WO2011034513A1

WO2011034513A1 - The granules with improved solubility and stability

Info

Publication number: WO2011034513A1
Application number: PCT/TR2010/000167
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2009-08-17
Filing date: 2010-08-13
Publication date: 2011-03-24
Also published as: EP2467129A1; TR200906322A2

Abstract

The present invention is related to the pharmaceutical compositions with improved solubility and stability properties comprising ramipril alone or in combination with a therapeutic agent such as HCTZ, preparation methods of these compositions and their medical use.

Description

THE GRANULES WITH IMPROVED SOLUBILITY AND STABILITY

Field of the Invention

The present invention relates to pharmaceutical compositions with improved solubility and stability comprising ramipril alone or in combination with a therapeutic agent like HCTZ, the preparation methods of these compositions and their medical usages.

Background of the Invention

The present invention provides a composition which is effective for the treatment of hypertension and congestive heart failure and for the reduction in mortality risk relative to paralysis, cardiovascular and myocardial infarction. This effect provided by the composition that is prepared in accordance with the invention is named as "desired effect" during the patent. Defined composition comprises ramipril as an antihypertensive agent alone or in combination with hydrochlorothiazide (HCTZ) which is a diuretic.

Inhibition of renin-angiotensin system has proved to be the most suitable method for the treatment of hypertension and congestive heart failure and the reduction in mortality risk relative to paralysis, cardiovascular and myocardial infarction. Among the medication used for this purpose usage of the angiotensin converting enzyme (ACE) inhibitors like ramipril are commonly preferred. Said drugs can be combined with other therapeutic agent and/or agents for the increasing effectiveness. For instance, when an angiotensin II (AT-II) receptor antagonist, which is also used as renin-angiotensin system inhibitor, is used with ACE inhibitors, it shows a synergic effect although their mechanisms of action are different. Similarly, the diuretics like HCTZ also increase the effectiveness of ACE inhibitors.

Chemical name of ramipril is (2S,3aS,6aS)-l-[[(S)-2-[(S)-l-ethoxycarbonyl-3- phenylpropyl]amino]propanoyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid (Formula

I)-

(I) Ramipril is first described in the patent numbered US5061722 A (, patents numbered EP0079022 A2, EP0150263 Al, US4727160 A, US4879403 A ve US5053519 A are present in its patent family). The patent discloses, processes for preparing ramipril, pharmaceutical compositions comprising ramipril and the usage of ramipril as ACE inhibitor.

Ramipril is an angiotensin converting enzyme (ACE) inhibitor that is used to treat hypertension and congestive heart failure. Ramipril is an inactive prodrug and is converted to the active metabolite ramiprilate in the liver. AT-II, is synthesized from AT-I by a reaction catalyzed by ACE. Ramipril competes with AT-I for binding to ACE and blocks the conversion of AT-I to AT-II. AT-II has some effects such as vasodilation, stimulation of the production and secretion of aldosterone, cardiac stimulation and the increase in the reabsorption of sodium from kidney tubulus. Since ramipril decreases the level of AT-II in the plasma, blood pressure decreases and the activity of plasma renin increases. Depending on reducing the secretion of aldosterone, sodium and water retention decreases and the potassium level increases slightly. Total peripheral resistance, renovascular resistance and left ventricle hypertrophy decrease.

HCTZ is a thiazide derivative diuretic with a chemical name of 6-chloro-3,4-dihydro-2H- l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide. (Formula II).

HCTZ has been firstly described in the patent numbered US3025292. In the patent, there are processes to prepare HCTZ.

HCTZ is a thiazide derivative diuretic which is used in the treatment of edema and hypertension. Thiazide derivative diuretic increases elimination of sodium, chloride and water by inhibing the passage of sodium from kidney tubulus. The diuretic effect of HCTZ indirectly decreases the plasma volume with the elevations of plasma renin activity, aldosterone secretion and loss of urinary potassium and with the decreases of serum potassium level. The connection of renin-aldosterone comes through angiotensin II. For this reason, the use of diuretics with angiotensin II receptor antagonist has a tendency to reverse potassium loss caused by diuretics. Thiazides generally do not influence blood pressure. At the beginning, they lower blood pressure by decreasing cardiac flow rate and lowering plasma and extracellular fluid volume. When the theraphy continues for a couple of weeks, lowered plasma volume slowly gets back to normal levels, however hypotensive effect continues. The diuresis starts 2 hours after orally taking HCTZ, reachs to the maximum level approximately in 4 hours and comes to an end in between 6-12 hours.

