MXPA06004777A - Pharmaceutical formulations for carrier-mediated transport statins and uses thereof - Google Patents

Abstract

The present invention relates to formulations comprising therapeutically effective amounts of at least one acid-stable, carrier-mediated transport statin, at least one poorly water-soluble, carrier-mediated transport statin, or at least one large molecular weight, carrier-mediated transport statin, such as atorvastatin and rosuvastatin, or a pharmaceutically acceptable salt thereof, and methods of their use. The present formulations and methods are designed to exhibit a controlled-release of a therapeutic amount of the statin in the small intestine, thereby limiting systemic exposure of the statin and maximizing liver-specific absorption of the drug. The formulations and methods of the present invention are particularly useful for treating and/or preventing conditions that are benefited by decreasing levels of lipids and/or cholesterol in the body.

Description

PHARMACEUTICAL FORMULATIONS FOR TRANSPORTATION STATUES MEASURED BY CARRIERS AND USES OF THE SAME FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations and methods for their use. In particular, it relates to formulations of, and methods for using, statins that are absorbed through the intestine and subsequently into the liver by means of carrier mediated transport mechanisms, and are also stable in acidic environments, have poor permeability of membrane due to its molecular size, and / or have poor solubility in water. The transport properties of these statins, as well as other physical characteristics, limit their hepatic bioavailability. The statin formulations of the present invention address the problems associated with these characteristics, and result in increased hepatic bioavailability. BACKGROUND OF THE INVENTION Statins are a class of compounds that competitively inhibit 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to evaluation, a limiting step of the early speed in cholesterol biosynthesis (Igel et al., (2002) J. Clin Pharmacol 42: 835). Statins lower lipid levels by reducing the biosynthesis of cholesterol in the liver. Therefore, statins are known for their ability to help reduce total cholesterol and low-density lipoprotein cholesterol levels, which is of primary importance in preventing coronary heart disease. Id. Because of the possible undesirable effects in non-liver tissues, the systemic availability of statins is considered undesirable. In addition, to increase the level of inhibition of HMG-CoA reductase, it is desirable to maximize hepatic bioavailability. Certain statins have properties that limit their therapeutic bioavailability, thus reducing their therapeutic effect and potentially increasing their systemic exposure. The inability to cross biological membranes by diffusion, for example, is one such property. Following its ingestion, statins are absorbed through the intestine in the hepatic portal vein and distributed to the liver, which is the primary site of action and the primary site of cholesterol synthesis. Statin compounds that are hydrophilic, lipophobic, and / or have high molecular weights often exhibit poor diffusive permeability in vivo through the biological membranes. Therefore transport through biological membranes is only possible via a carrier-mediated transport mechanism that typically requires energy, often supplied by the hydrolysis of ATP.

A particular route of statin assimilation involves absorption through the small intestine by the transport mechanism mediated by carriers, followed by absorption in the hepatocytes, also via the mechanism of transport mediated by carriers. The access to the site of action of the drugs are dependent on such mechanisms mediated by carriers depends largely on the capacity of the transport mechanism through the membrane. In the intestine, if a statin is present in an amount that exceeds the capacity of the transport mechanism, the excess drug will be excreted. In the hepatic portal vein, if a statin is present in an amount that saturates the rate of transfer across the membrane, the excess is available for systemic exposure and distribution to nonhepatic tissue, and can be detected in the blood. . Another property that can affect liver bioavailability is stability in an acidic environment. For example, certain statin compounds, such as pravastatin, are unstable in an acidic environment. Triscari et al., (1995) J. Clin. Pharmacol. 35: 142. If administered by mouth, these statins may undergo non-enzymatic conversion in the stomach to relatively inactive metabolites. Id. To avoid this problem, a protective coating is typically used to delay the release of the statin until it has passed from the acidic environment of the stomach to the small intestine. For acid stable statins, a protective coating is not required, but can be used as an additional control mechanism in a modified release formulation. Therefore, there is great flexibility in achieving increased hepatic bioavailability through a modified release formulation when acid-stable statins are used. An additional property that may limit the hepatic bioavailability of statins is the solubility in water. Some statin drugs are poorly soluble in water. Statins that are not soluble in water often have poor dissolution profiles, resulting in reduced bioavailability when administered in vivo. The lack of good water solubility properties of these drugs causes formulation difficulties that need to be addressed to improve their effectiveness. One more property that may limit the hepatic bioavailability of certain statins is diffusive membrane permeability. The difficulty of the drugs when diffusing through the biological membranes has a significant impact on the absorption of the drug. The poor membrane permeability can be due to several factors, including the molecular size and charge of the molecule, as well as its hydrophobic / hydrophilic nature. For example, several statins exhibit poor or negligible membrane diffusive permeability due to their large molecular size, and therefore effectively depend on being released at the sites of carrier mediated transport mechanisms to achieve absorption through the biological membranes. . In some cases, limited membrane permeability results in variable or incomplete liver bioavailability. In addition, even for statins with poor diffusive membrane permeability that have acceptable oral bioavailability, the rate of absorption is slow and may affect the time for the onset of action. In addition, some statins show an acceptable rate and extent of absorption in the upper gastrointestinal tract, but only if the drug is released in the optimal region of the gastrointestinal tract. For this category of statins, insofar as there may be a therapeutic benefit in altering the course of time for drug absorption and systemic exposure after oral administration, the application of conventional controlled-release technologies will not achieve the required extension of absorption because the natural site of absorption has been overlooked.

Therefore, for statins that show one or more of these properties, which limit liver bioavailability and may also increase their systemic exposure, there is a need in the art for new formulations that allow for the most optimal absorption in the intestine and in the intestine. the liver. In particular, there is a need for acid-stable carrier-mediated transport statin formulations which provide release rates that maximize absorption in the intestine and liver. There is also a need for modified release formulations that improve the hepatic bioavailability of poorly soluble statins in water by improving their solubility, and that improve the hepatic bioavailability of statins with large molecular weight by improving their permeability. Such modified release formulations would help maximize the absorption of statins in the intestine and liver, and would therefore limit systemic exposure and associated side effects. Specific examples of carrier-mediated transport statins showing the properties of acid stability, poor water solubility, and large molecular weight, discussed above include atorvastatin and rosuvastatin. Atorvastatin is a member of the class of astatin drugs and is a completely synthetic pyrrol pentasubstiuido that is stable in acidic environments. Due to its large molecular size (MW 1209 as the bis-calcium salt, MW 557 as the free acid), atorvastatin exhibits poor membrane permeability, despite its lipophilic nature. Atorvastatin is also poorly soluble in water, particularly in acidic environments. For example, as defined in the US Pharmacopeia (2002) atorvastatin is considered "very poorly soluble". It is thought that atorvastatin calcium (sold as LIPITOR®) shares the same mechanism in the liver as other statins through the competitive inhibition of HMG-CoA reductase. Therefore, atorvastatin is usually prescribed to reduce total cholesterol and low-density lipoprotein cholesterol (LDL-C), which are the main objectives in preventing coronary heart disease. Atorvastatin is particularly effective in reducing LDL-C levels (40-60% reduction) compared to other statins (25-35% reduction) (Malinowski (1998) Am J. Health-Syst Pharm 55: 2253) . In addition, it appears that atorvastatin reduces triglyceride levels more than other statins, although the mechanism has not been identified. Id. Atorvastatin is also more effective than other statins in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a rare lipid disorder characterized by an inability to produce functional LDL receptors. Among other actions, atorvastatin also reduces the number of atherosclerotic lesions and reduces the proliferation of vascular smooth muscle cells. Malinowski (1998) Am. J. Health-Syst. Pharm. 55: 2253. Unlike acid-labile statins such as pravastatin, atorvastatin is stable in acidic environments such as those found in the stomach. As with all carrier-mediated transport statins, once atorvastatin exits the stomach, it is absorbed in the intestine and then in the liver by transport mediated transport mechanisms. Approximately only 30% of orally administered atorvastatin is absorbed from the intestine. Similar to most other astatins, atorvastatin undergoes an extensive first pass metabolism in the liver. Approximately 70% or more of the atorvastatin absorbed from the intestine is absorbed by the liver, resulting in a systemic bioavailability of the main drug of approximately 12% and resulting in a systemic bioavailability of active inhibitors (including the main drug and its metabolites) of the 30 %. Id. Daily doses of more than 80 mg are not recommended. The maximum plasma levels of atorvastatin are reached from 1 to 4 hours after ingestion, while plasma levels in permanent state are reached in 32-72 hours. Id. When taken with food, the absorption rate of atorvastatin is reduced (Cmax is reduced by 50% and tmax is delayed by 10 hours), although the overall extent of absorption is reduced only slightly (the area under the curve concentration (AUC) is reduced by only 12%). Id. Several metabolites of atorvastatin appear to show inhibitory activity of HMG-CoA reductase that is similar to that of the main drug. These metabolites, which include the o-hydroxylated and p-hydroxylated products, account for 70% of the inhibitory activity of atorvastatin. Atorvastatin and its metabolites, as with other statins, are excreted through the bile and are not recirculated through the liver or intestine. The half-life (T? / 2) of atorvastatin in the plasma varies from 13-24 hours, and has an average value of 14 hours. Although the half-life of atorvastatin is less than 24 hours, it is usually administered only once a day since the duration of inhibition of HMG-CoA reductase is approximately 20-30 hours due to the inhibitory activity of the metabolites. This long-term inhibition of atorvastatin may explain the increased reduction observed in lipid levels (Malinowski (1998) Am J. Health Syst. Pharm 55: 2253).

Rosuvastatin is another new member of the statin family that is stable to acid and whose absorption is governed by carrier mediated transport mechanisms. Rosuvastatin (which recently received FDA approval under the name CRESTOR®) is a unique, fully synthetic enantiomeric hydroxy acid, which belongs to a new series of 3,5-dihydroxy-6-heptanoates N-methanesulfonamido pyrimidine and N-methanesulfonyl pyrrole replaced (Cheng-Lai (2002) Heart Diseases 5:72). Although rosuvastatin shares the common pharmacoporate of the statin, it has an additional methanesulfonamide group that increases its hydrophilicity. Because of its increased hydrophilic character and its large molecular size (MW 1001 as the bis calcium salt, MW 480 as the free acid), rosuvastatin has difficulty crossing the biological membranes. Rosuvastatin is also relatively poorly soluble in water under both acidic and basic conditions. For example, as defined by the Pharmacopeia of the United States (2002), rosuvastatin is considered "moderately soluble". As with other statins, rosuvastatin competitively inhibits HMG-CoA reductase and is therefore useful in reducing levels of LDL-C, total cholesterol, and triglycerides, as well as increasing high-density lipoprotein cholesterol (HDL-) levels. C). Although rosuvastatin has only recently received FDA approval, clinical studies suggest that it may be more effective in reducing LDL-C and total cholesterol levels than either pravastatin or simvastatin (Cheng-Lai (2003) Heart Disease 5:72). It is believed that the extra methane sulphonamide group in rosuvastatin results in an additional ionic bonding interaction with, and therefore greater affinity for, the HMG-CoA redustase. Accordingly, rosuvastatin has the lowest IC50 (0.16 nM in rat hepatocytes) and is the most potent inhibitor of sterol synthesis in hepatocytes of all statins (White (2002) J. Clin. Pharmacol 42: 963) . Rosuvastatin reduces LDL-C levels by 34% to 65%, depending on the dosage. Rosuvastatin also increases HDL-C levels by 9% to 14% and reduces triglyceride levels by 10% to 35%. (Igel et al., (2292) J. Clin Pharmacol 42: 835). In addition, rosuvastatin is well tolerated in humans at doses ranging from 1 to 40 mg, with side effects similar to those observed for pravastatin, atorvastatin, and simvastatin, such as rhabsomyolysis. Id. In particular, high doses of rosuvastatin (eg, 80 mg and higher) have been associated with myopathy in phase III clinical trials. Id. Rosuvastatin * is metabolized slowly in the liver, where metabolism is limited by cytochrome P450 isoenzymes. Although a major N-demethyl metabolite (consisting mainly of CYP2C9 and CYP2C19) has been identified, it is seven times less active than the main compound in inhibiting HMG-CoA reductase. Furthermore, it is believed that 90% of the inhibitory activity of rosuvastatin is due to the main compound (White (2002) J. Clin Pharmacol 42: 963). Consequently, as the metabolism of rosuvastatin is slow and limited, metabolically significant interactions mediated with other drugs are not likely (Cheng-Lai (2003) Heart Disease 5:72). Rosuvastatin is selectively adsorbed in hepatocytes based on a mediated mechanism by carriers, up to 90% of the absorbed dose extracted by the liver. (Igel et al., (2002) J. Clin. Pharmacol 42: 835). Although the presence of food reduces the rate of absorption, the overall extent of absorption remains constant. Maximum plasma concentrations (Cmax), as well as AUC, show a relatively linear relationship with respect to doses ranging from 5 to 80 mg, with a tmax ranging from 3 to 5 hours. (Igel et al., (2002) J. Clin Pharmacol 42: 835).

