WO2016132192A1 - Pharmaceutical compositions for treating hypertension, based on a novel drug combination - Google Patents

Pharmaceutical compositions for treating hypertension, based on a novel drug combination Download PDF

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WO2016132192A1
WO2016132192A1 PCT/IB2015/059751 IB2015059751W WO2016132192A1 WO 2016132192 A1 WO2016132192 A1 WO 2016132192A1 IB 2015059751 W IB2015059751 W IB 2015059751W WO 2016132192 A1 WO2016132192 A1 WO 2016132192A1
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lercanidipine
eprosartan
combination
active ingredients
pharmaceutical composition
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PCT/IB2015/059751
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Spanish (es)
French (fr)
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José Manuel Francisco LARA OCHOA
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Invekra, S.A.P.I. De C.V.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • compositions constituted by the blocker of the angiotensin II receptors of the generic name Eprosartan and the calcium antagonist of the generic name Lercanidipine were developed for the treatment of hypertension, same compositions that offer advantages in efficacy and tolerability in a single fixed dose in class, in relation to commercially available medications.
  • HA Arterial hypertension
  • Recommendation 9 of the JNC it is proposed in Recommendation 9 of the JNC to use even up to a triple combination, consisting of: a thiazide diuretic, an antagonistic calcium and either an inhibitor of ECA or a BRA. With respect to the latter alternative, it is specified in the same Recommendation 9 of the JNC not to use an ACE inhibitor or BRA together.
  • the advantages of combination therapy include: 1) greater reduction in blood pressure and a faster response rate than with monotherapy, caused by simultaneous effects on several regulatory systems involved in the abnormal elevation of blood pressure, 2) minor adverse effects, with consequent better tolerability and improved compliance with treatment and 3) probably lower treatment costs. (Lancet, 351, 1755-1762 (1998); BMJ, 317, 703-713 (1998); N. Engl. J. Med. 342, 145-153 (2000); JAMA, 288, 2981-2997 (2002) ; Am. J. Hypertens, 1 1, 73S-78S (1998); Drugs, 62, 443-462 (2002)).
  • compositions based on the combination of a second generation BRA antihypertensive drug that is Eprosartan and a third generation antagonist calcium that is Lercanidipine, to be used in cases recommended for this type. of combinations such as when there is no response with monotherapy, when there are additional disorders such as type II diabetes, chronic kidney disease and other concurrent conditions where the recommendation for pressure control is less than 140/90 mm Hg. DESCRIPTION OF THE INVENTION
  • compositions have been developed, using as combination active agents the combination of the antihypertensives acid (E) -3- [2- butyl-1 - [(4-carboxyphenyl) -methyl] -imidazol-5-yl] - 2- (2-thienylmethyl) -2-propanoic and generic name Eprosartan, combined with methyl 1,1,1-dimethyl-2- [N- (3,3-diphenylpropyl) -N-methylamino] ethyl 2,6-dimethyl -4- (3-nitrophenyl) -1, 4-dihydropyridine-3,5-dicarboxylate of generic name Lercanidipine or any of its pharmaceutically acceptable salts and Physiologically tolerated, preferably Eprosartan Mesylate combined with Lercanidipine Hydrochloride.
  • Eprosartan is an angiotensin II type I receptor blocker (BRA).
  • Lercanidipine is a drug that acts in the treatment of
  • the classic vision is to consider the renin / angiotensin / aldosterone system, which constitutes an adaptive mechanism to protect the integrity of vital organs.
  • This system is activated when there is a decrease in intravascular volume or inadequate tissue perfusion, in order to maintain proper blood flow.
  • This system consists of the kidney / liver / blood synthesis axis of angiotensin II, by means of the catalytic action of the conversion enzyme of Angiotensin I.
  • the renin / angiotensin system has been found in the brain, pituitary gland, blood vessels, heart and adrenal cortex, where the messenger RNAs of renin, angiotensin, angiotensinogen and ACE have been identified.
  • renin messenger RNAs of renin, angiotensin, angiotensinogen and ACE have been identified.
  • renin / angiotensin system plays a fundamental role in the physiology of HA, heart failure, and cardiovascular diabetic nephropathy.
  • the final consequence of hyperactivation of this system is an increase in morbidity and mortality (N. Engl. J. Med. 355, 637-645 (2000)).
  • renin / angiotensin system blockade at the cardiovascular level is that the potent vasoconstrictor effect of angiotensin II is eliminated and sodium reabsorption at the level of the proximal tubule is reduced, the left ventricular muscle mass is reduced, and there are a decrease in sympathetic stimulation (effect produced in part by an inhibition of adrenaline and nodurenaline secretion from the adrenal medulla (Drugdesk Editorial Staff. Eprosartan a drug evaluation monograph. In Hutchison, TA, Shahan, DR, Anderson, MN, eds Drugdex Englewood Colorado System. Micromedex Inc. 2000, 105.).
  • Eprosartan or (E) - - [2-butyl-1 - [(4-carboxyphenyl) methyl] -1 H -imidazol-5-yl] methylene-2-thiophenepapanoic acid is the only one in its group, which in addition to blocking the postsynaptic (vascular) AT1 receptors, also blocks presynaptic (neuronal) receptors, which implies greater pharmacological potency, since this stimulation results in a release of norepinephrine, which results in a vasoconstrictor effect.
  • cytochrome P450 is not involved in Eprosartan metabolism, interactions with other drugs are unlikely, including drugs with which there are usually interaction warnings such as Digoxin, Ranitidine, Hydrochlorothiazide, Fluconazole or Ketoconazole, which act as potent specific inhibitors of certain cytochrome isoenzymes (Pharmacotherapy, 19, 73S-83S (1999)). This differentiates them from Losartan, for which an important interaction with Fluconazole has been described, such that when they are supplied together, the hepatic transformation of Losartan into its main active metabolite does not occur (Clin. Pharmacol. Ther, 62, 417-425 (1997)). In a cross-controlled, placebo-controlled study, no pharmacodynamic interaction of Eprosartan was observed.
  • Lercanidipine has been classified by the FDA as a drug with low permeability and has a slow onset in its effects, but a longer duration of action than other dihydropyridines (Expert. Opin. Investig. Drugs, 8, 1043-1062 (1999)) .
  • the preferential distribution of the drug in the smooth muscle cell membranes results in a pharmacokinetics, characterized by a pharmacological effect. prolonged, resulting in a control of blood pressure up to 24 hours after the delivery of a dose (Vascular Health and Risk Management, 4, 1 159-1 166 (2008)).
  • the drug is highly vasoselective due to the high proportion of L-type calcium channels in arteries and has shown less negative ionotropic activity in vitro and in vivo than other dihydropyridines.
  • Lercanidipine is a well tolerated drug, with a low rate of adverse events due to its long-acting vasoselective calcium blocker activity and does not cause sympathetic activation and given its slow onset of action reflex tachycardia is rare (Heart Dis. 3, 398-407 (2001)). As a result, the total rate of adverse events is lower than that observed with other dihydropyridines (Int. J. Clin. Pract. 62, 723-728 (2008)).
  • Lercanidipine may have antiatherogenic effects (Vasc. Health Risk Manag. 3, 255-263 (2007)); Br. J. Pharmacol. 125, 1471-1476 (2003); Clin. Pharmacol Ther. 72, 302-307 (2007)). Another benefit reported is its renoprotective effect, which is related to its ability to induce both afferent and efferent arteriolar vasodilation (Ren. Fail. 27, 73-80 (2005); Diabetes Nutr. Metab. 17, 259-266 (2004) ). Lercanidipine was also superior to Ramipril in reducing albumin excretion in diabetic patients with microalbuminuria (Diabetes Nutr. Metab. 17, 259-266 (2004)).
  • Lercanidipine In diabetic patients with hypertension, treatment with Lercanidipine was able to decrease glycosylated hemoglobin levels significantly, without negatively affecting glucose homeostasis, raising glucose tolerance and reducing fasting blood glucose, with favorable values in the profile of lipids (Drugs, 63, 2449-2472 (2003); J. Cardiovasc. Pharmacol. 40, 133-139 (2002)). In addition, in diabetics with renal failure Lercanidipine has a good tolerability profile and neutral effect on plasma lipids with no weakening of renal function (Nefrologia, 24, 338-343 (2004)).
  • Lercanidipine In hypertensive patients with metabolic syndrome, Lercanidipine has a better tolerability profile and was associated with lower adverse effects related to vasodilation than other calcium channel blocker dihydropyridines (Int. J. Clin. Pract. 62, 723-728 (2008)) . In contrast to beta blockers and diuretics, which worsen insulin resistance (J. Hypertens, 23, 1779-1781 (2005)) and increase total cholesterol, high density lipoproteins and total glyceride levels ( Amer. Heart J., 21, 973-985 (2000)) and then the risk of diabetes (N. Engl. J. Med. 13, 905-912 (2000)) calcium antagonists are metabolically neutral.
  • Atenolol / Flumetazine was associated with a significant high risk of new onset of diabetes compared to the group treated with Perindopril and Amlodipine (Lancet, 366, 895-906)), especially when glucose Fasting plasma was 5 mmol / L (Diabetes Care, 31, 982-988).
  • the extensive use of calcium antagonists in clinical practice has been limited by a frequent side effect of peripheral edema.
  • peripheral edema developed in 23% of treated patients and was the main cause of the interruption of Amlodipine.
  • the main advantage of Lercanidipine is that it induces less peripheral edema than other dihydropyridines.
  • peripheral edema develops in 0.6% to 9% of treated patients (at the dose of 10 mg per day), which is considerably lower than that reported in the ASCOT study.
  • Observational studies have shown that in patients initially treated with a first-generation dihydropyridine and switched to Lercanidipine the probability of developing peripheral edema is reduced by approximately 50% (Blood Press Suppl., 1, 14-21 (2003)). In an observational study published by Burnier et al. (Expert. Opin. Pharmacother. 8, 2215-2223 (2007)) this percentage was even lower. Lercanidipine also reduces the signs and symptoms of ischemia and improves heart function in patients with angina (Am. J. Ther. 1 1, 423-432 (2004)).
  • Lercanidipine over first and second generation dihydropyridines is its lower incidence of adverse effects, in particular peripheral edema, better renal protection, less chronic renal damage and / or proteinuria and its metabolic neutrality (Hypertension, 35, 775 -779 (2000); Ren Fail, 1, 73-80 (2005)).
  • Several pharmacological reasoning have been used for the use of a combination therapy. In the first case, 30% to 50% of patients do not respond to monotherapy. In a second case there is a need to comply with the guidelines that increasingly seek treatments of the most aggressive levels of hypertension.
  • the "World Health Guidelines" have recommended a diastolic blood pressure of less than 85 millimeters of mercury and a systolic blood pressure of less than 130 millimeters of mercury in young patients and in diabetic patients.
  • Another case is the fact that multiple physiological systems participate in the control of blood pressure and it has been proposed that they trigger counter-regulatory mechanisms, which is why the loss of efficacy has been attributed to this after a certain time of using monotherapy.
  • a combination treatment increases the number of mechanisms potentially capable of reducing high blood pressure and reducing the speed and magnitude of the adverse effects produced by each drug.
  • Combination therapy is also recommended when a combination of drugs can allow the use of lower doses of each drug, reducing the risk of dose-related adverse reactions, while the sum of complementary mechanisms of action allows blood pressure to be sufficiently counteracted. .
  • ACEI angiotensin II converting enzyme
  • BRA angiotensin II receptor blocker
  • the ACEI has to attenuate vasoconstriction by reducing the vasoconstrictive effect of Angiotensin II and increasing the vasodilator kinins, while the antagonist calcium acts by attenuating the calcium flow through the membranes inhibiting calcium-mediated electromechanical coupling in the contractive tissue in response to numerous stimuli.
  • both classes of drugs They facilitate the excretion of salt and water by the kidney through different mechanisms.
  • the ACEI restores the renal-adrenal response to salt accumulation, while the antagonistic calcium possesses sodiournetic properties, probably acting through a mechanism of inhibition of tubular salt and water reabsorption (AJH, 1, 1, 163S - 169S (1998)). It has been proposed that calcium antagonists that do not share the mode of action of the renin / angiotensin / aldosterone system (ACE) inhibitors should provide synergistic and complementary effects to the latter (Patient Preference and Adherence, 6, 449-455, 2012) ; J. Cardiovasc. Pharmacol 21 (suppl.2), S49-S54 (1993)).
  • ACE angiotensin / aldosterone system
  • ACL and calcium antagonists such as the combinations of Ramipril and Felodipine, Benazepril and Amlodipine, Manidipine and Delapril, Trandolapril and Verapamil, Enalapril with Felidipine, Enalapril with Diltiazem, and Lercanidipine with Enalapril, among others Patient Preference and Adherence, 6, 449-455, 2012).
  • the EX-STAND clinical study showed that therapy in patients with hypertension 2 using BRA Valsartan also a member of the pans family, combined with the antagonistic calcium Amlodipine achieved greater reductions in blood pressure after 8 weeks of reaching treatment until a decrease of 33 mm of mercury while monotherapy with Amlodipine only reached a decrease of only 26.6 mm of mercury (J. Hum. Hypertens. 23, 479-489 (2009)).
  • the COACH study showed that therapy with the combination of BRA Olmesartan combined with Amlodipine was significantly more effective than treatment using only Amlodipine in patients in state 2 of hypertension (Clin. Ther. 30, 587-604 (2008)).
  • Losartan is a prodrug, which needs to be metabolized to be transformed into a more active metabolite, while Valsartan exerts its effect without being metabolized (J. Hum. Hypertens. 13 Suppl. 1, S1 1 - S20 (1999)).
  • the conclusions in general are that both Losartan Amlodipino and Valsartán Amlodipino combinations were well tolerated with a comparable incidence of adverse effects and these incidences were lower than those observed with Amlodipine monotherapy.
  • Eprosartan a second generation BRA antihypertensive
  • Lercanidipine shows greater efficacy and significant greater tolerance and with less adverse effects than monotherapy using other members of the family of analogs of 1,4 dihydropyridines such as Amlodipine, the most widely used drug in this family.
  • the purpose of the present invention is the development of pharmaceutical compositions based on the combination of BRA Eprosartan and calcium antagonist Lercanidipine.
  • Eprosartan shows superior efficacy to other members of the "sartanes" family such as Losartán, Valsartán, Candesartán and others.
  • calcium antagonist Lercanidipine has a greater efficacy and significant greater tolerance and with less adverse effects than monotherapy, with other members of the family of analogs of 1,4 dihydropyridine, As is Amlodipine, the most widely used drug in this family.
