CA2730665C

CA2730665C - Dosage form containing a statin

Info

Publication number: CA2730665C
Application number: CA2730665A
Authority: CA
Inventors: Mathew Philip; Naresh Talwar; Shruti Bhat
Original assignee: Pharmascience Inc
Current assignee: Pharmascience Inc
Priority date: 2008-07-15
Filing date: 2009-07-14
Publication date: 2017-01-03
Anticipated expiration: 2029-07-14
Also published as: CA2637977A1; CA2730665A1; WO2010006451A1

Abstract

The present invention relates to a novel stable pharmaceutical dosage form containing a statin and processes to prepare such dosage forms, wherein the dosage form is substantially free of stabilizing agents, and the statin is combined with the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.

Description

=
DOSAGE FORM CONTAINING A STAIN
HELD OF THE INVENTION
The present invention relates to a novel dosage form, a process for the manufacturing the same, as well as the composition of the novel dosage form. More specifically, the present invention relates to a dosage form comprising rosuvastatin calcium as a pharma.ceutiraliy acceptable active ingredient BACKGROUND OF THE INVENTION
Rosuvastatin calcium, known under the brand name Crestoa, is a synthetic lipid-lowering agent for oral administration. The chemical name for rosuvastatin calcium is bis[(E)-7-14-(4-fluoropheny1)-6-isopropyl-21methyl(methylsulfonyl)amino]
pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. It has the following structural formula:

' i Cr NN
sio,M0 ¨ 2 Rosuvastatin cakiu.m belongs to the class of medications known as "statins", which are known to inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA") reductase enzyme. HMG-CoA reductase is involved in regulating cholesterol levels.
Statins are used along with changes to diet and exercise to help control the amount of cholesterol produced by the body. Rosuvastatin calcium can help a person's body decrease low-density lipoprotein (LDL) cholesterol (i.e. bad cholesterol) and triglyceride levels;
increase high-density lipoprotein (HDL) cholesterol (i.e. good cholesterol) levels; and decrease the total cholesterol/HDL-cholesterol ratio (TC HDL-C Ratio). This ratio represents the balance between good and bad cholesterol_ Rosuvastatin calcium is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol, (Total-C), LDL-C, Apolipoprotein B ('ApoB"), the Total-C/HDL-C ratio and triglycerides arid for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including:
primary hypercholesterolernia (Type Ila including heterozygous familial hypercholesteroleinia and severe non-familial hypercholesterolemia), combined (mixed) dyslipidemia (Type Ilb), homozygous familial hypercholesteroleraia where rosuvastatin calcium is used either alone or as an adjunct to diet and other lipid lowering treatment such as apheresis.
Rosuvastatin calcium is also known to be a synthetic, enantiomerically pure lipid-lowering agent. It is a selective, potent and competitive inhibitor of HMG-CoA

reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis. Studies have also shown that rosuvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver by increasing the number of hepatic LDL receptors on the cell-surface for enhanced uptake and catabolism of LDL.
Additionally, rosuvastatin calcium inhibits the hepatic synthesis of very low density lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL
particles.
According to Canadian Patent No. 2,429,263 (issued March 17, 2009 to AstraZeneca), rosuvastatin, and pharmaceutically acceptable salts of rosuvastatin, can be used in the treatment of heterozygous fan-iilial h3rpercholesterolemia. According to Canadian Patent Application No. 2,560,167 (filed April 25, 2005 by Akon, Inc.), statins can also be used for the treatment of ocular hypertension and glaucoma.
The preparation of rosuvastatin is described in several references, including European Patent No. 0,521,471 and United States Patent No. 5,260,440 (both issued in 1993 to Shionogi Seiyaku Kabushiki. Kaisha and corresponding to Canadian Patent No

2,072,945), and by M. Watanabe et al. in Bioorg. Med. Chem. 5, 437 (1997).
Canadian Patent Applications Nos. 2,495,296, 2,527,314, 2,543,358, 2,573,857, 2,589,775 and 2,594,017, and international laid open patent applications W02007099561, W02007041666, W02007039287, W02007017117 also describe processes for preparing rosuvastatin_ Canadian Patent Application Na 2,450,820 (filed August 16, 2002 by Teva Pharmaceutical Industries Ltd.) is directed to processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the stitin by using calcium hydroxide, Canadian Patent Application No. 2,509,619 (filed December 10, 2002 by Ranbaxy Laboratories Ltd.) is directed to a synthetic route of preparing rosuvastatin.
Canadian Patent Application Nos. 2,495,296 and 2,527,314 (filed August 7, 2003 and June

