MXPA98003747A - Association at a fixed dose of an inhibitor of the angiotensin converter enzyme and an antagonist of calcium channels, a procedure for its preparation and its use for the treatment of cardiovascular diseases - Google Patents

Abstract

The present invention relates to: A fixed-dose combination of an inhibitor of angiotensin-converting enzyme and a calcium channel antagonist, characterized in that said association comprises a dose of (a) enalapril in the form of a sodium salt and other doses of (b) micronized nitrendipine, the dose of enalapril is 2.5 to 20 mg and the dose of nitrendipine is 5 to 20 mg, and in that it must be administrable in a dosage form

Description

ASSOCIATION AT A FIXED DOSE OF AN ANGIOTENSIN CONVERTER ENZYME INHIBITOR AND AN ANTAGONIST OF THE CHANNELS OF CALCIUM, PROCEDURE FOR ITS PREPARATION AND ITS UTILIZATION FOR THE TREATMENT OF CARDIOVASCULAR DISEASES Field of the invention The present invention relates to a new fixed-dose combination of an angiotensin-converting enzyme (ACE) inhibitor, enalapril, and a calcium channel antagonist (ACC), nitrendipine, to a method of preparing a composition pharmaceutical comprising said association at a fixed dose and its use in the treatment of diseases of the cardiovascular system, in particular arterial hypertension. The compositions of the present invention are presented in the form of solid unit doses with fixed amounts of enalapril and nitrendipine, so that with a single administration, once a day, the effect is achieved during the 24 hours after said dose. The pharmaceutical preparations of the present invention possess a good therapeutic effect in the treatment of hypertension and other diseases of the cardiovascular system even when the amounts of the active substances, enalapril and nitrendipine, are below the usual therapeutic doses administered in monotherapy. The preparations of the present invention have lower adverse effects related to the dose than those that occur in the administration of higher doses of each of the active ingredients separately to achieve the same therapeutic effect. The pharmaceutical compositions of this invention simplify the administration regimen and have a better acceptance by the patient.

