MX2012009583A

MX2012009583A - Oral pharmaceutical composition in the form of microspheres and preparation method.

Info

Publication number: MX2012009583A
Application number: MX2012009583A
Authority: MX
Inventors: Gustavo Barranco Hernández; María Del Coral Luna Guiza; Héctor Senosiain Arroyo
Original assignee: Senosiain S A De C V Lab
Priority date: 2012-08-17
Filing date: 2012-08-17
Publication date: 2014-02-26
Also published as: GT201500035A; MX351059B; WO2014027334A2; PE20150710A1; CR20150077A; CO7310526A2; DOP2015000028A; WO2014027334A3; CL2015000375A1

Abstract

A composition in the form of microparticles primarily made up of: a) an inert core; b) a layer of active principle formed by spraying onto the inert core, and c) optionally, a second coating comprising one or more layers of pharmaceutically acceptable excipient(s) and/or drug(s). Said composition may be used to treat conditions resulting from excessive retention of water and/or electrolytes, cardiovascular disease, renovascular disease, diabetes, endothelial dysfunction, cirrhosis, preeclampsia, nephropathy, peripheral vascular disease and hypertension, among others.

Description

ORAL PHARMACEUTICAL COMPOSITION IN THE FORM OF MICROSPHERES AND ELABORATION PROCESS FIELD OF THE INVENTION The present invention relates to a composition for oral administration in the form of microparticles, for example microspheres or pellets, as well as the process for its preparation. The invention also relates to a composition containing a diuretic and the use of the composition for the treatment of edema, cardiovascular disorders, hypertension, kidney damage, liver damage, among others.

BACKGROUND OF THE INVENTION Diuretics are a group of drugs used to treat various medical conditions, including edema, heart failure, hypertension, certain types of kidney and liver diseases, and increased intraocular pressure among others. It is called diuretic substance that causes a removal of water and sodium in the body through urine, these can be classified in diuretics, loop (by acting on the loop of Henle kidney), thiazide (thiazide derivatives), Carbonic anhydrase inhibitors, potassium-sparing, which can be of two kinds: Inhibitors of sodium channels and aldosterone antagonists, osmotic diuretics.

Hydrochlorothiazide (HCTZ) is a diuretic agent commonly used in the treatment of edema and hypertension. It is a white, odorless, crystalline powder. Its chemical name is 6-chloro-3,4-dihydro-2H-l, 2,4-benzothiadiazin-7-sulfonamide-1,1-dioxide. Its structural formula is: Hydrochlorothiazide is stable under neutral and relatively acid pH conditions, but is not stable in alkaline environments. Practically insoluble in water, poorly soluble in methanol and ethanol and soluble in sodium hydroxide.

Other examples of diuretics are: chlorothiazide, chlorthalidone, indapamide, metolazone, furosemide, bumetanide, torasemid, indapamide, bendroflumethiazine, amiloride and triamterene.

Diuretics reduce the water and sodium retention effects caused by some antihypertensive agents, and are therefore commonly used in combination with the latter. In particular, thiazide diuretics also help to relax the muscles in the walls of the vessels blood, facilitating blood flow. In addition, some clinical trials show that thiazide diuretics can help reduce mortality and morbidity from hypertension.

Hypertension frequently coexists with hyperlipidemia and both conditions are considered as the main risk factors for developing heart disease, a situation that also occurs in patients with metabolic syndrome. Therefore, it is beneficial to provide a single therapy for these diseases.

A dose of fixed administration of a combination of drugs, for example, in a capsule or tablet of daily administration, allows greater acceptance by the patient and favors compliance with the treatment. Other advantages of the combination therapy are that the adverse effects can be reduced, including the generation of additive or synergistic effects with the combination of two or more active ingredients, as well as prolonging the duration of the therapeutic effect. However, the instability of the active ingredients represents the main obstacle when combining these ingredients in the same pharmaceutical composition. It can not be predicted which dosage forms imply better product stability, pharmacological efficacy and reliable manufacturing method.

For example, a synergistic effect has been reported to treat blood pressure with the combination of thiazide diuretics such as hydrochlorothiazide and an angiotensin II receptor (ARB) antagonist, resulting in virtually no additional side effects. However, in the case of the combination of telmisartan and HCTZ, this approach is not feasible due to the incompatibility of HCTZ with basic compounds such as meglumine, which is a usual component of conventional telmisartan formulations.

