MX2007006092A - Pharmaceutical compositions combining a hydrogenated lipstatin derived agent and a hmg-coa reductase inhibiting agent. - Google Patents

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

PHARMACEUTICAL COMPOSITIONS COMPRISING THE COMBINATION OF A HYDROGENATED DERIVATIVE AGENT OF LIPSTATIN AND AN INHIBITOR AGENT OF HMG-CoA REDUCTASE. FIELD OF THE INVENTION The present invention is applied in the pharmaceutical industry and describes various pharmaceutical compositions composed by the synergistic combination of a hydrogenated derivative 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. The combination of the active principles mentioned above produces a greater synergistic effect when they are administered together in a single dose unit as opposed to when they are administered independently, generating benefits such as: lower dosages, faster action and lower side effects .

BACKGROUND OF THE INVENTION It has been controversial to elucidate whether obesity itself is an independent risk factor of certain diseases, such as atherosclerotic coronary heart disease or exerts its influence as a conditioning factor of other factors, especially: arterial hypertension, diabetes mellitus and dyslipidemias. The Framingham study showed prospectively that for every 10% increase in weight, blood pressure increases 6.5 mm Hg, plasma cholesterol 12 mg / dl. and the glycemia 2 mg./dl. The controversy to accept obesity as an independent risk factor is due, among other aspects, to differences in the designs, especially in the time of epidemiological observation and in the age of entry of the individuals under study. 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 of more 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 the increase in cholesterol, blood pressure and intolerance to glucose. Raskin (1977) with the Manitoba study applied to a population of young men, demonstrated that the BMI (body mass index) was a factor that predicted the manifestation of coronary disease, adjusted for age and blood pressure, only after 16 years of follow-up. 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 at present, as Pi-Sunyer points out, is that although there is controversy in accepting obesity as an independent risk factor for coronary heart disease, the most important evidence is that it has a long-term effect and that this is much more noticeable in the presence of other associated factors such as: arterial hypertension, dyslipidemia and diabetes. The distribution of body fat is an additional element in the relationship of obesity with atherosclerosis and its association with the factors mentioned above. Vague (1947 and 1956) showed that in predominantly thoracic-abdominal obesity there was a greater frequency of glucose intolerance, dyslipidemia, hyperuricemia and arterial hypertension, with increased cardiovascular risk.

