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WO2008143491A1 - Pharmaceutical compositions combining a hydrogenated lipstatin derived agent and a hmg-coa reductase inhibiting agent - Google Patents

Pharmaceutical compositions combining a hydrogenated lipstatin derived agent and a hmg-coa reductase inhibiting agent Download PDF

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Publication number
WO2008143491A1
WO2008143491A1 PCT/MX2008/000062 MX2008000062W WO2008143491A1 WO 2008143491 A1 WO2008143491 A1 WO 2008143491A1 MX 2008000062 W MX2008000062 W MX 2008000062W WO 2008143491 A1 WO2008143491 A1 WO 2008143491A1
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orlistat
hmg
simvastatin
coa reductase
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Spanish (es)
French (fr)
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Leopoldo de Jesús ESPINOSA ABDALA
María Elena GARCÍA ARMENTA
Josefina Santos Murillo
Victor Guillermo Alvarez Ochoa
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention is applied in the pharmaceutical industry and describes various pharmaceutical compositions composed of the synergistic combination of a hydrogenated derivative agent of lipstatin, such as: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, known as: Simvastatin and / or Rosuvastatin, - which are formulated in a single dosage unit, which are indicated for the prevention and / or treatment of hypercholesterolemia, triglyceridemia, overweight and obesity.
  • a hydrogenated derivative agent of lipstatin such as: Orlistat
  • an inhibitor of the enzyme HMG-CoA reductase known as: Simvastatin and / or Rosuvastatin
  • BMI body mass index
  • quartet of death by Kaplan (1989), consisting of thoracic-abdominal obesity, glucose intolerance, hypertriglice ⁇ demia and arterial hypertension.
  • Stamler describes the prevalence of arterial hypertension in a North American population close to one million people, determining that obese people between 20 and 39 years old have double and between 40 and 64 years 50% more hypertension than normal weight subjects.
  • Insulin resistance generates compensatory hyperinsulinemia, with over-stimulation of beta cells in the pancreas and also a reduction in the number of peripheral insulin receptors (down regulation phenomenon). Occasionally, this is combined with a genetic or acquired defect of insulin secretion.
  • fasting hyperglycemia is a consequence of increased hepatic glucose production that is not sufficiently inhibited by insulin.
  • the greater release of free fatty acids from the adipose tissue that the obese individual has stimulates hepatic neuglucogeny, which uses 3-carbon substrates for its production.
  • non-insulin dependent diabetes mellitus which is the most frequent form of primary diabetes
  • obesity is the environmental factor more relevant and possible to prevent and modify.
  • the weight reduction of an obese diabetic significantly improves its metabolic condition, facilitating the control of glycemia and dyslipidemia by producing insulin resistance, as has been repeatedly demonstrated. Therefore, treatment and, as far as possible, the prevention of obesity is of greater importance, so that in turn the development of diabetes is prevented.
  • obesity stands out. This is associated with insulin resistance syndrome frequently observed with excess fatty tissue, especially when there is a thoracic-abdominal or visceral distribution.
  • the most frequent thing to observe is hypertriglyceridemia, with a slight increase in total cholesterol, but with a noticeable decrease in HDL (high density lipoprotein) cholesterol, and therefore an increase in the total cholesterol / HDL cholesterol ratio.
  • the increase in triglycerides is due to a greater hepatic synthesis, due to an increase in the supply of free fatty acids in a state of insulin resistance hyperinsulinemia. Increases the secretion of cholesterol from VLDL (very low density lipoprotein) and therefore the highlight is hypertriglyceridemia.
  • VLDL very low density lipoprotein
  • the reduction of HDL cholesterol can be explained by hypertriglyceridemia, since in these circumstances, and by intravascular transfer of lipids, HDLs receive triglycerides and accelerate their catabolism through increased hepatic lipase activity. On the other hand, something similar happens with LDL cholesterol (low density lipoprotein).
  • LDLs receive triglycerides, which are partially metabolized by hepatic lipase and are transformed into small and dense LDLs, which have a greater atherogenic potential (greater susceptibility to oxidation and lower affinity with the apolipoprotein ⁇ receptors).
  • Weight reduction in dyslipidemic obese people is associated with a marked improvement in dyslipidemia, with a decrease in triglycerides and an increase in HDL cholesterol. If the answer is partial and even more so if there are other associated risk factors, a pharmacological therapy appropriate to the type of dyslipidemia present should be considered.
  • Today there are a wide variety of pharmaceutical products useful for the treatment of these conditions (obesity, dyslipidemias, high blood pressure, diabetes mellitus); However, the active ingredients included in the formulation of these medications are administered independently causing the relief of symptoms and signs manifested by these conditions and properly by the presence of the disease itself, Be slower and less effective. On the other hand, the interactions that occur with the administration of different active ingredients must be taken into account, thereby causing undesirable effects on patients, who must take prolonged treatments.
  • compositions were carried out pharmaceuticals described below.
  • compositions object of the present invention are composed of the combination synergistic of a hydrogenated derivative agent of lipstatin and an inhibitor of the enzyme HMG-CoA reductase, which produce a satisfactory therapeutic effect when administered together in a single oral dosing unit unlike when they are administered independent, generating benefits such as: lower concentrations of the active ingredients formulated, lower doses administered, faster action, greater efficacy of the therapeutic effect and lower adverse effects.
  • Orlistat is a potent, specific and long-lasting inhibitor of pancreatic lipases and gastrointestinal It is a derivative of lipstatin, a substance produced by Streptomyces toxitricini, partially hydrogenated and more stable, also known as tetrahydrolisptatin, which has a betalactone ring that gives it pancreatic and gastric lipase inhibitory activity. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of enzymes called gastric and pancreatic lipases, which have the function of breaking down triglycerides in the intestine.
  • Orlistat reduces body weight in overweight and obese patients;
  • our intention is to verify that combined with an HMG-CoA inhibitor has a synergistic effect, not only to reduce weight and cholesterol levels, but also has activity to reduce triglyceride levels, which is hardly achieved with the independent administration of HMG-CoA inhibitors, since in the cases of hypertriglyceridemia another type of drugs such as fibrates should be administered.
  • Simvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor to sterols, including cholesterol.
  • HMG-CoA reductase reduces mevalonate levels and hepatic cholesterol levels, which causes a sustained and regulated increase in the activity of LDL receptors and in the uptake of these lipoproteins from the circulation, resulting in a reduction in the production of LDL and the number of circulating LDL particles, as well as the decrease in cholesterol levels associated with LDL.
  • Simvastatin belongs to the family of statins and is indicated for the treatment of hypercholesterolemia, since it lowers the levels of high total cholesterol, LDL cholesterol and apolipoproteins B and increases HDL cholesterol levels, causing decrease the ratio LDL / HDL and total cholesterol / HDL.
  • VLDL Low density lipoproteins
  • Simvastatin acts by inhibiting in the liver the activity of the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) and cholesterol synthesis, thereby reducing plasma levels of cholesterol and lipoproteins, in addition to increasing the number of liver receptors for LDL on the cell surface, leading to an increase in the absorption and catabolism of LDL.
  • HMG-CoA reductase hydroxy-methyl-glutaryl-coenzyme A reductase
  • statins have antioxidant properties that protect mainly from the oxidation of LDL, some of them have a platelet antiaggregant effect and reduce prothrombotic factors in plasma.
  • Simvastatin is able to stabilize the atherosclerotic plaque by inducing structural changes, thereby reducing the risk of rupture.
  • the hypolipidemic potency of Simvastatin is determined by the necessary concentration of the drug to inhibit the activity of the enzyme by 50%, being 11 (IC 50 ) •
  • Rosuvastatin is another HMG-CoA reductase inhibitor that also belongs to the statin group; however, unlike the Simvastatin, it has a high hypolipidemic potency (IC 50 of 5), hydrophilic and is equipped with high liver selectivity is not metabolized by cytochrome P450 3A4, but the 2c-9 and 2c-19, so the Risk of drug interaction with other drugs is lower.
  • Rosuvastatin is a simple enantiomeric hydroxy acid that is administered as a calcium salt, which markedly reduces the levels of total cholesterol and LDL (low density lipoproteins); also lowering the levels of triglycerides and apolipoproteins B. It acts by inhibiting hepatic cholesterol synthesis, by blocking the enzyme 3-hydroxy-3- methylglutaryl-Coenzyme A (HMG-CoA), involved in the synthesis of mevalonic acid, metabolic precursor of cholesterol . It has high affinity for predominantly hepatic organic anion transporter protein C.
  • HMG-CoA 3-hydroxy-3- methylglutaryl-Coenzyme A
  • Rosuvastatin was found to have non-lipid lowering effects, such as improvement in endothelial function, anti-inflammatory effects, vascular, cardiac and cerebral protective effects, as well as improvement in neural function.
  • non-lipid lowering effects such as improvement in endothelial function, anti-inflammatory effects, vascular, cardiac and cerebral protective effects, as well as improvement in neural function.
  • Rosuvastatin are dose proportional, with little or no accumulation after repeated administration. In healthy volunteers, maximum plasma concentrations of 19 to 25 ⁇ g / L are reached after 3 to 5 hours of administering 40 mg. of Rosuvastatin in a single oral dose. The absolute bioavailability of Rosuvastatin is approximately 20%. Food increases its absorption rate by 20%, but the degree of absorption remains unchanged.
  • Rosuvastatin binds reversibly to plasma proteins (88%). You experience a very limited metabolism, which occurs primarily through the cytochrome P450 isoenzyme (CYP) 2C9. N-desmethyl rosuvastatin is the main metabolite. Rosuvastatin has a long elimination half-life in plasma (approximately 18 to 24 hours, after administering 40 mg in a single oral dose), and is predominantly eliminated via enterohepatic route (biliary excretion).
  • the hydrogenated derivative agent of lipstatin used in the pharmaceutical compositions object of The present invention is the active ingredient Orlistat, which is present in the formulation in a concentration range from 60.0 mg. up to 360.0 mg , preferably a concentration of 60.0 mg being used. at 120.0 mg per dose unit.
  • the HMG-CoA reductase enzyme inhibitor used in the pharmaceutical compositions object of the present invention is the active substance Simvastatin and / or Rosuvastatin, which are present in the formulation in a concentration range from 20.0 mg. up to 80.0 mg for Simvastatin, a concentration of 20.0 mg being preferably used. at 40.0 mg , and Rosuvastatin is present in the formulation in a concentration range from 5.0 mg. up to 45.0 mg , a concentration of 5.0 mg being preferably used. up to 10.0 mg per dose unit.
  • compositions protected by the present invention are formulated to be administered orally in a single dosage unit in the form of capsules or tablets, in which the synergistic combination of the active ingredients is contained: Orlistat plus Simvastatin and Orlistat plus Rosuvastatin, as well as pharmaceutically acceptable excipients.
  • compositions have been developed in order to provide a pharmaceutical alternative for the treatment of overweight, obesity, high cholesterol and high triglycerides, which offer significant advantages such as: lower concentrations of the active ingredients contained in the formulation , lower side effects and a satisfactory reduction in cholesterol, triglyceride and weight levels.
  • Results 90 patients were enrolled, 45 women and 45 men; with an average age of 56 years. Eighty completed the study, 42 women who were distributed as follows, Group 1: 15; Group 2: 13; Group 3: 14 and 38 men who were distributed as follows, Group 1: 15; Group 2: 10; Group 3: 13; The previous results are listed in Table 1.
  • Group 1 Orlistat
  • Group 2 Simvastatma
  • Group 3 Orhstat / Simvastatin combination Values are expressed as averages (SD) There were no significant differences between the groups Three Group 1 patients who received Orlistat had gastrointestinal adverse events (fecal urgency); however, there was no need to stop treatment. After two weeks of treatment the gastrointestinal adverse events disappeared.
  • CT Total Cholesterol
  • Group 1 Orlistat
  • Group 2 Simvastatin
  • Group 3 Orlistat / Simvastatin
  • C-LDL Low density lipoproteins
  • C-HDL High density lipoproteins
  • TG T ⁇ glice ⁇ dos Values expressed as average (DS)
  • Orlistat is a lipase inhibitor antiobesity agent, indicated for the long-term management of obesity and its comorbidities, produces a dose-dependent reduction in the absorption of the fat diet with a maximum inhibition of fat absorption of 30% a 120 mg dose. once a day.
  • Simvastatin is an HMG-CoA reductase inhibitor that produces a substantial reduction in LDL-C, along with a modest increase in HDL-C. It is generally well tolerated as monotherapy with a good safety profile and efficacy comparable to fenofibrate treatments.
  • Orlistat / Simvastatin All parameters improved significantly for the group that received the combination. i The 3 treatment groups improved significantly from the baseline parameters. Treatment with the combination Orlistat / Simvastatin showed significantly greater reductions in serum levels of total cholesterol, C-LDL, C-HDL, triglycerides, Body Mass Index, Waist Circumference, Weight Loss. There was also a small but significant difference found in blood pressure. The use of the combination allows reducing the doses administered to patients, thereby avoiding the manifestation of side effects. On the other hand, the combination reduces the risk of cardiovascular events in obese patients with hypercholesterolemia.
  • the patients that were chosen were obese with a Body Mass Index (BMI)> 30 kg / m 2 ; with borderline hypercholesterolemia (Total cholesterol 200- 240 rag / dl) or severe (Total cholesterol> 240 mg / dl); Normotensive patients (Systolic pressure ⁇ 140 mm Hg and diastolic pressure ⁇ 90 mm Hg).
  • BMI Body Mass Index
  • Treatment compliance was evaluated with capsule count and follow-up visits every 3 months. Serum total cholesterol, LDL-C, HDL-C, triglycerides and blood pressure were evaluated during the baseline visit and at 6 months and 12 months of treatment. The waist index was evaluated.
  • results 90 patients were enrolled, 45 women and 45 men; With an average age of 55 years. The 90 completed the study, 45 women who were distributed as follows, Group 1: 15; Group 2: 15; Group 3: 15 and 45 men who were distributed as follows, Group 1: 15; Group 2:15; Group 3: 15), the previous results are listed in table 5.
  • Group 1 Orhstat
  • Group 2 Rosuvastatma
  • Group 3 Orlistat / Rosuvastatin combination
  • BMI Body Mass Index
  • Group 1 Orlistat
  • Group 2 Rosuvastatin
  • Group 3 Orlistat / Rosuvastatin
  • RCC Waist circumference reduction
  • PP Weight Loss
  • Orlistat is a lipase inhibitor antiobesity agent, indicated for the long-term management of obesity and its comorbidities, produces a dose-dependent reduction in the absorption of the fat diet with a maximum inhibition of fat absorption of 30% a 120 mg dose. once a day.
  • Rosuvastatin is an HMG-CoA reductase inhibitor that produces a substantial reduction in LDL-C, along with a modest increase in HDL-C. It is generally well tolerated as monotherapy with a good safety and efficacy profile, with greater potency than Simvastatin. In this study obese patients with hypercholesterolemia benefited from the administration of Orlistat and Rosuvastatin independently and the combination of Orlistat / Rosuvastatin. All parameters improved significantly for the group that received the combination.
  • the 3 treatment groups improved significantly from the baseline parameters.
  • Treatment with the Orlistat / Rosuvastatin combination showed significantly greater serum reductions in total cholesterol, C-LDL, C-HDL, triglycerides, Body Mass Index, Waist Circumference, Weight Loss. There was also a small but significant difference found in blood pressure.
  • the use of the combination allows reducing the doses administered in patients, thereby avoiding the manifestation of side effects.
  • the combination reduces the risk of cardiovascular events in obese patients with hypercholesterolemia.
  • the combination shows a synergistic effect, for this reason, the concentrations of the active substances and the administered doses of the they are smaller than when administered individually.

