the cardiovascular protective activity of acetylsalicylic acid, but its antithrombotic, anti-platelet aggregating activities are probably highly significant in this regard. Acetylsalicylic acid irreversibly acetylates the enzyme cyclooxygenase, rendering it nonfunctional. Cyclooxygenase is essential for the synthesis of (among other compounds) prostaglandins, many of which are proinflammatory; thromboxane A2, which is synthesized by platelets to promote platelet aggregation and ultimately thrombosis (blood clotting); and prostacyclins, which hâve anti-platelet aggregating properties. Cyclooxygenases are synthesized in endothélial cells and not in platelets. Low doses of acetylsalicylic acid neutralize cyclooxygenase selectively in the platelets, while allowing continued cyclooxygenase and prostacyclin synthesis in the endothélial cells. The net effect is to reduce inflammation and platelet aggregation, and thus thrombosis, in the blood vessels.

As mentioned above, when the amount of coating for each acetylsalicylic acid dosage unit is above 6 mg/cm² and said coating comprises a water-soluble polymer, the détérioration in the stability of HMG-CoA reductase inhibitor, in particular, atorvastatin and rosuvastatin, is surprisingly reduced. Moreover, as it is shown in the Examples accompanying the présent invention, a dosage form according to the présent invention comprising acetylsalicylic acid in the form of two dosage units, wherein the amount of coating for said acetylsalicylic acid units is above 6 mg/cm², has the effect of reducing the amount of atorvastatin impurities produced in addition to maintaining a non-modified release profile for the acetylsalicylic acid dosage units.

As used herein, the amount of coating expressed in mg/cm² refers to the amount of coating per cm² of surface of the core of active ingrédient. In a particular embodiment of the invention, the amount of coating for acetylsalicylic acid dosage units is comprised from 6 to 12 mg/cm², more particularly, the amount of coating for acetylsalicylic acid dosage units is comprised from 7 to 11 mg/cm². In a preferred embodiment, the amount of coating for acetylsalicylic acid dosage units is comprised from 8 to 10 mg/cm².

According to the présent invention, acetylsalicylic acid dosage units (a) hâve a non-modified or conventional release profile. According to another particular embodiment, ail dosage units in the formulation of the invention hâve non-modified or conventional release profile.

As used herein the terms conventional release” or “non-modified release profile are used indistinctively and it is to be understood as pertaining a dosage form showing a release of the active substance(s) which is not deliberately modified by a spécial formulation design and/or manufacturing method. In the case of a solid dosage form the dissolution profile of the active substance dépends essentially on its intrinsic properties. It is also understood that non-modified or conventional release is, essentially, immédiate release of active ingrédients. This is further understood to be traditional or conventional release profile where no slow, delayed or extended release effect is incorporated. Preferably, means that a percentage equal to or greater than 65 % of the active ingrédient is dissolved within 60 minutes, preferably within 30 minutes and more preferably within 15 minutes in a US Pharmacopeia type 1 apparatus in 0.05 M acetate buffer, at pH 4.5, 100 rpm in a volume of 900 ml. More preferably the percentage of active ingrédient dissolved is greater than 75 %, more preferably greater than 80%.

The term “water-soluble polymer” as used herein refers to a wide range of highly varied families of products of natural or synthetic origin. These polymers are often used as thickeners, stabilizers, film formers, rheology modifiers, emulsifiers and lubricity aids. Basically, water soluble polymers are highly hydrophilic as a resuit of the presence of oxygen and nitrogen atoms: hydroxyl, carboxylic acid, sulfonate, phosphate, amino, imino groups etc. Examples of suitable water soluble polymers according to the présent invention include, for instance, water soluble cellulose dérivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, hydroxylethylmethyl cellulose carboxymethylcellulose calcium or sodium, methylcellulose or combinations thereof, sugars such as glucose, fructose or polydextrose, polyalcohols such as sorbitol, mannitol, maltitol, xylitol and isomalt, maltodextrin, polyethylene oxide, povidone, copovidone, gélatine, partly hydrolyzed polyvinyl alcohol, polyvinyl alcohol, poloxamer, or combinations thereof. In a particular embodiment of the invention, said the water-soluble polymer is selected from the group consisting of a watersoluble cellulose ether selected from methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose and mixtures thereof; a water-soluble polyvinyl dérivative selected from polyvinyl pyrrolidone, partly hydrolyzed polyvinyl alcohol and polyvinyl alcohol and mixtures thereof; an alkylene oxide polymer selected from polyethylene glycol and polypropylene glycol; and mixtures thereof.