3,2004, respectively, by AsiraZeneca) relates to a process for manufacture of (E)-744-(4-fluoropheriy1)-6-isopropy1-2-fmethyl(methylsu1fonyl) arainolpyrimidin-5-yly3R,5S)-3,5-clihydroxyhept-6-enoic acid calcium salt, which is useful for the prod-action of a pharmaceutical useful in the treatment of, inter alia, hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
Canadian Patent Application No. 2,537,962 relates to two polymorphic forms of bis[(E)-714-(4-fluoropheny1)-6-isopropyl-2-[methyl(methylsulfonyl)arninolpyr]miclin-5-A-(3R,5S)-3,5-dihyd.roxyhept-6-enoic acidl calcium salt, processes for malcing them and their use as HMG Co-A reductase inhibitors.
United States Patent No. 7,241,800 (issued July 10, 2007 to Mai De Ltd.) relates to anhydrous amorphous forms of rosuvastatin calcium, fluvastatin sodium and pitavastatin calcium, as well as to processes for their preparation, to pharmaceutical compositions containing them and to methods of treatment using the same.
A problem associated with the chemical compound rosuvastatin is that it readily undergoes degradation under certain conditions such as exposure to atmospheric conditions (i_e_ humidity, oxygen, air and light), thereby significantly reducing the storage life of any pharmaceutical compositions containing rosuvastatin or its salts, such as rosuvastatin calcium. This degradation problem is referred to in Canadian Patent Nos. 2,313,783 and 2,315,141 (both invented by N.A. Wiggins and J.R. Creekmore and issued to AstraZeneca). The major degradation products formed are the corresponding (3R,5S) lactone and an oxidation product in which the hydroxyl group adjacent to the carbon-carbon double bond is oxidized to a ketone functionality. Also another problem associated with rosuvastatin is that when it is exposed to light it undergoes photolytic degradation forming two diasteriomeric cyclic products. Such has been referred to in international laid open application W02007/071357 (filed December 18, 2006 by Lek Pharmaceuticals).
To address the issue of degradation in rosuvastatin calcium, pharmaceutical manufacturers have used stabilizing agents. For example, Canadian Patent No.
2,313,783 discloses the use of a tribasic phosphate salt in which the cation is multivalent to provide stability to the composition, thereby avoiding degradation. Canadian Patent No.
2,315,141 rlicrloses the use of an inorganic salt in which the cation is multivalent for stabilizing the rosuvastatin calcium structure.
Canadian Patent Application No. 2,543,716 (filed October 29, 2004 by Athpharma Ltd.) discloses formulations comprising therapeutically effective amounts of at least one acid-stable, carrier-mediated transport statin, at least one poorly water-soluble, carrier-mediated transport statin, or at least one large molecular weight, carrier-mediated transport statin, such as atorvastatin and rosuvastatin, or a pharmaceutically acceptable salt thereof, arid methods of their use.
International laid open application W02007/071357 teaches a formulation of (E)-744-(4-fluoropheny1)-6-isopropyl-2--fmethyl(methylsulfonyl)aminolpyrimidin-5-y1]-(3R,5$)-3,5-dihydroxyhept-6-enoic acid (i.e. rosuvastatin) or a pharmaceutically-acceptable salt thereof for oral use, such as tablets, capsules, powders, granules wherein the rosuvastatin is stabilized by the use of ingredients chosen from two groups.
The first group of ingredients stabilizes rosuvastaiin calcium against oxidation and consists of corn starch, silicified microcrystalline cellulose, croscarmellose sodium, and hyprornellose. The second group of ingredients inhibit the formation of lactooes consists of corn starch, marmitol, hydroxypropyl cellulose, and hypromellose.

4 Generally, the rosuvastatin calcium formulations of the prior art require the use of stabilizing agents, for example, inorganic salts in which the cation is multivalent, such as tribasic calcium phosphate, and some ingredients which specifically prevent degradation. Usage of stabilizing agents inherently renders the manufacturing process more costly due to the use of additional pharmaceutical excipients, and which, in turn, consumes more time.
There is thus a need for a novel dosage form that overcomes the problems of the prior art, such dosage form containing a pharmaceutically acceptable active substance (i.e.
rosuvastatin calcium), which is substantially free of any stabilizing agents used to stabilize the end product from degradation.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided a novel stable pharmaceutical dosage form containing a statin that is substantially free of stabilizing agents, said dosage form comprising a statin combined with the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose nionohydrate.
Preferably, the colloidal silicon dioxide is present in an amount ranging from 0.5 to 1.5%, the microcrystalline cellulose is present in an amount ranging from 25 to 35%, and lactose monohydrate is present in an amount ranging from 50 to 70% by weight of the dosage form.
In a preferred embodiment of the present invention, the staiin is rosuvastatin or a pharmaceutically acceptable salt thereof. More preferably, the statin is rosuvastatin calcium.
in a further aspect of the present invention, there is provided a rosuvastatin dosage form that allows a single daily adrrdnistra.tion with a prolonged effect, simplified production and is cost effective.
In another aspect of the present invention, there is provided a process for manufacturing the novel dosage form.