One way to resolve the incompatibility between the active ingredients is to place them in different dosage units, or in different portions of the same pharmaceutical form. Thus, the international application WO 2005/082329 refers to dosage forms comprising an active nucleus of valsartan and a coating layer containing hydrochlorothiazide. Application No. US 20120114753 relates to a multilayer tablet comprising an effervescent layer with hydrochlorothiazide and a layer containing telmisartan. The application CN201020197929 refers to a capsule containing an amlodipine pill, a valsartan pill and a hydrochlorothiazide pill. The application WO2006067601 refers to a composition of irbesartan and hydrochlorothiazide in the form of microparticles in which a first phase of particles contains an active principle and a second phase of particles contains the other active principle. The application WO2005048979 discloses a pharmaceutical composition consisting of a capsule comprising microtablets, which may contain different active ingredients, including hydrochlorothiazide and another antihypertensive agent.

The present invention constitutes an alternative to the compositions of the state of the art, by providing a composition of hydrochlorothiazide with proven stability, in the form of microparticles, for example pellets or microspheres, which allows to effectively solve the incompatibility problems mentioned above. In the case of compositions for combination therapy, the microparticles of the present invention allow the release of hydrochlorothiazide to be handled independently of the other active ingredients.

On the other hand, the processes of formation of microspheres and pellets from inert nuclei commonly involve the spraying on the inert core of a solution formed by an adhesive polymer or binder and the active principle. However, hydrochlorothiazide is very easily oxidized under these spray conditions. The present invention successfully solves the aforementioned problem, thanks to an optimization of the spray conditions and to the formation of a suspension of active principle with a homogeneous particle size.

SUMMARY OF THE INVENTION The present invention allows solving the problems of physicochemical instability of hydrochlorothiazide during the spraying process to form microspheres or pellets. The microspheres and pellets of the present invention in turn allow solving the problem of incompatibility between active ingredients. The microparticles of the present invention are stable per se and when combined with other active ingredients, make it possible to obtain a stable composition in the same dosage unit. The great versatility of the microparticles of the present invention allows their use in a dosage unit either alone or in combination with one or more active ingredients including, but not limited to: inhibitors of cholesterol absorption; aldosterone antagonists; inhibitors of acyl-CoA cholesteryl transferase; beta receptor blockers; angiotensin-converting enzyme inhibitors; calcium channel inhibitors; angiotensin II receptor antagonists; alpha receptor blockers; renin inhibitors; antiarrhythmia agents; antiplatelet agents; diuretics; dyslipidemic; inhibitors of HMG-CoA reductase; thrombolytic agents; inhibitors of neutral endopeptidase; and inhibitors of endogenous endothelin, among others.

In a first embodiment, the present invention provides a pharmaceutical composition in the form of hydrochlorothiazide microspheres, optionally coated with one or more layers of polymers for modified release, or polymeric covers that give protection to the microsphere from factors such as humidity and light, among others.

In a second embodiment, the present invention provides a pharmaceutical composition in the form of hydrochlorothiazide pellets, optionally coated with one or more layers of polymers for modified release, or polymeric covers that give protection to the microsphere from factors such as humidity and light, among others.

In another embodiment, the present invention provides a pharmaceutical composition in the form of hydrochlorothiazide microspheres or pellets which may contain layers of other drugs including, but not limited to, cardiovascular, antihypertensive or lipid-lowering agents.

In another embodiment, the present invention provides a pharmaceutical composition in the form of microparticles (microspheres or pellets) of hydrochlorothiazide in combination with other microparticles (microspheres or pellets) of other drugs including, but not limited to, cardiovascular, antihypertensive or lipid-lowering agents.

In another embodiment, the present invention provides a pharmaceutical composition in the form of microparticles (microspheres or pellets) of hydrochlorothiazide in combination with other dosage units including, for example, granules, microspheres, powders, pellets, solutions, suspensions and microtablets, containing other additional drugs including, but not limited to, cardiovascular, antihypertensive or lipid-lowering agents.

