WO2014027334A2

WO2014027334A2 - Oral pharmaceutical composition in the form of microspheres and preparation method

Info

Publication number: WO2014027334A2
Application number: PCT/IB2013/056690
Authority: WO
Inventors: Gustavo BARRANCO HERNÁNDEZ; María del Coral LUNA GUIZA; Héctor SENOSIAIN ARROYO
Original assignee: Laboratorios Senosiain, S.A. De C.V.
Priority date: 2012-08-17
Filing date: 2013-08-16
Publication date: 2014-02-20
Also published as: MX2012009583A; PE20150710A1; MX351059B; CR20150077A; CO7310526A2; WO2014027334A3; DOP2015000028A; CL2015000375A1; GT201500035A

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 FORM. OF MICROSPHERAS 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 their 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 infraocular pressure among others. The substance that causes the elimination of water and sodium in the body through urine is called diuretics, these can be classified as diuretics, loop (by acting in the loop of renal Henle), Thiazides (thiazide derivatives), Carbonic anhydrase inhibitors, potassium-sparing, which can be of two kinds: Sodium channel inhibitors 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 conditions of neutral and relatively acidic pH, but it is not very 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 effects of water and sodium retention caused by some antihypertensive agents, and therefore, are commonly used in combination with the latter. In particular, thiazide diuretics also help relax the muscles in the walls of blood vessels, facilitating blood flow. In addition some clinical trials show that thiazide diuretics can help decrease mortality and morbidity due to 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 fixed administration dose of a combination of drugs, for example, in a capsule or tablet of daily administration, allows greater acceptance by the patient and promotes compliance with the treatment. Other advantages of combination therapy consist in that the adverse effects can be reduced, even generating 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 cannot 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 antagonist of angiotensin II receptor (ARB), 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 dose units, or in different portions of the same pharmaceutical form. Thus, the international application WO 2005/082329 refers to dosage forms comprising an active core of valsartan and a coating layer containing hydrochlorothiazide. Application No. US 20120114753 refers to a multilayer tablet comprising an effervescent layer with hydrochlorothiazide and a layer containing telmisartan. 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. Application WO2005048979 discloses a pharmaceutical composition consisting of a capsule comprising microtablets, which may contain different active ingredients, including hydrochlorothiazide and another antihypertensive.

The present invention constitutes an alternative to the compositions of the state of the art, by providing a hydrochlorothiazide composition with proven stability, in the form of microparticles, for example pellets or microspheres, which effectively resolves the incompatibility problems mentioned above. In the case of compositions for combined therapy, the microparticles of the present invention make it possible to handle the release of hydrochlorothiazide independently of the other active ingredients.

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

SUMMARY OF THE INVENTION The present invention allows to solve 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, allow to obtain a stable composition in the same dose unit. The great versatility of the microparticles of the present invention allows their use in a dose unit either alone or in combination with one or more active ingredients including, but not limited to: cholesterol absorption inhibitors; aldosterone antagonists; acyl-CoA cholesteryl transferase inhibitors; beta receptor blockers; angiotensin converting enzyme inhibitors; calcium channel inhibitors; angiotensin II receptor antagonists; alpha receptor blockers; renin inhibitors; anti-arrhythmia agents; antiplatelet agents; diuretics; dyslipidemic; HMG-CoA reductase inhibitors; thrombolytic agents; neutral endopeptidase inhibitors; and endogenous endothelin inhibitors, 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 modified release polymers, or polymeric shells that They provide protection to the microsphere of 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 modified release polymers, or polymeric shells that confer protection to the microsphere of factors such as moisture and light, among others.

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

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

In other embodiments, the present invention provides methods for treating and / or preventing a 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 spraying on the inert core, the layer comprises at least one active principle and at least one binder polymer, wherein the active principle is hydrochlorothiazide or another drug that has poor physicochemical stability under spray conditions. Optionally, the microparticles may include a water soluble or non-soluble, modified-release polymer coating (for example, immediate or modified release). It can also include a polymeric coating that confers protection from factors such as humidity and light, among others.

The process of formation of microspheres or pellets from inert cores commonly involves spraying on said inert cores 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 substance is very poor, because hydrochlorothiazide oxidizes very easily under these dissolution conditions. In addition, during the spray stages the active ingredient is generally subjected to high temperatures and high oxygen concentration, further favoring the oxidation of the active ingredient.

To solve the aforementioned 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 hydrochlorothiazide suspension, which must also comply with the conditions necessary 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 substance 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 ingredient, but sufficient to achieve a suitable coating. Similarly, a spray pressure of approximately 1 bar allows to achieve a suitable coating and at the same time reduce the amount of air (oxygen) that degrades the active substance.

Another characteristic of the process that allows to reduce the risk of oxidation is that the suspension that is applied has such a concentration of active ingredient, which allows the coverage to be applied very quickly, which reduces the exposure time of the active substance to the conditions that promote oxidation.