The manufacturing process of the present invention is simple and less time consuming. The dosage forms according to the present invention substantially decrease the formation of lactone or oxidation degradation products in comparison to the commercially available dosage form containing rosuvastatin, hence they present greater stability than what was achieved in the Crestor product.
Other embodiments and further scope of applicability of the present invention will become apparent from the detailed description and examples given hereinafter. It should be understood that the detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Nomenclature Before the present formulations and methods of use are disclosed and described, it is to be understood by a person skilled in the art that unless otherwise indicated this invention is not limited to specific pharmacologically active agents, specific pharmaceutical carriers, or to particular administration regimens, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes mixtures of active agents, reference to "a pharmaceutical carrier" includes combinations of two or more carriers, and the like.
"Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

The terms or expressions "active agent", "active pharmaceutical ingredient', "drug", "pharmacologically active agent", "pharmaceutically active substance", "pharmaceutically acceptable active agent", "pharmaceutically acceptable active substance" are used interchangeably herein to refer to a chemical material or compound which, when administered to an organism. (human or animal, generally human) induces a desired pharmacologic effect. In the context of the present invention, the terms or expressions refer to a compound that is capable of being delivered orally_ According to the present invention, the pharmaceutically active substance is a stadia, for example, rosuvastatin. The term "rosuvastatin" as used herein includes all optical isomers, racemic mixtures and the like of the compound and all pharmaceutically acceptable salts, amides, procirugs and analogs thereof.
Similarly, a "pharmaceutirnily acceptable salt" or a "pharmaceutically acceptable ester"
of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable. A pharmaceutically acceptable salt of rosuvastatin is, for example, rosuvastatin calcium.
The terms "effective amount" or "pharmaceutically effective amount" of an active agent, as provided herein, are meant to be a nontoxic but sufficient amount of the active agent to provide the desired therapeutic effect The exact amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like. Thus, it is not possible to specify an exact "effective amount"; however, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As. noted below, the typical daily dosage of rosuvastatin calcium is in the range of about 5 mg to about 100 mg.
The term "excipient" refers to a generally pharmaceutically inactive or inert substance used as a diluent or vehicle for a drug. Different forms of drug administration may require a different excipient and a "pharmaceutically acceptable excipiene' includes a "pharmaceutically acceptable carrier". For example, tablets, troches, pills, capsules, and the like, may contain excipients including binders, such as gum tra.gacanth, acacia, corn starch or gelatin; a disintegrating agent suc.h as corn starch, potato starch, alginic acid;
and a lubricant such as magnesium stearate. Capsules may contain additional excipients such as a liquid carrier.
By "pharmaceutically acceptable carrier" is meant a carrier comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The term "carrier" is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus Includes diluents, binders, lubricants, disintegrants, fillers, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, arid the like_ The expression "subs taniia fly free' is intended to mean that the present invention does not contain any specific amount of stabilizing agent that is sufficient to stabilize the active substance, formulation or end product.
The term "stabilizing agent" refers to any substance or a mixture of substances, which when in contact with the active agent in appropriate quantities, will improve the physical and chemical characteiistics of the active agent.
According to the present invention, the expression "dosage form' may consist of granules, spheroids, beads, pellets, capsules, tablets or any other suitable unit rn the present invention, the dosage form is preferably a tablet As aforementioned, the present invention relates to a novel stable pharmaceutical dosage form containing a statin, wherein the dosage form is substantially free of stabilizing agents, said dosage form comprising a statin combined with at least the following pharmaceu tically acceptable excipients: colloidal silicon dioxide, rnicrocrystalline cellulose, and lactose monohydrate.

