MXPA06009500A - Pharmaceutical compositions comprising higher primary aliphatic alcohols and hmg coa reductase inhibitor and process of preparation thereof - Google Patents

Abstract

A novel pharmaceutical composition comprising a mixture of higher primary aliphatic alcohols from (24) to (39) carbon atoms;at least one another component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds, and HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof, preferably statins, optionally with pharmaceutically acceptable excipients, and process of preparation of such composition is provided. Also provided are method of treatment and use of such composition for reducing abnormal lipid parameters associated with hyperlipidemia.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ALCOHOLS PRIMARY PRIMARY ALIFATICS AND INHIBITOR OF 3-HIDROX1-3- METILGLUTARILO CO-ENZYME TO REDUCTASE AND PROCEDURE FOR THE PREPARATION OF THE SAME FIELD OF THE INVENTION The present invention relates to novel pharmaceutical compositions comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds, and HMG CoA reductase inhibitor, its salts, analogues or derivatives thereof optionally with pharmaceutically acceptable excipients, and methods for the preparation of said composition. The method of treatment and the use of said composition for the reduction of abnormal lipid parameters associated with hyperlipidemia are also described. Particularly, the present invention relates to compositions and methods for the decrease of the total level of cholesterol and triglycerides (TGs) or the raising of the level of high density lipoprotein cholesterol (HDL-C) in the blood of a mammal.

