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WO2014119989A2 - Composition pharmaceutique présentant un antagoniste des récepteurs de l'angiotensine ii et un bloqueur des canaux calciques pour le traitement de l'hypertension artérielle - Google Patents

Composition pharmaceutique présentant un antagoniste des récepteurs de l'angiotensine ii et un bloqueur des canaux calciques pour le traitement de l'hypertension artérielle Download PDF

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Publication number
WO2014119989A2
WO2014119989A2 PCT/MX2014/000034 MX2014000034W WO2014119989A2 WO 2014119989 A2 WO2014119989 A2 WO 2014119989A2 MX 2014000034 W MX2014000034 W MX 2014000034W WO 2014119989 A2 WO2014119989 A2 WO 2014119989A2
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Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
combinations
composition according
tablet
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Ceased
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English (en)
Spanish (es)
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WO2014119989A3 (fr
Inventor
Miguel Ángel GARCIA PÉREZ
Gabriel MARCELÍN JIMÉNEZ
Concepción Albina VÁZQUEZ FLORES
Laura Ivonne GALO MOJICA
Alionka Citlalli P. ANGELES MORENO
Octavio CARO RODRÍGUEZ
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Publication of WO2014119989A3 publication Critical patent/WO2014119989A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel tablet-tablet composition consisting of a combination of at least two active ingredients in two or more phases, one of which is at least one angiotesin II receptor antagonist which is released with zero order and / or order one kinetics without delay time; the other is a calcium channel blocker which is released with zero order kinetics.
  • the application of the composition is for the prophylaxis and / or treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy and associated disorders.
  • cardiovascular diseases have become the leading cause of death in all the industrialized countries of the world, epidemiological analysis has allowed us to recognize the existence of biological variables called risk factors for cardiovascular disease, which are able to influence the probability of the disease of strokes, coronary heart disease, heart failure or peripheral artery disease (Castells E., 2000).
  • cardiovascular disorders are: arterial hypertension, cardiac arrhythmias, atherosclerosis, angina pectoris, cardiomyopathies, cerebrovascular disorder, heart failure, hyperlipidemias, hypotension, shock, venous thromboembolism, preclampsia, among others.
  • Hypertension is the most important risk factor for cardiovascular diseases and when it is associated with other disorders such as obesity, high cholesterol, alcohol consumption or smoking, the likelihood of suffering a serious cardiac complication increases exponentially.
  • renal, neurological or any other organ or region of the body human (Sat ⁇ n J., 1999). 95% of the hypertension observed in clinical practice do not have one. defined etiology, constitute the so-called essential arterial hypertension (AHT), also called primary or idiopathic, while 5% are due to various causes among which the ones induced by drug use, drug use, disease stand out renovascular, renal failure, pheochromocytoma and hyperaldosteronism (aicas C, 2003).
  • AHT essential arterial hypertension
  • Blood pressure is a continuous variable, therefore there is no cut-off point to define the threshold below which blood pressure values are normal, however, high blood pressure corresponds to a persistent elevation of blood pressure over limits.
  • PAS when its value is greater than or equal to 140 mmHg it is defined as PAS or systolic blood pressure, when its value is greater than or equal to 90 mmHg it is defined as PAD or diastolic blood pressure. (Minsal, 2010).
  • Arterial hypertension is basically characterized by the existence of an endothelial dysfunction, with a break in the balance between other relaxing factors of the blood vessel (nitric oxide-NO, hyperpolarizing factor of the endothelium-EDHF), vasoconstrictor factors (mainly endothelin), decrease in level of the endothelium of prostacyclin-PG12 vasodepressant and relative increase in thromboxane-TXA2 intracellular vasoconstrictor.
  • nitric oxide-NO hyperpolarizing factor of the endothelium-EDHF
  • vasoconstrictor factors mainly endothelin
  • Endothelin very potent local vasoconstrictor factors, about 10 to 100 times more powerful than angiotesin II. It is known that this is a complex system: preproendothelin-proendothelin-ETl.
  • an endothelin converting enzyme acts, forming mainly ET1, but also to a lesser extent, ET2 and ET3. Only ET1 seems to have systemic vasoconstrictor action.
  • ET1 exerts various actions: on vascular tone, renal excretion of sodium and water, and the production of the extracellular matrix.
  • ETl is involved, in an important way, in the process of vascular remodeling and regulation of cell proliferation. It is an extraordinarily potent mitogenic substance that produces hyperplasia and hypertrophy of vascular smooth muscle.
  • the renin-angiotesin-aldosterone system is an extremely complex system, comprising a series of proteins and 4 angiotesins (I, II, III and IV) with their own specific activities.
  • the actions of angiotesin II include: contraction of arterial and venous vascular smooth muscle, stimulation of the synthesis and secretion of aldosterone, release of norepinephrine in sympathetic terminations, modulation of sodium (Na) transport by renal tubular cells, increased oxidative stress by activation of NADH and NADPH dependent oxidases, vasopressin stimulation / ADH, stimulation of the dipsogenic center in the central nervous system, antagonism of the natriuretic-natural atrial peptide system (BNP) and type C (CNP), increased production of endothelin (ET1) and vasoconstrictor prostaglandins (TXA2, PgF2a).
  • BNP natriuretic-natural atrial peptide system
  • CNP type C
  • angiotesin II and aldosterone increase the collagen tissue at the cardiac and vascular level, to inhibit the activity of metalloproteinase (MMP1) that destroys collagen and increase the specific tissue inhibitors of MMP1 (TIMPs).
  • MMP1 metalloproteinase
  • TRIPs specific tissue inhibitors of MMP1
