WO2009007808A1

WO2009007808A1 - Combined pharmaceutical composition

Info

Publication number: WO2009007808A1
Application number: PCT/IB2008/001538
Authority: WO
Inventors: José Eduardo SANTILLANA PORTOCARRERO; Angélica ARZOLA PANIAGUA; Martha Keyla Corona Ramirez
Original assignee: Laboratorios Senosiain S.A. De C.V.
Priority date: 2007-07-11
Filing date: 2008-06-14
Publication date: 2009-01-15
Also published as: MX2007008440A; WO2009007808A4; CL2008001895A1; UY31153A1; PE20090439A1; PA8785701A1; AR067110A1

Abstract

The present invention concerns a pharmaceutical composition in capsules with covered microspheres comprising the combination of amiodipine besylate and Pravastatine Sodium and pharmaceutically acceptable salts thereof, and in addtion pharmaceutically acceptable vehicles or excipients; also concerned is a method for production of the composition and the use of said composition for preparation of a medicine with synergistic therapeutic activity prescribed in the treatment of cardiovascular diseases such as high blood pressure and dislypidemia and comorbility thereof.

Description

COMBINED PHARMACEUTICAL COMPOSITION

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition in capsules with coated microspheres comprising the combination of amlodipine besylate and pravastatin sodium and its pharmaceutically acceptable salts, additionally pharmaceutically acceptable carriers or excipients; as well as a process for the manufacture of the composition and the use of said combination for the preparation of a medicament with synergistic therapeutic activity indicated in the treatment of cardiovascular diseases of the type of arterial hypertension and dyslipidemia and their comorbidity.

BACKGROUND OF THE INVENTION

Cardiovascular diseases and dyslipidemia are currently recurrent diseases. Cardiovascular disease is the fifth cause of death after cancer diseases, chronic obstructive diseases, accidents, diabetes and infectious diseases.

64% of hypertensive patients have dyslipidemia and 47% of dyslipidemic patients are hypertensive. This association could reflect the presence of metabolic abnormalities that may be the origin of both disorders. Another possibility is that high blood pressure and Hypercholesterolemia have a primary interaction in the pathophysiology of both. This observation can have very important clinical implications since some therapeutic measures can modify the risk of cardiovascular pathology (CV) and the possibility of intervening on both risk factors should be considered (Calabria F. January 2006).

It is clearly shown that small reductions in blood pressure (BP) and cholesterol levels cause significant reductions in cardiovascular disease. Hence, the urgent need to have a stable and safe formulation that includes a drug to treat hypertension and a drug to treat dyslipidemia and comorbidity of both conditions in a single dose unit, to be administered at least once at day.

The present invention aims to present a pharmaceutical formulation in the same dose unit that includes a pharmaceutical composition that addresses the conditions of arterial hypertension and dyslipidemia. The drugs selected for the present invention are a calcium channel blocker and a statin, selecting amlodipine besilato and pravastatin sodium respectively.

Within the different existing statins pravastatin was chosen because it is not significantly metabolized through the CYP3A4 system, a process that follows the other statins, and also used by amlodipine. When using amlodipine and pravastatin, the metabolic competition of drugs by the site of action in the organism is avoided, resulting in a formulation with synergistic therapeutic activity, indicated in the treatment of hypertension and dyslipidemia and their related morbidity. The resulting composition is therapeutically stable and effective.

Amlodipine is a suitable drug for the treatment of people suffering from blood pressure problems and pravastatin is a suitable drug in the treatment of dyslipidemia. For this reason, the present invention relates to a pharmaceutical form where the two drugs are present in a single dose unit.

Amlodipine is a derivative of the group of 1,4-dihydropyridines, a compound that inhibits the entry of calcium ions, that is, a channel blocker or calcium ion antagonist.

Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol, acid resistant and sensitive to basic degradation.

Amlodipine inhibits the flow of calcium through cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. It behaves like a peripheral arterial vasodilator that acts directly on the vascular smooth muscle causing a reduction in vascular resistance peripheral and a decrease in blood pressure which allows the flow of blood through the bloodstream.

Amlodipine in patients with angina of exertion or exercise dilates peripheral arterioles, reducing total peripheral resistance (afterload), against which the heart works and reduces pressure, as well as the demand for myocardial oxygen at any level of exercise.