In a preferred embodiment, said water soluble polymer is présent in an amount by weight above 40% of the total weight of the coating. In another preferred embodiment, said water soluble polymer is selected from hydroxypopyl methylcellulose, partly hydrolyzed polyvinyl alcohol and polyvinyl alcohol or a mixture thereof.

According to the présent invention, the acetylsalicylic acid dosage unit coating is substantially free from a water-insoluble polymer or an enteric polymer. The term “substantially free” as used here in refers to the presence of the substance (s) to which it refers, i.e. a water-insoluble polymer or an enteric polymer, in amounts ranging between 0 to 5% b.w., more preferably in amounts ranging between 0 to 1% by weight of the composition of the coating. In a preferred embodiment, said coating contains no more than about 0.1% by weight of the composition of the coating of a water-insoluble polymer or enteric polymer.

Examples of water-insoluble polymers; and synthetic or semisynthetic hydrophobie polymers such as ethyl cellulose, aminoalkyl méthacrylate copolymer RS, ethyl acrylate-methyl méthacrylate copolymer, polyvinyl chloride, polyvinyl acetate and cellulose acetate.

As it is known in the art, acetylsalicylic acid can lead to stomach diseases in long-term use. Thus, according to the présent invention, acetylsalicylic acid units can optionally comprise an enteric coating layer. Said coating layer would preferably be included between the acetylsalicylic acid core and the water-soluble polymer coating. Enteric or gastro-résistant coating is intended to resist the gastric fluid and to release the active substance or substances in the intestinal fluid.

Coating materials that can be used in enteric coating of said dosage forms can be selected from methacrylic copolymers for instance methacrylic acid/methyl méthacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl méthacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates or combinations thereof. Commonly used plasticizers as may be suitable for particular enteric polymers can be used. It will be appreciated that any polymer with suitable plasticizer can be used in aqueous or non-aqueous system to form an enteric coating on the acetylsalicylic acid dosage unit. The coating can, and usually does, contain a plasticizer to prevent the formation of pores and cracks that would permit the pénétration of the gastric fluids.

Enterically coated dosage forms may be manufactured using standard enteric coating procedures and equipment. For example, an enteric coating can be applied using a coating pan, an airless spray technique, fluidized bed coating equipment, or the like.

In addition to the active agent(s), the dosage units of the formulation of the invention prepared for oral administration will generally contain other pharmaceutically acceptable excipients such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like. The terms “pharmaceutically acceptable excipients”, “pharmaceutically compatible excipients”, and “excipients” are used interchangeably in this disclosure. They refer to non-API substances such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards.

Binders are used to impart cohesive qualities to a dosage form. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and water-washed smectite clays such as Veegum®.

Diluents are typically used to increase bulk so that a practical size dosage unit, for example a tablet, is ultimately obtained. Suitable diluents include alkali métal carbonates, cellulose dérivatives (microcrystalline cellulose, cellulose acetate, etc.), phosphates, maltodextrin, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, including direct compression lactose, maltose, mannitol, sorbitol, starch, talc, xylitol and/or hydrates thereof and/or dérivatives thereof.

Examples of suitable lubricants include, for example, metallic stéarates (such as magnésium stéarate, calcium stéarate, aluminum stéarate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, minerai oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfate (such as sodium lauryl sulfate, magnésium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, talc, siliconized talc and/or hydrates thereof.

Disintegrants used in the présent invention enable the dosage form to disperse in water easily and rapidly. Disintegrants can be selected from a group comprising polymers having high dispersing characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone; the products known under the trademarks Kollidon(R)

CL, Polyplasdone(R) or alginic acid, sodium alginate, corn starch.