BACKGROUND OF THE INVENTION High serum cholesterol levels (> 200 mg / dL) have been indicated as an important risk factor for heart disease, the leading cause of death worldwide. Atherosclerotic vascular diseases, especially coronary heart disease (CHD), are the main cause of morbidity and mortality in middle-aged and elderly people worldwide (Pyorala et al., 1994, Sans et al., 1997). Therefore, the primary and secondary prevention of morbidity and death from CHD represents a major problem in health care. However, the use of currently available inhibitors of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG CoA) reductase such as statins and fibrates should be used with caution especially for the population of patients with increased susceptibility to adverse effects. related to the drug and frequent consumption of several concomitant medications, such as elderly patients, patients with active liver diseases, etc. In addition, these drugs that decrease lipids are associated with adverse effects such as gastrointestinal alterations, increases in serum transaminases and creatinine kinase, myopathies, headache, cholelithiasis, impaired fertility, and decreased libido. Due to the fact that drugs that lower cholesterol must be administered on a long-term basis, There is a need for effective and well-tolerated novel hypocholesterolemic agents. The regulation of cholesterol homeostasis throughout the body in humans and animals includes the regulation of dietary cholesterol and the modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of lipoproteins in plasma containing cholesterol. The liver is the main organ responsible for cholesterol biosynthesis and catabolism, and for this reason it is a primary determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the predominant lipoproteins that carry cholesterol in the plasma and an increase in their concentration correlates with an increase in atherosclerosis. It has been documented that long chain aliphatic alcohols derived from plants reduce serum cholesterol levels in experimental models, and in type II hypercholesterolemic patients. The mixture of higher primary aliphatic alcohols has been employed in the treatment of elevated serum cholesterol levels. In recent years it has been shown that these mixtures promise a lot, as has been reported in numerous clinical trials published in humans. The mechanism of action of these mixtures is unknown, but several studies have revealed that these mixtures inhibit cholesterol biosynthesis, increase the number of LDL-C receptors, thus decreasing the levels of TC, LDL-C in serum and increasing HDL levels (Menendez et al., 1994). The patent of E.U.A. 5,856,316 describes a process for obtaining the mixture of higher primary aliphatic alcohols; from sugar cane wax and its use in the treatment of hypercholesterolemia. Said mixture from the sugar cane wax comprises a mixture of aliphatic alcohols of 24 to 34 carbon atoms and these were effective hypocholesterolemic agents administered in a daily dose of 1 to 100 mg. The publication of E.U.A. No. 20030232796 relates to compositions in the form of nanoparticles comprising particles of at least one mixture of concentrated n-alkyl alcohols or a salt thereof, wherein the particles have an effective average particle size of less than about 2000 nm; and at least one surface stabilizer preferably selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a surface zwitterionic stabilizer, and a surface ionic stabilizer. The additionally described compositions comprise one or more active agents that result from the group comprising cholesterol lowering agents such as statins; although no description has been made by way of examples for the preparation of said composition. However, said compositions in the form of nanoparticles are difficult to formulate and the particle size of the active agent becomes crucial for adequate bioavailability and mainly becomes a limiting aspect. PCT Publication No. WO 0390547 relates to compositions comprising an acidic serous component consisting of at least one acidic serous element with 23 to 50 carbon atoms and / or derivatives thereof and 0 to 99.99% by weight of at least a component with properties that affect the level of serum cholesterol and 0 to 20% by weight of at least one auxiliary for pharmaceutically acceptable formulation. The mechanism of action of the mixture of higher primary aliphatic alcohols is unknown, but in vitro studies revealed that the mixture of higher primary aliphatic alcohols inhibits the biosynthesis of cholesterol in a step located between the consumption of acetate and the production of mevalonate. In addition, in vitro studies also showed that these mixtures increase the number of LDL-C receptors (Menendez et al., 1994). This explains the ability of the mixture of higher primary aliphatic alcohols not only to decrease the total cholesterol level, but also to lower serum LDL levels and increase HDL levels. In vivo studies in correlation with in vitro studies showed that these mixtures inhibited TC and LDL-C levels induced by the atherogenic diet suggesting a possible inhibition of cholesterol biosynthesis (Menendez et al., 1996). In addition, the administration of these mixtures to diabetic patients significantly reduced the levels of TC and LDL-C in the blood (Omayda Torres et al., 1995). HMG CoA reductase inhibitors, commonly known as statins, are the competitive inhibitors of HMG CoA reductase, which catalyze an early, rate-limiting step in cholesterol biosynthesis in the liver. These can also reduce the levels of TGs caused by high levels of VLDL-C. They also increase the expression of the LDL receptor gene, improve transcription, and ultimately increase the synthesis of LDL receptors, and reduce the degradation of LDL receptors on the surface of hepatocytes that results in an increased removal of LDL. from the blood. In addition, these also reduce the level of LDL by improving the removal of LDL precursors and by reducing the synthesis of cholesterol, a required component of the VLDL and TGs therefore decreasing the production of TGs and the liver production of VLDL. However, the use of statins is frequently associated with rhabdomyolysis and hepatoxicity (Durrington and Lllingworth, 1998). It can be observed from the scientific literature that there is still a need for the development of novel drugs or combinations of existing antihyperlipidemic agents with possible additive, potentiating, or synergistic action and a method of administration which could provide a balanced alteration of the lipid by example reductions in TC, LDL-C, TGs, and apolipoprotein a (Lp (a)) as well as increases in HDL-C, with an acceptable safety profile, especially with respect to liver toxicity and effects on glucose metabolism and uric acid levels in hyperlipidemic patients; and which are effective in cost and easy to formulate; but still they are beneficial.