  • One of the pharmaceutical compositions that has been developed consists of immediate-release tablets.
  • the composition has been developed by preparing an independent granulate for each of the active ingredients.
  • the same procedure was followed to Lercanidipine, in which granules were used excipients that were stable in admixture with the active excipient and the dissolution profiles of the manufactured tablets were adjusted to meet the dissolution profiles of commercial drugs with Lercanidipine as a monopharmaceutical. These granules were mixed and a lubricant and a disintegrant were added. The new mixture was compressed to obtain tablets that met the appropriate hardness and friability.
  • the Hydrochloride salt shows a solubility in water of 5 mg / ml and in acid medium, although it increases slightly, however at pH 5 it is less than 20 mg / ml.
  • Lercanidipine has been classified by the FDA as a drug with low permeability.
  • Lercanidipine is a substrate of the citrochrome P450 3A4 isoenzyme which partially degrades the drug.
  • a powder presentation composition has been formulated to be reconstituted in suspension.
  • a pharmaceutical composition has also been developed as an intravenous injection.
  • EXAMPLE 1 Immediate-release tablets of the combination of Eprosartan Mesylate equivalent to 600 mg of Eprosartan with Lercanidipine Hydrochloride equivalent to 9.4 mg of Lercanidipine. Process of manufacturing tablets by wet granulation.
  • EXAMPLE 2 Prolonged-release tablets of the combination Eprosartan Mesylate equivalent to 600 mg of Eprosartan, with Hydrochloride Lercanidipine equivalent to 9.4 mg of Lercanidipine. Manufacturing process by wet granulation.
  • a sealing coating or protective coating serves to separate the assets (Eprosartan and Lercanidipine) of the extended release coating, it also acts as a seal to eliminate the porosity of the tablet.
  • Solution A (protective or sealing coating). Add purified water at room temperature (20-35 ° C) in a suitable capacity container and with continuous stirring add the White Opadry. Maintain stirring for 30 minutes or until complete dissolution.
  • Dispersion B extended release coating
  • purified water considering a final dispersion of 15% solids.
  • the Coating Solution A is sprayed on the cores using a coating drum, under the following conditions: inlet air temperature from 55 ° C to 75 ° C, product temperature from 38 ° C to 45 ° C, spray pressure from 1 .0 to 3.0 bar, sprinkler speed from 8 to 15 g / min.
  • inlet air temperature from 55 ° C to 75 ° C
  • product temperature from 38 ° C to 45 ° C
  • spray pressure from 1 .0 to 3.0 bar
  • sprinkler speed from 8 to 15 g / min.
  • EXAMPLE 3 Immediate-release tablets of Eprosartan Mesylate equivalent to 600 mg of Eprosartan and extended-release tablets of Lercanidipine Hydrochloride equivalent to 9.4 mg of Lercanidipine. Manufacturing process by wet granulation.
  • Crospovidone Polyplasdone XL 38.50
  • the Lercanidipine 50.94% of the microcrystalline cellulose, 21 .89% of the M200 lactose monohydrate, add the materials to the high-cut granulator and mix.
  • the agglutinate solution is prepared, in a container of adequate capacity add water purified and alcohol in a ratio of 60:40 and with continuous stirring add povidone K30, keep stirring until you have a homogeneous solution.
  • EXAMPLE 4 Powder for oral suspension, each 5 mL contains Eprosartan Mesylate equivalent to 600 mg of Eprosartan and Lercanidipine Hydrochloride equivalent to 9.4 mg of Lercanidipine.
  • Solution No. 3 With continuous agitation add to Solution No. 3, Solution No. 1 and Solution No. 2, perform the capacity and homogenize the solution. Under aseptic conditions the sterilization process is carried out which is by filtration, the filtering process is carried out through a 0.22 ⁇ filter, then the sterile area is packaged in amber glass bottle.

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Abstract

The invention relates to novel pharmaceutical compositions for treating patients with hypertension, which use, as active ingredients, the second-generation angiotensin II receptor type 1 blocker eprosartan combined with the third-generation calcium antagonist lercanidipine. These active ingredients, eprosartan and lercanidipine, have proven, as single agents, to be more effective and to have less adverse effects and an increased tolerance compared to other, commercially available, hypertensives. The combination is produced in the form of immediate-release and sustained-release tablets, as well as a powder for a suspension, the latter composition being useful for certain states of patients whose physical state does not allow the ingestion of tablets or capsules and an intravenous injectable form has been developed for cases where immediate bioavailability is required.

Description

COMPOSICIONES FARMACEUTICAS PARA EL TRATAMIENTO DE LA HIPERTENSIÓN CON BASE EN UNA NUEVA COMBINACION DE FARMACOS  PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF HYPERTENSION BASED ON A NEW COMBINATION OF PHARMACOS
CAMPO DE LA INVENCION FIELD OF THE INVENTION
Composiciones farmacéuticas constituidas por el bloqueador de los receptores I de la angiotensina II de nombre genérico Eprosartán y el calcio antagonista de nombre genérico Lercanidipino fueron desarrolladas para el tratamiento de la hipertensión, mismas composiciones que ofrecen en una sola dosis fija ventajas en eficacia y en tolerabilidad en su clase, en relación a los medicamentos disponibles comercialmente. Pharmaceutical compositions constituted by the blocker of the angiotensin II receptors of the generic name Eprosartan and the calcium antagonist of the generic name Lercanidipine were developed for the treatment of hypertension, same compositions that offer advantages in efficacy and tolerability in a single fixed dose in class, in relation to commercially available medications.
ANTECEDENTES BACKGROUND
La hipertensión arterial (HA) es un factor de riesgo cardiovascular, ya que está relacionado con la generación de insuficiencia congestiva cardiaca, infarto cerebral, infarto agudo del miocardio, falla renal crónica y varios padecimientos más (Guidelines Subcommitte of the WHO-ISH. 1999 World Health Organization-International Society of hypertension, Guidelines for the Management of Hypertension. J. Hypertens. 17,151 - 183 (1999)). Arterial hypertension (HA) is a cardiovascular risk factor, since it is related to the generation of congestive heart failure, cerebral infarction, acute myocardial infarction, chronic renal failure and several other conditions (Guidelines Subcommitte of the WHO-ISH. 1999 World Health Organization-International Society of hypertension, Guidelines for the Management of Hypertension, J. Hypertens, 17,151-183 (1999)).
El informe del panel nombrado para el Octavo "Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC8)" publicado en diciembre de 2013 (JAMA 2013;doi:10.1001 /jama.2013.284427) recomienda como meta de la presión arterial valores menores a 150/90 mm de Hg en personas de 60 años de edad y mayores. Para todos los demás, que incluyen personas con diabetes mellitus y nefropatía crónica los valores deberán ser menores a 140/90 mm de Hg. Además se establece que la terapia puede ser con base en cualquiera de cuatro clases de fármacos: diuréticos tiacídicos, calcio antagonistas, inhibidores de la enzima convertidora de angiotensina (IECA) o bloqueadores del receptor de angiotensina II (BRA). Si la presión arterial no está en los valores sugeridos, se propone en la Recomendación 9 de la JNC usar inclusive hasta una combinación triple, consistente en: un diurético tiacídico, un calcio antagonista y ya sea un inhibidor de la ECA o un BRA. Con respecto a esta última alternativa se especifica en la misma Recomendación 9 de la JNC no utilizar un inhibidor de la ECA o BRA juntos. The report of the panel named for the Eighth "Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC8)" published in December 2013 (JAMA 2013; doi: 10.1001 / jama.2013.284427) recommends as the goal of the Blood pressure values below 150/90 mm Hg in people 60 years of age and older. For all others, which include people with diabetes mellitus and chronic kidney disease, the values should be less than 140/90 mm Hg. It is also established that the therapy can be based on any of four classes of drugs: thiazide diuretics, calcium antagonists, angiotensin-converting enzyme (ACEI) inhibitors or angiotensin II receptor blockers (BRA). If the blood pressure is not within the suggested values, it is proposed in Recommendation 9 of the JNC to use even up to a triple combination, consisting of: a thiazide diuretic, an antagonistic calcium and either an inhibitor of ECA or a BRA. With respect to the latter alternative, it is specified in the same Recommendation 9 of the JNC not to use an ACE inhibitor or BRA together.
Estudios realizados de larga duración sugieren que pacientes hipertensos, especialmente los de alto riesgo como aquellos que concomitantemente padecen diabetes mellitus, enfermedades renales o evidencia de otro daño en órganos claves, necesitan dos o más medicamentos para alcanzar los valores de presión sanguínea (PS) recomendada. Entre las ventajas de la terapia de combinación se incluyen: 1 ) mayor reducción en la presión sanguínea y una más rápida velocidad de respuesta que con monoterapia, causada por efectos simultáneos sobre varios sistemas regulatorios involucrados en la anormal elevación de la presión sanguínea, 2) menores efectos adversos, con consecuente mejor tolerabilidad y mejorado cumplimiento con el tratamiento y 3) probablemente menores costos de tratamiento. (Lancet, 351 , 1755- 1762 (1998); BMJ, 317, 703-713 (1998); N. Engl. J. Med. 342, 145-153 (2000); JAMA, 288, 2981 -2997 (2002); Am. J. Hypertens, 1 1 , 73S-78S (1998); Drugs, 62, 443-462 (2002)). Long-term studies suggest that hypertensive patients, especially high-risk patients such as those who concomitantly suffer from diabetes mellitus, kidney disease or evidence of other damage to key organs, need two or more medications to reach the recommended blood pressure (PS) values. . The advantages of combination therapy include: 1) greater reduction in blood pressure and a faster response rate than with monotherapy, caused by simultaneous effects on several regulatory systems involved in the abnormal elevation of blood pressure, 2) minor adverse effects, with consequent better tolerability and improved compliance with treatment and 3) probably lower treatment costs. (Lancet, 351, 1755-1762 (1998); BMJ, 317, 703-713 (1998); N. Engl. J. Med. 342, 145-153 (2000); JAMA, 288, 2981-2997 (2002) ; Am. J. Hypertens, 1 1, 73S-78S (1998); Drugs, 62, 443-462 (2002)).
Dado el vasto arreglo de agentes antihipertensivos disponibles, el número de combinaciones es grande; sin embargo una selección racional debe estar basada en las características de cada fármaco buscando que entre ellos exista una complementaridad en los mecanismos de acción (Am. J. Hypertens, 1 1 , 73S-78S (1998); Drugs, 62, 443-462 (2002)). Las guías de tratamiento sugieren que la combinación de un bloqueador de los receptores tipo 1 de angiotensina II (BRA) y un calcio antagonista provee una efectiva opción para pacientes con HA ( Guidelines for the Management of Arterial Hypertension: The Task Forcé for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology, J. Hypertens, 25, 1 105-1 187 (2007)). Given the vast array of available antihypertensive agents, the number of combinations is large; however, a rational selection must be based on the characteristics of each drug, seeking that there is a complementarity between the mechanisms of action (Am. J. Hypertens, 1 1, 73S-78S (1998); Drugs, 62, 443-462 (2002)). Treatment guidelines suggest that the combination of an angiotensin II type 1 receptor (BRA) blocker and an antagonist calcium provides an effective option for patients with HA (Guidelines for the Management of Arterial Hypertension: The Task Forcé for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology, J. Hypertens, 25, 1 105-1 187 (2007)).
El usar esta clase de fármacos en una combinación farmacéutica presenta el potencial de alcanzar una reducción aditiva o sinérgica de la PS, al incidir con diferentes mecanismos involucrados en su regulación (Therapy, 4, 31 -40 (2007)). Los calcio antagonistas bloquean los canales de calcio en células vasculares de músculo liso, razón por la cual se reduce la resistencia vascular periférica (Therapy, 4, 31 -40 (2007)) y los BRA bloquean los receptores tipo I de la Angiotensina II promoviendo vasodilatación y la excreción de sodio (Pharmacotherapy, 25,1213-1229 (2005)). El impacto simultaneo sobre sistemas múltiples tiene beneficios adicionales en términos de sobreponerse a mecanismos potenciales de contraregulación, por ejemplo la activación compensatoria del sistema renina/angiotensina inducida por el calcio antagonista (Therapy, 4, 31 -40 (2007); J. Clin. Hypertens (Greenwich), 10 (1 suppl. 1 ), 27-32 (2008), mientras que el fármaco BRA previene o atenúa algunos de los efectos adversos del calcio antagonista tales como edemas en el tobillo y dolor de cabeza (J. Hum. Hypertens 21 , 220-224 (2007); Clin. Ther., 29, 563-580 (2007)). Además, tales fármacos al combinarse en una sola preparación farmacéutica proveen ventajas como es incrementar la tolerabilidad En general, combinar fármacos de clases complementarias es aproximadamente cinco veces más efectivo en disminuir la PS que incrementar la dosis de un medicamento (J. Amer. Soc. Hypertens. 4(2), 90-98 (2010). Using this class of drugs in a pharmaceutical combination has the potential to achieve an additive or synergistic reduction of PS, by affecting different mechanisms involved in its regulation (Therapy, 4, 31-40 (2007)). Calcium antagonists block calcium channels in vascular muscle cells smooth, which is why peripheral vascular resistance is reduced (Therapy, 4, 31 -40 (2007)) and BRA block Angiotensin II type I receptors promoting vasodilation and sodium excretion (Pharmacotherapy, 25,1213- 1229 (2005)). The simultaneous impact on multiple systems has additional benefits in terms of overcoming potential counter-regulation mechanisms, for example the compensatory activation of the renin / angiotensin system induced by the antagonist calcium (Therapy, 4, 31-40 (2007); J. Clin. Hypertens (Greenwich), 10 (1 suppl. 1), 27-32 (2008), while the drug BRA prevents or mitigates some of the adverse effects of antagonistic calcium such as edema in the ankle and headache (J. Hum Hypertens 21, 220-224 (2007); Clin. Ther., 29, 563-580 (2007) .In addition, such drugs when combined in a single pharmaceutical preparation provide advantages such as increasing tolerability In general, combining drugs of Complementary classes are approximately five times more effective in decreasing PS than increasing the dose of a drug (J. Amer. Soc. Hypertens. 4 (2), 90-98 (2010).