Basic agents of the présent invention are either water-soluble or water-insoluble and selected from a group comprising meglumine, tromethamol, sodium bicarbonate, sodium carbonate, sodium citrate, calcium gluconate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium tartrate, sodium acetate, calcium glycérophosphate, magnésium oxide, magnésium hydroxide, aluminum hydroxide, dihydroxy aluminum, sodium carbonate, calcium carbonate, aluminum carbonate, dihydroxy aluminum amino acetate, diethanolamine, triethanolamine, N-methyl-glucamine, glucosamine, ethylenediamine, triethyleneamine, isopropylamine, di-isopropyl amine or combinations thereof.

Stabilizers are used to inhibit or retard drug décomposition reactions that include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric, or nonionic surface-active agents. Surfactants that can optionally be used in the présent invention are selected from a group comprising sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin, dextran, sorbitan esters, polyoxy ethylene alkyl ethers, polyethylene glycols, polyethylene stéarates, collodial silicon dioxide.

Anti-adhesive agents can be used in the présent invention in order to prevent the mixture comprising active agents to adhéré onto device and machine surfaces and create rough surfaces. The substances used for this purpose can comprise one or more components selected from a group comprising talc, colloïdal silicone dioxide (Aerosil, Syloid, Cab-OSil), magnésium stéarate and corn starch.

Release rate déterminant polymers that can be used in the formulations of the présent invention can be pH-dependant polymers, non pH-dependant polymers, swellable polymers, non-swellable polymers, hydrophilic polymers, hydrophobie polymers and/or one or more hydrophobie substances; ionic polymers such as sodium alginate, carbomer, calcium carboxy methyl cellulose or carboxy methyl cellulose; non-ionic polymers such as hydroxy propyl methyl cellulose; natural or/synthetic polysaccharides such as alkyl celluloses, hydroxyl alkyl celluloses, cellulose ethers, nitrocellulose, dextrin, agar, carrageenan, pectin, starch and starch dérivatives or mixtures thereof; cellulosic polymers; méthacrylate polymers, méthacrylate copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, ethyl cellulose, cellulose acetate, cellulose propionate (high, medium and low molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polyvinyl acetate, polyvinyl chloride and mixtures thereof.

As mentioned above, acetylsalicylic acid dosage units (a) show a non-modified or conventional release profile. However, release rate déterminant polymers as the ones mentioned in the paragraph above, can also be used in the dosage form of the présent invention for the other dosage units. Therefore, the dosage units according to the invention may show a modified release profile. The term modified release as used herein includes ail types of modified release profiles such as controlled release, sustained release, delayed release, and the like.

The film coating materials of the présent invention can contain the following components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetine, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar dérivatives, polyvinyl dérivatives, waxes, fats and gelatins, triethyl citrate, glyceride, titanium oxide, talc, sodium alginate, stearic acid, lecithin.

The term therapeutically effective amount as used herein is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The dosage regimen utilizing an HMG-CoA reductase inhibitor in combination with acetylsalicylic acid will be selected in accordance with a variety of factors including type, species, âge, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the rénal and hepatic function of the patient; and the particular compound or sait or ester thereof employed. Since two or more different active agents are being used together in a combination therapy, the potency of each of the agents and the enhanced effects achieved by combining them together must also be taken into account. A considération of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective amounts of the drug combination needed to prevent, counter, or arrest the progress of the condition.

In a particular embodiment of the invention the amount of acetylsalicylic acid in the formulation is in the range of 10 - 400 mg per dosage unit. More préférable, the amount of acetylsalicylic acid is in the range of 30 - 100 mg per dosage unit. In a more preferred embodiment, the amount of acetylsalicylic acid per dosage unit is in the range of 40 - 85, more preferably 40 - 60 mg per dosage unit, even more preferably 50 mg.

The pharmaceutical dosage form of the invention will contain a HMG-CoA reductase inhibitor, in particular a statin selected from atorvastatin and rosuvastatin and salts thereof in an amount as normally employed for such statin. Thus, depending upon the particular statin, it may be employed in amounts within the range from about 0.1 mg to 2000 mg per day in single or divided doses, and preferably from about 0.2 to about 200 mg per day. The clinical dosage range for atorvastatin is 10 - 80 mg per day. Therefore, in a particular embodiment of the invention the amount of HMG-CoA reductase inhibitor in the dosage form of the invention can be in the range of 1 - 40 mg per dosage unit, more preferably, from 5 - 40, even more preferably from 5 - 20 mg per dosage unit. In a preferred embodiment of the invention, the HMG-CoA reductase inhibitor is in the form of two or more dosage units in the dosage form of the invention.