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide novel pharmaceutical compositions comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms of 2 to 99.9% by weight of the composition; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of HMG CoA reductase, its salts, analogs or derivatives thereof substantially lacking in any serous acid, optionally with pharmaceutically acceptable excipients from 0 to 99.9% by weight of the composition. It is an object of the present invention to provide a novel pharmaceutical composition comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms from 2 to 99.9% by weight of the composition; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of the HMG CoA reductase, its salts, analogs or derivatives thereof, preferably statins, substantially free of any serous acid, optionally with pharmaceutically acceptable excipients from 0 to 99.9% by weight of the composition. It is an object of the present invention to provide a process for the preparation of said composition which comprises the following steps: i) isolating the wax, ii) subjecting the wax to extraction with a liquid organic extractor in which the primary aliphatic alcohols and other organic components are soluble, iii) recovering said soluble mixture from said extractor, iv) purifying the extract by repeated washing and crystallization, v) drying the extract and making it into a powder form, vi) adding the HMG inhibitor. CoA reductase, its salts, analogs or derivatives, vii) optionally add pharmaceutically acceptable excipients and process them into a suitable dosage form. It is even another object of the present invention to provide a method for the reduction of serum cholesterol level, and the treatment of hyperlipidemia, which comprises the administration of a composition comprising a mixture of higher primary aliphatic alcohols of from 24 to 39 carbon atoms from 2 to 99.9% by weight of the composition; at least another organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of HMG CoA reductase, its salts, analogs or derivatives thereof , substantially lacking any serous acid, optionally with pharmaceutically acceptable excipients from 0 to 99.9% by weight of the composition. The compositions of the present invention preferably have a synergistic effect for the reduction of serum cholesterol level in mammals.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pharmaceutical composition comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms from 2 to 99.9% by weight of the composition; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of HMG CoA reductase, its salts, analogs or derivatives of them, preferably statins. The compositions of the present invention are substantially devoid of any serous acid, optionally with pharmaceutically acceptable excipients from 0 to 99.9% by weight of the composition. The mixture of higher primary aliphatic alcohols in the present invention is selected from, but is not limited to a group comprising 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-octacosanol, 1- nonacosanol, 1-tetratriacontanol, 1-triacontanol, 1-hexacontanol, eicosanol, 1-hexacosanol, 1-tetracosanol, 1-dotriacontanol, 1-tetracontanol, and the like. Preferably the mixture of higher primary aliphatic alcohols comprises 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-octacosanol, and 1-triacontanol. In a further embodiment, the present invention provides a composition, wherein the mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms comprising 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-octacosanol, and 1-triacontanol is present as at least 40% by weight of the composition. In a further embodiment, the present invention provides a composition, wherein the ratio of the mixture of higher primary aliphatic alcohols and the HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof is from 20: 1 to 1: twenty. In another embodiment of the present invention, the mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms and the other organic component (s) selected from the resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds comprises the following: 1-tetracosanol 0.0-2.0% 1-hexacosanol 0.2-2.0% 1-heptacosanol 0.0-1.0% 1-octacosanol 30.0-40.0% 1-triacontanol 6.0- 9.5% Resins and pigments 5.0-10.0% Hydrocarbons 1.0-10.0% Esters 1.0-10.0% Ketones and aldehydes 1.0-10.0% Phenolic compounds 0.0-5.0% In even a further embodiment of the present invention, the mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms and the other organic component (s) selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, phytosterols, and phenolic compounds comprises the following: 1-tetracosanol 0.0-2.0% 1-hexacosanol 0.2-2.0% 1-heptacosanol 0.0-1.0% 1-octacosanol 30.0-40.0% 1-triacontanol 6.0-9.5% Phytosterols 0.1-1.0% Resins and pigments 5.0-10.0% Hydrocarbons 1.0-10.0% Esters 1.0-10.0% Ketones and aldehydes 1.0-10.0% Phenolic compounds 0.0-5.0% The mixture of high molecular weight aliphatic alcohols of the present invention occurs naturally in a serosa form and they are characterized by fatty alcohol chains having from 20 to 39 carbon atoms in length. The main components of said mixture are the aliphatic alcohols 1-octacosanol and 1-triacontanol, and the component includes 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-octacosanol, 1-nonacosanol, 1-tetratriacontanol, 1-triacontanol, 1-hexacontanol, eicosanol, 1- hexacosanol, 1-tetracosanol, 1-dotriacontanol, 1-tetracontanol, and the like; and other organic components such as resins and pigments, hydrocarbons, esters, ketones and aldehydes, phytosterols, phenolic compounds, and the like. Said mixture of high molecular weight aliphatic alcohols and other organic components of the present invention are preferably isolated from numerous different sources, including sugarcane wax, beeswax, and rice bran wax, more preferably cane wax of sugar. However, it should be understood that the invention is not limited in this respect and that said mixture of high molecular weight aliphatic alcohols commonly available from other sources that occur naturally and from synthetic sources can be used.