Es propósito de la presente invención el desarrollo de composiciones farmacéuticas con base en la combinación de un fármaco antihipertensivo BRA de segunda generación que es el Eprosartán y un calcio antagonista de tercera generación que es el Lercanidipino, para ser usadas en los casos recomendados para este tipo de combinaciones como son cuando ya no hay respuesta con la monoterapia, cuando hay trastornos adicionales como son diabetes tipo II, nefropatía crónica y otros padecimientos concurrentes en donde la recomendación de control de la presión son menores a 140/90 mm de Hg. DESCRIPCION DE LA INVENCION It is the purpose of the present invention to develop pharmaceutical compositions based on the combination of a second generation BRA antihypertensive drug that is Eprosartan and a third generation antagonist calcium that is Lercanidipine, to be used in cases recommended for this type. of combinations such as when there is no response with monotherapy, when there are additional disorders such as type II diabetes, chronic kidney disease and other concurrent conditions where the recommendation for pressure control is less than 140/90 mm Hg. DESCRIPTION OF THE INVENTION
En la presente invención se han desarrollado composiciones farmacéuticas, usando como principios activos la combinación de los antihipertensivos ácido (E)-3-[2- butil-1 -[(4-carboxifenil)-metil]-imidazol-5-il]-2-(2-tienilmetil)-2-propanoico y de nombre genérico Eprosartán, combinado con el metil 1 ,1 -dimetil-2-[N-(3,3-difenilpropil)-N- metilamino]etil 2,6-dimetil-4-(3-nitrofenil)-1 ,4-dihidropiridina-3,5-dicarboxilato de nombre genérico Lercanidipino o alguna de sus sales farmacéuticamente aceptables y fisiológicamente toleradas, preferentemente el Mesilato de Eprosartán combinado con el Clorhidrato de Lercanidipino. El Eprosartán es un fármaco bloqueador de los receptores tipo I de la Angiotensina II (BRA). El Lercanidipino es un fármaco que actúa en el tratamiento de la hipertensión como calcio antagonista. In the present invention, pharmaceutical compositions have been developed, using as combination active agents the combination of the antihypertensives acid (E) -3- [2- butyl-1 - [(4-carboxyphenyl) -methyl] -imidazol-5-yl] - 2- (2-thienylmethyl) -2-propanoic and generic name Eprosartan, combined with methyl 1,1,1-dimethyl-2- [N- (3,3-diphenylpropyl) -N-methylamino] ethyl 2,6-dimethyl -4- (3-nitrophenyl) -1, 4-dihydropyridine-3,5-dicarboxylate of generic name Lercanidipine or any of its pharmaceutically acceptable salts and Physiologically tolerated, preferably Eprosartan Mesylate combined with Lercanidipine Hydrochloride. Eprosartan is an angiotensin II type I receptor blocker (BRA). Lercanidipine is a drug that acts in the treatment of hypertension as a calcium antagonist.
Para entender la acción de un BRA, la visión clásica es considerar el sistema renina/angiotensina/aldosterona, el cual constituye un mecanismo de adaptación para proteger la integridad de los órganos vitales. Este sistema se activa cuando se produce una disminución del volumen intravascular o una perfusión tisular inadecuada, con el fin de mantener un correcto flujo sanguíneo. Este sistema consiste en el eje riñón/hígado/ síntesis en sangre de la angiotensina II, mediante la acción catalizadora de la enzima de conversión de la Angiotensina I. Además de este sistema extrínseco, existe otra ruta intrínseca para la fabricación de la angiotensina II, localizada en numerosos tejidos. Por ejemplo se ha encontrado el sistema renina/angiotensina en el cerebro, hipófisis, vasos sanguíneos, corazón y corteza suprarrenal, en donde se han identificado los ARN mensajeros de renina, de angiotensina, de angiotensinógeno y ECA. La estimulación continuada de este sistema tisular se ha relacionado con una exacerbación de las funciones reparadoras de la angiotensina II y la aldosterona que causarían un aumento patológico de las resistencias vasculares periféricas, congestión circulatoria, fibrosis e hipertrofia miocardica, disfunción endotelial, rotura de placas de ateroma, y disminución de la fibrinólisis. Debido a esto el sistema renina/angiotensina desempeña un papel fundamental en la fisiología de la HA, de la insuficiencia cardiaca, y de la nefropatía diabética cardiovascular. La consecuencia final de la hiperactivación de este sistema es un incremento de la morbolidad y la mortalidad (N. Engl. J. Med. 355, 637-645 (2000)). To understand the action of a BRA, the classic vision is to consider the renin / angiotensin / aldosterone system, which constitutes an adaptive mechanism to protect the integrity of vital organs. This system is activated when there is a decrease in intravascular volume or inadequate tissue perfusion, in order to maintain proper blood flow. This system consists of the kidney / liver / blood synthesis axis of angiotensin II, by means of the catalytic action of the conversion enzyme of Angiotensin I. In addition to this extrinsic system, there is another intrinsic route for the manufacture of angiotensin II, located in numerous tissues. For example, the renin / angiotensin system has been found in the brain, pituitary gland, blood vessels, heart and adrenal cortex, where the messenger RNAs of renin, angiotensin, angiotensinogen and ACE have been identified. Continued stimulation of this tissue system has been linked to an exacerbation of the repairing functions of angiotensin II and aldosterone that would cause a pathological increase in peripheral vascular resistance, circulatory congestion, fibrosis and myocardial hypertrophy, endothelial dysfunction, rupture of plaques. atheroma, and decreased fibrinolysis. Because of this, the renin / angiotensin system plays a fundamental role in the physiology of HA, heart failure, and cardiovascular diabetic nephropathy. The final consequence of hyperactivation of this system is an increase in morbidity and mortality (N. Engl. J. Med. 355, 637-645 (2000)).
Entre los efectos benéficos del bloqueo del sistema renina/angiotensina a nivel cardiovascular está que se elimina el potente efecto vasoconstrictor de la angiotensina II y se reduce la reabsorción de sodio a nivel del túbulo proximal, se reduce la masa muscular del ventrículo izquierdo, y hay una disminución de la estimulación simpática (efecto producido en parte por una inhibición de la secreción de adrenalina y nodadrenalina de la medula adrenal (Drugdesk Editorial Staff. Eprosartán a drug evaluation monograph. En Hutchison,TA, Shahan, DR, Anderson, MN, eds. Drugdex. Englewood Colorado System. Micromedex Inc. 2000, 105.). Además, hay numerosos estudios en los que se demuestran otros efectos benéficos secundarios a este bloqueo. Así, se ha observado que posee una acción protectora vascular antiproliferativa y antimigratoria de las células musculares lisas, neutrofilos, y mononucleares, por lo que se produce una mejoría o restauración de la función endotelial y del tono arterial y da lugar a un incremento de la fibrinólisis endógena. También se han descrito efectos directos antiplaquetarios, antiaterogénicos, y un aumento de la sensibilidad a la insulina (Arch. Intern. Med. 160, 1905-191 1 , (2000). Los estudios realizados in vivo con dosis únicas en ratas demuestran que elAmong the beneficial effects of the renin / angiotensin system blockade at the cardiovascular level is that the potent vasoconstrictor effect of angiotensin II is eliminated and sodium reabsorption at the level of the proximal tubule is reduced, the left ventricular muscle mass is reduced, and there are a decrease in sympathetic stimulation (effect produced in part by an inhibition of adrenaline and nodurenaline secretion from the adrenal medulla (Drugdesk Editorial Staff. Eprosartan a drug evaluation monograph. In Hutchison, TA, Shahan, DR, Anderson, MN, eds Drugdex Englewood Colorado System. Micromedex Inc. 2000, 105.). In addition, there are numerous studies that demonstrate other beneficial effects secondary to this blockage. Thus, it has been observed that it has an antiproliferative and antimigratory vascular protective action of smooth, neutrophilic, and mononuclear muscle cells, so that there is an improvement or restoration of endothelial function and arterial tone and leads to an increase in endogenous fibrinolysis. Direct antiplatelet, antiatherogenic, and increased insulin sensitivity effects have also been described (Arch. Intern. Med. 160, 1905-191 1, (2000). In vivo studies with single doses in rats show that
Eprosartán o ácido (E)- -[2-butil-1 -[(4-carboxifenil)metil]-1 H-imidazol-5-il]metilen-2- tiofenpropanoico es el único en su grupo, que además de bloquear los receptores AT1 postsinápticos (vasculares), bloquea también los receptores presinápticos (neuronales), lo que implica una mayor potencia farmacológica, ya que esta estimulación da lugar a una liberación de noradrenalina, que se traduce en un efecto vasoconstrictor. Otros miembros de la familia como Losartán, Valsartán, entre otros de la familia sartán, solo bloquean los receptores AT1 postsinápticos (vasculares) (Pharmacology, 55, 244-251 , (1997)). En cuanto a su seguridad, el Eprosartán no posee efecto uricosúrico, en cambio el Losartán da lugar a un incremento en la excreción del ácido úrico que se manifiesta a las 4 horas de la administración del fármaco, disminuyendo significativamente los niveles de ácido úrico en sangre durante el primer día de tratamiento, tanto en pacientes con niveles normales de ácido úrico como en hiperuricémicos (J. Hypert. 17, 1033-1039 (1999)). La sal comercial es Mesilato de Eprosartán y los estudios farmacológicos se han realizado con esta sal. Al comparar la seguridad de la sal de Eprosartán en pacientes mayores y menores de 65 años no se observa ningún incremento en el número de reacciones adversas que usualmente aparecen con la edad. Por ejemplo, la incidencia de hipotensión ortostática fue de 0.3 % en menores de 65 años y de 0.4 % en mayores de 65 años. Las mialgias aparecieron en 3.1 % y 8.2 % respectivamente, mareo en 4 % y 5.1 % y fatiga en 3.2 % y 3 % (Pharmacoterapy, 19 (pte.2), 102-107 (1999)). El estudio de los datos clínicos indica los siguientes valores: hiperpotasemia en un 0.9 % de los pacientes mientras que con el placebo se obtuvo 0.3 %, en muy pocos casos se detectaron aumentos de transaminasas hepáticas y de la creatinina, así como leucopenia, neutropenia y trombocitopenia, aunque en algunos estudios se observó un ligero incremento en triglicéridos plasmáticos, las alteraciones en el perfil lipídico fueron similares a las alcanzadas con el placebo (J. Hypert. 17, 1033-1039 (1999)). Eprosartan or (E) - - [2-butyl-1 - [(4-carboxyphenyl) methyl] -1 H -imidazol-5-yl] methylene-2-thiophenepapanoic acid is the only one in its group, which in addition to blocking the postsynaptic (vascular) AT1 receptors, also blocks presynaptic (neuronal) receptors, which implies greater pharmacological potency, since this stimulation results in a release of norepinephrine, which results in a vasoconstrictor effect. Other family members such as Losartan, Valsartan, among others in the Sartan family, only block postsynaptic (vascular) AT1 receptors (Pharmacology, 55, 244-251, (1997)). As for its safety, Eprosartan does not have a uricosuric effect, however Losartan results in an increase in the excretion of uric acid that manifests itself within 4 hours of drug administration, significantly decreasing blood uric acid levels. during the first day of treatment, both in patients with normal uric acid levels and in hyperuricémicos (J. Hypert. 17, 1033-1039 (1999)). The commercial salt is Eprosartan Mesylate and pharmacological studies have been carried out with this salt. When comparing the safety of Eprosartan salt in patients older and younger than 65 years, there is no increase in the number of adverse reactions that usually appear with age. For example, the incidence of orthostatic hypotension was 0.3% in children under 65 and 0.4% in those over 65 years. Myalgias appeared in 3.1% and 8.2% respectively, dizziness in 4% and 5.1% and fatigue in 3.2% and 3% (Pharmacoterapy, 19 (pte.2), 102-107 (1999)). The study of clinical data indicates the following values: hyperkalemia in 0.9% of patients, while 0.3% was obtained with placebo, in very few cases increases in liver transaminase and creatinine were detected, as well as leukopenia, neutropenia and thrombocytopenia, although in some studies a slight increase in plasma triglycerides was observed, alterations in the lipid profile were similar to those achieved with placebo (J. Hypert. 17, 1033-1039 (1999)).
Debido a que en el metabolismo de Eprosartán no interviene el citocromo P450, son poco probables las interacciones con otros fármacos, inclusive con fármacos con los que habitualmente hay advertencias de interacción como la Digoxina, la Ranitidina, la Hidroclorotiazida, el Fluconazol o el Ketoconazol, que actúan como potentes inhibidores específicos de determinadas isoenzimas del Citocromo (Pharmacotherapy, 19, 73S-83S (1999)). Esto lo diferencia del Losartán, para el cual se ha descrito una importante interacción con el Fluconazol, tal que cuando se suministran conjuntamente no se produce la transformación hepática del Losartán en su principal metabolito activo (Clin. Pharmacol. Ther, 62, 417-425 (1997)). En un estudio cruzado y controlado con placebo no se observó ninguna interacción farmacodinámica del Eprosartán Because cytochrome P450 is not involved in Eprosartan metabolism, interactions with other drugs are unlikely, including drugs with which there are usually interaction warnings such as Digoxin, Ranitidine, Hydrochlorothiazide, Fluconazole or Ketoconazole, which act as potent specific inhibitors of certain cytochrome isoenzymes (Pharmacotherapy, 19, 73S-83S (1999)). This differentiates them from Losartan, for which an important interaction with Fluconazole has been described, such that when they are supplied together, the hepatic transformation of Losartan into its main active metabolite does not occur (Clin. Pharmacol. Ther, 62, 417-425 (1997)). In a cross-controlled, placebo-controlled study, no pharmacodynamic interaction of Eprosartan was observed.
y no se observó ningún cambio significativo en los niveles de glucosa plasmáticos, por lo que en pacientes de diabetes tipo II tratados con Glibenclamida no hay ninguna afectación (J. Clin Pharmacol. 37, 155-159 (1997)).  and no significant change in plasma glucose levels was observed, so that in patients with type II diabetes treated with Glibenclamide there is no involvement (J. Clin Pharmacol. 37, 155-159 (1997)).
