US 2008.0058292A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0058292 A1 Tawakol (43) Pub. Date: Mar. 6, 2008 (54) METHOD FOR INCREASING HDL AND A6II 3 L/455 (2006.01) HDL-2B LEVELS A6II 3 L/60 (2006.01) 76 ). A6IP 3/00 (2006.01) (76) Inventor: Raif Tawakol, Merced, CA (US) (52) U.S. Cl. ............................................ 514/161; 514/356 Correspondence Address: RONALD V. DAVIDGE 9900 STRLING ROAD (57) ABSTRACT SUTE 219 COOPER CITY, FL 33024 (US) The present invention provides a method for reducing flush (21) Appl. No.: 11/899,284 ing in a patient and for for increasing HDL and/or HDL-2b levels in a patient, with compositions being administered to 22) Filed: Sep.p 5, 2007 the ppatient onlyy twice a day,y from 30 to 60 minutes after lunch and 30 to 60 minutes after dinner. In some embodi Related U.S. Application Data ments, the compositions include an adipocyte G-protein (63) Continuation-in-part of application No. 10/977.508, antagonist, a PPAR-c. agonist , and a PPAR-y agonist in filed on Oct. 29, 2004. amounts effective in to provide a synergistic therapeutic HDL increasing effect, and/or a synergistic therapeutic (60) Provisional application No. 60/515,891, filed on Oct. HDL-2b increasing effect. 29, 2003. Publication Classification (51) Int. Cl. BREAKFAST LUNCH DINNER SLEEP Patent Application Publication Mar. 6, 2008 US 2008/0058292 A1 BREAKFAST LUNCH DINNER SLEEP FIG. 1 BREAKFAST LUNCH DINNER SLEEP FIG. 2 US 2008/0058292 A1 Mar. 6, 2008 METHOD FOR INCREASING HDL AND HDL-2B ingly, the combination of an adipocyte G-protein antagonist, LEVELS a peroxisome proliferator-activated receptor-C. PPAR-O.) agonist, and a peroxisome proliferator-activated receptors CROSS-REFERENCES TO RELATED agonist (PPARY) has been found to effectively increase APPLICATIONS levels of high density lipoproteins (HDLs) and/or HDL-2b 0001. This provisional application is continuation-in-part levels. Moreover, it has been discovered that co-administra of U.S. patent application Ser. No. 10/977,508, filed Oct. 29, tion of an NSAID with an adipocyte G-protein antagonist 2004, which claims the benefit of U.S. Provisional Appli over a period of less than 12 hours and not more than 4 hours cation No. 60/515,891, filed Oct. 29, 2003, provides a Superior reduction of flushing in patients while reducing or eliminating symptoms of liver damage relative BACKGROUND OF THE INVENTION to previously known formulations. 0002) 1. Field of the Invention 0010. In one aspect, the present invention a composition, 0003. This invention relates to a method for increasing including a first amount of an adipocyte G-protein antago HDL and HDL-2 levels in patients, and, more particularly, nist, a second amount of a peroxisome proliferator-activated to Such a method including the administration of niacin. receptor-O. agonist, and a third amount of a peroxisome proliferator-activated receptor-Y agonist, is administered 0004 2. Summary of the Background Art sixty to ninety minutes after lunch and dinner. The first 0005. A cluster of inter-related plasma lipid and lipopro amount, second amount, and third amount are together an tein abnormalities associated with alterations in HDL (high effective amount to provide a synergistic therapeutic HDL density lipoprotein) and HDL-2b metabolism contributes to increasing effect, and/or a synergistic therapeutic HDL-2b the risk of atherosclerosis and cardiovascular events in increasing effect. patients with insulin resistance and type 2 diabetes. HDL and HDL-2b levels control atherogenesis, vascular inflamma 0011. In another aspect, a solid unit dosage form is given tion, endothelial function and thrombogenicity. The alter sixty to ninety minutes after lunch and dinner, with the solid ation in particle size of both HDL and LDL (low density unit dosage form including a niacin, and a nonsteroidal lipoprotein) contribute to events and progression of disease. anti-inflammatory drug. The niacin and the nonsteroidal Therefore there is a need in the art for therapies that increase anti-inflammatory drug are present in a single layer of the HDL and HDL-2b levels. solid unit dosage. The niacin and nonsteroidal anti-inflam 0006 Niacin has been used in an attempt to raise HDL matory drug are provided in amounts effective to reduce levels and to lower very low density lipoprotein (VLDL) flushing in a patient relative to the amount of flushing triglycerides and LDL levels. When tolerated, it is effective observed with niacin alone. The niacin and nonsteroidal as either primary therapy or adjunctive therapy. Numerous anti-inflammatory drug may also be provided in amounts side effects limit its use in well over 50% of patients in effective to increase HDL and/or HDL-2b levels. which it is tried. These side effects include an intense 0012. In another aspect, a method is provided for treating inflammation, or flushing, and associate itching, or pruritus, hyperlipidemia, dyslipidemia, atherosclerosis, a hypercho that usually