In another embodiment, the present invention provides a pharmaceutical composition in the form of microparticles of hydrochlorothiazide in a first dose unit and one or more additional drugs in other dosage units, in the form of a pharmaceutical kit, wherein the additional drugs are, in a manner non-limiting, cardiovascular agents, antihypertensive agents and lipid-lowering agents.

In other embodiments, the present invention provides methods for treating and / or preventing cardiovascular disease comprising administering to a subject in need thereof, a pharmaceutical composition containing hydrochlorothiazide and optionally one or more cardiovascular, lipid lowering or antihypertensive agents.

DETAILED DESCRIPTION OF THE INVENTION The microparticles of the present invention comprise: (a) an inert core and (b) a layer formed by spray on the inert core, the layer comprises at least one active ingredient and at least one binder polymer, wherein the active ingredient is hydrochlorothiazide or another drug that exhibits poor physicochemical stability under spray conditions. Optionally, the microparticles can include a soluble or water insoluble, modified release polymer coating (e.g., immediate or modified release). It can also include a polymeric coating that provides protection from factors such as humidity and light, among others.

The process of forming microspheres or pellets from inert cores commonly involves spraying said inert cores with a solution formed by an adhesive or binder polymer and the active ingredient. However, in the particular case of hydrochlorothiazide, the solution is feasible, but the physicochemical stability of the active principle is very poor, because hydrochlorothiazide is very easily oxidized under these dissolution conditions. Furthermore, during the spraying stages, the active principle is generally subjected to high temperatures and high concentration of oxygen, further favoring the oxidation of the active principle.

To solve the mentioned stability problem, tests were carried out with different excipients under different conditions. From these results it was found that the solution to the problem of instability consists essentially in the formation of a suspension of hydrochlorothiazide, which must also comply with the necessary conditions for its subsequent spraying. For this, an additional stage of homogenization of the particle size was carried out.

Another fundamental factor to minimize the risk of degradation of the active principle, is the optimization of spray conditions. For example; it was found that a temperature of approximately 25 to 30 ° C is the minimum temperature necessary to avoid oxidation of the active principle, but sufficient to achieve an adequate coating. Likewise, a spray pressure of approximately 1 bar allows to achieve an adequate coating and at the same time reduce the amount of air (oxygen) that degrades the active principle.

Another feature of the process that reduces the risk of oxidation is that the suspension. that is applied has such concentration of active principle, which allows the application of the coverage very quickly, which decreases the time of exposure of the active principle to the conditions that promote oxidation.

An important feature of the process of the present invention is that the step in which the active principle is dispersed until its adhesion on the inert core, is instantaneous, whereby the particle size deposited is very small, approximately 15 microns.

This size allows to achieve a thickness of the cover on the inert core of approximately 40 to 50 microns.

The process for the preparation of the microspheres or pellets of the present invention is as follows: 1. Dissolve at least one binder polymer by mechanical agitation in a solvent selected from water, isopropyl alcohol, methylene chloride or other suitable vehicle. Optionally add solubilizing agents, antioxidants, surfactants, buffers, humectants, antistatics, lubricants and anti-adherents; 2. Disperse the active ingredient in the solution obtained in the previous step; 3. Uniformize the particle size of the previous dispersion by means of a homogenizer, obtaining a suspension in which the average particle size of the active principle is approximately 15 microns; 4. Sprinkle the suspension obtained from the previous step on the inert nuclei; 5. Optionally apply one or more modified release covers and / or protective covers over the microparticles.

Obviously, it is feasible to apply the process of the present invention to any active principle, but it is especially appropriate for drugs that present the problem of physicochemical instability during training of the solution to be sprinkled, for example, hydrochlorothiazide, vitamin Bl, vitamin B6, vitamin B12, rosuvastatin, simvastatin, amlodipine, lercanidipine, ezetimibe, famotidine, acetylsalicylic acid and compounds of the azole group.

The microparticles of the present invention can be used to make compositions containing from 6.5 mg to 100 mg of hydrochlorothiazide per unit dose. The weight percentage of hydrochlorothiazide in the present composition is from about 5 to 20%.