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Abstract

The invention relates to different pharmaceutical compositions comprising a synergic combination of a hydrogenated lipstatin derived agent such as the active principle orlistat and a HMG-CoA reductase enzyme inhibiting agent such as the active principles simvastatin and/or rosuvastatin, as well as pharmaceutically acceptable excipients, which are formulated in a single dosage unit for oral administration, said compositions being intended for the prevention and/or treatment of hypercholesterolaemia, triglyceridaemia, overweight and obesity.

Description

COMPOSICIONES FARMACÉUTICAS QUE COMPRENDEN LA PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THE

COMBINACIÓN DE UN AGENTE DERIVADO HIDROGENADO DECOMBINATION OF A HYDROGEN DERIVED AGENT FROM

LIPSTATINA Y UN AGENTE INHIBIDOR DE HMG-COA REDUCTASA.LIPSTATIN AND AN INHIBITING AGENT OF HMG-COA REDUCTASA.

CAMPO DE LA INVENCIÓN La presente invención es aplicada en la industria farmacéutica y describe diversas composiciones farmacéuticas compuestas por la combinación sinérgica de un agente derivado hidrogenado de lipstatina, tal como: Orlistat y un agente inhibidor de la enzima HMG- CoA reductasa, conocido como: Simvastatina y/o Rosuvastatina,- los cuales se encuentran formulados en una sola unidad de dosificación, mismas que están indicadas para la prevención y/o tratamiento de la hipercolesterolemia, trigliceridemia, el sobrepeso y la obesidad.FIELD OF THE INVENTION The present invention is applied in the pharmaceutical industry and describes various pharmaceutical compositions composed of the synergistic combination of a hydrogenated derivative agent of lipstatin, such as: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, known as: Simvastatin and / or Rosuvastatin, - which are formulated in a single dosage unit, which are indicated for the prevention and / or treatment of hypercholesterolemia, triglyceridemia, overweight and obesity.

La combinación de los principios activos antes mencionados produce un mayor efecto sinérgico cuando son administrados en conjunto en una sola unidad de dosis a diferencia de cuando estos se administran de forma independiente, generando beneficios como lo son: menores dosificaciones, mayor rapidez de acción y menores efectos secundarios. ANTECEDENTES DE LA INVENCIÓNThe combination of the aforementioned active ingredients produces a greater synergistic effect when they are administered together in a single dose unit unlike when they are administered independently, generating benefits such as: lower dosages, faster action and lower side effects. BACKGROUND OF THE INVENTION

Ha sido motivo de controversia dilucidar si la obesidad por si misma es un factor de riesgo independiente de ciertas enfermedades, tales como la cardiopatía coronaria ateroesclerótica o ejerce su influencia como elemento condicionante de otros factores, especialmente: hipertensión arterial, diabetes mellitus y dislipidemias . El estudio de Framingham demostró prospectivamente que por cada 10% de incremento del peso, la presión arterial aumenta 6.5 mm Hg, el colesterol plasmático 12 mg./dl. y la glicemia 2 mg./dl.It has been a matter of controversy to determine whether obesity itself is an independent risk factor for certain diseases, such as atherosclerotic coronary heart disease or exerts its influence as a conditioning element of other factors, especially: arterial hypertension, diabetes mellitus and dyslipidemias. Framingham's study showed prospectively that for every 10% weight gain, blood pressure increases 6.5 mm Hg, plasma cholesterol 12 mg / dl. and glycemia 2 mg./dl.

La controversia para aceptar la obesidad como un factor de riesgo independiente se debe, entre otros aspectos, a diferencias en los diseños, especialmente en el tiempo de observación epidemiológica y en la edad de ingreso de los individuos en estudio.The controversy to accept obesity as an independent risk factor is due, among other aspects, to differences in designs, especially in the time of epidemiological observation and in the age of admission of the individuals under study.

El impacto es mayor cuando se incorporan individuos jóvenes (menores de 40 años) y especialmente cuando el análisis se realiza en poblaciones con seguimientos mayores a 10 años. Así, Keys encontró en 1972 que la obesidad en hombres de poblaciones europeas y norteamericanas, se comportó como un factor de riesgo independiente de cardiopatía coronaria, pero que la mitad de su efecto era mediado por el incremento de colesterol, de la presión arterial e intolerancia a la glucosa.The impact is greater when young individuals (under 40 years old) are incorporated and especially when the analysis is carried out in populations with follow-ups older than 10 years. Thus, Keys found in 1972 that obesity in men from European and North American populations, behaved as an independent risk factor for coronary heart disease, but that half of its effect was mediated by increased cholesterol, blood pressure and intolerance. to glucose

Raskin (1977) con el estudio de Manitoba aplicado a una población de hombres jóvenes, demostró que el IMC (índice de masa corporal) fue un factor que predijo la manifestación de enfermedad coronaria, ajustado por edad y presión arterial, solo después de 16 años de seguimiento .Raskin (1977) with the Manitoba study applied to a population of young men, showed that BMI (body mass index) was a factor that predicted the manifestation of coronary heart disease, adjusted for age and blood pressure, only after 16 years of follow up .

Hubert (1983) analizando la población de Framingham, también encontró una asociación independiente luego de diez años de observación, demostrando que en hombres jóvenes la incidencia de enfermedad cardiovascular se duplica en sujetos con índice de peso relativo mayor a 130 al compararlos con los de índice menor de 110. En consecuencia, el concepto mas aceptado en la actualidad, como señala Pi-Sunyer, es que si bien existe controversia en aceptar a la obesidad como un factor de riesgo independiente de la enfermedad coronaria, la evidencia más importante orienta a que tiene un efecto a largo plazo y que éste es mucho mas notorio en presencia de otros factores asociados como: hipertensión arterial, dislipidemia y diabetes. La distribución de la grasa corporal es un elemento adicional en la relación de obesidad con ateroesclerosis y su asociación con los factores antes señalados .Hubert (1983), analyzing the population of Framingham, also found an independent association after ten years of observation, demonstrating that in young men the incidence of cardiovascular disease doubles in subjects with a relative weight index greater than 130 when compared with those of index less than 110. Consequently, the most accepted concept today, as Pi-Sunyer points out, is that although there is controversy in accepting obesity as a risk factor independent of the disease coronary, the most important evidence indicates that it has a long-term effect and that it is much more noticeable in the presence of other associated factors such as: hypertension, dyslipidemia and diabetes. The distribution of body fat is an additional element in the relationship between obesity and atherosclerosis and its association with the aforementioned factors.

Vague (1947 y 1956) demostró que en obesidad de predominio torácico-abdommal había mayor frecuencia de intolerancia a la glucosa, dislipidemia, hiperuπcemia e hipertensión arterial, con aumento del riesgo cardiovascular .Vague (1947 and 1956) showed that in thoracic-abdominal obesity there was a higher frequency of glucose intolerance, dyslipidemia, hyperuπcemia and arterial hypertension, with increased cardiovascular risk.

Esto ha sido corroborado por varios autores los cuales le han dado diversas denominaciones, como elThis has been corroborated by several authors who have given it various denominations, such as

"cuarteto de la muerte" de Kaplan (1989), consistente en obesidad torácico-abdommal, intolerancia a la glucosa, hipertrigliceπdemia e hipertensión arterial."quartet of death" by Kaplan (1989), consisting of thoracic-abdominal obesity, glucose intolerance, hypertrigliceπdemia and arterial hypertension.

Aunque Reaven no consideró a la obesidad en la descripción del síndrome X (hiperinsulmemia, intolerancia a la glucosa, hipertensión arterial y dislipidemia) , un aumento de la grasa visceral y especialmente la obesidad torácico-abdommal se asocia al Síndrome de Resistencia a la Insulina condicionando un Síndrome Plurimetabólico con elevado riesgo cardiovascular .Although Reaven did not consider obesity in the description of syndrome X (hyperinsulmemia, glucose intolerance, hypertension and dyslipidemia), an increase in visceral fat and especially thoracic-abdominal obesity is associated to Insulin Resistance Syndrome conditioning a Plurimetabolic Syndrome with high cardiovascular risk.