An important feature of the process of the present invention is that the step in which the active ingredient is dispersed until its adhesion on the inert core is instantaneous, whereby the deposited particle size 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 non-sticks;

2. Disperse the active substance 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 substance 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 on the microparticles.

Obviously, it is feasible to apply the process of the present invention to any active ingredient, but it is especially suitable for drugs that present the problem of physicochemical instability during the formation of the solution to be sprayed, for example, hydrochlorothiazide, vitamin Bl, vitamin B6, vitamin B12, rosuvastatin, simvastatin, amlodipine, lercanidipine, ezetimibe, famotidine, acetylsalicylic acid and azole group compounds. The microparticles of the present invention can be used to make compositions containing from 6.5 mg to 100 mg of hydrochlorothiazide per dose unit. The weight percentage of hydrochlorothiazide in the present composition is approximately 5 to 20%.

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

For example, a second layer consisting of a coating can 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 hydroxypropyl methylcellulose (HPMC) and Opadry®. The additional layer (s) can 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, citric acid esters, propylene glycol, HPC, HPMC, glycerin and diethyl phthalate. The inert nucleus of the microparticles is made of any pharmaceutically acceptable material, including but not limited to cellulose, sugars selected from lactose, glucose, dextrose or sucrose; or starch, or mixtures thereof. The adhesive or binder polymer is selected from hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (povidone), methacrylates, cellulose derivatives such as carboxymethyl cellulose, microcrystalline cellulose and methylcellulose, alginic acid and alginates, sucrose, gelatin, glucose, starch, polyethylene gum , polymethacrylates; hydroxypropyl cellulose (Klucel ®); ethyl cellulose (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. The Additional excipients contemplated in the present invention include, but are not limited to, vehicles, diluents, solubilizers, lubricants or glidants, surfactants, disintegrants and / or anti-sticks. Examples of solubilizers include 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 derivatives , cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers such as methoxy PEG; amides, such as ε-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, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone, β-butyrolactone acetamide, dimethyl isosorbide, N-methyl pyrrolidones and water, as well as mixtures thereof.

Possible lubricating or sliding agents 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, benzoate. sodium, 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 (copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecithins, sorbitan esters and fatty acids, polyoxyethylene sorbitan esters and fatty acids, Cremophor ^® , polyoxyethylene stearates, or combinations thereof.

Dyes, flavorings, sweeteners, antioxidants, preservatives, chelating agents, opacifiers and / or viscomodulators can also be used in the preparation of the pharmaceutical compositions of the present invention.

An advantage of the microspheres and pellets of the present invention is that it allows to obtain a product with a very good solution unlike commercial tablets. This is due to the fact that the contact area of the active ingredient available is larger 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 virtually any combination with other active principle (s) generating stable compositions. Hydrochlorothiazide and the additional drug (s) may be co-formulated as a single dose unit or may 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, multilayer), or 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-adherent, dyes, flavorings, sweeteners, antioxidants, preservatives, chelating agents, opacifiers, viscomodulators and mixtures thereof. For example, a dispersion or suspension of microspheres can be formed in water-miscible but non-aqueous liquid vehicles, such as alcohols, oils and polyethylene glycol, among others, and combinations thereof. Another example is the combination of 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 dose unit, or they can be formulated with other active ingredients in the same dose 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 may be coated with layers of another active ingredient (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 ingredient (s) and placed in the same dose unit; in another mode, 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 another active principle (s) are present in another dose unit, for example, tablet, capsule, sachet , suspension, solution or dispersion. In yet another embodiment, the microparticles of the present invention are formulated with another active principle in the same dose unit and other active principle (s) are present in another dose 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; acyl-CoA cholesteryl transferase inhibitors 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, philipylopa, thiliphilipropylimino, thymethylimino, mothylimono, pylimothylimino, pylimine, mothylimono, pylimine 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 aliskiren, detikirene, terlakirene and zankirene; anti-arrhythmia 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 aliskiren; dyslipidemic like fenofibrate, ezetimibe, colsevelam, laropiprant, dalcetrapib, sobetiroma and eprotiroma; HMG-CoA reductase inhibitors 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, azepinones, ecadotril, fasidotril, fasidotrilat, omapatrilat, sampatrilat, BMS 189921, Z 13752 A and the like; endogenous endothelin inhibitors; 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 telmisartan solution in soft gelatin capsules or hard gelatin capsules; b) hydrochlorothiazide microspheres with amlodipine microspheres (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 verapamil granules in the form of tablets; e) hydrochlorothiazide microspheres with telmisartan microspheres and lercanidipine microspheres in hard gelatin capsules; f) hydrochlorothiazide microspheres with a suspension of propanolol in soft gelatin capsules; g) hydrochlorothiazide microspheres with powder from a sartan 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) hard capsule hydrochlorothiazide microspheres.

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

Below are examples of compositions that employ the microspheres and pellets of the present invention:

Table 1. ORAL GENERAL FORMULATION.

Range of use of the ingredients in the composition% weight

COMPONENTS

Active ingredient 1.25 - 10

Inert cores 60 - 85

Adhesive or binder 6.0 - 8.0

Solvent plasticizer 0.6 - 0.9

Sliding lubricant 0.8 - 1.2

Cbp water

Capsule Table 2. ORAL GENERAL FORMULATION.