In addition, rosuvastatin has a long elimination life (t? / 2). The elimination of rosuvastatin occurs mainly through biliary excretion (90%), while 10% is excreted in the urine (Cheng-Lai (2003) Heart Disease 5: 72). Unlike pravastatin (but like atorvastatin), rosuvastatin is stable in acidic environments such as that found in the stomach. Once rosuvastatin exits the stomach, it is thought to enter the circulation by a transport mechanism mediated by carriers in the small intestine. Following absorption, rosuvastatin enters the hepatocytes through a transport mechanism mediated by carriers. It is thought that the organic anion transport polypeptide C, which is expressed at high levels in hepatocytes, plays a key role in selectively supplying rosuvastatin to the target enzyme of HMG-CoA reductase in the liver (White (2002) J. Clin. Pharmacol 42: 963). Accordingly, the amount of rosuvastatin that is ultimately absorbed by the liver and that which is available for binding to HMG-CoA reductase depends on the absorption rates in the intestine and liver. BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods for increasing the hepatic bioavailability of acid-stable, carrier-mediated transport statins, comprising administering to a subject a therapeutically effective amount of the carrier mediated transport statin, stable to the patient. acid, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation. In certain embodiments, the formulation results in the release of the statin in the stomach and releases the statin at a rate that avoids saturating the intestinal absorption mechanisms and hepatocytes. In other embodiments, the formulation results in a delayed release of substantial amounts of the statin until the composition has left the stomach, and then releases the statin at a rate that avoids saturating the intestinal and hepatocyte absorption mechanisms. In one embodiment of this method, the carrier-mediated transport statin, acid stable, is atorvastatin. In another embodiment, the carrier-mediated, acid-stable transport statin is rosuvastatin. In a further embodiment, the administration achieves a relative systemic bioavailability of the acid-stable, carrier-mediated transport statin, when compared to an equally effective dose of a conventional release formulation, or less than about 90%. In another embodiment, the administration achieves a relative systemic bioavailability of the acid-stable carrier-mediated transport statin when compared to an equally effective dose of a conventional release formulation of less than about 80%. The present invention also encompasses methods for increasing the hepatic bioavailability of the statin by administering statin formulations that release more than about 80% of their statin content over a period of from about 1 hour to about 8 hours. The present invention also relates to methods of treating hypercholesterolemia, which comprise administering to a subject in need of such treatment, a therapeutically effective amount of an acid-stable, carrier-mediated statin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation releases the carrier mediated transport statin, stable to the acid for a period greater than about 2 hours. In one embodiment of this method, the carrier-mediated transport statin, stable to acid, is atorvastatin. In another embodiment, the carrier-mediated transport statin, stable to the acid is rosuvastatin.

The present invention also encompasses methods for treating hypercholesterolemia by administering a statin formulation wherein the formulation exhibits a carrier-mediated transport statin release rate, stable to the acid as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%. The present invention further encompasses modified release formulations comprising a therapeutically effective amount of an acid-stable, carrier-mediated transport statin, or a pharmaceutically acceptable salt thereof, which formulation releases carrier mediated transport statin, stable to the acid at a rate that is approximately equal to or less than the absorption rate in the intestine and in the liver.

In one embodiment of these formulations, the carrier-mediated transport statin, stable to acid, is atorvastatin. In another embodiment, the carrier-mediated transport statin, stable to the acid is rosuvastatin. In a further embodiment, the formulation exhibits a release rate of the carrier mediated transport statin, stable to the acid as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.

The invention also relates to methods for increasing the hepatic bioavailability of large molecular weight carrier-mediated transport statins comprising administering to a subject a therapeutically effective amount of carrier-mediated transport statins of large molecular weight, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation comprises a membrane permeability improver and wherein the formulation releases the carrier-mediated transport statins, of large molecular weight, at a rate that avoids saturating the mechanisms of intestinal absorption and hepatocyte. In one embodiment, of this method the carrier-mediated transport statin, of large molecular weight, is atorvastatin. In another embodiment, the carrier-mediated transport statin of large molecular weight is rosuvastatin. In a further embodiment, these methods use formulations that release more than about 80% of their content over a period of from about 1 hour to about 8 hours. In a further embodiment, these methods utilize formulations that achieve a relative systemic bioavailability of carrier-mediated transport statin, of large molecular weight, when compared to an effective dose equally of a conventional release formulation, less than about 90% or less than about 80%. The present invention also includes methods for treating hypercholesterolemia comprising administering to a subject in need of such treatment, a therapeutically effective amount of carrier mediated transport statin, large molecular weight, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation comprises membrane permeability improvers and wherein the formulation releases the carrier-mediated transport statin of large molecular weight over a period greater than about 2 hours. In one embodiment of this method, the carrier-mediated transport statin of large molecular weight is atorvastatin. In another embodiment, the carrier-mediated transport statin of large molecular weight is rosuvastatin. In a further embodiment, the formulation exhibits a carrier-mediated transport statin release of large molecular weight as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.

The invention also relates to modified release formulations comprising a therapeutically effective amount of carrier mediated transport statins, large molecular weight, or a pharmaceutically acceptable salt thereof, and membrane permeability improvers, and wherein the formulation it releases the carrier-mediated transport statins of large molecular weight at a rate that is approximately equal to or less than the absorption rate in the intestine and in the liver. In one embodiment of these formulations, the carrier-mediated transport statin of large molecular weight is atorvastatin. In another embodiment, the carrier-mediated transport statin of large molecular weight is rosuvastatin. In another embodiment, the formulation exhibits a release rate of carrier-mediated transport statin of large molecular weight as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%. The present invention also includes methods for increasing the hepatic bioavailability of poorly water soluble carrier-mediated transport statins, comprising administering to a subject a therapeutically effective amount of the carrier-mediated transport statin, sparingly soluble in water, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein a method of improving the solubility to carrier-mediated transport statin has been applied, poorly soluble in water and wherein the formulation releases the statin at a rate that avoids saturate the intestinal and hepatic absorption mechanisms. In one embodiment of this method, the carrier mediated transport statin, which is poorly soluble in water, is atorvastatin. In another modality, the carrier-mediated transport statin, which is poorly soluble in water, is rosuvastatin. In another embodiment, the formulation releases approximately more than 80% of its statin content over a period of about 1 hour to about 8 hours. In another embodiment, administration of the formulation achieves a relative systemic bioavailability of carrier-mediated transport statin, poorly soluble in water, when compared to an equally effective dose of a conventional release formulation of less than about 90% or less of approximately 80%.

The present invention also relates to methods for treating hypercholesterolemia, comprising administering to a subject in need of such treatment, a therapeutically effective amount of carrier-mediated transport statins, poorly soluble in water, or a pharmaceutically accept salt thereof. , in a pharmaceutical formulation, where a method of improving the solubility to carrier mediated transport statin has been applied, poorly soluble in water and where the formulation releases carrier-mediated transport statin, poorly soluble in water during a period greater than about 2 hours. In one embodiment of this method, the carrier mediated transport statin, which is poorly soluble in water, is atorvastatin. In another embodiment, the carrier mediated transport statin, which is poorly soluble in water, is rosuvastatin. In a further embodiment, the formulation exhibits a release rate of carrier mediated transport statin, poorly soluble in water, as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%. The present invention also relates to modified release formulations comprising a therapeutically effective amount of a carrier-mediated transport statin, sparingly soluble in water, or a pharmaceutically accept salt thereof, wherein a method of improving the carrier-mediated transport-mediated statin solubility, which is poorly soluble in water and which formulation releases carrier-mediated transport statin, poorly soluble in water at a rate that is approximately equal to or less than the rate of absorption in the intestine and in the liver. In one embodiment of these formulations, the carrier mediated transport statin, which is poorly soluble in water, is atorvastatin. In another embodiment, the carrier mediated transport statin, which is poorly soluble in water, is rosuvastatin. In another embodiment, the formulation exhibits a release rate of carrier-mediated transport statin, poorly soluble in water as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%. DETAILED DESCRIPTION OF THE INVENTION The absorption of certain statins in the intestine and in the liver is governed by transport mechanisms mediated by carriers. As used herein, the phrase "carrier-mediated transport mechanism" refers to any mechanism of transporting selective biological membranes, and therefore requires additional carrier molecules to transport a given molecule through a membrane. Such transport mechanisms mediated by carriers include active transport mechanisms, which may require the hydrolysis of ATP. As used herein, the phrase "carrier-mediated transport statin" includes a group of compounds that belong to the class of statins, drugs that are transported through biological membranes in vivo by a carrier-mediated transport mechanism. , and therefore whose absorption rates are limited generally by the speed of the transport mechanism. The phrase "carrier-mediated transport statin" also includes any statin whose absorption rate at its primary site of action is dependent on the velocity of at least one transport mechanism mediated by carriers crossing the biological membrane. Examples of carrier-mediated transport statins include pravastatin, atorvastatin, and rosuvastatin. The phrase "carrier-mediated transport statin" also includes any pharmaceutically accept salt or stereoisomers of a carrier-mediated transport statin. How it is used here, the terms "atorvastatin" and "rosuvastatin" include atorvastatin, rosuvastatin, and any pharmaceutically acceptable salt, or stereoisomers, thereof. As used herein, the term "pharmaceutically acceptable salt" includes salts that are physiologically tolerated by a patient. Such salts are typically prepared from inorganic acids or bases and / or organic acids or bases. Examples of these acids and bases are well known to those of ordinary skill in the art. Some statins are stable under acidic conditions. As used herein, the phrase "acid-stable statin" refers to a group of compounds that belong to the class of statin drugs, and that do not substantially degrade or undergo conversion to metabolites under acidic conditions. For example, acid-stable statins are those wherein approximately less than 25% of the compound is degraded or converted to metabolites in an environment with a pH of less than about 4. For example, in one embodiment, an acid-stable statin may be an statin where about 20% of the compound is degraded in an environment with a pH of less than about 4. In a further embodiment, an acid-stable statin is a statin where about 15% of the compound is degraded in an environment with a pH of less than about 4. In a further embodiment, an acid-stable statin is a statin wherein about 10% of the compound is degraded in an environment with a pH of approximately less than 4. An acid-stable statin can also be a statin where about 5% or less The compound is degraded in an environment with a pH of approximately less than 4. The phrase "acid-stable statin" also includes any of the salts or pharmaceutically acceptable stereoisomers of an acid stable statin. Examples of acid stable statins include simvastatin, lovastatin, fluvastatin, atorvastatin, and rosuvastatin, the derivatives thereof, and their pharmaceutically acceptable salts, and their stereoisomers. Other statins are poorly soluble in water. As used herein, the term "poorly water soluble statin" refers to a group of compounds belonging to the statin class of drugs which typically have a solubility that is rated as "sparingly soluble", or less, how this term is defined by the Pharmacopeia of the United States (2002) (page 8). The United States Pharmacopeia defines several such levels of solubility as follows "sparingly soluble" refers to an aqueous solubility ranging from about 1/30 to about 1/100 (mg / ml); "Slightly soluble" refers to an aqueous solubility ranging from about l / 100 to about 1/1000 (mg / ml), "very slightly soluble" refers to an aqueous solubility ranging from about 1 / 1,000 to about 1 / 10,000 (mg / ml); and "practically insoluble, or insoluble" refers to an aqueous solubility that is 1 / 10,000 (mg / ml) or less. The phrase "poorly insoluble statin" also includes any of the pharmaceutically acceptable salts, or stereoisomers, or a statin poorly soluble in water. Statins poorly insoluble in water include, for example, simvastatin, lovastatin, atorvastatin and rosuvastatin, the derivatives and stereoisomers thereof, and their pharmaceutically acceptable salts. Due to their large molecular size, other statins are poorly permeable by diffusion through lipid membranes. As used herein, the term "large molecular weight statin" refers to any statin with a molecular weight greater than about 475 Daltons. For example, large molecular weight statins include statins with molecular weights greater than about 475, greater than about 500, greater than about 600, greater than about 700, greater than about 800, greater than about 900, or greater than about 1000. Dalton. The phrase "large molecular weight statin" also includes any pharmaceutically acceptable salt, and any stereoisomer, of a large molecular weight statin. Examples of large molecular weight statins include atorvastatin and rosuvastatin, derivatives and stereoisomers thereof, and their pharmaceutically acceptable salts. A person skilled in the art will appreciate that the characteristics and properties of the statins discussed above are not mutually exclusive and that a given statin may have one or more of these properties. For example, as used herein, the term "acid-stable carrier-mediated transport statin" refers to a statin having the characteristics of an acid-stable statin. (as discussed above) and is also a transport mediated transport statin (as discussed above). Similarly, as used herein, the term "carrier-mediated transport statin, very sparingly soluble in water" refers to statins having the characteristics of a statin almost insoluble in water (as described above) as well as it is a transport statin mediated by carriers. In addition, for example, as used herein, the term "carrier-mediated transport statin, of large molecular weight" refers to a statin which is a large molecular weight statin (as described above) and is also a statin of transport mediated by carriers. Examples of high molecular weight, almost insoluble water carrier mediated transport statins include atorvastatin and rosuvastatin, as well as their pharmaceutically acceptable salts, and their stereoisomers. There is a need in the art for modified release formulations that release carrier-mediated transport statins that are either stable in acids, poorly water soluble, and / or have large molecular weights, at rates that do not saturate the absorption rate in the small intestine and subsequently in the liver. Providing carrier-mediated transport statins at such speeds maximizes its specific hepatic absorption and therefore concentrates statins within the liver. The concentration of carrier mediated transport statins in the liver subsequently limits its systemic exposure, resulting in improved safety and tolerance profiles. As used herein, the term "hepatic bioavailability" means the amount of drug that is absorbed in the hepatocytes. As used herein, the phrase "modified release" dosage formulation or dosage form includes a pharmaceutical preparation that achieves a desired release of the drug from the formulation. For example, a modified release formulation can extend the influence or effect of a therapeutically effective dose of an active compound on a patient. In addition to maintaining the therapeutic levels of the active compound, a modified release formulation can also be designed to retard the release of the active compound for a specific period.