La asociación entre obesidad e hipertensión arterial es un hecho frecuente. Stamler describe la prevalencia de hipertensión arterial en una población norteamericana cercana a un millón de personas, determinando que los obesos entre 20 y 39 años presentan el doble y entre 40 y 64 años un 50% más de hipertensión arterial que los sujetos de peso normal.The association between obesity and high blood pressure is a frequent occurrence. Stamler describes the prevalence of arterial hypertension in a North American population close to one million people, determining that obese people between 20 and 39 years old have double and between 40 and 64 years 50% more hypertension than normal weight subjects.

Hay estudios longitudinales que demuestran que el aumento de peso produce un significativo incremento de la presión arterial, mientras una baja de peso de pacientes obesos reduce las cifras tensionales. Los mecanismos patogénicos no son claros, pero se ha postulado que la obesidad podría explicar esta asociación al generar resistencia insulínica, con la consiguiente hiperinsulinemia . La insulina reduce la excreción renal de sodio y a través de ello podría expandir el volumen extracelular y la volemia, aumentando el gasto cardiaco y la resistencia periférica, que son los principales componentes reguladores de la presión arterial. Además, la hiperinsulinemia aumenta el tono simpático y altera los iones intracelulares (retención de Na y Ca y alcalosis) , lo que aumenta la reactividad vascular y la proliferación celular. Todo lo anterior favorece la hipertensión arterial; sin embargo, hay argumentos que discuten el rol de la hiperinsulinemia, como son algunas experiencias en animales y la ausencia de hipertensión arterial en pacientes con insulinomas. A pesar de todo, es un hecho indiscutible que una de las medidas mas efectivas para mejorar la hipertensión arterial en un individuo obeso es la reducción del peso. Más aún, en pacientes con dietas hipocalóricas muy restrictivas debe vigilarse la aparición de hipotensión ortostática. La experiencia clínica y epidemiológica ha demostrado una indiscutible asociación entre obesidad y diabetes mellitus no insulino dependiente e intolerancia a la glucosa. Grados moderados de obesidad pueden elevar el riesgo de diabetes hasta 10 veces y el riesgo crece mientras mayor es la intensidad de la obesidad. También se relaciona al tipo de obesidad, en cuanto a la distribución de la grasa corporal, siendo mayor en obesidad de tipo torácico-abdominal . Los estudios de sensibilidad a la insulina y de clamp euglicémico son concordantes en demostrar que la obesidad genera una resistencia a la insulina. Esto se debe a un defecto de acción insulínica, especialmente a nivel post-receptor , demostrada especialmente en el músculo esquelético. La resistencia a la insulina genera una hiperinsulinemia compensadora, con sobre- estímulo de las células beta del páncreas y también una reducción del número de receptores periféricos a la insulina (fenómeno de down regulation) . En ocasiones, esto se conjuga con un defecto genético o adquirido de secreción insulínica. Por otra parte, la hiperglicemia de ayuno es consecuencia de una mayor producción hepática de glucosa que no es suficientemente inhibida por la insulina. La mayor liberación de ácidos grasos libres desde el tejido adiposo que tiene el individuo obeso (fenómeno que incluso es mas acentuado en la obesidad de distribución abdominal y visceral) estimula la neuglucogenia hepática, que emplea sustratos de 3 carbonos para su producción.There are longitudinal studies that show that weight gain produces a significant increase in blood pressure, while a low weight of obese patients reduces blood pressure. The pathogenic mechanisms are not clear, but it has been postulated that obesity could explain this association by generating insulin resistance, with consequent hyperinsulinemia. Insulin reduces renal sodium excretion and through it could expand extracellular volume and volemia, increasing cardiac output and peripheral resistance, which are the main regulating components of blood pressure. In addition, hyperinsulinemia increases sympathetic tone and alters intracellular ions (retention of Na and Ca and alkalosis), which increases vascular reactivity and cell proliferation. All of the above favors high blood pressure; However, there are arguments that discuss the role of hyperinsulinemia, such as some experiences in animals and the absence of arterial hypertension in patients with insulinomas. In spite of everything, it is an indisputable fact that one of the most effective measures to improve hypertension in an obese individual is weight reduction. Moreover, in patients with very restrictive hypocaloric diets the appearance of orthostatic hypotension should be monitored. Clinical and epidemiological experience has demonstrated an undeniable association between obesity and non-insulin dependent diabetes mellitus and glucose intolerance. Moderate degrees of obesity can raise the risk of diabetes up to 10 times and the risk increases as the intensity of obesity increases. It is also related to the type of obesity, in terms of the distribution of body fat, being higher in thoracic-abdominal obesity. Insulin sensitivity and euglycemic clamp studies are consistent in demonstrating that obesity generates insulin resistance. This is due to a defect in insulin action, especially at the post-receptor level, especially demonstrated in skeletal muscle. Insulin resistance generates compensatory hyperinsulinemia, with over-stimulation of beta cells in the pancreas and also a reduction in the number of peripheral insulin receptors (down regulation phenomenon). Occasionally, this is combined with a genetic or acquired defect of insulin secretion. On the other hand, fasting hyperglycemia is a consequence of increased hepatic glucose production that is not sufficiently inhibited by insulin. The greater release of free fatty acids from the adipose tissue that the obese individual has (a phenomenon that is even more pronounced in abdominal and visceral distribution obesity) stimulates hepatic neuglucogeny, which uses 3-carbon substrates for its production.

En síntesis, en la patogenia de la diabetes mellitus no insulino dependiente, que es la forma de diabetes primaria mas frecuente, la obesidad es el factor ambiental mas relevante y posible de prevenir y modificar. A su vez, la reducción de peso de un diabético obeso mejora notoriamente su condición metabólica, facilitando el control de la glicemia y de la dislipidemia al producir la resistencia insulínica, como ha sido reiteradamente demostrado. Por ello, es de mayor importancia el tratamiento y en lo posible la prevención de la obesidad, para que a su vez se prevenga el desarrollo de diabetes. Entre las causas mas frecuentes de dislipidemias secundarias, destaca la obesidad. Ello se asocia al síndrome de resistencia insulínica frecuentemente observado con el exceso de tejido graso, más aun cuando hay una distribución torácico-abdominal o visceral. Lo mas frecuente de observar es una hipertrigliceridemia, con aumento leve del colesterol total, pero con una notoria disminución del colesterol de las HDL (lipoproteína de alta densidad), y por consiguiente un aumento de la relación colesterol total / colesterol HDL.In summary, in the pathogenesis of non-insulin dependent diabetes mellitus, which is the most frequent form of primary diabetes, obesity is the environmental factor more relevant and possible to prevent and modify. In turn, the weight reduction of an obese diabetic significantly improves its metabolic condition, facilitating the control of glycemia and dyslipidemia by producing insulin resistance, as has been repeatedly demonstrated. Therefore, treatment and, as far as possible, the prevention of obesity is of greater importance, so that in turn the development of diabetes is prevented. Among the most frequent causes of secondary dyslipidemias, obesity stands out. This is associated with insulin resistance syndrome frequently observed with excess fatty tissue, especially when there is a thoracic-abdominal or visceral distribution. The most frequent thing to observe is hypertriglyceridemia, with a slight increase in total cholesterol, but with a noticeable decrease in HDL (high density lipoprotein) cholesterol, and therefore an increase in the total cholesterol / HDL cholesterol ratio.

El incremento de triglicéridos se debe a una mayor síntesis hepática, proveniente de un aumento de la oferta de ácidos grasos libres en un estado de hiperinsulinemia por resistencia insulínica. Aumenta la secreción de colesterol de las VLDL (lipoproteína de muy baja densidad) y por ello lo destacable es la hipertrigliceridemia . La reducción del colesterol HDL es explicable por la hipertrigliceridemia, ya que en estas circunstancias, y por transferencia intravascular de lipidos, las HDL reciben triglicéridos y aceleran su catabolismo a través de una mayor actividad de la lipasa hepática. Por otra parte, algo similar sucede con el colesterol de la LDL (lipoproteína de baja densidad) . Las LDL reciben triglicéridos, que son metabolizados parcialmente por la lipasa hepática y se transforman en LDL pequeñas y densas, las cuales tienen un mayor potencial aterogénico (mayor susceptibilidad a la oxidación y menor afinidad con los receptores de las apolipoproteínas β) .The increase in triglycerides is due to a greater hepatic synthesis, due to an increase in the supply of free fatty acids in a state of insulin resistance hyperinsulinemia. Increases the secretion of cholesterol from VLDL (very low density lipoprotein) and therefore the highlight is hypertriglyceridemia. The reduction of HDL cholesterol can be explained by hypertriglyceridemia, since in these circumstances, and by intravascular transfer of lipids, HDLs receive triglycerides and accelerate their catabolism through increased hepatic lipase activity. On the other hand, something similar happens with LDL cholesterol (low density lipoprotein). LDLs receive triglycerides, which are partially metabolized by hepatic lipase and are transformed into small and dense LDLs, which have a greater atherogenic potential (greater susceptibility to oxidation and lower affinity with the apolipoprotein β receptors).

Recientemente, estudios de metanálisis tienden a demostrar que los triglicéridos elevados constituyen un riesgo en la población general y mayor aún en diabéticos y en mujeres. Independientemente de si los triglicéridos son o no un factor de riesgo, su asociación al déficit de HDL y producción de LDL con una interrelación fisiopatológica demostrada, explican el incremento de riesgo en estos pacientes. Un aumento del colesterol LDL, no es un hecho frecuente entre los obesos; sin embargo, ello puede observarse en casos de una asociación con una dislipidemia genética (hipercolesterolemia familiar, dislipidemia familiar combinada) o secundaria a hipotiroidismo o a una dieta alta en grasas saturadas y colesterol.Recently, meta-analysis studies tend to show that high triglycerides constitute a risk in the general population and even greater in diabetics and women. Regardless of whether triglycerides are a risk factor or not, their association with HDL deficiency and LDL production with a proven pathophysiological interrelation, they explain the increased risk in these patients. An increase in LDL cholesterol is not a common occurrence among obese people; However, this can be observed in cases of an association with a genetic dyslipidemia (familial hypercholesterolemia, combined family dyslipidemia) or secondary to hypothyroidism or a diet high in saturated fat and cholesterol.

La reducción de peso en los obesos dislipidémicos se asocia a una mejoría notoria de la dislipidemia, con disminución de los triglicéridos y aumento del colesterol HDL. Si la respuesta es parcial y mas aún si hay otros factores de riesgo asociados, se debe plantear una terapia farmacológica apropiada al tipo de dislipidemia presente. Hoy en día existen una gran variedad de productos farmacéuticos útiles para el tratamiento de estos padecimientos (obesidad, dislipidemias , hipertensión arterial, diabetes mellitus) ; sin embargo, los principios activos incluidos en la formulación de dichos medicamentos son administrados de forma independiente provocando que el alivio de los síntomas y signos manifestados por estos padecimientos y propiamente por la presencia de la enfermedad en sí, sea mas lento y poco efectivo. Por otra parte, deben tomarse en cuenta las interacciones que se suceden con la administración de diferentes principios activos, provocando con ello, efectos indeseables en los pacientes, que deben tomar tratamientos de forma prolongada .Weight reduction in dyslipidemic obese people is associated with a marked improvement in dyslipidemia, with a decrease in triglycerides and an increase in HDL cholesterol. If the answer is partial and even more so if there are other associated risk factors, a pharmacological therapy appropriate to the type of dyslipidemia present should be considered. Today there are a wide variety of pharmaceutical products useful for the treatment of these conditions (obesity, dyslipidemias, high blood pressure, diabetes mellitus); However, the active ingredients included in the formulation of these medications are administered independently causing the relief of symptoms and signs manifested by these conditions and properly by the presence of the disease itself, Be slower and less effective. On the other hand, the interactions that occur with the administration of different active ingredients must be taken into account, thereby causing undesirable effects on patients, who must take prolonged treatments.

SUMARIO DE LA INVENCIÓNSUMMARY OF THE INVENTION

Con el objeto de ofrecer una alternativa farmacéutica que logre una mejor calidad de vida en los pacientes que padecen enfermedades como el sobrepeso, obesidad, dislipidemias, así como otras enfermedades relacionadas como diabetes mellitus e hipertensión arterial, se llevó a cabo el desarrollo de las composiciones farmacéuticas que a continuación se describen.In order to offer a pharmaceutical alternative that achieves a better quality of life in patients suffering from diseases such as overweight, obesity, dyslipidemias, as well as other related diseases such as diabetes mellitus and arterial hypertension, the development of the compositions was carried out pharmaceuticals described below.