(i) Core Composition (or tablet composition) Generally, a tablet composition is made of several components, such as for example at least one pharmaceutically acceptable active substance (e.g.. a statin, rosuvastatin or pharmaceutically acceptable salt thereof) combined with at least one pharmaceutically acceptable excipient. In the present invention, the pharmaceutically acceptable substance is combined with at least three pharmaceutically acceptable excipients, being colloidal silicon dioxide, rnicrocrystalline cellulose, and lactose monohydrate.
(a) Pharmaceutically acceptable active substance Pharmaceutically acceptable active agents include statins. Suitable statins include, for example, atorvastathl, ceriva.statin, fluvasta tin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin Rosuvastaiin and salts thereof are particularly preferred pharmaceutically acceptable active agents, and rosuvastatin calcium is the most preferred.
The pharmaceutically acceptable active agent could be co-administered with another active agent known to a person skilled in the art, such as, for example, simvastatin could be co-administered with ezetimibe (Vytorin0), lovastatin with niacin (Advicore), and atorvastatin with arnlodipine (CaduetS).
Each of the active agents in the individual tablets may be in the form of a pharmaceutically acceptable salt, ester, amide, prodrug or other derivative or analog, including active agents modified by appending one or more appropriate functionalities to enhance selected biological properties. Such modifications are known in the art and/or are described in the pertinent texts and literature.
(h) Pharmaceutically acceptable excipients As aforementioned the pharmaceutically acceptable active substance of the present invention is combined with three pharmaceutically acceptable excipients, being colloidal silicon dioxide, inicrocrystalline cellulose, and lactose rnonohydrate. The dosage forms of the present invention may include additional pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, glidants, and the like.
Diluents, also termed "fillers", are typically necessary to increase the bulk of a tablet so that a practical size is provided for compression. Suitable diluents include, for exainple, lactose, spray dried lactose, a-lactose, (3-lactose, Tabletose , various grades of Pharmatose , IVIicrotose , Fast Flow , sorbitol, microcrystalline cellulose, various grades of Avicel , Vivacel , Vivapur , powdered cellulose, kaolin, starch, hydrolyzed starches, pregelatinized starch, alumina, sucrose, dextrins, dextrose, fructose, rnaltodextrins, and the like.
Disintegrants are used to facilitate tablet disintegration or "breakup" after administration, and are generally starches, clays, cellulose and cellulose derivatives, alginic acid or alginates, gums, crospovidone, polarcrilllri. por2q.cium, sodium starch glycollate, pregelatinized starch, and the like.
Binders are used to impart cohesive qualities to a tablet formulation, and thus ensure that a tablet remains intact after compression. Suitable binder materials include, but are not limited, to starch (including corn starch and pregelatinized starch), gelatin., sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., acacia, tragacanth, sodium alginate, celluloses, and Veegum), and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, hydroxypropylruethykellulose (HPMC), methylcellulose, polyethylene oxide, and the like.
Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include magnesium stearate, calcium stearate, stearic acid, glyceryI behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C1.81-13602), zinc stearate, sodium stearyl fum.erate, calcium stearate, and light mineral oil.
The lubricants are preferably present at no more than approximately 0.5 to 2.5 wt. %
relative to tablet weight.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02) (Aerosii ), magnesium silicate, starch, talc, magnesium trisilicate, etc. Colloidal silicon dioxides are also known to function as an absorbent, anti-caking agent, emulsion stabilizer; glidant;
suspending agent; and tablet disintegrant If desired, the dosage forms may also contain minor amounts of nontoxic auxiliary substances such as antioxidants, for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyl anisole, butylated hydroxyl toulerte, potassium meta bisulfite, propyl gallate, sodium thiosulfate, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, hypophosphorous add, fumaric acid, mortothioglycerol; coloring agents, flavouring agents, surface active agents, such as for example, sodium lauryl sulfate, poly oxyethylerte sorbitan fatty acid esters (fween series), Myrje series, Solutol HS, poly oxyethylene allcyl ethers (By11(g) series), poly oxyethylerte, castor oil derivatives, polyoxyethylene stearates, sorbitan esters (i.e.
sorbitan fatty acid esters), poloxamers, sucrose fatty acid ester, vitamin E
TPGS, polyethylene glycol fatty acid esters, wetting or emulsifying agents, buffering agents, including for example, citric acid, sodium citrate, dilute HC1, sodium hydroxide, fumaric acid, tartaric acid, mak add, succinic acid, preservatives, such as methyl and propyl parabens, BKC, thiomersal, and the like. Examples of each the aforementioned agents can also be found in the Handbook of Pharmaceutical Excipients (5th edition) by Raymond C. Rowe, Paul J. Sheskey and Sian C. Owen.
Coaling Composition The coating composition of the present invention can be made of several components.
For example, the coating composition can include a coating agent, alone or in combination with any other pharmaceutically acceptable excipient such as a film forming polymer, anti-tacking agents, glidants, diluents, lubricants, plasticizers, additives, surface active agents, and solvents.
For example, the coating composition of an embodiment of the present invention can comprise a coating agent, such as Opadry II , manufactured by Colorcon.
(iii) Additional Coats The end product can further be coated with a non-functional or top coat so as to improve the appearance of the dosage form, such as a tablet_ In this connection, conventional coating procedures and equipment may be used to coat the dosage units (the drug-containing tablets, beads or particles).
For detailed information concerning materials, equipment and processes for preparing tablets, beads, drug particles, and delayed release dosage forms, reference may be had to Pharmaceutical Dosage Forms: Tablets, eds. Lieberman a at. (New York: Marcel Dekker, Inc., 1989), and to Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 66, ed. (Media, PA: Williams & Wilkins, 1995).
Utility The novel drug dosage forms of the present invention are to be administered orally to a mammal and can be used to administer rosuvastatin calcium to treat or prevent a variety of disorders, conditions arid diseases. In accordance with the present invention, administration of rosuvastatin calcium may be carried out in order to treat any disorder, condition or disease for which rosuvastatin calcium is generally indicated.
Such disorders, conditions and diseases include those described in the background of the present invention.
For administration of rosuvastatin calcium, the typical daily dose is in the range of approximately 5 mg to 100 mg, preferably 5 mg to 60 mg, and more preferably 40 m.g.
The exact dosage regimen will depend on a number of factors, including age, the general condition of the patient, the particular condition or disorder being treated, the severity of the patient's condition or disorder, and the like. A standard dose of 10 mg for oral administration, once daily, is recommended in most patients.
EXAMPLES
All of the percentages given hereinabove and below are percentages by weight.
Examples of various formulations of rosuvastatin calcium capsules and/or tablets are provided below.