Optionally, the microparticles of the present invention can include one or more additional layers on the active ingredient layer, for example, retardant layer (s), enteric layer (s) and / or layers of another (s). ) the active substance (s) selected: inhibitors of cholesterol absorption; aldosterone antagonists; inhibitors of acyl-CoA cholesteryl transferase; beta receptor blockers; angiotensin-converting enzyme inhibitors; calcium channel inhibitors; angiotensin II receptor antagonists; alpha receptor blockers; renin inhibitors; antiarrhythmia agents; antiplatelet agents; diuretics; dyslipidemic; inhibitors of HMG-CoA reductase; thrombolytic agents; inhibitors of neutral endopeptidase; and inhibitors of endogenous endothelin.

For example, a second layer consisting of a coating may be included to improve the durability, appearance and / or handling of the composition of the pellets. Examples of polymers used in this second layer include, but are not limited to hydroxypropylmethylcellulose (HPMC) and Opadry®.

The additional layer (s) may also be formed with polymer (s) for modified release (immediate or delayed) using, for example, acrylic polymers or cellulose derivatives. An effective amount of one or more plasticizers may be included in the release modification layer, to improve the physical properties of said layer. Examples of plasticizers include, but are not limited to, esters of citric acid, propylene glycol, HPC, HPMC, glycerin and diethyl phthalate.

The inert core of the microparticles is comprised of any pharmaceutically acceptable material, including but not limited to cellulose, selected sugars of lactose, glucose, dextrose or sucrose; or starch, or mixtures thereof.

The adhesive polymer or binder is selected from hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (povidone), methacrylates, cellulose derivatives such as carboxymethylcellulose, microcrystalline cellulose and methylcellulose, alginic acid and alginates, sucrose, gelatin, glucose, starch, polyethylene glycol, guar gum, polymethacrylates; hydroxypropylcellulose (Klucel ®); ethylcellulose (Ethocel®) and pregelatinized starch, among others, as well as mixtures thereof.

The pharmaceutical compositions of the present invention may include additional excipients to improve handling, processing properties and / or dissolution properties of the active ingredient. Additional excipients contemplated by the present invention include, but are not limited to, vehicles, diluents, solubilizers, lubricants or glidants, surfactants, disintegrants and / or anti-adrends.

Examples of solubilizers are alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, butanediols, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl, polyethylene glycol, propylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives. , cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers such as methoxy PEG; amides, such as e-caprolactam, N-alkylpyrrolidone, DI-hydroxyalkylpyrrolidone, N-alkylpiperidone, Dialkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, ethyl oleate, ethyl caprylate, butyrate ethyl, propylene glycol monoacetate, propylene glycol diacetate, e-caprolactone and its isomers, d-valerolactone and its isomers, β-butyrolactone and isomers, dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones and water, as well as mixtures thereof.

Possible lubricants or glidants include, but are not limited to, glyceryl behenate, metal stearates (e.g., magnesium stearate, calcium and sodium), stearic acid, hydrogenated vegetable oils, talc, waxes, boric acid, sodium benzoate , sodium acetate, sodium chloride, DL-leucine, polyethylene glycol, sodium acetate, SDS, magnesium lauryl sulfate, starch, calcium carbonate, calcium phosphate, titanium dioxide or combinations thereof.

The surfactants of the present invention include but are not limited to: sodium lauryl sulfate, poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthetic lecithins, sorbitan esters and fatty acids, polyoxyethylene sorbitan esters and fatty acids, Cremophor®, polyoxyethylene stearates, or combinations thereof.

Dyes, flavors, sweeteners, antioxidants, etc. can also be used in the preparation of the pharmaceutical compositions of the present invention. conservatives, chelating agents, opacifiers and / or viscometers.

An advantage of the microspheres and pellets of the present invention is that it makes it possible to obtain a product with a very good dissolution, unlike commercial tablets. This is because the contact area of the available active ingredient is greater than in the case of a tablet, which allows to improve the dissolution of the drug. This property is particularly useful when it comes to active ingredients with low solubility, such as lercanidipine and telmisartan.

An additional advantage of the microparticles of the present invention is that the release of the active ingredients can be handled independently even when they are in the same dose unit.

Another advantage of the microparticles of the present application consists in the versatility to form practically any combination with other active principle (s) generating stable compositions.

Hydrochlorothiazide and. The additional drug (s) can be co-formulated as a single dose unit or can be formulated as two or more dose units for coordinated, combined or concomitant administration.