The methods and formulations of this invention can be used with other drugs that are therapeutically beneficial for lowering lipid levels. These drugs include other inhibitors of HMG-CoA reductase, such as pravastatin, fluvastatin, simvastatin, or lovastatin; fibrates, such as gemfibrozil; cholesterol absorption modifiers, such as ezetimibe; bile acid binding resins, such as colestipol and cholestyramine; and / or other agents, such as fish oils, nicotinic acid, and probucol. The formulations and methods of this invention, when co-administered with other lipid-lowering agents, can be used to reduce the limiting side effects that can be observed when conventional release statin formulations co-administer with other reducing agents. lipids. . Carrier Mediated Transport Statins An aspect of the present invention relates to compositions comprising a therapeutically effective amount of at least one carrier mediated transport statin (or a stereoisomer thereof), or a pharmaceutically acceptable salt thereof, and the methods for its use. As used herein, the phrase "therapeutically effective amount" includes the amounts of carrier-mediated transport statins (or stereoisomers thereof), or the pharmaceutically acceptable salts thereof, which individually and / or in combination with others. drugs, provide a benefit in the prevention, treatment, and / or management of one or more conditions or diseases that are associated with high cholesterol and / or high lipid levels or may otherwise benefit a decrease in blood levels of lipids or cholesterol levels. Such conditions or diseases include, but are not limited to hypercholesterolemia, hyperlipidemia, myocardial infarction, atherosclerosis, stroke, ischemia, coronary atherosclerosis, coronary death, and / or cardiovascular mortality. The one or more diseases that can be treated, managed and / or prevented by the formulations and / or methods of the present invention also include cardiovascular diseases that are not secondary to hypercholesterolemia. In one embodiment, a therapeutically effective amount of a carrier-mediated transport statin is the amount required to inhibit and / or reduce the activity of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The compositions can be designed to augment and / or optimize the specific liver uptake of carrier mediated transport statins from the intestine, thus limiting systemic exposure for carrier-mediated transport statins and reducing at least one undesirable side effect that resulting from such exposure, for example, when a transport formulation mediated by conventional release carriers is administered. As used herein, the term "conventional release formulation" means a formulation that, when evaluated in a USP dissolution bath in buffer pH 6.8, releases more than about 80% of its statin content in less than 1 hour. As used herein, the term "conventional delayed release formulation" means a formulation that (when evaluated in a USP dissolution bath in buffer pH 6.8) after exposure to an acidic environment for 2 hours, releases more than about 70 % of your statin content in less than about 1 hour. The reduction of undesirable side effects is achieved by administering at least one carrier mediated transport statin to the liver in a manner that provides a cholesterol lowering effect for the subject receiving the drug, without significantly inhibiting the systemic synthesis of ubiquinone. In particular, the release of carrier-mediated transport statins from the compositions of the invention is directed to the upper small intestine (the primary site of absorption), at a rate designed to avoid saturating the intestinal absorption apparatus. The inventive compositions may also achieve a lower absorption rate than conventional release formulations, which improves administration to the liver, such that the rate of administration is more consistent with the rate of absorption in the hepatocytes. This can maximize the uptake of carrier-mediated transport statins and maximize subsequent extraction by the liver, providing a dose-saving effect and significantly reducing the amount of carrier mediated transport statin diverted into the systemic circulation. While not wishing to be bound by any particular theory, the compositions of the present invention can prevent the development of iopathy associated with the depletion or drastic reduction of ubiquinone in peripheral tissues. The optimization of hepatic absorption also allows for less use of carrier-mediated transport statins in the compositions of the present invention, relative to the amounts required in the conventional forms of these drugs. Due to the more efficient administration of carrier-mediated transport statins achieved by the present compositions, it is possible to reduce the amount of carrier-mediated transport statins included in these compositions. For example, in the compositions of atorvastatin and rosuvastatin, it is possible to reduce the amount of atorvastatin and rosuvastatin included, by from about 10% to about 90% or from about 10% to about 80%, or from about 10% to about 70%, or in approximately 20% to approximately 70%, or at about 20% to about 60%, or about 25% to about 50%, relative to a conventional drug release formulation. In one embodiment, the amount of atorvastatin in the composition of the present invention can be reduced to approximately 25%, relative to a dose of LIPITOR®. In another embodiment, the amount of rosuvastatin in the composition of the present invention can be reduced to approximately 25%, relative to a dose of CRESTOR®. The modified release formulations of the present invention also provide advantages in that equivalent or greater doses of carrier-mediated transport statins can be used, with better efficiency and / or fewer side effects observed. For example, the atorvastatin formulations of the present invention can include, for example, from 100% to 200% of the amount of atorvastatin in conventional release formulations. Even further, for example, the rosuvastatin formulations of the present invention can include, for example, 100% to 200% of the amount of rosuvastatin in conventional release formulations. However, even with these higher doses, the formulations of the present invention achieve better efficiency and fewer side effects. The compositions of the present invention are suitable for treating and / or preventing conditions or diseases that are benefited by the decreasing levels of lipids and / or cholesterol in the body. Such conditions include those that are typically treated and / or prevented with carrier-mediated transport statin compositions, such as coronary events in hypercholesterolemic patients who lack clinically evident coronary heart disease, and coronary events in hypercholesterolemic patients who they exhibit clinically evident arterycoronary disease. The present compositions can also be used as a complementary therapy (to dietary restrictions and exercise) to reduce high levels of total cholesterol (total C), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B ), and triglycerides, and to increase high-density lipoprotein (HDL-C) cholesterol levels in subjects with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson type Ha and Hb), elevated serum triglyceride levels (Fredrickson Type IV) ), and disbetaliproteinemia (Fredrickson Type III), in patients who do not respond adequately to dietary restrictions. The present compositions and methods can also be used to treat, manage and / or prevent one or more cardiovascular diseases that are not secondary to hypercholesterolemia. Stable Acid Statins The present invention is also directed to modified release formulations comprising a therapeutically effective amount of at least one acid-stable, carrier mediated transport statin, or a pharmaceutically acceptable salt thereof, and methods for use, where the formulation does not result in a delayed release during the passage from the stomach to the intestine. Optionally, the invention also encompasses formulations of such statins where the release of the statin is delayed until the drug has passed from the stomach to the intestine. Since the statins used in the compositions are stable under acidic conditions, the compositions do not require a protective coating to prevent the conversion of the statin in the stomach to metabolites prior to absorption in the intestine. Although not required, such protective coatings may, however, be used if a delayed release is desired. The option of using, or not using a protective coating is desirable since this allows a greater degree of flexibility in designing the modified release formulations that release the statins at the desired rate. Thus, when administered to a patient, the compositions of the present invention may or may not retard the release of substantial amounts of the acid-stable, carrier-mediated transport statins until the composition has passed from the stomach and into the intestine. The compositions can be designed to increase and / or optimize the specific liver uptake of acid-stable, carrier-mediated transport statins from the intestine, thus limiting systemic exposure and reducing at least an undesirable side effect resulting from such exposure. , for example, when a carrier-mediated, acid-stable transport formulation is administered. The reduction of undesirable side effects is achieved by administering at least one carrier-mediated transport statin, stable in acids to the liver in a manner that provides a cholesterol lowering effect for the subject receiving the drug, without significantly inhibiting systemic synthesis of ubiquinone. In particular, the release of the acid-stable, carrier-mediated transport statins from the compositions of the invention targets the upper small intestine (the primary site of absorption), at a rate designed to avoid saturation of the respiratory apparatus. intestinal absorption. The inventive compositions may also achieve a lower absorption rate than conventional release formulations, which improves administration to the liver, such that the rate of administration is more consistent with the rate of absorption in the hepatocytes. This can maximize the absorption of carrier-mediated transport statins, stable in acids and maximizes their subsequent extraction by the liver, providing a dose-saving effect and significantly reducing the amount of carrier-mediated statin transport, stable in acids diverted to the systemic circulation. While not wishing to be bound by any particular theory, the compositions of the present invention can prevent the development of myopathy associated with the depletion or drastic reduction of ubiquinone in peripheral tissues. The optimization of the absorption in the liver also allows the use of fewer carrier mediated transport statins, stable in acids in the compositions of the present invention, in relation to the amounts required in the conventional forms of these drugs. Due to the more efficient administration of acid-stable carrier-mediated transport statins achieved by the present compositions, it is possible to reduce the amounts of carrier-mediated transport statins, stable in acids included in these compositions. For example, in the compositions of atorvastatin and rosuvastatin, it is possible to reduce the amount of atorvastatin or rosuvastatin included in from about 10% to about 90%, or in about 10% to about 80%, or in about 10% to about 70%, or at about 20% to about 70%, or about 20% to about 60%, or about 25% to about 50%, relative to a conventional drug release formulation. In one embodiment, the amount of atorvastatin in the compositions of the present invention can be reduced by approximately 25%, relative to a dose of LIPITOR®. In another embodiment, the amount of rosuvastatin in the compositions of the present invention can be reduced by approximately 25%, relative to a dose of CRESTOR®. The modified release formulations of the present invention also provide advantages because equivalent, or higher, doses of acid-stable, carrier mediated transport statins can be used with improved efficiency and / or fewer side effects observed. For example, the atorvastatin formulations of the present invention can include, for example, from 100% to 200% of the amount of atorvastatin in the conventional release formulations. Even further, for example, the rosuvastatin formulations of the present invention may include, for example, 100% to 200% of the amount of rosuvastatin in conventional release formulations. However, even with these higher doses, the formulations of the present invention achieve better efficiency and fewer side effects.

The compositions of the present invention are suitable for treating and / or preventing conditions or diseases that are benefited by the decreasing levels of lipids and / or cholesterol in the body. Such conditions include those that are typically treated and / or prevented with carrier-mediated transport statin compositions, stable in conventional acids, such as coronary events in hypercholesterolemic patients who do not have clinically evident coronary heart disease, and / or coronaries in hypercholesterolemic patients who exhibit clinically evident coronary artery disease. The present compositions can also be used as a complementary therapy (to dietary restrictions and exercise) to reduce elevated levels of total cholesterol (Total C), apolipoprotein B (Apo B), and triglycerides, and to increase HDL levels -C in subjects with primary hypercholesterolemia and mixed dyslipidemia (Fredickson Type Ha and Hb), elevated levels of serum triglycerides (Fredickson type IV), and disbetalipoproteinemia (Fredrickson Type III) in patients who do not respond adequately to dietary restrictions. The present compositions and methods can also be used to treat, manage, and / or prevent one or more cardiovascular diseases that are not secondary to hypercholesterolemia. Slightly Soluble Statins in Water The invention also encompasses modified release formulations comprising a therapeutically effective amount of at least one carrier-mediated transport statin, sparingly soluble in water, or a pharmaceutically acceptable salt thereof, and methods for its use. , where the solubility of the statin has been improved. Increasing the solubility of a poorly soluble statin in water may increase the rate of absorption in the lumen of the intestine. This increase in absorption, however, can be designed such that the plasma levels of the absorbed statin do not saturate the rate of subsequent absorption in the liver. Improving the solubility of a poorly soluble statin in water can be achieved using several methods. As used herein, the term "solubility-improving method" refers to any method that, when used as part of the formulation, improves the solubility of a poorly water-soluble statin at at least one level of solubility as define in the Pharmacopeia of the United States (2002). For example, in one embodiment the solubility is improved from "slightly soluble" to "moderately soluble". In another embodiment, the solubility is improved from "very slightly soluble" to "slightly soluble." In a further embodiment, the solubility is improved from "practically insoluble or insoluble" to "very slightly soluble". In one embodiment, the solubility of the poorly soluble statin can be improved by micronization, this is achieved by conventional micronization techniques known to those skilled in the art, for example, jet milling, impact milling, milling with auxiliaries. (aqueous or solvent), crushing in a ball mill, grinding in a bar mill, or grinding in a fluidized bed. In one embodiment of the invention, approximately 90% of the drug particles have a size of less than about 20 microns. In another embodiment, approximately 50% of the drug particles do not have a size greater than 10 microns. In some embodiments, the particles of the poorly soluble statin in water are prepared as even smaller size, for example, sub-microns. Additionally, excipients may be included in the formulation to improve the solubility / dissolution of poorly water soluble drugs. For example, surfactants, detergents, or any other agent that improves the dissolution of statins may be included in the formulation. Such surfactants include, but are not limited to, sodium laurel sulfate. The formulations of this invention also contemplate the incorporation of suitable excipients to maintain the integrity of the particles of the active ingredient. The compositions can be designed to augment and / or optimize the specific liver uptake of carrier-mediated transport statins., poorly soluble in water from the intestine, thereby limiting its systemic exposure and reducing at least one undesirable side effect resulting from such exposure, for example, when a carrier-mediated transport formulation, poorly soluble in water, is administered. The reduction of undesirable side effects is achieved by administering at least one carrier-mediated transport statin, poorly soluble in water to the liver in a manner that provides a cholesterol lowering effect for the subject receiving the drug, without significantly inhibiting the synthesis Systemic of ubiquinone. In particular, the release of carrier mediated transport statins, poorly soluble in water from the compositions of the invention, targets the upper small intestine (the main absorption site), at a rate designed to avoid saturation of the intestinal absorption. The inventive compositions may also achieve a lower absorption rate than conventional release formulations, which improves administration to the liver, such that the rate of administration is more consistent with the rate of absorption in the hepatocytes. This can maximize the absorption of carrier mediated transport-mediated statins, poorly soluble in water and maximizes subsequent extraction by the liver, providing a dose-saving effect and significantly reducing the amount of carrier mediated transport statin, poorly soluble in water diverted to the systemic circulation. While not wishing to be bound by any particular theory, the compositions of the present invention can prevent the development of myopathy associated with depletion or drastic reduction of ubiquinone in peripheral tissues. The optimization of the absorption in the liver also allows the use of less carriage-mediated transport statin, poorly soluble in water in the compositions of the present invention, in relation to the amounts required in the conventional forms of these drugs. Due to the more efficient administration of carrier-mediated transport statins, which are poorly soluble in water achieved by the present compositions, it is possible to reduce the amount of carrier-mediated transport statins, which are poorly soluble in water, included in these compositions. For example, in the compositions of atorvastatin and rosuvastatin, it is possible to reduce the amount of atorvastatin or rosuvastatin included in from about 10% to about 90%, or in about 10% to about 80%, or in about 10% to about 70%, or at about 20% to about 70%, or about 20% to about 60%, or about 25% to about 50%, relative to a conventional drug release formulation. In one embodiment, the amount of atorvastatin in the composition of the present invention can be reduced by about 25%, relative to a dose of LIPITOR®. In another embodiment, the amount of rosuvastatin in the composition of the present invention can be reduced by approximately 25%, relative to a dose of CRESTOR®. The modified release formulations of the present invention also provide advantages because equivalent, or higher, doses of acid-stable, carrier mediated transport statins can be used with improved efficiency and / or fewer side effects observed. For example, the formulations of atorvastatin. of the present invention can include, for example, from 100% to 200% of the amount of atorvastatin in conventional release formulations. Even further, for example, the rosuvastatin formulations of the present invention can include, for example, 100% to 200% of the amount of rosuvastatin in conventional release formulations. However, even with these higher doses, the formulations of the present invention achieve better efficiency and fewer side effects.