Table 1 Comparative Formula of the dosage form according to preferred embodiments of the present invention vs. Crestor (Astra2eneca) Rosuvastatin % w/w Function Crestor Function tablets of present invention _ _ Rosuvastatin as 5.0%- Active Rosuvastatin as Active Rosuvastatin calcium 14% Rosuvastatin calcium Colloidal Silicon 0.5-1.5% Glidant Dioxide Aerosil _________________________________ Tribasic calcium Stabilizer phosphate ¨Lactose Monohydrate 50-70% Diluent Lactose Diluent Monohydrate Microcrystalline 25-35% Diluent Microcrystalline Diluent cellulose (Aykele) cellulose Crospovidone 3-3.0% Disinte_grant Crospoviclone Disintegrant Magnesium stearate 0,5-1.0% Lubricant Magnesium stearate Lubricant Opadry II Pink Coating agent Ferric oxide Red Colorant Opadry II Yellow Coating agent Ferric oxide Yellow Colorant Hydroxypropyl Film former ' methyl cellulose Glyceryl triacetate Plasticizer _ Titanium Dioxide pacifier Example #1 Table 2 Lot Size - 974 Tablets Rosuvastatin 5 mg % w/w Qty for the lot (g) 1 Rosuvastatin calcium 5.21 5.329 2 Colloidal Silicon Dioxide Aerosile 0.5 0.487 3 Microcrystalline cellulose (Avice)) 34,0 33.116 4 Lactose Manohydrate 54_54 52_88 Crospovidone_ _ 5.0 4.870 6 Magnesium stearate 0.75 0.731 7 Opadry II Yellow 3.0% of the tablet weight Manufacturing Process:
Step 1. - rosuvastatin calcium and portion of lactose monohydrate (10.0 g) are blended together and screened through 420 um. mesh (blend #1).
Step 2 - Aerosil, microcrystalline cellulose (Avicelq and crospovidone are screened through 420 p.n and blended with blend #1 for 1 minute to form blend #2.
Step 3 - the remaining portion of lactose monohydrate is screened through 600 um mesh and blended with blend #2 for 1 to 2 minutes to form blend #3.
Step 4 - magnesium stearate is screened through 420 ttm mesh (425 pm) and is then blended with blend #3 for several minutes (i.e. 1-2 minutes) to form the final blend.
Step 5 - the final blend is compressed using a rotary press, so as to form, for example, tablets. The resulting tablets are then coated with, for example Opadry 11114 (from Colorcon) to a weight gain of 2% to 3.0% w/w.
The coating process can be performed with conventional coating equipment for example O'HARA Lab Coat.
Example #2 Table 3 Lot Size - 123 Tablets Rosuvastatin 40 mg % w/w Qty for the lot (g) ' 1 Rosuvastatin calcium 9.80 5.41 2 Colloidal Silicon Dioxide Aerosil 0.5 0.261 3 Microcrystalline cellulose (Avice181 34.0 17.8 4 Lactose Monohydrate 50.0 25.82 Crospoviaone 5.0 2.61 6 Magnesium stearate 0.75 0.392 7 Opachy U Pink 3.0% of the tablet weight Manufacturing Process:
Step 1 - rosuvastatin calcium and portion of lactose mon.ohydrate (10.0 g) are blended together and screened through 420 um mesh (blend #1).
Step 2 - Aerosil, microcrystalline cellulose (Avice1G) and crospovidone are screened through 420 jim and blended with blend #1 for 1 minute to form blend #2.