Most HMG CoA reductase inhibitors are produced by fermentation using microorganisms from different species identified as species belonging to the genus Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium, some are obtained by treating the fermentation products using the chemical synthesis methods or are the products of the total chemical synthesis. The present invention relates to novel compositions comprising the mixture of high molecular weight aliphatic alcohols and an inhibitor of HMG CoA reductase, wherein the compounds can be from a natural source and can also be analogs or salts of a subsequent biotechnological modification of the semi-synthetic and synthetic preparation of the HMG CoA reductase inhibitors. In one embodiment, the present invention employs statin or a compound other than the statin itself that the body metabolizes to statin, thus producing the same effect as described in the present invention. The other compounds include cholesterol lowering agent (s), preferably HMG CoA reductase inhibitors, which are selected from, but not limited to the following: pravastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, and the like, or their salts, analogs or derivatives thereof. Each of said compounds will be collectively referred to in the present invention as "statin".

The mixture of higher primary aliphatic alcohols and the statin decreases serum cholesterol levels by two independent and unrelated mechanisms of action. Interestingly, when the mixture of higher primary aliphatic alcohols and the statin are combined within a composition, a significant synergistic effect is observed. The mixture of higher primary aliphatic alcohols inhibits a localized passage between acetate consumption and mevalonate production while statins inhibit HMG CoA reductase, a key enzyme in cholesterol biosynthesis, respectively, in the liver and both agents increase the number of LDL-C receptors in the liver. In addition, statins act through multiple mechanisms on lipid metabolism in the liver thus decreasing the levels of TGs, VLDL, apoB, and increasing the level of HDL-C. Therefore, the combination of both agents within a particular composition provides a more effective treatment for high serum cholesterol level compared to what would be expected from the additive effect of both compounds provided separately. In one embodiment, the present invention provides pharmaceutical compositions suitable for lowering the levels of LDL-C and TGs or for raising the level of HDL-C in the blood of a mammal or both, by incorporating a combination of the mixture of alcohols high molecular weight aliphatics, and at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds; with the HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof within certain suitable dosage forms such as tablets or capsules or both which may also comprise a pharmaceutically acceptable excipient (s) such as a coloring agent, antioxidant , binder, stabilizer, and the like. The present invention provides processes for the preparation of a fixed dose combination comprising the mixture of high molecular weight aliphatic alcohols, and at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds; with the HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof optionally with pharmaceutically acceptable excipients, which may be formulated as oral dosage forms such as tablets, pills, capsules, gels, finely divided powders, dispersions, suspensions, solutions, emulsions, etc; forms for pulmonary and nasal doses such as sprays, aerosols, etc .; topical dosage forms such as gels, ointments, creams, etc; parenteral dosage forms; controlled release formulations; fast melt formulations, lyophilized formulations, delayed release formulations, sustained release formulations, extended release formulations, pulse release formulations, and immediate release mixed formulations and controlled release formulations. The compositions of the present invention can be formulated for administration by the route selected from group consisting of oral, pulmonary, rectal, colonic, parenteral, local, buccal, nasal, and topical route. In one embodiment of the present invention, the compositions can preferably be incorporated into compositions in the form of capsules. These capsules may also comprise pharmaceutically acceptable excipients such as diluents, antioxidants, coloring agents, stabilizers, and the like. The composition may also be provided in the form of tablets comprising a combination of the mixture of high molecular weight aliphatic alcohols, and at least one other organic component selected from the resins and pigments., hydrocarbons, esters, ketones and aldehydes, and phenolic compounds with ezetimibe, its salts, analogues or derivatives thereof which may also comprise excipients such as diluents, coloring agents, antioxidants, binders, stabilizers, and the like. In one embodiment of the present invention, the composition in the form of tablets / capsules or any other suitable dosage form is intended for lowering the level of LDL-C or raising the level of HDL-C in mammals. In one embodiment of the present invention, the ratio of the mixture of higher primary aliphatic alcohols or esters thereof and of the HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof is from 20: 1 to 1: twenty.

In a further embodiment, the composition comprising a mixture of a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms comprising 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-octacosanol, and 1-triacontanol; phytosterols; resins and pigments; hydrocarbons; esters; ketones and aldehydes; and phenolic compounds with the HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof, optionally comprises pharmaceutically acceptable excipients. In a further embodiment, the pharmaceutically acceptable excipients are selected from, but not limited to, a group comprising diluents, disintegrants, fillers, dough forming agents, vehicles, pH adjusting agents, stabilizers, anti-oxidants, binders, pH regulators, lubricants, anti-adherents, coating agents, preservatives, emulsifiers, suspending agents, release control agents, polymers, colorants, flavoring agents, plasticizers, solvents, preservatives, glidants, chelating agents and the like; used either alone or in combination with them. In the present invention, the diluent is selected from, but is not limited to a group comprising lactose, cellulose, microcrystalline cellulose, mannitol, dicalcium phosphate, pregelatinized starch, and the like, used either alone or in combination with the same.

In the present invention, the binder is selected from, but is not limited to a group comprising polyvinylpyrrolidone, cellulose derivatives such as hydroxypropyl methylcellulose, methacrylic acid polymers, acrylic acid polymers, and the like. The release control agents and / or polymers of the present invention comprising at least one release controlling polymer are selected from, but not limited to a group comprising polyvinylpyrrolidone / polyvinylacetate copolymer (Kollidon® SR), methacrylic acid polymers, acrylic acid polymers, cellulose derivatives, and the like. The methacrylic acid polymer is selected from a group comprising but not limited to Eudragit® (Degussa) such as ammonium methacrylate copolymer type A USP (Eudragit® RL), ammonium methacrylate copolymer type B USP (Eudragit® RS), Eudragit® RSPO, Eudragit® RLPO, and Eudragit® RS30D. In one embodiment, the lubricant (s) used in the present invention is selected from, but is not limited to, a group comprising stearic acid, magnesium stearate, zinc stearate, glyceryl behenate, ketoestearyl alcohol, hydrogenated vegetable oil, and the similar ones used either alone or in combination with them. In a further embodiment, the pharmaceutically acceptable excipients are present in about 0.5-80.0% by weight of the composition.

In a further embodiment of the present invention, a process for the preparation of a composition which comprises the following steps: i) isolating the wax, ii) subjecting the wax to extraction with a liquid organic extractor in which the primary aliphatic alcohols and other organic components are soluble, iii) recover said soluble mixture from said extractor, iv) purify the extract by repeated washing and crystallization, v) dry the extract at temperature preferably below 70 ° C and processed into a powder form, vi) adding the HMG CoA reductase inhibitor, its salts, analogues or derivatives, vii) optionally adding pharmaceutically acceptable excipients and working them into a suitable dosage form. The wax is preferably isolated from numerous different sources, including sugar cane wax, beeswax, and rice bran wax, more preferably sugar cane wax. The liquid organic extractor of the present invention is selected from, but is not limited to a group comprising hexane, heptane, petroleum ether, chlorinated hydrocarbons, methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, ethyl methyl ketone. , and the like, or mixtures thereof.

