CA2637977A1

CA2637977A1 - Dosage form containing a statin

Info

Publication number: CA2637977A1
Application number: CA002637977A
Authority: CA
Inventors: Mathew Philip; Naresh Talwar; Shruti Bhat
Original assignee: Pharmascience Inc
Current assignee: Pharmascience Inc
Priority date: 2008-07-15
Filing date: 2008-07-15
Publication date: 2010-01-15
Also published as: CA2730665C; WO2010006451A1; CA2730665A1

Abstract

The present invention relates to a novel stable pharmaceutical dosage form containing an HMG-CoA reductase inhibitor and free of stabilizing agents, said dosage form comprising an HMG-CoA reductase inhibitor combined with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate and processes to make such.

Description

DOSAGE FORM CONTAINING A STATIN
FIELD 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 dosage form. More specifically, the present invention relates to a dosage form comprising Rosuvastatin calcium as pharmaceutically acceptable active ingredient.

BACKGROUND OF THE INVENTION
Rosuvastatin calcium, known under the trade name Crestor , is a synthetic lipid-lowering agent for oral administration. The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl]
(3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. It has the following structural formula:

F
~..

C$2+
N'` o_ sa~a Rosuvastatin calcium belongs to the class of medications known as "statins", more specifically called HMG-CoA reductase inhibitors. HMG-CoA reductase is an enzyme 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 persons body decrease LDL (bad) cholesterol and triglyceride levels;
increase HDL (good) cholesterol levels; and decrease the Total Cholesterol/HDL-Cholesterol Ratio (TC: HDL-C Ratio). The 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, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including: primary hypercholesterolemia (Type Ila including heterozygous familial hypercholesterolemia and severe non-familial hypercholesterolemia), combined (mixed) dyslipidemia (Type IIb), homozygous familial hypercholesterolemia 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 3-hydroxy-3-methylglutaryl-coenzyme A(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 low density lipoprotein (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 application 2,429,263, rosuvastatin can be used in the treatment of heterozygous familial hypercholsetrolemia, and according to Canadian patent application no. 2,560,167, statins can also be used for the treatment of ocular hypertension and glaucoma.

The preparation of rosuvastatin is described in, for example European patent no.
521 471 and U.S. patent no. 5,260,440 (both 1993 to Shionogi and corresponding to Canadian patent no. 2,072,945); by M. Watanabe et al. in Bioorg. Med. Chem. 5, (1997), Canadian patent applications nos. 2,495,296; 2,527,314; 2,543,358; and 2,573,857, and in, for example, International laid open applications W02007099561, W02007041666, W02007039287, W02007017117, W02006067456 (corresponding to CA 2,589,775) and W02006091771 (corresponding to CA 2,594,017).

Canadian patent application no. 2,450,820 is directed to processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the statin by using calcium hydroxide Canadian patent application no. 2,509,619 is directed to a synthetic route of preparing rosuvastatin.

Canadian patent application nos. 2,495,296 and 2,527,314 relates to a process for manufacture of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt, which is useful for the production 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)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6 -enoic acid] calcium salt, processes for making them and their use as HMG Co-A reductase inhibitors.

U.S. patent no. 7,241,800 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 calcium, is that it readily undergoes degradation under certain conditions like, exposure to atmospheric conditions (i.e. humidity, oxygen, air and light), thereby significantly reducing the storage life. Such has been referred to in Canadian patent 2,313,783 and 2,315,141.
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 also been referred to in International laid open application W02007071357 (which is based on US2005/0187234A1).

To solve this issue of degradation in rosuvastatin calcium, pharmaceutical manufacturers have used stabilizing agents (or material or substance). For example, Canadian patent no. 2,313,783 (corresponding to EP 1 223 918 and U.S. patent nos.

