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  Pravastatin pharmaceutical formulations and methods of their useUSPTO Application #: 20050277691Title: Pravastatin pharmaceutical formulations and methods of their use Abstract: The present invention relates to formulations comprising a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, and methods of their use. The present formulations and methods are designed to release little or no pravastatin in the stomach but release a therapeutic amount of pravastatin in the small intestine, thereby limiting systemic exposure of the body to pravastatin and maximizing hepatic-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. (end of abstract) Agent: Duane Morris LLP - Washington, DC, US Inventors: Jackie Butler, John Devane, Paul Stark USPTO Applicaton #: 20050277691 - Class: 514460000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Oxygen Containing Hetero Ring, The Hetero Ring Is Six-membered, Chalcogen Bonded Directly To Ring Carbon Of The Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20050277691. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of priority of U.S. Provisional Patent Applications Nos. 60/347,775, filed Jan. 11, 2002, and 60/407,269, filed Sep. 3, 2002, the entire disclosure of each of which is incorporated by reference herein. [0002] Pravastatin is an HMG-CoA reductase inhibitor that lowers blood lipid levels by reducing cholesterol biosynthesis in the liver. It is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. [0003] Pravastatin sodium (sold as PRAVACHOL.RTM.) is commercially available for oral administration in 10 mg, 20 mg, 40 mg and 80 mg tablets. It is generally prescribed for lowering cholesterol and blood lipid levels. The drug has been found to be useful in preventing coronary events in hypercholesterolemic patients that do not have coronary heart disease and as a secondary preventative of coronary cardiovascular events in hypercholesterolemic patients that have coronary artery disease. The drug is also used as an adjunctive therapy (to supplement dietary restrictions and exercise) in reducing elevated Total-C, LDL-C, Apo B and TG levels, and to increase HDL-C levels in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb), elevated serum triglyceride levels (Fredrickson Type IV), and primary dysbetalipoproteinemia (Fredrickson Type III) in patients who do not respond adequately to dietary restrictions. [0004] Pravastatin sodium is typically administered orally in its active form. In clinical pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of the drug attained 1 to 1.5 hours following ingestion. Based on urinary recovery of radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. PRAVACHOL.RTM. Package Insert. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour before meals. PRAVACHOL.RTM. Package Insert. [0005] Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66), which is its primary site of action, and the primary site of cholesterol synthesis and LDL-C clearance. In vitro studies have shown that pravastatin is easily transported into hepatocytes with substantially less uptake into other cells. In view of pravastatin's extensive first-pass hepatic metabolism, plasma levels may not necessarily correlate with lipid-lowering efficacy. Pravastatin plasma concentrations (observed as: area under the concentration-time curve (AUC), peak (C.sub.max), and steady-state minimum (C.sub.min)) are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime (PM) dose was decreased 60% compared to the bioavailability following a morning (AM) dose. [0006] Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered in the evening was marginally more effective than the efficacy of the morning dose. This finding suggests that there is greater hepatic extraction of the drug when it is administered in the evening. [0007] Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The coefficient of variation, based on between-subject variability, was 50% to 60% AUC. Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal healthy volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes, i.e., biliary excretion and biotransformation. Since there are dual routes of elimination, the potential exists both for compensatory excretion by the alternate route, as well as for accumulation of drug and/or metabolites in patients with renal or hepatic insufficiency. [0008] Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi pravastatin and the 3.alpha.-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring hydroxylation to SQ 31,945, (c) .omega.-1 oxidation of the ester side chain, (d) .alpha.-oxidation of the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a hydroxyl group to a keto group, and (g) conjugation. The major degradation product is the 3.alpha.