BACKGROUND OF THE INVENTION There is an international consensus regarding the initial treatment of mild-moderate hypertension (HT). The hygienic-dietetic measures constitute an unavoidable first step in the approach of the hypertensive patient. If these measures do not achieve adequate control of the blood pressure figures, a pharmacological treatment should be initiated. The pharmacological treatments recommended as first choice have been changing over the past years. Initially, thiazide diuretics were added, then 0-blockers were added, and this condition has now been extended to other pharmacological groups such as ACE inhibitors, ACCs and x-blockers. All the pharmacological groups mentioned have a similar efficacy with regard to the control of blood pressure figures and are recognized as alternatives of first choice. Currently, monotherapy continues to be a mandatory practice as the first step in the pharmacological treatment of hypertension. Faced with a failure in the initial therapy, the various committees of experts consider several possibilities. In general, the one that maintains blood pressure figures below 140/90 mmHg is assessed as an adequate response. If this objective has not been reached after a period of time ranging from 1 to 3 months, several possibilities are contemplated which, although very similar in fundamental terms, present some differences depending on the organism that proposes them. Faced with a failure in initial therapy, WHO recommends replacing the initial drug with another drug belonging to a different group. If the response has been partial, it is considered preferable to add a second drug from another group at low doses, instead of increasing the dose of the first. Despite the undoubted benefits in terms of morbidity and mortality resulting from the treatment of hypertension, the results are not always as encouraging as might be expected and the treated patient continues to be at greater risk of cardiovascular complications than the normotensive subjects . One of the factors that contributes to this relative failure of antihypertensive therapy is the poor or suboptimal control that, in a good number of cases, is made of the hypertensive patient as a consequence of the adverse reactions associated with high doses of antihypertensive drugs and depletion. in compliance originated by multiple therapy. On the other hand, 35-50% of hypertensive patients do not present a satisfactory response to initial monotherapy (Medical Research Council Working Party, Trial of treatment of mild hypertension: main results, Br. Med. J., 1985; 291: 97-104 and Moser M. The fifth report on the Joint National Committee on detection, evaluation, and treatment of high blood pressure: a critique. Primary Cardiol. 1993; 16: 66-73). One of the causes of this high lack of response in the treatment of hypertension is the implementation of counterregulatory mechanisms that partially limit the antihypertensive effect. When any of the regulatory systems of blood pressure is modified, a compensatory response of the remaining factors of that control occurs. Each pharmacological group acts in a more specific way on any of these mechanisms, so that one of the primordial justifications of combined treatment is to affect at the same time on more than one of the triggering elements of arterial hypertension. Fixed-dose combinations of antihypertensive drugs should thus fulfill a threefold objective: increase in efficacy, by simultaneously acting on more than one of the blood pressure regulating mechanisms; improvement of tolerability ', by being administered at lower doses than each of its components separately; and improvement of therapeutic compliance as fewer doses are needed. Hence, the interest in the development of an association of an ACEI and an ACC seeking a synergistic action in the reduction of blood pressure, a reduction in the adverse effects of the ACC and an improvement in the therapeutic compliance since it is a single dose. The mechanism by which both active principles could be enhanced is complex. The ACCs give rise to ur. negative sodium balance that stimulates the renin-angiotensin system, an effect that is counteracted by ACE inhibitors. In addition, the administration of ACE inhibitors produces an increase in the vagal tone that would compensate for the sympathetic activation and tachycardia induced by the ACCs of the dihydropyridine group. The choice of enalapril as ACEI in the association of the present invention is motivated because it lowers blood pressure in all grades of essential and renovascular hypertension. It is at least as effective as other ACE inhibitors and other antihypertensive drugs from other pharmacological groups such as diuretics, β-blockers, ACCs and < *! - blockers. Its efficacy and safety has been demonstrated in numerous comparative clinical trials, and it has been commercialized in many countries for several years. The dose range usually used is 5 to 40 mg, once a day. The usual initial dose is 10 mg once a day in mild hypertension and 20 mg once a day in other degrees of high blood pressure. The usual maintenance dose is 20 mg once a day, which can be adjusted up to a maximum of 40 mg once a day, according to the individual needs of each patient.

In patients who do not usually respond to monotherapy, another drug from a different drug group may be added to provide an additional response. 5 ACEIs also improve survival in patients with congestive heart failure and can prevent or delay the development of left ventricular dilatation and heart failure in patients with symptomatic and asymptomatic left ventricular dysfunction.

The hemodynamic changes associated with both acute and long-term treatment with enalapril in patients with congestive heart failure include decrease in systemic vascular resistance (from 20% to 45%), decrease in mean arterial pressure (by 7%) yet 15%), decreased pulmonary capillary pressure (from 25% to 50%) and increased cardiac index (from 25% to 30%). Mortality and morbidity rates after long-term treatment (more than one year) improved by approximately 15% in patients with mild heart failure and moderate (SOLVD study N. Engl. J. Med. 1987; 316: 1429- 1435) and in approximately 30% in patients with severe heart failure (CONSENSUS study, N. Engl. J. Med. 1991; 325: 293 -302). The doses of enalapril recommended for this indication are 2.5 mg / day initially, increasing up to 10 to 20 mg / day according to the clinical response. Diabetic nephropathy is a clinical syndrome characterized by persistent proteinuria, progressive decrease in glomerular filtration rate and increased of blood pressure. Preceding these changes there is a silent period of variable duration during which the diabetic patient shows a persistent icroalbuminuria. The presence of microalbuminuria is important since it has been shown to be a predictor for clinical development of diabetic nephropathy. In normotensive patients with non-insulin-dependent or hypertensive diabetes mellitus controlled with nifedipine, the addition of enalapril 5 mg / day significantly decreases microalbuminuria, from 40% to 50%, over a period of 48 months. In follow-ups of 5 to 5 years, enalapril stabilizes microalbuminuria in normotensive patients with non-insulin-dependent diabetes mellitus better than placebo. The choice of nitrendipine as ACC in the association of the present invention is motivated by the fact that it possesses predominantly peripheral vasodilator properties, which induces sustained decreases in systolic and diastolic blood pressure. From different clinical trials it has been observed that nitrendipine lowers blood pressure in patients with mild-moderate hypertension and that this effect is maintained after long-term administration. In comparative clinical trials with diuretics, β-blockers and other ACCs it has been observed that nitrendipine has a similar efficacy -in the control of mild-moderate hypertension. He nitrendipino has been marketed in many countries for several years. The usual initial dose in patients with mild-moderate hypertension is 5 to 20 mg once a day. Depending on the response, the dose can be adjusted between 5 and 20 mg once or twice a day, either in monotherapy or combined with a diuretic or a / 3-blocker. Several have been the associations of ACEIs and ACCs that have been studied: cilazapril and nitrendipine (Nakanishi et al., Curr. Ther.Res. 1992; 52: 514-523), captopril and nitrendipine (Gennari et al., Cardiovasc. Ther. 1989; 3: 319-325), enalapril and felodipine (Morgan et al., Kidney International 1992; 41 (suppl.36): S78-S81). From these and other studies conducted on associations between ACEIs and ACCs, it can be concluded that the combined treatment is more effective and better tolerated than the treatment in monotherapy with each of them.