Amlodipine in vasospastic angina blocks the constriction and restores the flow in the coronary arteries and arterioles in response to calcium, potassium, adrenaline, serotonia and the thromboxane analog A2.

After oral administration, amlodipine has a slow and almost complete absorption; the absolute bioavailability of the drug fluctuates between 64% and 90%, approximately 97% of the circulating amlodipine is bound to plasma proteins; its peak plasma concentration appears between 6 and 12 hours, and has a wide volume of distribution (Vd = 211 / kg), its binding to plasma proteins is 95%.

In its elimination, amlodipine is extensively metabolized slowly in the liver to inactive metabolites with 60% renal excretion and 20 to 25% by feces. Plasma removal is biphasic, with a terminal elimination half-life of 30 to 50 hours.

Chronic oral administration of a daily intake maintains the antihypertensive effect for 24 hours, - Plasma stability levels are reached after 7 or 8 days of consecutive daily shots.

Amlodipine is well tolerated, the most commonly observed side reactions are: in the body in general, fatigue, - in autonomic nervous system, hot flashes; in the Cardiovascular System, edema; in the Central and Peripheral Nervous System, headache and dizziness; in the Gastrointestinal System, abdominal pain and nausea, - in heart rhythm, palpitations and psychiatric level, drowsiness.

Pravastatin sodium is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, the initial limiting step of cholesterol biosynthesis.

Pravastatin is soluble in water and methanol, its pH in 5% aqueous solution ranges from 7.2 to 9.0, in the presence of acidic media it is very sensitive, which causes it to degrade. It is hygroscopic and absorbs moisture from the environment. Therefore, because it is sensitive to pH and humidity, it is necessary to protect it from the interactions of its surroundings.

The metabolism of pravastatin is carried out through several mechanisms such as isomerization to 6-epi-pravastatin, aromatic hydroxylation, conjugation, among others. It is noteworthy that none of these metabolic reactions is carried out through CYP3A4, so the Interactions with amlodipine besylate metabolism using the CYP3A4 system are relatively nil. Therefore, the properties of both drugs can be used to the fullest.

Pravastatin reduces the risk of a first myocardial infarction, a relapse or a stroke, unlike other statins that have not demonstrated this therapeutic effect.

Pravastatin experiences an important hepatic first-pass effect, this being its main site of action, this is the fundamental organ in cholesterol biosynthesis and cholesterol-LDL clearance.

Pravastatin is rapidly absorbed, with maximum plasma concentration levels reached after 1 to 1.5 hours after administration. Although the presence of food in the gastrointestinal tract reduces systemic bioavailability, the hypolipidemic effect of the drug is similar whether it is administered with or without the intake. Plasma concentrations of pravastatin are directly proportional to the dose administered, and drug accumulation has not been demonstrated. Approximately 50% of the circulating drug is bound to plasma proteins. The plasma elimination half-life (oral) is 1.5 to 2.0 hours. The side effects of pravastatin are related to those caused by statins, the most important effect being rhabdomyolysis, which manifests as muscle aches, muscle weakness accompanied by malaise or fever and even kidney failure.

Patent CA2296726 refers to a composition comprising: a) an amount of amlodipine or a salt, b) an amount of statin or a salt, c) a pharmaceutically acceptable carrier or diluent, where the statin is selected from: fluvastatin, Rivastatin and simvastatin or a pharmaceutically acceptable salt thereof, these compositions are presented in a package or kit that individually and separately contains the amlodipine composition and the statin composition to be administered individually or together.

The present invention, unlike the cited patent, relates to a specific composition of amlodipine besilato and pravastatin sodium in a single dose unit, which is presented in one of its preferred embodiments of capsules with coated microspheres, to be administered at least once a day.

Jukema et al. (Oct 15, 1995), in a study conducted to evaluate the benefits of the combination of a lipid-lowering agent and a calcium channel blocker, shows a significant benefit in the therapeutic treatment to slow the progression of coronary atherosclerosis.

This study evaluated combinations of active ingredients containing pravastatin and calcium channel blockers within those classified as dihydropyridines such as nifedipine, amlodipine and other second and third generation dihydropyridines and nondihydropyridines such as dithliazem and verapamil.