The compositions of the present invention are suitable for treating and / or preventing conditions or diseases that are benefited by the decreasing levels of lipids and / or cholesterol in the body. Such conditions include those that are typically treated and / or prevented with carrier-mediated transport statin compositions, stable in conventional acids, such as coronary events in hypercholesterolemic patients who do not have clinically evident coronary heart disease, and / or coronaries in hypercholesterolemic patients who exhibit clinically evident coronary artery disease. The present compositions can also be used as a complementary therapy (to dietary restrictions and exercise) to reduce elevated levels of total cholesterol (Total C), apolipoprotein B (Apo B), and triglycerides, and to increase HDL levels -C in subjects with primary hypercholesterolemia and mixed dyslipidemia (Fredickson Type Ha and Hb), elevated levels of serum triglycerides (Fredickson type IV), and disbetalipoproteinemia (Fredrickson Type III) in patients who do not respond adequately to dietary restrictions. The present compositions and methods can also be used to treat, manage, and / or prevent one or more cardiovascular diseases that are not secondary to hypercholesterolemia. Large Molecular Weight Statins The present invention also relates to modified release formulations comprising a therapeutically effective amount of at least one carrier-mediated transport statin, large molecular weight, or a pharmaceutically acceptable salt thereof, and methods for use, where the membrane permeability of the large molecular weight statin is enhanced by the addition of a brewing agent. Such formulations where the permeability of the large molecular weight statin is improved can increase its overall bioavailability. As used herein, the term "membrane permeability enhancer" refers to any agent that improves the membrane permeability of a large molecular weight statin. Various approaches can be used to achieve improved intestinal permeability for statins that have poor permeability characteristics due to their large molecular size. For example, permeation enhancing agents can be used successfully to produce a transient and reversible alteration in gastrointestinal permeability. This approach can be used to improve the intestinal absorption of large molecular weight statins. Although intestinal absorption can be increased in this way, intestinal absorption rates that subsequently saturate the rate of absorption in the liver should be avoided to minimize the systemic bioavailability of the statin. Enhancing agents that can be used to increase intestinal absorption include, but are not limited to. medium-chain fatty acids, such as the six-carbon to twenty-carbon fatty acids, and in particular the eight- and ten-carbon forms, such as sodium caprate. Such agents include, but are not limited to, fatty acids, fatty acid esters, fatty alcohols. Such compounds can be hydrophobic or have limited solubility in water, and the compounds can have a molecular weight of from about 150 to about 300 Daltons. Fatty alcohols include, but are not limited to, stearyl alcohol, and oleyl alcohol. Fatty acids include, but are not limited to, oleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, capric acid, monoglycerides, diglycerides, acylines, caprylic acids, acylcarnitins, sodium caprate, and palmitoleic acid . Esters of fatty acids containing more than 10 to 12 carbons can also be used. Examples of fatty acid esters include, but are not limited to, isopropyl myristate and the methyl and ethyl esters of oleic and lauric acid.

Ionic enhancers can also be used. Examples of ionic builders that may be used include, but are not limited to, sodium laurel sulfate, sodium laurate, polyoxyethylene 20-cetylether, lauret-9, sodium dodecylisulfate, and sodium dioctyl sulfosuccinate. Bile salts can also be used. Examples of bile salts that can be used include, but are not limited to sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, and sodium glycohydrofusidate. Chelating agents can be used. Examples of chelating agents that can be used include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citric acid, and salicylates. Another group of builders includes the low molecular weight alcohols. Such alcohols may have a molecular weight less than about 200 Daltons, less than about 150 Daltons, or less than about 100 Dalton. These may also be hydrophilic, having a solubility in water of greater than about 2% by weight, about 5% by weight or about 10% by weight at room temperature. Examples of such alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol, butanol, benzyl alcohol, glycerin, polyethylene glycol, propanediol, and propylene glycol. Sulfoxides can also be used. Examples of sulfoxides include, but are not limited to, dimethyl sulfoxide and decmethyl sulfoxide. Other enhancers that can be used include urea and its derivatives, cyclic unsaturated ureas, 1-dodecylazacycloheptan-2-one, cyclodextrins, enamine derivatives, -terpenes, liposomes, acyl carnitines, hills, peptides (including polyarginine sequences or arginine), peptide mimetics, hexyl diethyl phthalate, octyldodecyl myristate, isostearyl isostearate, caprylic triglycerides / caprices, glyceryl oleate, and various oils (such as gualteria or eucalyptol). Other examples of suitable enhancers for use in the present invention are provided by Santus et al. , (1993) Journal of Controlled Relay 25: 1, and Remington, both of which are incorporated herein by reference for their discussion of breeders. The compositions can be designed to augment and / or optimize the specific liver uptake of carrier-mediated transport statins of large molecular weight from the intestine, thereby limiting their systemic exposure and reducing at least one undesirable side effect resulting from such exposure, for example, when a carrier-mediated transport statin formulation of conventional large molecular weight is administered. The reduction of undesirable side effects is achieved by administering at least one carrier-mediated transport statin, of large molecular weight to the liver in a manner that provides a cholesterol lowering effect for the subject receiving the drug, without significantly inhibiting the synthesis Systemic of ubiquinone. In particular, the release of carrier-mediated transport statins of large molecular weight from the compositions of the invention targets the upper small intestine (the primary site of absorption) at a rate designed to avoid saturation of the intestinal absorption. The inventive compositions may also achieve a lower absorption rate than conventional release formulations, which improves administration to the liver, such that the rate of administration is more consistent with the rate of absorption in the hepatocytes. This can maximize the uptake of carrier-mediated transport statins and maximize subsequent extraction by the liver, providing a dose-saving effect and significantly reducing the amount of carrier mediated transport statin diverted into the systemic circulation. As long as you do not want to be linked to any particular theory, the compositions of the present invention can prevent the development of myopathy associated with the depletion or drastic reduction of ubiquinone in peripheral tissues. The optimization of hepatic absorption also allows for less use of carrier-mediated transport statin in the compositions of the present invention, relative to the amounts required in the conventional forms of these drugs. Due to the more efficient administration of carrier-mediated transport statins achieved by the present compositions, it is possible to reduce the amount of carrier-mediated transport statins included in these compositions. For example, in the compositions of atorvastatin and rosuvastatin, it is possible to reduce the amount of atorvastatin and rosuvastatin included, by from about 10% to about 90% or from about 10% to about 80%, or from about 10% to about 70%, or at about 20% to about 70%, or about 20% to about 60%, or about 25% to about 50%, relative to a conventional drug release formulation. In one embodiment, the amount of atorvastatin in the composition of the present invention can be reduced to approximately 25%, relative to a dose of LIPITOR®. In another embodiment, the amount of rosuvastatin in the composition of the present invention can be reduced to approximately 25%, relative to a dose of CRESTOR®. The modified release formulations of the present invention also provide advantages because equivalent or greater doses of carrier-mediated transport statins can be used, with better efficiency and / or fewer side effects observed. For example, the atorvastatin formulations of the present invention can include, for example, from 100% to 200% of the amount of atorvastatin in conventional release formulations. Even further, for example, the rosuvastatin formulations of the present invention can include, for example, 100% to 200% of the amount of rosuvastatin in conventional release formulations. However, even with these higher doses, the formulations of the present invention achieve better efficiency and fewer side effects. The compositions of the present invention are suitable for treating and / or preventing conditions or diseases that are benefited by the decreasing levels of lipids and / or cholesterol in the body. Such conditions include those that are typically treated and / or prevented with carrier-mediated transport statin compositions, stable in conventional acids, such as coronary events in hypercholesterolemic patients who do not have clinically evident coronary heart disease, and / or coronaries in hypercholesterolemic patients who exhibit clinically evident coronary artery disease. The present compositions can also be used as a complementary therapy (to dietary restrictions and exercise) to reduce elevated levels of total cholesterol (Total C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase HDL-C levels in subjects with primary hypercholesterolemia and mixed dyslipidemia (Fredickson Type Ha and Hb), elevated serum triglyceride levels (Fredickson type IV), and disbetalipoproteinemia (Fredrickson Type III) in patients who do not respond adequately to dietary restrictions. The present compositions and methods can also be used to treat, manage, and / or prevent one or more cardiovascular diseases that are not secondary to hypercholesterolemia. The compositions of the present invention can be formulated in a dosage form that modifies the release of carrier-mediated transport statins. Examples of suitable modified release formulations that can be used in accordance with the present invention include, but are not limited to, matrix systems, osmotic pumps, and membrane controlled dosage forms. These formulations may be single-unit or multi-unit compositions. The formulations of the present invention may comprise at least one carrier-mediated transport statin, which may also be either acid stable, poorly soluble in water, and / or have a large molecular weight, such as, for example, atorvastatin and rosuvastatin, derivatives or stereoisomers thereof, or pharmaceutically acceptable salts thereof. Each of these types of dosage forms is briefly described below. A more detailed discussion of such forms can also be found, for example, in The Handbook of Pharmaceutical Controlled Relay Technology, D. L. Wise (ed.), Marcel Dekker, Inc., New York (2000); and also in Treatise on Controlled Drug Delivery: Fundamentals, Optimization, and Applications, A. Kydonieus (ed.), Marcel Dekker, Inc. New York, (1992), the relevant contents of which are incorporated herein as reference for this purpose. Matrix-Based Dosage Forms In some embodiments, the modified release formulations of the present invention are provided as matrix-based dosage forms. Matrix formulations according to the invention can include, for example, water-soluble, and / or hydrophobic, for example, water-insoluble polymers. The matrix formulations of the present invention can optionally be prepared with functional coatings, which may be enteric, for example, which exhibit a pH-dependent solubility, or non-enteric, for example, which exhibit a pH-independent solubility. The matrix formulations of the present invention can be prepared using, for example, direct compression or wet granulation. A functional coating, as indicated above, may be applied after the invention. Additionally, a barrier coating or sealant may be applied on a matrix tablet core prior to the application of a functional coating. The barrier or barrier coating may have the purpose of separating an active ingredient from a functional coating, which may interact with the active ingredient, or this may prevent the moisture from contacting the active ingredient. Details about barriers and sealants are provided below. In a matrix-based dosage form according to the present invention, the carrier-mediated transport statin and the pharmaceutically acceptable excipient (s) are dispersed within a polymer matrix, which typically comprises one or more soluble polymers. in water and / or one or more water-insoluble polymers. The drug can be released from the dosage form by diffusion and / or erosion. Such matrix systems are described in detail by Wise and Kydonieus, supra. Suitable water-soluble polymers include, but are not limited to polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, or polyethylene glycol, and / or mixtures thereof. Suitable water-insoluble polymers include, but are not limited to ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polymethyl methacrylate ), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate) , poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), low density poly (ethylene), high density poly (ethylene), poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride), polyurethane, and / or mixtures thereof. As used herein, the term "pharmaceutically acceptable excipients" includes those ingredients that are compatible with the other ingredients in a pharmaceutical formulation, in particular the active ingredients, and not deleterious to the patient when used. administer in acceptable amounts. Suitable pharmaceutically acceptable excipients include, but are not limited to carriers, such as sodium citrate and calcium phosphate, fillers or adjuvants, such as stearates, silicas, gypsum, starches, lactose, sucrose, glucose, mannitol, talc, and acid silicic; binders, such as hydroxypropyl methylcellulose, hydroxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; humectants, such as glycerol; disintegrating agents, such as agar, calcium carbonate, potato starch and tapioca, alginic acid certain silicates, EXPLO ™, crospovidone, and sodium carbonate; dissolving retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; absorbents, such as kaolin clay and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium laurel sulfate; stabilizers, such as fumaric acid; coloring agents; damping agents; dispersing agents; conservatives; organic acids; and organic bases. The excipients cited above are given as examples only and are not considered to include all possible choices. Additionally, many excipients may have more than one paper or function, or they are classified in more than one group. Such classifications are only descriptive, and are not intended to limit any use of a particular excipient. In one embodiment, a matrix-based dosage form comprises atorvastatin; at least one diluent such as lactose or microcrystalline cellulose (AVICEL ™); at least one controlled release polymer such as METHOCEL ™ or polyvinyl pyrrolidone; a permeability improver such as sodium caprate; a glidant such as colloidal silicon dioxide; a lubricant such as "magnesium stalk; and a surfactant, such as sodium laurel sulfate." This composition is compressed into a polymer matrix comprising at least one water-soluble polymer such as hydroxypropylmethylcellulose, the amounts and types of polymers, and The ratio of water-soluble polymers to water-insoluble polymers in the inventive formulations is generally selected to achieve a desired release profile of at least one carrier-mediated transport statin, as described below. of water-insoluble polymer in relation to the amount of water-soluble polymer, the release of the drug can be retarded or slowed down.This is partly due to an increased impermeability of the polymeric matrix, and in some cases, at a decreased speed of erosion during transit through the Gl tract Dosage Forms of Osmotic Bopiba In another modality of the The modified release formulations of the present invention are provided as osmotic pump dosage forms. In an osmotic pump dosage form, a core containing carrier-mediated transport statin and optionally one or more osmotic excipients is typically coated with a selectively permeable membrane, having at least one hole. The selectively permeable membrane is generally permeable to water, but impermeable to the drug. When the system is exposed to bodily fluids, water penetrates through the selectively permeable membrane into the core containing the drug and the optional osmotic excipients. The osmotic pressure increases within the dosage form. Consequently, the drug is released through the orifice (s) in an attempt to level the osmotic pressure through the selectively permeable membrane. In more complex pumps, the dosage form may contain two internal compartments in the core. The first compartment contains the drug and the second compartment may contain a polymer, which is swollen by contact with the aqueous fluid. After ingestion, this polymer swells within the compartment containing the drug, decreasing the volume occupied by the drug, thereby administering the drug from the device at a controlled rate for an extended period of time. Such dosage forms are frequently used when a zero order release profile is desired. Osmotic pumps are well known in the art. For example, U.S. Patent Nos. 4,088,864, 4,200,098, and 5,573,776, each of which is incorporated herein by reference for this purpose, describe osmotic pumps and the methods for their manufacture. Osmotic pumps useful in accordance with the present invention can be manufactured by compressing a tablet of an osmotically active drug, or an osmotically inactive drug in combination with an osmotically active agent, and then coating the tablet with a selectively permeable membrane which is permeable to a fluid based on external water but impermeable to the drug and / or the osmotic agent. One or more delivery ports may be pierced through the wall of the selectively permeable membrane. Alternatively, one or more holes in the wall can be formed by incorporating pore-forming materials that can be leached into the wall. In operation, the exterior aqueous base fluid is impregnated through the permeable membrane wall selectively and contacts the drug to form a solution or suspension of the drug. The solution or suspension of the drug is then pumped through the orifice when the fresh fluid is impregnated through the selectively permeable membrane. Typical materials for the selectively permeable membrane include selectively permeable polymers known in the art for use in osmosis and reverse osmosis membranes, such as cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, polyurethanes, sulfonated polystyrenes, cellulose acetate phthalate, methyl cellulose acetate carbamate, succinate acetate cellulose, cellulose acetate dimethyl amino acetate, ethyl carbamate cellulose acetate, cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose acetate succinate, cellulose propionate, succinate, methyl cellulose, p-toluene sulfonate cellulose acetate, bu cellulose acetate thiolate, lightly crosslinked polystyrene derivatives, poly (sodium styrene sulfate), poly (vinylbenzyltrimethyl ammonium chloride), and / or mixtures thereof. The osmotic agents that can be used in the pump are typically soluble in the fluid entering the device, following the administration, resulting in an osmotic pressure gradient across the wall selectively permeable against the outside fluid. Suitable osmotic agents include, but are not limited to, magnesium sulfate, calcium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium, sodium sulfate, d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, hydrophilic polymers such as cellulose polymers, and / or mixtures thereof. As discussed above, the osmotic pump dosage form may contain a second compartment containing a swellable polymer. Suitable polymers that can swell typically interact with water or aqueous biological fluids, causing them to swell or expand to a state of equilibrium. Acceptable polymers exhibit the ability to swell in water and / or biological fluids impregnated within their polymer structure to increase the hydrostatic pressure within the dosage form. The polymers can swell or expand to a very high degree, usually exhibiting an increase of 2 to 50 times their volume. The polymers can be cross-linked or not cross-linked. In one embodiment, the polymers that can swell are hydrophilic polymers. Suitable polymers include, but are not limited to, poly (hydroxy alkyl methacrylate) ng a molecular weight of from about 30,000 to about 5,000,000; kappa-carrageenan; polyvinylpyrrolidone having a molecular weight of from about 10,000 to about 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; poly (vinyl alcohol) having small amounts of acetate, cross-linked with glyoxal, formaldehyde or glutaraldehyde, and having a degree of polymerization of about 200 to about 30,000; a mixture that includes methyl cellulose, crosslinked agar and carboxymethyl cellulose; a water-swellable, water-insoluble copolymer produced by forming a dispersion of maleic anhydride finely divided with styrene, ethylene, propylene, butylene, or isobutylene; polymers that can be swollen in water of N-vinyl lactams; and / or mixtures of any of the foregoing. The term "orifice" as used herein, comprises the means and methods suitable for releasing the drug from the dosage form. The term includes one or more openings or orifices that have been pierced through the permeable membrane selectively, by mechanical means. Alternatively, an orifice can be formed by incorporating an erodible element, such as a gelatin plug, into the selectively permeable membrane. In such cases, the pores of the permeable membrane selectively form a "passage" for the passage of the drug. Such "passage" formulations are described, for example, in U.S. Patent Nos. 3,845,770 and 3,916,899, the relevant descriptions of which are incorporated herein by reference for this purpose. Osmotic pumps useful in accordance with this invention can be manufactured by techniques known in the art, for example, the drug and other ingredients can be comminuted together and pressed into a solid having the desired dimensions (eg, corresponding to the first compartment). The swellable polymer is then prepared, contacted with the drug, and both are surrounded with the selectively permeable agent. If desired, the drug component and the polymer component can be pressed together before applying the selectively permeable membrane. The selectively permeable membrane can be applied by any suitable method, for example, by molding, spraying or dipping. Membrane Controlled Dosage Forms The modified release formulations of the present invention can also be provided as membrane controlled formulations. The membrane-controlled formulations of the present invention can be manufactured by preparing a quick-release core, which may be of the monolithic type (eg, tablets), or of multiple units (eg, granules), and coating the core with a membrane. The membrane-controlled core can then be coated with a functional coating. In the middle of the membrane-controlled core and the functional coating, a barrier or sealant can be applied. The barrier or sealant may alternatively or additionally be provided between the quick release core and the membrane coating. Details of the membrane-controlled dosage forms are provided below.