The microspheres and pellets of the present invention can be placed in a pharmaceutical form suitable for oral administration, for example, hard or soft capsules. The microspheres can also be compressed to form tablets (coated tablets, bilayer, muíticapa), or be placed in sachets or processed to form granules, dispersions or suspensions. The capsules can be formed, for example, from gelatin or HPMC.

The microparticles of the present invention can be combined with pharmaceutically acceptable carriers or excipients selected from solvents, diluents, solubilizers, lubricants or glidants, disintegrants, surfactants, anti-adherents, colorants, flavors, sweeteners, antioxidants, preservatives, chelating agents, opacifiers, viscometers and mixtures thereof. For example, a dispersion or suspension of microspheres can be formed in liquid vehicles miscible in water but non-aqueous in nature, such as alcohols, oils and polyethylene glycol, among others, and combinations thereof. Another example consists of combining the microspheres with powders such as talc or other solid excipients. The dispersion, suspension or mixture of microspheres with powders can be placed in a gelatin capsule, HPMC capsule, sachet or other suitable dosage form.

The microparticles of the present invention can be formulated in a dosage unit, or can be co-formulated with other active ingredients in the same dosage unit, or even formulated individually in separate dose units as a pharmaceutical kit.

When it is desired to co-administer two or more active ingredients, the microspheres or pellets in one embodiment can be coated with layers of other active principle (s). In another embodiment, the microspheres or pellets of the present invention can be combined with other pharmaceutical compositions in the form of suspensions, solutions, dispersions, pellets, granules, microspheres, powders, microcapsules, etc. containing another active principle (s) and placed in the same dose unit; in another embodiment, when it is desired to co-administer two or more separate units, the HCTZ microparticles are present in a first unit, for example a capsule or tablet, and other active principle (s) are present in another dosage unit, for example, tablet, capsule, sachet, suspension, solution or dispersion. In still another embodiment, the microparticles of the present invention are formulated with another active ingredient in the same dosage unit and other active principle (s) are present in another dosage unit.

Examples of other active ingredients that can be used in combination with the microparticles of the present invention are one or more of: cholesterol absorption inhibitors such as ezetimibe, and simvastatin; aldosterone antagonists such as eplerenone and aldactone; inhibitors of acyl-CoA cholesteryl transferase such as CI-1011 (Avasimibe, Pfizer) and CS-505 (Pactimibe sulfate, Sankyo Pharma); beta receptor blockers such as atenolol, acebutolol, carvediol, nadolol, nevibolol, pindolol and propranolol; ACE inhibitors such as enalapril, lisinopril, benazepril, captopril, cilazapril, enaliprilat, trandolapril, moexipril, fentiapril, fosinopril, indopril, lisonopril, moexipril, perindopril, quinapril, ramipril and spirapril; calcium channel inhibitors such as lercanidipine, amlodipine, nifedipine, felodipine, isradipine, lacidipine, nicardipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, riosidine, anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamino, tiapamil and verapamil; angiotensin II receptor antagonists such as irbesartan, olmesartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, telmisartan and valsartan, alpha receptor blockers such as clonidine, doxazosin, methyldopa, terazosin and prazosin; renin inhibitors such as aliskirene, detikirene, terlakirene and zankireno; antiarrhythmia agents such as adenosine, amiodarone, digoxin, disopyramide, flecamide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride and tocamide; antiplatelet agents such as aspirin, adeparin, clopidogrel, danaparoid, deltaparin, denaparoid, ticlopidine, cilostazol, abciximab, eptifibatide, tirofiban, defibrotide, enoxaparin, dipyridamole, and tinzaparin; other diuretics such as torsemide, ethacrynic acid, furosemide, spironolactone, ethacrynic acid, triamterene, indapamide, chlorothiazide and aliskirene; dyslipidemics such as fenofibrate, ezetimibe, colsevelam, laropiprant, dalcetrapib, sobetiroma and eprotiroma; inhibitors of HMG-CoA reductase such as atorvastatin, simvastatin, lovastatin, fluvastatin, pravastatin, rosuvastatin and mevastatin; thrombolytic agents such as fondoparinux, dalteparin, enoxaparin, apixaban and PD-348292; neutral endopeptidase inhibitors such as diazapine, azepinone, ecadotril, fasidotril, fasidotrilat, omapatrilat, sampatrilat, BMS 189921, z 13752 A and the like; inhibitors of endogenous endothelin; as well as its salts, hydrates, solvates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs and derivatives of any of the above drugs. The combinations can be formed with two, three or more active ingredients.