Step 3 - the remaining portion of lactose monohydrate is screened through 600 pm mesh and blended with blend #2 for 1 to 2 minutes to form blend #3.
Step 4- magnesium stearate is screened through 420 um mesh (425 Ant) and is then blended with blend #3 for several minutes (i.e. 1-2 minutes) to form the final blend.
Step 5 - the final blend is compressed using a rotary press, so as to form, for example, tablets. The resulting tablets are then coated with, for example Opadry 1141.1 (from Colorcon) to a weight gain of 2% to 3.0% w,/ w.
The coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM.
Example #3 Table 4 Lot Size - 25000 Tablets Rosnvastatin 20 mg % FA ; Qty for the lot (g) 1 Rosuvastatin calcium _ 6.946 521.0 2 Colloidal Silicon Dioxide Aerosil 0.5 37.5 -3 Micromystalline cellulose (Avicel 101) _ 10.0 750.0 4 Mkrocrystalline cellulose (Avicel 102) 150 1125.0 Lactose Monohydrate 63.8 4783.3 6 Crospovidone 3.0 225.0 7 Magnesium stearate 0.75 56.3 8 Opadry 11 Pink 3.0% of the tablet weight Ma.nufa.cturing Process:
Step 1 - Rosuvastatin calcium and irdcrocrystalline cellulose (Avice1(101) are blended together in a V blender for 3 minutes and screened through 225-250 um mesh (blend #1).
Step 2 - Aerosil, microcrystalline cellulose (Avice10102) and crospovidone are blended together in a V-blender for 3 minutes and screened through 1000-1200 um mesh to form blend #2.
Step 3 - lactose inonohydrate is screened through 1000-1200 um mesh and blended with blend #1 and blend #2 for 21 minutes in a Bin Blender to form blend *3.

Step 4 - Magnesium stearate is screened through 420 um mesh and is then blended with blend #3 for 3 minutes in a Bin Blender to form. the final blend.
Step 5 - the final blend is compressed -using a rotary press, so as to form, for example, tablets. The resulting tablets are then coated with, for example Opadry II
(from Colorcon) to a weight gain of 2% to 3.0% wiw.
The coating process can be performed with conventional coating equipment, for example O'HARA Lab CoatTM.
In other words, the process for manufacturing the nova dosage form according to the present invention generally comprises:
- a first step (or steps) of combining a statin with the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcaystalline cellulose, and lactose monohydrate so as to form a blend;
- a second step of compressing said blend; and - optionally, a third step of applying a coating composition.
Direct compression of powder is a preferred manufacturing technique. However, it is worth mentioning that other dosage forms can be envisaged; though for the purposes of the present invention, the tablet form is preferred.
The dosage form, for example a tablet, of the present invention was subjected to accelerated stability studies as per ICI-1 guideline conditions in their primary packaging.
A primary packaging includes tablets packed in high-density polyethylene (HDPE) packs with a desiccant and further induction sealed and also in blister packs.
One (1) month and three (3) months stability studies were conducted and tested for degradation.
A comparative study of the stability results for the composition of the present invention versus compositions stabilized with tribasic calcium. phosphate (i.e. Crestor) are provided in the following tables.

