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WO2008143491A1 - COMPOSITIONS PHARMACEUTIQUES COMPRENANT UNE COMBINAISON D'UN AGENT DÉRIVÉ HYDROGÉNÉ DE LIPSTATINE ET D'UN AGENT INHIBITEUR DE HMG-CoA RÉDUCTASE - Google Patents

COMPOSITIONS PHARMACEUTIQUES COMPRENANT UNE COMBINAISON D'UN AGENT DÉRIVÉ HYDROGÉNÉ DE LIPSTATINE ET D'UN AGENT INHIBITEUR DE HMG-CoA RÉDUCTASE 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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WIPO (PCT)
Prior art keywords
group
orlistat
hmg
simvastatin
coa reductase
Prior art date
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Ceased
Application number
PCT/MX2008/000062
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English (en)
Spanish (es)
Inventor
Leopoldo de Jesús ESPINOSA ABDALA
María Elena GARCÍA ARMENTA
Josefina Santos Murillo
Victor Guillermo Alvarez Ochoa
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Individual
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Priority to ARP080102158A priority Critical patent/AR066667A1/es
Publication of WO2008143491A1 publication Critical patent/WO2008143491A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne diverses compositions pharmaceutiques renfermant une combinaison synergique d'un agent dérivé hydrogéné de lipstatine, tel que le principe actif orlistat, et d'un agent inhibiteur de l'enzyme HMG-CoA réductase, tel que les principes actifs simvastatine et/ou rosuvastatine, ainsi que des excipients pharmaceutiquement acceptables. Ces compositions sont formulées en une seule unité de dosage en vue d'une administration par voie orale, et sont indiquées dans la prévention et/ou le traitement de l'hypercholestérolémie, de la triglycéridémie, du surpoids et de l'obésité.
PCT/MX2008/000062 2007-05-21 2008-05-19 COMPOSITIONS PHARMACEUTIQUES COMPRENANT UNE COMBINAISON D'UN AGENT DÉRIVÉ HYDROGÉNÉ DE LIPSTATINE ET D'UN AGENT INHIBITEUR DE HMG-CoA RÉDUCTASE Ceased WO2008143491A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
ARP080102158A AR066667A1 (es) 2007-05-21 2008-05-21 Composiciones farmaceuticas que comrenden la combinacion de un agente derivado hidrogenado de lipstatina y un agente inhibidor de hmg coa reductasa

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2007006092A MX2007006092A (es) 2007-05-21 2007-05-21 Composiciones farmaceuticas que comprenden la combinacion de un agente derivado hidrogenado de lipstatina y un agente inhibidor de hmg-coa reductasa.
MXMX/A/2007/006092 2007-05-21

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WO2008143491A1 true WO2008143491A1 (fr) 2008-11-27

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AR (1) AR066667A1 (fr)
MX (1) MX2007006092A (fr)
UY (1) UY31096A1 (fr)
WO (1) WO2008143491A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110314232A (zh) * 2019-08-03 2019-10-11 黄泳华 由脂肪酶抑制剂与羟甲戊二酰辅酶a还原酶抑制剂构成的组合物
CN110357812A (zh) * 2019-08-03 2019-10-22 黄泳华 由脂肪酶抑制剂与羟甲戊二酰辅酶a还原酶抑制剂构成的共晶复合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004066963A2 (fr) * 2003-01-17 2004-08-12 Merck & Co., Inc. Derives de n-cyclohexylaminocarbonyl benzenesulfonamide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004066963A2 (fr) * 2003-01-17 2004-08-12 Merck & Co., Inc. Derives de n-cyclohexylaminocarbonyl benzenesulfonamide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DEROSA G. ET AL., CURRENT THERAPEUTIC RESEARCH, vol. 63, no. 9, September 2002 (2002-09-01), pages 621 - 633 *
ROBLES TORRES F.J. ET AL.: "EFICACIA DEL ORLISTAT ASOCIADO A SIMVASTATINA EN PACIENTES CON DISLIPIDEMIA MIXTA", REV. MED. CARDIOL., vol. 13, no. 3, 2002, pages 102, XP003024091 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110314232A (zh) * 2019-08-03 2019-10-11 黄泳华 由脂肪酶抑制剂与羟甲戊二酰辅酶a还原酶抑制剂构成的组合物
CN110357812A (zh) * 2019-08-03 2019-10-22 黄泳华 由脂肪酶抑制剂与羟甲戊二酰辅酶a还原酶抑制剂构成的共晶复合物

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UY31096A1 (es) 2008-11-28
MX2007006092A (es) 2009-02-25
AR066667A1 (es) 2009-09-02

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