DESCRIPCIÓN DETALLADA DE LA INVENCIÓNDETAILED DESCRIPTION OF THE INVENTION

En la actualidad la mayoría de los medicamentos encontrados en el mercado para el tratamiento del sobrepeso, obesidad y dislipidemias están compuestos por principios activos que se encuentran formulados de forma independiente, mismos que cumplen con una actividad terapéutica específica; sin embargo, su administración independiente, produce un incremento de la frecuencia de las dosis administradas, de las concentraciones administradas, de la posibilidad de interacciones negativas entre sí y por consecuencia del riesgo de aparición de eventos adversos.Currently, most of the drugs found in the market for the treatment of overweight, obesity and dyslipidemias are composed of active ingredients that are formulated independently, which comply with a specific therapeutic activity; However, their independent administration, produces an increase in the frequency of the administered doses, of the administered concentrations, of the possibility of negative interactions with each other and as a consequence of the risk of occurrence of adverse events.

Por tal motivo y con el fin de suprimir todos los inconvenientes que se presentan cuando se administran los principios activos de forma independiente, es que se llevó a cabo el desarrollo de las composiciones farmacéuticas objeto de la presente invención, las cuales están compuestas por la combinación sinérgica de un agente derivado hidrogenado de lipstatina y un agente inhibidor de la enzima HMG-CoA reductasa, los cuales producen un efecto terapéutico satisfactorio al ser administrados en conjunto en una sola unidad de dosificación por vía oral a diferencia de cuando estos son administrados de forma independiente, generando beneficios como lo son: menores concentraciones de los principios activos formulados, menores dosis administradas, mayor rapidez de acción, mayor eficacia del efecto terapéutico y menores efectos adversos.For this reason and in order to eliminate all the inconveniences that arise when the active ingredients are administered independently, it is that the development of the pharmaceutical compositions object of the present invention was carried out, which are composed of the combination synergistic of a hydrogenated derivative agent of lipstatin and an inhibitor of the enzyme HMG-CoA reductase, which produce a satisfactory therapeutic effect when administered together in a single oral dosing unit unlike when they are administered independent, generating benefits such as: lower concentrations of the active ingredients formulated, lower doses administered, faster action, greater efficacy of the therapeutic effect and lower adverse effects.

El Orlistat es un inhibidor potente, específico y de larga duración de las lipasas pancreáticas y gastrointestinales. Es un derivado de la lipstatina, una sustancia producida por Streptomyces toxitricini, parcialmente hidrogenado y más estable, también conocido como tetrahidrolisptatina, que tiene un anillo betalactona que le confiere actividad inhibitoria de la lipasa pancreática y gástrica. Ejerce su actividad terapéutica en el lumen del estómago y del intestino delgado mediante la formación de un enlace covalente con el sitio activo de la serina de las enzimas denominadas lipasas gástricas y pancreáticas, que tienen la función de descomponer los triglicéridos en el intestino.Orlistat is a potent, specific and long-lasting inhibitor of pancreatic lipases and gastrointestinal It is a derivative of lipstatin, a substance produced by Streptomyces toxitricini, partially hydrogenated and more stable, also known as tetrahydrolisptatin, which has a betalactone ring that gives it pancreatic and gastric lipase inhibitory activity. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of enzymes called gastric and pancreatic lipases, which have the function of breaking down triglycerides in the intestine.

La ausencia de dichas enzimas inactiva la hidrólisis de las grasas contenidas en la dieta en forma de triglicéridos, evitando que éstos sean transformados en ácidos grasos libres absorbibles y monoglicéridos , provocando con ello que sean excretados sin ser digeridos.The absence of said enzymes inactivates the hydrolysis of fats contained in the diet in the form of triglycerides, preventing them from being transformed into absorbable free fatty acids and monoglycerides, thereby causing them to be excreted without being digested.

Su función principal la desempeña como agente reductor de peso en pacientes que padecen sobrepeso y obesidad, evitando la absorción de las grasas de la dieta, reduciendo con esto la ingesta de calorías en exceso. Su eliminación es llevada a cabo a través de las heces fecales .Its main function is played as a weight reducing agent in patients suffering from overweight and obesity, avoiding the absorption of dietary fats, thereby reducing calorie intake in excess. Its elimination is carried out through feces.

Se ha demostrado en diferentes investigaciones que el Orlistat reduce el peso corporal en pacientes con sobrepeso y obesidad; sin embargo, nuestra intención es comprobar que combinado con un inhibidor de la HMG-CoA tiene un efecto sinérgico, no solo para reducir el peso y los niveles de colesterol, sino que además tiene actividad para reducir los niveles de triglicéridos , lo cual difícilmente se logra con la administración de forma independiente de inhibidores de la HMG-CoA, ya que en los casos de hipertrigliceridemia debe administrarse otro tipo de fármacos como son los fibratos . La Simvastatina es un inhibidor selectivo y competitivo de la HMG-CoA reductasa, la enzima responsable de la conversión del 3-hidroxi-3 -metil- glutaril-coenzima A en mevalonato, un precursor de los esteróles, incluyendo el colesterol. La inhibición de la HMG-CoA reductasa reduce los niveles de mevalonato y los niveles hepáticos de colesterol, lo cual provoca un aumento sostenido y regulado en la actividad de los receptores para las LDL y en la captación de estas lipoproteínas de la circulación, dando como resultado una reducción de la producción de las LDL y del número de partículas de LDL circulantes, así como la disminución de los niveles de colesterol asociado a las LDL.It has been shown in different investigations that Orlistat reduces body weight in overweight and obese patients; However, our intention is to verify that combined with an HMG-CoA inhibitor has a synergistic effect, not only to reduce weight and cholesterol levels, but also has activity to reduce triglyceride levels, which is hardly achieved with the independent administration of HMG-CoA inhibitors, since in the cases of hypertriglyceridemia another type of drugs such as fibrates should be administered. Simvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor to sterols, including cholesterol. Inhibition of HMG-CoA reductase reduces mevalonate levels and hepatic cholesterol levels, which causes a sustained and regulated increase in the activity of LDL receptors and in the uptake of these lipoproteins from the circulation, resulting in a reduction in the production of LDL and the number of circulating LDL particles, as well as the decrease in cholesterol levels associated with LDL.

La Simvastatina pertenece a la familia de las estatinas y esta indicada para el tratamiento de la hipercolesterolemia, ya que disminuye los niveles de colesterol total elevado, colesterol de las LDL y de las apolipoproteínas B y aumenta los niveles de colesterol de la HDL, provocando que disminuya la relación LDL/HDL y colesterol total/HDL.Simvastatin belongs to the family of statins and is indicated for the treatment of hypercholesterolemia, since it lowers the levels of high total cholesterol, LDL cholesterol and apolipoproteins B and increases HDL cholesterol levels, causing decrease the ratio LDL / HDL and total cholesterol / HDL.

En el hígado se incorporan los triglicéridos y el colesterol a las VLDL y son liberadas al plasma para que se realice su distribución en los tejidos periféricos. Las lipoproteínas de baja densidad (LDL) son formadas a partir de las VLDL y se catabolizan principalmente mediante la elevada afinidad del receptor para la LDL. La Simvastatina actúa inhibiendo en el hígado la actividad de la enzima hidroxi-metil-glutaril-coenzima A reductasa (HMG-CoA reductasa) y la síntesis del colesterol , reduciendo con esto los niveles plasmáticos de colesterol y de las lipoproteínas , además de que aumenta el número de receptores hepáticos para la LDL en la superficie celular, dando lugar a un incremento de la absorción y el catabolismo de las LDL. Se ha descrito que los pacientes tratados con Simvastatina presentan una mejoría de la función endotelial, es decir, logran una mejor dilatación vascular de las funciones del endotelio. También se ha descrito que las estatinas poseen propiedades antioxidantes que protegen principalmente de la oxidación de las LDL, algunas de ellas tienen un efecto antiagregante plaquetario y reducen los factores protrombóticos en el plasma.Triglycerides and cholesterol are incorporated into VLDL in the liver and released into plasma for distribution to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDLs and are catabolized primarily by the high affinity of the LDL receptor. Simvastatin acts by inhibiting in the liver the activity of the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) and cholesterol synthesis, thereby reducing plasma levels of cholesterol and lipoproteins, in addition to increasing the number of liver receptors for LDL on the cell surface, leading to an increase in the absorption and catabolism of LDL. It has been described that patients treated with Simvastatin have an improvement in endothelial function, that is, they achieve a better vascular dilation of endothelial functions. It has also been described that statins have antioxidant properties that protect mainly from the oxidation of LDL, some of them have a platelet antiaggregant effect and reduce prothrombotic factors in plasma.

La Simvastatina es capaz de estabilizar la placa ateroesclerótica mediante la inducción de cambios estructurales con lo que disminuye así el riesgo de ruptura. La potencia hipolipemiante de la Simvastatina está determinada por la concentración necesaria del fármaco para inhibir la actividad de la enzima en un 50%, siendo esta de 11 (CI50) •Simvastatin is able to stabilize the atherosclerotic plaque by inducing structural changes, thereby reducing the risk of rupture. The hypolipidemic potency of Simvastatin is determined by the necessary concentration of the drug to inhibit the activity of the enzyme by 50%, being 11 (IC 50 ) •

La Rosuvastatina es otro inhibidor de la HMG-CoA reductasa que también pertenece al grupo de las estatinas; sin embargo, a diferencia de la Simvastatina, ésta tiene una alta potencia hipolipemiante (CI50 de 5) , hidrofílica y esta dotada de gran selectividad hepática, no se metaboliza en el citocromo P450 3A4 , sino en el 2c-9 y en el 2c-19, por lo que el riesgo de interacción farmacológica con otros fármacos es menor.Rosuvastatin is another HMG-CoA reductase inhibitor that also belongs to the statin group; however, unlike the Simvastatin, it has a high hypolipidemic potency (IC 50 of 5), hydrophilic and is equipped with high liver selectivity is not metabolized by cytochrome P450 3A4, but the 2c-9 and 2c-19, so the Risk of drug interaction with other drugs is lower.

La Rosuvastatina es un hidroxiácido enantiomérico simple que se administra como sal calcica, la cual reduce marcadamente los niveles de colesterol total y de LDL (lipoproteínas de baja densidad); disminuyendo también los niveles de triglicéridos y apolipoproteínas B. Actúa inhibiendo la síntesis hepática del colesterol, al bloquear la enzima 3-hidroxi-3- metilglutaril-Coenzima A (HMG-CoA) , involucrada en la síntesis del ácido mevalónico, precursor metabólico del colesterol. Tiene alta afinidad por la proteína C transportadora de aniones orgánicos predominantemente hepáticos. En estudios realizados in vivo e in vitro, se encontró que la Rosuvastatina manifiesta efectos no hipolipemiantes , como mejoría en la función endotelial, efectos antiinflamatorios, efectos protectores vasculares, cardíacos y cerebrales, además de mejoría en la función neural . Las propiedades farmacocinéticas de laRosuvastatin is a simple enantiomeric hydroxy acid that is administered as a calcium salt, which markedly reduces the levels of total cholesterol and LDL (low density lipoproteins); also lowering the levels of triglycerides and apolipoproteins B. It acts by inhibiting hepatic cholesterol synthesis, by blocking the enzyme 3-hydroxy-3- methylglutaryl-Coenzyme A (HMG-CoA), involved in the synthesis of mevalonic acid, metabolic precursor of cholesterol . It has high affinity for predominantly hepatic organic anion transporter protein C. In studies conducted in vivo and in vitro, Rosuvastatin was found to have non-lipid lowering effects, such as improvement in endothelial function, anti-inflammatory effects, vascular, cardiac and cerebral protective effects, as well as improvement in neural function. The pharmacokinetic properties of the

Rosuvastatina son proporcionales a la dosis, con acumulación escasa o nula luego de la administración repetida. En voluntarios sanos, se alcanzan concentraciones plasmáticas máximas de 19 a 25 μg/L después de 3 a 5 horas de haber administrado 40 mg. de Rosuvastatina en una sola dosis oral. La biodisponibilidad absoluta de la Rosuvastatina es aproximadamente del 20%. Los alimentos aumentan su velocidad de absorción en un 20%, pero el grado de absorción permanece invariable.Rosuvastatin are dose proportional, with little or no accumulation after repeated administration. In healthy volunteers, maximum plasma concentrations of 19 to 25 μg / L are reached after 3 to 5 hours of administering 40 mg. of Rosuvastatin in a single oral dose. The absolute bioavailability of Rosuvastatin is approximately 20%. Food increases its absorption rate by 20%, but the degree of absorption remains unchanged.