Examples of drug combinations are presented below: a) amlodipine pellets dispersed in a solution of telmisartan in soft gelatine capsules or hard gelatine capsules; b) hydrochlorothiazide microspheres with microspheres of amlodipine (besylate or camsylate or isomers thereof) or lercanidipine or lercarnidipine hydrochloride in capsules; c) hydrochlorothiazide microspheres with pellets from a sartan selected from olmesartan, telmisartan, losartan and candesartan, in gelatin capsules d) Ezetimibe pellets with granules of verapamil in the form of tablets; e) hydrochlorothiazide microspheres with telmisartan microspheres and lercanidipine microspheres in hard gelatin capsules; f) hydrochlorothiazide microspheres with a propranolol suspension in soft gelatin capsules; g) hydrochlorothiazide microspheres with a sartan powder selected from olmesartan, telmisartan, losartan and candesartan in the form of tablets; h) microspheres with a first layer containing hydrochlorothiazide and a second layer containing telmisartan in hard gelatin capsules; i) hydrochlorothiazide microspheres in hard capsule.

The microparticles of the present invention can also be combined with another active principle (s) such as those described above, in the form of a kit.

Following are examples of compositions employing the microspheres and pellets of the present invention: Table 1. ORAL GENERAL FORMULATION.

ORAL GENERAL FORMULATION Range of use of the ingredients Table 3 SPECIFIC FORMULATION. TO.

The pharmaceutical composition or dosage forms of the present invention can be administered to a subject in need of treatment of (a) conditions resulting from excessive retention of water and / or electrolytes; (b) cardiovascular diseases; (c) renovascular diseases; (d) diabetes; (e) endothelial dysfunctions; (g) cirrhosis; (h) preeclampsia; (i) nephropathy; (j) peripheral vascular disease; (k) hypertension, among others.

The present invention is not limited by the scope of the specific embodiments described in the present application. Various modifications in addition to those described in the present application will be apparent to a person skilled in the art from the foregoing description and are within the scope of the appended claims.

Claims

1. A pharmaceutical composition in the form of microparticles comprising: (a) an inert core and (b) at least one first layer of active ingredient formed by spraying on the inert core, wherein the first layer comprises at least one adhesive polymer or binder and at least one active ingredient unstable at high temperatures and high concentration of oxygen.

2. The pharmaceutical composition of claim 1, wherein the microparticles further include one or more layers selected from: modified release coating (s) (immediate or delayed), enteric layer (s), protective cover (s) (s) ), coating to improve the durability, appearance and / or handling of the microsphere composition, and cover (s) with one or more additional active ingredients.

3. The pharmaceutical composition of claim 2, wherein the modified release coating (s) contains (s) acrylic polymers or cellulose derivatives and / or one or more piastifiers selected from esters of citric acid, propylene glycol, HPC, HPMC , glycerin and diethyl phthalate.

4. The pharmaceutical composition of claim 2, wherein the coating includes HPMC and / or Opadry®.

5. The composition of claim 1, wherein the active ingredient of the first layer is selected from: hydrochlorothiazide, vitamin Bl, vitamin B6, vitamin B12, rosuvastatin, simvastatin, amlodipine, lercanidipine, ezetimibe, famotidine, acetylsalicylic acid and compounds of the group of the azoles.

6. The pharmaceutical composition of claim 5, wherein the active ingredient of the first layer is hydrochlorothiazide.

7. The pharmaceutical composition of claim 6, wherein the weight percentage of hydrochlorothiazide is from 5 to 20%.

8. The pharmaceutical composition of claim 1, wherein the inert core is constituted of a material selected from cellulose, starch, lactose, glucose, dextrose, sucrose, or mixtures thereof.