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 modalities described in the present application. Various modifications in addition to those described in this application will be apparent to a person with skill in the art from the above 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 unstable active substance at elevated temperatures and high oxygen concentration.

2. The pharmaceutical composition of claim 1, wherein the microparticles additionally include one or more layers selected from: modified release (immediate or delayed) cover (s), 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 cover (s) contains (n) acrylic polymers or cellulose derivatives and / or one or more plasticizers selected from citric acid esters, propylene glycol, HPC , HPMC, glycerin and diethylphthalate.

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 azole group compounds.

6. The pharmaceutical composition of the claim

5, wherein the active ingredient of the first layer is hydrochlorothiazide.

7. The pharmaceutical composition of the claim

6, wherein the weight percentage of hydrochlorothiazide is 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 the claim

1, wherein the adhesive or binder polymer is selected from HPMC, polyvinylpyrrolidone, methacrylates, cellulose derivatives such as carboxymethyl cellulose, microcrystalline cellulose and methyl cellulose, alginic acid and alginates, sucrose, gelatin, glucose, starch, polyethylene glycol, guar gum, polymethacrylate ; hydroxypropyl cellulose (Klucel ®); ethyl cellulose (Ethocel®) and pregelatinized starch, or mixtures thereof.

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

11. The pharmaceutical composition according to any one of the preceding claims, wherein the microparticles are in a pharmaceutical form selected from 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 carriers in the same dose 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 dose 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 active ingredient (s) additional (s).

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

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, ramipinodipino, spiraipinodipino, spiraipinodipino, spiraipinodipino, spirandino, spiraipinodipino, spiraipinodipino, spiraipinodipino, spiraipinodipino, spiraipinodipino, spirandino, spirandino, spiraipinodipropyl, felipinodipino, spiraipinodipino, spiraipinodipino, spiraipinodipino, spirandine, spiraipinodipino, spiraipinodipropyl, dipyprine nicardipine, niguldipine, niludipino, nimodipine, nisoldipine, nitrendipine, nivaldipine, ryosidine, anipamil, diltiazem, fendilino, flunarizino, gallopamil, mibefradil, prenilamino, tiapamil, verapamil, irbesartan, olmesartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, Telmisartan, valsartan, clonidine, doxazosin, methyldopa, terazosin, prazosin, aliskiren, detikirene, terlakirene, zankirene, adenosine, amiodarone, digoxin, disopyramide, flecamide, lidocaine, mexiletine, procainamide, quinidone glucanedin, quinidine, aspirin clopidogrel, danaparoid, deltaparin, denaparoid, ticlopidine, cilostazol, abciximab, eptifibatide, ti rofiban, defibrotide, enoxaparin, dipyridamole, tinzaparin, torsemide, ethacrynic acid, furosemide, spironolactone, ethacrynic acid, triamterene, indapamide, chlorothiazide, aliskiren, fenofibrate, ezetimibe, colsevelam, laropiptin, simropibrate, daropottin, simprovatin, simropoltin, attravastatin, simprovatin, attravastatin, simprovatin, attribatine, simprovatin, attribattin, simprovatin, attribattin, simoprivatin, attribrate, simoprivatin, simoprivatin, attribromine, daropottin, simoprivatin, attributtin, simropoltin, attribottin, simoptatin 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, hydrates, esters, hydrates 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, bilayer or multilayer tablets.

21. The pharmaceutical composition of claim 12, wherein the excipients or vehicles are selected from diluents, solvents, solubilizers, lubricants or glidants, disintegrants, surfactants, anti-adherent agents, colorants, flavorings, sweeteners, antioxidants, preservatives, chelating agents, opacifiers, viscomodulators 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, DL-leucine, polyethylene glycol, sodium acetate, SDS and magnesium lauryl sulfate, starch, carbonate of calcium, 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 (copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecithins, sorbitan esters and fatty acids, polyoxyethylene sorbitan esters and acids fatty, Cremophor ^® , polyoxyethylene stearates, or combinations thereof.

25. The pharmaceutical composition of the 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, polypropyl alcohol, polypropyl alcohol and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers such as methoxy PEG; amides, such as ε-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, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone, β-butyrolactone 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, to develop 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 of microparticle formation by sprinkling of inert nuclei comprising the following steps: a) Dissolve at least one binder polymer;

b) Disperse the active substance 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 step of dissolving 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 step of dissolving the binder polymer includes the addition of one or more antioxidants, surfactants, buffers, solubilizers, humectants, antistatics, lubricants and non-sticks.

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

32. The process of claim 28, wherein 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 azole group compounds.

34. The pharmaceutical composition of the claim

33, where the microspheres are placed in a hard or soft capsule.

35. The pharmaceutical composition of the claim

34, wherein the capsule also contains other particles containing one plus additional active ingredients selected from cardiovascular, antihypertensive or lipid lowering agents.