It is proved that the usage of of ramipril alone or in combination with some therapeutic agents like HCTZ is effective in the treatment of cardiovascular diseases and in the reduction of the mortality risk originating from cardiovascular diseases with some clinical researches : · Breitstadt A., Cairns V., et al. Short report: Ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. Journal of Hypertension 1993; 11 (2).

• Vuong A. D. Ramipril for the Prevention and Treatment of Cardiovascular Disease. The Annals of Pharmacother py 37 (3), pp. 412-419. · Tsouli S. G. Combined Treatment With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers: A Review of the Current Evidence. Journal of Cardiovascular Pharmacology and Therapeutics 2006; 11 (1), pp. 1-15.

The present invention is related to obtaining pharmaceutical compositions which have rampril alone or in combination with therapeutic agents like HCTZ and provides the desired effect. To achieve the desired effect, an aspect of the invention is to formulate this agent as a pharmaceutical form like tablet by providing a formulation in accordance with the invention comprising a pharmaceutically acceptable, non-toxic and therapeutically effective amount of rampril. Said composition can further comprise pharmaceutically acceptable, non-toxic and therapeutically effective amount of HCTZ. The prodrugs that are used orally should be designed in a way that increase the oral bioavailability of the drug and enable the drug reach the target. However, in the mean time the biological activity should be protected. For this purpose, the oil solubility, water solubility, partition coefficient and stability of the drug should be optimized. Prodrugs that are used orally are classified as salts having low solubility, the oil soluble (lipophilic) prodrugs including esters or complexes, the water soluble prodrugs including highly soluble salts, esters or complexes. The diffusion coeeficient which depends on the oil-solubility of the drug plays an important role in the inhibition of ACE. Therefore, the most common method used for increasing the oil-solubility of the drug is the usage of the lipophilic esters whose ester part diffuses into tissues much easily. However, the water-solubility of the lipophilic esters is low, thus their oral bio-avaliability is low. Ramipril is also a lipophilic ester having low water-solubility.

One of the most common method to solve the solubility problems of low soluable drugs like ramipril is to decrease the particle size of the drug. Since the dissolution rate of a solid generally depends on the surface area and the surface area of the substance increases with the decrease in the particle size, decreasing particle size can increase the dissolution rate. On the other hand, decreasing particle size may not always effect the dissolution rate of the drug. Because hydrophobic drugs like ramipril, which are converted into larger particles during the production process of the pharmaceutical dosage form, depending on the decrease in the active surface area, they tend to agglomerate robustly.

Another method used for increasing surface area of the drug is nanoparticle technology. However, this technology faces some problems such as the technical and mechanical restraints preventing the drug particles from breaking into nanoparticles and problems like the stabilization of quite small drug particles.

In the patent applications numbered US20080188539 Al, US20080171775 Al and US20080167364 Al are related to an aminoacid, amlodipine and amine salt of ramipril, respectively. Generally, it is claimed that the salt forms of ramipril increase the solubility, dissolution and/or hygroscopicity, provide the stability and improve the tableting properties. However, it is not certain that these salts are equal to free acid in the sense of therapeutical activity and safety.

The patent applications numbered US20080188539 Al, US20080171775 Al and US20080167364 Al are respectively related to; the capsules that are composed of micro- tablets including a ACE inhibitor, the controlled release formulations comprising microcapsules, fast disintegrating ramipril formulations and ramipril formulations comprising a controlled release agent, respectively. Generally, the patent applications increase bioavailability of drug by changing its release properties in the applications. However, changing the release properties only for improving tableting properties is not a preferable method. Another method used for increasing absorption, thus bio-availability is to use the additional substances like absorption increasing agent and metabolism inhibitor. However, absoption enhancers can cause mucosal damage and systemic toxicity. Although choosing metabolism inhibitors from the foods is a good aletrnative in the sense of cost and clinical suitability, it is not certain that the foods will provide the desired effectiveness.

The other methods used for increasing oral bio-avaliability of a drug having low solubility are ion duplication and complex formation. On the other hand, said methods are not applicable for all drugs and it requires a complex production process.

