| 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.
THIS ARTICLE IS FOR YOUR REFERENCE ONLY. DISCUSS WITH YOUR
INVESTMENT CONSULTANT BEFORE ANY INVESTMENT. CONSULT YOUR
DOCTOR FOR ANY MEDICAL QUESTION. CONSULT YOUR ADVISOR BEFORE
DEVELOPING PRODUCTS. PUBLISHER DOES NOT GUARRANTEE THE
ACCURACY OF THIS ARTICLE. ALL RIGHT RESERVED 2005. DO NOT COPY
NOR TRANSFER THE CONTENT TO OTHER WEBSITES OR OTHER FORMS OF
PUBLICATIONS.
REFERENCE [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
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.
THIS ARTICLE IS FOR YOUR REFERENCE ONLY. DISCUSS WITH YOUR
INVESTMENT CONSULTANT BEFORE ANY INVESTMENT. CONSULT YOUR
DOCTOR FOR ANY MEDICAL QUESTION. CONSULT YOUR ADVISOR BEFORE
DEVELOPING PRODUCTS. PUBLISHER DOES NOT GUARRANTEE THE
ACCURACY OF THIS ARTICLE. ALL RIGHT RESERVED 2005. DO NOT COPY
NOR TRANSFER THE CONTENT TO OTHER WEBSITES OR OTHER FORMS OF
PUBLICATIONS.
REFERENCE [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
PHARMCEUTICAL
INDUSTRY
Foundamental
Science
Colloidal
Stabilization
Drug Product
Development
Patent Application
Product
Development
Product
Ingredients
Colorant
Scale up a batch 1
Drug Delivery
Industry
Drug Delivery -
Smart Bomb
Lotion, Cream,
Preps
Enteric
Coating-Eudragit
Enteric
Coating-Nutrateric
SR
Coating-Aquacoat
Drug Industry
Drug
Competitions
Drug in
Development
Cholesterol-loweri
ng
Drug-Terminologi
es
Packaging
Materials
Market
Drug Dev- 2004
Drug Dev -
2005Q1
Drug Dev- 2005Q2
Drug
Dev-2005Summer
Drug Dev-2005Q3
Orphan Drug
Protein Drug
Niche Market
Novo Norkdisk
R&D
Equipment
Blenders
CONTRACT
MANUFACT.
Nutrition
Supplements
NEW DRUGS
Arranon
Actoplus Met
Alfuzosin
Ambien CR
Avastin
Asmanex(R)
Erbitux
(cetuximab)
Gardasil
GRN163
Herceptin
Increlex (rhIGF-1)
Lidoerm
(Lidocaine)
Liraglutide
Lyrica (pregabalin)
Rozerem
Sorafenib
Sutent
Tamsulosin
Torcetrapib
Zometa
OLD DRUGS
Lithium Carbonate
DRUG NOTES
[CONSTRUCT]
Clinical Research
Terminologies
FDA ALERTS
Protein Drug
Market
Niche Market
Orphan Drug
levothyroxine
Protein Drug 1
Protein Drug2
Double-blind
Study
INDUSTRY
Foundamental
Science
Colloidal
Stabilization
Drug Product
Development
Patent Application
Product
Development
Product
Ingredients
Colorant
Scale up a batch 1
Drug Delivery
Industry
Drug Delivery -
Smart Bomb
Lotion, Cream,
Preps
Enteric
Coating-Eudragit
Enteric
Coating-Nutrateric
SR
Coating-Aquacoat
Drug Industry
Drug
Competitions
Drug in
Development
Cholesterol-loweri
ng
Drug-Terminologi
es
Packaging
Materials
Market
Drug Dev- 2004
Drug Dev -
2005Q1
Drug Dev- 2005Q2
Drug
Dev-2005Summer
Drug Dev-2005Q3
Orphan Drug
Protein Drug
Niche Market
Novo Norkdisk
R&D
Equipment
Blenders
CONTRACT
MANUFACT.
Nutrition
Supplements
NEW DRUGS
Arranon
Actoplus Met
Alfuzosin
Ambien CR
Avastin
Asmanex(R)
Erbitux
(cetuximab)
Gardasil
GRN163
Herceptin
Increlex (rhIGF-1)
Lidoerm
(Lidocaine)
Liraglutide
Lyrica (pregabalin)
Rozerem
Sorafenib
Sutent
Tamsulosin
Torcetrapib
Zometa
OLD DRUGS
Lithium Carbonate
DRUG NOTES
[CONSTRUCT]
Clinical Research
Terminologies
FDA ALERTS
Protein Drug
Market
Niche Market
Orphan Drug
levothyroxine
Protein Drug 1
Protein Drug2
Double-blind
Study
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