In said process, the soluble mixture from said extractor is recovered by distillation, with or without the application of vacuum. The extract is preferably purified by repeated washing and crystallization. The solvents used for washing are selected from, but not limited to hexane, heptane, petroleum ether, methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, ethyl methyl ketone, and the like, or mixtures thereof. and the solvents for crystallization are selected from, but not limited to, hexane, heptane, petroleum ether, chlorinated hydrocarbons, methanol, ethanol, ethylpropyl alcohol, ethyl acetate, acetone, ethyl methyl ketone, toluene, and the like. similar, or mixtures thereof. The extract is dried by subjecting it to a hot air oven, or by a fluid bed dryer, preferably at a temperature below 70 ° C. The present invention also provides a method for the reduction of serum cholesterol level, and the treatment of hyperlipidemia, which comprises administering a composition comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms from 2 to 99.9 % by weight of the composition; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of HMG CoA reductase, its salts, analogs or derivatives thereof, substantially lacking any serous acid, optionally with excipients from 0 to 99.9% by weight of the composition. The compositions of the present invention preferably have a synergistic effect for the reduction of serum cholesterol level, and for the treatment of hyperlipidemia, particularly in mammals. The ability of the mixture of higher primary aliphatic alcohols to inhibit the synthesis of cholesterol and the HMG CoA reductase inhibitor, its salts, analogs or derivatives thereof to decrease the level of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), TGs, and lipoprotein (a) (Lp (a)) while increasing HDL-C; when combined in the present invention it preferably results in a synergistic effect for the decrease of serum cholesterol. In one embodiment, the compositions for lowering the level of LDL-C or for raising the level of HDL-C in the blood of a mammal or both, comprise a mixture of higher primary aliphatic alcohols, and at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds; with the HMG CoA reductase inhibitor, its salts, analogues or derivatives thereof, and a method for lowering the level of LDL-C and / or TGs or for raising the level of HDL-C in the blood of a mammal or both, comprises the oral administration to said mammal, of said compositions. In one aspect of the present invention, lipid lowering compositions comprise a mixture of aliphatic alcohols higher primary; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds; and HMG CoA reductase inhibitor, its salts, analogues or derivatives thereof are associated with a reduction in the dose of the HMG CoA reductase inhibitor, its salts, analogues or derivatives thereof and increase compliance of the patient. In the present invention, the mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms; and other organic components such as resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds; they are denoted as "Extract-A".

Determination of biological activity Hypercholesterolemia induced by casein-starch in rabbits The observed effect of synergistic lipid decrease in an unexpected way by the combination of extract-A and atorvastatin is evidenced by the test performed in rabbits. Rabbits of either sex were procured from the installation of Central Animal House; Panacea Biotec Ltd., India. Animals weighing 1.5-2.0 Kg were used at the time of the test. All the animals were dosed sequentially by the oral route with extract-A and / or atorvastatin suspended in 0.5% carboxymethyl cellulose (CMC). A dosing volume of 2 ml / kg was used for each sequential suspension.

The fasting profile of serum lipids (TC, TGs, LDL-C, HDL-C) was estimated before the start of the experiment. The total duration of the study was 90 days. Hypercholesterolemia was induced by feeding the rabbits with a wheat-starch casein diet (g / kg) containing 333 wheat flour, 300 cellulose, 270 casein, 20 water, 10 corn oil, and mineral mixture (Kroon et al., 1982) for 60 days. The feed intake was restricted to 100 g / day per animal. The cholesterol level was estimated every 15 days. After 60 days the animals with total cholesterol level > 150 mg / dl were taken at random for the treatment (n = 6 / group). Subsequently, various doses of extract-A and / or atorvastatin were administered for a further 60 days during which time the animals were fed a casein-starch diet. Blood samples were collected from fasting rabbits and analyzed for any alteration in the serum lipid profile after 60 days of administration of the test compound (s). All data are expressed as means ± S.E.M. (standard error of the average). Student's t test was used to compare lipid parameters between animals fed a standard diet and fed a hypercholesterolemic diet. The difference between the groups treated with various drugs was analyzed by ANOVA followed by the Dunnett test. A value of P < 0.05 was considered statistically significant. Rabbits fed a hypercholesterolemic diet for 60 days produced an increase in the level of total cholesterol in serum and in the LDL-C level in a time dependent manner. Extract-A (100 and 200 mg / kg, p.o.) and atorvastatin (2.5 and 5 mg / kg, p.o.) reversed TC and LDL-C levels compared to hypercholesterolemic control rabbits. The lower doses of extract-A (100 and 200 mg / kg) and atorvastatin (2.5 and 5 mg / kg) administered in combination resulted in a synergistic reduction in TC and LDL-C levels (Figures 1 and 2; 1 and 2). There was no significant change in the body weight of the animals fed the casein-starch diet compared to the initial body weight. The data for the study are presented in tables 1 and 2, and shown in diagram in figures 1 and 2.

