WO2011060943A1

WO2011060943A1 - Pharmaceutical formulations containing beta- blocking active ingredient capsules and polyunsaturated fatty acid esters

Info

Publication number: WO2011060943A1
Application number: PCT/EP2010/007023
Authority: WO
Inventors: Antonio PARENTE DUEÑA; Paolo Carminati
Original assignee: Gp Pharm, S.A.; Defiante Farmaceutica, S.A.; Singrossi, Maria Gabriella; Carminati, Silvia; Carminati, Giuseppe, Paolo
Priority date: 2009-11-20
Filing date: 2010-11-19
Publication date: 2011-05-26
Also published as: ES2363965B1; TW201138862A; ES2363965A1; AR079430A1

Abstract

Pharmaceutical composition for oral administration which contains polyunsaturated fatty acid alkyl esters (PUFA) and active pharmaceutical ingredients for the treatment and/or prevention of cardiovascular diseases.

Description

PHARMACEUTICAL FORMULATIONS CONTAINING BETA- BLOCKING

ACTIVE INGREDIENT CAPSULES AND POLYUNSATURATED FATTY ACID ESTERS

FIELD OF THE INVENTION This invention relates to an pharmaceutical composition for oral administration which comprises a suspension of polymeric microcapsules suspended in an oil which contains alkyl esters of polyunsaturated fatty acids (PUFA), wherein the microcapsules contain at least one polymer and one beta-blocking active ingredient, and its use for the treatment and/or prevention of cardiovascular diseases.

BACKGROUND OF THE INVENTION

Among the most used active pharmaceutical ingredients for the treatment of cardiovascular diseases there are beta blockers.

Beta blockers are competitive antagonists of the beta-adrenergic receptors and are used for the treatment of cardiovascular diseases such as hypertension, angina pectoris, cardiac dysrhythmia, myocardial infarction and heart failure. They are also used to control alcohol withdrawal symptoms, in anxiety disorders, in hyperthyroidism and in tremors, as well as in migraine prophylaxis and bleeding of varicose veins associated with portal hypertension. Polyunsaturated fatty acids (PUFA) also possess a known beneficial effect on the prevention of cardiovascular events and are often used in combination therapy in patients who have suffered some type of cardiovascular episode. There are numerous studies on anti-hypertensive, reduction of serum cholesterol, anti-hypertriglyceridemic, antiarrhythmic, antiplatelet and anti-inflammatory effects of PUFAs [Bucher H.C. et a/. Am. J. Med. 112: 298-304 (2002); Benatti P. et al. J. Am.. Coll. Nutr. 23: 281-302 (2004); Lee J.H. ef al. Mayo Clin. Proc. 83: 324-332 (2008); Heinz R. Adv. Ther. 26: 675-690 (2009)].

PUFAs are essential fatty acids and should be obtained from a person's diet. They are divided into omega-3 and omega-6 fatty acids depending on the position of the first unsaturation (n-3 and n-6 respectively). The principal omega-3 fatty acids are found in fish oils, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). PUFAs can be found in the form of triglycerides or aikyl esters. Commercial compositions of omega-3 fatty acid alkyl esters vary in purity and content of fatty acids and are normally expressed in relation to the content in EPA and DHA.

PUFAs, in any of their forms, are easily oxidized and should be stored under an inert atmosphere and protected from light. Commercial compositions contain antioxidants to minimize their degradation.

It is known that formulations based on lipids increase the bioavailability of certain active pharmaceutical ingredients. Examples of formulations which increase the bioavailability of active ingredients through the use of PUFA are described in the literature, generally by the formation of emulsions. The preparation of microemulsions formed by nanoparticles of biocompatible oils such as eicosapentaenoic acid (EPA) are described in WO 2006/135415 A2, these contain active pharmaceutical ingredients such as the beta blockers, among others. In US 2007009559 A1 an improvement of the bioavailability of different active pharmaceutical ingredients which are poorly soluble in water, such as carvedilol, among others, is proposed, through their incorporation in compositions which contain unsaturated fatty acids, such as linoleic acid or ethyl linoleate, as well as water, a surfactant, a polyol and phospholipids. In all these cases contact with PUFAs or with excipients of the formulation would not be avoided, which is a cause of degradation for these active ingredients.