This has been corroborated by several authors who have given various names, such as Kaplan's "death quartet" (1989), consisting of thoracic-abdominal obesity, glucose intolerance, hypertriglyceridemia and hypertension. Although Reaven did not consider obesity in the description of syndrome X (hyperinsulinemia, glucose intolerance, hypertension and dyslipidemia), an increase in visceral fat and especially thoracic-abdominal obesity is associated with the Insulin Resistance Syndrome, conditioning a Plurimetabolic Syndrome with high cardiovascular risk. The association between obesity and hypertension is a frequent occurrence. Stamler describes the prevalence of hypertension in a North American population close to one million people, determining that the obese between 20 and 39 years have double and between 40 and 64 years 50% more hypertension than subjects of normal weight. 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. Pathogenic mechanisms are not clear, but it has been postulated that obesity could explain this association when generating insulin resistance, with the consequent hyperinsulinemia. Insulin reduces renal excretion of sodium and through this could expand extracellular volume and blood volume, 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 the above favors arterial hypertension; 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. Furthermore, in patients with very restrictive hypocaloric diets, the onset of orthostatic hypotension should be monitored. Clinical and epidemiological experience has shown an indisputable 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 grows the greater the intensity of obesity. It is also related to the type of obesity, in terms of the distribution of body fat, being higher in thoracic-abdominal type obesity. Studies of insulin sensitivity and euglycemic clamp are concordant in demonstrating that obesity generates insulin resistance. This is due to a defect of insulin action, especially at the postreceptor level, demonstrated especially in skeletal muscle. Insulin resistance generates compensatory hyperinsulinemia, with over-stimulation of the beta cells of the pancreas and also a reduction in the number of peripheral receptors to insulin (phenomenon of down regulation). Sometimes, this is combined with a genetic defect or acquired insulin secretion. On the other hand, fasting hyperglycemia results from increased hepatic glucose production that is not sufficiently inhibited by insulin. The greater release of free fatty acids from adipose tissue that the obese individual has (a phenomenon that is even more pronounced in obesity of abdominal and visceral distribution) stimulates hepatic neuglycogenesis, which uses 3-carbon substrates for its production. In summary, in the pathogenesis of non-insulin-dependent diabetes mellitus, which is the form of diabetes Most frequent primary obesity is the most relevant and possible environmental factor to prevent and modify. In turn, the weight reduction of an obese diabetic significantly improves their metabolic condition, facilitating the control of glycemia and dyslipidemia by producing insulin resistance, as has been repeatedly demonstrated. Therefore, it is of greater importance the treatment and as far as possible the prevention of obesity, so that in turn prevents the development of diabetes. Among the most frequent causes of secondary dyslipidemias, obesity stands out. This is associated with the insulin resistance syndrome frequently observed with excess fatty tissue, even more so when there is a thoracic-abdominal or visceral distribution. The most frequent to observe is a hypertriglyceridemia, with a slight increase in total cholesterol, but with a marked decrease in HDL cholesterol (high density lipoprotein), and consequently an increase in the total cholesterol / HDL cholesterol ratio. The increase in triglycerides is due to a greater hepatic synthesis, stemming from an increase in the supply of free fatty acids in a state of hyperinsulinemia due to insulin resistance. It increases the secretion of cholesterol of the VLDL (lipoprotein of very low density) and therefore the highlight is the hypertriglyceridemia. The HDL cholesterol reduction is explained by hypertriglyceridemia, since under 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 the LDL cholesterol (low density lipoprotein). LDLs receive triglycerides, which are partially metabolized by hepatic lipase and are transformed into small, dense LDL, which have a higher atherogenic potential (greater susceptibility to oxidation and lower affinity with apolipoprotein β receptors). Recently, meta-analysis studies tend to show that elevated triglycerides are a risk in the general population and even higher in diabetics and women. Regardless of whether or not triglycerides are a risk factor, their association with HDL deficiency and LDL production with a demonstrated pathophysiological interrelation explain the increased risk in these patients. An increase in LDL cholesterol is not common among obese people; however, this can be observed in cases of an association with genetic dyslipidemia (familial hypercholesterolemia, combined familial dyslipidemia) or secondary to hypothyroidism or a diet high in saturated fats and cholesterol.

Weight reduction in dyslipidemic obese patients is associated with a marked improvement in dyslipidemia, with a decrease in triglycerides and an increase in HDL cholesterol. If the response is partial and even more so if there are other associated risk factors, an appropriate pharmacological therapy should be proposed for the type of dyslipidemia present. Nowadays there is a wide variety of pharmaceutical products useful for the treatment of these conditions (obesity, dyslipidemia, hypertension, 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, is slower and less effective. On the other hand, the interactions that occur with the administration of different active principles must be taken into account, thus causing undesirable effects in patients, who must take prolonged treatments. SUMMARY OF THE INVENTION 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 as diabetes mellitus and arterial hypertension, the development of the pharmaceutical compositions described below was carried out.

DETAILED DESCRIPTION OF THE INVENTION At present most of the drugs found on 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, its independent administration produces an increase in the frequency of doses administered, in the concentrations administered, in the possibility of negative interactions with each other and as a consequence of the risk of the appearance of adverse events. For this reason and in order to eliminate all the disadvantages that arise when the active ingredients are administered independently, it is that the development of the pharmaceutical compositions object of the present invention, which are composed by the combination, was carried out. synergy of a hydrogenated derivative of lipstatin and an inhibitor of the enzyme HMG-CoA reductase, which produce a satisfactory therapeutic effect when administered together in a single dosage unit orally as opposed to when they are administered independently, generating benefits such as: lower concentrations of active ingredients formulated, lower doses administered, greater speed of action, greater efficacy of the therapeutic effect and lower Adverse effects.

Orlistat is a potent, specific and long-lasting inhibitor of pancreatic and gastrointestinal lipases. 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 inhibitory activity of pancreatic and gastric lipase. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active site of serine enzymes called gastric and pancreatic lipases, which have the function of breaking down triglycerides in the intestine. The absence of these 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, causing them to be excreted without being digested.