For these reasons, new methods are necessary to solve solubility problems of the drugs having low solubility like ramipril.

Ramipril faces with stability problem in addition to the solubility problem. The formulations comprising ramipril tend to degrade when exposed to heat, light, air, moisture and mechanic effect, in unsuitable conditions and as a consequence of some interactions.

There are some formulation suggestions related to controlling moisture for developing the stability in the known method. The patent application numbered WO2004064809 Al is related to the pharmaceutical compositions having low moisture content that are composed of ramipril and/or a salt and at least one excipient. The patent application numbered WO2008000040 Al is related to the pharmaceutical compositions comprising an ACE inhibitor or a salt, a basic stabilizing agent, auxiliary agents and also moisture controller substances.

Another preferable method for increasing stability is to add into the composition some substance that will slow down or decrease the degradation of the composition. For this purpose, the patent applications numbered WO2003028707 Al , US2005069586 Al, WO2008132756 Al, WO9962560 A1, US20060188568 Al, US20080038342 Al and US20080234353 Al are related to the formulations comprising lactose monohydrate, a lubricant, lactic acid with magnesium salts, hydrolysis minimizing agent with magnesium oxide, meglumine, a Ci6-C₂8 glyceride and sodium hydrogen carbonate with calcium sulfate dihydrate, respectively.

There are some formulation suggestions in which the carbonate salts of some substances are used as stabilizing agent. The patent applications numbered WO2005011737 A2, US20030215526 Al, US4743450 A and WO03059388 Al are related to the formulations comprising at least one saccharide and at least one amino acid carbonate salt; one alkali metal or alkaline earth metal carbonate and one carrier; one alkali metal or alkaline earth metal carbonate and one saccharite; alkaline earth metal carbonate and insoluable alkali metal salt of hydrogen phosphate and one alkali metal or alkaline earth metal carbonate, respectively.

There are also some formulation suggestions concerning that some polymers are used in order to increase stability. The patent applications numbered WO2008133537 Al ve US20060045911 Al are respctively related to the formulations including basic copolymers of butyl methacrylate and amoniamethacrylate copolymers in a suitable carrier medium.

Moreover, there are some patent applications in which production methods that provide stability are developed. The patent applications numbered US2006134213 Al, US20050202081 Al, US5151433 A ve US20030225124 Al are related to the pharmaceutical compositions containing ramipril covered by blending agent, the pharmaceutical compositions comprising pressed tablets coated by at least one ACE inhibitor, the pharmaceutical compositions wherein granulated ramipril is stabilized by a coating with a polymeric preserving agent and a production method where a metal compund is added to the dispersion obtained by mixing a ACE inhibitor and an alcohol, respectively.

Abovementioned patent applications or patents are only related to some methods for increasing stability and do not focus on the solubility problem of ramipril. Therefore, new methods are required for solving both solubility and stability problems of ramipril.

Unlike ramipril, HCTZ is a substance that can be dissolved in aqueous solutions easily. However, it is incompatible with basic agents. Therefore, for the combination of ramipril and HCTZ, in addition to the stability and solubility problems of ramipril the incompatibility between the substances forming the composition emerges. Because, when basic agents increasing ramipril stability interact with HCTZ, it leads to incompatibility. Due to the incompatibility, the stability problem is observed in the tablets. In current state of the art, there are some formulation suggestions about the combination of ramipril and HCTZ. The patent application numbered US20070116762 Al is related to pharmaceutical compositions including rampril coated by a blending agent and HCTZ as an active agent. Furthermore, the patent application numbered WO2008001 184 A2 is related to pharmaceutical compositions containing a ACE inhibitor in blended or pellet form and a diuretic in tablet form . In said applications, the combinations in which some methods are employed to solve the stability problem of ramipril are described however, solubility problem of ramipril is not considered. Therefore, it is necessary to search for new methods aimed at solving both the solubility and stability problems of ramipril and prevent a probable compatibility problem in case HCTZ is included in the formulation.

The present invention presents a new composition for formulating ramipril without any solubility or stability problems or combining ramipril and HCTZ without any incompatibility problem and an uncomplicated production method.