In this study in a very general way, it is evident that calcium channel blocker drugs combined with statins such as pravastatin, have significant benefits to slow the progression of coronary atherosclerosis. However, it is important to note that this study does not present pharmaceutical formulations that show a physicochemical stability.

As described above, there remains the challenge of formulating a pharmaceutical composition that is physicochemically stable and therapeutically effective and that integrates in a single dose unit drugs that are capable of caring for patients suffering from hypertension, dyslipidemia and related morbidity.

The present invention presents a formulation containing a calcium channel blocker drug that reduces arterial hypertension, such as amlodipine besylate, and a hypolipidemic drug, pravastatin statin, in a single dose unit. The contact between Amlodipine and pravastatin within the same dose unit, causes oxidative degradation of these assets, reducing their therapeutic reach. Said problem was satisfactorily found in the present invention. From a pharmacodynamic point of view, the combination of a calcium channel blocker and a statin for the concomitant treatment of hypertension and dyslipidemia and its comorbidity is quite rational.

However, there is the problem of physicochemical interactions such as: instability against different pH media, hygroscopic assets; Pharmacokinetic interactions such as difference in elimination half-life and / or metabolic absorption sites among others. With all this it is not possible to obtain a formulation with the single drug binding of the two therapeutic groups in a conventional formulation.

The present invention presents a formulation containing a calcium hypertension reducing calcium channel blocking drug, which is amlodipine, and a hypolipidemic drug, pravastatin, in a single dose unit. This formulation offers a medication with synergistic therapeutic activity, indicated in the treatment as antihypertensive and dyslipidemic and its comorbidity of both conditions. For the present invention, the selected statin is pravastatin since it is not significantly metabolized to through the CYP3A4 system. That is why, unlike the rest of the statins, pravastatin has a lower risk of interaction at the level of liver metabolism.

Currently there are formulations of amlodipine besylate - atorvastatin and amlodipine - simvastatin. These formulations have the disadvantage of containing drugs that compete in the body for the metabolic absorption site, which causes the optimization of the therapeutic effect to be compromised unfavorably, so that the risks of adverse effects can also be increased.

As already described, the physicochemical characteristics of the active ingredients amlodipine and pravastatin cause the assets to be incompatible with each other and, being in direct contact under certain conditions, suffer from physicochemical degradation.

Another factor considered during the development of the present invention for the combination of amlodipine and pravastatin is metabolic interactions. The metabolism of drugs in general occurs in two phases: phase I encompasses the processes of oxidation, reduction and hydrolysis; in phase II the conjugation processes with glucoronic acid, sulfate and glutathione occur, among others.

The oxidative phase I reactions are carried out in the cytochrome P-450, which is part of the oxidative system of liver microsomes. Cytochrome P-450 is the largest liver enzyme complex involved in drug metabolism, which in turn is divided into families and this into subfamilies. The subfamilies contain various isoenzymes, with CYP3A4 being the most important since it is the isoenzyme responsible for the metabolism of most statins.

Amlodipine besylate is an antagonist of the calcium channels of the dihydropyridine type and is metabolized through CYP3A4. Statins in general are metabolized by the CYP3A4 system.

In this way, the combination of amlodipine with a statin, for example simvastatin or atorvastatin, being in the organism can present a metabolic competence for the CYP3A4 site of action and, in turn, can cause the therapeutic efficacy of the combination and possibly also increase adverse effects.

Pravastatin is a statin that is not metabolized by the CYP3A4 enzyme system. Therefore, if combined in a composition with amlodipine, the risks of metabolic competition are reduced.

The half-life of amlodipine is considered a long half-life and is prescribed once a day; Pravastatin has a short half-life and is indicated once or twice a day depending on the characteristics of the patients. As described, the combination of pravastatin with a drug of the type of channel blockers Calcium has a therapeutic activity higher than expected in monopharmaceutical therapies.

Considering the half-life of the drugs and the superior therapeutic activity shown when combining these drugs, it is possible that the formulation of the present invention is indicated at least once a day, thereby reducing the number of doses per day, improving the follow-up of the indicated treatment.

In developing the present invention due to the physicochemical characteristics of hygrospicity and humidity sensitivity of the environment by pravastatin, the need arises to create a system that provides protection to the composition as a finished product of its physical environment. The system developed for the protection of the terminal formulation consists in using a container that contains the capsules and is inert and impermeable, so that the capsule is protected from the external environment.