Its main function is as a weight-reducing agent in patients suffering from overweight and obesity, avoiding the absorption of fats from the diet, thereby reducing the intake of excess calories. Its elimination is carried out through feces. 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 a 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 difficult It achieves the administration of HMG-CoA inhibitors independently, since in the case of hypertriglyceridemia other types of drugs must be administered, such as fibrates. 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 into mevalonate, a precursor of sterols, including cholesterol. The inhibition of HMG-CoA reductase reduces the levels of mevalonate and the hepatic cholesterol levels, which causes a sustained and regulated increase in the activity of the receptors for LDL 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 decreases the levels of high total cholesterol, LDL cholesterol and apolipoproteins B and increases HDL cholesterol levels, causing decrease the LDL / HDL ratio and total cholesterol / HDL. In the liver, triglycerides and cholesterol are incorporated into the VLDL and released into the plasma for its distribution in the peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL and are catabolized mainly by the high affinity of the receptor for LDL. Simvastatin works by inhibiting the activity of the enzyme hydroxymethyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) and cholesterol synthesis, thereby reducing plasma cholesterol and lipoprotein levels, as well as increasing the number of hepatic 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 dilatation of the endothelium functions. It has also been described that statins have antioxidant properties that protect mainly from the oxidation of LDL, some of them have an antiplatelet effect platelet and reduce the prothrombotic factors in the plasma. Simvastatin is able to stabilize the atherosclerotic plaque by inducing structural changes thereby decreasing the risk of rupture. The lipid-lowering potency of Simvastatin is determined by the necessary concentration of the drug to inhibit the activity of the enzyme by 50%, which is 11 (IC50) · Rosuvastatin is another inhibitor of H-G CoA reductase that also belongs to the group of statins; however, unlike Simvastatin, it has a high lipid-lowering potency (IC50 of 5), hydrophilic and is endowed with great hepatic selectivity, it is not metabolized in cytochrome P450 3A4, but in 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 decreases the levels of triglycerides and apolipoproteins B. It acts by inhibiting the hepatic synthesis of cholesterol, by blocking the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A (H G-CoA), involved in the synthesis of mevalonic acid, the metabolic precursor of cholesterol. It has high affinity for protein C transporting predominantly hepatic organic anions. In studies carried out in vivo and in vitro, it was found that Rosuvastatin manifests 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 Rosuvastatin are proportional to the dose, 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 after administering 40 mg. of Rosuvastatin in a single oral dose. The absolute bioavailability of Rosuvastatin is approximately 20%. Foods increase their absorption rate by 20%, but the degree of absorption remains unchanged. Rosuvastatin binds reversibly to plasma proteins (88%). He experiences a very limited metabolism, which occurs mainly 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 (biliary excretion). The hydrogenated derivative 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. , a concentration of 60.0 mg being preferably used. at 120.0 mg. per unit dose. The inhibiting agent of the enzyme HMG-CoA reductase used in the pharmaceutical compositions object of the present invention is the active ingredient 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, being preferably used a .0 mg concentration. at 40.0 mg. , and Rosuvastatin is present in the formulation in a concentration range of 5.0 mg. up to 45.0 mg. , a concentration of 5.0 mg being preferably used. up to 10.0 mg. per unit dose. 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. Said pharmaceutical compositions have been developed with the purpose of providing 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 of cholesterol, triglycerides and weight levels. To evaluate the efficiency and tolerance of the pharmaceutical compositions 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 carried out in which the aforementioned active principles, as well as the combination thereof, were administered separately. COMPARATIVE CLINICAL STUDY OF ORLISTAT, SIMVASTATINA AND THE COMBINATION OF ORLISTAT / SIMVASTATIN IN OBESE PATIENTS AND WITH HYPERCHOLESTEROLEMIA. A one-year follow-up randomized study evaluating the effects of Orlistat, Simvastatin and the combination of Orlistat / Simvastatin applied on the lipid profile, body weight and blood pressure of obese patients with hypercholesterolemia was performed. Methods: Patients who were chosen were obese with a Body Mass Index (BMI) > 30 kg / m2; 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). 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 compartment. Group 3: received the combination Orlistat / Simvastatin 1 capsule (120 mg./20 mg., Respectively) in the main meal. The compliance with the treatment was evaluated with the capsule count and with follow-up visits every 3 months. Total cholesterol, LDL-C, HDL-C, Triglycerides and blood pressure during the baseline visit were evaluated in serum. and at 6 months and 12 months of treatment. The waist index was evaluated. Results: 90 patients, 45 women and 45 men were enrolled; 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 above results are listed in table 1.