The instability of the aforementioned beta-blocking active ingredients is known. In the beta blockers, the presence of the secondary amino group in alpha position relative to the hydroxyl group affords them chemical instability, due to possible interactions with the excipients, and this represents a problem during their storage. Therefore, the amino group of the beta blockers can react with aldehyde or ester functional groups, as is described, for example, for carvedilol in WO 2005/051383 A1. It would be an advantage to have a stable formulation which contained the two active ingredients, PUFA and beta blockers, avoiding the degradation caused by the interaction of the reactive amino functional group in alpha position to the hydroxyl group of beta blockers with the ester functional groups of PUFAs.

In WO 2007/103557 A2 the physical separation of the components in a hard or soft gelatin capsule is proposed as a solution to the problems of chemical incompatibilities in compositions with two or more active ingredients. This capsule should contain a first active ingredient such as omega-3 fatty acids, with one or more internal capsule coatings wherein at least one of them consists of a polymer combined with another active ingredient, and the coating which contains this active ingredient should be isolated from the capsule and optionally from the outside by additional coatings. In WO 2008/063323 A2 the combination therapy is achieved by successive internal coatings of a capsule which contains omega-3 fatty acids with coatings which comprise antiarrhythmic active ingredients, among them beta blockers. The manufacturing process is complex due to the fragility and solubility in water of the gelatin coating and requires rigorous control of the temperature and speed of deposition during coating.

In WO 2006/081518 A2, with the aim of achieving a modified release of multiple active ingredients, among them beta blockers, complexes of the active ingredients with ion exchange resins (resinates) are prepared, polymerically coated or not, suspended in a non-ionic and non-aqueous vehicle ("NINA" vehicle) such as alcohols, polyols, polyethers, oils, triglycerides or waxes, among them omega-3. The type of "NINA" vehicle used allows controlling the contact of the resin with water. In the examples of the aforementioned document, the application of these formulations is solely by topical route. The use of resinates for oral administration is controversial since the administration of large quantities of ion exchange resins or their prolonged use in chronic treatments can change the ionic force of the gastrointestinal fluids and cause electrolyte imbalances.

Therefore, the problem arising from the technique is the need to find a stable pharmaceutical composition for oral administration which comprises two active ingredients of cardiovascular use such as beta blockers and PUFAs and whose preparation is simpler and does not cause the problems described. The solution proposed by this invention is an pharmaceutical composition for oral administration which incorporates the described agents, with the active ingredient isolated by means of a polymer, and which does not use excipiehts which may cause adverse secondary effects in a chronic treatment.

The subject-matter of this invention is pharmaceutical composition for oral administration which contains a suspension of microcapsules of beta-blocking active ingredients in an oil which contains polyunsaturated fatty acids alkyl esters. This composition provides greater protection of the beta-blocking active pharmaceutical ingredients against their chemical interaction with the alkyl esters of PUFA, as well as against moisture, light and oxidizing agents.

DESCRIPTION OF THE INVENTION Therefore, this invention relates to a new pharmaceutical composition for oral administration which avoids the problems of degradation of beta-blocking active ingredients when they are formulated together with oils which contain alkyl esters of PUFA. In a first aspect, this invention relates to an pharmaceutical composition for oral administration which comprises a suspension of polymeric microcapsules which comprise at least one polymer and a beta-blocking active ingredient, these microcapsules being suspended in an oil which contains polyunsaturated fatty acid alkyl esters. The polymer of the microcapsules constitutes their external part and provides a complete coating for the encapsulated active pharmaceutical ingredient.

In the pharmaceutical composition of this invention, the beta-blocking active ingredients are found in the inside of the polymeric microcapsules in suspension in an oil which contains alkyl esters of PUFA. The beta-blocking active ingredients are isolated both from the outside medium and from the alkyl esters of PUFA by the polymer, which easily disintegrates in the gastrointestinal medium. The pharmaceutical composition of this invention allows, as well as the joint administration of active pharmaceutical ingredients in a combination therapy, the beta-blocking active ingredient to be isolated from the alkyl esters of PUFA. The polymeric coating provides stability to these beta blockers, avoiding the formation of degradation products caused by the interaction of the reactive amino functional group in alpha position in relation to the hydroxyl group with the ester groups of the alkyl esters of PUFA.