El Lercanidipino o 1 ,4-dihidro-2,6-dimetil-4-(3-nitrofenil)-acido 3,5- piridindicarboxilico 2-[(3,3-difenilpropil)metilamino]-1 ,1 -dimetiletil metil ester o también (metil 1 ,1 ,N-trimetil-N-(3,3-difenilpropil)-2-aminoetil 1 ,4-dihidro-2,6-dimetil-4-(3- nitrofenil)piridina-3,5-dicarboxilato) es una dihidropiridina que actúa bloqueando los canales de calcio, lo cual inhibe la entrada de calcio a través de los canales de calcio tipo L en células de músculo liso del sistema cardiovascular, conduciendo a la vasodilatación periférica ejerciendo así su efecto antihipertensivo (Drugs, 60, 1 123- 1 140 (2000)). El Lercanidipino ha sido clasificado por la FDA como un fármaco con baja permeabilidad y tiene un lento inicio en sus efectos, pero una duración de acción mayor que otras dihidropiridinas (Expert. Opin. Investig. Drugs, 8, 1043-1062 (1999)). De hecho, la distribución preferencial del fármaco en las membranas de las células de músculo liso resulta en una farmacocinética, caracterizada por un efecto farmacológico prolongado, resultando en un control de la presión sanguínea hasta 24 horas después del suministro de una dosis (Vascular Health and Risk Management, 4, 1 159-1 166 (2008)). Además, el fármaco es altamente vasoselectivo debido a la alta proporción de canales de calcio tipo L en arterias y ha mostrado menos actividad ionotrópica negativa in vitro y in vivo que otras dihidropiridinas. El Lercanidipino es un fármaco bien tolerado, con baja velocidad de eventos adversos debido a su actividad bloqueadora de entrada de calcio vasoselectiva y de larga duración y no causa activación simpatética y dado su lento inicio de acción la taquicardia de reflejo es rara (Heart Dis. 3, 398-407 (2001 )). Como resultado, la velocidad total de eventos adversos es menor que la observada con otras dihidropiridinas (Int. J. Clin. Pract. 62, 723-728 (2008)). Algunos estudios sugieren que el Lercanidipino puede tener efectos antiaterogénicos (Vasc. Health Risk Manag. 3, 255-263 (2007)); Br. J. Pharmacol. 125, 1471 -1476 (2003); Clin. Pharmacol. Ther. 72, 302-307 (2007)). Otro beneficio reportado es su efecto renoprotectivo, el cual está relacionado con su habilidad de inducir ambos vasodilatacion arteriolar aferente y eferente (Ren. Fail. 27, 73-80 (2005); Diabetes Nutr. Metab. 17, 259-266 (2004)). Lercanidipino fue también superior a Ramipril en reducir excreción de albúmina en pacientes diabéticos con microalbuminuria (Diabetes Nutr. Metab. 17, 259-266 (2004)). Lercanidipine or 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridindicarboxylic acid 2 - [(3,3-diphenylpropyl) methylamino] -1, 1-dimethyl ethyl methyl ester or also (methyl 1, 1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1, 4-dihydro-2,6-dimethyl-4- (3- nitrophenyl) pyridine-3,5-dicarboxylate ) is a dihydropyridine that acts by blocking calcium channels, which inhibits the entry of calcium through L-type calcium channels into smooth muscle cells of the cardiovascular system, leading to peripheral vasodilation thus exerting its antihypertensive effect (Drugs, 60, 1 123-140 (2000)). Lercanidipine has been classified by the FDA as a drug with low permeability and has a slow onset in its effects, but a longer duration of action than other dihydropyridines (Expert. Opin. Investig. Drugs, 8, 1043-1062 (1999)) . In fact, the preferential distribution of the drug in the smooth muscle cell membranes results in a pharmacokinetics, characterized by a pharmacological effect. prolonged, resulting in a control of blood pressure up to 24 hours after the delivery of a dose (Vascular Health and Risk Management, 4, 1 159-1 166 (2008)). In addition, the drug is highly vasoselective due to the high proportion of L-type calcium channels in arteries and has shown less negative ionotropic activity in vitro and in vivo than other dihydropyridines. Lercanidipine is a well tolerated drug, with a low rate of adverse events due to its long-acting vasoselective calcium blocker activity and does not cause sympathetic activation and given its slow onset of action reflex tachycardia is rare (Heart Dis. 3, 398-407 (2001)). As a result, the total rate of adverse events is lower than that observed with other dihydropyridines (Int. J. Clin. Pract. 62, 723-728 (2008)). Some studies suggest that Lercanidipine may have antiatherogenic effects (Vasc. Health Risk Manag. 3, 255-263 (2007)); Br. J. Pharmacol. 125, 1471-1476 (2003); Clin. Pharmacol Ther. 72, 302-307 (2007)). Another benefit reported is its renoprotective effect, which is related to its ability to induce both afferent and efferent arteriolar vasodilation (Ren. Fail. 27, 73-80 (2005); Diabetes Nutr. Metab. 17, 259-266 (2004) ). Lercanidipine was also superior to Ramipril in reducing albumin excretion in diabetic patients with microalbuminuria (Diabetes Nutr. Metab. 17, 259-266 (2004)).
En pacientes diabéticos con hipertensión, el tratamiento con Lercanidipino fue capaz de disminuir los niveles de hemoglobina glicosilada significativamente, sin afectar negativamente la homeostasis de glucosa, elevar la tolerancia a glucosa y reducir la glucosa en sangre en ayunas, con valores favorables en el perfil de lípidos (Drugs, 63, 2449-2472 (2003); J. Cardiovasc. Pharmacol. 40, 133-139 (2002)). Además, en diabéticos con falla renal el Lercanidipino tiene un buen perfil de tolerabilidad y efecto neutro en lípidos del plasma con ningún debilitamiento de la función renal (Nefrologia, 24, 338-343 (2004)). En pacientes hipertensivos con síndrome metabólico el Lercanidipino tiene un mejor perfil de tolerabilidad y fue asociado con menores efectos adversos relacionados con vasodilatacion que otras dihidropiridinas bloqueadoras del canal de calcio (Int. J. Clin. Pract. 62, 723-728 (2008)). En contraste con los beta bloqueadores y los diuréticos, los cuales empeoran la resistencia a la insulina (J. Hypertens, 23, 1779-1781 (2005)) e incrementan el colesterol total, las lipoproteínas de alta densidad y los niveles de glicéridos totales (Amer. Heart J., 21 , 973-985 (2000)) y entonces el riesgo de diabetes (N. Engl. J. Med. 13, 905-912 (2000)) los antagonistas de calcio son metabólicamente neutros. Por ejemplo, en el estudio denominado ASCOT la combinación de Atenolol/Flumetazina fue asociada con un significativo alto riesgo de nuevo inicio de diabetes comparado con el grupo tratado con Perindopril y Amlodipino (Lancet, 366, 895-906)), especialmente cuando la glucosa en plasma en ayunas fue de 5 mmol/L (Diabetes Care, 31 , 982- 988)). Sin embargo, el amplio uso de antagonistas de calcio en la práctica clínica se ha visto limitada por un frecuente efecto lateral el edema periférico. En el Estudio Ascot, el edema periférico se desarrolló en 23 % de los pacientes tratados y fue la principal causa de la interrupción del Amlodipino. La principal ventaja del Lercanidipino es que induce menos edema periférico que otras dihidropiridinas. En promedio, el edema periférico se desarrolla en 0.6 % a 9 % de los pacientes tratados (a la dosis de 10 mg por día), lo cual es considerablemente menor que el reportado en el estudio ASCOT. Estudios observacionales han mostrado que en pacientes tratados inicialmente con una dihidropiridina de primera generación y cambiados a Lercanidipino se reduce la probabilidad de desarrollar edema periférico en aproximadamente 50 % (Blood Press Suppl., 1 , 14-21 (2003)). En un estudio observacional publicado por Burnier y colaboradores (Expert. Opin. Pharmacother. 8, 2215-2223 (2007)) este porcentaje fue aún menor. El Lercanidipino también reduce los signos y síntomas de isquemia y mejora la función del corazón en pacientes con angina (Am. J. Ther. 1 1 , 423-432 (2004)). In diabetic patients with hypertension, treatment with Lercanidipine was able to decrease glycosylated hemoglobin levels significantly, without negatively affecting glucose homeostasis, raising glucose tolerance and reducing fasting blood glucose, with favorable values in the profile of lipids (Drugs, 63, 2449-2472 (2003); J. Cardiovasc. Pharmacol. 40, 133-139 (2002)). In addition, in diabetics with renal failure Lercanidipine has a good tolerability profile and neutral effect on plasma lipids with no weakening of renal function (Nefrologia, 24, 338-343 (2004)). In hypertensive patients with metabolic syndrome, Lercanidipine has a better tolerability profile and was associated with lower adverse effects related to vasodilation than other calcium channel blocker dihydropyridines (Int. J. Clin. Pract. 62, 723-728 (2008)) . In contrast to beta blockers and diuretics, which worsen insulin resistance (J. Hypertens, 23, 1779-1781 (2005)) and increase total cholesterol, high density lipoproteins and total glyceride levels ( Amer. Heart J., 21, 973-985 (2000)) and then the risk of diabetes (N. Engl. J. Med. 13, 905-912 (2000)) calcium antagonists are metabolically neutral. For example, in the study called ASCOT the combination of Atenolol / Flumetazine was associated with a significant high risk of new onset of diabetes compared to the group treated with Perindopril and Amlodipine (Lancet, 366, 895-906)), especially when glucose Fasting plasma was 5 mmol / L (Diabetes Care, 31, 982-988). However, the extensive use of calcium antagonists in clinical practice has been limited by a frequent side effect of peripheral edema. In the Ascot Study, peripheral edema developed in 23% of treated patients and was the main cause of the interruption of Amlodipine. The main advantage of Lercanidipine is that it induces less peripheral edema than other dihydropyridines. On average, peripheral edema develops in 0.6% to 9% of treated patients (at the dose of 10 mg per day), which is considerably lower than that reported in the ASCOT study. Observational studies have shown that in patients initially treated with a first-generation dihydropyridine and switched to Lercanidipine the probability of developing peripheral edema is reduced by approximately 50% (Blood Press Suppl., 1, 14-21 (2003)). In an observational study published by Burnier et al. (Expert. Opin. Pharmacother. 8, 2215-2223 (2007)) this percentage was even lower. Lercanidipine also reduces the signs and symptoms of ischemia and improves heart function in patients with angina (Am. J. Ther. 1 1, 423-432 (2004)).
En consecuencia, las principales ventajas del Lercanidipino sobre dihidropiridinas de primera y segunda generación es su menor incidencia de efectos adversos, en particular edema periférica, mejor protección renal, menor daño renal crónico y/o proteinuria y su neutralidad metabólica (Hypertension, 35, 775-779 (2000); Ren Fail, 1 , 73-80 (2005)). Varios razonamientos farmacológicos se han usado para el empleo de una terapia de combinación. En un primer caso se tiene que del 30 % al 50 % de los pacientes no responden a monoterapia. En un segundo caso se tiene la necesidad de cumplir con las guías que pretenden cada vez tratamientos de los niveles de hipertensión más agresivos. Así, las "World Health Guidelines" han recomendado una presión sanguínea diastólica menor a 85 milímetros de mercurio y una presión sanguínea sistólica menor a 130 milímetros de mercurio en pacientes jóvenes y en pacientes diabéticos. Otro caso es el hecho de que múltiple sistemas fisiológicos participan en el control de la presión sanguínea y se ha propuesto que desencadenan mecanismos contraregulatorios, razón por la cual se ha atribuido a esto la pérdida de eficacia después de un cierto tiempo de emplear la monoterapia. Un tratamiento en combinación incrementa el número de mecanismos potencialmente capaces de reducir la presión sanguínea elevada y de reducir la velocidad y magnitud de los efectos adversos producidos por cada fármaco. También la terapia de combinación se recomienda cuando una combinación de fármacos puede permitir la utilización de dosis menores de cada fármaco reduciendo el riesgo de reacciones adversas relacionadas con la dosis, mientras que la suma de mecanismos de acción complementarios permite contrarrestar de manera suficiente la presión sanguínea. Estas metas, en ciertos tipos de pacientes de alto riesgo como son los diabéticos, en los padecimientos renales o en pacientes con evidencia de daño en otros órganos se ha logrado con la terapia de combinación de dos fármacos, que actúan a través de dos diferentes mecanismos como es un calcio antagonista combinado con un inhibidor de la enzima convertidora de angiotensina II (IECA) (Patient Preference and Adherence, 6,449-455 (2012)) o un calcio antagonista combinado con un bloqueador de los receptores de angiotensina II (BRA) (Vascular Health and Risk Management, 6, 87-93 ( 2010)). Consequently, the main advantages of Lercanidipine over first and second generation dihydropyridines is its lower incidence of adverse effects, in particular peripheral edema, better renal protection, less chronic renal damage and / or proteinuria and its metabolic neutrality (Hypertension, 35, 775 -779 (2000); Ren Fail, 1, 73-80 (2005)). Several pharmacological reasoning have been used for the use of a combination therapy. In the first case, 30% to 50% of patients do not respond to monotherapy. In a second case there is a need to comply with the guidelines that increasingly seek treatments of the most aggressive levels of hypertension. Thus, the "World Health Guidelines" have recommended a diastolic blood pressure of less than 85 millimeters of mercury and a systolic blood pressure of less than 130 millimeters of mercury in young patients and in diabetic patients. Another case is the fact that multiple physiological systems participate in the control of blood pressure and it has been proposed that they trigger counter-regulatory mechanisms, which is why the loss of efficacy has been attributed to this after a certain time of using monotherapy. A combination treatment increases the number of mechanisms potentially capable of reducing high blood pressure and reducing the speed and magnitude of the adverse effects produced by each drug. Combination therapy is also recommended when a combination of drugs can allow the use of lower doses of each drug, reducing the risk of dose-related adverse reactions, while the sum of complementary mechanisms of action allows blood pressure to be sufficiently counteracted. . These goals, in certain types of high-risk patients such as diabetics, in kidney disease or in patients with evidence of damage to other organs has been achieved with the combination therapy of two drugs, which act through two different mechanisms such as an calcium antagonist combined with an angiotensin II converting enzyme (ACEI) inhibitor (Patient Preference and Adherence, 6,449-455 (2012)) or an calcium antagonist combined with an angiotensin II receptor blocker (BRA) ( Vascular Health and Risk Management, 6, 87-93 (2010)).