The capsules are contained in a container-closure or packing-closure system using an aluminum-polyvinylidene chloride (PVDC) blister. This package contains inside the developed composition, thus preserving its physicochemical and therapeutic properties.

Amlodipine has acidic characteristics, therefore, in the presence of basic media it is sensitive and suffers from degradation. Pravastatin sodium has basic characteristics with a pH in solution that fluctuates between 7.2 and 9.0. During the manufacturing process of the formulation, it was observed that when containing pravastatin in acidic medium it undergoes a marked degradation, showing a pH between 2.5 and 5.0, due to this, its therapeutic characteristics are unfavorably compromised.

Because of their sensitivity to basic and acidic media, both amlodipine and pravastatin should be protected from their surroundings. If they are in contact with each other, the acidic characteristics of amlodipine predominate in the formulation and degrade pravastatin to a greater extent than what happens from pravastatin to amlodipine. v

It should be avoided that they are in direct contact in the same dose unit and with each other at certain conditions, since if they are together they degrade, with this the concentration of the active ingredients in the formulation decreases from a

100% up to about 20%.

In the present invention, the combination of drugs does not compete in the body for metabolic sites as it could occur between calcium channel blockers and most statins.

With the development of the present invention a physicochemically stable formulation is offered, where a acid-base balance, which does not interfere with the stability and immediate release of the active ingredients, which allows you to achieve the desired therapeutic effect.

The application of an insulating cover between the two active ingredients provides an appropriate micro-average for the necessary stability and appropriate release characteristics.

The microsphere manufacturing process for the present invention guarantees the uniformity of the content of the composition, the adequate release of the active ingredients and the physicochemical stability of the formulation.

By virtue of the foregoing, the present invention provides a stable pharmaceutical composition, in a single dose unit, in capsules with coated microspheres comprising a calcium channel blocking drug and a statin, which are physicochemical and pharmacokinetically different. .

The formulation was achieved by developing a capsule composition containing inert nuclei coated with successive and independent layers containing the pharmaceutically acceptable active ingredients and excipients compatible with the drugs. The excipients were selected from the results obtained during pharmaceutical development. The compositions of the present invention contain therapeutically effective amounts of amlodipine and pravastatin, the ranges of the respective amounts accordingly vary in this manner. Preferably the weight ratio of amlodipine to pravastatin or its pharmaceutically acceptable salts, ranges from 1: 1 to 1:32.

When amlodipine and pravastatin are incorporated into the same dose unit, the dose unit preferably comprises from once the mass of amlodipine to twice the mass of pravastatin or from one to four times this ratio, that is, from 5 mg from amlodipine to 10 mg of pravastatin (1: 2) or from 5 mg of amlodipine to 20 mg of pravastatin (1: 4).

The resulting formulation of the present invention offers a stable, safe and effective medicament indicated in the treatment as antihypertensive, dyslipidemic and its related morbidities, the formulation is immediate release and can be administered once daily.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the structure of the microsphere, which is composed of four phases that are gradually integrate the inert core during the manufacturing process.

SUMMARY OF THE INVENTION

The present invention relates to an oral, physicochemically stable pharmaceutical composition in a unit, characterized in that it comprises therapeutically effective amounts of the active ingredients amlodipine besylate and sodium pravastatin, or their pharmaceutically acceptable salts, in combination with pharmaceutically acceptable excipients.

The pharmaceutical composition of the present invention includes coated microspheres comprising:

Inert cores;

Cover one, which includes the active ingredient one, at least one antioxidant, at least one plasticizer, at least one buffer, and at least one binding binder adhesive polymer;

Insulating cover that includes at least one polymer in aqueous solution;

Cover that includes at least two active ingredient, at least one antioxidant, at least one plasticizer, at least one buffer, and at least one binding binder adhesive polymer; Y Protective coating cover, which includes at least one coating polymer and at least one excipient.

The pharmaceutical composition of the invention is presented orally, preferably in capsules and tablets.