Preferably, the fatty acids of the alkyl esters of PUFA belong to the omega-3 series. Preferably, the PUFAs are selected from the group formed by the (all-cis)-5, 8,11 ,14,17- eicosapentaenoic or eicosapentaenoic (EPA) or timnodonic acid or icosapent (C20:5 n-3), the ^a//-c/^'s -4,7,10,13,16,19-docosahexaenoic or docosahexaenoic (DHA) or cervonic acid or doconexent (C22:6 n-3), and/or mixtures thereof, such as Omacor^®, Lovaza^® or Zodin^®, among others. In a preferred embodiment, the EPA:DHA relationship can range between 100:0 and 0:100, preferably between 4:1 and 1 :4, and more preferably between 1 :2 and 2:1. The PUFAs can comprise just EPA or just DHA. Preferably, the alkyl radical of the alkyl esters of PUFA is selected from the group formed by short chain alkyl radicals, with from 1 to 8 carbon atoms. Preferably, the alkyl radical is selected from the group formed by ethyl, methyl, propyl, butyl and/or mixtures thereof. More preferably, the alkyl radical is an ethyl group. Preferably, the oil containing alkyi esters of PUFA is an oil enriched in alkyi esters of PUFA, preferably, the oil contains more than 50% of alkyi esters of PUFA, more preferably more than 60% of alkyi esters of PUFA and even more preferably, more than 85% of alkyi esters of PUFA. In a preferred embodiment, the quantity of alkyi esters of PUFA contained in the pharmaceutical capsule of the invention is comprised between 0.01 and 4 g, preferably between 0.1 and 2 g.

In a particular embodiment, the beta-blocking active ingredient, is selected, without restriction, from the group formed by acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, esatenolol, esmolol, indenolol, labetalol, landiolol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, talinolol, tertatolol, tilisolol, timolol, butoxamine, and/or their pharmaceutically acceptable salts. The polymer of the microcapsules of the pharmaceutical capsule of this invention is selected, without restriction, from the group formed by proteins, polysaccharides, polyesters, polyacrylates, polycyanoacrylates, polyethylene glycol and/or mixtures thereof. Preferably, the polymer of the microcapsules is selected from the group formed by gelatin, albumin, alginates, carrageenans, pectins, gum arabic, chitosan, carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose (HPMC), nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate-succinate, polyvinyl acetate phthalate, poly(8-caprolactone), poly(p-dioxanone), poly(5-valerolactone), poly(p-hydroxybutyrate), poly( -hydroxybutyrate) copolymers and β-hydroxyvalerate, poly(p-hydroxypropionate), methacrylic acid copolymers (Eudragit^® L and S), dimethylaminoethyl methacrylate copolymers (Eudragit^® E), trimethylammonium ethyl methacrylate copolymers (Eudragit^® RL and RS), polymers and copolymers of lactic and glycolic acids, polymers and copolymers of lactic and glycolic acids and polyethylene glycol and/or mixtures thereof. More preferably, the polymer is formed by copolymers of methacrylic acid (Eudragit^® L and S), polymers and copolymers of lactic, and glycolic acids, polymers and copolymers of lactic and glycolic acids and polyethylene glycol, and/or mixtures thereof.

Optionally, the polymer of the microcapsules of the pharmaceutical capsule of this invention can comprise a plasticizer additive. The plasticizer additive is selected, without restriction, from the group formed by alkyl esters of the citric acid such as triethyl citrate, tributyl citrate, acetyl tributyl citrate and acetyl triethyl citrate, phthalates such as butyl phthalate and diethyl phthalate, glycerin, sorbitol, maltitol, propylene glycol, polyethylene glycol, glucose, sucrose, lanolin, palmitic acid, oleic acid, stearic acid, metal salts of fatty acids such as stearic acid or palmitic acid, sodium stearate, potassium stearate, propylene glycol monostearate, acetylated monoglycerides such as monoacetylated glycerin and glyceryl triacetate or triacetin, glyceryl lecithin, glyceryl monostearate, alkyl sebacates such as dibutyl sebacate or diethyl sebacate, alkyl fumarates, alkyl succinates, medium chain triglycerides (MCT), ricin oil, hydrogenated vegetable oils, wax and/or mixtures.