Different associations of ACE inhibitors and ACCs, of the dihydropyridine type, have also been described for the treatment of arterial hypertension in several patents, for example EP 488059, EP 180785, EP 265685, WO 9607400, EP 272177. However, it must be taken into account. that the first requirements to consider in the development of a fixed dose association is that both components are compatible from the pharmacokinetic and pharmacodynamic point of view.

Description of the invention Taking into account the above background, in the present invention we have proceeded to develop a fixed dose association of an angiotensin-converting enzyme (ACE) inhibitor, enalapril, and a calcium channel antagonist (ACC) , nitrendipine, drugs that, in monotherapy, have an efficacy and safety widely demonstrated in the treatment of hypertension and other cardiovascular diseases. In addition, enalapril and nitrendipine belong to different pharmacological groups with antihypertensive effect, so that their combined administration allows acting simultaneously on more than one of the blood pressure regulating mechanisms. The present invention also relates to a new pharmaceutical composition and its preparation process for oral administration and for its use in the treatment of arterial hypertension and other diseases of the cardiovascular system. This pharmaceutical composition consists of a single dose form containing fixed amounts of enalapril and nitrendipine. The molecule corresponding to enalapril (Formula I) has three chiral centers and therefore there can be eight different enantiomeric forms. The enantiomer which is known by the name of enalapril and which is used in this invention is 1- (N- ((S) -l-ethoxycarbonyl-3-phenylpropyl) -L-alanyl) -L-proline. Enalapril salts, such as salts with organic and inorganic acids, can be used (maleate, hydrochloride, ...) and salts with bases (sodium, potassium, magnesium salt). ._ " Formula I Nitrendipine (Formula II) has a chiral center and, therefore, can occur in two enantiomeric forms. However, the commercial product is the racemic mixture of the two isomers of the ethyl and methyl ester of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid. Nitrendipine salts can be used with organic and inorganic acids.