En el caso de la combinación de un inhibidor ECA con un calcio antagonista, se tiene que el IECA atenúa la vasoconstricción a través de reducir el efecto vasoconstrictivo de la Angiotensina II y el incremento de las kininas vasodilatoras, mientras que el calcio antagonista actúa atenuando el flujo de calcio a través de las membranas inhibiendo el acoplamiento electromecánico mediado por calcio en el tejido contractivo en respuesta a numerosos estímulos. Además, ambas clases de fármacos facilitan la excreción de sal y agua por el riñon a través de diferentes mecanismos. Con esta terapia de combinación se logra cumplir con las metas del World Health Guidelines, las cuales recomiendan alcanzar una presión diastólica menor a 85 mm de mercurio y una presión sistólica menor a 130 mm de mercurio. También, el IECA restaura la respuesta renal-adrenal a la acumulación de sal, mientras que el calcio antagonista posee propiedades sodiouréticas actuando probablemente al través de un mecanismo de inhibición de la sal tubular y de la reabsorción de agua (AJH, 1 1 , 163S- 169S (1998)). Se ha propuesto que los calcio antagonistas que no comparten el modo de acción de los inhibidores del sistema renina/angiotensina/aldosterona (lECAs) deben proveer efectos sinergéticos y complementarios a estos últimos (Patient Preference and Adherence, 6, 449-455, 2012); J. Cardiovasc. Pharmacol. 21 (suppl.2), S49-S54 (1993)). Por otro lado, la concomitancia de ambos tratamientos puede reducir la incidencia de efectos adversos, en particular de edema periférica. Finalmente se ha demostrado que una combinación a dosis fijas permite una mayor adherencia del paciente al tratamiento con dos fármacos (Patient Preference and Adherence, 6, 449- 455, 2012). In the case of the combination of an ACE inhibitor with an antagonistic calcium, the ACEI has to attenuate vasoconstriction by reducing the vasoconstrictive effect of Angiotensin II and increasing the vasodilator kinins, while the antagonist calcium acts by attenuating the calcium flow through the membranes inhibiting calcium-mediated electromechanical coupling in the contractive tissue in response to numerous stimuli. In addition, both classes of drugs They facilitate the excretion of salt and water by the kidney through different mechanisms. With this combination therapy, the goals of the World Health Guidelines are achieved, which recommend reaching a diastolic pressure of less than 85 mm of mercury and a systolic pressure of less than 130 mm of mercury. Also, the ACEI restores the renal-adrenal response to salt accumulation, while the antagonistic calcium possesses sodiournetic properties, probably acting through a mechanism of inhibition of tubular salt and water reabsorption (AJH, 1, 1, 163S - 169S (1998)). It has been proposed that calcium antagonists that do not share the mode of action of the renin / angiotensin / aldosterone system (ACE) inhibitors should provide synergistic and complementary effects to the latter (Patient Preference and Adherence, 6, 449-455, 2012) ; J. Cardiovasc. Pharmacol 21 (suppl.2), S49-S54 (1993)). On the other hand, the concomitance of both treatments can reduce the incidence of adverse effects, particularly peripheral edema. Finally, it has been shown that a combination at fixed doses allows greater adherence of the patient to treatment with two drugs (Patient Preference and Adherence, 6, 449-455, 2012).
Así se tienen varias combinaciones fijas comerciales de lECAs y calcio antagonistas, como son las combinaciones de Ramipril y Felodipino, Benazepril y Amlodipino, Manidipino y Delapril, Trandolapril y Verapamil, Enalapril con Felidipino, Enalapril con Diltiazem, y Lercanidipino con Enalapril, entre otras (Patient Preference and Adherence, 6, 449-455, 2012). En el estudio denominado SELECT (Systolic Evaluation of Lotrel Efficacy and Comparative Therapies) la terapia con un calcio antagonista y un IECA, Amlodipino y Benzapril, fue más efectiva en reducir la presión sistólica y la presión de pulso en pacientes con severa hipertensión sistólica que cualquier otro hipertensivo usado en monoterapia. La combinación de Manidipino y Delapril fue también más efectiva en reducir la presión sanguínea en 73 % de los pacientes que cualquiera de los fármacos de la combinación usados por separado. Datos del estudio ASCOT mostraron que el tratamiento con Amlodipino mas Perindopril frente Atenolol (un beta bloqueador) mas Bendroflumetiazida (un diurético), la primera combinación fue más efectiva en reducir los riesgos del infarto miocardial no fatal o la enfermedad coronaria fatal, apoplejía fatal y no fatal (derrame cerebral), y eventos cardiovasculares fatales. En el caso de la combinación de Lercanidipino y Enalapril se ha encontrado en diversas pruebas clínicas que tiene mejor eficacia y tolerabilidad que la monoterapia con cualquiera de los componentes (J. Hypertens. 24, 185-192 (2006); CLP1 -0019, Milán, Italia, Recordati SpA, 2004; J. Hum. Hypertens. 21 , 917-924 (2007)). En un ensayo con pacientes hipertensos sin respuesta a la monoterapia con cualquiera de los componentes Lercanidipino o Enalapril, después de 12 semanas de tratamiento con la combinación fija Lercanidipino Enalapril, una significativa proporción de pacientes había normalizado su presión sanguínea (J. Hypertens. 24, 185-192 (2006); CLP1 -0019, Milán, Italia, Recordati SpA, 2004; J. Hum. Hypertens. 21 , 917-924 (2007)). En otra prueba clínica se demostró que la reducción en la presión sanguínea fue mayor en pacientes que recibieron la combinación Lercanidipino Enalapril que la monoterapia con alguno de los componentes de la combinación (Am. J. Cardiol. 2, R1 -R14 (1998)). La combinación fue bien tolerada en todos los estudios publicados, con efectos adversos similares a los de los fármacos componentes en monoterapia (J. Hypertens. 24, 185-192 (2006); CLP1 -0019, Milán, Italia, Recordati SpA, 2004; J. Hum. Hypertens. 21 , 917-924 (2007)). Los efectos adversos fueron en general transitorios y de severidad suave y no hubo reportes de edema periférica. Tal y como ha sido encontrado con el Lercanidipino en monoterapia, en la combinación hubo ausencia de efectos sobre el metabolismo de lípidos y de la glucosa (Drugs, 67, 95-106 (2007)). En un estudio observacional con más de 8,000 pacientes, los médicos en general opinaron que la eficacia de la combinación fue evaluada como buena o muy buena por 94 % de los médicos. Los médicos también evaluaron tolerabilidad evaluando 97 % de ellos conformidad con muy bueno y bueno (Arzneimittelforschung, 60, 124-130 (2010)). Otro tipo de combinaciones que también han demostrado ser altamente efectivas y bien toleradas son las de un fármaco calcio antagonista con un fármaco bloqueador de los receptores tipo I de la Angiotensina II (BRA) (J. Hypertens, 25, 1 105-1 187 (2007), errata en J. Hypertens. 25, 1749 (2007)). Con estas combinaciones, el mecanismo que promueve la vasodilatación y la excreción del sodio por acción del BRA se suma a la acción del calcio antagonista que actúa sobre células de músculo liso reduciendo la resistencia vascular periférica (Therapy, 4, 31 -40 (2007); Pharmacotherapy, 25, 1213-1229 (2005)). Atacando sistemas múltiples tiene beneficios en términos de superar los mecanismos potenciales contraregulatorios, por ejemplo la activación compensatoria del sistema renina/angiotensina inducida por los calcio antagonistas (Therapy, 4, 31 -40 (2007); J. Clin. Hypertens (Greenwich), 10 (1 Suppl.1 ), 27-32 (2008)). Además, tal combinación de fármacos provee ventajas en incrementar la tolerabilidad, en que el BRA previene o atenúa algunos de los efectos adversos del calcio antagonista tales como edema de tobillo y dolor de cabeza (J. Hum. Hypertens, 21 , 220-224 (2007)). En particular, la combinación de Losartán (BRA) con Amlodipino (calcio antagonista), en estudios con ratas demostró que significativamente disminuía la presión sistólica en comparación con los efectos logrados con los componentes individualmente (Arch. Phar. Res. 32, 353-358 (2009)). Además se observó una positiva correlación entre la reducción en la presión sanguínea y el mejoramiento en la relajación arterial dependiente del endotelio. Además, la terapia de combinación disminuía la masa cardiaca y el peso del ventrículo izquierdo a una mayor extensión que con cualquiera de los componentes Amlodipino o Losartán. El contenido de colágeno en el tejido cardiaco fue también significativamente menor después de 4 semanas de tratamiento. Lo que demostró que la terapia de combinación era superior al tratamiento con monoterapia, habiéndose demostrado efectos hipertensivos sinérgicos. Resultados similares fueron alcanzados en estudios al azar, doble ciego, multicentros con 180 pacientes humanos adultos (BMC Research Notes 4, 461 -469 (201 1 )). Los resultados logrados indican que después de 6 semanas se alcanzan valores en la presión sistólica menores a 140 mm de mercurio y presión diastolica menores a 90 mm de mercurio. Los efectos adversos fueron monitoreados habiéndose encontrado que la mayoría fueron reportados como suaves, 3 sujetos reportaron moderados efectos similares al número con Amlodipino solo y en un caso se obtuvo efectos adversos severos. No se reportó ningún caso de muerte. La conclusión del estudio es que en general la combinación es bien tolerada y provee una opción terapéutica de primera elección para pacientes con hipertensión estado 2. Thus there are several commercial fixed combinations of ACL and calcium antagonists, such as the combinations of Ramipril and Felodipine, Benazepril and Amlodipine, Manidipine and Delapril, Trandolapril and Verapamil, Enalapril with Felidipine, Enalapril with Diltiazem, and Lercanidipine with Enalapril, among others Patient Preference and Adherence, 6, 449-455, 2012). In the study called SELECT (Systolic Evaluation of Lotrel Efficacy and Comparative Therapies) therapy with an antagonistic calcium and an ACEI, Amlodipine and Benzapril, was more effective in reducing systolic pressure and pulse pressure in patients with severe systolic hypertension than any another hypertensive used in monotherapy. The combination of Manidipine and Delapril was also more effective in reducing blood pressure in 73% of patients than any of the combination drugs used separately. Data from the ASCOT study showed that treatment with Amlodipine plus Perindopril versus Atenolol (a beta blocker) plus Bendroflumetiazide (a diuretic), the first combination was more effective in reducing the risks of non-fatal myocardial infarction or fatal coronary heart disease, fatal stroke and nonfatal (stroke), and events Fatal cardiovascular In the case of the combination of Lercanidipine and Enalapril, it has been found in various clinical trials that have better efficacy and tolerability than monotherapy with any of the components (J. Hypertens. 24, 185-192 (2006); CLP1-0019, Milan , Italy, Recordati SpA, 2004; J. Hum. Hypertens. 21, 917-924 (2007)). In a trial with hypertensive patients without response to monotherapy with any of the components Lercanidipine or Enalapril, after 12 weeks of treatment with the fixed combination Lercanidipine Enalapril, a significant proportion of patients had normalized their blood pressure (J. Hypertens. 24, 185-192 (2006); CLP1-0019, Milan, Italy, Recordati SpA, 2004; J. Hum. Hypertens. 21, 917-924 (2007)). Another clinical trial showed that the reduction in blood pressure was greater in patients who received the Lercanidipine Enalapril combination than monotherapy with any of the components of the combination (Am. J. Cardiol. 2, R1 -R14 (1998)) . The combination was well tolerated in all published studies, with adverse effects similar to those of the monotherapy component drugs (J. Hypertens. 24, 185-192 (2006); CLP1-0019, Milan, Italy, Recordati SpA, 2004; J. Hum. Hypertens. 21, 917-924 (2007)). Adverse effects were generally transient and of mild severity and there were no reports of peripheral edema. As it has been found with Lercanidipine alone, in the combination there was an absence of effects on the metabolism of lipids and glucose (Drugs, 67, 95-106 (2007)). In an observational study with more than 8,000 patients, doctors generally felt that the effectiveness of the combination was evaluated as good or very good by 94% of doctors. Doctors also evaluated tolerability by evaluating 97% of them in accordance with very good and good (Arzneimittelforschung, 60, 124-130 (2010)). Other types of combinations that have also proven to be highly effective and well tolerated are those of a calcium antagonist drug with an Angiotensin II type I (BRA) receptor blocking drug (J. Hypertens, 25, 1 105-1 187 ( 2007), typo in J. Hypertens. 25, 1749 (2007)). With these combinations, the mechanism that promotes vasodilation and sodium excretion by BRA is added to the action of antagonistic calcium that acts on smooth muscle cells reducing peripheral vascular resistance (Therapy, 4, 31-40 (2007) ; Pharmacotherapy, 25, 1213-1229 (2005)). Attacking multiple systems has benefits in terms of overcoming potential counter-regulatory mechanisms, for example compensatory activation of the renin / angiotensin system induced by calcium antagonists (Therapy, 4, 31-40 (2007); J. Clin. Hypertens (Greenwich), 10 (1 Suppl. 1), 27-32 (2008)). In addition, such a combination of drugs provides advantages in increasing tolerability, in which BRA prevents or mitigates some of the adverse effects of antagonistic calcium such as ankle edema and headache (J. Hum. Hypertens, 21, 220-224 ( 2007)). In particular, the combination of Losartan (BRA) with Amlodipine (calcium antagonist), in studies with rats, showed that systolic pressure significantly decreased compared to the effects achieved with the components individually (Arch. Phar. Res. 32, 353-358 (2009)). In addition, a positive correlation was observed between the reduction in blood pressure and the improvement in endothelial-dependent arterial relaxation. In addition, combination therapy lowered the heart mass and weight of the left ventricle to a greater extent than with any of the Amlodipine or Losartan components. The collagen content in cardiac tissue was also significantly lower after 4 weeks of treatment. Which showed that the combination therapy was superior to the monotherapy treatment, having shown synergistic hypertensive effects. Similar results were achieved in randomized, double-blind, multi-center studies with 180 adult human patients (BMC Research Notes 4, 461-469 (201 1)). The results obtained indicate that after 6 weeks values in systolic pressure less than 140 mm of mercury and diastolic pressure less than 90 mm of mercury are reached. Adverse effects were monitored having found that the majority were reported as mild, 3 subjects reported moderate effects similar to the number with Amlodipine alone and in one case severe adverse effects were obtained. No case of death was reported. The conclusion of the study is that in general the combination is well tolerated and provides a therapeutic option of first choice for patients with state 2 hypertension.
