Pfizer ends the development of torcetrapib due to an imbalance of mortality and cardiovascular events. Torcetrapib is very important to Pfizer, Pifzer was counting on it to spur profit growth and boost its stock price. [Update 1-Pfizer ends development of key cholesterol drug Reuters Dec 2, 2006]
CHOLESTEROL, ATHEROSCLEROSIS, CORONARY HEART DISEASE AND STATINS
WHAT IS MISSED WITH ATORVASTATIN? It has been observed that elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risks for atherosclerotic coronary heart disease (CHD). Lipitor (atorvastatin calcium) is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Lipitor (atorvastatin calcium) has also been shown to significantly reduce atherosclerotic coronary heart disease (CHD) events. However, as with all statins (and all other monotherapy lipid-altering drugs), Lipitor (atorvastatin calcium) alone reduces the risk of atherosclerotic coronary heart disease (CHD) in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased atherosclerotic coronary heart disease (CHD) risk. 
WHAT ADVANTAGES DOES torcetrapib have? Torcetrapib, a cholesteryl ester transfer protein inhibitor, raises high-density lipoprotein cholesterol levels. And, cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits.  A 4 week-study of 19 subjects has shown that a daily dose of 120 mg of torcetrapib alone could improve the good cholesterol (HDL) levels by 61 percents, while with statin up by 46%. Researchers also demonstrated that doubling the torcetrapib dose to 240 milligrams daily could significantly raise the HDL cholesterol levels.  Taken together, Lipitor (atorvastatin calcium) and torcetrapib may provide striking improvements in lipid levels, and complementary actions upon important lipid parameters. 
Consequently, Pfizer is developing a combination tablet containing torcetrapib and atorvastatin for the potential treatment of atherosclerosis and hypercholesterolemia at late stage of development.  Pfizer has undertaken the largest and most comprehensive clinical trial development program ever. Torcetrapib/atorvastatin's clinical program will involve 25,000 patients at hundreds of medical centers worldwide at a cost of about $800 million. 
Pfizer probably develops a dosage form comprises torcetrapib in a solubility-improved form and atorvastatin, wherein the dosage form provides immediate release of the atorvastatin and controlled release of torcetrapib. 
HOW IS TORCETRAPIB/ATORVASTATIN TABLET MADE? Based on Pfizer's patent application, the process of preparation for this atorvastatin/torcetrapib combo tablet may be as follows:  They dissolved 12% hydroxypropyl methylcellulose acetate succinate and 4% torcetrapib in 84% acetone and then spray-dried the solution at high temperature. After the drying of the polymer and drug, they got a solid amorphous dispersion of torcetrapib in hydroxypropyl methylcellulose acetate succinate.  They blended 48% torcetrapib solid amorphous dispersion, 23% polyoxy, 23% xylitol, 5% sodium starch glycolate and 1% magnesium stearate to form the drug-containing composition (drug layer). They also blended 75% sodium croscarmellose, 24.4% silicified-microcrystalline cellulose, 0.5% magnesium stearate and 0.1% red lake#50 to form the water-swellable (push-layer) composition. They then compress these two compositions together into a bilayer-tablet (13/32 inch standard round concave; weight 500 mg, hardness 16 Kp).  They then coated the tablet with a water-permeable membrane [acetone/aqueous coating solution containing cellulose acetate and polyethylene glycol] to form the osmotic controlled-release tablet of torceptrapib.  Then, they coated this tablet with an immediate-release layer of atorvastatin by dipping each tablet in the following solution: 92.5 wt % water, 1.5 wt % Opadry. clear, 2.0 wt % lactose monohydrate, and 4.0 wt % atorvastatin. In vitro-dissolution studies, this tablet provided immediate release of atorvastatin, providing 93% release in one hour and provided controlled release of the torcetrapib, with the time to release 70 wt % of the drug from the dosage form being about 15 hours. This is just one of the several methods to prepare the torcetrapib/atorvastatin combo tablet. When they launch the product, they may use other method of preparations or compositions.
WHERE DOES PFIZER PRODUCE THE TORCETRAPIB/ATORVASTATIN TABLET? Pfizer has begun production at a $90 million plant expansion in Loughbeg, Ireland. When the facility expansion is fully operational, it will require 40 Employees. 
WHAT IS THE STORY BEHIND? In 1990, The New England Journal of Medicine reported that a group of Japanese patients who were lacking the CETP protein had high HDL levels and a low incidence of coronary artery disease. Thus, Pfizer scientists spent years trying to find a compound that could inhibit CETP. In 1993-4, they found a promising compound -- CP-529,414, now known as torcetrapib. In 1999,first human trials demonstrated how CP-529,414 (torcetrapib) works in the body. In 2003, Pfizer initiated phase III trials to test the prospective medicine's activity against disease.  If they prove the hypothesis, torcetrapib/atorvastatin has the potential to benefit millions of lives around the world.
 Bays H et al, Torcetrapib/atorvastatin combination therapy. Expert Rev Cardiovasc Ther. 2005 Sep;3(5):789-820.  Burnett JR Torcetrapib + atorvastatin (Pfizer). Curr Opin Investig Drugs. 2005 Sep;6(9):944-50.  Curatolo, William J. et al, Dosage forms of cholesteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors Patient Application Serial No. 903433 Trial Drug Lifts 'Good' Cholesterol Levels, Study to test whether it prevents cardiovascular disease HealthDay April 7 2005 First Batch Produced at New $90 Million Plant Expansion in Loughbeg, Ireland, PRNewswire, June 22 2005