  • FDE endogenous digitalis
  • vasoactive intestinal peptide is intensely vasodilator
  • coherin is vasoconstrictor
  • cholecystokinin is vasodilator
  • substance P is also vasodilator, like bombesin, endorphins and eicosanoids (Wagner P., 2010) .
  • angiotesin-converting enzyme ACEI
  • Angiotesin II receptor antagonists ARA II
  • ACEI angiotesin II receptor antagonists
  • ARA II angiotesin II receptor antagonists
  • angiotesin II receptors include valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan ⁇ and eprosartan, among others.
  • Losartan is the oldest and best evaluated drug in this group, being the only agent of this type approved for the treatment of heart failure. It has proven to be an effective antihypertensive orally, with additional uricosuric activity, has an active metabolite of the order of 10-40 times more potent than losartan, for this reason in patients with chronic hepatopathy may lose effectiveness by hindering their metabolism and decreasing the generation of their active metabolite. Some of its characteristics is that it reaches its maximum plasma concentration in 1 hour and its active metabolite in about 3 to 4 hours, it has an absolute bioavailability of 33%, with a elimination half-life of 2.6 to 9 hours, it joins proteins in a percentage of 98.7% (Cadime, 2000).
  • Losartan when suffering the substantial metabolism of the first step by the cytochrome P-450 enzymes, is metabolized to an active metabolite which is the. 5-carboxylic acid, said metabolite is responsible for most of the effects of Losartan on the angiotensin receptor (Rodr ⁇ guez C, 2002).
  • nifedipine amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine and nisoldipine, among others.
  • Felodipine is an antagonist of the calcium channels of the dihydropyridine group, which has an oral bioavailability of 15%, as a result of intense first-pass metabolism. It has a volume of distribution of 10 L / kg and binds to plasma proteins in a proportion greater than 99%. Almost 100% of the dose is metabolized in the liver, forming inactive metabolites that are mostly eliminated in the urine.
  • the present invention relates to a pharmaceutical composition in the form of a tablet or tablet of two or more phases comprising a first tablet with a release system having a kinetic of zero order and / or of order one without delay time than at less a calcium channel blocking agent; and, a second tablet with a release system that exhibits a zero order kinetics of at least one angiotesin II receptor antagonist agent.
  • Said composition is useful for the treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy or associated disorders.
  • FIGURE 1 Dissolution profile of 25mg / 5mg Losartan / Felodipine tablets VS 5mg Felodipine tablets.
  • FIGURE 2 Dissolution profile of tablets
  • the present invention relates to a novel pharmaceutical composition in the form of a two-phase tablet-tablet which comprises: a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker, its pharmaceutically acceptable salts, derivatives, metabolites, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet with a release system that exhibits zero order and / or order one kinetics without delay time which contains at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives , prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally c) one or more pharmaceutically acceptable excipients, all of them in an oral administration system.
  • the internal tablet with a release system that has zero order kinetics containing at least one calcium channel blocker was developed in this way in the novel composition object of this invention, taking into account that its usefulness to prevent cardiovascular events in hypertensive patients is proven when they are in a long-acting system compared to those of short-acting that increase the probability of coronary events and mortality and therefore are not used as hypertensive.
  • the external tablet with a release system that presents a kinetic of zero order and / or of order one without delay time which, preferably of order one, was developed in this way in order to perform at least a delivery of at least one angiotesin II receptor antagonist agent and thus obtain a better synergistic effect with the calcium channel blocking agent. Decreasing peripheral vascular resistance, blood pressure and afterload.
  • At least one calcium channel blocking agent is selected from the following group: nifedipine, amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine, nisoldipine, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, same that is contained in the internal tablet within the composition.
  • At least one angiotesin II receptor antagonist agent is selected from the group consisting of valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof.
  • composition described in the present invention its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, are preferably used, but not limited to, a blocker of calcium channels to felodipine.
  • concentration range between 1 mg and 10 mg, more preferably in a range of 3 mg to 7 mg.
  • the angiotesin II receptor antagonist agent that is preferably used, but not limited to, is losartan, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, in a concentration range between 5 mg and 60 mg and more preferably from 17 to 35 mg.
  • the internal tablet of the composition in addition to containing at least one calcium channel blocking agent, may contain one or more excipients.
  • the internal tablet and the external tablet of the The composition may contain at least one pharmaceutically acceptable excipient, which is selected from; alginic acid, crospovidone, ion exchange resins, aluminum silicate, magnesium silicate, microcrystalline cellulose, starch, sodium starch glycol, modified cellulose gum, PVP, sodium dodecyl sulfate corn starch, rice starch, N-vinyl -2- crosslinked pyrrolidone, croscarmellose sodium, formaldehyde-casein, sorbitol, starch, pregentalized starch, corn starch, sucrose, sugar, compressible sugar, isomalt, tragacanth, talcum, trehalose, xylitol, acacia, agar, algic acid, carbonate of calcium, calcium lactate, carbomer, calcium carboxymethylcellulose, myocrystalline