Summary of the Invention

The present invention is related to a pharmaceutical composition comprising a therapeutically effective amount of ramipril alone or in combination with a therapeutically effective amount of HCTZ for use in the production of an effective drug for the treatment of hypertension and congestive heart failure and the reduction in mortality risk relative to paralysis, cardiovascular and myocardial infarction, characterized in that in said pharmaceutical composition the microcrystalline cellulose granules are coated by a coating solution which comprises ramipril dissolved said solution and that it has improved solubility and stability properties.

The method for the preparation of pharmaceutical formulations, which are suitable for the present invention and include ramipril alone, contains the following steps:

1. The granulation solution is obtained by dissolving ramipril in pharmaceutically acceptable binding agents chosen from an alcohol, ketone, cellulose derivative, water or a mixture of them, more preferably 1-propanol, 2-propanol, ethyl alcohol, acetone, HPMC, water or a pure solvent or solvent mixture which is a mixture of them;

2. The granules coated with ramipril is obtained by spraying the granulation solution mentioned in Step 1 on microcrystalline cellulose in the fluidized-bed granulator;

3. The granules obtained in Step2 are dried and sieved;

4. The granules dried and sieved in Step 3 are mixed with at least one pharmaceutically acceptable excipient preferably chosen from binding agent, diluent, dispersing agent, glidant and stabilizing agents;

5. the mixture obtained in Step 4 is preferably mixed with a pharmaceutically acceptable surfactant;

6. The mixture obtained in Step 5 is fed to tablet pressing machine and the tablets are compressed in accordance with tablet specifications;

7. The tablets obtained in Step 6 are preferably coated by film coating. The method for the preparation of the pharmaceutical formulations in accord with the present invention comprising ramipril and HCTZ is a two-stage method where in the first stage comprises the five steps given above, the second stage comprises the following steps:

6. HCTZ is mixed with at least one pharmaceutically acceptable excipient preferably chosen from diluent, dispersing agents, glidant and stabilizing agents and sieved;

7. Preferably a pharmaceutically acceptable surfactant is added to the mixture obtained in Step 6 and mixed;

8. The mixture obtained by mixing the mixtures from Step 5 and 7, is fed to the tablet pressing machine or each mixture is fed to the tablet pressing machine separately for obtaining a layered tablet;

9. The tablets obtained in Step 8 are preferably covered by film coating.

Detailed Description of the Invention

The present invention is related pharmaceutical compositions which contain ramipril alone or in combination with a therapeutic agent like HCTZ and provide the desired effect. However, as it is stated before, both solubility and stability problems are faced in the formulation studies including only ramipril. In the studies of the ramipril and HCTZ In addition to the problems of ramipril, a probable incompatibility of the components forming the composition arises and thus a probable stability problem constitutes a risk. It is required that the solubility and stability problems of ramipril and the incompatibility problem of the substances forming the composition should be solved by an incomplicated method so that the compositions comprising rampril alone or in combination with a therapeutic agent like HCTZ can provide the desired effect. Furthermore, pharmaceutically effective amount of active compound/compounds and suitable amount of excipients should be found.

As a result of the previous studies, it is found that a pharmaceutical composition including the granules obtained by applying a manufacturing process in which microcrystalline cellulose is coated by a coating solution comprising dissolved ramipril, has both improved solubility and stability properties and provides the desired effect.

The first aspect of the invention is to obtain the diluent granules coated by a coating solution comprising dissolved ramipril. The pharmaceutical compositions according to the invention comprise microcrystalline cellulose as a diluent to be coated. The microcrystalline cellulose which is stable, reliable and physiologically inert becomes compact quickly at the minimum pressure. This feature provides an opportunity for pressing tablets without being exposed to a high pressure. Microcrystalline cellulose makes tablets stiff. As a result of these features, the tendency of ramipril degradation under mechanic effect is kept under control. The binding and carrying capacity of microcrystalline cellulose are high. This way, it can carry ramipril particules without any agglomeration by binding the ramipril solution which is coated on it. In addition to that, by showing lubricating effect it improves the fluidity property of the pharmaceutical powder. Furthermore, having the property of spreading quickly, it develops the solubility property of the tablets. Based on the studies, microcrystalline cellulose granules coated with a coating solution comprising dissolved ramipril have made a contribution to the improvement of both solubility and stability.