De la misma manera, el estudio clínico EX-STAND mostró que la terapia en pacientes con hipertensión 2 utilizando el BRA Valsartán también miembro de la familia de los sartanes, combinado con el calcio antagonista Amlodipino alcanzaba mayores reducciones en presión sanguínea después de 8 semanas de tratamiento alcanzando hasta una disminución de 33 mm de mercurio mientras que la monoterapia con Amlodipino solo alcanzaba una disminución de solo 26.6 mm de mercurio (J. Hum. Hypertens. 23, 479-489 (2009)). El estudio COACH demostró que la terapia con la combinación del BRA Olmesartán combinado con Amlodipino fue significativamente más efectiva que el tratamiento empleando solo Amlodipino en pacientes en estado 2 de hipertensión (Clin. Ther. 30, 587-604 (2008)). In the same way, the EX-STAND clinical study showed that therapy in patients with hypertension 2 using BRA Valsartan also a member of the pans family, combined with the antagonistic calcium Amlodipine achieved greater reductions in blood pressure after 8 weeks of reaching treatment until a decrease of 33 mm of mercury while monotherapy with Amlodipine only reached a decrease of only 26.6 mm of mercury (J. Hum. Hypertens. 23, 479-489 (2009)). The COACH study showed that therapy with the combination of BRA Olmesartan combined with Amlodipine was significantly more effective than treatment using only Amlodipine in patients in state 2 of hypertension (Clin. Ther. 30, 587-604 (2008)).
Un estudio clínico más reciente demuestra una significativa superioridad de la combinación de Valsartán con el calcio antagonista Amlodipino sobre la combinación Losartán con Amlodipino, en pacientes con moderada hipertensión (Vascular Health and Risk Management 6, 87-93 (2010)). Tal diferencia en eficacia se atribuye a los diferentes efectos farmacológicos de los BRA, debido a sus diferentes estructuras químicas y a sus diferentes propiedades farmacocinéticas. Losartán siendo un derivado del imidazol con una cadena lateral de bifeniltetrazol, mientras que Valsartán es un derivado tetrazol/bifenil/valina y con una sola estructura heterocíclica. También puede ser importante en esta diferencia el que Losartán es un profármaco, que necesita ser metabolizado para ser transformado en un metabolito más activo, mientras que Valsartán ejerce su efecto sin ser metabolizado (J. Hum. Hypertens. 13 Suppl. 1 , S1 1 - S20 (1999)). En cuanto a la tolerancia, las conclusiones en general son que ambas combinaciones Losartán Amlodipino y Valsartán Amlodipino fueron bien tolerados con una comparable incidencia de efectos adversos y estas incidencias fueron menores que las observadas con la monoterapia con Amlodipino. A more recent clinical study demonstrates a significant superiority of the combination of Valsartan with the calcium antagonist Amlodipine over the combination Losartan with Amlodipine, in patients with moderate hypertension (Vascular Health and Risk Management 6, 87-93 (2010)). Such difference in efficacy is attributed to the different pharmacological effects of BRA, due to their different chemical structures and their different pharmacokinetic properties. Losartan being an imidazole derivative with a biphenyltetrazole side chain, while Valsartan is a tetrazol / biphenyl / valine derivative and with a single heterocyclic structure. It may also be important in this difference that Losartan is a prodrug, which needs to be metabolized to be transformed into a more active metabolite, while Valsartan exerts its effect without being metabolized (J. Hum. Hypertens. 13 Suppl. 1, S1 1 - S20 (1999)). Regarding tolerance, the conclusions in general are that both Losartan Amlodipino and Valsartán Amlodipino combinations were well tolerated with a comparable incidence of adverse effects and these incidences were lower than those observed with Amlodipine monotherapy.
Con estos antecedentes es manifiesto que en las combinaciones de BRAs con calcio antagonistas las propiedades del BRA han demostrado ser importantes por el grado de eficacia significativa así como su tolerancia. With this background it is clear that in BRA combinations with calcium antagonists the properties of BRA have proven to be important due to the degree of significant efficacy as well as their tolerance.
En la presente invención se ha mostrado, tal y como se describió en la sección de antecedentes, que Eprosartán un antihipertensivo BRA de segunda generación, muestra una eficacia superior a otros miembros de la familia de los sartanes como son Losartán, Valsartán, Candesartán, etc.. Asimismo se ha mostrado, con base en diferentes estudios realizados con calcio antagonistas, que Lercanidipino un antihipertensivo de tercera generación, muestra una mayor eficacia y una significativa mayor tolerancia y con menores efectos adversos que la monoterapia empleando otros miembros de la familia de análogos de la 1 ,4 dihidropiridinas como es el Amlodipino, el fármaco más ampliamente usado de esta familia. In the present invention it has been shown, as described in the background section, that Eprosartan, a second generation BRA antihypertensive, shows superior efficacy to other members of the pans family such as Losartan, Valsartan, Candesartan, etc. .. It has also been shown, based on different studies conducted with calcium antagonists, that Lercanidipine a Third generation antihypertensive, shows greater efficacy and significant greater tolerance and with less adverse effects than monotherapy using other members of the family of analogs of 1,4 dihydropyridines such as Amlodipine, the most widely used drug in this family.
Además, se han mostrado resultados de estudios clínicos obtenidos con la combinación de calcio antagonistas que no comparten el modo de acción de los inhibidores del sistema renina/angiotensina/aldosterona (lECAs) pero que proveen efectos sinergéticos y complementarios a estos últimos (Patient Preference and Adherence, 6, 449-455, (2012), J. Cardiovasc. Pharmacol. 21 (suppl.2), S49-S54 (1993)). Por otro lado, la concomitancia de ambos tratamientos puede reducir la incidencia de efectos adversos, en particular el edema periférico. Como se describió, esta complementaridad entre un calcio antagonista como Lercanidipino y el IECA Enalapril, ha demostrado una mayor eficacia y menores efectos secundarios que los componentes y que otras combinaciones de Lercanidipino con otros lECAs. In addition, results of clinical studies obtained with the combination of calcium antagonists have been shown that do not share the mode of action of the renin / angiotensin / aldosterone system inhibitors (ACEIs) but that provide synergistic and complementary effects to the latter (Patient Preference and Adherence, 6, 449-455, (2012), J. Cardiovasc. Pharmacol. 21 (suppl.2), S49-S54 (1993)). On the other hand, the concomitance of both treatments can reduce the incidence of adverse effects, particularly peripheral edema. As described, this complementarity between a calcium antagonist such as Lercanidipine and IECA Enalapril, has shown greater efficacy and lower side effects than the components and other combinations of Lercanidipine with other LECAs.
El propósito de la presente invención es el desarrollo de composiciones farmacéuticas con base en la combinación del BRA Eprosartán y el calcio antagonista Lercanidipino. En la presente invención se ha ilustrado, con base en estudios clínicos existentes, que Eprosartán muestra una eficacia superior a otros miembros de la familia de los "sartanes" como son Losartán, Valsartán, Candesartán y otros. Asimismo se ha mostrado, con base en diferentes estudios realizados previamente que el calcio antagonista Lercanidipino tiene una mayor eficacia y una significativa mayor tolerancia y con menores efectos adversos que la monoterapia, con otros miembros de la familia de análogos de la 1 ,4 dihidropiridina, como es el Amlodipino el fármaco más ampliamente usado de esta familia. Con base en estos resultados es claro que se ha seleccionado a los mejores y más avanzados miembros de la familia de los BRA y de los calcio antagonistas Eprosartán y Lercanidipino respectivamente y que incluso han demostrado en resultados previos sinergias establecidas con otros antihipertensivos. Es evidente entonces la contundencia de la combinación y la clara superioridad de esta combinación sobre otras existentes para el tratamiento de la hipertensión. De esta forma, la combinación de estos fármacos ofrece una alternativa superior a las combinaciones existentes para los siguientes casos: a) el tratamiento de la hipertensión severa, b) cuando ya no se responde a la monoterapia, c) para el tratamiento de enfermos de hipertensión denominados débiles, d) para cumplir con las guías sujetándose a los nuevos límites de hipertensión que no deben sobrepasarse, para no quedar expuestos a complicaciones cardiovasculares. The purpose of the present invention is the development of pharmaceutical compositions based on the combination of BRA Eprosartan and calcium antagonist Lercanidipine. In the present invention it has been illustrated, based on existing clinical studies, that Eprosartan shows superior efficacy to other members of the "sartanes" family such as Losartán, Valsartán, Candesartán and others. It has also been shown, based on different studies previously carried out that calcium antagonist Lercanidipine has a greater efficacy and significant greater tolerance and with less adverse effects than monotherapy, with other members of the family of analogs of 1,4 dihydropyridine, As is Amlodipine, the most widely used drug in this family. Based on these results, it is clear that the best and most advanced members of the BRA family and the antagonist calcium Eprosartan and Lercanidipine have been selected respectively and have even demonstrated in previous results synergies established with other antihypertensives. It is evident then the strength of the combination and the clear superiority of this combination over other existing ones for the treatment of hypertension. In this way, the combination of these drugs offers a superior alternative to existing combinations for the following cases: a) the treatment of severe hypertension, b) when monotherapy is no longer responding, c) for the treatment of patients with hypertension called weak, d) to comply with the guidelines subject to the new ones hypertension limits that should not be exceeded, so as not to be exposed to cardiovascular complications.
Una de las composiciones farmacéuticas que ha sido desarrollada consiste en tabletas de liberación inmediata. La composición se ha desarrollado elaborando un granulado independiente para cada uno de los principios activos. La fabricación del granulado de Eprosartán se realizó utilizando excipientes que no interactúan con el principio activo y los perfiles de disolución se ajustaron a fármacos comerciales de Eprosartán como monofármaco, hasta obtener un factor de similitud superior a F2 = 65. El mismo procedimiento se siguió para Lercanidipino, en cuyo granulado se emplearon excipientes que fueran estables en mezcla con el excipiente activo y los perfiles de disolución de las tabletas fabricadas se ajustaron hasta cumplir con los perfiles de disolución de medicamentos comerciales con Lercanidipino como monofármaco. Estos granulados se mezclaron y se agregó un lubricante y un desintegrante. La nueva mezcla fue comprimida para obtener tabletas que cumplieran con la dureza y friabilidad adecuadas. One of the pharmaceutical compositions that has been developed consists of immediate-release tablets. The composition has been developed by preparing an independent granulate for each of the active ingredients. The manufacturing of the Eprosartan granulate was carried out using excipients that do not interact with the active substance and the dissolution profiles were adjusted to commercial Eprosartan drugs as a monopharmaceutical, until a similarity factor greater than F2 = 65 was obtained. The same procedure was followed to Lercanidipine, in which granules were used excipients that were stable in admixture with the active excipient and the dissolution profiles of the manufactured tablets were adjusted to meet the dissolution profiles of commercial drugs with Lercanidipine as a monopharmaceutical. These granules were mixed and a lubricant and a disintegrant were added. The new mixture was compressed to obtain tablets that met the appropriate hardness and friability.
Además, estudios con Lercanidipino han demostrado que ingerir alimentos al mismo tiempo que se suministra Lercanidipino incrementa la biodisponibilidad de Lercanidipino en una cantidad significativa, por lo que aumenta su eficacia. Los estudios que se han realizado han demostrado que el acompañar la ingestión de Lercanidipino con los alimentos incrementa su absorción entre 3 y 4 veces en relación a cuando no se suministran los alimentos. En este último caso inclusive se ha encontrado que el Lercanidipino en ausencia de la ingestión de alimentos no es absorbido completamente, lo cual provoca una biodisponibilidad variable y baja (patente US 2006/0165789 A1 de Julio 27 de 2006). Además se tiene que Lercanidipino y sus sales muestran una pobre solubilidad. En particular, la sal de Clorhidrato muestra una solubilidad en agua de 5 mg/ml y en medio ácido, aunque se incrementa ligeramente, no obstante a pH 5 es menor a 20 mg/ml. Además, como ya antes se mencionó Lercanidipino ha sido clasificado por la FDA como un fármaco con baja permeabilidad. Finalmente, Lercanidipino es un sustrato de la isoenzima citrocromo P450 3A4 la cual degrada parcialmente al fármaco. Estos varios elementos provocan una baja sustancial en la concentración del fármaco que provoca una biodisponibilidad altamente variable. Todas estas características del fármaco motivan el desarrollo de una composición farmacéutica de liberación prolongada y constante en plasma durante un periodo entre 20 y 24 horas, cuidando que la concentración disponible en plasma no sea menor a la dosis terapéutica requerida. Con esta base se ha desarrollado una composición farmacéutica en la que en la tableta o capsula el activo Lercanidipino sea formulado de liberación prolongada, mientras que el activo Eprosartán sea liberado de manera inmediata. Asimismo, se ha desarrollado una formulación de liberación controlada en la que ambos activos son formulados de liberación prolongada, asegurando el suministro de ambos activos de manera constante durante un lapso de hasta 24 horas. In addition, studies with Lercanidipine have shown that eating food at the same time that Lercanidipine is supplied increases the bioavailability of Lercanidipine by a significant amount, thus increasing its effectiveness. Studies that have been conducted have shown that accompanying the intake of Lercanidipine with food increases its absorption between 3 and 4 times in relation to when food is not supplied. In the latter case it has even been found that Lercanidipine in the absence of food intake is not fully absorbed, which causes a variable and low bioavailability (US Patent 2006/0165789 A1 of July 27, 2006). In addition, Lercanidipine and its salts have poor solubility. In particular, the Hydrochloride salt shows a solubility in water of 5 mg / ml and in acid medium, although it increases slightly, however at pH 5 it is less than 20 mg / ml. In addition, as already previously mentioned Lercanidipine has been classified by the FDA as a drug with low permeability. Finally, Lercanidipine is a substrate of the citrochrome P450 3A4 isoenzyme which partially degrades the drug. These various elements cause a substantial decrease in the concentration of the drug that causes a highly variable bioavailability. All these characteristics of the drug motivate the development of a pharmaceutical composition of prolonged and constant release in plasma for a period between 20 and 24 hours, taking care that the concentration available in plasma is not less than the required therapeutic dose. With this base a pharmaceutical composition has been developed in which the Lercanidipine active ingredient is formulated in the tablet or capsule, while the active Eprosartan is released immediately. Likewise, a controlled release formulation has been developed in which both assets are formulated for prolonged release, ensuring the supply of both assets constantly for up to 24 hours.
Para el caso en que el paciente está limitado físicamente para ingerir medicación en forma de tabletas o capsulas se ha formulado una composición en presentación de polvo para reconstituirse en suspensión. Para el caso en que el paciente requiere una inmediata disposición del medicamento, como es en la crisis hipertensiva, también se ha desarrollado una composición farmacéutica en presentación inyectable por vía intravenosa. In the case where the patient is physically limited to ingest medication in the form of tablets or capsules, a powder presentation composition has been formulated to be reconstituted in suspension. For the case in which the patient requires an immediate disposition of the medication, as it is in the hypertensive crisis, a pharmaceutical composition has also been developed as an intravenous injection.
