Technology and Products

Combo Therapy: Statins and Fibrates

Statins are not effective at increasing HDL-C. However, various other materials such as fibrates can increase the level of HDL-C "good cholesterol." Combined statin and fibrate therapy is often imperative for the improvement of the serum lipid profile in patients with mixed hyperlipidemia. However, the potential risk of myopathy has limited the widespread use of such therapy. Current combination therapies recommend separate dosing to minimize peak dose interactions. Thus, dosing regimens can include weekly administration of a material such as a fibrate together with daily statin treatment. Other treatment regimens may include a fibrate prescribed in the morning and a statin prescribed at night to minimize peak dose interactions. Such dosing complexity can lead to compliance problems and less than desirable dose response in a patient.

Thus, it would be desirable to develop formulations of water-soluble salts of statin dihydroxy open acid and other suitable components having suitable effect on cholesterol, triglyceride, or related blood chemistries. It would also be desirable to provide a formulation of such materials in a single pill or dose form in order to address the overall lipid abnormalities. It would also be desirable to provide a dose form in which the water-soluble statin dihydroxy acid salt and other lipid addressing materials are present in a form that would enable formulation of a combination drug that can be administered at therapeutically effective low doses in order to eliminate undesirable side effects.

Similar dosing complexities exist in treating other medical conditions for which HMG-CoA reductase inhibitors can be utilized. Thus, it would be desirable to provide therapeutic compositions that combine HMG-CoA reductase inhibitors and other complementary agents in a single dose form for treating various illnesses and conditions that are moderated or controlled by HMG-CoA reductase.

Statins are very effective in lowering LDL levels, but recent retrospective real-life clinical studies only show reduction in CHD in 30-35% of patients. This means 60-70% of patients taking a statin still had major coronary events and suggests that statins are not effective enough in solving CHD. While LDL is responsible for the delivery of cholesterol from the liver to tissues in the body, HDL transports cholesterol from the tissues of the body back to the liver where it is degraded and eliminated thus protecting against the developments of atherosclerosis. Also, clinical studies recently demonstrated the benefit of raising HDL levels: 1 mg/dL increase in HDL cholesterol translates to a 3% reduction in heart disease. Thus, there is real potential to reduce coronary events by 70-90% by combining potent LDL-lowering and HDL-raising therapies. Excellent candidates for combination would be established drugs such as statin with either niacin or fibrate. Indeed, a statin/niacin combination is already available in the market, namely lovastatin and niacin (Advicor). However, niacin comes with side effects including total body flushing, glucose intolerance, increased uric acid levels and liver-function abnormalities. Thus, Advicor may not be indicated for patients with active peptic ulcer disease, gout or diabetes.

While niacin is not indicated for diabetes, most recent studies indicate that fibrates, particularly fenofibrate, to be effective for the treatment of type 2 diabetes, obesity and metabolic syndrome. In this regard, a statin/fenofibrate combination would be ideal for such patients. Indeed, several clinical trials have proven the efficacy of such combinations in reducing cardiac events, particularly simvastatin/fenofibrate and atorvastatin/fenofibrate. Also, AstraZeneca and Abbott have recently announced plans to develop a combination drug of Crestor and Tricor.

The above drugs are either prodrugs (simvastatin, fenofibrate), lipophilic in nature (simvastatin, fenofibrate) or fluorophenyl derivative (atorvastatin, rosuvastatin), which have to be processed in the liver to be converted to water-soluble metabolites. Fluorophenyl derivatives are often associated with liver damage as well. Compounds that are processed in the liver are likely to cause drug interaction when other lipophilic drugs are administered.

JJP-10 and JJP-11 were developed as water-soluble drugs in an attempt to minimize liver and muscle toxicity as well as prevent any drug interactions.