involves the face and upper part of the body, lesterolemia, cardiovascular disease, diabetes, insulin resis often involving the entire body. tance, and/or metabolic syndrome in a patient in need of 0007 While niacin has many beneficial properties, it also Such treatment. The method includes administering to the possesses at least two important side effects. First is hepa patient sixty to ninety minutes after lunch and dinner, a totoxicity. High doses of niacin have adverse effects on the composition having a first amount of an adipocyte G-protein liver. Cases of severe hepatic toxicity, including fulminant antagonist, a second amount of a PPAR-O. agonist, and a hepatic necrosis have occurred in patients who have Substi third amount of a PPAR-Yagonist. The first amount, second tuted sustained-release (discussed below)(otherwise known amount, and third amount are together an effective amount as modified-release or timed-release) niacin products for to provide a synergistic therapeutic HDL increasing effect, immediate-release (crystalline) niacin at equivalent doses. and/or a synergistic therapeutic HDL-2b increasing effect. The second important side effect is flushing. Niacin, even in low doses, stimulates the production of prostaglandins, 0013 In another aspect, a method is provided for reduc which participate in the body's defenses against infection. ing flushing in a subject receiving niacin. The method Increased prostaglandin synthesis induces the production of includes co-administering the niacin and a nonsteroidal the inflammatory cytokines, cyclooxygenase, and also plays anti-inflammatory drug to the Subject sixty to ninety minutes a part in causing inflammation in the body. Thus, ingestion after lunch and dinner. of niacin manifests itselfin an increase in inflammation, also known as flushing. BRIEF DESCRIPTION OF THE FIGURES 0008 Aspects of the present invention address these and 0014 FIG. 1 is a graphical view of daily variations in the other problems. level of free fatty acids in a patient’s bloodstream during treatment in accordance with the method of the invention; SUMMARY OF THE INVENTION and 0009. The present invention describes a method for the 0015 FIG. 2 is a graphical view of daily variations in the treatment of diabetes, insulin resistance, metabolic Syn level of free fatty acids in a patient’s bloodstream during drome, hyperlipidemia, dyslipidemia, cardiovascular dis treatment with a method composed to providing a single ease, atherosclerosis, and hypercholesterolemia. Surpris dose of niacin at bedtime. US 2008/0058292 A1 Mar. 6, 2008 DETAILED DESCRIPTION OF THE tein antagonist, a second amount of a peroxisome prolifera INVENTION tor-activated receptor-O. agonist, and a third amount of a peroxisome proliferator-activated receptors agonist. The 0016 U.S. patent application Ser. No. 10/997,508, filed first amount, second amount, and third amount are together Oct. 29, 2004 and having a common inventor with the an effective amount to provide a synergistic therapeutic present application, the disclosure of which is incorporated HDL increasing effect, or a synergistic therapeutic HDL-2b herein by reference, describes compositions for increasing increasing effect. HDL and/or HDL-2b levels within a patient. In some embodiments, the compositions include an adipocyte G-pro 0020. In some embodiments, the first amount, second tein antagonist, a PPAR-O. agonist, and a PPAR-Yagonist in amount, and third amount further provide complimentary amounts effective in to provide a synergistic therapeutic action between the adipocyte G-protein antagonist, PPAR-C. HDL increasing effect, and/or a synergistic therapeutic agonist, and PPAR-Y agonist components such that HDL HDL-2b increasing effect. In general, a composition is and/or HDL-2b levels are raised while minimizing undesired provided by a method allowing sustained release of the side effects of any one component. active agents within the compound over a period of less than 0021 For example, it is well known that niacin, an 12 hours and more than 4 hours. adipocyte G-protein antagonist, may increase blood Sugar 0017. In accordance with the present invention, com levels in subjects with early on-set diabetes thereby exac pounds described in detail below or within U.S. patent erbating the diabetic condition. See Wang et al., Am J application Ser. No. 10/997.508 are formulated for more Physiol Endocrinol Metab 279:E50-9 (2000). Therefore, nearly intermediate delivery (i.e. in a period substantially although niacin may moderately increase HDL levels in a more 2 hours and less than 6 hours), with these compounds subject with early on-set diabetes, the fact that niacin being administered to the patient 30 to 60 minutes after increases blood Sugar levels prevents the clinical application lunch and 30 to 60 minutes after dinner. The compounds are of niacin to the early on-set diabetic patient population. never administered to the patient after breakfast.