TABLE 1 Effect of extract-a and / or atorvastatin alone or in combination on total serum cholesterol levels in rabbits CNT: Control; At: Atorvastatin * P < 0.05 compared to the control (CNT); aP < 0.05 compared to extract-A 100 and 200 mg / kg, p. or., atorvastatin (At) 2.5 and 5 mg / kg, p. or TABLE 2 Effect of extract-A v / o atorvastatin alone or in combination on the LDL-C level in rabbits * P < 0.05 compared to the control (CNT); aP < 0.05 compared to extract-A 100 and 200 mg / kg, p. or., atorvastatin (At) 2.5 and 5 mg / kg, p.o.

BRIEF DESCRIPTION OF THE FIGURES Figure 1: Effect of the extract-Ay / o atorvastatin alone or in combination on the total serum cholesterol level in rabbits Figure 2: Effect of the extract-A and / or atorvasiafin alone or in combination on the LDL-C level in rabbits The examples provided below serve to illustrate the modalities of the present invention. However, these are not intended to limit the scope of the present invention.

EXAMPLES Extraction Preparation EXAMPLE 1 4 kg of sugar concentrated in the ground filter, dried in the air (or in the press for sludge) were obtained as a by-product during the elaboration of sugar from cane sugar, pulverized and expelled four times by boiling with 20 L of dichloroeanum each time. The dichloroethane extract was filtered and the solvent was filed to obtain a dark green residue (400 g). The residue was extracted with 4 L of boiling meianol 3 times and the extract was filtered to remove the alkylamine.

Meanwhile, it was still warm (temperature above 50 ° C). The filigreed extract was filed to remove the melanol until a green residue (200 g) was obluded. The residue was dissolved in 2 L of boiling methyl ethyl ketone and allowed to stand for crystallization. After the crystallization completes the solvent is filtered, he concentrated himself on the mifad of his volume by means of desylation, and he let himself rest for the second harvest of the chrysalis. Both crops were pooled and washed with cold hexane. Chilling and washing procedures were repeated once more. The final washed chrysolics were dried under a stream of air at a temperature not exceeding 70 ° C. The resulting creamy yellow lumps were pulverized to a fine powder (50 g).

EXAMPLE 2 The beeswax obtained after the extraction of the honey from the honeycomb was dried and pulverized and exfoliated every few times by boiling with ethyl alcohol each time. The alcoholic filtrate was filtered and the solvent was desilylated to obtain a residue. The residue was boiled with boiling meianol 3 times and the extract was filtered to remove the alkylan while still hot (temperature greater than 50 ° C). The filigreed extract was deionized to remove the melanol until a green residue was obfuscated. The residue was dissolved in boiling fuel oil and allowed to stand for chilling. After complete crystallization the solvenite was filtered, He concentrated his vision on the volume of medium desirability and allowed himself to rest for the second harvest of crisisation. Both crops were pooled and washed with cold hexane. Chilling and washing procedures were repeated once more. The final washed chrysolics were dried under a stream of air at a temperature not exceeding 70 ° C. The resulting lumps were pulverized to a fine powder.

EXAMPLE 3 4 kg of concentrated sugar in the ground, air dried (or in the mud press) were pulverized and exfoliated four times by boiling with 20 L of hexane each time. The hexane extract was filtered and the solvent was deionized to obtain a dark green residue (350 g). The residue was extracted with 3.5 L of boiling methanol 3 times and the extractant was filtered to remove the alkylan while it was still hot (temperature greater than 50 ° C). The filtered extract was deionized to remove the mefanol until a green residue (200 g) was obtained. The residue was dissolved in 2 L of boiling acetylene and allowed to stand for chilling. After the crlissization the solvenie was filtered, it was concentrated to the mifad of its volume by means of a parade, and it was left to rest for the second harvest of the cauliflower. Both crops were pooled and washed with cold hexane. The chilling and washing procedures were repeated once more. The final washed chrysolics were dried under a air flow at an temperature not exceeding 70 ° C. The resulting creamy yellow lumps were pulverized to a fine powder (45 g).