Formula II It is known the instability of enalapril maleate, as well as the great insolubility of nitrendipine. For these reasons, it has been developed, and is the object of the present invention, a process for the preparation of a galenic formulation that achieves a good stability of enalapril, in the form of a sodium salt, and a good solubility of nitrendipine, with which a rapid cession of the enalapril-nitrendipino association. The process of preparing the formulation consists, on the one hand, in the preparation of a granulating solution by dissolving the enalapril maleate and the sodium bicarbonate in sufficient quantity of water. On the other hand, the remaining components are mixed with the exception of a fraction of the disintegrating excipients (starch, microcrystalline cellulose) and lubricant (magnesium stearate). Said mixture is granulated with the granulant solution mentioned above. After drying the granules, a mass with a highly hydrophilic environment is obtained, which together with the action of the humectant (sodium lauryl sulphate) favors the dissolution of nitrendipine. The binder and mojante (polyvinylpyrrolidone and sodium lauryl sulphate) can be optionally incorporated into the granulating solution. In this way, a granulate is obtained which, after being dried to a residual humidity of less than 1.5%, calibrated and to which the remaining excipients are incorporated, can be compressed in a conventional press, obtaining stable tablets with quick release of both active principles. . The dose range of enalapril in the unit dose forms set in the association is between 2.5-20 mg, preferably between 10 and 20 mg. The dosage range of nitrendipine in the unit dosage forms set in the association is between 5-20 mg, preferably between 5 and 10 mg. With this form of administration of a single dose, the intake regimen is facilitated and acceptance by the patient is improved. Then, in the examples 1 and 2 two pharmaceutical formulations different from the association of enalapril and nitrendipino object of the present invention are described, as well as their obtaining procedure. In example 3 the results of the dissolution tests of enalapril and nitrendipine of the formulations obtained in examples 1 and 2 are described. In example 4 the pharmacological effect of the association of enalapril and nitrendipine evaluated in two experimental models is described : a) experimentally hypertensive rat and b) normotensive beagle dog. In Example 5 the pharmacokinetic compatibility is described and in Example 6 the effectiveness of the pharmaceutical formulations of the present invention in comparative clinical trials between enalapril, nitrendipinc and a solid dosage form of the fixed dose association of enalapril and nitrendipine.

EXAMPLE 1 This example describes the quantitative composition of a preferred formulation of the association of the present invention, as well as its manufacturing process.

Quantitative composition MALAATE OF ENALAPRIL 10.00 g MICRONIZED NITRENDIPINE 10.00 mg SODIUM BICARBONATE 5.00 mg MAIZE STARCH 64.50 mg SODIUM LAURYL SULPHATE 2.00 mg LACTOSE MONOHYDRATE 170.00 mg POLYVINYL PYRROLIDONE 8.00 mg MICROCRYSTALINE CELLULOSE 33.00 mg ESTEARATE OF MAGNESIUM 1,15 mg Manufacturing procedure: a) - Dissolve the enalapril maleate and the corresponding amount of sodium bicarbonate in a sufficient amount of demineralized water. b) - Properly mix nitrendipine with 80% of corn starch, sodium lauryl sulfate, lactose monohydrate, polyvinylpyrrolidone and 20% of microcrystalline cellulose, previously sieved, c) -. - Granulate in high speed granulation equipment the homogenized products in section 2 with the solution obtained in section 1. d). - Dry the granulated mass in fluid bed equipment until obtaining a value of. residual humidity less than 1.5%. e) .- Calibrate the dry granulate. Incorporate the remaining 20% of corn starch and the remaining 80% of microcrystalline cellulose and magnesium stearate, previously sieved and homogenize with the calibrated granulate, f) .- Compress in conventional press.

The stability results of enalapril and nitrendipine in this formulation as a function of time are indicated in the attached tables 1 and 2. For this, the formation of the degradation products is quantified: diketopiperazine and enalaprilic acid in the case of enalapril, and pyridinic derivative in the case of nitrendipine.

Table 1.- Stalapril stability results of the formulation of example 1 as a function of time.

Degradation products Content in% of Enalapril Dicetopiperazine Enalaprilic acid Initial T. Amb. 103.1 0.04 0.04 3 months T. Amb. 103.7 0.00 0.08 3 months 40 ° C 102.3 0.04 0.12 3 months 40 ° C + 75% RH 102.6 0.04 0.12 3 months 50 ° C I02"3 0.19 0.41 Table 2.- Ritrendipine stability results of the formulation of example 1 as a function of time.

EXAMPLE 2 In this example another preferred formulation of the association of enalapril and nitrendipine and its manufacturing process is described.