Optionally other technical additives of the polymer can be incorporated which improve or facilitate the encapsulation process such as fluidifying agents, such as talc, colloidal silicon dioxide, glycerin, polyethylene glycol, glycerin monostearate and/or metal stearate salts. Optionally, the pharmaceutical capsule of this invention comprises at least one antioxidant, such as and not restricted to, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), gallic acid esters such as propyl gallate, tocopherols such as vitamin E acetate, ascorbic acid esters such as ascorbyl palmitate and ascorbyl acetate, carnitine and/or mixtures thereof. Preferably, the antioxidant is vitamin E acetate.

In a particular embodiment, the microcapsules represent between 0.001% and 80% of the total weight of the pharmaceutical composition of this invention, preferably between 0.01 % and 60%, and more preferably between 0.1 % and 50% of the total weight of the pharmaceutical composition of this invention. The amount of beta-blocking active pharmaceutical ingredient incorporated in these microcapsules is comprised between 1% and 80% in weight, preferably between 1% and 60% in weight with respect to the total weight of the microcapsules. The total amount of active pharmaceutical ingredient included in the pharmaceutical composition of this invention depends on the recommended daily doses. In another particular embodiment, the pharmaceutical composition for oral administration of this invention is presented in capsule form, preferably in soft capsule form. This capsule can be a gelatin capsule or any usual polymer in the preparation of capsules in the pharmaceutical industry, such as and not restricted to, hydroxypropyl methylcellulose (HPMC), pullulan, modified starches, carrageenans and/or mixtures thereof. Optionally, the capsule has an .enteric coating. The capsule's coating can contain other additives such as plasticizers, colorants, pigments, opacifiers, preservatives, moisturizers, surfactants, sweeteners and/or flavorings. The preparation of the capsule is carried out through the usual procedures in the pharmaceutical industry, and can be any form and size known by the person skilled in the art.

The preparation of the microcapsules can be carried out by following any of the procedures described in the literature. As a description and not restricted to them, the different procedures for obtaining microcapsules can be grouped in the following sections: A) Simple coacervation procedure

A solution of the polymer together with its possible additives is prepared in an appropriate solvent. In this solution of the polymer the active pharmaceutical ingredient to be encapsulated is suspended and a solvent in which the polymer is not soluble is added to force the polymer deposition on the crystals of the active ingredient. Examples of these procedures can be found in documents such as ES

2009346 A6, EP 0052510 A2 and EP 0346879 A1.

B) Complex coacervation procedure

It is based on the interaction between two colloids with an opposite electrical charge to generate an insoluble complex which is deposited on the particles of the active pharmaceutical ingredient to be encapsulated forming a membrane which isolates it. Examples of these procedures can be found in documents such as GB 1393805 A.

C) Double emulsion procedure

The active pharmaceutical ingredient to be encapsulated is dissolved in water or in a solution of another coadjuvant and is emulsified in a solution of the polymer and additives in an appropriate solvent such as dichloromethane. The resulting emulsion is in turn emulsified in water or in an aqueous solution of an emulsifier such as polyvinyl alcohol. Once this second emulsion has been carried out the solvent in which the polymer and the plasticizer were dissolved in is eliminated by evaporation or extraction. The resulting microcapsules are directly obtained by filtration or evaporation. Examples of these procedures can be found in documents such as US 4652441 A. D) Simple emulsion procedure

The active pharmaceutical ingredient to be encapsulated, the polymer and the additives are jointly dissolved in an appropriate organic solvent. This solution is emulsified in water or in a solution of an emulsifier such as polyvinyl alcohol and the organic solvent is eliminated by evaporation or extraction. The resulting microcapsules are recovered by filtration or drying. Examples of these procedures can be found in documents such as US 5445832 A.

E) Solvent evaporation procedure

The active pharmaceutical ingredient to be encapsulated, the polymer and the additives are jointly dissolved in an appropriate solvent. This solution is evaporated and the resulting residue is micronized to obtain the suitable size, or it is dried by spray-drying. Examples of this procedure can be found in documents such as GB 2209937 A.

Another aspect of this invention relates to the use of the pharmaceutical composition for oral administration of the invention in the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases. Preferably, these cardiovascular diseases are selected from among cardiac dysrhythmia, hypertension, angina pectoris, myocardial infarction and heart failure.