In one embodiment, carrier-mediated transport statins are provided in ultiparticulate membrane-controlled formulations. Carrier-mediated transport statins can be formed in an active core by applying the drug to a dragee seed having an average diameter in the range of about 0.4 to about 1.1 mm or about 0.85 to about 1.00 mm. The carrier-mediated transport statin can be applied with or without additional excipients on the inert cores, and can be sprayed by solution or suspension using a fluidized bed coater (e.g., the Wurster coater) or tray coating system. Alternatively, carrier-mediated transport statins can be applied as a powder onto the inert cores using a binder to adhere carrier-mediated transport statins onto the cores. The active cores can also be formed by extruding the core with plasticizers (described below) and any other processing aid as needed. The modified release formulations of the present invention comprise at least one polymeric material, which is applied as a membrane coating to the nuclei containing the drug. Suitable water-soluble polymers include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or polyethylene glycol, and / or mixtures thereof. Suitable water-insoluble polymers include, but are not limited to ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), pole (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), low density poly (ethylene), high density poly (ethylene), poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride), or polyurethane, and / or mixtures thereof. EUDRAGIT ™ polymers (available from Rohm Pharma) are polymer lacquer substances based on acrylates and / or methacrylates. A suitable polymer that is freely permeable to the active ingredient and water is the EUDRAGIT ™ RL. A suitable polymer that is slightly permeable to the active ingredient or water is EUDRAGIT ™ RS. Other suitable polymers which are slightly permeable to the active ingredient and water, and which exhibit pH-dependent permeability include, but are not limited to, EUDRAGIT ™ L, EUDRAGIT ™ S, and EUDRAGIT ™ E. EUDRAGIT ™ RL and RS are acrylic resins comprising copolymers of esters of acrylic and methacrylic acid with a low content of quaternary ammonium groups. The ammonium groups are present as salts and give rise to the permeability of the lacquer films. EUDRAGIT ™ RL and RS are freely permeable (RL) and slightly permeable (RS), respectively, independent of pH. Polymers swell in water and digestive juices, in a manner independent of pH. In the swollen state, they are permeable to water and dissolved active compounds. EUDRAGIT ™ L is an anionic polymer synthesized from methyl ester of methacrylic acid and methacrylic acid. This is insoluble in acids and pure water. It is vulva soluble in neutral to weakly alkaline conditions. The permeability of EUDRAGIT ™ L is pH dependent. Above pH 5 the polymer becomes increasingly permeable. In an embodiment comprising the membrane-controlled dosage form, the polymeric material comprises methacrylic acid copolymers, ammonium methacrylate copolymers, or a mixture thereof. Methacrylic acid copolymers such as EUDRAGIT ™ S and EUDRAGIT ™ L (Rohm Pharma) are particularly suitable for use in the controlled release formulations of the present invention. These polymers are gastroresistant and enterosoluble polymers. Its polymeric films are insoluble in pure water and diluting acids. These dissolve at higher pH, depending on their carboxylic acid content. EUDRAGIT ™ S and EUDRAGIT ™ L can be used as individual components in the polymer coating or in combination, in any ratio. Using a combination of polymers, the polymeric material can exhibit a solubility at a pH between the pHs at which EUDRAGIT ™ L and EUDRAGIT ™ S are soluble separately. The membrane coating may comprise a polymeric material comprising a greater proportion (ie, greater than 50% of the total polymer content) of one or more pharmaceutically acceptable water soluble polymers, and optionally a minor (ie, less than 50% of the total polymer content) of one or more pharmaceutically acceptable water insoluble polymers. Alternatively, the membrane coating may comprise a polymeric material comprising a greater proportion (ie, greater than 50% of the total polymer content) of one or more pharmaceutically acceptable water insoluble polymers, and optionally a minor proportion (ie, less than 50% of the total polymer content) of one. or more pharmaceutically acceptable water soluble polymers.

Ammonium methacrylate copolymers such as EUDRAGIT ™ RS and EUDRAGIT ™ RL (Rohm Pharma) are suitable for use in the controlled release formulations of the present invention. These polymers are insoluble in pure water, dilute acids, buffer solutions, or digestive fluids through the full range of physiological pH. The polymers swell in water and digestive fluids regardless of pH. In the swollen state these are then permeable to water and the dissolved therapeutic agents. The permeability of polymers depends on the ratio of ethyl acrylate (EA), methyl methacrylate (MMA), and trimethylammonium ethyl methacrylate (TAMCI) in the polymer. Those who have relationships of EA: MMA: TAMCI of 1: 2: 0.2 (EUDRAGIT ™ RL) are more permeable than those with ratios of 1: 2: 0.1 (EUDRAGIT ™ RS). The EUDRAGIT ™ RL polymers are insoluble polymers with high permeability. The EUDRAGIT ™ RS polymers are insoluble films with low permeability. The ammonium methacrylate copolymers can be combined in any desired ratio. For example, a ratio of EUDRAGIT ™ RS: EUDRAGIT ™ RL (90:10) can be used. The ratios can be further adjusted to provide a delay in drug release. For example, the ratio of EUDRAGIT ™ RS: EUDRAGIT ™ RL can be from about 100: 0 to about 80:20, about 100: 0 to about 90:10, or any intermediate relationship. In such formulations, the less permeable EUDRAGIT ™ RS polymer would generally comprise the majority of the polymeric material. The ammonium methacrylate copolymers can be combined with the methacrylic acid copolymers within the polymeric material to achieve the desired retardation in drug release. Ammonium methacrylate copolymer ratios (e.g., EUDRAGIT ™ RS) can be used to methacrylic acid copolymers in the range of 99: 1 to about 20:80. The two types of polymers can also be combined in the same polymeric material, or are provided as separate coatings that are applied to the core. In addition to the EUDRAGIT ™ polymers described above, many other such copolymers can be used to control the release of the drug. These include methacrylate ester copolymers (e.g. EUDRAGIT ™ NE 30D). Additional information on EUDRAGIT ™ polymers can be found in "Chemistry and Application Properties of Polymethacrylate Coating Systems", in Aqueous Polymeric Coatings for Pharmaceutical dosage Forms, ed. James McGinity, Marcel Dekker Inc., New York, (pp. 109-114). In addition to the EUDRAGIT ™ polymers discussed above, other enteric, or pH dependent, polymers can be used. Such polymers may include the phthalate, butyrate, succinate and / or meltamate groups. Such polymers include, but are not limited to, cellulose acetate phthalate, cellulose acetate succinate, cellulose hydrogen phthalate, cellulose acetate trimellitate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, starch acetate phthalate, amylose acetate phthalate, polyvinyl acetate phthalate, and polyvinyl phthalate butyrate. The coating membrane may further comprise one or more soluble excipients to increase the permeability of the polymeric material. Suitably, the soluble excipient is selected from a soluble polymer, a surfactant, an alkali metal salt, an organic acid, a sugar, and a sugar alcohol. Such soluble excipients include, but are not limited to polyvinyl pyrrolidone, polyethylene glycol, sodium chloride, surfactants such as sodium laurel sulfate and polysorbates, organic acids such as acetic acid, adipic acid, citric acid, fumaric acid, glutaric acid, acid malic, succinic acid, and tartaric acid, sugars such as dextrose, fructose, glucose, lactose, and sucrose, sugar alcohols such as lactitol, maltitol, mannitol, sorbitol and xylitol, xanthan gum, dextrins, and maltodextrins. In some embodiments, polyvinyl pyrrolidone, mannitol, and / or polyethylene glycol can be used as the soluble excipients. The soluble excipient (s) can be used in an amount of from about 1% to about 10% by weight, based on the total dry weight of the polymer. In another embodiment, the polymeric material comprises one or more water-insoluble polymers, which are also insoluble in gastrointestinal fluids, and one or more water-soluble pore-forming compounds. For example, the water-insoluble polymer may comprise a terpolymer of polyvinyl chloride, polyvinyl acetate, and / or polyvinylalcohol. Water-soluble, pore-forming compounds include, but are not limited to, sucrose, sodium chloride, potassium chloride, polyvinylpyrrolidone, and / or polyethylene glycol. The pore-forming compounds can be uniformly and randomly distributed throughout the water-insoluble polymer. Typically, the pore-forming compounds comprise about 1 part to about 35 parts by about 1 to about 10 parts of the water-insoluble polymers. When such dosage forms come into contact with the dissolution medium (eg, intestinal fluids), the pore-forming compounds within the polymeric material dissolve to produce a porous structure through which the drug diffuses. Such formulations are described in more detail in U.S. Patent No. 4,557,925, the relevant part of which is incorporated herein by reference for this purpose. The porous membrane can also be coated with an enteric coating as described herein, to inhibit release in the stomach. In one embodiment, a diffusion-controlled release dosage form comprises rosuvastatin; at least one diluent such as anhydrous lactose or microcrystalline cellulose (AVICEL ™); at least one lubricant, such as magnesium stearate; a velocity control membrane of at least one water-insoluble polymer, such as polyvinyl acetate and at least one water-soluble polymer such as sucrose. The polymeric material may also include one or more auxiliary agents such as fillers, plasticizers, and / or antifoaming agents. Representative fillers include talc, fumed silica, glyceryl monostearate, magnesium stearate, calcium stearate, kaolin, colloidal silica, gypsum, micronized silica, and magnesium trisilicate.