9. The pharmaceutical composition of claim 1, wherein the adhesive polymer or binder is selected from HPMC, polyvinylpyrrolidone, methacrylates, cellulose derivatives such as for example carboxymethylcellulose, microcrystalline cellulose and methylcellulose, alginic acid and alginates, sucrose, gelatin, glucose, starch, polyethylene glycol, guar gum, polymethacrylates; hydroxypropylcellulose (Klucel ®); ethylcellulose (Ethocel®) and pregelatinized starch, or mixtures thereof.

10. The pharmaceutical composition according to any of the preceding claims, which further includes excipients selected from vehicles, diluents, solubilizers, lubricants or glidants, disintegrants, surfactants, anti-adherents, colorants, flavors, sweeteners, antioxidants, preservatives, chelating agents, opacifiers. , viscommodulators and mixtures thereof.

11. The pharmaceutical composition according to any of the preceding claims, wherein the microparticles are in a selected pharmaceutical form of hard or soft capsules, tablets, sachets, granules, dispersions and suspensions.

12. The pharmaceutical composition according to any of the preceding claims, wherein the microparticles are combined with one or more pharmaceutically acceptable excipients or vehicles in the same dosage unit.

13. The pharmaceutical composition according to any of the preceding claims, wherein the microparticles are co-formulated with one or more additional active ingredients in the same dosage unit.

14. The pharmaceutical composition of claim 11 for use in a pharmaceutical kit with at least one other separate pharmaceutical unit selected from hard or soft capsule, tablet, sachet, suspension, solution and dispersion, which contains additional active ingredient (s) ( is ) .

15. The pharmaceutical composition of claims 13 or 14, wherein the additional active ingredient (s) is also in the form of microparticles.

16. The pharmaceutical composition of claims 13 or 14, wherein the additional drugs are in the form of granules, powders, pellets, solutions, suspensions, dispersions, microtablets, microspheres and microcapsules.

17. The pharmaceutical composition according to any of claims 2, 13 or 14, wherein the additional active ingredient (s) is selected from: inhibitors of cholesterol absorption; aldosterone antagonists; inhibitors of acyl-CoA cholesteryl transferase; beta receptor blockers; angiotensin-converting enzyme inhibitors; calcium channel inhibitors; angiotensin II receptor antagonists; alpha receptor blockers; renin inhibitors; antiarrhythmia agents; antiplatelet agents; diuretics; dyslipidemic; inhibitors of HMG-CoA reductase; agents thrombolytics; inhibitors of neutral endopeptidase; and inhibitors of endogenous endothelin.

18. The pharmaceutical composition according to any of claims 2, 13 or 14, wherein the additional active ingredients are selected from: avasimibe, pactimibe sulfate, ezetimibe, simvastatin, eplerenone, aldactone, atenolol, acebutolol, carvediol, nadolol, nevibolol, pindolol, propranolol , enalapril, lisinopril, benazepril, captopril, cilazapril, enaliprilat, trandolapril, moexipril, fentiapril, fosinopril, indopril, lisonopril, moexipril, perindopril, quinapril, ramipril and spirapril, lercanidipine, amlodipine, nifedipine, felodipine, isradipine, lacidipine, nicardipine, niguldipine , niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, riosidine, anipamil, diltiazem, fendilino, flunarizine, gallopamil, mibefradil, phenylamino, tiapamil, verapamil, irbesartan, olmesartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, telmisartan, valsartan , clonidine, doxazosin, methyldopa, terazosin, prazosin, aliskiren, detikireno, terlakireno, zan kirene, adenosine, amiodarone, digoxin, disopyramide, flecamide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, tocamide, aspirin, adeparin, clopidogrel, danaparoid, deltaparin, denaparoid, ticlopidine, cilostazol, abciximab, eptifibatide, tirofiban, defibrotide, enoxaparin, dipyridamole, tinzaparin, torsemide, ethacrynic acid, furosemide, spironolactone, ethacrynic acid, triamterene, indapamide, chlorothiazide, aliskirene, fenofibrate, ezetimibe, colsevelam, laropiprant, dalcetrapib, sobetiroma, eprotiroma, atorvastatin, simvastatin, lovastatin, fluvastatin, pravastatin, rosuvastatin, mevastatin, fondoparinux, dalteparin, enoxaparin, apixaban, PD-348292 , ecadotril, fasidotril, fasidotrilat, omapatrilat, sampatrilat, BMS 189921 and Z 13752 A, as well as their salts, hydrates, solvates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs and derivatives of any of the above drugs.