Quantitative composition ENALAPRIL MALEATE 20.00mg MICRONIZED NITRENDIPIN 5.00 mg SODIUM BICARBONATE 10.00 g MAIZE STARCH 40.00 mg SODIUM LAURYL SULPHATE 7.50 g LACTOZE MONOHYDRATE 116.75 mg POLYVINYL PYRROLIDONE 11.20 mg MICROCRYSTALINE CELLULOSE 80.00 mg ESTEARATE MAGNESIUM 2.20 mg Manufacturing procedure a) .- Dissolve the enalapril maleate and the corresponding amount of sodium bicarbonate in a sufficient amount of demineralized water. b) - Properly mix Nitrendipine with 90% of corn starch, sodium lauryl sulfate, lactose monohydrate, polyvinylpyrrolidone and microcrystalline cellulose, previously sieved. c) .- Granulate in fluid bed equipment the products homogenized in section 2 with the solution obtained in section 1. d). - Dry the granulated mass in fluid bed equipment until a residual moisture value of less than 1.5% is obtained. e) .- Calibrate the dry granulate. Incorporate the remaining 10% of corn starch and magnesium stearate, previously sieved and homogenize with the calibrated granulate. f) - Compress in conventional press.

The results of stability of the two active principles, enalapril and nitrendipine, in the formulation of this example, as a function of time, are described below in Tables 3 and 4.

Table 3. - Results of enalapril stability of the formulation of example 2 as a function of time.

Table 4.- Stability results of the nitrendipmo of the formulation of example 2 as a function of time.

EXAMPLE 3 In vitro dissolution tests have been carried out 6 tablets of each of the formulations described in examples 1 and 2. The average results obtained for enalapril and nitrendipine are described in the following Boards .

Table 5: Enalapril dissolution results of the formulations of examples 1 and 2 as a function of time.

Table 6: Nitrendipine dissolution results of the formulations of examples 1 and 2 as a function of time.

The above results are shown in the following figures 1 and 2, in which the cumulative profiles of the m vitro solution of enalapril and nitrendipine are shown for the 6 tablets tested in the formulations of examples 1 and 2.

- * - Epa prll EJßmplol - * - Enalaprll EJ «? Rplo 2 Figure 1. Cumulative profile of in vitro dissolution of enalapril for the 6 tablets tested in the formulations of examples 1 and 2.

? - Nltrßn lplno Example 1 - * - Nltrßndlplno EJ «rtplo 2 Figure 2. Cumulative profile of in vitro dissolution of nitrendipine for the 6 tablets tested of the formulations of examples 1 and 2.