Table 1. Demographic characteristics of the patients under study (N = 80).

Group 1 Group 2 Group 3 (n = 30) (n = 23) (n = 27) M H M H M H Character. (n = 15) (n = 15) (n = 13) (n = 10) (n = 14) (n = 13) Age 56 (9) 55 (10) 56 (9) 56 (10) 55 (10) 56 (10) Weight (Kg.) 96 (9) 95 (10) 96 (10) 95 (8) 95 (8) 94 (8) Height (cm.) 165 (9) 166 (10) 160 (7) 165 (7) 164 (7) 168 (9) Circumference 99 (7) 96 (7) 98 (9) 97 (3) 100 (7) 99 (6) (cm.) Group 1 = Orlistat; Group 2 = Simvastatin; Group 3 = Orlistat / Simvastatin combination. The values are expressed as averages (DS). There were no significant differences between the groups.

Three patients in Group 1 who received Orlistat presented gastrointestinal adverse events (fecal urgency); however, there was no need to stop treatment. After two weeks of treatment, the gastrointestinal adverse events disappeared. Patients in Group 2 who received Simvastatin did not present alterations in relation to serum transaminases or in the activity of creatine phosphokinase. No adverse events were reported in Group 3 that received the combination of Orlistat / Simvastatin. There were no significant differences in demographic characteristics, lipid profile, body weight, blood pressure within or between groups.

The results showed some variations significant within the groups in the lipid profile (Table 2) from the baseline to 6 months of treatment in Total cholesterol.

Table 2. Comparison of the lipid profile (cholesterol triglycerides (mg / dl), baseline at 6 months and 1 year of treatment.

Component Baseline 6 months 1 year change from baseline to 1 year (% CT Group 1 255 (25) 236 (22) 219 (25) -13.1 * Group 2 258 (23) 198 (21) * 184 (23) -27.0 * 'Group 3 256 (25) 183 (23) ** 169 (27) ** -33.5 * LDL-C Group 1 188 (22) 163 (20) 156 (24) -17.1 * Group 2 192 (24) 150 ( 22) * 107 (22) -33.4 * Group 3 187 (21) 121 (21) ** 106 (22) ** -43.0 * HDL-C Group 1 41 (4) 42 (6) 44 (6) 4.8 Group 2 41 (3) 43 (4) 45 (4) 12.3 * Group 3 40 (3) 47 (4) ** 48 (5) 18.0 *** TG Group 1 139 (35) 117 (23) 97 (21) -30-0 ** Group 2 147 (30) 128 (28) 112 (27) -25.2 * Group 3 145 (29) 117 (25) * 89 (29) -37.5 ** CT = Total cholesterol; Group 1 = Orlistat; Group 2 = Simvastatin; Group 3 = Orlistat / Simvastatin; C-LDL = Low density lipoproteins; HDL-C = high density lipoproteins; TG = Triglycerides. Values expressed as average (DS). * P < 0.05 versus basal. ** P < 0.02 versus basal. *** P < 001 versus basal The results also showed significant differences within the basal groups at 6 months of Treatment: Body Mass Index, Circumference of waist, the above results are listed in table 3.

Table 3. Comparison of body weight (body mass index [BMI]), waist circumference reduction [RCC] and baseline weight loss [PP] at 6 months and 1 year of treatment.