The amount of filler used typically ranges from about 2% to about 300% by weight, and can vary from about 20% to about 100% based on the total dry weight of the polymer. In one mode, talc is the filler. The coating membranes, and also the functional coatings may also include a material that improves the processing of the polymers. Such materials are generally known as plasticizers and include, for example, adipates, azelates, benzoates, citrates, isoebucates, phthalates, sebacates, stearates and glycols. Representative plasticizers include acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, ethylene glycol, propylene glycol, triacetin citrate, triacetin, tripropionine, diacetin, dibutyl phthalate. , acetyl monoglyceride, polyethylene glycols, castor oil, triethyl citrate, polyhydric alcohols, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, octal butyl phthalate, diisononyl phthalate, octal phthalate butyl, dioctyl azelate, epoxidized talate, trisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, phthalate of di-n-tridecyl, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyca monocaprylate rile, and glyceryl monocaprate. In one embodiment, the plasticizer is dibutyl sebacate. In one embodiment, the plasticizer is dibutyl sebacate. The amount of plasticizer used in the polymeric material ranges from about 10% to about 50%, for example, about 10, 20, 30, 40, or 50% based on the weight of the dry polymer. Antifoaming agents may also be included. In one embodiment, the antifoaming agent is simethicone. The amount of antifoaming agent used typically comprises from about 0% to about 0.5% of the final formulation. The amount of polymer to be used in the membrane-controlled formulations is typically adjusted to achieve the desired properties of drug administration, including the amount of drug to be administered, the rate and location of drug administration, the time delay of drug release, and the size of the microparticulates in the formulation. The amount of polymer applied typically provides a weight gain of about 10% to about 100% for the cores.

In one embodiment, the weight gain of the polymeric material varies from about 25% to about 70%. A polymeric membrane may include additional components to the polymers, such as, for example, fillers, plasticizers, stabilizers, or other excipients and processing aids. An example of an additional component of the membrane is sodium hydrogen carbonate, which can act as a stabilizer. The combination of all the solid components of the polymeric material, including the copolymers, fillers, plasticizers, and optional excipients and processing aids, typically provides a weight gain in the cores from about 10% to about 450%. In one embodiment, the weight gain is from about 30% to about 160%. The polymeric material can be applied by any known method, for example, by spraying using a fluidized bed coater (e.g., Wurster coating) or the tray coating system. The coated cores are typically dried or cured after application of the polymeric material. Curing means that the microparticles are maintained at a controlled temperature for a sufficient time to provide stable release rates. The curing can be carried out, for example, in an oven or in a fluidized bed dryer. Curing may be carried out at a temperature above the vitreous transition temperature of the polymeric material used in the formulation, for example, at about 30 ° C, 40 ° C, 50 ° C, or 60 ° C, depending on the polymer . A sealant or barrier can also be applied to the polymeric coating. Alternatively or additionally, a sealing or barrier layer can be applied to the core before applying the polymeric material. A sealer or barrier layer is not generally intended to modify the release of carrier-mediated transport statins. Suitable sealants or barriers are permeable or soluble agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, and xanthan gum. An exterior sealant / barrier, for example, could be used to improve the moisture resistance of the entire formulation. A sealant / barrier between the core and the coating, for example, could be used to protect the contents of the core of an outer polymeric coating that can exhibit pH-dependent or pH-independent dissolution properties. Additionally, there may be cases in which both effects are desired, i.e., moisture resistance and core protection, in which a sealant / barrier is applied between the core and the polymeric membrane coating, and then outside the coating of the core. polymer membrane Other agents can be added to improve the processability of a sealing or barrier layer. Such agents include talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate, and magnesium stearate, or a mixture thereof. The sealing or barrier layer can be applied from solution (eg aqueous) or suspension using any known means, such as fluidized bed coater (eg, Wurster coating) or tray coating system. Suitable sealants or barriers include, for example, WHITE OPADRY Y-1-700 and WHITE OY / B28920 OPADRY, each of which is available from Colorcon Limited, England. The invention also provides an oral dosage form containing a microparticulate carrier-mediated transport statin formulation as defined hereinbefore, in the form of oblong tablets, capsules, particles for suspension before dosing, sachets, or tablets. When the dosage form is in the form of tablets, the tablets may be disintegration tablets, fast-dissolving tablets, effervescent tablets, fast-melting tablets, and / or mini-tablets. The dosage form may be in any form suitable for oral administration of a drug, such as spheroidal, oval-shaped, or ellipsoidal. Dosage forms can be prepared from multiply-linked in a manner known in the art and include suitable pharmaceutically acceptable excipients, as desired. Soft Gelatin Capsules The formulations of the present invention can also be prepared as liquids, which can be filled into soft gelatine capsules. For example, the liguid may include a solution, suspension, emulsion, microemulsion, precipitate, or any other desired liquid medium carrying the carrier-mediated transport statins. The liquid can be designed to improve the solubility of carrier-mediated transport statins after release, or they can be designed to form an emulsion containing the drug or the dispersed phase after release. Examples of such techniques are well known in the art. The soft gelatin capsules can be coated, as desired, with a functional coating to retard drug release. Functional Coatings All the particular modalities described above, including, but not limited to, those based on matrix, based on osmotic pumps, soft gelatin capsules, and / or membrane controlled forms, which can also take the form of monolithic dosage forms and / or dose units multiple, may have a functional coating. Such coatings generally serve the purpose of delaying the release of the drug for a predetermined period. For example, such coatings may allow the dosage form to pass through the stomach to be subjected to stomach acid or digestive juices. For the acid-stable statins used in the formulations of the present invention, such protective coatings are not required, but may be used as another way to control the time and place of administration of the drug. Therefore such coatings can dissolve or erode upon reaching a desired point in the gastrointestinal tract, such as the upper intestine. Such functional coatings can exhibit pH-dependent (enteric) or pH-independent (non-enteric) solubility profiles. Those with independent pH profiles generally erode or dissolve after a predetermined period, and the period is generally related to the thickness and composition of the coating. Those with pH-dependent profiles, on the other hand, can maintain their integrity while at the pH of stomach acid, but quickly erode or dissolve after entering the more basic upper intestine. Therefore, a matrix-based, osmotic pump-based or membrane-controlled formulation can be further coated with a functional coating that retards drug release. For example, a membrane-controlled formulation can be coated with an enteric coating that delays exposure of the membrane-controlled formulation until the upper intestine is reached. After leaving the stomach acid and enter the most basic intestine. The enteric coating dissolves. The membrane-controlled formulation is then exposed to the gastrointestinal fluid, and then releases at least one transport mediated transport statin for a prolonged period, according to the invention. Examples of functional coatings such as those well known to those skilled in the art. In one embodiment, carrier-mediated transport statin formulations retard drug release. Following the delay, the formulation can rapidly release the drug. Such formulations would provide a faster and / or immediate therapeutic effect for the subject. The formulations of the present invention may further comprise pH modifying agents, for example, agents that exhibit a pKa of from 1 to about 6.5. Such agents include, but are not limited to, dicarboxylic acids. Dicarboxylic acids include, but are not limited to, 2-ethanedioic (oxalic), 3-propanedioic (malonic), 4-butanedioic (succinic), 5-pentanedioic (glutaric), 6-hexanedioic (adipic), cis- butenodioic (maleic), trans-bitenodioic (fumaric), 2,3-dihydroxybutanedioic (tartaric), 2-hydroxy-l, 2,3-propane carboxylic (citric), pimelic, suberic, azelaic, and sebacic. In some embodiments, one or more dicarboxylic acids are included in the formulation. In some embodiments, the formulation is substantially free of monocarboxylic acids. As used in this context, "substantially free" means that the monocarboxylic acids are not added to the formulation, but may be present otherwise. Monocarboxylic acids include, but are not limited to methanoic (formic), ethanoic (acetic), propanoic acids (propionic), butanoic (butyric), pentanoic (valeric), hexanoic (capric), heptanoic (enanthanic), 1-hydroxypropanoic (lactic), 3-benzyl-2-propenoic (cinnamic), and 2-oxopropanoic (pyruvic). The formulations of the present invention may include pH modifying agents that create a microenvironment around the transport mediated transport statin when exposed to aqueous fluids. For example, these agents can create a microenvironment around the carrier-mediated transport statin having a pH of from about 3 to about 6, or for example, a pH of about 5. Put simply, the formulations and methods of The present invention administers a therapeutic dose in the environment of use, which is the small intestine. Since it is believed that the uptake of carrier-mediated transport statins occurs almost completely in the small intestine, and that the absorption of the large intestine is negligible, the methods and formulations of this invention are designed to maximize the release of the drug in the intestine. thin. Therefore, absorption efficiency is maximized, and little drug is wasted. Unlike unstable statins in acids such as pravastatin, acid-stable statins, such as atorvastatin and rosuvastatin can be formulated with or without a protective coating. Upon administration to the patient, when the protective coating is not applied to the acid-stable statin, the methods and formulations of the present invention generally exhibit an extended release for about 1 to about 5 hours. The formulations and methods of the present invention may also make use of a protective coating, in which case there is minimal release in general terms or no release in the stomach, followed by controlled but complete release in the small intestine. Therefore, some methods and formulations of the present invention completely release at least one transport mediated transport statin in the environment of use in less than six hours. That is, more than 80% is released in a time before about 6 hours immediately after administration. "Completely released" means that more than 80% of the carrier mediated transport statin is released in the formulation. Using the compositions of the present invention, the systemic bioavailability of carrier-mediated transport statins can be reduced. For example, the absolute systemic bioavailability of LIPITOR® is approximately 12% (LIPITOR®, instructions for use (1997) Parke-Davis, Morris Plains NJ). Using the compositions of the present invention, the systemic bioavailability of atorvastatin can be reduced below 12%, for example, about 10%, 8%, 5%, or 0%, or any amount less than about 12%. When compared to an equally effective dose of LIPITOR®, or any formulation of conventionally released atorvastatin, administration of the compositions of the present invention achieves a reduction in systemic bioavailability to less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 25%, of that of the conventional release formulation. This is known here as the "relative" systemic bioavailability. In addition, for example, the absolute systemic biodispersibility of CRESTOR® is approximately 20%, CRESTOR®, instructions for use (2003) AstraZeneca, Wilmington, DE). Using the compositions of the present invention, the systemic bioavailability of rosuvastatin below about 20%, for example, about 18%, 15%, 10%, 5% or 0%, or any amount less than about 20%, can be reduced. . When compared to an equally effective dose of CRESTOR®, or any conventionally-released rosuvastatin formulation, administration of the compositions of the present invention achieves a reduction in systemic bioavailability to less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 25%, of that of the conventional release formulation. This is known here as the "relative" systemic bioavailability. The compositions of the present invention can also be used to increase specific liver extraction of carrier-mediated transport statins. For example, the hepatic extraction of atorvastatin from LIPITOR® is approximately 70% (Igel et al., (2002) J. Clin Pharmacol 42: 835). Using the compositions of the present invention, the extraction of atorvastatin may be increased to approximately more than 70%, for example, to approximately 75%, 80%, 85%, 90%, 95%, or 100%, or any greater amount 70% Furthermore, for example, in the case of CRESTOR®, the hepatic extraction of rosuvastatin is approximately 90% (Igel et al., (2002) J. Clin Pharmacol 42: 835). Using the compositions of the present invention, the hepatic extraction of rosuvastatin can be increased to more than about 90%, for example, to about 95% to 100%, or any amount greater than 90%. The maximum plasma concentration or Cmax of carrier-mediated transport statins can be reduced by the formulations and compositions of the present invention, when compared to equally effective doses of other conventional carrier-mediated delivery release formulations. For example, Cmax can be reduced by the formulations and compositions of the present invention when compared to an equally affective dose of LIPITOR®, or any conventional release of atorvastatin formulation. For example, when compared to the Cma? resulting from the use of the equally effective dose of LIPITOR®, or any formulation of conventionally released atorvastatin, Cmax can be reduced to less than about 80%, 70%, 60%, 50%, 40%, 30%, or %. In addition, for example, Cmax can be reduced by the formulations and compositions of the present invention when compared to an equally effective dose of CRESTOR®, or any other rosuvastatin formulation of conventional release. For example, when compared to Cmax resulting from the use of an equally effective dose of CRESTOR®, or any conventionally-released rosuvastatin formulation, Cmax can be reduced to less than about 80%, 70%, 60%, 50% , 40%, 30%, or 25%. The therapeutic level is the minimum concentration of carrier-mediated transport statin that is therapeutically effective in a particular patient. Of course, a person skilled in the art will recognize that the therapeutic level may vary depending on the individual to be treated and the severity of the condition. For example, the age, body weight, and medical history of the individual patient may affect the therapeutic efficacy of the therapy. A competent physician can consider these factors and adjust the dosage regimen to ensure that the dose is achieving the desired therapeutic result without undue experimentation. It is also noted that the clinical specialist and / or treating physician will know how and when to interrupt, adjust, and / or terminate the therapy in conjunction with the response of the individual patient. The total daily dose of carrier-mediated transport statin formulations, for example, can vary from about 1 mg to about 200 mg. For example, in general, the total daily dose of atorvastatin in the formulations of the present invention ranges from about 1 to about 200 mg, about 1 to about 160 mg, about 1 to about 80 mg, about 5 to about 80 mg, about 10 to about 80 mg, or any whole number or intermediate fractional amount. An individual dose can be formulated to contain about 1, 5, 10, 15, 20, 25, 30, 35, 40, 60, 80, 100, 120, 140, 160, 180, or 200 mg- of atorvastatin. In one embodiment, an individual dose contains approximately 5, 10, 15, 20, 40, 60, or 80 mg of atorvastatin.