EXAMPLE 4 The pharmacological effect of the association of enalapril and nitrendipine of the present invention has been evaluated in two experimental models: a) Antihypertensive activity in experimentally hypertensive rat by aortic coarctation The antihypertensive activity of the association of enalapril and nitrendipine with each of the components isolated in a model of experimental hypertension by rat aortic coarctation. The measurement of blood pressure has been made with the conscious animal. The doses tested were the following: - Enalapril Maleate 1 mg / Kg (p.o.) - Nitrendipine 3 mg / Kg (p.o.) - Enalapril Maleate and Nitrendipine (1 and 3) mg / Kg (p.o.) - Enalaprily Maleate Nitrendipine (0.5 and 1.5) mg / Kg (p.o.) The control group received the vehicle (CMC 1% in distilled water), the volume of administration being 10 mg / Kg (p.o.). The data obtained are shown in table 7 and figure 3. The oral administration of enalapril maleate (1 mg / kg) showed a moderate antihypertensive effect, but persistent until 6 hours after administration. Oral administration of nitrendipine (3 mg / Kg) produced a marked but little sustained antihypertensive effect, returning to baseline values at 4 hours after administration. The coadministration of enalapril maleate (1 mg / kg, p.o.) and nitrendipine (3 mg / kg, p.o.) produced an antihypertensive effect superior to that of enalapril administered alone (1 mg / kg, p.o.). The trial of doses lower than the initially used of the association, (0.5 and 1.5 mg / Kg, po) of enalapril maleate and nitrendipine has shown an antihypertensive effect equivalent to the association (1 and 3 mg / Kg) , po) of enalapril and nitrendipine maleate, as well as an extension of the duration of the antihypertensive effect obtained with the individual treatments, so that the synergistic effect of the association can be concluded. vo El'ccto anli ipcitcnsivo cp lala Inpcrtcnsa by aortic coarctation. Blood pressure (systolic and diastere), mean values b) Hypotensive activity in normotensive beagle dog The hypotensive effect of the association of enalapril and nitrendipine (1: 1) in beagle dog has been studied, obtaining physiological data from a 26-week chronic toxicity study; enalapril maleate and nitrendipine (1: 1) have been administered at doses of 1 and 1; 3 and 3; .and 6 and 6 mg / Kg / day orally for 26 weeks in the form of capsules. During the treatment period, systolic, diastolic blood pressure was recorded and the mean pressure was calculated in baseline conditions and after 1, 4, 13 and 26 weeks of treatment. In each of these times blood pressure has been recorded before administration and at 4 and 8 hours after administration. The results obtained are shown in table 8. The oral administration maleate enaiapril and nitrendipine (1: 1) for 26 weeks at doses of 1 and 1; 3 and 3; and 6 and 6 mg / Kg / day manifests an appreciable hypotensive effect already in the week of treatment. The maximum effect appears at 4 hours after administration and is still maintained at 8 hours after the same. This hypotensive effect intensifies with the time of treatment, with the lowest blood pressure records appearing at 13 weeks. Thus in this study a clear pharmacological effect of the association of enalaprii maleate and nitrendipine (1: 1) at the doses of 1 and 1 is observed; 3 and 3; and 6 and 6 mg / Kg / day (p.o.) 8 Hypotensive effect of the association of enalapril maleate and nitrendipine (1: 1) in normotensive beagle dog. Administration for 26 weeks. Blood pressure. Mean values and standard deviation O BASAL ATTACK WEEK 1 WEEK 4 WEEK 13 WEEK 26 mg / Kg / day Oh 4h 8h Oh 4h Sh Oh 4h 8h Oh 4h 8h Sis. 124 120 123 130 119 1 18 123 123 120 119 127 125 133 (16.2) (23.7) (18.5) (10.3) (20.8) (17.5) (14.5) ( 19.4) (18.4) (16.8) (20.3) (14.5) (18.4) Days. 80 78 82 83 76 75 75 78 78 76 84 79 84 Control (12.7) (14.7) (13.2) (8.4) (12.8) (11.2) (10.5) (12.9) (16.7) (13.3 ) (14.5) (9.5) (1.3) Med. 95 92 95 99 90 90 91 93 92 91 98 95 100 (13.7) (17.4) (14.6) (8.5) (15.3) (12.6) (U, 4) (14.7) (16.8) (13.9) (16.2) (10.8) (13.6) Sis. 120 1 13 104 1 19 112 103 112 112 103 109 113 107 1 13 (15.6) (16.5) (9.9) (13.5) (12.5) (13.6) (11.0 ) (15.3) (16.0) (20.9) (16.9) (18.9) (17.1) to enalapril and Dias. 81 74 66 75 76 63 66 73 65 72 73 68 71 yield (1: 1) (8.2) (9.4) (9.8) (6.0) (6.8) (6.0) ( 10.3) (8.0) (7.6) (15.3) (7.0) (7.5) (9.9) 1 ivy 1 i Med. 94 87 79 90 88 16 82 86 78 84 87 81 85 (10,1) (11,5) (9,1) (8,2) (8.1) (8,2) (10, 3) (9.9) (10.0) (16.7) (10.0) (11.1) (11.3) Sis. 126 132 96 121 118 98 113 116 93 108 123 99 111 (13,7) (18,9) (14,0) (14,1) (12,5) (14,1) (20,4) (13 , 0) (11.0) (13.1) (19.8) (14.3) (17.1) to enalappl and Days. 83 83 55 73 72 58 70 73 61 68 80 59 69 endipin (1: 1) (8.5) (9.6) (6.5) (8.0) (7.0) (10.0) ( 9.6) (7.6) (7.8) (1.3) (10.7) (1.3) (1.5) 3 and 3 Med. 97 99 68 89 87 72 84 87 72 81 94 72 83 (9.5) (1 1, 9) (8.0) (9.2) (8.7) (1 1.0) (12.7) (9.3) (8, 6) (11.1) (13.4) (1.9) (13.0) Sis 125 127 93 1 13 113 92 103 116 85 100 117 92 100 (15.2) (13.5) (12, 1) (8.3) (12.1) (6.9) (13.9) (12.5) (1.1) (12.3) (15.6, 1.8) (11.6) to enalappl and Days. 81 83 55 67 75 51 60 74 53 57 78 55 61 endipin (1 1) (10,8) (10,3) (6,2) (6,2) (10,1) (8,3 (11, 1) (8.6) (6.6) (8.6) (11.5) (6.6) (9.3) 6 and 6 Med. 96 98 69 86 87 65 74 88 64 71 91 68 74 (1 1, 2) (10,8) (6,0) (10,7) (10,3) (6,5) (1 1,9) (9,6) (7,1) (9, 2) (12.5) (7.1) (9.7) systolic blood pressure Days = diastolic blood pressure Med. = Mean arterial pressure EXAMPLE 5 A pharmacokinetic interaction study was performed after a single dose of enalapril 20 mg, nitrendipine 20 mg and the fixed-dose association of enalapril and nitrendipine 20 mg of each of the active ingredients, in 24 healthy volunteers (10 men and 14 women). For this, a randomized, open and crossed clinical trial with 3 treatment periods was designed, according to a 3x3 Latin square, with a 15-day laundering period between each of the treatment periods. In each treatment period, 16 blood samples were taken from each volunteer, from baseline to +96 hours postadministration, and the plasmatic concentrations of enalaprilat and nitrendipine were determined. From these data, the pharmacokinetic parameters that measure the bioavailability in magnitude (AUC0-infinity) and velocity (C ^, C ^ / AUC0.infinite 7 tmai) were calculated and a statistical analysis (ANOVA) was performed to evaluate the significance statistics of the differences between the means of each of these parameters. This analysis showed no statistically significant differences between the isolated intake of nitrendipine or enalapril and the joint intake in the fixed dose combination. The relative bioavailability (AUC0.lnfin? To) of enalaprilat after its combined intake compared to its isolated intake is 1.12. The relative bioavailability (AUC0.?nfin?to) of nitrendipine after its combined intake compared to its isolated intake is 0.91. Therefore, it can be concluded that there is no clinically relevant pharmacokinetic interaction between nitrendipine and enalapril after the administration of a single dose of 20 mg of each of the active ingredients separately and in their fixed dose combination in the pharmaceutical formulations of the present invention .