La Rosuvastatina se une de manera reversible a las proteínas plasmáticas (88%) . Experimenta un metabolismo muy limitado, el cual ocurre principalmente a través de la isoenzima (CYP) 2C9 del citocromo P450. El N- desmetil rosuvastatina es el metabolito principal. La Rosuvastatina tiene una larga vida media de eliminación en plasma (aproximadamente de 18 a 24 horas, después de administrar 40 mg . en una sola dosis oral) , y se elimina predominantemente por vía enterohepática (excreción biliar) .Rosuvastatin binds reversibly to plasma proteins (88%). You experience a very limited metabolism, which occurs primarily through the cytochrome P450 isoenzyme (CYP) 2C9. N-desmethyl rosuvastatin is the main metabolite. Rosuvastatin has a long elimination half-life in plasma (approximately 18 to 24 hours, after administering 40 mg in a single oral dose), and is predominantly eliminated via enterohepatic route (biliary excretion).

El agente derivado hidrogenado de lipstatina utilizado en las composiciones farmacéuticas objeto de la presente invención es el principio activo Orlistat, el cual esta presente en la formulación en un rango de concentración desde 60.0 mg . hasta 360.0 mg . , siendo preferentemente utilizada una concentración de 60.0 mg . a 120.0 mg. por unidad de dosis.The hydrogenated derivative agent of lipstatin used in the pharmaceutical compositions object of The present invention is the active ingredient Orlistat, which is present in the formulation in a concentration range from 60.0 mg. up to 360.0 mg , preferably a concentration of 60.0 mg being used. at 120.0 mg per dose unit.

El agente inhibidor de la enzima HMG-CoA reductasa utilizado en las composiciones farmacéuticas objeto de la presente invención es el principio activo Simvastatina y/o Rosuvastatina, los cuales están presentes en la formulación en un rango de concentración desde 20.0 mg . hasta 80.0 mg . para la Simvastatina, siendo preferentemente utilizada una concentración de 20.0 mg . a 40.0 mg . , y la Rosuvastatina esta presente en la formulación en un rango de concentración desde 5.0 mg . hasta 45.0 mg . , siendo preferentemente utilizada una concentración de 5.0 mg . hasta 10.0 mg. por unidad de dosis.The HMG-CoA reductase enzyme inhibitor used in the pharmaceutical compositions object of the present invention is the active substance Simvastatin and / or Rosuvastatin, which are present in the formulation in a concentration range from 20.0 mg. up to 80.0 mg for Simvastatin, a concentration of 20.0 mg being preferably used. at 40.0 mg , and Rosuvastatin is present in the formulation in a concentration range from 5.0 mg. up to 45.0 mg , a concentration of 5.0 mg being preferably used. up to 10.0 mg per dose unit.

La composiciones farmacéuticas protegidas mediante la presente invención están formuladas para ser administradas por vía oral en una sola unidad de dosificación en forma de cápsulas o tabletas, en las cuales se encuentra contenida la combinación sinérgica de los principios activos: Orlistat más Simvastatina y Orlistat más Rosuvastatina, así como excipientes farmacéuticamente aceptables .The pharmaceutical compositions protected by the present invention are formulated to be administered orally in a single dosage unit in the form of capsules or tablets, in which the synergistic combination of the active ingredients is contained: Orlistat plus Simvastatin and Orlistat plus Rosuvastatin, as well as pharmaceutically acceptable excipients.

Dichas composiciones farmacéuticas ha sido desarrolladas con la finalidad de brindar una alternativa farmacéutica para el tratamiento del sobrepeso, la obesidad, el colesterol elevado y los triglicéridos elevados, mismas que ofrecen significativas ventajas como lo son: menores concentraciones de los principios activos contenidos en la formulación, menores efectos secundarios y una reducción satisfactoria de los niveles de colesterol, triglicéridos y peso.These pharmaceutical compositions have been developed in order to provide a pharmaceutical alternative for the treatment of overweight, obesity, high cholesterol and high triglycerides, which offer significant advantages such as: lower concentrations of the active ingredients contained in the formulation , lower side effects and a satisfactory reduction in cholesterol, triglyceride and weight levels.

Para evaluar la eficiencia y tolerancia de las composiciones farmacéuticas motivo de la presente invención, así como el efecto sinérgico de los principios activos Orlistat, Simvastatina y Rosuvastatina combinados en una sola unidad de dosificación, se realizaron estudios clínicos comparativos en los cuales se administraron por separado los principios activos antes mencionados, así como la combinación de éstos. ESTUDIO CLÍNICO COMPARATIVO DE ORLISTAT,To evaluate the efficiency and tolerance of the pharmaceutical compositions that are the subject of the present invention, as well as the synergistic effect of the active ingredients Orlistat, Simvastatin and Rosuvastatin combined in a single dosage unit, comparative clinical studies were conducted in which they were administered separately. the active ingredients mentioned above, as well as the combination of these. ORLISTAT COMPARATIVE CLINICAL STUDY,

SIMVASTATINA Y LA COMBINACIÓN DE ORLISTAT / SIMVASTATINA EN PACIENTES OBESOS Y CON HIPERCOLESTEROLEMIA. Se realizó un estudio clínico con un año de seguimiento, randomizado que evaluó los efectos del tratamiento con Orlistat, Simvastatina y la combinación de Orlistat / Simvastatina aplicado en el perfil de lípidos, peso corporal y presión sanguínea de pacientes obesos con hipercolesterolemia.SIMVASTATIN AND THE COMBINATION OF ORLISTAT / SIMVASTATIN IN OBESENT PATIENTS AND WITH HYPERCHOLESTEROLEMIA. A randomized, one-year follow-up clinical study was conducted that evaluated the effects of treatment with Orlistat, Simvastatin and the combination of Orlistat / Simvastatin applied to the lipid profile, body weight and blood pressure of obese patients with hypercholesterolemia.

Métodos : Los pacientes que se eligieron fueron obesos con un índice de Masa Corporal (IMC) > 30 kg/m2; con hipercolesterolemia límite (Colesterol total 200- 240 mg/dl) o severa (Colesterol total > 240 mg/dl) ; pacientes normotensos (Presión sistólica <140 mm Hg y presión diastólica < 90 mm Hg) .Methods: Patients chosen were obese with a Body Mass Index (BMI)> 30 kg / m 2; with borderline hypercholesterolemia (Total cholesterol 200-240 mg / dl) or severe (Total cholesterol> 240 mg / dl); Normotensive patients (Systolic pressure <140 mm Hg and diastolic pressure <90 mm Hg).

Los pacientes tuvieron una edad promedio > 50 años. Los pacientes fueron randomizados para recibir el grupo 1: Orlistat 1 cápsula (120 mg . ) en la comida principal. El grupo 2: recibió Simvastatina 1 cápsula (20 mg . ) en la comida principal. El grupo 3: recibió la combinación Orlistat/Simvastatina 1 cápsula (120 mg./20 mg . , respectivamente) en la comida principal. Se evaluó el cumplimiento del tratamiento con el conteo de las cápsulas y con visitas de seguimiento cada 3 meses. Se evaluaron en suero el Colesterol total, C-LDL, C-HDL, Triglicéridos y la presión sanguínea durante la visita basal y a los 6 meses y 12 meses de tratamiento. Se evaluó el índice de cintura.The patients had an average age> 50 years. Patients were randomized to receive group 1: Orlistat 1 capsule (120 mg.) In the main meal. Group 2: received Simvastatin 1 capsule (20 mg.) In the main meal. Group 3: received the combination Orlistat / Simvastatin 1 capsule (120 mg./20 mg., Respectively) in the main meal. Treatment compliance was evaluated with capsule count and follow-up visits every 3 months. Serum total cholesterol, LDL-C, HDL-C, triglycerides and blood pressure were evaluated during the baseline visit and at 6 months and 12 months of treatment. The waist index was evaluated.

Resultados : Se enrolaron 90 pacientes, 45 mujeres y 45 hombres; con una edad promedio de 56 años. Ochenta completaron el estudio, 42 mujeres que estaban distribuidas de la siguiente manera, Grupo 1: 15; Grupo 2: 13; Grupo 3: 14 y 38 hombres que estaban distribuidos de la siguiente manera, Grupo 1: 15; Grupo 2: 10; Grupo 3: 13; los anteriores resultados se listan en la tabla 1.Results: 90 patients were enrolled, 45 women and 45 men; with an average age of 56 years. Eighty completed the study, 42 women who were distributed as follows, Group 1: 15; Group 2: 13; Group 3: 14 and 38 men who were distributed as follows, Group 1: 15; Group 2: 10; Group 3: 13; The previous results are listed in Table 1.

Tabla 1. Características demográficas de los pacientes en estudio (N = 80) .Table 1. Demographic characteristics of the patients under study (N = 80).

Grupo 1 Grupo 2 Grupo 3 (n=30) (n=23) (n=27)Group 1 Group 2 Group 3 (n = 30) (n = 23) (n = 27)

M H M H M HM H M H M H

Carácter (n=15) (n=15) (n=13) (n=10) (n=14) (n=13)Character (n = 15) (n = 15) (n = 13) (n = 10) (n = 14) (n = 13)

Edad 56(9) 55(10) 56(9) 56(10) 55(10) 56(10)Age 56 (9) 55 (10) 56 (9) 56 (10) 55 (10) 56 (10)

Peso (Kg ) 96(9) 95(10) 96(10) 95(8) 95(8) 94(8)Weight (Kg) 96 (9) 95 (10) 96 (10) 95 (8) 95 (8) 94 (8)

Altura (cm ) 165(9) 166(10) 160(7) 165(7) 164(7) 168(9)Height (cm) 165 (9) 166 (10) 160 (7) 165 (7) 164 (7) 168 (9)

Circunferencia 99(7) 96(7) 98(9) 97(3) 100(7) 99(6) (cm )Circumference 99 (7) 96 (7) 98 (9) 97 (3) 100 (7) 99 (6) (cm)

Grupo 1 = Orlistat, Grupo 2 = Simvastatma, Grupo 3 = Combinación Orhstat/Simvastatina Los valores son expresados como promedios (DS) No hubo diferencias significativas entre los grupos Tres pacientes del Grupo 1 que recibieron Orlistat presentaron eventos adversos gastrointestinales (urgencia fecal) ; sin embargo, no hubo necesidad de suspender el tratamiento. Después de dos semanas de tratamiento los eventos adversos gastrointestinales desaparecieron .Group 1 = Orlistat, Group 2 = Simvastatma, Group 3 = Orhstat / Simvastatin combination Values are expressed as averages (SD) There were no significant differences between the groups Three Group 1 patients who received Orlistat had gastrointestinal adverse events (fecal urgency); however, there was no need to stop treatment. After two weeks of treatment the gastrointestinal adverse events disappeared.

Los pacientes del Grupo 2 que recibieron Simvastatina no presentaron alteraciones en relación a transaminasas séricas o en la actividad de la creatinfosfoquinasa.Group 2 patients who received Simvastatin did not show alterations in relation to serum transaminase or creatinphosphokinase activity.

No se reportaron eventos adversos en el Grupo 3 que recibió la combinación de Orlistat/Simvastatina .No adverse events were reported in Group 3 that received the Orlistat / Simvastatin combination.