Likewise, the invention reveals a process for obtaining the pharmaceutical composition characterized in that sprinkler is added to the inert nuclei:

a) a cover with active ingredient one, which includes the active ingredient, at least one antioxidant, at least one buffer, and at least one binding binder adhesive polymer;

b) an insulating cover that includes at least one polymer in aqueous solution;

c) a cover with active ingredient two, which includes the active ingredient with excipients; Y

d) a protective coating covering, which includes at least one coating polymer and at least one excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition useful in the therapeutic treatment of conditions. related hypertension, dyslipidemia and its related comorbidity in a single dose unit, to be administered according to the patient's response, preferably only once a day.

The present invention provides a pharmaceutical composition that specifically comprises amlodipine besilato and pravastatin sodium in a single dose unit to be administered only once a day.

The association of amlodipine and pravastatin besylate in a single dose unit represents a technological challenge since, due to their acidic and basic physicochemical characteristics, the two active ingredients are physicochemically incompatible.

If the two drugs are in direct contact, the concentration of the active substances decreases considerably and this prevents them from complying with their therapeutic activity, avoiding offering a stable composition.

In a study of characterization of the properties of the active ingredients, where the active ingredients were placed individually and combined in acidic, basic and oxidative media, it was shown that amlodipine is stable in acidic and oxidative media, is slightly sensitive to the media basic; Pravastatin is stable in basic and oxidative media and very sensitive to acidic media, degrading even more than amlodipine in basic media. By combining the assets and placing them in the degradation media, pravastatin is the most affected asset in its stability of its physicochemical properties.

To solve this problem, a formulation of coated cores, also called microspheres, was developed. In this formulation the coexistence of drugs in the same unit is possible since the active ingredients are protected and isolated from having contact with each other and the environment.

Spray-coated cores in a fluid bed are obtained by directing a liquid stream sprayed in microdroplets over cores, the sprayed liquid referred to as a cover, contains the active ingredients in solution or suspension and vehicles and / or excipients, which will be adhered on the surface of the nuclei when the liquid that drives them evaporates. Evaporation is achieved by passing a stream of hot air upward, which keeps the cores floating and moving.

For this formulation, a drug formulation was developed where it is known that amlodipine has a long half-life and, therefore, is prescribed only once a day. On the other hand, pravastatin, although it has a short half-life, is indicated once or twice a day, depending on the characteristics of the patient's condition. Because of this, it is likely that they can be combined into a formulation that is indicated once a day.

The microsphere is integrated as follows:

1. Inert core. Inert solid core, this component is located in the innermost part of the microsphere, it gives support to the microsphere.

2. Cover one, which includes the active substance pravastatin sodium, which may be contained between 2.0% and 27.0%, is mixed with at least one antioxidant and at least one buffer that preserves and stabilizes the active; it is an adhesive binder bonding polymer that provides cohesion to the microsphere; These excipients vary in concentration according to the presentation of the capsules.

3. Insulating cover that serves as a barrier and protection enters the layers containing the active ingredients, is obtained by dispersing at least one polymer in an aqueous solution, the excipient varies in concentration according to the presentation of the capsules.

4. Cover that includes active principle two. This cover integrates the active substance amlodipine besylate, with excipients that give it plasticity and protection, the excipients vary in concentration according to the presentation of the capsules. 5. Protective coating cover. This external cover is a barrier that gives protection to the microsphere of its surroundings, providing stability. In this cover you can add a color coating that improves the appearance of the microsphere, the excipients vary in concentration according to the presentation of the capsules.

In the formulation of the present invention, it is possible that the phases containing the active principles and the excipients can change the order of addition in the microsphere, the active one being the active principle two and vice versa.

FORMULATIONS

The formulation and manufacturing process of the pharmaceutical formulation in capsules with coated cores or also called coated microspheres, containing active ingredients or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients as described below, are described below. - Active principles comprising:

Amlodipine besylate or pharmaceutically acceptable salts thereof.

Pravastatin sodium or pharmaceutically acceptable salts thereof. - Excipients or vehicles comprising:

* Base of inert nuclei that can be cellulose or sugar, selected from: cellulose, starch, glucose, dextrose or mixtures thereof. This base will confer support to the active ingredients and to the vehicles or excipients of the microsphere.

* Binder bonding adhesive polymer selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl-pyrridone, hypromellose or mixtures thereof. This polymer confers adherence and cohesion to the microsphere, as well as protection of the active substance.