The second aspect of the invention is to obtain a suitable pure solvent or solvent mixture in which ramipril can dissolve before coating it on the microcrystalline cellulose and thus increase the solubility of ramipril. While ramipril tends to agglomerate, the granules which are obtained by spraying the granulation solution (coating solution) including ramipril, which is dissolved in a suitable pure solvent or solvent mixture on microcrystalline cellulose and then dried so as to have maximum 1.5 % moisture ratio and sieved, have represented a solubility of > 98 % at the first 5 minutes in a dissolution medium that is suitable for ramipril. Pure solvent or solvent mixture that is according to the present invention is chosen from pharmaceutically acceptable binding agents, preferably, it is an alcohol, ketone, cellulose derivative, water or a suitable mixture of them, more preferably 1-propanol, 2-propanol, ethyl alcohol, acetone, HPMC, water or a suitable mixture of them. The third aspect of the invention is to determine a suitable excipient composition and manufacturing method in order to further improve the solubility and stability features of the granules that were obtained with improved solubility and stability features. Considering the probability of degradation of ramipril, preferably pregelatinized starch, which is resistant to moisture and mechanic effect, is added to the microcrystalline cellulose granules covered by ramipril solution. It provides an opportunity for pressing tablets without being exposed to high pressure due to its improved compressibility. Moreover, it improves the solubility of the tablets with a lower cost since its dispersing effect is as high as super dispersant. It has been found that it is more effective on improving the solubility and stability properties of pharmaceutically acceptable compositions when it is used over the commonly used range of 5-10%. The mentioned properties have revealed that it can have both diluent and dispersant effect when used in high amounts. Its effect on developing the fluidity properties of the pharmaceutical powder is increased by adding preferably colloidal silicon dioxide. Photo- protector like iron oxide as stabilizing agent can be used at this stage for the pharmaceutical compositions in accord with the invention comprising ramipril alone, and can be used at the stage of the preparation of the second mixture which will be between two compositions for the pharmaceutical compositions in accord with the invention including ramipril in combination.

The fourth aspect of the invention is to develop an incomplicated manufacturing procedure where active components are formulated seperately to prevent a probable incompatibility problem in the event of adding HCTZ to the formulation and to choose suitable excipients. For this purpose, two seperate formulations including ramipril and HCTZ and two separate manufacturing procedures are developed. No basic excipient is added to the mixture in which HCTZ is formulated. The use of the excipients which is included in the first mixture is tried in terms of compatibility and no stability problems were observed. This way, taking into account the advantages mentioned previously and the fact that no compatibility problems were observed preferably microcrystalline cellulose, pregelatinized starch or colloidal silicon dioxide are added to the said mixture. Moreover, when the preparation method for the ramipril formulations in accord with the invention is applied for the combination of ramipril and HCTZ, no incompatibility and thus stability problems were observed. Hence, it is observed that the said manufacturing procedure can be applied to not only formulations including ramipril but also the combinations via formulating the active agents separately.

The fifth aspect of the invention is to decide on the lubricant that will be added to the mentioned mixture or mixtures as the last excipient. Said lubricant should be a kind of substance that does not delay spreading, is not affected by the blending time, does not cause degradation under mechanic effect and does not affect stability adversely. The pharmaceutical compositions in accord with the invention preferably comprise sodium stearil fumarate as lubricant to meet all these needs.

The preparation method of the pharmaceutical compositions in accord with the invention including ramipril alone includes the following steps:

1. The granulation solution is obtained by dissolving ramipril in a solvent chosen from pharmaceutically acceptable binding agents, preferably in an alcohol, ketone, cellulose derivative, water or a mixture of them, more preferably 1-propanol, 2-propanol, ethyl alcohol, acetone, HPMC, water or a pure solvent or solvent mixture which is a mixture of them.

2. The granules coated by ramipril are obtained by spraying the granulation solution mentioned in Step 1 onto microcrystalline cellulose in the fluidized-bed granulator.

3. The granules obtained in Step 2 are dried and sieved. 4. The granules dried and sieved in Step 3 are mixed with at least one pharmaceutically acceptable excipient chosen from preferably binder, diluent, dispersing agent, glidant and stabilizing agents.

5. Preferably a pharmaceutically acceptable lubricant is added to the mixture obtained in Step 4 and mixed.

6. The mixture obtained in Step 5 is fed to tablet pressing machine and the tablets are compressed in accordance with their specifications.