  • the internal tablet of the composition in addition to containing at least one calcium channel blocking agent, is formed by one or more monosaccharides, one or more polyethylene oxides, one or more cellulose derivatives, one or more salts of silica and one or more lubricating agents; and the external tablet of the composition, in addition to containing at least one angiotesin II receptor antagonist agent, is made up of one or more cellulose polymers, one or more silica salts, one or more monosaccharides and one or more agents.
  • lubricants in addition to containing at least one calcium channel blocking agent, is formed by one or more monosaccharides, one or more polyethylene oxides, one or more cellulose derivatives, one or more salts of silica and one or more lubricating agents.
  • the monosaccharides can be fructose, lactose, mannitol, xylol, sorbitol, anhydrous lactose and / or lactose monohydrate and / or combinations thereof;
  • the polyethylene oxides may be selected from polyox N-10, polyox N-80, polyox N12-k, polyox N60-k and / or polyox N-301 or combinations thereof;
  • Cellulose derivatives may be microcrystalline cellulose, sodium carboxymethylcellulose, silicified microcrystalline cellulose, cellulose, hydroxypropylmethyl cellulose, calcium microcrystalline cellulose, hydroxyethyl cellulose, microcrystalline cellulose, calcium microcrystalline cellulose, hydroxypropyl cellulose and / or combinations thereof;
  • the silicon salt can be silicon oxide, calcium silicate, magnesium aluminum silicate, aluminum silicate, magnesium silicate, colloidal silicon dioxide, magnesium aluminum metasilicate, siliconized microcrystalline cellulose, magnesium trisilicate, silicon dioxide and / or colloidal
  • the pharmacokinetics of the active ingredients losartan (A) and felodipine (B) administered independently in a single dose administered orally is the same as the pharmacokinetics of the same co-administered active ingredients (C) in their pharmaceutical form.
  • the pharmacokinetics of the active ingredients losartan (A) and felodipine (B) administered independently in a single dose administered orally is different from the pharmacokinetics of the same co-administered active ingredients (C) in their pharmaceutical form.
  • the study design was developed with 12 healthy volunteers, "longitudinal sexes both, 18 to 55 years of age by cross pattern, randomized, prospective, single - blind, single - center, single - dose under fasting conditions, three sessions , six sequences (ABC, ACB, BAC, BCA, CAB, CBA), seven days of washing between each study session, to determine the pharmacokinetic parameters and bioavailability in fixed doses of losartan, felodipine and losartan-felodipine.
  • the groups were balanced with the same number of volunteers for each sequence.
  • the study was run in darkness, due to the photosensitivity of the felodipine; The medication was administered with 250 mL of 10-hour fasting electrolyte solution; and the volunteers remained in bed for 4 hours or until they could return to the rest of the group, as long as their vital signs were normal.
  • the average values corresponding to the losartan metabolite EXP3174 for the pharmacokinetic parameters were obtained using WinNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of 25 mg losartan from the reference medicine (A) and the tablet-tablet medicine (C) containing the combined dose of 25 mg losartan and 5 mg felodipine: these are shown in the table 4 including the Student t test for the comparison of means without assuming equal variances for considering different formulations with an alpha value of 0-05 for the rejection of the null hypothesis of equality as well as the value of bioavailability from the relationship between the tablet-tablet formulation (C) with respect to the formulation of the reference medicine (A).
  • the The developed composition has an "in vivo" release system that allows intact molecules to pass through the body for a time not less than 2.5 hours for Losartan and not less than 8.5 hours for the metabolite of losartan EXP3174.
  • Table 5 Values of felodipine pharmacokinetic parameters obtained for each of the volunteers who participated in the study.
  • the composition Developed presents an "in vivo" release system that allows intact molecules to pass through the body for a time not less than 12 hours for Felodipine.
  • composition developed from the present invention allows the delivery of the active ingredients losartan and felodipine without manifesting negative interaction that delays or prevents the absorption, metabolism or distribution thereof when administered in combination compared to its pharmacokinetic behavior when administered independently.
  • the tablet-tablet formulation (C) does not alter the pharmacokinetic behavior of the active ingredients, once the composition comprising a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker is administered, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet having zero order and / or order one kinetics without delay time containing at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally
  • compositions used during the development of the invention are presented below as illustrative, but not limited to, examples:
  • Example 1 Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
  • Example 2 Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
  • Example 3 Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
  • the present compositions have a dissolution profile of the active ingredients such that, as seen in Figure 1, the felodipine begins to release at 2 hours reaching approximately 20 percent dissolved active ingredient and at approximately 10 hours it has dissolved 100 percent of the active substance.
  • the above was compared with a composition in form of tablets, observing that in said composition the dissolution is carried out more quickly at the beginning, however, at 10 hours of the test, it is not possible to dissolve 100 percent felodipine.
  • the dissolution profile of Losartan ( Figure 2), begins to be released in such a way that at 5 minutes, there is 40 percent dissolved losartan reaching approximately 100 percent of active ingredient dissolved at 45 minutes , an equivalent dissolution profile was obtained when compared with a composition in the form of Losartan tablets of 12.5 mg.