Another aspect of this invention relates to the use of the pharmaceutical composition for oral administration of the invention in the preparation of a medicament for the treatment and/or prevention of disorders and/or pathologies selected from the group formed by alcohol withdrawal symptoms, anxiety disorders, hyperthyroidism, tremors, migraines, pheochromocytoma and/or bleeding of varicose veins associated with portal hypertension. Another aspect of the invention is a method of treatment and/or prevention of cardiovascular diseases, which comprises administering a pharmaceutically efficient dose of the pharmaceutical composition of this invention. Preferably, these cardiovascular diseases are selected from among cardiac dysrhythmia, hypertension, angina pectoris, myocardial infarction and heart failure. Another aspect of the invention is a method of treatment and/or prevention of disorders and/or pathologies selected from the group formed by alcohol withdrawal symptoms, anxiety disorders, in hyperthyroidism, tremors, migraines, pheochromocytoma and/or bleeding of varicose veins associated with portal hypertension, which comprises administering a pharmaceutically efficient dose of the pharmaceutical composition of this invention.

The following specific examples provided here serve to illustrate the nature of this invention. These examples are included solely for illustrative purposes and should not be interpreted as a limitation to the invention claimed herein.

EXAMPLES

Example 1. Preparation of pharmaceutical capsules which contain carvedilol microcapsules with gelatin through a simple coacervation procedure. A 1 % solution of gelatin in water was prepared.

100 ml_ of this solution were taken and 1 g of carvedilol powder was dispersed in it. Then 30 mL of saturated sodium sulfate solution in water were added. The mixture was stirred for 1 hour and 0.5 mL of 50% glutaraldehyde solution in water were added.

The microcapsules formed by filtration were collected, they were washed with water and dried in a vacuum drying oven. The content in carvedilol of these microcapsules was 39%.

The resulting microcapsule powder was dispersed directly in oil containing a minimum of 90% of ethyl esters of PUFA, with a minimum EPA/DHA content of 85% in a ratio of 1.2:1 (1.63 g of the microcapsules suspension obtained per 100 g of oil). Next, 1.00 g of the dispersion of microcapsules in oil was incorporated to a soft gelatin capsule, to obtain a dose of 6.25 mg of carvedilol per capsule.

Example 2. Preparation of pharmaceutical capsules which contain atenolol microcapsules with polyethylene glycol. A 10% solution of polyethylene glycol in water with a molecular weight of 35000 (PEG- 35000) was prepared.

5 g of atenolol were dispersed in 100 mL of this solution by intense stirring. , Once a lump-free, fine dispersion was obtained the solution was dried by spray-drying.

The microcapsule powder obtained showed a concentration of atenolol of 33%, and was directly dispersed in oil containing a minimum of 65% of ethyl esters of PUFA, with a minimum EPA/DHA content of 45% in a ratio of 1.2:1 (17.9 g of the suspension of microcapsules obtained per 100 g of oil). Next, 1.00 g of the microcapsule dispersion in oil was incorporated to a soft gelatin capsule, to obtain a dose of 50 mg of atenolol per capsule.

Example 3. Preparation of pharmaceutical capsules which contain propranolol microcapsules with poly(lactic-co-glycolic acid) (PLGA) and vitamin E.

Solution A: 100 ml_ of 10% solution in PLGA dichloromethane with an intrinsic viscosity (I.V.) of 0.17 and lactic/glycolic ratio of 1 :1 were prepared. Solution B: 4 g of propranolol hydrochloride and 1 g of vitamin E acetate were dissolved in 200 ml_ of ethanol.

Solutions A and B were mixed under continuous stirring. During this stirring, a nitrogen current was passed through the previous solution for two hours to eliminate most of the dichloromethane and ethanol. Subsequently the resulting suspension was frozen and lyophilized. A powder was obtained which was washed with a great amount of water to eliminate the excess of ethanol and was dried at reduced pressure.

The microcapsule powder obtained contained 26% of propranolol, and was directly dispersed in oil containing a minimum of 90% de ethyl esters of PUFA, with a minimum EPA/DHA content of 85% in a ratio of 1.2:1. Next, the dispersion of microcapsules in oil obtained was incorporated to a soft gelatin capsule. The quantities used to prepare capsules of different sizes and doses of propranolol are shown in Table 1.

Table 1 Example 4. Studies of stability of the suspension of carvedilol, atenolol and propranolol microcapsules in an oil which contains alkyl esters of PUFA.