EXAMPLE 4 kg of concentrated sugar in the ground, air-dried (or in the mud press) were pulverized and exfoliated four times by boiling with 50 L of melanol each time. The exudate of meianol was filtered and the solvent distilled to obtain a dark green residue (650 g). The residue was extracted with 6.5 L of boiling methanol 3 times and the extractant was filtered to remove the alkylan while still hot (temperature above 50 ° C). The filtered extract was distilled to remove methanol until a green residue (500 g) was obtained. The residue was dissolved in 2 L of boiling ethyl acetamide and allowed to stand for crystallization. After crystallization, the solvenle was filtered, concentrated to the volume by distillation and allowed to stand for crystallization of the second crop. Both crops were pooled and washed with cold hexane. The crystallization and washing procedures were repeated once more. The final washed chrysolics were dried under a stream of air at a temperature not exceeding 70 ° C. The creamy yellow creamy crumbs were pulverized to a fine powder (102 g).

Preparation of the compositions EXAMPLE 5 (Capsule) Ingredienie mg / capsule Excipient-A 80.0 Aforvasiaíina 80.0 Cellulose microcrisíalina 200.8 Manniíol 72.0 Talcum 3.2 Glicolaio of sodium starch 12.0 colloidal silicon dioxide 12.0 Procedure: 1) Extraction-A, alorvasíafina, microcrystalline cellulose and mannitol were mixed and mixed together. 2) Talcum, glycolylate of sodium starch and colloidal silicon dioxide were passed through fine individual molds and then mixed together. 3) The materials of step 1 and 2 are mixed and used to fill empty hard gelatin capsules EXAMPLE 6 (Tablet not coated) Ingredienie mg / iableta Extraction-A 80.0 Simvasfaíina 80.0 Microcrisfalina cellulose 120.0 Mannifol 80.0 Croscarmellose sodium 10.0 Lacíosa 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0 Procedure: 1) Exíraclo-A, simvaslaíina, microcrisfalina cellulose, manniíol, croscarmellose sodium and lactose were lamizados and mixed junios. 2) The material of step 1 was compacted. 3) The compacts from step 2 were passed through a mold and mixed. 4) Talc, colloidal silicon dioxide and croscarmellose sodium were passed to a fine lamix and mixed together. 5) The material of step 3 was mixed with the material of step 4. 6) The material from step 5 was compressed into tablets.

EXAMPLE 7 (Tablet coated with film) Ingredient mg / table Composition of the core table Exíracío-A 100.0 Aíorvasiaíina 40.0 Microcrystalline cellulose 120.0 Manniol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0 Film coating composition Hydroxypropyl methylcellulose (E-15) 12.0 Polyethylene glycol 400 (PEG 400) 2.4 Red iron oxide 0.75 Yellow iron oxide 0.50 Tiianium dioxide 0.25 Isopropyl alcohol q. s. (loss in processing) Dichloromethane q. s. (loss in processing) Procedure: 1) Extraction-A, aorvastatin, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose were mixed and mixed together. 2) The material from step 1 was compacted. 3) The compacts from step 2 were passed through a mold and mixed. 4) Talc, colloidal silicon dioxide, and croscarmellose sodium were passed to a fine iris and mixed together. 5) The material from step 3 was mixed with the material of step 4. 6) The material from step 5 was compressed into tablets. 7) Hydroxypropylmethylcellulose was dispersed in a mixture of isopropyl alcohol and dichloromethane with coninuous mixing in a homogenizer. 8) PEG 400 was added to the above-mentioned solution from step 7 and mixed. 9) Red iron oxide, yellow iron oxide and titanium dioxide were passed through a fine sieve and mixed.

) The material from step 9 was added to the material from step 8 and mixed by 30 min. 11) The core diameters were loaded into the coating container and coated with the coating solution of step 10 until an average weight gain of the board of -2-3% was reached.

EXAMPLE 8 (Tablet coated with film) Ingredient mg / tablet Composition of core tablet Extract-A 100.0 Simvastatin 40.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0 Film coating composition Hydroxypropylmethylcellulose (E-15) 12.0 Polyethylene glycol 400 (PEG 400) 2.4 Red iron oxide 0.75 Yellow iron oxide 0.50 Titanium dioxide 0.25 Sopropyl alcohol q. s. (loss in processing) Dichloromethane q. s. (loss in processing) Procedure: 1) Extract-A, simvastatin, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose were sieved and mixed together. 2) The material from step 1 was compacted. 3) The compacts from step 2 were passed through a screen and mixed. 4) Talc, colloidal silicon dioxide and croscarmellose sodium were passed through a fine sieve and mixed together. 5) The material from step 3 was mixed with the material from step 4. 6) The material from step 5 was compressed towards fableies. 7) Hydroxypropyl methylcellulose was dispersed in a mixture of isopropyl alcohol and dichloromethane with continuous mixing in a homogenizer. 8) PEG 400 was added to the aforementioned solution of step 7 and mixed. 9) Red iron oxide, yellow iron oxide and phydanium dioxide were passed to a fine cone and mixed. 10) The material from step 9 was added to the material from step 8 and mixed for 30 minutes. 11) The core variables were loaded into the container for backing and were revised with the solution for step 10 reversal until an average weight gain of -2-3% was reached.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A novel pharmaceutical composition comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms from 2 to 99.9% by weight of the composition; at least other organic compound selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of HMG CoA reducfasa, its salts, analogs or derivatives thereof, substantially devoid of any serous acid, optionally with pharmaceutically acceptable excipients from 0 to 99.9% by weight of the composition.