7. The tablets obtained in Step 6 are preferably coated by film coating. The method for the preparation of the pharmaceutical formulations in accord with the present invention comprising ramipril and HCTZ has two stages. The preparation stage of the first mixture containing ramipril has the first five steps describe above. The preparation stage of the second mixture including HCTZ has the following steps:

6. HCTZ is mixed with at least one pharmaceutically acceptable excipent preferably chosen from diluent, dispersing agent, glidant and stabilizing agents and sieved;

7. A pharmaceutically acceptable lubricant is preferably added to the mixture obtained in Step 6 and mixed;

8. The resultant mixture obtained by mixing the mixtures from Step 5 and 7, is fed to the tablet pressing machine or each mixture is fed to the tablet pressing machine separately for obtaining a layered tablet;

9. The tablets obtained in Step 8 are preferably coated by film coating.

The sixth aspect of the invention is to determine the suitable composition comprsing ramipril in a certain ratio and in case of combination a certain ratio of HCTZ and at least one pharmaceutically acceptable excipient chosen from the additives like binder, diluent, dispersant, glidant, stabilizing agent and lubricant for obtaining the desired therapeutical effectiveness.

The expression of "in a certain ratio" corresponds to ramipril in the range of 0.1-20% by weight and HCTZ in the range of 0.1-20% by weight.

The pharmaceutically acceptable binding agents can be chosen from a group comprising starch (such as patato starch, corn starch, wheat starch); the sugars like sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic resins (like accacia), gelatin, cellulose derivatives (such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrrolidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols (such as sorbitol, xylitol, mannitol) and water. The pharmaceutical compositions in accordance with the invention preferably includes an alcohol, ketone, cellulose derivative, water or a suitable mixture of them, more preferably 1-propanol, 2-propanol, ethyl alcohol, acetone, HPMC, water or a suitable mixture of them as binding agent. The solid binding agents are present in the pharmaceutical composition in an amount up to 10% by weight. On the other hand, liquid binding agents are added to the composition in sufficient amounts.

The pharmaceutically acceptable diluents can be chosen from lactose, microcrystalline cellulose, starch, pre-gelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, kaolin, lactilol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol. The pharmaceutical compositions in accord with the invention preferably contain microcrystalline cellulose as a diluent to be coated on. Said pharmaceutical compositions optionally include at least one more diluent chosen from the group described above. The diluent is present in the composition in an amount up to 85% by weight.

The pharmaceutically acceptable dispersing agents can be chosen from starch (corn starch, patato starch), sodium starch glycolate, pre-gelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone, crospovidon, alginic acid, soldium alginate, clays (like xanthan gum or Veegum), ion-exchange resins effervescent systems, based on food acids and alkali carbonate compounds. The pharmaceutical compositions according to the invention preferably includes pre-gelatinized starch as dispersing agent. The dispersing agent is present in the composition in an amout up to 85% by weight.

The pharmaceutically acceptable glidants can be chosen from silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talk, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfates. The pharmaceutical compositions according to the invention preferably include silicon dioxide as gilidant. The glidant is present in the composition in an amount lower than 1% by weight.

The pharmaceutically acceptable stabilizing agent or agents can be chosen from among some agents such as antioxidants, chelating agents, alkalinizing agents and photo-protectors. The pharmaceutical compositions according to the invention preferably includes iron oxide as stabilizing agents. The stabilizing agent or agents is present in the composition in an amount up to 10% by weight. Antioxidants can be chosen from some substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, gallates (like propil gallates), tocoferole, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate. Chelating agents can be chosen from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or their combinations.

Alkalinizing agents can be chosen from the organic compounds such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, alkali metal salts like sodium aluminate; calcium carbonate, calcium hydroxide, dibasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, the alkaline earth metal salts like magnesium aluminate, primary, secondary and tertiary amines, cyclic amines, Ν,Ν'- dibenzylethylenediamin, dietanolamine, ethylenediamin, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate.

Photo-protecting agents can be chosen from metal oxides such as titanium oxide, iron oxide or zinc oxide

The pharmaceutically acceptable lubricants can be chosen from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (like sodium stearyl fumarate), fatty acids (like stearic acid), fatty alcohols, glyceril behenate, mineral oil, paraffines, hydrogen vegetable oil, leucine, polyethylene glycols, metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talk. The pharmaceutical compositions according to the invention preferably include sodium stearyl fumarate as lubricant. The lubricant is preferably present in the composition in an amount up to 10% by weight.