In a particular embodiment of the invention, the composition further comprises one or more single separate dosage units comprising an inhibitor of the rennin-angiotensin system as a third active agent.

The renin aldostérone angiotensin system (RAAS) plays an important rôle in the régulation of blood pressure and volume homeostasis, and pivotai rôles in the pathophysiology of cardiovascular, rénal, and metabolic diseases. Renin is secreted by the kidney in response to a decrease in circulating volume and blood pressure, and cleaves the substrate angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang 11) by angiotensin converting enzyme (ACE). Ang II interacts with cellular receptors, in particular ATI receptors, inducing vasoconstriction and release of catecholamines from the adrenal medulla and pre-junctional nerve endings. It also promotes aldostérone sécrétion and sodium reabsorption. In addition, Ang II inhibits renin release, thus providing a négative feedback to the system. Accordingly, Ang II acts at various levels (e.g. vasculature, sympathetic nervous system, cortex and medulla of the adrenal gland) to increase vascular résistance and blood pressure.

The RAAS can be blocked at various levels. Renin inhibitors, ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) represent major drug classes that block the RAAS. Each individual drug class has a different mode of action and thus blocks the RAAS at a different level: Renin inhibitors block the first, rate-limiting step of RAAS cascade by competitively inhibiting the enzyme renin, thereby preventing the formation of Ang I from angiotensinogen. ACEi block the second step of the RAAS cascade by competitively inhibiting the enzyme ACE, thereby preventing the formation of Ang II. Finally, ARBs block the third and last step of the RAAS cascade by binding to and occupying the ATI receptors without activating them. Thereby, ARBs prevent binding and activation of said ATI receptors by Ang II. It has been disclosed that certain gene polymorphisms reflecting on cardiovascular Systems are useful as biomarkers for predicting disease susceptibility or progression, or as a guide for individualized therapy, including drug therapy.

The renin inhibitors to which the présent invention applies are any of those having renin inhibitory activity in vivo. Renin inhibitors for use herein include, but are not limited to, those disclosed in EP 678.503, WO 00/64887, WO 00/064873, WO 2005/051895, WO 2006/095020, US 2009/0076062, WO 2011/056126, Yokokawa et al. (Expert Opin. Ther. Patents 18(6):581602, 2008), and Maibaum et al. (Expert Opin. Ther. Patents 13(5):589-603, 2003). Moreover, suitable renin inhibitors include compounds having different structural features. In one embodiment, the renin inhibitor is preferably selected from aliskiren, ditekiren, terlakiren, zankiren, RO 66- 1132, RO 66-1168, VTP27999, ACT-280778, and TAK-272, and pharmaceutically acceptable salts, prodrugs, dérivatives and isomers thereof.

An ARB according to the invention is any molécule that can specifically antagonize or block the action of angiotensin II type 1 receptors (ATI receptors). ARBs suitable for use herein include, but are not limited to, losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, tasosartan, zolarsartan, azilsartan, olmesartan, saprisartan, forasartan, E-4177, and ZD-8731, and pharmaceutically acceptable salts, prodrugs, dérivatives and isomers thereof.

In a preferred embodiment, the inhibitor of the rennin-angiotensin System is an angiotensinconverting enzyme (ACE) inhibitor. An ACEi according to the invention is any molécule that can specifically inhibit the enzymatic activity of angiotensin converting enzyme. ACEi suitable for use herein include, but are not limited to, benazepril, benazeprilat, captopril, zofenopril, enalapril, enaprilat, fosinopril, ceronapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, alacepril, cilazapril, delapril, imidapril, rentiapril, spirapril, temocapril, and moveltipril, and pharmaceutically acceptable salts, prodrugs, dérivatives and isomers thereof. In one embodiment, the preferred ACEi is ramipril and pharmaceutically acceptable salts thereof.