In addition, for example, in general, the total daily dosage of rosuvastatin in the formulations of the present invention ranges from about 1 mg to about 200 mg, about 1 to about 160 mg, about 1 to about 80 mg, about 5 to about 80 mg, about 10 to about 80 mg, or any whole number or intermediate fractional amount. An individual dose may be formulated to contain about 1, 5, 10, 15, 20, 25, 30, 35, 40, 60, 80, 100, 120, 140, 160, 180, or 200 mg of rosuvastatin. In one embodiment, an individual dose contains approximately 5, 10, 15, 20, 40, 60, or 80 mg of rosuvastatin. Carrier-mediated transport statin formulations of the present invention can be described by their dissolution profiles. A person skilled in the art is familiar with the techniques used to determine such dissolution profiles. The standard methodologies established in the Pharmacopeia of the United States can be used, which methodologies are incorporated here as reference in the relevant part. For example, the dissolution profile can be measured either in Type I Apparatus of the United States Pharmacopeia (baskets) or a Type II Apparatus of the United States Pharmacopeia (pallets). For the independent formulations of the pH, the formulations can be evaluated in phosphate buffer at pH 6.8 or higher, 37 ° C and 50-100 rpm. For pH-dependent formulations, the formulations can be evaluated in HCl 0.01-0.1 N for the first 2 hours at 37 ° C and 50-100 rpm, followed by transfer to phosphate buffer at pH 6.8 or higher for the remainder of the proof. Other suitable buffer systems for measuring the dissolution profile for the pH-dependent and pH-independent formulations are well known to those skilled in the art. For both pH-dependent and pH-independent formulations, surfactants (e.g., 1% sodium laurel sulfate) may be included in the dissolution medium, especially for the poorly water soluble drugs by FDA directives. In vitro evaluation of dissolution profiles (http: // www .dada.gov./cder/guidance/1306fnl.pdf). For example, the in vitro dissolution profile for carrier mediated transport statin formulations, without protective coating, of the present invention may correspond to the following: (1) about 30% release after 1-2 hours; (2) about 50% release after about 4 hours; (3) about 70% release after about 6 hours; and (4) about more than 80% release after about 8 hours. Alternatively, the profile may correspond to: (1) approximately 20% release after 1.2 hours; (2) about 20% to about 40% release after about 4 hours; and (3) approximately more than 80% release after 6 hours. For the formulations of the present invention where the protective coating is not used, the drug begins the release immediately in the stomach where there is no initial delay while the drug is in the stomach. In one embodiment, the formulations of the present invention without protective coatings may exhibit a release rate, when measured in a Type II dissolution apparatus, in a buffer of pH 6.8 or higher, of the following: 1-2 hours: less than 30% approximately; 4 hours less than 60% approximately; 6 hours: less than 80% approximately; 8-10 hours: more than 80% approximately. Such formulations may also exhibit a release rate, when measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 1-2 hours: less than about 25%; 4 hours: less than 50% approximately, - 8 hours less than 80% approximately. The in vitro dissolution profile of the enteric coated carrier mediated transport statin compositions of the present invention, which can additionally control bioavailability, may correspond to the following, when evaluated in acid for 2 hours followed by pH 6.8 buffer. or higher: (1) minimum release after 2 hours; and (2) complete release after 8 hours. Alternatively, the profile may correspond to: (1) approximately less than 50% release after about 2 hours; (2) about 20% to about 80% release after 4 hours; and (3) about more than 60% release after about 6-8 hours. When an enteric coating is used, the release of the drug from the formulations can be retarded in acid for 1-2 hours. In buffer of pH 6.8 or higher, the release of the drug is in a manner consistent with transit in the small intestine, the site of absorption of transport-mediated transport statins.

The in vitro dissolution profile of carrier mediated transport statin compositions without enteric coating of the present invention may correspond to the following: (1) minimal release after approximately 1-2 hours; and () complete release after 8 hours. Alternatively, the profile may correspond to: (1) less than about 50% of the carrier-mediated transport statin is released after approximately 1-2 hours; (2) about 20% to about 80% is released after about 4 hours; and (3) more than about 60% is released after approximately 6-8 hours. For formulations without enteric coatings, the release of the drug from the compositions is delayed for 1-2 hours, regardless of the pH of the dissolution medium. After 1-2 hours, which coincides with the emptying of the dosage form from the stomach to the small intestine, the drug is released in a manner consistent with the transit of the dosage form through the small intestine, the absorption site of transport-mediated transport statins.

Any of the pharmaceutical compositions described above may further comprise one or more pharmaceutically active compounds different from the carrier mediated transport statins, discussed above. Such compounds can be provided to treat the same condition that is treated with a carrier-mediated transport statin, or a different one. Those skilled in the art will be familiar with examples of techniques for incorporating additional active ingredients into the formulations of the present invention. Alternatively, such additional pharmaceutical compounds can be provided in a separate formulation and co-administered to a patient with a carrier-mediated transport statin composition. Such separate formulations may be administered before, after, or concurrently with the administration of the carrier-mediated transport statin. The invention is further illustrated by reference to the following examples. It will be apparent to those skilled in the art that many modifications can be predicted, both to materials and methods, without departing from the purpose and scope of the invention.

EXAMPLES Example 1; Production of 10 mg Atorvastatin / Modified Release Matrix Tablets, Using METHOCEL ™ K100LV Premium CR by Direct Compression The atorvastatin formulations, comprising the components set forth in Table 1, are produced as follows. Table 1 Each ingredient is weighed first. Lactose, atorvastatin, colloidal silicon dioxide, METHOCEL ™, and AVICELL ™ are placed in a mixer and mixed for 15 minutes until homogeneous. The magnesium stearate is then added to the mixer and the mixture is stirred for an additional 5 minutes. The mixture is compressed into oval tablets in a suitable tabletting machine. The target weight of each tablet is 200 mg.

Example 2: Production of Matrix Tablets of 10 ptg of Atorvastatin Modified Release / Using METHOCEL ™ K100M Premium CR # and Laurel Sodium Sulphate / by Direct Compression The modified release formulations as set forth in Table 2 are produced as follows.

Table 2 First weigh each ingredient. Lactose, atorvastatin, sodium laurel sulfate, colloidal silicon dioxide, METHOCEL ™, and AVICELL ™ are placed in a mixer and mixed for 15 minutes until homogeneous. The magnesium stearate is then added to the mixer and the mixture is stirred for an additional 5 minutes. The mixture is compressed into oval tablets in a suitable tabletting machine. The target weight of each tablet is 200 mg.

Example 3; Production of 5 mg Atorvastatin / Modified Release Matrix Tablets, Using METHOCEL ™ K100LV Premium CR by Wet Granulation Modified release formulations of atorvastatin as set forth in Table 6 are produced as follows, Table 3 First weigh each ingredient. Atorvastatin dissolves in isopropyl alcohol (IPA). The polyvinyl pyrrolidone (PVP) is then dissolved in the IPA / atorvastatin solution. Then, 50% of Avicel and 50% lactose are placed in a suitable mixer, such as a planetary mixer (Hobart) or a high cut rate mixer (Diosna / Fielder), and mixed for 15 minutes to produce a homogeneous mixture . While continuing to mix the solution, the atorvastatin / PVP solution is added, which serves as the granulation fluid. Mixing is continued until a suitable granulation endpoint is reached, adding more isopropyl alcohol if necessary to produce suitable granules. The granules are then dried (using either an oven or fluidization equipment) until they contain an acceptable level of moisture (eg, approximately less than 1.0%) and an acceptable content of isopropyl alcohol (eg, approximately less than 0.5. %). The dried granules are then passed through a suitable spray equipment (for example, Co-mill, Fitzpatrick mill) which has been equipped with a suitably sized mesh (for example 100-500 microns). The resulting granules are then placed in a mixer to which colloidal silicon dioxide is added, and the rest of the Avicel and lactose are mixed for 15 minutes. Then the magnesium stearate is added and mixed for an additional 5 minutes. The mixture is then compressed into oval shaped tablets using a suitable tabletting machine. The target weight of each tablet is 100 mg. Alternatively, the PVP can be dissolved in the isopropyl alcohol and the atorvastatin is added before the drying and granulation processes described above. Another alternative is to dissolve the atorvastatin in the isopropyl alcohol (or any suitable solvent) and the PVP is then added before the drying and granulation process described above.

Example 4; Production of 5 mg Atorvastatin Modified Release Matrix Tablets, Using METHOCEL ™ K100M Premium CR, Sodium Caprate, and Sodium Lauryl Sulfate / by Granulation The modified release formulations of atorvastatin as set forth in Table 4 are produced according to the process of example 3, with the addition of sodium lauryl sulfate and sodium caprate to the initial mixture of lactose and AVICELL ™. Alternatively, sodium lauryl sulfate and sodium caprate can be added after the granulated mixture is obtained. Table 4 In vitro dissolution tests for examples 1-4 were carried out on atorvastatin modified release core tablets, using the following parameters: USP (711); paddle at 50 rpm; medium: phosphate buffer, pH 6.8; a suitable surfactant, (for example, 1% sodium lauryl sulfate) and UV absorbance at the appropriate wavelength. Example 5: Rosuvastatin 10 mg Rapid Release Tablet Core The fast release tablet cores, comprising the components set forth in Table 5, are produced as follows. These cores can be used in membrane-controlled formulations Table 5 Each ingredient is weighed using a suitable balance. The AVICELL ™, rosuvastatin, and lactose are mixed in a V-type mixer for 30 minutes until a homogenous mixture is reached. Magnesium stearate is added and the ingredients are mixed for an additional 5 minutes. The mixture is then divided and compressed into tablets in a suitable tabletting machine, using a flat oval tool. The target weight of each tablet is 100 mg. Example 6: Rosuvastatin Rapid Release Tablet Membrane Coating (Membrane Controlled) The rosuvastatin formulations set forth in Example 5 above are coated with the coatings shown in Table 6. Table 6 Polymer = polyvinyl chloride terpolymer, polyvinyl acetate, and polyvinyl alcohol (PVC / PVAc / PVOH) The solvents are removed during processing. The tablets of Example 5 are placed in a suitable coating machine (e.g. Acelacota) and heated to the required temperature. A sufficient amount of the polymer solution indicated in Table 6 is then sprayed onto the tablets, and the tablets are dried in the coating machine. In vitro dissolution tests are carried out on the modified-release, membrane-controlled formulations, using the following parameters; USP (711); paddle at 50 rpm; medium: phosphate buffer, pH 6.8; and UV absorbance at the appropriate wavelength. Example 7: Entropically coated Membrane Tablets Any of the dosage forms according to the present invention can be coated with an enteric coating suspension. To determine the amount of enteric coating required on the modified release tablets, coating experiments are carried out. The coating test is carried out on selected 10 mg resistant formulation prototypes (batch size approximately 1-2 kg). Details of the composition for the enteric coating suspension: Table 7 The coating is applied to the membrane coated tablets using EUDRAGIT ™ L30 D55, 5%, 10%, 15%, and 20% thickness of coating polymer (ie, percentage weight gain over the tablet coating) . The coating is applied onto the cores of membrane-coated tablets using the appropriate coating equipment. In vitro dissolution tests are carried out on the enteric coated modified release tablets, using the following parameters: USP (711); pallet at 50 RPM; medium: HCl 0.01 to 0.1 N for 2 hours, followed by phosphate buffer, pH 6.8 or higher, for the rest of the test; UV absorbance at the appropriate wavelength. The samples are collected and subjected to the dissolution test. The objective in vivo solution for the enteric coated tablets is shown below: Half Time Point% Released (Hours) Acid 2.0 < 10% 1.0 10-40 2.0 30-70 Shock absorber 3.0 > 45 pH6.8 4.0 > 60 5.0 > 75 6.0 > 80 Example 8: Functional pH Independent Functional Coatings Any of the dosage forms according to the present invention can be coated with a pH independent coating, for example, as provided in Table 8 below. Table 8 In vitro dissolution tests are carried out on the modified release tablets, with functional coating independent of pH using the following parameters: USP (711); 50 RPM palette; medium: phosphate buffer, pH 6.8; and UV absorbance at the appropriate wavelength. The objective in vitro solution for tablets with functional coating independent of pH are shown below.

