TORCETRAPIB ATORVASTATIN TABLET

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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