Basal Changes (%) Baseline Measurement 6 Months 1 Year 6 Months 1 Year BMI (kg / m2) Group 1 33.5 (1.5) 30.5 (1.4) 28.5 (1.0) -7.6 * -13.7 ** Group 2 33.4 (1.3) 31.4 (1.4) 29.0 (1.5) -5.8 -12.4 * Group 3 33.7 ( 1.6) 30.5 (1.6) 29.1 (0.9) -8.7 * -15.2 *** RCC (cm.) Group 1 -2.0 (0.8) -4.0 (1.0) -2.0 * -4.5 * Group 2 -1.7 (0.8) -3.3 (1.1) -1.9 -3.6 * Group 3 -3.7 (0.8) -6.0 ( 0.7) *** -3.7 * -5.9 *** PP Group 1 -4.5 (1.3) -8.5 (1.6) -4.7 * -8.4 ** Group 2 -3.8 (1.1) -7.1 (1.2) -3.8 -7.2 * Group 3 -8.0 (1.3) * -13.0 (1.4) * -8.5 * -14.0 *** BMI = Body Mass Index; Group 1 = Orlistat; Group 2 = Simvastatin; Group 3 = Orlistat / Simvastatin; RCC: Reduction of waist circumference; PP = Weight Loss. P < 0.05 versus basal. ** P < 0.02 versus basal. *** P < 0.01 versus basal.

The results showed significant changes in Basal blood pressure at 6 months and 1 year treatment, the above results are listed in table 4 Table 4. Comparison of blood pressure (systolic [SBP] mm Hg and diastolic [DBP] mm Hg) from baseline to 6 months and 1 year of treatment.

Basal Changes (%) Basal Pressure 6 Months 1 Year 6 Months 1 Year Systolic Group 1 132 (4) 131 (3) 127 (3) -1.5 -4.5 * Group 2 135 (4) 131 (4) 127 (4) -2.3 -4.4 * Group 3 134 (5) 127 (4) 122 (4) -3.9 * -7.0 *** Diastolic Group 1 87 (4) 83 (3) 82 (3) -1.1 -4.5 * Group 2 87 (4) 85 (3) 83 (4) -2-2 -4.5 * Group 3 87 (4) 81 (4) 79 (3) ** -2.5 -7.3 *** Conclusions: Orlistat is an anti-obesity agent that inhibits lipases, indicated for long-term management of the obesity and its comorbidities, produces a dose reduction - dependent on the absorption of the fatty diet with a maximum inhibition of fat absorption of 30% at doses of 120 mg. once a day. Simvastatin is an inhibitor of HMG-CoA reductase that produces a substantial reduction of LDL-C, along with a modest increase in HDL-C. It is usually well tolerated as monotherapy with a good profile of safety and efficacy comparable to treatments with fenofibrates. In this study, obese patients with hypercholesterolemia benefited from the administration of Orlistat and Simvastatin independently and from the combination of Orlistat / Simvastatin. 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 / Simvastatin combination showed significantly greater reductions in serum levels of total cholesterol, LDL-C, HDL-C, 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, thus avoiding the manifestation of side effects. On the other hand, the combination reduces the risk of cardiovascular events in obese patients with hypercholesterolemia.

COMPARATIVE CLINICAL STUDY OF ORLISTAT, ROSUVASTATINA AND THE COMBINATION ORLISTAT / ROSUVASTATINA IN OBESE PATIENTS AND WITH HYPERCHOLESTEROLEMIA. A one-year, randomized clinical study evaluating the effects of treatment with Orlistat, Rosuvastatin and the Orlistat / Rosuvastatin combination applied to the lipid profile, body weight and blood pressure of obese patients with hypercholesterolemia was performed. Methods: Patients who were chosen were obese with a Body Mass Index (BMI) >; 30 kg / m2; 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). 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 / mg, respectively) in the main meal. Treatment compliance with capsule counting and follow-up visits every 3 was evaluated months Total cholesterol, LDL-C, HDL-C, Triglycerides and blood pressure were evaluated in serum during the baseline visit and at 6 months and 12 months of treatment. The waist index was evaluated. Results: 90 patients enrolled, 45 women and 4 5 mens; with an average age of 55 years. The 90 completed the study, 4 5 women who were distributed as follows, Group 1: 15; Group 2: 15; Group 3 : 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.

Table 5. Demographic characteristics of the patients under study (N = 80).