4 Polymer for an insulating shell selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl-pyrridone, hypromellose, methacrylic acid, polyvinyl alcohol or mixtures thereof. This polymer gives protection and stability to the active substance.

4 Plasticizer selected from triethyl citrate, polyethylene glycol, propylene glycol, polyvinyl alcohol or mixtures thereof. It gives resistance and plasticity characteristics to the microsphere.

* Antioxidants selected from sodium metabisulfite, sodium sulfite, ascorbic acid, citric acid or mixtures thereof. They give protection to the composition against oxidative degradation. * Buffering solution, selected from acidic solutions such as hydrochloric acid or citric acid and / or basic solutions such as sodium hydroxide, ammonium hydroxide, phosphates, bicarbonates or mixtures thereof. This solution gives stability to the active principle before the means of application. * Coating polymer, selected from polyvinyl alcohol, cellulose derivatives and methacrylates, methacrylate derivatives such as Eudragit L-30 or D-55, Eudragit 100-55, Eudragit L-100, Eudragit S-100 or mixtures thereof. This component protects the microsphere, improving its resistance to handling and stability during storage, masking unpleasant taste or smell in addition to providing a good appearance.

Below are examples of proposed formulations. EXAMPLES 1, 2, 3 AND 4. FORMULATIONS OF CAPSULES WITH MICROSPHERES

EXAMPLE 5, 6, 7 AND 8. FORMULATIONS OF CAPSULES WITH MICROSPHERES

EXAMPLE 9, 10, 11 and 12. FORMULATIONS OF CAPSULES WITH MICROSPHERES

Preparation of capsule formulation.

Ensure that materials and equipment correspond to the manufacture of the formulation. The process for preparing the preferred formulation is as follows: 1. The components of the formula are weighed

2. Weigh the adhesive polymer and disperse in water.

3. Add the plasticizer to the solution in step 2.

4. Add buffer solution to adjust the pH of the preparation of point 3, this step is performed slowly.

5. Add the antioxidant in solution to the preparation of point 4.

6. Add pravastatin to the solution in point 5.

7. Place inert cores in the fluidized bed equipment. 8. Sprinkle the solution of point 6 over the nuclei of point 7.

9. Dry the coated cores and keep in the fluidized bed equipment.

10. Disperse the insulating polymer in water. 11. Apply the dispersion of point 10 over the nuclei of point 9.

12. Dry coated cores "microspheres".

13. Disperse the adhesive polymer in water.

14. Add plasticizer to the solution of item 13. 15. Disperse amlodipine besylate in the solution of item 14. 16. Sprinkle the solution of point 15 over the coated cores of point 12.

17. Dry the coated cores and keep in the fluidized bed equipment. 18. Disperse a coating polymer in water.

19. Sprinkle the solution of point 18 over the coated cores of point 17.

20. Dry the coated "microsphere" cores.

21. Fill the microspheres in hard gelatin capsules. 22. Fill the hard gelatin capsules in primary container, consisting of aluminum, with an inert bubble of PVDC.

In the process of manufacturing the microspheres, it is vitally important that the solutions used are prepared and controlled properly since the pH variation in particular pravastatin is very susceptible to pH variations, as well as the temperature at which they are prepared and sprinkled on the cores can cause the assets to be degraded or problems in the manufacture of the microspheres, such as: phase separation, non-homogeneous coating or fracture of the coating.

Likewise, once the coating operation has started, the temperature of the coating chamber must be controlled, the air inlet temperature must fluctuate between 45 ° C and 65 ⁰ C, product temperature between 38 ° C and 50 ⁰ C. The operating humidity must be maintained between 0.5 and not more than 2.5%.

For the other operating conditions, they must be controlled in a general way as in the fluidized bed microsphere processes, the conditions to be controlled are: air flow rate, air volume, microsphere drying times, among others.

If these operating parameters are not controlled, problems such as degradation of the assets may occur, that the coating does not adhere to the cores, that the coating fractures, that the coverage is not homogeneous or that the cores are burned and melted to cover.

The application of an insulating cover between the two active ingredients provides an appropriate micro-average for the necessary stability and appropriate release characteristics. The excipient for the insulating cover selected preferably is polyvinyl alcohol.

The composition of the present invention was manufactured in three different batches to assess its stability, this was done by subjecting them to a stability study.