Ramipril is a prodrug, which is rapidly hydrolysed after absorption to the active métabolite ramiprilat. Ramipril and ramiprilat inhibit angiotensin-converting enzyme (ACE). ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulâtes aldostérone sécrétion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldostérone sécrétion. The latter decrease may resuit in a small increase of sérum potassium. The effect of ramipril on hypertension appears to resuit at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma. Administration of ramipril to patients with mild to moderate hypertension results in a réduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are sait- and/or volume-depleted. Ramipril can significantly reduce the incidence of Ml, stroke or death from cardiovascular causes in patients aged > or =55 years who are at increased risk for the development of ischaemic cardiovascular events.

In a particular embodiment of the invention, the ACE inhibitor dosage units hâve an unmodified release profile. In another particular embodiment, said ACE inhibitor is in the form of one or more single separate dosage units selected from the group consisting of tablets, particles, granules, pellets and capsules. In a preferred embodiment, said dosage units are coated dosage units.

On average, the daily dose of ramipril in a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to about 20 mg/kg, preferably 1 mg/kg, of body weight. In a particular embodiment of the invention, the amount of ramipril in said formulation is in the range of 1-100 mg per dosage unit, more preferably in the range of 2 - 50 mg per dosage unit.

The following examples are put forth so as to provide those of ordinary skill in the art with a complété disclosure and description of how to make and use the présent invention, and are not intended to limit the scope of the invention or to represent that the experiments below are ail or the only experiments performed. Efforts hâve been made to ensure accuracy with respect to numbers used (e.g., amounts, température, and the like), but some experimental errors and déviations may be présent.

EXAMPLES

Film-coated tablets comprising acetylsalicylic acid (ASA), atorvastatin and ramipril were manufactured and encapsulated (AAR capsules).

As mentioned above, different film-forming polymers can be used according to the présent invention. The term PVA as used herein refers to a partly hydrolyzed polyvinyl alcohol.

Manufacture of atorvastatin coated tablets

Atorvastatin tablets were manufactured by wet granulation using a high shear mixer and fluid bed dryer. Granulation solution was prepared dispersing polysorbate 80 and hydroxypropyl cellulose in purified water. The intragranular components (see Table 2) were incorporated to the blend to be granulated. Finally, the extragranular components (see Table 2) were added and blended with the obtained granules. Each blend was compressed in a rotary press machine. After tabletting, cores obtained were film coated.

Manufacture of ASA coated tablets

Acetylsalicylic acid, sodium starch glycolate and microcrystalline cellulose were sieved in the appropriate proportions (see Table 5) and blended. The talc (lubricant) was sieved and blended with the previously obtained blend and the final blend compressed. The resulting core was coated with the aqueous film-forming solution.

Atorvastatin (10 mg or 20 mg) and ASA (40.5; 50 mg or 100 mg) film coated tablets were manufactured as described above and encapsulated along with ramipril (2.5, 5 or 10 mg) film coated tablets. Ramipril film coated tablets are commercially available.

The composition of the manufactured capsules was as follows:

Table 1: Composition of AAR capsules

Component	Example 1 AAR capsules	Example 2 AAR capsules
	(tablet/capsule)	(tablet/capsule)
ASA 100 mg film coated tablets	1
ASA 50 mg film coated tablets	-	2
Atorvastatin 10/20 mg film coated tablets	2	2
Ramipril 10 mg film coated	1	1

tablets

Table 2: atorvastatin 10 mg film-coated tablets composition

Component	(mg/tablet)
Intragranuiar
atorvastatin calcium trihydrate(1)	10.845
lactose monohydrate	36.805
pregelatinised starch	21.000
calcium carbonate	29.600
hydroxypropylcellulose	3.000
Polysorbate 80	1.000
purified water(2)	22.000

total (mg)	Extragranular	102.25
crospovidone		6.000
silica colloïdal anhydrous	1.000
magnésium stéarate	0.750
total (mg)	Film coating	110.000
Hydroxypropylmethyl	3.300
cellulose coating
purified water(2)		22.000
Total (mg)		113.300

(1) Equivalent to 10 mg atorvastatin. Atorvastatin calcium trihydrate purity is corrected with lactose monohydrate.