Studies of accelerated stability (40±2 °C, 75±5 % RH) were carried out on the beta- blocking active ingredients in an oil which contained alkyl esters of PUFA wherein: a) The active pharmaceutical ingredient does not have a polymeric coating, and, therefore, is not in contact with the alkyl esters of PUFA (control composition). b) The active pharmaceutical ingredient is in microcapsules prepared according to the previous examples (composition of the invention).

The percentages of the active pharmaceutical ingredient were determined through HPLC after storage of the microcapsule suspensions in amber glass containers for 1 month, 2 months, 3 months and 4 months. The percentages of the active pharmaceutical ingredient are shown in Table 2.

The stability of PUFAs was also studied (concentration of alkyl esters of EPA and DHA, as well as the EPA/DHA ratio) through gas chromatography, although no variations were observed in the composition.

Table 2

Claims

1. Pharmaceutical composition for oral administration which comprises a suspension of polymeric microcapsules which comprise at least one polymer and a beta-blocking active ingredient, these microcapsules being suspended in an oil which contains polyunsaturated fatty acid alkyl esters.

2. Pharmaceutical composition according to claim 1 , wherein the polyunsaturated fatty acids of these alkyl esters belong to the omega-3 series. 3. Pharmaceutical composition according to claim 2, wherein the polyunsaturated fatty acids of these alkyl esters are selected from the group formed by eicosapentaenoic acid, docosahexaenoic acid, and/or mixtures thereof.

4. Pharmaceutical composition according to claim 1 , wherein the alkyl radical of these alkyl esters is selected from the group formed by short chain alkyl radicals, with from 1 to 8 carbon atoms.

5. Pharmaceutical composition according to claim 4, wherein the alkyl radical of these alkyl esters is selected from the group formed by ethyl, methyl, propyl, butyl and/or mixtures thereof. 6. Pharmaceutical composition according to claim 1 , wherein this oil contains more than 50% of polyunsaturated fatty acid alkyl esters.

7. Pharmaceutical composition according to claim 1 , wherein this beta- blocking active ingredient is selected from the group formed by acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, esatenolol, esmolol, indenolol, labetalol, landiolol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, talinolol, tertatolol, tilisolol, timolol, butoxamine, and/or their pharmaceutically acceptable salts. 8. Pharmaceutical composition according to claim 1 , wherein the polymer of these microcapsules is selected from the group formed by proteins, polyesters, polyacrylates, polycyanoacrylates, polysaccharides, polyethylene glycol and/or mixtures thereof.

9. Pharmaceutical composition according to claim 8, wherein the polymer of these microcapsules is selected from the group formed by gelatin, albumin, alginates, carrageenans, pectins, gum arabic, chitosan, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate-succinate, polyvinyl acetate phthalate, poly(8-caprolactone), poly(p-dioxanone), poly(5- valerolactone), poly(p-hydroxybutyrate), poly(p-hydroxybutyrate) and β- hydroxyvalerate copolymers, poly(p-hydroxypropionate), methacrylic acid copolymers, dimethylaminoethyl methacrylate copolymers, trimethylammonium ethyl methacrylate polymers, polymers and copolymers of the lactic and glycolic acids, polymers and copolymers of the lactic and glycolic acids and polyethylene glycol and/or mixtures thereof.

10. Pharmaceutical composition according to claim 1 , wherein these microcapsules represent between 0.001% and 80% of the total weight of the composition. 1. Pharmaceutical composition according to claim 1 , wherein the amount of the active pharmaceutical ingredient incorporated in these microcapsules is comprised between 1 % and 80% in weight.

12. Pharmaceutical composition according to claim 1 , wherein the polymer of these microcapsules contains at least a plasticizer, a fluidifying agent and/or an antioxidant.

13. Pharmaceutical composition according to claim 1 , which is presented in capsule form.

14. Pharmaceutical composition according to claim 13, wherein this capsule is a soft capsule.

15. Pharmaceutical composition according to claim 13, wherein the composition of the coating of this capsule is selected from the group formed by gelatin, hydroxypropyl methylcellulose, pullulan, modified starches, carrageenans and/or mixtures thereof.

16. Pharmaceutical composition according to claim 13, wherein this capsule comprises an enteric coating.

17. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases.

18. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for the treatment and/or prevention of disorders and/or pathologies selected from the group formed by alcohol withdrawal symptoms, anxiety disorders, hyperthyroidism, tremors, migraines, pheochromocytoma and/or bleeding of varicose veins associated with portal hypertension.