TORCETRAPIB ATORVASTATIN
zhion October 20 2005
TORCETRAPIB ATORVASTATIN TABLETS

IMPORTANT NEWS

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]

LINKS: Methods lowering cholesterol
Improving Cholesterol Profiles without taking a drug product.

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. [1]

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. [1] 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. [4] Taken together, Lipitor (atorvastatin calcium) and torcetrapib
may provide striking improvements in lipid levels, and complementary actions upon
important lipid parameters. [1]

Consequently, Pfizer is developing a combination tablet containing torcetrapib and
atorvastatin for the potential treatment of atherosclerosis and hypercholesterolemia at
late stage of development. [2] 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. [5]

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. [3]

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: [1] 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. [2] 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). [3] 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. [4] 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. [5]

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. [5] If they prove the hypothesis, torcetrapib/atorvastatin has the
potential to benefit millions of lives around the world.

[1] Bays H et al, Torcetrapib/atorvastatin combination therapy. Expert Rev Cardiovasc Ther. 2005 Sep;3(5):789-820. [2] Burnett JR Torcetrapib
+ atorvastatin (Pfizer). Curr Opin Investig Drugs. 2005 Sep;6(9):944-50. [3] Curatolo, William J. et al, Dosage forms of cholesteryl ester transfer
protein inhibitors and HMG-CoA reductase inhibitors Patient Application Serial No. 903433[4] Trial Drug Lifts 'Good' Cholesterol Levels, Study
to test whether it prevents cardiovascular disease HealthDay April 7 2005[5] First Batch Produced at New $90 Million Plant Expansion in
Loughbeg, Ireland, PRNewswire, June 22 2005
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