No hubo diferencias significativas en las características demográficas, perfil de lípidos, peso corporal, presión sanguínea dentro o entre los grupos.There were no significant differences in demographic characteristics, lipid profile, body weight, blood pressure within or between groups.

Los resultados mostraron algunas variaciones significativas dentro de los grupos en el perfil de lípidos (Tabla 2) de la línea basal a 6 meses de tratamiento en Colesterol total. Tabla 2. Comparación del perfil de lipidos (colesterol y triglicéridos (mg/dl) , basal a 6 meses y 1 año de tratamiento .The results showed some significant variations within the groups in the lipid profile (Table 2) of the baseline at 6 months of treatment in Total Cholesterol. Table 2. Comparison of the lipid profile (cholesterol and triglycerides (mg / dl), baseline at 6 months and 1 year of treatment.

Componente Basal 6 meses 1 año cambio de basal a 1 año (%)Baseline Component 6 months 1 year change from baseline to 1 year (%)

CTCT

Grupo 1 255 (25) 236 (22) 219(25) -131*Group 1 255 (25) 236 (22) 219 (25) -131 *

Grupo 2 258 (23) 198(21)* 184(23) -270** Group 2 258 (23) 198 (21) * 184 (23) -270 **

Grupo 3 256 (25) 183(23)** 169 (27)** -335*** Group 3 256 (25) 183 (23) ** 169 (27) ** -335 ***

C-LDLC-LDL

Grupo 1 188(22) 163(20) 156(24) -171* Group 1 188 (22) 163 (20 ) 156 (24) -171 *

Grupo 2 192(24) 150(22)* 107(22) -334** Group 2 192 (24) 150 (22) * 107 (22) -334 **

Grupo 3 187(21) 121 (21)** 106(22)** -430*** Group 3 187 (21) 121 (21) ** 106 (22) ** -430 ***

C-HDLC-HDL

Grupo 1 41 (4) 42(6) 44(6) 48Group 1 41 (4) 42 (6) 44 (6) 48

Grupo 2 41 (3) 43(4) 45(4) 123** Group 2 41 (3) 43 (4) 45 (4) 123 **

Grupo 3 40(3) 47 (4)** 48(5) 180*** Group 3 40 (3) 47 (4) ** 48 (5) 180 ***

TGTG

Grupo 1 139(35) 117(23) 97 (21) -30-0** Group 1 139 (35) 117 (23) 97 (21) -30-0 **

Grupo 2 147(30) 128(28) 112(27) -252* Group 2 147 (30) 128 (28) 112 (27) -252 *

Grupo 3 145(29) 117(25)* 89 (29) -375** Group 3 145 (29) 117 (25 ) * 89 (29) -375 **

CT = Colesterol Total, Grupo 1= Orlistat, Grupo 2= Simvastatina Grupo 3= Orlistat/Simvastatina, C-LDL = Lipoproteinas de baja densidad C-HDL = Lipoproteiπas de alta densidad TG = Tπgliceπdos Valores expresados como promedio (DS)CT = Total Cholesterol, Group 1 = Orlistat, Group 2 = Simvastatin Group 3 = Orlistat / Simvastatin, C-LDL = Low density lipoproteins C-HDL = High density lipoproteins TG = Tπgliceπdos Values expressed as average (DS)

P < 005 versus basal ** P < 002 versus basal *** P < 001 versus basalP <005 versus baseline * * P <002 versus baseline * ** P <001 versus baseline

Los resultados también mostraron diferencias significativas dentro de los grupos del basal a 6 meses de tratamiento: índice de Masa Corporal, Circunferencia de cintura, los anteriores resultados se listan en la tabla 3. Tabla 3. Comparación de peso corporal (índice de masa corporal [IMC] ) , reducción de la circunferencia de cintura [RCC] y pérdida de peso [PP] basal a 6 meses yThe results also showed significant differences within the baseline groups at 6 months of treatment: Body Mass Index, Waist Circumference, the previous results are listed in Table 3. Table 3. Comparison of body weight (body mass index [BMI]), reduction of waist circumference [RCC] and weight loss [PP] at baseline at 6 months and

1 año de tratamiento.1 year of treatment

Cambios de Basal (%)Baseline Changes (%)

Medición Basal 6 Meses 1 Año 6 Meses 1 AñoBaseline Measurement 6 Months 1 Year 6 Months 1 Year

IMC (kg/m2)BMI (kg / m 2 )

Grupo 1 33 5 (1 5) 30 5 (1 4) 28 5 (1 0) -7 6* -13 7** Group 1 33 5 (1 5) 30 5 (1 4) 28 5 (1 0) -7 6 * -13 7 **

Grupo 2 33 4 (1 3) 31 4 (1 4) 29 0 (1 5) -5 8 -12 4* Group 2 33 4 (1 3) 31 4 (1 4) 29 0 (1 5) -5 8 -12 4 *

Grupo 3 33 7 (1 6) 30 5 (1 6) 29 1 (0 9) -8 7* -15 2*** Group 3 33 7 (1 6) 30 5 (1 6) 29 1 (0 9) -8 7 * -15 2 ***

RCC (cm )RCC (cm)

Grupo 1 -2 0 (0 8) -4 0 (1 0) -2 0* -4 5* Group 1 -2 0 (0 8) -4 0 (1 0) -2 0 * -4 5 *

Grupo 2 -1 7 (0 8) -3 3 (1 1 ) -1 9 -3 6* Group 2 -1 7 (0 8) -3 3 (1 1) -1 9 -3 6 *

Grupo 3 -3 7 (0 8) -6 0 (0 7)*** -3 7* -5 9*** Group 3 -3 7 (0 8) -6 0 (0 7) *** -3 7 * -5 9 ***

PPPP

Grupo 1 -4 5 (1 3) -8 5 (1 6) -4 7* -8 4**Group 1 -4 5 (1 3) -8 5 (1 6) -4 7 * -8 4 **

Grupo 2 -3 8 (1 1 ) -7 1 (1 2) -3 8 -7 2*Group 2 -3 8 (1 1) -7 1 (1 2) -3 8 -7 2 *

Grupo 3 -8 0 (1 3)* -13 0 (1 4)* -8 5* -14 0*** Group 3 -8 0 (1 3) * -13 0 (1 4) * -8 5 * -14 0 ***

IMC = índice de Masa Corporal Grupo 1 = Orlistat Grupo 2= Simvastatma Grupo 3= Orlistat/Simvastatina RCC : Reducción circunferencia de cintura PP = Perdida de PesoBMI = Body Mass Index Group 1 = Orlistat Group 2 = Simvastatma Group 3 = Orlistat / Simvastatin RCC : Reduction of waist circumference PP = Weight Loss

P < 0 05 versus basal ** P < 0 02 versus basalP <0 05 versus baseline * * P <0 02 versus baseline

*** P < 0 01 versus basal *** P <0 01 versus baseline

Los resultados mostraron cambios significativos en la presión sanguínea de basal a 6 meses y 1 año de tratamiento, los anteriores resultados se listan en la tabla 4. Tabla 4. Comparación de presión sanguínea (sistólica [PAS] mm Hg y diastólica [PAD] mm Hg) de basal a 6 meses y 1 año de tratamiento.The results showed significant changes in blood pressure from baseline to 6 months and 1 year of treatment, the previous results are listed in Table 4. Table 4. Comparison of blood pressure (systolic [PAS] mm Hg and diastolic [PAD] mm Hg) from baseline to 6 months and 1 year of treatment.

Cambios Basal (%)Basal Changes (%)

Presión Basal 6 Meses 1 Año 6 Meses 1 AñoBasal Pressure 6 Months 1 Year 6 Months 1 Year

SistólicaSystolic

Grupo 1 132 (4) 131 (3) 127 (3) -1 5 -4 5* Group 1 132 (4) 131 (3) 127 (3) -1 5 -4 5 *

Grupo 2 135 (4) 131 (4) 127 (4) -2 3 -4 4* Group 2 135 (4) 131 (4) 127 (4) -2 3 -4 4 *

Grupo 3 134 (5) 127 (4) 122 (4) -3 9* -7 0*** Group 3 134 (5) 127 (4) 122 (4) -3 9 * -7 0 ***

DiastólicaDiastolic

Grupo 1 87 (4) 83 (3) 82 (3) -1 1 -4 5* Group 1 87 (4) 83 (3) 82 (3) -1 1 -4 5 *

Grupo 2 87 (4) 85 (3) 83 (4) -2-2 -4 5* Group 2 87 (4) 85 (3) 83 (4) -2-2 -4 5 *

Grupo 3 87 (4) 81 (4) 79 (3)** -2 5 -7 3*** Conclusiones :Group 3 87 (4) 81 (4) 79 (3) ** -2 5 -7 3 *** Conclusions:

El Orlistat es un agente antiobesidad inhibidor de las lipasas, indicado para el manejo a largo plazo de la obesidad y sus comorbilidades , produce una reducción dosis - dependiente en la absorción de la dieta grasa con una inhibición máxima de la absorción grasa del 30% a dosis de 120 mg . una vez al día.Orlistat is a lipase inhibitor antiobesity agent, indicated for the long-term management of obesity and its comorbidities, produces a dose-dependent reduction in the absorption of the fat diet with a maximum inhibition of fat absorption of 30% a 120 mg dose. once a day.

La Simvastatina es un inhibidor de la HMG-CoA reductasa que produce una reducción sustancial del C- LDL, junto con un modesto incremento en C-HDL. Generalmente es bien tolerada como monoterapia con un buen perfil de seguridad y eficacia comparable con los tratamientos con fenofibratos .Simvastatin is an HMG-CoA reductase inhibitor that produces a substantial reduction in LDL-C, along with a modest increase in HDL-C. It is generally well tolerated as monotherapy with a good safety profile and efficacy comparable to fenofibrate treatments.

En este estudio los pacientes obesos con hipercolesterolemia se beneficiaron de la administración de Orlistat y Simvastatina de forma independiente y de la combinación deIn this study obese patients with hypercholesterolemia benefited from the administration of Orlistat and Simvastatin independently and from the combination of

Orlistat/Simvastatina . Todos los parámetros mejoraron significativamente para el grupo que recibió la combinación. i Los 3 grupos de tratamiento mejoraron significativamente desde los parámetros básales. El tratamiento con la combinación Orlistat / Simvastatina mostró significativamente mayores reducciones de los niveles en suero de colesterol total, C-LDL, C-HDL, triglicéridos , índice de Masa Corporal, Circunferencia de Cintura, Pérdida de peso. También hubo una pequeña pero significativa diferencia encontrada en la presión sanguínea. El uso de la combinación permite reducir las dosis administradas a los pacientes, evitando con esto la manifestación de efectos secundarios. Por otra parte, la combinación reduce el riesgo de eventos cardiovasculares en pacientes obesos con hipercolesterolemia .Orlistat / Simvastatin. All parameters improved significantly for the group that received the combination. i The 3 treatment groups improved significantly from the baseline parameters. Treatment with the combination Orlistat / Simvastatin showed significantly greater reductions in serum levels of total cholesterol, C-LDL, C-HDL, triglycerides, Body Mass Index, Waist Circumference, Weight Loss. There was also a small but significant difference found in blood pressure. The use of the combination allows reducing the doses administered to patients, thereby avoiding the manifestation of side effects. On the other hand, the combination reduces the risk of cardiovascular events in obese patients with hypercholesterolemia.

ESTUDIO CLÍNICO COMPARATIVO DE ORLISTAT, ROSUVASTATINA Y LA COMBINACIÓN ORLISTAT / ROSUVASTATINA EN PACIENTES OBESOS Y CON HIPERCOLESTEROLEMIA. Se realizó un estudio clínico con un año de seguimiento, randomizado que evaluó los efectos del tratamiento con Orlistat, Rosuvastatina y la combinación de Orlistat / Rosuvastatina aplicado en el perfil de lípidos, peso corporal y presión sanguínea de pacientes obesos con hipercolesterolemia.COMPARATIVE CLINICAL STUDY OF ORLISTAT, ROSUVASTATINA AND THE COMBINATION ORLISTAT / ROSUVASTATINA IN OBESOS PATIENTS AND WITH HYPERCHOLESTEROLEMIA. A randomized, one-year follow-up clinical study was conducted that evaluated the effects of treatment with Orlistat, Rosuvastatin and the combination of Orlistat / Rosuvastatin applied to the lipid profile, body weight and blood pressure of obese patients with hypercholesterolemia.