Group 1 Group 2 (Group 3 (n = 30) (n = 30) (n = 30) M H M H M H Character. (n = 15) (n = 15) (n = 15) (n = 15) (n = 15) (n = 15) Age 56 (9) 57 (9) 56 (9) 57 (9) 55 (9) 56 (9) Weight (Kg.) 96 (10) 95 (10) 96 (10) 95 (9) 95 (8) 97 (8) Height (cms.) 166 (9) 168 (10) 163 (8) 166 (7) 164 (7) 170 (9) Circumference 99 (8) 97 (7) 98 (9) 99 (3) 100 (7) 99 (6) Group 1 = Orlistat; Group 2 = Rosuvastatin; Group 3 = Orlistat / Rosuvastatin combination. The values are expressed as averages (DS). There were no significant differences between the groups.

Two patients in Group 1 who received Orlistat presented gastrointestinal adverse events (fecal urgency); however, there was no need to suspend the treatment. After two weeks of treatment, the gastrointestinal adverse events disappeared. The patients in Group 2 who received Rosuvastatin did not present alterations in relation to serum transaminases or in the activity of creatine phosphokinase. No adverse events were reported in Group 3 that received the combination of Orlistat / Rosuvastatin. There were no significant differences in demographic characteristics, lipid profile, body weight, blood pressure within or between groups. The results showed some significant variations within the groups in the lipid profile (Table 6) of the baseline at 6 months of total cholesterol treatment: Table 6. Comparison of the lipid profile (cholesterol triglycerides (mg / dl), baseline at 6 months and 1 year of treatment.

Component Baseline 6 months 1 year change of year% CT Group 1 254 (25) 235 (22) 221 (25) -13.3 * Group 2 260 (23) 199 (21) * 186 (23) -27.5 ** Group 3 258 (24) 180 (23) ** 160 (29) ** -35.5 *** C-LDL Group 1 186 (21) 164 (21) 154 (23) -17.3 * Group 2 195 (25) 152 (22) * 109 (23) -33. ** Group 3 189 (22) 120 (21) ** 102 (23) ** -45.0 *** C-HDL Group 1 40 (3) 43 (5) 44 (6) 4.9 Group 2 40 (3) 44 (5) 45 (5) 12.4 ** Group 3 40 (3) 48 (5) ** 50 (6) 20.0 * ***** TG Group 1 140 (36) 119 (24) 98 (22) -30-7 * Group 2 145 (31) 126 (29) 111 (28) -25.5 * Group 3 149 (28) 112 (24) * 83 ( 27) -40.0 * The results also showed differences significant within the groups of the baseline to 6 months of Treatment: Body Mass Index, Circumference of waist, these results are listed in table 7.

Table 7. Comparison of body weight (body mass index [BMI], waist circumference reduction [RCC] and baseline weight loss [PP] at 6 months and 1 year of treatment.

Basal Changes (%) Baseline Measurement 6 Months 1 Year 6 Months 1 Year BMI (kg / m2) Group 1) 33.7 (1.5) 30.3 (1 .4) 27.5 (1 .3) -7.8 * -13.9 ** Group 2 33.6 (1.5) 31.0 (1 .3) 29.2 (1 .4) -5.9 -12.5 * Group 3 33.9 (1.5) 30.1 (1 .4) 28.1 (0.8) -8.9 * -15.9 *** RCC (cm.) Group 1 -2.1 (0.7) -4.1 (1 .1) -2.1 * -4.6 * Group 2 -1.5 (0.7) -3.1 (1 .1) -1.8 -3.7 * Group 3 -3.9 (0.9 ) -6.5 (0.9) *** -3.9 * -6.1 *** PP Group 1 -4. (1.2) -8.6 (1.5) -4.8 * -8.5 ** Group 2 -3.7 (1.1) -7.3 (1.2) -3.9 -7.5 * Group 3 -8.5 (1.4) * -13.5 (1.5) * -8.8 * -14.6 *** BMI = Body Mass Index; Group 1 = Orlistat; Group 2 = Rosuvastatin; Group 3 = Orlistat / Rosuvastatin; RCC Reduction of waist circumference; PP = Weight Loss. P < 0.05 versus basal. ** P < 0.02 versus basal. ** "P <0.01 versus baseline.