Table 5 Comparative stability of the dosage form according to a preferred embodiment of the present invention (Rosuvastatin calcium 40 mg) vs. CrestorTi 40mg (AstraZeneca) Composition accordingi; a Cream. 40 mg preferred embodiment of the present invention Rosuvastatin calcium 40mg .Exposed conditkm 40 C/75% RH 40 C/75% R1-1 Pack HDPE Pack* Blister pack , T=0 'Month 3 Months TO [Month 3 Month Degradation (Known compounds) Comp 1 0.10% 0.11% 0.10% 0.13 % 0.13% 0.25%
Comp 2 0.04% ______________ 0.04% 0.04% ND ND
Comp 3** ND 7 0_04% 0.10% 0_53 %
0.64%
Comp 4'-* 0.06% 0.07% 0.13% 0-03% 1111% 0.22%
Camp 5 ND ND ND ND ND NlD
=
Total Known 0.20% 0.26% 036% 0.69% 0.88% 1.32%
Individual unknown compounds 0.05% 0.05% 0.05% 0.05% 0.05% 0.03%
0.03% 0_03% 0.05% 0.04%
Total unknown 0.08% 0.08% 7.05% AO % 0.09% 0.05%
Total Related 0.27% 0.34% 0.41% 0.79% 0.97% 1.37%
* HOPE pack - 50 tablets in 60 cc HDPE bottle with 7 x 1_0 g Trisorb and induction sealed " Comp 3- keto acid (major degradation product) Comp 4- lactone (major degradation product) ND - No Detected T =-- 0- time zero analysis Table 6 Comparative Stability of the dosage form according to a preferred embodiment of the present invention (Rosnvastatiri 5 mg) vs. Crestor 5rrig (AstraZeneca) - ___________________ --Composition according to a Crestor 5mg preferred embodiment of the present invention Rosuvastatin 5 mg -Exposed condition 40*C/75% RH 40*C/75% RH
...
Pack HDPE Pack* Blister pack .
T7,1 1Month I 3 Months T=0 1Month 3 Month -, Degradation (Known compounds) .
Comp 1 0.11% 0.12% 0.09% 0.12% 0.12% 0.25%
Comp 2 ND NI) ND ND ND ND
Comp 3* 0.64% 0.09% 0.22% 0.75% 0.87% 1.04% .
Comp 4* 0.05% 0.06% .. 0.10% - 0.06% 0.26%
0.61%
_ _ Comp 5 . ____________ . _ Total Known 0.20% 0.27/0 0.41% 0-93% 1.25% 1.90%
Individual unknown compounds 0.03% 0.03% 0.08% 0.03% 0.04%
. - _ 0.03% 0_04% ,0.06% 0.03%
0.04% .
- Total unknown 0.06% 0.03% -_ _ 0.12% 0.13% 0.07%
Total Related 0.26% 0.30% (141% 1.06% 1.38% 1.97%
* HDPE pack -45 tablets in 150 cc .1-1DPE bottle with 1.0 g Trisorh and induceon sealed.
** Comp 3- keto acid (major degradation product) Comp 4- lactone (major degradation product) ND - Not Detected -I .. 0- time zero analysis Table 7 Comparative stability data of the dosage form according to a preferred embodiment of , the present invention (Rosuvastatin calcium 20mg) in different packaging Composition according to a Composition according to a preferred embodiment of the preferred embodiment of the present invention present invention Rosuvastatin calcium 20 mg Rosuvastatin calcium 20 mg Exposed condition 40 C/75% RH 40"C/75% RH
Pack 1-113PE Pack* Blister pack"
T=0 1Month 3 lvlonths T=.0 1Month 3 Month Degradation (Known compounds) Comp 1I 0.09% 013% 0.11% 0.09% 0.12% 0.12%
Comp 2 <0_06% <0.06% <0.06% <0.06% <0.06%
Comp 3*** <0.06% 0.09% 0.16% <0.06% <0.06%
0_06%
Comp 4*** <0.06% 0.06% 0.09% <0.06% 0.08%
0.13%
Comp 5 <0.06% 1 <0_06% <0.06% 40,06%
<0.06% _ <0.06%
Individual unknown compounds <0.06% <0.06% <0.06% <0.06% <0_06%
Total Related 0.09% 158% 0_36% 0.09% 0.20 /o 031%
" HDPE pack -100 tablets in1.50 cc HDPE bottle with 1.0 g Trisorb and induction sealed.
Blister pack- Cold Forming blister with push-through aluminum foil.
Comp - keto add (major degradation product) Comp 4- lactone (major degradation product) ND-Not Detected T = 0 - time zero analysis Excellent chromatographic resolution between the main peak and its degradation products or irnpurities was achieved usin.g a C18 reversed column with acidic ammonium acetate and an increasing gradient using acetonitrile and tetrahydrofuran.
Degradation products were quantified at 280 run. The reporting limit of the degradation products was set at 0.03%.
As can be seen from Tables 5 and 6, the dosage forms according to the present invention substantially avoids the formation of lactone or oxidation degradation products in comparison to the commercially available dosage form containing rosuvastatin calcium, presenting greater stability than what was achieved in the Crestor product.
As can be seen from Table 7, the level of degradation of the active pharmaceutical ingredient in HDPE packs and blister packs is approximately the same, with 0.16% of =

the oxidation product and 0.09% of the lactone detected in the HDPE packs versus 0.06%
of the oxidation product and 0.13% of the lactone in the blister packs after 3 months storage at 40 C and 75% relative humidity.
From the results provided in Tables 5 to 7, it can clearly be understood that the composition (or formulation) of the present invention is stable without the addition of any stabilizers. The major degradation products, being the lactone and the keto-acid (oxidation product), are well controlled.