Métodos : Los pacientes que se eligieron fueron obesos con un índice de Masa Corporal (IMC) > 30 kg/m2 ; con hipercolesterolemia límite (Colesterol total 200- 240 rag/dl) o severa (Colesterol total > 240 mg/dl) ; pacientes normotensos (Presión sistólica <140 mm Hg y presión diastólica < 90 mm Hg) .Methods: The patients that were chosen were obese with a Body Mass Index (BMI)> 30 kg / m 2 ; with borderline hypercholesterolemia (Total cholesterol 200- 240 rag / dl) or severe (Total cholesterol> 240 mg / dl); Normotensive patients (Systolic pressure <140 mm Hg and diastolic pressure <90 mm Hg).

Los pacientes tuvieron una edad promedio > 50 años. Los pacientes fueron randomizados para recibir el grupo 1: Orlistat 1 cápsula (120 mg.) en la comida principal. El grupo 2: recibió Rosuvastatina 1 cápsula (10 mg.) en la comida principal. El grupo 3: recibió la combinación Orlistat/Rosuvastatina 1 cápsula (120 mg./lO mg . , respectivamente) en la comida principal.The patients had an average age> 50 years. Patients were randomized to receive group 1: Orlistat 1 capsule (120 mg.) In the main meal. Group 2: received Rosuvastatin 1 capsule (10 mg.) In the main meal. Group 3: received the combination Orlistat / Rosuvastatin 1 capsule (120 mg./lO mg., Respectively) in the main meal.

Se evaluó el cumplimiento del tratamiento con el conteo de las cápsulas y con visitas de seguimiento cada 3 meses. Se evaluaron en suero el Colesterol total, C-LDL, C-HDL, Triglicéridos y la presión sanguínea durante la visita basal y a los 6 meses y 12 meses de tratamiento. Se evaluó el índice de cintura.Treatment compliance was evaluated with capsule count and follow-up visits every 3 months. Serum total cholesterol, LDL-C, HDL-C, triglycerides and blood pressure were evaluated during the baseline visit and at 6 months and 12 months of treatment. The waist index was evaluated.

Resultados : Se enrolaron 90 pacientes, 45 mujeres y 45 hombres; con una edad promedio de 55 años. Los 90 completaron el estudio, 45 mujeres que estaban distribuidas de la siguiente manera, Grupo 1: 15; Grupo 2: 15; Grupo 3: 15 y 45 hombres que estaban distribuidos de la siguiente manera, Grupo 1: 15; Grupo 2: 15; Grupo 3: 15), los resultados anteriores se listan en la tabla 5.Results: 90 patients were enrolled, 45 women and 45 men; With an average age of 55 years. The 90 completed the study, 45 women who were distributed as follows, Group 1: 15; Group 2: 15; Group 3: 15 and 45 men who were distributed as follows, Group 1: 15; Group 2:15; Group 3: 15), the previous results are listed in table 5.

Tabla 5. Características demográficas de los pacientes en estudio (N = 80) .Table 5. Demographic characteristics of the patients under study (N = 80).

Grupo 1 Grupo 2 (Grupo 3Group 1 Group 2 (Group 3

(n=30) (n=30) (n=30)(n = 30) (n = 30) (n = 30)

M H M H M HM H M H M H

Carácter (n=15) (n=15) (n=15) (n=15) (n=15) (n=15)Character (n = 15) (n = 15) (n = 15) (n = 15) (n = 15) (n = 15)

Edad 56(9) 57(9) 56(9) 57(9) 55(9) 56(9)Age 56 (9) 57 (9) 56 (9) 57 (9) 55 (9) 56 (9)

Peso (Kg ) 96(10) 95(10) 96(10) 95(9) 95(8) 97(8)Weight (Kg) 96 (10) 95 (10) 96 (10) 95 (9) 95 (8) 97 (8)

Altura (cms ) 166(9) 168(10) 163(8) 166(7) 164(7) 170(9)Height (cms) 166 (9) 168 (10) 163 (8) 166 (7) 164 (7) 170 (9)

Circunferencia 99(8) 97(7) 98(9) 99(3) 100(7) 99(6)Circumference 99 (8) 97 (7) 98 (9) 99 (3) 100 (7) 99 (6)

Grupo 1 = Orhstat, Grupo 2= Rosuvastatma, Grupo 3= Combinación Orlistat/RosuvastatinaGroup 1 = Orhstat, Group 2 = Rosuvastatma, Group 3 = Orlistat / Rosuvastatin combination

Los valores son expresados como promedios (DS) No hubo diferencias significativas entre los gruposValues are expressed as averages (SD). There were no significant differences between the groups.

Dos pacientes del Grupo 1 que recibieron Orlistat presentaron eventos adversos gastrointestinalesTwo Group 1 patients who received Orlistat had gastrointestinal adverse events

(urgencia fecal) ; sin embargo, no hubo necesidad de suspender el tratamiento. Después de dos semanas de tratamiento los eventos adversos gastrointestinales desaparecieron .(fecal urgency); however, there was no need to stop treatment. After two weeks of treatment the gastrointestinal adverse events disappeared.

Los pacientes del Grupo 2 que recibieron Rosuvastatina no presentaron alteraciones en relación a transaminasas séricas o en la actividad de la creatinfosfoquinasa . No se reportaron eventos adversos en el Grupo 3 que recibió la combinación de Orlistat/Rosuvastatina.Group 2 patients who received Rosuvastatin did not show alterations in relation to serum transaminase or creatinphosphokinase activity. No adverse events were reported in Group 3 that received the Orlistat / Rosuvastatin combination.

No hubo diferencias significativas en las características demográficas, perfil de lípidos, peso corporal, presión sanguínea dentro o entre los grupos.There were no significant differences in demographic characteristics, lipid profile, body weight, blood pressure within or between groups.

Los resultados mostraron algunas variaciones significativas dentro de los grupos en el perfil de lípidos (Tabla 6) de la línea basal a 6 meses de tratamiento en Colesterol total : Tabla 6. Comparación del perfil de lípidos (colesterol y triglicéridos (mg/dl), basal a 6 meses y 1 año de tratamiento.The results showed some significant variations within the groups in the lipid profile (Table 6) of the baseline at 6 months of treatment in Total Cholesterol: Table 6. Comparison of the lipid profile (cholesterol and triglycerides (mg / dl), Baseline at 6 months and 1 year of treatment.

Componente Basal 6 meses 1 año cambio de basal a 1 año %Baseline Component 6 months 1 year change from baseline to 1 year%

CTCT

Grupo 1 254 (25) 235 (22) 221 (25) -133* Grupo 2 260 (23) 199(21)* 186(23) -275** Grupo 3 258 (24) 180(23)** 160(29)** -355*** Group 1 254 (25) 235 (22) 221 (25) -133 * Group 2 260 (23) 199 (21) * 186 (23) -275 ** Group 3 258 (24) 180 (23) ** 160 ( 29) -355 ** ***

C-LDL Grupo 1 186(21) 164(21) 154(23) -173* Grupo 2 195(25) 152(22)* 109(23) -33** Grupo 3 189(22) 120(21)** 102(23)** -450*** C-HDL Grupo 1 40(3) 43(5) 44(6) 49C-LDL Group 1 186 (21) 164 (21) 154 (23) -173 * Group 2 195 (25) 152 (22) * 109 (23) -33 ** Group 3 189 (22) 120 (21) * * 102 (23) ** -450 * ** C-HDL Group 1 40 (3) 43 (5) 44 (6) 49

Grupo 2 40(3) 44(5) 45(5) 124**Group 2 40 (3) 44 (5) 45 (5) 124 **

Grupo 3 40(3) 48 (5)** 50(6) 200***Group 3 40 (3) 48 (5) ** 50 (6) 200 ***

TGTG

Grupo 1 140(36) 119(24) 98 (22) -30-7** Grupo 2 145(31) 126(29) 111 (28) -255* Grupo 3 149(28) 112 (24)* 83 (27) -400** Los resultados también mostraron diferencias significativas dentro de los grupos del basal a 6 meses de tratamiento: índice de Masa Corporal, Circunferencia de cintura, dichos resultados se listan en la tabla 7.Group 1 140 (36) 119 (24 ) 98 (22) -30-7 ** Group 2 145 (31) 126 (29 ) 111 (28) -255 * Group 3 149 (28) 112 (24) * 83 ( 27) -400 ** The results also showed significant differences within the baseline groups at 6 months of treatment: Body Mass Index, Waist Circumference, these results are listed in Table 7.

Tabla 7. Comparación de peso corporal (índice de masa corporal [IMC] , reducción de la circunferencia de cintura [RCC] y pérdida de peso [PP] basal a 6 meses yTable 7. Comparison of body weight (body mass index [BMI], reduction in waist circumference [RCC] and weight loss [PP] at baseline at 6 months and

1 año de tratamiento.1 year of treatment

Cambios de Basal (%)Baseline Changes (%)

Medición Basal 6 Meses 1 Año 6 Meses 1 AñoBaseline Measurement 6 Months 1 Year 6 Months 1 Year

IMC (kg/m2)BMI (kg / m 2 )

Grupo 1 ) 33 7 (1 5) 30 3 (1 4) 27 5 (1 3) -7 8* -13 9** Group 1) 33 7 (1 5) 30 3 (1 4) 27 5 (1 3) -7 8 * -13 9 **

Grupo 2 33 6 (1 5) 31 0 (1 3) 29 2 (1 4) -5 9 -12 5* Group 2 33 6 (1 5) 31 0 (1 3) 29 2 (1 4) -5 9 -12 5 *

Grupo 3 33 9 (1 5) 30 1 (1 4) 28 1 (0 8) -8 9* -15 9*** Group 3 33 9 (1 5) 30 1 (1 4) 28 1 (0 8) -8 9 * -15 9 ***

RCC (cm )RCC (cm)

Grupo 1 -2 1 (0 7) -4 1 (1 1 ) -2 1 * -4 6* Group 1 -2 1 (0 7) -4 1 (1 1) -2 1 * -4 6 *

Grupo 2 -1 5 (0 7) -3 1 (1 1 ) -1 8 -3 7* Group 2 -1 5 (0 7) -3 1 (1 1) -1 8 -3 7 *

Grupo 3 -3 9 (0 9) -6 5 (0 9)*" -3 9* -6 1*** Group 3 -3 9 (0 9) -6 5 (0 9) * "-3 9 * -6 1 ***

PPPP

Grupo 1 -4 (1 2) -8 6 (1 5) -4 8* -8 5** Group 1 -4 (1 2) -8 6 (1 5) -4 8 * -8 5 **

Grupo 2 -3 7 (1 1 ) -7 3 (1 2) -3 9 -7 5* Group 2 -3 7 (1 1) -7 3 (1 2) -3 9 -7 5 *

Grupo 3 -8 5 (1 4)* -13 5 (1 5)* -8 8* -14 6*** Group 3 -8 5 (1 4) * -13 5 (1 5) * -8 8 * -14 6 ***

IMC = índice de Masa Corporal Grupo 1 = Orlistat Grupo 2= Rosuvastatina, Grupo 3= Orlistat/Rosuvastatina, RCC= Reducción circunferencia de cintura, PP= Perdida de PesoBMI = Body Mass Index Group 1 = Orlistat Group 2 = Rosuvastatin, Group 3 = Orlistat / Rosuvastatin, RCC = Waist circumference reduction, PP = Weight Loss

P < 0 05 versus basal ** P < 0 02 versus basal **- P < 0 01 versus basalP <0 05 versus baseline * * P <0 02 versus baseline * * - P <0 01 versus baseline

Los resultados mostraron cambios significativos en la presión sanguínea de basal a 6 meses y 1 año de tratamiento, dichos resultados se listan en la tabla 8. Tabla 8. Comparación de presión sanguíneaThe results showed significant changes in blood pressure from baseline to 6 months and 1 year of treatment, these results are listed in Table 8. Table 8. Comparison of blood pressure

(sistólica [PAS] mm Hg y diastólica [PAD] mm Hg) de basal a 6 meses y 1 año de tratamiento.(systolic [PAS] mm Hg and diastolic [PAD] mm Hg) from baseline to 6 months and 1 year of treatment.