During the study and at the end of the study, periodic evaluations of appearance, dissolution and concentration were carried out at different times. Table 1. Results of the stability study of formulations 1, 7 and 12.

With the results of the study, it was demonstrated that an unusually high stability composition was obtained since the analysis of physicochemical tests was satisfactory. The formulations that were used in the stability study were formulations 1 with 2.5 mg of amlodipine besylate and 10 mg of pravastatin; 7 with 5.0 mg of amlodipine besylate and 40 mg of pravastatin and 12 with 10 mg of amlodipine besylate and 80 mg of pravastatin.

It is worth mentioning that the mentioned process for capsule formulations with microspheres is not limiting in order to present the composition of amlodipine and pravastatin in tablets. The analyzes of the tests performed, such as aspect of the formulation, show capsules with integral microspheres during and at the end of the study, without residues due to microsphere fractures or color migration; In solution the capsules comply with this test for solid formulations and with respect to the content of assets this was maintained within the specifications allowed to comply with a therapeutic effect.

As previously described, the present invention has a pharmaceutical composition comprising an anti-hypertensive and dyslipidemic drug that can be administered in the same dose unit, stable and effective in its therapeutic effect.

The present formulation, despite presenting two incompatible active principles, is stable and safe, this is achieved by developing a composition where inert nuclei are covered with successive layers, where in an isolated and independent way the active principles and excipients are added, avoiding This way the degradation interactions that would arise between the active principles.

This combination of drugs does not compete in the body for metabolic sites, as could occur between calcium channel blockers and most statins.

With the development of the present invention, a physico-chemically stable formulation is offered where an acid-base balance is achieved and does not interfere with the immediate release of the active ingredients and the desired therapeutic effect is obtained.

By administering a capsule that releases medicine contained in microspheres, the incidence and severity of the side effects of the drugs, the possible gastric lesions are reduced since the content of the capsule is distributed over a contact surface that covers the entire gastric space, unlike tablets that are deposited in a single area, which can cause injury to the site where it is deposited.

The present formulation offers a better control of the plasma levels of the drugs when distributed uniformly in the gastrointestinal tract resulting in a lower variability of its bioavailability and a reduced risk of local toxicity, with this it is possible to achieve a better control of its administration.

In the present invention, when considering the elimination half-life of the drugs, the drugs will be combined in such a way that the formulation is indicated once a day, depending on the characteristics of the patients.

Together with the development of the pharmaceutical capsule formulation, a protective packaging system was developed. The so-called container-closure system consists of an aluminum blister and PVDC polyvinylidene chloride, which protects you from environmental interactions, thus preserving its physicochemical and therapeutic properties during storage time until consumption.

By virtue of the foregoing, the present invention provides a pharmaceutical composition in capsules with coated microspheres comprising a calcium channel blocking drug and a statin in the same unit of dose that in direct contact, without the protection developed in the present invention, is physicochemical and fartnacokinetically unstable.

This composition is achieved by developing a capsule formulation containing inert coated and protected nuclei, which prevents contact between the active ingredients, providing the composition with an appropriate micro-environment that provides stability and safety, without compromising the proper release of the drugs

The compositions of the present invention contain therapeutically effective amounts of amlodipine and pravastatin.

According to the preferred embodiment, the amount of amlodipine used can be from once the mass of amlodipine to once the mass of pravastatin as illustrated by formulation nine where the formulation is: amlodipine 10 mg and pravastatin 10 mg (1: 1 ); or even once the mass of amlodipine up to thirty-two times the pravastatin content as shown in formulation four where the formulation is: amlodipine 2.5 mg and pravastatin 80mg (1:32).

When amlodipine and pravastatin are incorporated into the same dose unit, the dose unit preferably comprises from once the mass of amlodipine to twice the mass of pravastatin or from one to four times this ratio, that is, from 5 mg of amlodipine to 10 mg of pravastatin (1: 2) or from 5 mg of amlodipine to 20 mg of pravastatin (1: 4).

The resulting formulation of the present invention allows to offer a stable, safe and effective medicament indicated in the treatment as antihypertensive, dyslipidemic and its related morbidities, of immediate release that can be administered once a day.

