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Document Type and Number:
WIPO Patent Application WO/2005/030183
Kind Code:
The present invention provides a stabile oral formulation of a HMG-CoA reductase inhibitor compound, atorvastatin calcium, with improved bioavailability. Manufacturing process and composition of such formulation is also disclosed in this invention.

Seyed Farshi, Farhad (Biofarma Ilaç Sanayi ve Ticaret A.S, Veysel Karani Mah. Fatih Cad. No:2 Kartal, Istanbul, 81470, TR)
Application Number:
Publication Date:
April 07, 2005
Filing Date:
September 24, 2004
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Biofarma, Ilaç Sanayi Ticaret VE. A. S. (Veysel Karani Mah. Fatih Cad, No:2 Kartal, Istanbul, 81470, TR)
Seyed Farshi, Farhad (Biofarma Ilaç Sanayi ve Ticaret A.S, Veysel Karani Mah. Fatih Cad. No:2 Kartal, Istanbul, 81470, TR)
International Classes:
A61K9/20; A61K9/28; A61K9/36; A61K31/40; (IPC1-7): A61K9/36
Domestic Patent References:
Foreign References:
Other References:
PATENT ABSTRACTS OF JAPAN vol. 1995, no. 07, 31 August 1995 (1995-08-31) & JP 07 089875 A (DAI ICHI SEIYAKU CO LTD), 4 April 1995 (1995-04-04)
Attorney, Agent or Firm:
Kayacan, Vildan (Portakal Çiçegi Sok. No:5/1, A. Ayranci, Ankara, 06690, TR)
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1. 1) A new pharmacetical formulation of atorvastatin calcium to lower elevated levels of total cholesterol, LDLcholesterol, apoB and triglycerid levels.
2. A composition according to claim 1 wherein magnesium stearate and sucrose stearate are used together.
3. A composition according to claim 2 which comprises 1 to 5 wt % sucrose stearate.
4. A composition according to claim 2 which comprises 0.2 tolwt % magnesium stearate.
5. A composition according to claim 1 and claim 2 where direct compression is used as manufacturing process.
6. A composition according to claim 1 and claim 2 wherein dosage form is tablet or a film coated tablet.
DESCRIPTION A NEW METHOD FOR THE PREPARATION OF ATORVASTATIN CALCIUM TABLETS The present invention relates to a novel, stabil pharmaceutical formulation of atorvastatin. Furthermore the present invention relates to improved bioavalaibility of atorvastatin by increasing its solubility and dissolution rate in aqueous solutions.

7-substituted pyrrolyl-3,5-dihydroxy heptanoic acid derivatives are known as potent inhibitors of the enzyme 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor. These compounds are destabilised by environmental factors such as temperature, light, pH, moisture and by interactions with pharmaceutical ingredients used in the formulations such as fillers, binders, lubricants, glidants and disintegrating agents. Degradation may occur because of beta, delta hydroxy heptanoic acid skeletal and double bonds in their structure.

Consequently it is not easy to perform a stabil formulation of these compounds. It is also not easy to improve the bioavalability of these compounds since increasing their solubility and dissolution rate is problematic.

The subject of this study is a HMG-CoA reductase inhibitor compound atorvastatin, in the structure of (pR, oR)-2- (4-Fluorophenyl)-p-o-dihydroxy-5- (l- methylethyl)-3-phenyl-4 [ (phenylamino) carbonyl]-IH-pyrole-l-heptanoic acid.

Atorvastatin is a selective, competetive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin increases the number of hepatic LDL receptors, also reduces LDL production and the number of LDL particles.

It is used to to reduce the elevated levels of total-cholesterol, LDL cholesterol, apoB and triglycerides.

Atorvastatin is known to be sensitive to light, temperature, pH and excipients.

Atorvastatin is destabilized on contact with excipients. So the excipients used in the

formulations of atorvastatin is an impotant fact for the stability of the formulation.

Various attempts have been made to stabilize atorvastatin formulations. Also atorvastatin is known to have solubility and dissolution problems which may affect bioavailibilty.

The object of this study is to perform a stabil formulation of atorvastatin with increased solubility and improved bioavalability.

It is the object of this study to solve the formulation problems such as direct compression, stability and dissolution.

This study relates to use of magnesium stearate and sucrose stearate together at constant concentrations.

This study also relates to use of direct compression method as manufacturing process.

Magnesium stearate is widely used lubricant in tablet manufacture at concentration 0.25-5 %. W002072073 and US5686104 relates to atorvastatin formulations where magnesium stearate is used as lubricant and where granulation method is used as manufacturing process. W002072073 describes an atorvastatin formulation with increased solubility and dissolution rate by using alkalising substance in the formulation where magnesium stearate and granulation process was used. But when magnesium stearate is used alone in the formulation a hydrophobic barrier is set up, tablet solubility reduces (Table 1) and problems occures while compressing, and in this study it is shown that required solubility can be obtained by using sucrose stearate together with magnesium stearate. Dissolution problem is solved with alkalising substance addition in W002072073 where magnesium stearate is also used, but in this invention dissolution problem is solved by simple manufacturing method direct compression where sucrose stearate is added to the formulation.

A non-ionic surface active agent sucrose is used in the oral formulations as binder and sweetining agent. Sucrose stearate is a sucrose ester which increases the dissolution rate of hyrophobic drugs. It is also used to stabilize suspensions and used as food additive. Sucrose stearate has not been used in atorvastatin formulations before.

Required result is only obtained whe n sucrose stearate and magnesium stearate are used together at constant part. Using magnesium stearate at the ratio 0.2-1% and sucrose stearate 1-5% was found suitable (Table 2).

TIME SOLUBILITY % 0 0 5 82, 13 10 86, 97 15 88, 69 20 89, 91 30 88, 82 45 90, 85 Table 1 : solubility of the formulation including 0.5 % magnesium stearate. TIME SOLUBILITY % 0 0 5 77, 14 10 87, 37 15 91, 09 20 93, 31 30 94, 40 45 99, 75 Table 2: solubility of the formulation including 0.5 % magnesium stearate and 2% sucrose stearate Calcium carbonate, lactose, microcrystalline cellulose, croscarmellos sodium is also used in the formulation.


INGREDIENT AMOUNT (mg) Atorvastatin calcium 43.40 Calcium carbonate 240.00 Lactose 127.80 Microcrystalline cellulose 149.80 Croscarmellos sodium 24.00 Sucrose stearate 12.00 Magnesium stearate 3.0 Active ingredient and excipients are sieved. Atorvastatin calcium and lactose are mixed. Calcium carbonate, microcrystalline cellulose, croscarmellos sodium, sucrose stearate and magnesium stearate are added sequentially to the mixture, mixed and tablet compressed. Compressed tablets are coated with hydroxypropyl methyl cellulose, titanium dioxide and polyethylene mixture.