In addition to them, other pharmaceutically acceptable excipients such as solubility modulators, electrolytes, flavoring, colorant and coating agents can also be used in the formulation.

The pharmaceutical formulation examples in accord with the invention are represented below. These examples are given to explain the topic of the invention and the invention should not limited by these examples. EXAMPLES

Example 1. The pharmaceutical composition comprising 2.5 mg ramipril

Example 2. The pharmaceutical formulation comprising 5 mg ramipril

Example 3. The pharmaceutical formulation comprising 10 mg ramipril

Content Amount (mg)

Ramipril 10.0

Microcrystalline cellulose 73.0

Pregelatinized starch 15.0

Sodium stearyl fumarate 2.0

Acetone Sufficient amount

Deionized water Sufficient amount

Total tablet weight 100 Example 4. The pharmaceutical composition comprising 2.5 mg ramipril / 12.5 mg HCTZ

Example 5. The pharmaceutical composition comprising 2,5 mg ramipril / 25 mg HCTZ

Example 6. The production method of pharmaceutical formulation comprising 5 mg ramipril

The granulation solution is obtained by dissolving 2,5 mg ramipril and 2,0 mg HPMC in a mixture comprising 25,0 mg 1-propanol and 10.0 mg deionized water.

The granules coated by ramipril is obtained by spraying the granulation solution mentioned above onto 74.2 mg microcrystalline cellulose in fludized bed granulator.

- Granules obtained is dried so as to have maximum 1.5% moisture ratio and sieved.

Dried and sieved granules is mixed with 15.0 mg pregelatinezed starch,4.0 mg HPMC 0.2 mg iron oxide, and 0.1 mg colloidal silicone dioxide.

2.0 mg sodium stearyl fumarate is added to the obtained mixture and mixed. The tablets are pressed according to their specifications by feeding the obtained mixture to the tablet pressing machine.

Example 7. The production method of pharmaceutical composition comprising 2.5 mg ramipril/ 12.5 mg HCTZ - The granulation solution is obtained by dissolving 2,5 mg ramipril in a mixture comprising 25,0 mg 2-propanol and 10.0 mg deionized water.

The granules coated by ramipril is obtained by spraying the granulation solution mentioned above onto 7,5 mg microcrystalline cellulose in fludized bed granulator.

Granules obtained is dried so as to have maximum 1.5% moisture ratio and sieved.

- Dried and sieved granules are mixed with 29.31 mg pregelatinezed starch and 0.05 mg colloidal silicone dioxide.

The first mixture is obtained by adding 0.5 mg sodium stearyl fumarate to the obtained mixture and mixing

12.5 mg HCTZ, 19.54 mg pregelatined starch, 7.5 mg microcrystalline cellulose, 0.05 mg colloidal silicone dioxide and 0.05 mg iron oxide are mixed and sieved.

The second mixture is obtained by adding 0.5 mg sodium stearyl fumarate to the obtained mixture and mixing.

The resultant mixture obtained by mixing the obtained mixtures is fed to the tablet pressing machine or both mixtures are fed to the tablet pressing machine separately to get a layered tablet.

Claims

1. The pharmaceutical composition comprising a therapeutically effective amount of ramipril alone or in combination with a therapeutically effective amount of HCTZ for use in the manufacture of a medicament effective for the treatment of hypertension and congestive heart failure and for decrease in mortality risk originating from myocardial infarction, paralysis and cardiovascular characterized in that said composition comprises microcrystalline cellulose granules that are coated by a coating solution comprising ramipril in a dissolved state and that it has improved solubility and stability.

2. The preparation method of pharmaceutical composition comprising ramipril alone according to claim 1 wherein,

The granulation solution is obtained by dissolving ramipril in pure solvent or a mixture of solvents.

The granules coated by ramipril are obtained by spraying granulation solution on microcrystalline cellulose in fludized bed granulator.

The granules are dried and sieved.

The granules dried and sieved are mixed with at least one pharmaceutically acceptable excipient preferably chosen from diluent, dispersant, binder, glidant and stabilizing agent.