Cambios Basal, % Presión Basal 6 Meses 1 Año 6 Meses 1 AñoChanges Basal,% Basal Pressure 6 Months 1 Year 6 Months 1 Year

SistólicaSystolic

Grupo 1 133 (4) 131 (3) 128 (3) -1 6 -4 6*Group 1 133 (4) 131 (3) 128 (3) -1 6 -4 6 *

Grupo 2 136 (4) 131 (4) 126 (4) -2 5 -4 5* Group 2 136 (4) 131 (4) 126 (4) -2 5 -4 5 *

Grupo 3 136 (5) 125 (4) 120 (4) -4 0* -7 9*** Group 3 136 (5) 125 (4) 120 (4) -4 0 * -7 9 ***

DiastólicaDiastolic

Grupo 1 88 (3) 82 (3) 81 (3) -1 2 -4 4*Group 1 88 (3) 82 (3) 81 (3) -1 2 -4 4 *

Grupo 2 86 (4) 85 (4) 83 (3) -2-1 -4 4*Group 2 86 (4) 85 (4) 83 (3) -2-1 -4 4 *

Grupo 3 87 (3) 80 (4) 76 (4)** -2 7 _7 7***Group 3 87 (3) 80 (4) 76 (4) ** -2 7 _7 7 ***

Conclusiones :Conclusions:

El Orlistat es un agente antiobesidad inhibidor de las lipasas, indicado para el manejo a largo plazo de la obesidad y sus comorbilidades , produce una reducción dosis - dependiente en la absorción de la dieta grasa con una inhibición máxima de la absorción grasa del 30% a dosis de 120 mg. una vez al día.Orlistat is a lipase inhibitor antiobesity agent, indicated for the long-term management of obesity and its comorbidities, produces a dose-dependent reduction in the absorption of the fat diet with a maximum inhibition of fat absorption of 30% a 120 mg dose. once a day.

La Rosuvastatina es un inhibidor de la HMG-CoA reductasa que produce una reducción sustancial del C- LDL, junto con un modesto incremento en C-HDL. Generalmente es bien tolerado como monoterapia con un buen perfil de seguridad y eficacia, con mayor potencia que la Simvastatina . En este estudio los pacientes obesos con hipercolesterolemia se beneficiaron de la administración de Orlistat y Rosuvastatina de forma independiente y de la combinación de Orlistat/Rosuvastatina. Todos los parámetros mejoraron significativamente para el grupo que recibió la combinación .Rosuvastatin is an HMG-CoA reductase inhibitor that produces a substantial reduction in LDL-C, along with a modest increase in HDL-C. It is generally well tolerated as monotherapy with a good safety and efficacy profile, with greater potency than Simvastatin. In this study obese patients with hypercholesterolemia benefited from the administration of Orlistat and Rosuvastatin independently and the combination of Orlistat / Rosuvastatin. All parameters improved significantly for the group that received the combination.

Los 3 grupos de tratamiento mejoraron significativamente desde los parámetros básales. El tratamiento con la combinación Orlistat / Rosuvastatina mostró significativamente mayores reducciones en suero del colesterol total, C-LDL, C-HDL, triglicéridos , índice de Masa Corporal, Circunferencia de Cintura, Pérdida de peso. También hubo una pequeña pero significativa diferencia encontrada en la presión sanguínea. El uso de la combinación permite reducir las dosis administradas en los pacientes, evitando con esto la manifestación de efectos secundarios. Por otra parte, la combinación reduce el riesgo de eventos cardiovasculares en pacientes obesos con hipercolesterolemia. La combinación muestra un efecto sinérgico, por tal razón, las concentraciones de los principios activos y las dosis administradas de los mismos son menores que cuando se administran de forma individual . The 3 treatment groups improved significantly from the baseline parameters. Treatment with the Orlistat / Rosuvastatin combination showed significantly greater serum reductions in total cholesterol, C-LDL, C-HDL, triglycerides, Body Mass Index, Waist Circumference, Weight Loss. There was also a small but significant difference found in blood pressure. The use of the combination allows reducing the doses administered in patients, thereby avoiding the manifestation of side effects. On the other hand, the combination reduces the risk of cardiovascular events in obese patients with hypercholesterolemia. The combination shows a synergistic effect, for this reason, the concentrations of the active substances and the administered doses of the they are smaller than when administered individually.

Claims

NOVEDAD DE LA INVENCIÓNHabiendo descrito la presente invención, se considera como novedad y por lo tanto, se reclama como propiedad lo contenido en las siguientesREIVINDICACIONES NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore, what is contained in the following claims is claimed as property 1.- Composiciones farmacéuticas caracterizadas por estar compuestas por la combinación sinérgica de un agente derivado hidrogenado de lipstatina, tal como lo es el principio activo: Orlistat y un agente inhibidor de la enzima HMG-CoA reductasa, tal como lo son los principios activos: Simvastatina y/o Rosuvastatina, además de excipientes farmacéuticamente aceptables; en donde los rangos de concentración que se encuentran presentes en la formulación para el Orlistat son de 60.0 mg. a 120.0 mg., para la Simvastatina son de 20.0 mg . a 40.0 mg . y para la Rosuvastatina son de 5.0 a 10.0 mg; mismos que se encuentran formulados en una sola unidad de dosificación para ser administradas por vía oral, las cuales están indicadas para la prevención y/o tratamiento de la hipercolesterolemia, trigliceridemia, el sobrepeso y la obesidad. 1. Pharmaceutical compositions characterized by being composed of the synergistic combination of a hydrogenated derivative agent of lipstatin, such as the active substance: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, such as the active ingredients: Simvastatin and / or Rosuvastatin, in addition to pharmaceutically acceptable excipients; where the concentration ranges that are present in the formulation for Orlistat are 60.0 mg. at 120.0 mg., for Simvastatin they are 20.0 mg. at 40.0 mg and for Rosuvastatin they are 5.0 to 10.0 mg; same that are formulated in a single dosage unit to be administered orally, which are indicated for the prevention and / or treatment of hypercholesterolemia, triglyceridemia, overweight and obesity. 2. - Composición farmacéutica de conformidad con la reivindicación 1, caracterizada por estar compuesta por la combinación sinérgica de un agente derivado hidrogenado de lipstatina, tal como lo es el principio activo: Orlistat y un agente inhibidor de la enzima HMG-CoA reductasa, tal como lo es el principio activo: Simvastatina, mismos que se encuentra formulados en una sola unidad de dosificación.2. - Pharmaceutical composition according to claim 1, characterized in that it is composed of the synergistic combination of a hydrogenated derivative agent of lipstatin, such as the active ingredient: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, such as is the active substance: Simvastatin, which is formulated in a single dosage unit. 3. - Composición farmacéutica de conformidad con las reivindicaciones 1 y 2, caracterizada porque el agente derivado hidrogenado de lipstatina, tal como lo es el principio activo: Orlistat, se encuentra presente en la formulación en un rango de concentración de 60.0 mg . a 120.0 mg . , siendo preferentemente utilizada una concentración de 120.0 mg. y el agente inhibidor de la enzima HMG-CoA reductasa, tal como lo es el principio activo: Simvastatina, se encuentra presente en la formulación en un rango de concentración de 20.0 mg . a 40.0 mg . , siendo preferentemente utilizada una concentración de 20.0 mg., por unidad de dosificación.3. - Pharmaceutical composition according to claims 1 and 2, characterized in that the hydrogenated derivative agent of lipstatin, such as the active ingredient: Orlistat, is present in the formulation in a concentration range of 60.0 mg. at 120.0 mg , preferably a concentration of 120.0 mg being used. and the HMG-CoA reductase enzyme inhibitor, such as the active substance: Simvastatin, is present in the formulation in a concentration range of 20.0 mg. at 40.0 mg , preferably a concentration of 20.0 mg being used, per dosage unit. 4. - Composición farmacéutica de conformidad con las reivindicaciones 1 a 3, caracterizada por estar formulada en una sola unidad de dosis para ser administrada por vía oral en forma de cápsula o tableta.4. - Pharmaceutical composition according to claims 1 to 3, characterized in that it is formulated in a single dose unit to be administered orally in capsule or tablet form. 5. - Composición farmacéutica de conformidad con las reivindicaciones 1 a 4, caracterizada por estar indicada para la prevención y/o tratamiento de la hipercolesterolemia, tπgliceπdemia, el sobrepeso y la obesidad.5. - Pharmaceutical composition according to claims 1 to 4, characterized in that it is indicated for the prevention and / or treatment of hypercholesterolemia, tπgliceπdemia, overweight and obesity. 6.- Composición farmacéutica de conformidad con la reivindicación 1, caracterizada por estar compuesta por la combinación sinérgica de un agente derivado hidrogenado de lipstatma, tal como lo es el principio activo- OrIistat y un agente inhibidor de la enzima HMG-CoA reductasa, tal como lo es el principio activo: Rosuvastatma, mismos que se encuentra formulados en una sola unidad de dosificación.6. Pharmaceutical composition according to claim 1, characterized in that it is composed of the synergistic combination of a hydrogenated derivative agent of lipstatma, such as the active ingredient - OrIistat and an inhibitor of the enzyme HMG-CoA reductase, such as is the active substance: Rosuvastatma, which is formulated in a single dosage unit. 7 - Composición farmacéutica de conformidad con las reivindicaciones 1 y 6, caracterizada porque el agente derivado hidrogenado de lipstatma, tal como lo es el principio activo: Orlistat, se encuentra presente en la formulación en un rango de concentración de 60 0 mg . a 120.0 mg., siendo preferentemente utilizada una concentración de 60.0 mg. y 120.0 mg . y el agente inhibidor de la enzima HMG-CoA reductasa, tal como lo es el principio activo: Rosuvastatina, se encuentra presente en la formulación en un rango de concentración de 5.0 a 10.0 mg., siendo preferentemente utilizada una concentración de 10.0 mg . , por unidad de dosificación. 8. - Composición farmacéutica de conformidad con las reivindicaciones 1, 6 y I1 caracterizada por estar formulada en una sola unidad de dosis para ser administrada por vía oral en forma de tableta o cápsula . 9.- Composición farmacéutica de conformidad con las reivindicaciones 1, 6, 7 y 8, caracterizada por estar indicada para la prevención y/o tratamiento de la hipercolesterolemia, trigliceridemia, el sobrepeso y la obesidad . 7 - Pharmaceutical composition according to claims 1 and 6, characterized in that the hydrogenated derivative agent of lipstatma, such as the active ingredient: Orlistat, is present in the formulation in a concentration range of 60 mg. at 120.0 mg., a concentration of 60.0 mg being preferably used. and 120.0 mg. and the HMG-CoA reductase enzyme inhibitor, as It is the active substance: Rosuvastatin, is present in the formulation in a concentration range of 5.0 to 10.0 mg., a concentration of 10.0 mg is preferably used. , per dosage unit. 8. - Pharmaceutical composition according to claims 1, 6 and I 1 characterized in that it is formulated in a single dose unit to be administered orally as a tablet or capsule. 9. Pharmaceutical composition according to claims 1, 6, 7 and 8, characterized in that it is indicated for the prevention and / or treatment of hypercholesterolemia, triglyceridemia, overweight and obesity.
PCT/MX2008/000062 2007-05-21 2008-05-19 Pharmaceutical compositions combining a hydrogenated lipstatin derived agent and a hmg-coa reductase inhibiting agent Ceased WO2008143491A1 (en)

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CN110357812A (en) * 2019-08-03 2019-10-22 黄泳华 The eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor

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