Title of Invention	"A PROCESS FOR PREPARATION OF STABLE PHARMAEUTICAL COMPOSITION OF AMORPHOUS ATORV ASTATIN"
Abstract	The present invention relates to a process for the preparation of a pharmaceutical composition comprising milling amorphous atorvastatin to reduce the mean particle size (d50) to less than 100 µm, mixing it with small quantity of an alkali metal additive and other pharmaceutically acceptable excipients.

Full Text

The present invention relates to a process for preparation of stable pharmaceutical composition of amorphous atorvastatin Atorvastatin, which is an inhibitor of the enzyme 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase), is commercially available for the treatment of pnmary hypercholesterolemia, dysbetalipoproteniemia and homozygous familial hypercholesterolemia. Although cholesterol is an indispensable component of all cell membranes as well as a precursor of a vahety of steroid hormones and bile acids, excessively high levels of blood cholesterol and lipids increase the risk of the onset of atherosclerosis and coronary heart disease. The blood cholesterol pool is generally dependent upon dietary uptake of cholesterol and the biosynthesis of cholesterol. HMG-CoA reductase enzyme inhibitors such as atorvastatin, bring about a reduction in the levels of blood cholesterol, especially the low density lipoproteins by inhibiting the synthesis of cholesterol. They are therefore excellent candidates for controlling the blood cholesterol levels. As per the summary basis of approval (SBA), atorvastatin is present in multiple amorphous and crystalline forms. Originally atorvastatin was synthesized in the amorphous form and most of the clinical pharmacology studies were conducted on tablets prepared from this material. This form of atorvastatin was reported to be hygroscopic and unstable when exposed to oxygen Later, a more stable crystalline form of atorvastatin was developed. Clinical studies on crystalline atorvastatin did not show any adverse implications over the amorphous form. Bioavailabilities studies on the tablets prepared using the crystalline form of atorvastatin, on the other hand, showed that the rate of atorvastatin absorption was significantly higher (about 50% increase in Cmax) for these tablets than for tablets prepared by using amorphous form of atorvastatin. The extent of atorvastatin absorption as determined from the area under the plasma concentration-time curve (AUC), was however the same for the two formulations. Due to its better stability and faster absorption from the gastrointestinal tract, crystalline atorvastatin was chosen to be used in the marketed formulation. Despite its better stability, crystalline atorvastatin is highly susceptible to heat, moisture, low pH environment and light. It is also further destabilized on contact with excipients such as binders, diluents, surfactants and the like when formulated in the form of tablets, powders or other dosage forms Various attempts have been made to stabilize atorvastatin. US patent numbers 5,686,104 and US 6,126,971 describes stable oral pharmaceutical formulations of atorvastatin wherein the formulation is stabilized by the addition atleast one pharmaceutically acceptable alkaline earth metal salt. In accordance with these patents large amounts (5% - 75%) of alkaline earth metal salt are required to stabilize the formulation. WO 00/35425 filed by Lek Pharmaceuticals discloses stable formulations containing HMG-CoA reductase inhibitor capable of providing a pH in the range from 7 to 11 and the use of a buffering agent for stabilizing these drugs. No attempts have however been made to stabilize the amorphous form of atorvastatin or to improve its bioavailability profile. We have surprisingly found that by reducing of the particle size of amorphous atorvastatin, we can increase its bioavailability and achieve the same (or even a higher) rate (Cmax) and extent of absorption (AUG) from the gastrointestinal tract as that achieved by the crystalline form marketed under the trade name "Lipitor™' in the USA. We have further surprisingly found that amorphous atorvastatin formulation, can be stabilized by the use of very small (upto 5% w/w) amounts of an alkali metal salt additive. Accordingly, the present invention thus relates to a process for the preparation of a stable pharmaceutical composition of amorphous atorvastatin comprising milling amorphous atorvastatin in the concentration 1 to 50% w/w to reduce the mean particle size (dgo) to 5-100 jim as herein described, mixing it with an alkali metal additive in the concentration 0.05 to 5% w/w of the composition of the kind as herein described and the rest being other known pharmaceutically acceptable excipients selected from the group consisting of diluents, surfactants, antioxidants, disintegrants, binders and chelating agents and tabletting the mixture using conventional methods. It is an object of the present invention to describe a process for the preparation of a stable oral pharmaceutical formulation of amorphous atorvastatin comprising milling amorphous atorvastatin to reduce the particle size to less than 100 |im, mixing it with an alkali metal alkali metal additive and other pharmaceutically acceptable excipient followed by tabletting the mixture; wherein the rate and the extent of absorption of the amorphous tablet is comparable or higher than that obtained by the commercially available crystalline atorvastatin formulation sold under the trade name LipitorTM in the USA. Amorphous atorvastatin was subjected to particle size reduction using conventional milling techniques such as airjet mill, ball mill, cad mill, multi mill and the like. The particle size was reduced to a mean particle size (d50) of less tnan 100 µm, preferably the mean particle size is between 5 µm to 50 µm. Analysis of the particle size was earned out using any conventional particle size analyzer (e.g. the Malvern Master Sizer), Amorphous atorvastatin is present in the formulation at a dosage of between 1% to about 50% by weight of the composition. The stabilizing