The pharmaceutically acceptable lubricant is preferably added to mixture and mixed. - The obtained mixture is fed to tablet pressing machine and tablets are pressed in accordance with their specifications.

The tablets are preferably coated by film coating.

3. The preparation method of pharmaceutical composition comprising ramipril and HCTZ according to claim 1 characterized in that,

- The granulation solution is obtained by dissolving ramipril in pure solvent or in a solvent mixture.

The granules coated by ramipril are obtained by spraying granulation solution onto microcrystalline cellulose in fludized bed granulator

The granules are dried and sieved

- Dried and sieved granules are mixed with at least one pharmaceutically

acceptable excipient preferably chosen from diluent, dispersant, binder, glidant and stabilizing agent.

By preferably adding a pharmaceutically acceptable lubricant in mixture and mixing the first mixture is obtained, HCTZ is mixed with at least one pharmaceutically acceptable excipient preferably chosen from diluent, dispersant, binder, glidant and stabilizing agent and sieved.

By preferably adding a pharmaceutically acceptable surfactant in mixture and mixing the second mixture is obtained

- The resultant mixture obtained by mixing the obtained mixtures is fed to the tablet pressing machine or both mixtures are fed to the tablet pressing machine seperately to get a layered tablet.

The tablets are preferably coated by film coating.

4. The pharmaceutical composition prepared by a method according to claim 2, characterized in that ramipril is present in an amount in the range of 0.1 -20 % by weight.

5. The pharmaceutical composition prepared by a method according to claim 3, characterized in that ramipril is present in an amount in the range of 0.1-20 % by weight and HCTZ is present in an amount in the range of 0.1 -20 % by weight.

6. The pharmaceutical composition prepared by a method according to claim 2 and 3, characterized in that a pure solvent or mixture of solvents are chosen from pharmaceutically acceptable binding agents.

7. The pharmaceutical composition according to claim 6, characterized in that binding agents are preferably chosen from alcohol, ketone, cellulose derivatives, water or mixture of them, more preferably chosen from 1-propanol, 2-propanol, ethyl alcohol, acetone, HPMC, water or mixture of them.

8. The pharmaceutical composition according to claim 6, characterized in that binding agent is present in an amount up to 10% .

9. The pharmaceutical composition prepared by a method according to claim 2 or 3, characterized in that it comprises at least one pharmaceutically acceptable diluent.

10. The pharmaceutical composition according to claim 9, characterized in that it comprises microcrystalline cellulose as a diluent to be coated on.

11. The pharmaceutical composition according to claim 10, characterized in that diluent is present in an amount up to 85%.

12. The pharmaceutical composition prepared by a method according to claim 2 and 3, characterized in that it includes a pharmaceutically acceptable dispersant.

13. The pharmaceutical composition according to claim 12, characterized in that it preferably comprises a starch derivative as a dispersant.

14. The pharmaceutical composition according to claim 13, characterized in that dispersant is present in an amount up to 85%.

15. The pharmaceutical composition prepared by a method according to claim 2 and 3, characterized in that it comprises a pharmaceutically acceptable glidant.

16. The pharmaceutical composition according to claim 15, characterized in that it comprises silicone dioxide as a glidant.

17. The pharmaceutical composition according to claim 16, characterized in that glidant is present in an amount less than 1%.

18. The pharmaceutical composition prepared by method according to claim 2 and 3, characterized in that it comprises at least one pharmaceutically acceptable stabilizing agent.

19. The pharmaceutical composition according to claim 18, characterized in that it preferably comprises iron oxide as a stabilizing agent.

20. The pharmaceutical composition according to claim 19, characterized in that stabilizing agent is present in an amount up to 10%.

21. The pharmaceutical composition prepared by a method according to claim 2 or 3, characterized in that it comprises a pharmaceutically acceptable lubricant.

22. The pharmaceutical composition according to claim 21, characterized in that it comprises sodium stearyl fumarate as a lubricant.

23. The pharmaceutical composition according to claim 22, characterized in that lubricant is present in an amount up to 10%.

24. The pharmaceutical composition according to any of the previous claims, characterized in that it is in the solid dosage form for oral use.

25. The pharmaceutical composition according to claim 24, characterized in that solid dosage form is present in tablet form or preferably film tablet form.