EXAMPLE 6 An open-label, placebo-controlled clinical trial was conducted in male patients with mild-moderate hypertension, defined as systolic blood pressure (SBP) values between 165 and 144 mmHg and diastolic blood pressure (DBP) between 95 and 105 mmHg, taken in decubitus position after 5 minutes of rest. After a 2-week placebo-lasting period, patients who met the criteria for mild-moderate hypertension were treated with nitrendipine 5 mg once daily (9 patients) or enalapril 5 mg once daily (11 patients) during 2 weeks, at the end of which the patients who did not respond to the treatment (TAD <; 90 mmHg) received combination treatment with the fixed-dose combination of nitrendipine and enalapril 5 mg of each of the components, once a day, for a period of 2 more weeks of treatment. Treatment with monotherapy only normalized blood pressure in 3 patients (15%), 2 treated with enalapril and 1 treated with nitrendipine. The combined treatment with the association normalized blood pressure in 14 patients (82%). The mean decrease in the TAS and TAD figures compared to the end of the placebo period was 5 mmHg / 2 mmHg after the treatment period with monotherapy (non-significant differences) and 24 mmHg / 16 mmHg after the period of combined treatment with the fixed dose association (p <0.001). It can therefore be concluded that the combined administration of nitrendipine and enalapril in a fixed dose combination achieves effective control of mild to moderate hypertension in the majority of patients with doses that, administered as monotherapy, do not have a clinically relevant effect in the treatment. Of the same .