The invention has been described sufficiently that a person with average knowledge in the field can reproduce and obtain the results mentioned in the present description. However, any skilled person in the field of the art that is in charge of the present invention may be able to make modifications not described in the present application. However, if the subject matter claimed in the following claims is required for the application of these modifications in a given composition, said compositions should be within the scope of the present invention.

Claims

1. An oral, physicochemically stable pharmaceutical composition in one unit, characterized in that it comprises therapeutically effective amounts of the active ingredients amlodipine besylate and pravastatin sodium, or their pharmaceutically acceptable salts, in combination with pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1 characterized in that it comprises coated microspheres.

3. The pharmaceutical composition of claim 2 characterized in that the coated microspheres comprise:

Inert cores;

Insulating cover that includes at least one polymer in aqueous solution;

4. The pharmaceutical composition of claim 3, wherein the cover with active ingredient one includes sodium pravastatin and the cover with active ingredient two includes amlodipine besylate.

5. The pharmaceutical composition of claim 3, wherein the cover with active ingredient one includes amlodipine besylate and the cover with active ingredient two includes sodium pravastatin.

6. The pharmaceutical composition of claim 3, wherein the inert nuclei are selected from cellulose, starch, glucose or dextrose.

7. The pharmaceutical composition of claim 3, wherein the binder binder adhesive polymer is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl-pyrridone, hypromellose or mixture thereof.

8. The pharmaceutical composition of claim 3, wherein the plasticizer is selected from triethyl citrate, polyethylene glycol, propylene glycol, polyvinyl alcohol or mixture thereof.

9. The pharmaceutical composition of claim 3, wherein the antioxidant is selected from sodium metabisulfite, sodium sulphite, ascorbic acid, citric acid or mixture thereof.

10. The pharmaceutical composition of claim 3, wherein the buffer solution is selected from acidic solutions such as hydrochloric acid or citric acid and / or basic solutions of the solution type of sodium hydroxide, ammonium hydroxide, phosphates, bicarbonates or mixture of the same.

11. The pharmaceutical composition of claim 3, wherein the polymer for an insulating shell is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrridone, hypromellose, methacrylic acid, polyvinyl alcohol or mixture thereof.

12. The pharmaceutical composition of claim 3, wherein the coating polymer is selected from polyvinyl alcohol, cellulose derivatives and methacrylates, methacrylate derivatives such as Eudragit L-30 or D-55, Eudragit 100-55, Eudragit L- 100, Eudragit S-100 or mixture thereof.

13. The pharmaceutical composition of claim 1, characterized in that it is in the form of capsules.

14. The pharmaceutical composition of claim 1, characterized in that it is presented in the form of tablets.

15. The pharmaceutical composition of claim 1, wherein the weight ratio of amlodipine to pravastatin or its pharmaceutically acceptable salts ranges from 1: 1 to 1:32.

16. The pharmaceutical composition of claim 1, wherein preferably amolodipine besylate is 2.5 mg to 10 mg and sodium pravastatin is 10 mg to 80 mg.

17. The pharmaceutical composition of claim 16, wherein preferably amolodipine besylate is 5.0 mg and sodium pravastatin is 10 mg.

18. The pharmaceutical composition of claim 16, wherein preferably amolodipine besylate is 5.0 mg and sodium pravastatin is 20 mg.

19. The pharmaceutical composition of claim 16, wherein preferably amolodipine besylate is 5.0 mg and pravastatin sodium is 40 mg.

20. The pharmaceutical composition of claim 16, wherein preferably amolodipine besylate is 5.0 mg and sodium pravastatin is 80 mg.

21. The use of the pharmaceutical composition of claim 1 for the preparation of a medicament indicated in the treatment of cardiovascular diseases of the type of arterial hypertension associated with dyslipidemia.

22. The process for the preparation of the coated microspheres of claim 1, characterized in that the coating step is carried out with an air inlet temperature that fluctuates between 45 ° C and 65 ° C, and a product temperature between 38 ° C and 50 ⁰ C.

23. The process for the preparation of the coated microspheres of claim 1, characterized in that the coating step is carried out with a humidity between 0.5 and not more than 2.5%.

24. A process for obtaining the pharmaceutical composition of claim 3, characterized in that spray is added to the inert nuclei:

b) an insulating cover that includes at least one polymer in aqueous solution;