Claims

1. A novel stable pharmaceutical dosage form comprising rosuvastatin or a pharmaceutically acceptable salt thereof as a pharmaceutically active agent and a pharmaceutically acceptable carrier;
wherein the dosage form is substantially free of stabilizing agents;
the pharmaceutically acceptable carrier comprises the following pharmaceutically acceptable excipients: colloidal silicon dioxide in an amount ranging from about 0.5 to 2.5 % by weight of the dosage form, microcrystalline cellulose in an amount ranging from about 15 to 55% by weight of the dosage form, and lactose monohydrate in amount ranging from about 30 to 70% by weight of the dosage form.

2. The stable dosage form according to claim 1, wherein the colloidal silicon dioxide is present in an amount ranging from 0.5 to 1.5% by weight of the dosage form, the microcrystalline cellulose is present in an amount ranging from 25 to 35% by weight of the dosage form, and lactose monohydrate is present in an amount ranging from 50 to 70% by weight of the dosage form.

3. The stable dosage form according to claim 1 or 2, wherein the pharmaceutically active agent is rosuvastatin calcium.

4. The stable dosage form according to any one of claims 1 to 3, further comprising a lubricant and/or a disintegrant.

5. The stable dosage form according to claim 4, wherein the lubricant is magnesium stearate.

6. The stable dosage form according to claim 4, wherein the disintegrant is crospovidone.

7. The stable dosage form according to any one of claims 1 to 6, wherein the dosage form is in the form of a capsule.

8. The stable dosage form according to any one of claims 1 to 6, wherein the dosage form is in the form of a tablet.

9. The stable pharmaceutical dosage form according to any one of claims 1 to 8 further comprising a coating composition that comprises a coating agent, alone or in combination with any other pharmaceutically acceptable excipient selected from the group consisting of: a film forming polymer, anti tacking agents, glidants, diluents, lubricants, plasticizers, additives, surface active agents, and solvents.

10. The stable pharmaceutical dosage form according to any one of claims 1 to 9, wherein the pharmaceutically active agent remains substantially free of degradation after storage in high-density polyethylene (HDPE) packs at 40 °C and 75% relative humidity for 3 months, and whereby the level of degradation provides about 0.10 % to about 0.22% of the oxidation product and from about 0.09% to about 0.13% of the lactone product.

11. The stable pharmaceutical dosage form according to any one of claims 1 to 9, wherein the pharmaceutically active agent remains substantially free of degradation after storage in blister packs at 40 °C and 75% relative humidity for 3 months, and whereby the level of degradation provides about 0.10 % to about 0.22% of the oxidation product and from about 0.09% to about 0.13% of the lactone product.

12. A process for manufacturing the stable dosage form according to any one of claims 1 to 11, wherein said process comprises the following steps:
(i) a first step (or steps) of combining rosuvastatin or a pharmaceutically acceptable salt thereof with the following pharmaceutically acceptable excipients:
colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate so as to form a blend;
(ii) a second step of compressing said blend obtained in step 1; and (iii) optionally, a third step of applying a coating composition.

13. A novel stable pharmaceutical dosage form comprising a core composition and a coating composition;
wherein the core composition comprises rosuvastatin or a pharmaceutically acceptable salt thereof as a pharmaceutically active agent and a pharmaceutically acceptable carrier;

wherein the pharmaceutically acceptable carrier comprises the following pharmaceutically acceptable excipients: colloidal silicon dioxide in an amount ranging from about 0.5 to 2.5 % by weight of the dosage form, microcrystalline cellulose in an amount ranging from about 15 to 55% by weight of the dosage form, and lactose monohydrate in amount ranging from about 30 to 70% by weight of the dosage form; and the dosage form is substantially free of stabilizing agents.

14. The stable pharmaceutical dosage form according to claim 13, wherein the coating composition comprises a coating agent, alone or in combination with any other pharmaceutically acceptable excipient, including a film forming polymer, anti-tacking agents, glidants, diluents, lubricants, plasticizers, additives, surface active agents, and solvents.

15. The dosage form according to claim 14, wherein the coating agent is combined with a film forming polymer and the film forming polymer is Opadry® or Opadry II®.