Half Time Point Released (Hours) 1. 0 > 10% 2.0 10-40% Shock absorber 3.0 30-70% pH 6.8 4.0 > 45% 5.0 > 60% 6.0 > 75% 7.0. > 80% Example 9: Comparison of Modified Release Atorvastatin Formulation and Conventional Release Atorvastatin Formulation When Reducing Cholesterol in a Patient To evaluate the efficacy of the modified release formulations of the present invention, the formulations were evaluated by the cholesterol reduction in patients with primary hypercholesterolemia and mixed dyslipidemia, and were compared with LIPITOR® at the same dose. Low doses were also evaluated to show that the formulations present are more effective at lower doses than LIPITOR®. The present formulations are also evaluated for their effect on the exhaustion of systemic ubiquinone in relation to exhaustion caused by LIPITOR®. The results will show that the present formulations cause significantly less systemic ubiquinone depletion relative to conventional release formulations of atorvastatin, such as LIPITOR®. The study begins with at least a four-week placebo period where patients receive dietary guidance. Patients are randomized into groups that receive: A. Conventional atorvastatin (LIPITOR®) at 20 milligrams daily for 6 weeks, subsequently increased to 40 mg daily for 6 weeks, - B. The inventive formulation at 5 mg daily for 6 weeks. At the end of that period, patients are randomized to receive either 5 mg or 10 mg daily for an additional 6 weeks; C. The inventive formulation at 10 mg daily for 6 weeks. At the end of that period, patients are randomized to receive either 10 mg or 20 mg daily for an additional 6 weeks; or D. The inventive formulation at 20 mg for 6 weeks, subsequently increased to 40 mg daily for 6 weeks. Groups A and D each contain 20 patients, while Groups B and C each contain 40 patients, to allow randomization in groups of 20 patients in week 6. This design allows a period of placebo, and a comparison of response to the dosage of the formulations present with the conventional product. Cholesterol levels are measured before entering the study, before randomization (baseline) and in weeks 3, 6, 9 and 12. Systemic ubiquinone levels are measured before randomization, and in weeks 6 and 12, to determine the relative exhaustion of the levels of systemic ubiquinone. The liver baseline enzymes are measured at weeks 3, 6, 9 and 12. Plasma atorvastatin concentrations are obtained for population analysis at weeks 6 and 12. Efficiency endpoints include changing the baseline in total cholesterol (C), LDL-C, triglycerides (TG), HDL-C, VLDL-C and the ratios of Total-C / HDL-C and LDL / HDL-C. Safety will be evaluated considering, among other things, the change of baseline in systemic ubiquinone levels and the change of baseline in liver transaminase enzymes. Example 10; Comparison of the Modified Release Rosuvastatin Formulation and the Conventional Release of Rosuvastatin Formulation in Lowering a Patient Cholesterol To evaluate the efficacy of the modified release formulations of the present invention, the formulations are evaluated for cholesterol reduction in patients with primary hypercholesterolemia and mixed dyslipidemia, and compared with CRESTOR® at the same dose. Low doses are also evaluated to show that the formulations present are more effective at lower doses than CRESTOR®. The present formulations are also evaluated in terms of their effect on the depletion of systemic ubiquinone in relation to the exhaustion caused by CRESTOR®. The results will show that the present formulations cause significantly less systemic ubiquinone depletion relative to conventional release formulations of rosuvastatin, such as CRESTOR®. The study begins with at least a four-week placebo period, where patients receive dietary guidance. Patients are randomized into groups that receive: A. Conventional rosuvastatin (CRESTOR®) at 10 milligrams daily for 6 weeks, subsequently increased to 20 mg daily for 6 weeks; B. The inventive formulation at 2.5 mg daily for 6 weeks. At the end of that period, patients are randomized to receive either 2.5 mg or 5 mg daily for an additional 6 weeks; C. The inventive formulation at 5 mg daily for 6 weeks. At the end of that period, patients are randomized to receive either 5 mg or 10 mg daily for an additional 6 weeks; or D. The inventive formulation at 10 mg for 6 weeks, subsequently increased to 20 mg daily for 6 weeks. Groups A and D each contain 20 patients, while Groups B and C each contain 40 patients, to allow randomization in groups of 20 patients in week 6. This design allows a period of placebo, and a comparison of response to the dosage of the formulations present with the conventional product. Cholesterol levels are measured before entry into the study, before randomization (baseline) and at weeks 3, 6, 9 and 12. Systemic ubiquinone levels are measured before randomization, and in weeks 6 and 12, to determine the relative exhaustion of systemic ubiquinone levels. The liver baseline enzymes are measured at weeks 3, 6, 9 and 12. Plasma rosuvastatin concentrations are obtained for population analysis at weeks 6 and 12. Efficiency endpoints include the change of the baseline in total cholesterol (C), LDL-C, triglycerides (TG), HDL-C, VLDL-C and the ratios of Total-C / HDL-C and LDL / HDL-C. Safety will be evaluated considering, among other things, the change of baseline in systemic ubiquinone levels and the change of baseline in liver transaminase enzymes.

Claims (44)

1. CLAIMS 1. A method for increasing the hepatic bioavailability of at least one carrier-mediated, acid-stable transport statin, comprising administering to a subject a therapeutically effective amount of the at least one carrier-mediated, acid-stable transport statin. , or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, characterized in that the formulation releases the statin at a rate that prevents saturation of the intestinal and hepatocytic absorption mechanisms.
2. 2. The method of claim 1, characterized in that the formulation does not retard the release of the statin in the stomach.
3. 3. The method of claim 1, characterized in that the formulation delays the release of substantial amounts of the statin until the formulation has passed from the stomach.
4. The method of claim 1, characterized in that the at least one carrier-mediated transport statin, stable in acids, is atorvastatin.
5. The method of claim 1, characterized in that the at least one carrier mediated transport statin, stable in acids, is rosuvastatin.
6. The method of claim 1, characterized in that the formulation releases approximately more than 80% of its statin content over a period of from about 1 hour to about 8 hours.
7. The method of claim 1, characterized in that the administration achieves a relative systemic bioavailability of the at least one carrier-mediated transport statin, stable in acids, when compared to an equally effective dose of a conventional release formulation, less than about 90%.
8. The method according to claim 7, characterized in that the administration achieves a relative systemic bioavailability of the at least one carrier-mediated transport statin, stable in acids, when compared to an equally effective dose of a release formulation conventional, less than about 80%.
9. A method for treating hypercholesterolemia comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one carrier mediated transport statin, acid stable, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, characterized in that the formulation releases at least one carrier-mediated transport statin, stable in acids for a period greater than about 2 hours.
10. The method of claim 9, characterized in that the at least one carrier-mediated transport statin, stable in acids, is atorvastatin.
11. The method of claim 9, characterized in that the at least one carrier mediated transport statin, acid stable, is rosuvastatin.
12. The method of claim 9, characterized in that, the formulation exhibits a rate of release of the carrier mediated transport statin, stable in acids as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.
13. A modified release formulation comprising a therapeutically effective amount of at least one carrier-mediated transport statin, acid stable, or a pharmaceutically acceptable salt thereof, which formulation releases the at least one transport mediated transport statin. carriers, stable in acids at a rate that is approximately equal to or less than the absorption rate in the intestine and in the liver.
14. The formulation of claim 13, characterized in that the at least one carrier-mediated transport statin, stable in acids, is atorvastatin.
15. The formulation of claim 13, characterized in that the at least one carrier mediated transport statin, acid stable, is rosuvastatin.
16. 16. The formulation according to claim 13, characterized in that, the formulation exhibits a carrier-mediated transport statin release, stable in acids as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.
17. 17. A method for increasing the hepatic bioavailability of at least one carrier-mediated transport statin of large molecular weight, comprising administering to a subject a therapeutically effective amount of the at least one mediated transport statin of molecular weight carriers or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, characterized in that, the formulation comprises a membrane permeability improver and wherein the formulation releases the at least one carrier mediated transport statin, of large molecular weight to a speed that avoids the saturation of the intestinal and hepatocytic absorption mechanisms.
18. 18. The method of claim 17, characterized in that the at least one carrier mediated transport statin of large molecular weight is atorvastatin.
19. 19. The method of claim 17, characterized in that the at least one medium-mediated transport statin of large molecular weight is rosuvastatin.
20. The method of claim 17, characterized in that the formulation releases approximately more than 80% of its statin content over a period of from about 1 hour to about 8 hours.
21. The method of claim 17, characterized in that the administration achieves a relative systemic bioavailability of less than about 90% of the at least one carrier mediated transport statin of large molecular weight when compared to an equally effective dose of a conventional release formulation.
22. 22. The method according to claim 17, characterized in that the administration achieves a relative systemic bioavailability of the at least one carrier-mediated transport statin of large molecular weight when compared to an equally effective dose of a carrier formulation. conventional release, less than about 80%.
23. 23. A method for treating hypercholesterolemia comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one carrier-mediated transport statin, of a large molecular weight, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, characterized in that the formulation comprises at least one membrane permeability improver and wherein the formulation releases the at least one medium-mediated transport statin of large molecular weight over a period greater than about 2 hours.
24. The method of claim 23, characterized in that the at least one carrier-mediated transport statin of large molecular weight is atorvastatin.
25. 25. The method of claim 23, characterized in that the at least one carrier-mediated transport statin of large molecular weight is rosuvastatin.
26. 26. The method of claim 23, characterized in that, the formulation exhibits a carrier-mediated transport statin release rate of large molecular weight as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.
27. 27. A modified release formulation comprising a therapeutically effective amount of at least one carrier mediated transport statin, of a large molecular weight, or a pharmaceutically acceptable salt thereof, and at least one membrane permeation enhancer, and characterized because, the formulation releases the at least one carrier mediated transport statin of large molecular weight at a rate that is approximately equal to or less than the rate of absorption in the intestine and liver.
28. The formulation of claim 27, characterized in that, the at least one carrier-mediated transport statin, large molecular weight is atorvastatin.
29. 29. The formulation of claim 27, characterized in that the at least one carrier-mediated transport statin of large molecular weight is rosuvastatin.
30. The formulation according to claim 27, characterized in that, the formulation exhibits a carrier-mediated transport statin release of large molecular weight as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.
31. 31. A method for increasing the hepatic bioavailability of at least one carrier-mediated transport statin, sparingly soluble in water, comprising administering to a subject a therapeutically effective amount of the at least one carrier-mediated transport statin, sparingly soluble in water, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, characterized in that, a method of improving solubility has been applied to carrier-mediated transport statin, poorly soluble in water and wherein the formulation releases the less a carrier-mediated transport statin, poorly soluble in water at a rate that prevents saturation of intestinal and hepatocytic absorption mechanisms.
32. 32. The method of claim 31, characterized in that the at least one carrier-mediated transport statin, which is poorly soluble in water, is atorvastatin.
33. 33. The method of claim 31, characterized in that the at least one mediated transport statin, sparingly soluble in water, is rosuvastatin.
34. 34. The method of claim 31, characterized in that the formulation releases approximately more than 80% of its statin content over a period of from about 1 hour to about 8 hours.
35. 35. The method of claim 31, characterized in that the administration achieves a relative systemic bioavailability of less than about 90% of the at least one carrier mediated transport statin, poorly soluble in water, when compared to an equally effective dose of a conventional release formulation.
36. 36. The method according to claim 31, characterized in that the administration achieves a relative systemic bioavailability of the at least one carrier-mediated transport statin, which is poorly soluble in water, when compared to an equally effective dose of a drug formulation. conventional release, less than about 80%.
37. 37. A method for treating hypercholesterolemia comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one carrier-mediated transport statin, poorly soluble in water, or a pharmaceutically acceptable salt thereof, in A pharmaceutical formulation, characterized in that a method of improving the solubility of the carrier-mediated transport statin has been applied, which is poorly soluble in water and where the formulation releases at least one carrier mediated transport statin, which is poorly soluble in water. water for a period greater than about 2 hours.
38. 38. The method of claim 37, characterized in that at least one carrier mediated transport statin, sparingly soluble in water is atorvastatin.
39. 39. The method of claim 37, characterized in that the at least one mediated transport statin, sparingly soluble in water, is rosuvastatin.
40. 40. The method of claim 37, characterized in that, the formulation exhibits a release rate of the carrier-mediated transport statin, poorly soluble in water as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.
41. 41. A modified release formulation comprising a therapeutically effective amount of at least one carrier mediated transport statin, sparingly soluble in water, or a pharmaceutically acceptable salt thereof, characterized in that it has been applied to the mediated transport statin per carrier, poorly soluble in water a method of improving solubility, and which formulation releases at least one transport mediated carrier statin, poorly soluble in water at a rate that is approximately equal to or less than the absorption rate in the intestine and in the liver.
42. 42. The formulation of claim 41, characterized in that the at least one transport mediated transport statin, which is poorly soluble in water, is atorvastatin.
43. 43. The formulation of claim 41, characterized in that the at least one mediated transport statin, sparingly soluble in water, is rosuvastatin.
44. 44. The formulation according to claim 41, characterized in that, the formulation exhibits a release of carrier mediated transport statin, poorly soluble in water as follows: 2 hours: approximately less than or equal to 40%; 4 hours: approximately between 20% and approximately 80%; and 6 hours: approximately more than 70%.