2. The composition according to claim 1, further characterized in that the mixture of higher primary aliphatic alcohols comprises 1-thioracosanol, 1-hexacosanol, 1-hepíacosanol, 1-ociacosanol, and 1-Iriaconanol.

3. The composition according to claims 1 and 2, further characterized in that the mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms comprising 1-acetylasanol, 1-hexacosanol, 1-hepfacosanol, 1-ociaccosol, and 1-friaconianol esfá presents at least 40% by weight of the composition.

4. - The composition according to claim 1, further characterized in that the ratio of the mixture of higher primary aliphatic alcohols and HMG CoA reductase inhibitor, its salts, analogues or derivatives thereof is from 20: 1 to 1: 20.

5. The composition according to claims 1-4, further characterized in that the HMG CoA reductase inhibitor is a siaphine, its salts, analogs or derivatives thereof.

6. The composition according to claim 5, further characterized in that the siadphine is selected from a group comprising lovasiaine, pravasiaine, simvasiaine, aurorasfain, fluvasiaine, rosuvasin, pitavaslafin, or its salts, analogs or derivatives thereof. the same.

7. The composition according to claims 1-6, further characterized in that pharmaceutically acceptable excipients are selected from a group comprising diluents, disintegrants, fillers, dough-forming agents, vehicles, agents for pH adjustment, esiabilizaníes, anfi-oxidaníes, agluíinanfes, pH regulators, lubricants, anti-adherents, coating agents, preservatives, emulsifiers, agents for suspension, agents for the control of the release, polymers, dyes, flavor agencies, plasfificaníes, solveníes, conservatives , sliders, Kenyan Agents and the like; used either alone or in combination with them.

8. The composition according to claims 1-7, further characterized in that it is formulated as oral dosage forms such as tablets, pills, capsules, gels, finely divided powders, dispersions, suspensions, solutions, emulsions, etc. forms for pulmonary and nasal doses such as sprays, aerosols, efe; topical dosage forms such as gels, ointments, creams, etc; parenteral dosage forms; Conírolated release formulations; fast melt formulations, lyophilized formulations, re-release release formulations, sustained release formulations, extended release formulations, pulse release formulations, and immediate release mixed formulations and controlled release formulations.

9. A process for the preparation of a pharmaceutical composition according to claim 1 which comprises the following steps: i) isolating the wax, ii) subjecting the wax to exiration with a liquid organic exiractor in which the primary aliphatic alcohols and other organic compounds are soluble, iii) recover said soluble mixture from said extractor, iv) purify the extract by means of repetitive washing and crystallization, v) dry the extract at a temperature below 70 ° C and process it to a powder, vi) adding the HMG CoA reductase inhibitor, its salts, analogs or derivatives, vii) optionally adding pharmaceutically acceptable excipients and working it into a suitable dosage form.

10. - The process according to claim 9, further characterized in that the mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms comprising 1-tetracosanol, 1-hexacosanol, 1-heptacosanol, 1-ociaccosol, and 1-iacoconlanol is have at least 40% by weight of the composition.

11. The process according to claims 9 and 10, further characterized in that the ratio of the mixture of higher primary aliphatic alcohols and HMG CoA reductase inhibitor, its salts, analogues or derivatives thereof is 20: 1 to 1: 20

12. The use of a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms of 2 to 99.9% by weight of the composition; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ketones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and inhibitor of HMG CoA reductase, its salts, analogues or derivatives of them, substantially devoid of any serous acid, for the preparation of a composition for the reduction of the serum cholesterol level, and the treatment of hyperlipidemia.

13. A composition comprising a mixture of higher primary aliphatic alcohols of 24 to 39 carbon atoms of 2 to 99.9% by weight of the composition; at least one other organic component selected from resins and pigments, hydrocarbons, esters, ceiones and aldehydes, and phenolic compounds from 0.1 to 70% by weight of the composition, and the inhibitor of the HMG CoA reductase, its salts, analogs or derivatives thereof, substantially lacking any serous acid, as described in the present invention and illustrated by the examples.