-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA reductase inhibitory activity of the parent compound. [0009] Pravastatin is absorbed from the intestine by a carrier-mediated mechanism. The absorption is not uniform throughout the intestinal tract; it is thought to largely occur in the small intestine, but the absorption is low in the distal small intestine (ileum) and colon (Lennernas & Fager, 1997). The uptake of pravastatin in the intestine takes place by an apparently saturable mechanism in the presence of a proton gradient; and the uptake is inhibited by monocarboxylic acids (Tamai et al, 1995). [0010] Following absorption from the intestine, pravastatin is taken up into the liver by an active transport mechanism exhibiting a high hepatic extraction ratio (0.66) (Quion & Jones, 1994) or reasonably high hepatic extraction ratio (0.45) (Lennernas & Fager, 1997), which refers to the proportion of the drug that is extracted by the liver. This uptake of pravastatin into the hepatocytes may be mediated by a multispecific anion transporter (Yamazaki et al, 1993) believed to be OATP2 (Hsiang et al, 1999), and appears to be saturable (Nakai et al, 2001). [0011] Pravastatin that is not absorbed by the hepatic system is delivered systemically to the rest of the body and can be detected in the blood plasma. Systemic pravastatin may cause unwanted effects in non-hepatic tissues. For example, one of the most significant adverse effects of HMG-CoA reductase inhibitors, such as pravastatin, is muscle necrosis, manifested as myalgia, limb weakness, elevation of serum creatinine kinase, and myoglobinuria (Rhabdomylosis) (Hunninghake, 1992). Severe myopathy has been observed in patients treated with pravastatin (Schalke et al, 1992). [0012] Pravastatin is a relatively polar hydrophilic compound. FIG. 2 illustrates the fate of pravastatin in the body. The drug shows poor stability in acidic conditions, such as the environment of the stomach. If left unprotected, pravastatin undergoes non-enzymatic conversion in the stomach to a relatively inactive metabolite (Triscari et al, 1995). [0013] Enteric coatings may be used to protect the drug from the acidic environment of the stomach. However, the coatings themselves often have acidic properties. As a result, pravastatin can be rendered less active by an acidic coating, reducing the overall efficacy of the treatment. [0014] Enteric coatings can be combined with excipients having a basic pH. However, such basic excipients prevent optimal intestinal absorption, which occurs at a slightly acidic pH of about 5 in the intestine. To compensate for the inefficient absorption that occurs with basic excipients, higher concentrations of pravastatin must be provided in each dose. Consequently, each dose is more expensive and a significant portion of the active ingredient never reaches the site of action in the liver. [0015] Thus, there exists a need in the art for new pravastatin formulations that survive the acidic environment of the stomach, while allowing for more optimal absorption in the intestine and then in the liver. [0016] Pravastatin inhibits HMG-CoA reductase, which is responsible for the conversion of HMG-CoA into mevalonate. Pravastatin interferes with cholesterol synthesis by inhibiting the formation of mevalonate, a cholesterol precursor. However, mevalonate is also a precursor of ubiquinone (Coenzyme Q), an essential component of the electron transport chain in mitochondria (Goldstein & Brown, 1990). FIG. 1 illustrates the biosynthesis of cholesterol and ubiquinone. Thus, pravastatin not only interferes with the biosynthesis of cholesterol, but also with other metabolic pathways that require mevalonate. Thus, in non-hepatic tissues, pravastatin may exert undesirable effects on important metabolic pathways. It is believed that pravastatin-mediated myopathy results from depletion of ubiquinone (coenzyme Q) levels in muscle tissue. [0017] Again, there exists a need in the art for pravastatin formulations that limit systemic exposure of the body to pravastatin, and maximize hepatic-specific absorption of the drug, thus increasing the efficacy of pravastatin treatments and reducing undesirable side effects. BRIEF DESCRIPTION OF THE DRAWINGS [0018] FIG. 1 illustrates the biosynthesis of cholesterol and ubiquinone. [0019] FIG. 2 illustrates the pharmacokinetics of pravastatin. [0020] As used herein, the phrase "modified-release" 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 may extend the influence or effect of a therapeutically effective dose of an active compound in a patient. Such formulations are referred to herein as "extended-release" formulations. In addition to maintaining therapeutic levels of the active compound, a modified release formulation may also be designed to delay the release of the active compound for a specified period. Such compounds are referred to herein as "delayed onset" formulations or dosage forms. Still further, modified-release formulations may exhibit properties of both delayed and extended release formulations, and thus be referred to as "delayed-onset, extended-release" formulations. [0021] As used herein, the term "conventional rapid release pravastatin formulation" means a formulation that, when tested in a USP dissolution bath in pH 6.8 buffer, releases greater than 80% of its content in less than about 1 hour. [0022] As used herein, the term "pravastatin" includes pravastatin, and any pharmaceutically acceptable salts thereof. [0023] As used herein, the term "pharmaceutically acceptable excipient" includes ingredients that are compatible with the other ingredients in a pharmaceutical formulation, in particular the active ingredients, and not injurious to the patient when administered in acceptable amounts. Continue reading... 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