(2) Removed during manufacturing process

Table 3: atorvastatin 20 mg film-coated tablets intragranular composition

Component (mg/tablet)

Intragranular

atorvastatin calcium trihydrate(1)	21.690
lactose monohydrate	35.360
pregelatinised starch	21.000
calcium carbonate	49.200
hydroxypropylcellulose	3.000
Polysorbate 80	2.000
purified water(2)	27.000
total (mg)	132.250
Extragranular
Crospovidone	6.000
silica colloïdal anhydrous	1.000
magnésium stéarate	0.750
total (mg)	140.000
Film coating
Hydroxypropylmethyl	4 200
cellulose coating
purified water(2)	28.000
Total (mg)	144.200

(1) Equivalent to 20 mg atorvastatin. Atorvastatin calcium trihydrate purity is corrected with lactose monohydrate.

(2) Removed during manufacturing process

Table 4: composition of 100 mg, 50 mg and 40.5 mg ASA film-coated tablets

	QUANTITY	QUANTITY	QUANTITY
COMPOSITION	FUNCTION	(mg)	(mg)	(mg)
acetylsalicylic acid	active ingrédient	100.0	50.0	40.50
sodium starch glycolate	disintegrant	3.75	7.50	7.10
microcrystalline cellulose	diluent	20.00	41.50	51.00
talc	lubricant	1.25	1.00	1.00
TOTAL:		125.00	100.00	100.00

In the finished product film coated tablets of atorvastatin were placed inside a capsule along with film coated tablets of ramipril and film coated tablets of acetylsalicylic acid (ASA).

In order to improve the stability of the formulation, a partly hydrolyzed polyvinyl alcohol, was used as film forming agent for acetylsalicylic acid (ASA) tablets. Different amounts of film coating for ASA tablets were tested: 2.17 mg/cm², 4.3 mg/cm² and 8.7 mg/cm².

Table 5: composition of PVA coating

Component	w/w %
partially hydrolysed polyvinyl alcohol	45.50
titanium dioxide	30.00
Talc	22.00
soy lecithin	2.00
xanthan gum	0.50
Total	100.00

Presence of atorvastatin impurities in capsules comprising ASA film-coated tablets (one tablet of 100 mg ASA or 2x50 mg) under different stress conditions (40 °C, 30 °C, and 25 °C) was tested.

As it is shown in Table 6, in ail cases (40 °C, 30 °C, and 25 °C) aspirin tablets with 8.7 mg/cm² coating, yielded lower levels of lactone H than tablets with 4.3 mg/cm² coating (standard level).

Table 6: Atorvastatin impurities when ASA is coated with different thickness of PVA coatings (4.3 mg/cm² and 8.7 mg/cm²):

Example 1 AAR capsules:

ASA 100 mg 4.3 mg/cm2	Initial	40°C 3 months	30°C 3 months	25°C 3 months
ASA		100.2	100.6	98.6	100.1
Assay
Impuritie Q
O	Salycilic acid	0.05	0.71	0.28	0.12
	Total	0.05	0.76	0.35	0.19
	impurities
ATV		98.7	100.5	99.9	101.9
Assay
Impuritie c
o	Impurity D	0.10	0.09	0.09	0.09
	Impurity H	0.10	0.57	0.43	0.41
	Total	0.20	0.79	0.55	0.53

impurities

Example 2 AAR capsules:

ASA 50 mg x2 8.7 mg/cm2	Initial	40°C 3 months	30°C 3 months	25°C 3 months
ASA Assay Impuritie c		97.6	101.3	97.7	98.7
o	Salycilic acid	0.09	0.19	0.13	0.18
	Total impurities	0.19	0.32	0.18	0.33
ATV Assay Impuritie Q		99.5	97.4	96.8	98.3
O	Impurity D	0.05	0.06	0.05	0.06
	Impurity H	0.08	0.15	0.05	0.08
	Total impurities	0.22	0.58	0.30	0.47

Dissolution profile of ASA tablets mg or 40.5 mg strength formulations of ASA tablets (see Table 4) were prepared in order to check whether the dissolution rate could be improved by reducing the strength of the 5 formulations.