Claims (12)

R E I V I ND I C A C I O N S

1. Fixed-dose association of an angiotensin-converting enzyme inhibitor and an antagonist of 5 calcium channels, characterized in that said association comprises a dose of (a) enalapril or a pharmaceutically acceptable salt thereof and another dose of (b) nitrendipine or a pharmaceutically acceptable salt thereof and by the fact that it is administered in galenic form 10 of unit dose.

2. Fixed dose association according to claim 1, characterized in that the dose of enalapril or a pharmaceutically acceptable salt thereof is between 2.5 and 20 mg, preferably between 10 and 20 15 mg. Association according to claim 1, characterized in that the dose of nitrendipine or a pharmaceutically acceptable salt thereof is between 5 and 20 mg, preferably between 5 and 20 mg. 20 10 mg. 4. Fixed dose association according to any of claims 1 to 3, characterized in that the unit dose form is a capsule. 5. Fixed dose association according to any of claims 1 to 3, characterized in that the unit dose form is a tablet. 6. Fixed dose association according to any of claims 1 to 3, characterized in that the unit dose form is single-dose sachets with powder 30 for extemporaneous solution. 7. Fixed dose association according to any of claims 1 to 6, characterized in that enalapril is in the form of a sodium salt. 8. Fixed dose association according to any of claims 1 to 6, characterized in that the nitrendipine is micronized. A pharmaceutically acceptable composition comprising a fixed dose association according to any of the claims ß, characterized in that the galenic formulation further comprises a plastic diluent, preferably microcrystalline cellulose, a fragmentary diluent, preferably lactose, a disintegrating agent, preferably corn starch, a binding agent, preferably polyvinylpyrrolidone, a wetting agent, preferably sodium lauryl sulfate, and a lubricating agent, preferably magnesium stearate. 10. Process for obtaining a pharmaceutically acceptable composition according to claim 9, characterized in that it comprises: (a) - dissolving enalapril maleate in water with an inorganic salt, preferably sodium bicarbonate; (b) - mixing the micronized nitrendipine with a fraction of the disintegrating excipients, preferably corn starch, the wetting agent, preferably sodium lauryl sulfate, the fragmentary diluent, preferably lactose monohydrate, the binding agent, preferably polyvinylpyrrolidone and the diluent plastic, preferably microcrystalline cellulose, previously sieved; (c) - granulate the homogenised products in the section (b) with the solution obtained in section (a); (d) - drying the granulated mass to a residual moisture of less than 3%, preferably less than 1.5%; (e) - incorporating the lubricating agent, preferably magnesium stearate, and the remaining fraction of the disintegrating excipients and homogenizing the calibrated granulate; (f) - compress the granulate, or fill the capsules or the single-dose envelopes. The process according to claim 10, characterized in that the moistening agent and the binding agent of step (b) are previously dissolved in step (a). 12. Use of a fixed dose combination of a dose of enalapril and another dose of nitrendipine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diseases of the cardiovascular system, in particular arterial hypertension in mammals, especially in man, by means of an administration of an effective amount of the fixed-dose association of enalapril and nitrendipine. SUMMARY It comprises (a) enalapril or a pharmaceutically acceptable salt thereof and (b) nitrendipine or a pharmaceutically acceptable salt thereof, which is administered in dosage unit dosage form. The procedure comprises: a) dissolving enalapril - in water with an inorganic salt, b) mixing the nitrendipine with a fraction of the disintegrating excipients, wetting agent, fragmentary diluent, binder and plastic diluent, previously sieved; c) granulating the mixture of section (b) with the solution obtained in section (a); (d) drying the granulated mass, (e) incorporating the lubricating agent and the remaining fraction of excipients and homogenizing the calibrated granji side; Cf) compress the granulate. Use of said association for the manufacture of a medically for the treatment of Sikh diseases. cardiovascular theme.