Los ejemplos que a continuación se describen ilustran algunas de las composiciones farmacéuticas que se formularon; sin embargo, los propósitos de la invención se extienden mas allá, considerando que con esta idea el conocedor del estado del arte puede hacer modificaciones que no son originales y que solo implican variaciones sobre esta propuesta, por lo que la patente no está limitada a estos ejemplos. The examples described below illustrate some of the pharmaceutical compositions that were formulated; however, the purposes of the invention extend further, considering that with this idea the person skilled in the state of the art can make modifications that are not original and that only imply variations on this proposal, so the patent is not limited to these examples.
EJEMPLOS EJEMPLO 1 . Tabletas de liberación inmediata de la combinación Mesilato de Eprosartán equivalente a 600 mg de Eprosartán con Clorhidrato de Lercanidipino equivalente a 9.4 mg de Lercanidipino. Proceso de fabricación de tabletas por granulación vía húmeda. EXAMPLES EXAMPLE 1 . Immediate-release tablets of the combination of Eprosartan Mesylate equivalent to 600 mg of Eprosartan with Lercanidipine Hydrochloride equivalent to 9.4 mg of Lercanidipine. Process of manufacturing tablets by wet granulation.
FORMULACIÓN  FORMULATION
Figure imgf000018_0001
Figure imgf000018_0001
*Se evapora durante el proceso * It evaporates during the process
DESCRIPCION DEL PROCESO DE FABRICACIÓN. DESCRIPTION OF THE MANUFACTURING PROCESS.
A) Granulación vía húmeda. Granulado No. 1  A) Wet granulation. Granulate No. 1
Tamizar por malla No. 40 el Eprosartán, 57% de la celulosa microcristalina, 64.5% de la lactosa monohidratada M200, el almidón pregelatinizado 1500, Adicionar los materiales tamizados al granulador de alto corte y mezclar. Realizar el proceso de granulación adicionando agua purificada. Mezclar hasta encontrar el punto de granulación. Tamizar la mezcla húmeda a través de una malla de 0.375 pulgadas utilizando el granulador cónico, a continuación realizar el proceso de secado del granulado húmedo a temperatura de 60°C ± 5°C, tamizar el granulado por malla 0.062 utilizando un granulador cónico. Sieve by mesh No. 40 the Eprosartan, 57% of the microcrystalline cellulose, 64.5% of the M200 lactose monohydrate, the pregelatinized starch 1500, Add the screened materials to the high-cut granulator and mix. Perform the granulation process by adding purified water. Mix until you find the point of granulation. Sift the wet mixture through a 0.375 inch mesh using the conical granulator, then perform The drying process of the wet granulate at a temperature of 60 ° C ± 5 ° C, screen the 0.062 mesh granulate using a conical granulator.
B) Granulación vía húmeda. Granulado No. 2. B) Wet granulation. Granulate No. 2.
Tamizar por malla No. 40 el Lercanidipino, 43% de la celulosa microcristalina, 35.5% de la lactosa monohidratada M200, el almidón, el glicolato de sodio, adicionar los materiales al granulador de alto corte y mezclar. Por separado, colocar en un contenedor de capacidad adecuada agua purificada y con agitación continua adicionar povidona K30, mantener la agitación hasta tener una solución homogénea. Realizar el proceso de granulación adicionando la solución de povidona K30 a la mezcla de polvos contenidos en el granulador de alto corte, mantener el mezclado hasta encontrar el punto de granulación, tamizar la mezcla húmeda a través de malla de 0.375 pulgadas utilizando un granulador cónico, realizar el proceso de secado del granulado húmedo a temperatura de 45°C ± 5°C, una vez seco el granulado tamizar por malla 0.062 utilizando un granulador cónico.  Sift through mesh No. 40 the Lercanidipine, 43% of the microcrystalline cellulose, 35.5% of the M200 lactose monohydrate, the starch, the sodium glycolate, add the materials to the high-cut granulator and mix. Separately, place in a container of suitable capacity purified water and with continuous stirring add povidone K30, keep stirring until you have a homogeneous solution. Perform the granulation process by adding the povidone K30 solution to the powder mixture contained in the high-cut granulator, keep mixing until the granulation point is found, sift the wet mixture through 0.375-inch mesh using a conical granulator, Perform the drying process of the wet granulate at a temperature of 45 ° C ± 5 ° C, once the granulate has been dry sifted by 0.062 mesh using a conical granulator.
C) Granulado final. C) Final granulate.
Colocar en un mezclador en "V" el granulado No. 1 que contiene Eprosartán y el granulado No.2 que contiene Lercanidipino y mezclar; adicionar al mezclador crospovidona XL10 previamente tamizada por malla No. 30 y mezclar. Finalmente realizar el proceso de lubricado adicionando al mezclador el estearato de magnesio previamente tamizado por malla No. 30 y mezclar.  Place the No. 1 granule containing Eprosartan and granulate No.2 containing Lercanidipine in a "V" mixer and mix; add to the crospovidone XL10 mixer previously sieved by mesh No. 30 and mix. Finally, carry out the lubrication process by adding the magnesium stearate previously sieved by mesh No. 30 to the mixer and mixing.
D) Compresión D) Compression
Finalmente realizar el proceso de compresión del granulado final, utilizando una tableteadora rotativa de velocidad variable con punzones bicóncavos. La velocidad de alimentación y la velocidad de compresión se ajustan para controlar el peso de la tableta.  Finally perform the compression process of the final granulate, using a rotary tableteadora of variable speed with biconcave punches. The feed rate and compression rate are adjusted to control the weight of the tablet.
EJEMPLO 2. Tabletas de liberación prolongada de la combinación Mesilato de Eprosartán equivalente a 600 mg de Eprosartán, con Clorhidrato de Lercanidipino equivalente a 9.4 mg de Lercanidipino. Proceso de fabricación por granulación vía húmeda. EXAMPLE 2. Prolonged-release tablets of the combination Eprosartan Mesylate equivalent to 600 mg of Eprosartan, with Hydrochloride Lercanidipine equivalent to 9.4 mg of Lercanidipine. Manufacturing process by wet granulation.
FORMULACIÓN  FORMULATION
Figure imgf000020_0001
Figure imgf000020_0001
*Se evapora durante el proceso * It evaporates during the process
DESCRIPCION DEL PROCESO DE FABRICACIÓN. DESCRIPTION OF THE MANUFACTURING PROCESS.
A) Granulación vía húmeda. Granulado No. 1  A) Wet granulation. Granulate No. 1
Tamizar por malla No. 40 el Eprosartán, 57% de la celulosa microcristalina, 64.5% de la lactosa monohidratada M200, el almidón pregelatinizado 1500, Adicionar los materiales tamizados al granulador de alto corte y mezclar. Sieve by mesh No. 40 the Eprosartan, 57% of the microcrystalline cellulose, 64.5% of the M200 lactose monohydrate, the pregelatinized starch 1500, Add the screened materials to the high-cut granulator and mix.
Realizar el proceso de granulación adicionando agua purificada, mezclar hasta encontrar el punto de granulación, tamizar la mezcla húmeda a través de una malla de 0.375 pulgadas utilizando el granulador cónico, a continuación realizar el proceso de secado del granulado húmedo a temperatura de 60°C ± 5°C, tamizar el granulado por una malla de 0.062 pulgadas utilizando un granulador cónico. Perform the granulation process by adding purified water, mix until you find the granulation point, sift the wet mixture through a 0.375 inch mesh using the conical granulator, then perform the wet granulate drying process at a temperature of 60 ° C ± 5 ° C, Sift the granulate through a 0.062 inch mesh using a conical granulator.
B) Granulación vía húmeda. Granulado No. 2. B) Wet granulation. Granulate No. 2.
Tamizar por malla No. 40 el Lercanidipino, 43% de la celulosa microcristalina, Sift through mesh No. 40 Lercanidipine, 43% of microcrystalline cellulose,
35.5% de la Lactosa monohidratada M200, adicionar los materiales al granulador de alto corte y mezclar. Por separado colocar en un contenedor de capacidad adecuada agua purificada y con agitación continua adicionar povidona K30, mantener la agitación hasta tener una solución homogénea. Realizar el proceso de granulación adicionando la solución de povidona K30 a la mezcla de polvos contenidos en el granulador de alto corte, mantener el mezclado hasta encontrar el punto de granulación, tamizar la mezcla húmeda a través de malla 0.375 pulgadas utilizando un granulador cónico, realizar el proceso de secado del granulado húmedo a temperatura de 45°C ± 5°C, una vez seco el granulado tamizar por malla 0.062 utilizando un granulador cónico. 35.5% of M200 lactose monohydrate, add the materials to the high-cut granulator and mix. Separately place in a container of suitable capacity purified water and with continuous stirring add povidone K30, keep stirring until you have a homogeneous solution. Perform the granulation process by adding the povidone K30 solution to the mixture of powders contained in the high-cut granulator, keep mixing until finding the point of granulation, sift the wet mixture through 0.375 inch mesh using a conical granulator, perform The drying process of the wet granulate at a temperature of 45 ° C ± 5 ° C, once the granulate is screened by 0.062 mesh using a conical granulator.
C) Granulado final. C) Final granulate.
Colocar en un mezclador en "V" el granulado No. 1 que contiene Eprosartán y el granulado No. 2 que contiene Lercanidipino y mezclar, finalmente realizar el proceso de lubricado adicionando al mezclador el estearato de magnesio previamente tamizado por malla No. 30 y mezclar.  Place the No. 1 granule containing Eprosartan and the granule No. 2 containing Lercanidipine in a "V" mixer and mix, finally carry out the lubrication process by adding the magnesium stearate previously sieved by mesh No. 30 to the mixer and mix .
D) Compresión. D) Compression.
Finalmente realizar el proceso de compresión del granulado final, utilizando una tableteadora rotativa de velocidad variable con punzones bicóncavos. La velocidad de alimentación y la velocidad de compresión se ajustan para controlar el peso de la tableta.  Finally perform the compression process of the final granulate, using a rotary tableteadora of variable speed with biconcave punches. The feed rate and compression rate are adjusted to control the weight of the tablet.
E) Proceso de recubrimiento de liberación extendida. E) Extended release coating process.
De inicio se aplica un recubrimiento de sellado o recubrimiento protector, dicho recubrimiento hace la función de separar los activos (Eprosartán y Lercanidipino) del recubrimiento de liberación extendida, así mismo actúa como un sello para eliminar la porosidad de la tableta. Initially, a sealing coating or protective coating is applied, said coating serves to separate the assets (Eprosartan and Lercanidipine) of the extended release coating, it also acts as a seal to eliminate the porosity of the tablet.
Solución A (recubrimiento protector o de sellado). Adicionar en un contenedor de capacidad adecuada agua purificada a temperatura ambiente (20- 35°C) y con agitación continua adicionar el Opadry Blanco. Mantener la agitación durante 30 minutos o hasta disolución total. Solution A (protective or sealing coating). Add purified water at room temperature (20-35 ° C) in a suitable capacity container and with continuous stirring add the White Opadry. Maintain stirring for 30 minutes or until complete dissolution.
Dispersión B (recubrimiento de liberación prolongada). En un contenedor de capacidad adecuada adicionar agua purificada considerando una dispersión final de 15% en sólidos. Adicionar el polímero de recubrimiento Surelease, manteniendo la agitación durante 10 minutos y adicionar la parte correspondiente de Opadry Blanco (responsable de formar canales que favorecen la liberación del fármaco) y mantener la agitación durante 40 minutos. Dispersion B (extended release coating). In a container of adequate capacity add purified water considering a final dispersion of 15% solids. Add the Surelease coating polymer, maintaining the stirring for 10 minutes and adding the corresponding part of White Opadry (responsible for forming channels that favor drug release) and keep stirring for 40 minutes.
La Solución A de recubrimiento es asperjada sobre los núcleos usando un bombo de recubrimiento, bajo las siguientes condiciones: temperatura de aire de entrada de 55°C a 75°C, temperatura del producto de 38°C a 45°C, presión de aspersión de 1 .0 a 3.0 bar, velocidad de aspersión de 8 a 15 g/min. Al terminar de asperjar la Solución A, continuar el proceso de recubrimiento asperjando la Dispersión B, conservando las mismas condiciones de proceso que para la solución A. The Coating Solution A is sprayed on the cores using a coating drum, under the following conditions: inlet air temperature from 55 ° C to 75 ° C, product temperature from 38 ° C to 45 ° C, spray pressure from 1 .0 to 3.0 bar, sprinkler speed from 8 to 15 g / min. When you have finished spraying Solution A, continue the coating process by sprinkling Dispersion B, keeping the same process conditions as for solution A.
EJEMPLO 3. Tabletas de liberación inmediata de Mesilato de Eprosartán equivalente a 600 mg de Eprosartán y de liberación extendida de Clorhidrato de Lercanidipino equivalente a 9.4 mg de Lercanidipino. Proceso de fabricación por granulación vía húmeda. EXAMPLE 3. Immediate-release tablets of Eprosartan Mesylate equivalent to 600 mg of Eprosartan and extended-release tablets of Lercanidipine Hydrochloride equivalent to 9.4 mg of Lercanidipine. Manufacturing process by wet granulation.
FORMULACION FORMULATION
Componente mg /Tableta  Mg / tablet component
Mesilato de Eprosartán equivalente a  Eprosartan Mesylate equivalent to
735.80  735.80
600 mg de Eprosartán Lercanidipino Clorhidrato equivalente 600 mg of Eprosartan Lercanidipine Hydrochloride equivalent
10.00  10.00
a 9.4 mg de Lercanidipino  to 9.4 mg of Lercanidipine
Celulosa microcristalina PH 101 106.00  Microcrystalline cellulose PH 101 106.00
Lactosa monohidratada M200 68.50  Lactose monohydrate M200 68.50
Almidón pregelatinizado (Starch 1500) 52.00  Pregelatinized starch (Starch 1500) 52.00
Crospovidona (Polyplasdone XL) 38.50  Crospovidone (Polyplasdone XL) 38.50
Povidona K30 6.00  Povidona K30 6.00
Ethocel 100 premium FP (Etil celulosa) 26.00 Ethocel 100 premium FP (Ethyl Cellulose) 26.00
Estearato de magnesio vegetal (Parteck  Vegetable Magnesium Stearate (Parteck
7.20  7.20
LUB MST  LUB MST
Opadry II color blanco 40.00  Opadry II white color 40.00
Agua purificada * CS. Purified water * CS.
*Se evapora durante el proceso * It evaporates during the process
DESCRIPCION DEL PROCESO DE FABRICACIÓN. DESCRIPTION OF THE MANUFACTURING PROCESS.