Table 7: Comparative dissolution rate of 100 mg and 50 mg ASA strength formulations

FORMULATION 100 mg 50 mg (x2)

PARAMETER UNITS RESULTS RESULTS

Dissolution test minutes , % 5 Mean = 38 % 5 Mean = 58 %

(0.05 M Acetate buffer pH	CV = 23.44 %	CV = 8.52 %
4.5;	15	Mean = 96 %	15	Mean = 103 %
50 rpm; 500 ml)	CV = 5.32 %	CV = 3.21 %
		Mean = 99 %		Mean = 105 %
	30	CV = 2.84 %	30	CV = 3.09 %

Dissolution tests were performed under the following conditions: 0.05 M acetate buffer pH 4.5; 50 rpm US Pharmacopeia type 1 apparatus; 500 ml.

Dissolution data showed (See Figure 1 and Table 7) an improvement in dissolution profile of the ASA tablets when the strength of the formulation is reduced. Dissolution rate of two tablets of acetylsalicylic acid 50 mg is faster than one of acetylsalicylic acid 100 mg.

Next step was to test if similar results are obtained when using film-coated tablets. The effect of PVA coating in the dissolution profile of film-coated tablets of 50 mg ASA compared to 100 mg ASA tablets was tested. Different amounts of film coating agent were tested: 2.17 mg/cm², 4.3 mg/cm² and 8.7 mg/cm².

As it is shown in Table 8 and Figure 2, by increasing the amount of coating by more than 4.3 mg/cm2, the dissolution profile of the 100 mg ASA tablets is affected. Mean values of % dissolved at 15 minutes are over 85 % in ASA tablets comprising 2.17 mg/cm² and 4.3 mg/cm² coating. However, said value is below 75% in tablets comprising 8.7 mg/cm² coating.

Dissolution test conditions:

Apparatus: USP 1 (basket)

Stirring speed: 50 rpm

Dissolution Volume: 500 mL

Dissolution media: pH 4.5 acetate buffer

Table 8: ASA 100 mg film-coated tablets (PVA coating) dissolution results

Time (min)	ASA 100 mg film-coated tablets 2,17 mg/cm2	ASA 100 mg film-coated tablets 4.3 mg/cm2	ASA 100 mg film-coated tablets 8.7 mg/cm2
0	0	0	0
5	22	33	13
15	88	87	72
30	105	97	101

However, as it is shown in Table 9, 50 mg ASA tablets comprising 8.7 mg/cm² coating do not show any négative effect on the dissolution profile, as at 15 minutes mean values of % dissolved are over 85 %.

Table 9: 2x50 mg ASA PVA coated tablets dissolution results

Time (min)	ASA 50 mg film-coated tablets 2.17 mg/cm2	ASA 50 mg film-coated tablets 4.3 mg/cm2	ASA 50 mg film-coated tablets 8.7 mg/cm2
0	0	0	0
5	41	47	33
15	94	96	101
30	101	106	115

Dissolution results (see Figure 3; Tables 8 and 9) show that the dissolution rate of 2 tablets of 50 mg ASA is in ail cases (2.17 mg/cm², 4.3 mg/cm² and 8.7 mg/cm²) faster than that of one tablet of 100 mg ASA. Also, comparing the dissolution profile of 50 mg tablets and 100 mg tablets with 4.3 mg/cm² and 8.7 mg/cm² coating, it can be observed that 50 mg (2x) tablets with

8.7 mg/cm² coating dissolve faster than 100 mg tablets with 4.3 mg/cm²coating.

Dissolution profiles of AAR capsules containing ASA 50 mg x 2 film-coated tablets with 8.7 mg/cm² were also performed at different conditions:

Dissolution test conditions:

Apparatus: USP 1 (basket)

Stirring speed: 100 rpm

Dissolution Volume: 900 mL

Dissolution media: pH 4.5 acetate buffer

Results (Table 10 and Figure 4) were as follows:

Table 10: % ASA dissolved in AAR capsules dissolution results

Time (min)	AAR capsule % ASA dissolved
0 15 20 30 45	0 81.3 90.7 94.4 95.5

Dissolution test conditions:

Apparatus: USP 1 (basket)

Stirring speed: 100 rpm

Dissolution Volume: 900 mL

Dissolution media: pH 6.8 phosphate buffer

Results (Table 11 and Figure 5) were as follows:

Table 11: % ASA dissolved in AAR capsules dissolution results

	AAR capsule
Time (min) 0 15 20 30 45	% ASA dissolved 0 73.1 86.2 95.3 97.3

As shown in Table 10 and Table 11, AAR capsule containing 50 mg ASA film-coated tablets x

2, comprising 8.7 mg/cm^{* 2}of tablet coating, show mean values over 80% at 15 minutes in the case of pH 4.5 and close to 75 % at pH 6.8.