6,316,460 and 6,548,513) discloses the use of a tri-basic phosphate salt in which the cation is multivalent to provide stability to the composition, thereby avoiding degradation.
Canadian patent no. 2,315,141 discloses the use of an inorganic salt in which the cation is multivalent for stabilizing the rosuvastatin calcium structure.

International laid open application no. W02005041939 (corresponding to US2005119331A1) 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, and methods of their use.

International laid open application W02007071357 teaches a formulation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically-acceptable salt thereof for oral use, such as tablets, capsules, powders, granules by the use of ingredients chosen from two groups. The first group stabilizes rosuvastatin calcium against oxidation and the other group inhibits the formation of lactones.

Generally, the rosuvastatin calcium formulations of the prior art require the use of stabilizing agents, for example, inorganic salts, tribasic calcium phosphate in which the cation is multivalent, and some ingredients which specifically prevents 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

An object of the present invention is to provide a novel stable pharmaceutical dosage form containing an HMG-CoA reductase inhibitor and free of stabilizing agents, said dosage form comprising a HMG-CoA reductase inhibitor combined with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.

Preferably, wherein 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%.

Preferably, the HMG-CoA reductase inhibitor is a statin. More preferably, the statin is rosuvastatin or a pharmaceutically acceptable salt thereof. Most preferably, the statin is rosuvastatin calcium.

Another object of the present invention is to provide a rosuvastatin dosage form that allows a single daily administration with a prolonged effect, simplified production and is cost effective.

Yet another object of the present invention is to provide a process for manufacturing the novel dosage form.

It is also worth mentioning that the present invention is considered to be inventive because the manufacturing process 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, however, that this detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art.

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," "drug", "pharmacologically active agent", "pharmaceutically acceptable active agent" and/or "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 can be a statin, 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, prodrugs and analogs thereof.

Similarly, a "pharmaceutically 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.

By the terms "effective amount" or "pharmaceutically effective amount" of an agent as provided herein are meant a nontoxic but sufficient amount of the 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.

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 excipient" includes a "pharmaceutically acceptable carrier." For example, tablets, troches, pills, capsules, and the like, may contain excipients including binders, such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid; 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, coloring agents, wetting or emulsifying agents, pH
buffering agents, preservatives, and the like.

The expression "substantially 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 characteristics 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. In the present invention, the dosage form is preferably a tablet.

As aforementioned, the present invention relates to a novel stable pharmaceutical dosage form containing an HMG-CoA reductase inhibitor, wherein the dosage form is free of stabilizing agents, said dosage form comprising an HMG-CoA reductase inhibitor combined with at least the following pharmaceutically acceptable excipients:
colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.

(i) Core Composition (or tablet composition) The tablet composition of the present invention is made of several components, such as for example at least one pharmaceutically acceptable active substance (i.e. a statin, rosuvastatin or pharmaceutically acceptable salt thereof) combined with and at least one pharmaceutically acceptable excipient.

(a) Pharmaceutically acceptable active substance Pharmaceutically acceptable active agents or substances include and are not limited to statins. Suitable statins include, for example, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
Rosuvastatin and salts thereof are particularly preferred pharmaceutically acceptable active agents.

It is worth mentioning that the pharmaceutically acceptable active agent or substance could be co-administered with another active agent known to a person skilled in the art, such as, for example, simvastatin and ezetimibe (Vytorin ), lovastatin and niacin (advicor@) and atorvastatin and amlodipine (caduet ).

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.

(b) Pharmaceutically acceptable excipients As aforementioned the pharmaceutically acceptable active substance can be combined with and at least one pharmaceutically acceptable excipient. Acceptable pharmaceutically acceptable excipients, include for example 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 example, lactose, spray dried lactose ,a-lactose, R-lactose , Tabletose , various grades of Pharmatose , Microtose , Fast Flow , sorbitol, microcrystalline cellulose, various grades of Avicel, Vivacel , Vivapur , powdered cellulose, kaolin, starch, hydrolyzed starches, pregelatinized starch, alumina, sucrose, dextrins, dextrose, fructose, maltodextrins, 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, polarcrillin potassium, 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, hydroxypropylmethylcellulose (HPMC), methylcellulose, polyethylene oxide, and the like.

Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, talc, stearic acid (chemically designated as octadecanoic acid, C18H3602), zinc stearate, sodium stearyl fumerate, calcium stearate, light mineral oil and 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) (aerosil ), magnesium silicate, starch, talc, magnesium trisilcate, etc. Colloidal silicion dioxides are also known to function as an absorbent; anti-caking agent; emulsion stabilizer; glidant;
suspending agent; and tablet disintegrant.

If desired, the tablets may also contain minor amounts of nontoxic auxiliary substances such as antioxidants, such as for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyl anisole, butylated hydroxyl toulene, potassium meta bisulfite, propyl gallate, sodium thiosulfate, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, hypophosphorous acid, fumaric acid, monothioglycerol;
coloring agents, flavouring agents, surface active agents, such as for example, Sodium lauryl sulfate, poly oxyethylene sorbitan fatty acid esters (Tween series), Myrj series, Solutol HS, poly oxyethylene alkyl ethers (Byrj series), poly oxyethylene, 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 HCI, sodium hydroxide, fumaric acid, tartaric acid, malic acid, 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 for example, the Handbook of Pharmaceutical Excipients (5th edition) by Raymond C. Rowe, Paul J.
Sheskey and Sian C. Owen.

(ii) Coating 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, including for example, film forming polymer, anti-tacking agents, glidants, diluents, lubricants, plasticizers, additives, surface active agents, and solvents.

For example, the coating composition of the present invention can comprise of a coating agent, such as Opadry II manufactured by Colorcon.

(iii) Additional coats It is worth mentioning that the end product can further be coated with a non-functional or top coat so as to improve the appearance of the dosage form, i.e. a tablet. In this connection, conventional coating procedures and equipment may be used to coat the dosage units, i.e., 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 et al. (New York:
Marcel Dekker, Inc., 1989), and to Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6^th Ed. (Media, PA: Williams & Wilkins, 1995).

Utility The novel drug dosage forms 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 and 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, for example, described in the background of the 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 mg;
although 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.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention.
Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

EXAMPLES
The following examples are illustrative of the wide range of applicability of the present invention and are not intended to limit its scope. Modifications and variations can be made therein without depending from the spirit and scope of the invention.
Although any method and material whether similar or equivalent to those described herein can be used in the practice for testing the present invention, the preferred methods and materials as described.

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 herein below.

Table I
Comparative Formula of the dosage form according to preferred embodiments of the present invention vs. Crestor@ (Astra Zeneca) Rosuvastatin %w/w Function Crestor Function tablets of present invention 1 Rosuvastatin as 5.0%- Active Rosuvastatin as Active Rosuvastatin 14% Rosuvastatin calcium calcium 2 Collloidal Silicon 0.5- Glidant Calcium Stabilizer Dioxide Aerosil 1.5% phosphate 3 Microcrystalline 25-35% Diluent Lactose Diluent cellulose Avicel Monohydrate 4 Lactose 50-70% Diluent Microcrystalline Diluent Monohydrate cellulose Crospovidone 3-5.0% Disintegrant Crospovidone Disintegrant 6 Magnesium stearate 0.5- Lubricant Magnesium Lubricant 1.0% stearate 7 Opadry II Pink Coating Ferric oxide Red Colorant agent 8 Opadry II Yellow Coating Ferric oxide Yellow Colorant agent 9 - - - Hydroxy propyl Film former methyl cellulose - - - GI ce I triacetate Plasticizer 11 - - - Titanium Dioxide Opacifier Example #1 Table 2 Lot Size - 974 Tablets Rosuvastatin 5 mg (ROST 025) %w/w Qty for the lot (gm) 1 Rosuvastatin as Rosuvastatin 5.21 5.329 calcium 2 Collloidal Silicon Dioxide Aerosil 0.5 0.487 3 Microcrystalline cellulose Avicel 34.0 33.116 4 Lactose Monohydrate 54.54 52.88 5 Crospovidone 5.0 4.870 6 Magnesium stearate 0.75 0.731 7 Opadry II Yellow 3.0% of the tablet weight Manufacturing Process:

In a first step (i.e. step #1), rosuvastatin calcium and portion of lactose monohydrate (10.0 Gm) are blended together and screened through 420 pm mesh (blend #1). In a second step (i.e. step #2), aerosil, microcrystalline cellulose (Avicel ) and crospovidone are screened through 420 pm and blended with blend of step # 1 for 1 minute (blend #2).
In a third step (step #3), the remaining portion of lactose monohydrate was screened through 600 pm mesh and blended with blend #2 for 1 to 2 minutes (blend #3).
In a fourth step (step #4), magnesium stearate is screened through 420 pm mesh (425 pm) and is then blended with blend # 3 for several minutes (i.e. 1-2 minutes).
Afterwards, in a fifth step #5, the final blend, containing the elements of steps #1 to # 4, was compressed using a rotary press, so as to form, for example, tablets. The resulting tablets were then coated with, for example Opadry II (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 CoatT"".

Example #2 Table 3 Lot Size - 123 Tablets Rosuvastatin 40 mg ( ROST 026) %w/w Qty for the lot (gm) 1 Rosuvastatin as Rosuvastatin 9.80 5.41 calcium 2 Collloidal Silicon Dioxide Aerosil 0.5 0.261 3 Microcrystalline cellulose Avicel 34.0 17.8 4 Lactose Monohydrate 50.0 25.82 Crospovidone 5.0 2.61 6 Magnesium stearate 0.75 0.392 7 Opadry II Pink 3.0% of the tablet weight Manufacturing Process:
In a first step (i.e. step #1), rosuvastatin calcium and portion of lactose Monohydrate (10.0 Gm) are blended together and screened through 420 pm mesh (blend #1). In a second step (i.e. step #2), aerosil, microcrystalline cellulose (Avicel ) and crospovidone are screened through 420 pm and blended with blend of step # 1 for 1 minute (blend #2).
In a third step (step #3), remaining portion of Lactose Monohydrate was screened through 600 pm mesh and blended with blend #2 for 1 to 2 minutes (blend #3).
In a fourth step (step #4), magnesium stearate is screened through 420 pm mesh and is then blended with blend # 3 for 1-2 minutes. Afterwards, in a fifth step #5, the final blend, containing the elements of steps #1 to # 4, was compressed using a rotary press, so as to form, for example, tablets. The resulting tablets were then coated with, for example Opadry II (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 Rosuvastatin 20 mg ( P-1751) %w/w Qty for the lot (gm) 1 Rosuvastatin as Rosuvastatin 6.946 521.0 calcium 2 Collloidal Silicon Dioxide Aerosil 0.5 37.5 3 Microcrystalline cellulose (Avicel 10.0 750.0 101) 4 Microcrystalline cellulose (Avicel 15.0 1125.0 102) Lactose Monohydrate 63.8 4785.3 6 Crospovidone 3.0 225.0 7 Magnesium stearate 0.75 56.3 8 Opadry II Pink 3.0% of the tablet weight Manufacturing Process:
In a first step (i.e. step #1), rosuvastatin calcium Microcrystalline cellulose Avicel Ph 101 are blended together in a V blender for 3 minutes and screened through 225-250 pm mesh (blend #1). In a second step (i.e. step #2), aerosil, microcrystalline cellulose (Avicel 102) and crospovidone are blended together in a V -blender for 3 minutes and screened through 1000-1200 pm mesh (blend #2). In a third step (step #3), Lactose Monohydrate was screened through 1000-1200 pm mesh and blended with blend # 1&
blend #2 for 21 minutes in a Bin Blender (blend #3). In a fourth step (step #4), magnesium stearate is screened through 420 pm mesh and is then blended with blend #
3 for 3 minutes in a Bin Blender. Afterwards, in a fifth step #5, the final blend, containing the elements of steps #1 to # 4, was compressed using a rotary press, so as to form, for example, tablets. The resulting tablets were then coated with, for example Opadry II
(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 CoatT"".