The results showed significant changes in Basal blood pressure at 6 months and 1 year treatment, these results are listed in Table 8.

Table 8. Comparison of blood pressure (systolic [SBP] mm Hg and diastolic [DBP] mm Hg) from baseline to 6 months and 1 year of treatment.

Basal Changes,% Basal Pressure 6 Months 1 Year 6 Months 1 Year Systolic Group 1 133 (4) 131 (3) 128 (3) -1.6 -4.6 * Group 2 136 (4) 131 (4) 126 (4) -2.5 -4.5 * Group 3 136 (5) 125 (4) 120 (4) -4.0 * -7.9 *** Diastolic Group 1 88 (3) 82 (3) 81 (3) -1.2 -4.4 * Group 2 86 (4) 85 (4) 83 (3) -2-1 -4.4 * Group 3 87 (3) 80 (4) 76 (4) ** -2.7 -7.7 *** Conclusions: Orlistat is an antiobesity agent inhibitor of lipases, 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. % at a dose of 120 mg. once a day. Rosuvastatin is an inhibitor of HMG-CoA reductase that produces a substantial reduction of LDL-C, together with a modest increase in HDL-C. It is generally well tolerated as monotherapy with a good safety and efficacy profile, with more power than Simvastatin.

In this study, obese patients with hypercholesterolemia benefited from the administration of Orlistat and Rosuvastatin independently and from the Orlistat / Rosuvastatin combination. 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, LDL-C, HDL-C, triglycerides, Body Mass Index, Waist Circumference, and Weight Loss. There was also a small but significant difference found in blood pressure. The use of the combination allows to reduce the doses administered in the patients, avoiding with this 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 principles and the administered doses thereof are lower than when they are administered individually.

Claims (9)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, what is contained in the following is claimed as property.
2. CLAIMS 1. - Pharmaceutical compositions characterized by being composed of the synergistic combination of a hydrogenated derivative of lipstatin, such as the active ingredient: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, as are 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 from 5.0 to 10.0 mg; They 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. - Pharmaceutical composition according to claim 1, characterized by being composed of the synergistic combination of a hydrogenated derivative of lipstatin, such as the active ingredient: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, such as the active ingredient: Simvastatin, which is formulated in a single unit of dosage.
3. 3. - Pharmaceutical composition according to claims 1 and 2, characterized in that the hydrogenated derivative 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. , a concentration of 120.0 mg being preferably used. and the enzyme inhibitor of the HMG-CoA reductase enzyme, such as the active ingredient: Simvastatin, is present in the formulation in a concentration range of 20.0 mg. at 40.0 mg. , a concentration of 20.0 mg being preferably used. , per dosage unit.
4. 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 the form of a capsule or tablet.
5. 5. Pharmaceutical composition according to claims 1 to 4, characterized by being indicated for the prevention and / or treatment of the hypercholesterolemia, triglyceridemia, overweight and obesity.
6. 6. - Pharmaceutical composition according to claim 1, characterized by being composed of the synergistic combination of a hydrogenated derivative of lipstatin, such as the active ingredient: Orlistat and an inhibitor of the enzyme HMG-CoA reductase, such as is the active ingredient: Rosuvastatin, which is formulated in a single dosage unit.
7. 7. - Pharmaceutical composition according to claims 1 and 6, characterized in that the hydrogenated derivative 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. , a concentration of 60.0 mg being preferably used. and 120.0 mg. and the inhibiting agent of the HMG-CoA reductase enzyme, such as the active ingredient: Rosuvastatin, is present in the formulation in a concentration range of 5.0 to 10.0 mg. , a concentration of 10.0 mg being preferably used. , per dosage unit.
8. 8. - Pharmaceutical composition according to claims 1, 6 and 7, characterized by being formulated in a single dose unit to be administered orally in the form of a tablet or capsule.
9. 9. - Pharmaceutical composition according to claims 1, 6, 7 and 8, characterized by being indicated for the prevention and / or treatment of hypercholes erolemia, triglyceridemia, overweight and obesity.