A formulation comprising ASA tablets with 8.7 mg/cm² coating provides more protection and isolation to the acetylsalicylic acid tablet, making more difficult that salicylic acid can sublime and it can trigger the dégradation of the other components, in particular, of atorvastatin or rosuvastatin inside the final capsule.

Claims (11)

1. An orally administrable pharmaceutical dosage form for use in the prévention and/or treatment of a cardiovascular disease comprising:

(a) acetylsalicylic acid as a first active agent; and (b) HMG-CoA reductase inhibitor as a second active agent, wherein said HMG- CoA reductase inhibitor is selected from atorvastatin and rosuvastatin and salts thereof, and wherein (a) are two or more single separate coated dosage units comprising one or more water-soluble polymer in said coating and being said coating substantially free from a water-insoluble polymer or an enteric polymer which means in an amount ranging between 0 to 5% by weight of the composition of the coating; and wherein the amount of coating is comprised from 8 to 12 mg/cm2; and showing a non-modified release profile; and (b) is one or more single separate coated dosage units;

the dosage units are in the form of tablets, and the water soluble polymer is présent in an amount by weight above 40% of the total weight of the coating and is selected from the group consisting of; a water-soluble polyvinyl dérivative selected from polyvinyl pyrrolidone, partly hydrolyzed polyvinyl alcohol, polyvinyl alcohol, and mixtures thereof.

2. The pharmaceutical dosage form according to claim 1, wherein said dosage form is in the form of a capsule.

3. The pharmaceutical dosage form according to any of the preceding claims, wherein the water-soluble polymer is partly hydrolyzed polyvinyl alcohol, polyvinyl alcohol, and mixtures thereof.

4. The pharmaceutical dosage form according to any of the preceding claims, wherein acetylsalicylic acid dosage units (a) show a percentage equal to or greater than 65 %, preferably greater than 75 %, more preferably greater than 80% and even more preferably greater than 85% of acetylsalicylic acid dissolved within 60 minutes, preferably within 30 minutes and more preferably within 15 minutes in a US Pharmacopeia type 1 apparatus in 0.05 M acetate buffer, at pH 4.5, 100 rpm in a volume of 900 ml.

5. The pharmaceutical dosage form according to any of the preceding claims, wherein (a) and (b) dosage units are in the form of coated tablets.

6. The pharmaceutical dosage form according to any of the preceding claims, wherein the amount of acetylsalicylic acid in said dosage form is in the range of 10 to 400 mg per dosage unit.

7. The pharmaceutical dosage form according to any of the preceding claims, wherein the amount of HMG-CoA reductase inhibitor in said dosage form is in the range of 5 to 40 mg per dosage unit.

8. The pharmaceutical dosage form according to any of the preceding claims, wherein the HMG-CoA reductase inhibitor is in the form of two or more dosage units.

9. The pharmaceutical dosage form according to any of the preceding claims, further comprising one or more single separate dosage units comprising an inhibitor of the renninangiotensin system as a third active agent.

10. The pharmaceutical dosage form according to the preceding claim, wherein the inhibitor of the rennin-angiotensin system is an ACE inhibitor selected from the group consisting of ramipril, captopril, cilazapril, delapril, enalapril, fentiapril, fosinopril, indolapril, lisinopril, perindopril, pivopril, quinapril, spirapril, trandolapril, and zofenopril and pharmaceutically acceptable salts or an angiotensin receptor blocker selected from the group consisting of losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, tasosartan, zolarsartan, azilsartan, olmesartan, saprisartan, forasartan, E-4177, and ZD-8731, and pharmaceutically acceptable salts.

11. Pharmaceutical dosage form according to the preceding claim, wherein said ACE inhibitor is ramipril and pharmaceutically acceptable salts.