alkali metal salt additive to selected from amongst sodium carbonate, sodium hydroxide, sodium silicate, sodium dihydrogen phosphate, sodium aluminate and the like. Preferably it is selected from amongst sodium carbonate and sodium dihydrogen phosphate. The alkali metal salt additive is present at a concentration of between 0 01% to about 5% by weight of the composition. The formulation may further contain other pharmaceuticaily acceptable excipients belonging to the categories of binders, diluents, disintegrants, surfactants, lubricants antioxidants and chelating agents The binders in accordance with the present invention are selected from amongst those conventionally known in the art such as starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyicellulose, carboxymethylcellulose and the like. The diluent in accordance with the present invention is one or more selected from amongst lactose, microcrystalline cellulose, corn starch, sucrose, silicic anhydride and the like. The diluent is present from about 30% to 75% w/w of the formulation. The disintegrant is selected from the group consisting of crosscarmellose sodium, starch and others known in the art. Surfactants are selected from amongst polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer The lubricants are selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, talc, aerosil and the like. Pharmaceutically acceptable antioxidants are selected from amongst butylated hydroxyanisole (BHA), sodium ascorbate. butylated hydroxytoluene (BHT), sodium metabisulfate, citric acid, malic acid, ascorbic acid and the like The chelating agent used in accordance with this invention is disodium edetate and it is present at a concentration upto 5% w/w of the formulation. The following examples further exemplify the invention and are not intended to limit the scope of the invention Amorphous atorvastatin was milled to reduce its mean particle size d50 to around 20µm and d90 to around 80 µm. Tablets were prepared using the milled atorvastatin with and without an alkali metal salt and disodium edetate (EDTA) as given in Table 1. Table 1 (Table Removed) Amorphous atorvastatin, microcrystalline cellulose and lactose were mixed followed by the addition of the dry binder (hydroxypropyl celiulose-L) and disintegrant (cross canneliolose sodium) This was followed by the addition of the alkali metal salt. EDTA surfactant and colloidal silicon dioxide. The mixture was lubricated with magnesium stearate and compressed into tablets. The tablets thus formulated were subjected to accelerated stability testing at 400C for three months and exhibited very good stability characteristics over the period tested. Tablets prepared according to examples given above were subjected to dissolution testing (Table2) Table 2 (Table Removed) These tablets were then subjected to a randomised three treatment three period, three sequence single dose, crossover comparative bioavailability study against "LipitorTM 80 mg tablets manufactured by Warner -Lambert Ltd in healthy adult, male human subjects under fasting conditions (Table 3) Table 3 (Table Removed) As can be seen from the AUG and Cmax values given above the formulation made in accordance with example 1 comprising amorphous atorvastatin having a mean particle size (d50) of around 20 µm was bioequivalent to the commercially available crystalline formulation of atorvastatin sold under the tradename LipitorTM Both the Cmax and the AUG values of this formulation fall within the 0.8-1 25 interval mandated by the USFDA for bioequivalence. The formulation made in accordance with example2 showed a higher bioavailability than the marketed crystalline formulation of atorvastatin sold under The tradename LipitorTM We have not only been able to develop an amorphous atorvastatin formulation which is stable but also shows similar or even higher bioavailability than LipitorTM made from crystalline atorvastatin. WE CLAIM : 1. A process for the preparation of a stable pharmaceutical composition of amorphous atorvastatin comprising milling amorphous atorvastatin in the concentration 1 to 50% w/w to reduce the mean particle size (d50) to 5-100 µm as herein described, mixing it with an alkali metal additive in the concentration 0.05 to 5% w/w of the composition of the kind as herein described and the rest being other known pharmaceutically acceptable excipients selected from the group consisting of diluents, surfactants, antioxidants, disintegrants, binders and chelating agents and tabletting the mixture using conventional methods. 2. The process as claimed in claim 1 wherein the mean particle size (d50) of amorphous atorvastatin is between 5-50 µm, 3. The process as claimed in claim 1 wherein the alkali metal additive is selected from amongst sodium carbonate, sodium hydroxide, sodium silicate, sodium dihydrogen phosphate, sodium aluminate. 4. The process as claimed in claim 1 wherein the diluents are selected from amongst lactose, microcrystalline cellulose and sucrose. 5. The process as claimed in claim 1 wherein the surfactants are selected from amongst polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer. 6. The process as claimed in claim 1 wherein the antioxidant is selected form amongst butylated hydroxyanisole butylated hydroxy toluene, citric acid, malic acid, ascorbic acid, sodium ascorbate and sodium metabisulfite. 7. The process as claimed in claim 1 wherein the disintegrant is selected from amongst crosscarmellose sodium and starch. 8. The process as claimed in claim 1 wherein the binder is selected from amongst polyvinyl pyrrolidone, starch, hydroxypropyl cellulose, hydroxypropyl methylcelluiose and carboxymethyl cellulose.

Documents:

112-del-2002-abstract.pdf

112-del-2002-claims(cancelled).pdf

112-del-2002-claims.pdf

112-del-2002-complete specification(granted).pdf

112-del-2002-correspondence-others.pdf

112-del-2002-correspondence-po.pdf

112-del-2002-description (complete).pdf

112-del-2002-form-1.pdf

112-del-2002-form-2.pdf

112-del-2002-form-3.pdf

112-del-2002-pct-210.pdf

112-del-2002-petition-138.pdf