A) Granulación vía húmeda. Granulado No. 1  A) Wet granulation. Granulate No. 1
Tamizar por malla No. 40 el Eprosartán, 49.06% de la celulosa microcristalina, 78.1 1 % de la lactosa monohidratada M200, el almidón pregelatinizado 1500. Adicionar los materiales tamizados al granulador de alto corte y mezclar. Realizar el proceso de granulación adicionando agua purificada, mezclar hasta encontrar el punto de granulación, tamizar la mezcla húmeda a través de una malla de 0.375 pulgadas utilizando el granulador cónico, a continuación realizar el proceso de secado del granulado húmedo a temperatura de 60°C ± 5°C, tamizar el granulado por una malla de 0.062 pulgadas utilizando un granulador cónico.  Sieve by mesh No. 40 the Eprosartan, 49.06% of the microcrystalline cellulose, 78.1 1% of the M200 lactose monohydrate, the pregelatinized starch 1500. Add the screened materials to the high-cut granulator and mix. Perform the granulation process by adding purified water, mix until you find the granulation point, sift the wet mixture through a 0.375 inch mesh using the conical granulator, then perform the wet granulate drying process at a temperature of 60 ° C ± 5 ° C, sift the granulate through a 0.062 inch mesh using a conical granulator.
B) Granulado de liberación extendida. Granulado No. 2. B) Extended release granulate. Granulate No. 2.
Tamizar por una malla No. 40 el Lercanidipino, 50.94% de la celulosa microcristalina, 21 .89% de la lactosa monohidratada M200, adicionar los materiales al granulador de alto corte y mezclar. Por separado se prepara la solución aglutínate, en un contenedor de capacidad adecuada adicionar agua purificada y alcohol en una relación de 60:40 y con agitación continua agregar povidona K30, mantener la agitación hasta tener una solución homogénea. Realizar el proceso de granulación adicionando la solución de povidona K30 a la mezcla de polvos contenidos en el granulador de alto corte, una vez terminada la adición de la solución adicionar a la mezcla humectada ethocel 100 premium FP (Etil celulosa) y mezclar durante 10 minutos, tamizar la mezcla húmeda a través de una malla de 0.375 pulgadas utilizando un granulador cónico, realizar el proceso de secado del granulado húmedo a temperatura de 45°C ± 5°C, una vez seco el granulado tamizar por una malla de 0.062 pulgadas utilizando un granulador cónico. Sift through a mesh No. 40 the Lercanidipine, 50.94% of the microcrystalline cellulose, 21 .89% of the M200 lactose monohydrate, add the materials to the high-cut granulator and mix. Separately the agglutinate solution is prepared, in a container of adequate capacity add water purified and alcohol in a ratio of 60:40 and with continuous stirring add povidone K30, keep stirring until you have a homogeneous solution. Perform the granulation process by adding the povidone K30 solution to the powder mixture contained in the high-cut granulator, once the solution has been added, add to the ethocel 100 premium FP (Ethyl cellulose) moisturized mixture and mix for 10 minutes , sift the wet mixture through a 0.375 inch mesh using a conical granulator, perform the drying process of the wet granulate at a temperature of 45 ° C ± 5 ° C, once the granulate is dry sift through a 0.062 inch mesh using a conical granulator.
C) Granulado final. C) Final granulate.
Colocar en un mezclador en "V" el granulado No. 1 que contiene Eprosartán y el granulado No.2 que contiene Lercanidipino y mezclar. Adicionar al mezclador crospovidona XL10 previamente tamizada por una malla 30 y mezclar. Finalmente realizar el proceso de lubricado adicionando al mezclador el estearato de magnesio previamente tamizado por una malla 30 y mezclar.  Place the No. 1 granule containing Eprosartan and granulate No.2 containing Lercanidipine in a "V" mixer and mix. Add the crospovidone XL10 mixer previously sieved through a 30 mesh and mix. Finally, carry out the lubrication process by adding the magnesium stearate previously sieved through a 30 mesh to the mixer and mixing.
D) Compresión D) Compression
Finalmente realizar el proceso de compresión del granulado final, utilizando una tableteadora rotativa de velocidad variable con punzones bicóncavos. La velocidad de alimentación y la velocidad de compresión se ajustan para controlar el peso de la tableta.  Finally perform the compression process of the final granulate, using a rotary tableteadora of variable speed with biconcave punches. The feed rate and compression rate are adjusted to control the weight of the tablet.
EJEMPLO 4. Polvo para suspensión oral, cada 5 mL contienen Mesilato de Eprosartán equivalente a 600 mg de Eprosartán y Clorhidrato de Lercanidipino equivalente a 9.4 mg de Lercanidipino. EXAMPLE 4. Powder for oral suspension, each 5 mL contains Eprosartan Mesylate equivalent to 600 mg of Eprosartan and Lercanidipine Hydrochloride equivalent to 9.4 mg of Lercanidipine.
FORMULACION  FORMULATION
Componente W/W %  Component W / W%
Mesilato de Eprosartán  Eprosartan Mesylate
equivalente a 600 mg de 14.72  equivalent to 600 mg of 14.72
Eprosartán por cada 5 mi Lercanidipino Clorhidrato Eprosartan for every 5 mi Lercanidipine Hydrochloride
equivalente a 9.4mg de 0.2  equivalent to 9.4mg of 0.2
Lercanidipino por cada 5 mi  Lercanidipine for every 5 mi
Goma Xantana 0.36  Xantana rubber 0.36
Dióxido de silicio coloidal 0.18  Colloidal Silicon Dioxide 0.18
Sucralosa 0.42  Sucralose 0.42
Azúcar granulada 70.00  70.00 granulated sugar
Kyron 7134 0.24  Kyron 7134 0.24
Sabor frambuesa 0.50  Raspberry Flavor 0.50
Amarillo no. 6 0.006  Yellow no. 6 0.006
Agua purificada cbp. 100  Purified water cbp. 100
DESCRIPCION DEL PROCESO DE FABRICACIÓN. DESCRIPTION OF THE MANUFACTURING PROCESS.
A) Tamizar por una malla 40 el Mesilato de Eprosartán, el Lercanidipino Clorhidrato, el Kyron 7134, la sucralosa, el sabor frambuesa, el Amarillo 6, el dióxido de silicio coloidal y 20% de azúcar granular. Adicionar los materiales tamizados a un mezclador en "V" y mezclar durante 10 minutos. Por separado tamizar por una malla 30 goma xantana y el 80% restante del azúcar granular y adicionar al mezclador en "V", dar un tiempo de mezclado de 15 minutos.  A) Sift through a mesh 40 Eprosartan Mesylate, Lercanidipine Hydrochloride, Kyron 7134, sucralose, raspberry flavor, Yellow 6, colloidal silicon dioxide and 20% granular sugar. Add the screened materials to a "V" mixer and mix for 10 minutes. Separately sift through a mesh 30 xanthan gum and the remaining 80% of the granular sugar and add to the mixer in "V", give a mixing time of 15 minutes.
B) Dosificar la mezcla de polvo en frasco de polietileno de alta densidad, depositar en el frasco la cantidad de polvo requerido conforme al número de dosis requerido y colocar una tapa de polipropileno con cintillo de seguridad. EJEMPLO 5. Solución inyectable, cada 50 mL contiene 600 mg de Eprosartan y 10 mg de Lercanidipino.  B) Dose the powder mixture in a high density polyethylene bottle, deposit the required amount of powder in the bottle according to the number of doses required and place a polypropylene cap with a safety belt. EXAMPLE 5. Solution for injection, each 50 mL contains 600 mg of Eprosartan and 10 mg of Lercanidipine.
FORMULACION FORMULATION
Componente W/V %  Component W / V%
Mesilato de Eprosartán 1 .4716 Lercanidipino clorhidrato 0.0212 Eprosartan Mesylate 1 .4716 Lercanidipine hydrochloride 0.0212
Propilenglicol 20.0000  Propylene Glycol 20.0000
Etanol USP 5.0000  Ethanol USP 5.0000
Cloruro de sodio USP 0.8000  Sodium Chloride USP 0.8000
Acido cítrico anhidro 0.1000  0.1000 anhydrous citric acid
Fosfato de sodio dibásico  Dibasic sodium phosphate
89.60  89.60
anhidro USP  anhydrous USP
Agua grado inyectable cbp. 100.0000  Water injection grade cbp. 100.0000
DESCRIPCION DEL PROCESO DE FABRICACIÓN. DESCRIPTION OF THE MANUFACTURING PROCESS.
A) Solución No. 1 . Colocar en un contenedor de acero inoxidable el Propilenglicol junto con Etanol y homogenizar, con agitación continua adicionar el Mesilato de Eprosartán y mantener la agitación hasta disolución total.  A) Solution No. 1. Place the Propylene Glycol in a stainless steel container together with Ethanol and homogenize, with continuous stirring, add the Eprosartan Mesylate and keep stirring until completely dissolved.
B) Solución No. 2. Por separado en un contenedor de acero inoxidable adicionar agua grado inyectable y con agitación continua adicionar Acido cítrico y disolver, manteniendo la agitación adicionar el Clorhidrato de Lercanidipino y conservar la agitación hasta la disolución de dicho activo.  B) Solution No. 2. Separately in a stainless steel container add injectable grade water and with continuous stirring add citric acid and dissolve, keeping the stirring add Lercanidipine Hydrochloride and keep stirring until said active agent dissolves.
C) Solución No. 3. Colocar en un contenedor de acero inoxidable agua purificada y con agitación continua disolver Cloruro de sodio USP y Fosfato de sodio dibásico anhidro USP.  C) Solution No. 3. Place in a stainless steel container purified water and with continuous stirring dissolve USP sodium chloride and USP anhydrous dibasic sodium phosphate.
D) Con agitación continua adicionar a la Solución No. 3, la Solución No. 1 y la Solución No. 2, realizar el aforo y homogenizar la solución. En condiciones asépticas se realiza el proceso de esterilización el cual es por filtración, el proceso de filtrado se realiza a través de un filtro de 0.22 μιη, a continuación se realiza el envasado en área estéril en frasco de vidrio ámbar.  D) With continuous agitation add to Solution No. 3, Solution No. 1 and Solution No. 2, perform the capacity and homogenize the solution. Under aseptic conditions the sterilization process is carried out which is by filtration, the filtering process is carried out through a 0.22 μιη filter, then the sterile area is packaged in amber glass bottle.

Claims

REIVINDICACIONES
1 . Una composición farmacéutica caracterizada porque comprende como principio activo la combinación del ácido (E)-3-[2-butil-1 -[(4-carboxifenil)-metil]-imidazol-5- il]-2-(2-tienilmetil)-2-propanoico de nombre genérico Eprosartán combinado con el metil 1 ,1 -dimetil-2-[N-(3,3-difenilpropil)-N-metilamino]etil 2,6-dimetil-4-(3- nitrofenil)-1 ,4-dihidropiridina-3,5-dicarboxilato de nombre genérico Lercanidipino o alguna de sus sales farmacéuticamente aceptables de cualquiera de los dos principios activos. one . A pharmaceutical composition characterized in that it comprises as an active ingredient the combination of (E) -3- [2-butyl-1 - [(4-carboxyphenyl) -methyl] -imidazol-5- yl] -2- (2-thienylmethyl) acid -2-propanoic acid generic name Eprosartan combined with methyl 1,1-dimethyl-2- [N- (3,3-diphenylpropyl) -N-methylamino] ethyl 2,6-dimethyl-4- (3- nitrophenyl) - 1,4-dihydropyridine-3,5-dicarboxylate of the generic name Lercanidipine or any of its pharmaceutically acceptable salts of any of the two active ingredients.
2. La composición farmacéutica de conformidad con la reivindicación 1 , caracterizada además porque se encuentra en forma de tabletas o cápsulas de liberación inmediata conteniendo como principios activos a la combinación de Eprosartán con Lercanidipino.  2. The pharmaceutical composition according to claim 1, further characterized in that it is in the form of immediate-release tablets or capsules containing as active ingredients the combination of Eprosartan with Lercanidipine.
3. La composición farmacéutica de conformidad con la reivindicación 1 , caracterizada además porque se encuentra en forma de tabletas o cápsulas con la combinación de los principios activos Eprosartán y Lercanidipino ambos de liberación prolongada.  3. The pharmaceutical composition according to claim 1, further characterized in that it is in the form of tablets or capsules with the combination of the active ingredients Eprosartan and Lercanidipine both prolonged release.
4. La composición farmacéutica de conformidad con la reivindicación 1 , caracterizada además porque se encuentra en forma de tabletas o cápsulas empleando como principios activos al Eprosartán formulado de liberación inmediata y el Lercanidipino formulado de liberación prolongada.  4. The pharmaceutical composition according to claim 1, further characterized in that it is in the form of tablets or capsules using as active ingredients the formulated immediate release Eprosartan and the formulated extended release Lercanidipine.
5. La composición farmacéutica de conformidad con la reivindicación 1 , caracterizada además porque se encuentra en forma de polvos para suspensión oral, conteniendo como principios activos el Eprosartán y el Lercanidipino.  5. The pharmaceutical composition according to claim 1, further characterized in that it is in the form of powders for oral suspension, containing as active ingredients Eprosartan and Lercanidipine.
6. La composición farmacéutica de conformidad con la reivindicación 1 , caracterizada además porque se encuentra en forma de un liofilizado para una solución inyectable intravenosa.  6. The pharmaceutical composition according to claim 1, further characterized in that it is in the form of a lyophilisate for an intravenous injectable solution.
7. La composición farmacéutica de las reivindicaciones 1 a 6 para usarse en el tratamiento de hipertensión.  7. The pharmaceutical composition of claims 1 to 6 for use in the treatment of hypertension.
PCT/IB2015/059751 2015-02-18 2015-12-17 Pharmaceutical compositions for treating hypertension, based on a novel drug combination WO2016132192A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075892A2 (en) * 2003-02-28 2004-09-10 Recordati Ireland Limited Combination therapy for hypertension using lercanidipine and an angiotensin ii receptor blocker

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075892A2 (en) * 2003-02-28 2004-09-10 Recordati Ireland Limited Combination therapy for hypertension using lercanidipine and an angiotensin ii receptor blocker

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CHRYSANT, S.G. ET AL.: "The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study.", CLIN THER., vol. 30, no. 4, April 2008 (2008-04-01), pages 587 - 604, XP022671119, DOI: doi:10.1016/j.clinthera.2008.04.002 *
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