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Abstract

La présente invention concerne une composition pharmaceutique sous forme de pastille-pastille d'au moins deux phases qui comprend une pastille interne qui présente une cinétique d'ordre zéro d'au moins un agent bloqueur des canaux calciques; et, une pastille externe qui présente une cinétique d'ordre zéro et/ou d'ordre un sans temps de retard d'au moins un agent antagoniste des récepteurs de l'angiotensine II. Ladite composition est utile pour le traitement de l'hypertension artérielle, de l'insuffisance cardiaque congestive, de l'angine de poitrine instable, de l'infarctus aigu du myocarde, de la néphropathie diabétique ou de troubles associés.
PCT/MX2014/000034 2013-01-31 2014-01-30 Composition pharmaceutique présentant un antagoniste des récepteurs de l'angiotensine ii et un bloqueur des canaux calciques pour le traitement de l'hypertension artérielle Ceased WO2014119989A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2013001277A MX2013001277A (es) 2013-01-31 2013-01-31 Composicion farmaceutica con un antagonista de los receptores de la angiotensina ii y un bloqueador de los canales de calcio para el tratamiento de la hipertension arterial.
MXMX/A/2013/001277 2013-01-31

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WO2014119989A2 true WO2014119989A2 (fr) 2014-08-07
WO2014119989A3 WO2014119989A3 (fr) 2014-11-27

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI407978B (zh) * 2005-06-27 2013-09-11 Sankyo Co 濕粒狀藥物之製備方法
WO2007001067A2 (fr) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Forme posologique solide
KR100888131B1 (ko) * 2006-10-10 2009-03-11 한올제약주식회사 시간차 투약 원리를 이용한 심혈관계 질환 치료용 복합제제
WO2010065492A1 (fr) * 2008-12-02 2010-06-10 Sciele Pharma, Inc. Composition d’agoniste alpha2-adrénergique et d’inhibiteur calcique

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WO2014119989A3 (fr) 2014-11-27

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