19. The pharmaceutical composition of any of claims 11 or 14, wherein the capsules are formed of gelatin or HPMC.

20. The pharmaceutical composition of any of claims 11 or 14, wherein the tablets are coated tablets, bilayer or multilayer.

21. The pharmaceutical composition of claim 12, wherein the excipients or vehicles are selected from diluents, solvents, solubilizers, lubricants or glidants, disintegrants, surfactants, anti-adherents, colorants, flavors, sweeteners, antioxidants, preservatives, chelating agents, opacifiers, viscometers and mixtures thereof.

22. The pharmaceutical composition of claim 12, wherein the vehicles are selected from alcohols, oils and polyethylene glycol and mixtures thereof.

23. The pharmaceutical composition of claim 10 or 21, wherein the lubricants or glidants are selected from glyceryl behenate, metal stearates, stearic acid, hydrogenated vegetable oils, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, sodium, DL-leucine, polyethylene glycol, sodium acetate, SDS and magnesium lauryl sulfate, starch, calcium carbonate, calcium phosphate, titanium dioxide or combinations thereof.

24. The pharmaceutical composition of claim 10 or 21, wherein the surfactants are selected from sodium lauryl sulfate, poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthetic lecithins, sorbitan and fatty acid esters, polyoxyethylene sorbitan esters and fatty acids, Cremophor®, polyoxyethylene stearates, or combinations thereof.

25. The pharmaceutical composition of claim 10 or 21, wherein the solubilizers are selected from alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl, polyethylene glycol. , polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers such as methoxy PEG; amides, such as e-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, propylene glycol monoacetate, propylene glycol diacetate, e-caprolactone and its isomers, d-valerolactone and its isomers, β-butyrolactone and isomers, dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones and water, as well as mixtures thereof.

26. The pharmaceutical composition according to any of the preceding claims, wherein the microparticles are selected from microspheres and pellets.

27. The use of the pharmaceutical composition according to any of the preceding claims, for preparing a medicament useful for treating and / or preventing (a) conditions resulting from excessive retention of water and / or electrolytes; (b) cardiovascular diseases; (c) renovascular diseases; (d) diabetes; (e) endothelial dysfunctions, - (g) cirrhosis; (h) preeclampsia; (i) nephropathy; (j) peripheral vascular disease; and (k) hypertension.

28. A process for forming microparticles by spraying inert nuclei comprising the following steps: a) Dissolve at least one binder polymer; b) Disperse the active ingredient in the solution obtained in the previous step; c) Uniformize the particle size of the previous dispersion by means of a homogenizer to obtain a suspension; Y d) Sprinkle the suspension obtained from the previous step on the inert nuclei.

29. The process of claim 28, wherein the dissolving step of the binder polymer is carried out in a solvent selected from water, isopropyl alcohol, methylene chloride or other suitable vehicle.

30. The process of claim 28, wherein the dissolving step of the binder polymer includes the addition of one or more antioxidants, surfactants, buffers, solubilizers, humectants, antistats, lubricants and anti-adherents.

31. The process of claim 28, which further includes the step of applying to the obtained microsphere, one or more layers selected from: modified release covers, protective covers, layers retardants, enteric layers and / or layers of other active principles.

32. The process of claim 28, where the spray temperature is about 25 to 30 ° C and the spray pressure is about 1 bar.

33. A pharmaceutical composition in the form of microspheres comprising: (a) an inert core and (b) at least one first layer of active ingredient formed by spraying on the inert core, wherein the first layer comprises at least one adhesive polymer or binder and wherein the active ingredient is selected from hydrochlorothiazide, vitamin Bl, vitamin B6, vitamin B12, rosuvastatin, simvastatin, amlodipine, lercanidipine, ezetimibe, famotidine, acetylsalicylic acid and compounds of the azole group.

34. The pharmaceutical composition of claim 33, wherein the microspheres are placed in a hard or soft capsule.

35. The pharmaceutical composition of claim 34, wherein the capsule further contains other particles that contain one or more additional active ingredients selected from cardiovascular, antihypertensive or lipid-lowering agents.