In other words, the process for manufacturing the novel dosage form according to the present invention generally comprises:
- a first step of combining an HMG-CoA reductase inhibitor with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate so as to form a blend;
- a second step of compressing said blend obtained in step 1; 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.

It is worth mentioning that the dosage form, for example a tablet, of the present invention was subjected to accelerated stability studies as per ICH conditions in their primary packaging. A primary packaging includes tablets packed in HDPE packs with a dessicant 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 by tribasic calcium phosphate are provided in the following tables.

Table 5 Comparative stability of the dosage form according to a preferred embodiment of the present invention (i.e. Rosuvastatin 40 mg) vs. Crestor@ 40mg (Astra Zeneca) Composition according to a Crestor 40 mg preferred embodiment of the Lot No( 103960A) present invention Rosuvastatin 40 mg Lot No : ROST 026 Exposed condition 40 C/75% RH 40 C/75% RH
Pack HDPE Pack* Blister pack T=0 1 Month 3 Months T=0 1 Month 3 Month Degradation Known com ounds Comp 1 0.10% 0.11% 0.10% 0.13% 0.13% 0.25%
Comp 2 0.04% 0.04% 0.04% ND ND ND
Comp 3* ND 0.04% 0.10% 0.53 % 0.64% 0.85%
Comp 4* 0.06% 0.07% 0.13% 0.03% 0.11% 0.22%
Comp 5 ND ND ND ND ND ND
Total Known 0.20% 0.26% 0.36% 0.69% 0.88% 1.32%
Individual unknown compounds 0.05% 0.05% 0.05% 0.05% 0.05% 0.05%
0.03% 0.03% 0.05% 0.04%

Total unknown 0.08% 0.08% 0.05% 0.10 % 0.09% 0.05%
Total Related 0.27% 0.34 /u 0.41% 0.79% 0.97% 1.37%
*HDPE pack - 50 tablets in 60 cc HDPE bottle with 1 x 1.0 g Trisorb and induction sealed.

Table 6 Comparative Stability of the dosage form according to a preferred embodiment of the present invention (Rosuvastatin 5 mg) vs. Crestor 5mg (Astra Zeneca) Composition according to a Crestor 5mg preferred embodiment of the Lot No( 104063C) present invention Rosuvastatin 5 mg Lot No : ROST 025 Exposed condition 40 C/75% RH 40 C/75% RH
Pack HDPE Pack * Blister pack T=0 lMonth 3 Months T=0 1 Month 3 Month Degradation Known com ounds Comp 1 0.11% 0.12% 0.09% 0.12% 0.12% 0.25%
Com 2 ND ND ND ND ND ND
Comp 3* 0.04% 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% 0.41% 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% 0.41% 1.06% 1.38% 1.97%
*HDPE pack - 45 tablets in 150 cc HDPE bottle with 1.0 g Trisorb and induction sealed.

Table 7 Comparative stability data of the dosage form according to a preferred embodiment of the present invention (i.e. Rosuvastatin 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 20 mg Rosuvastatin 20 mg Lot No: P-1751 Lot No : P-1751 Exposed condition 40 C/75% RH 40 C/75% RH
Pack HDPE Pack* Blister pack**
T=0 lMonth 3 Months T=0 1 Month 3 Month Degradation (Known compounds) Comp 1 0.09% 0.13% 0.11% 0.09% 0.12% 0.12%
Comp 2 <0.06% <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% <0.06% <0.06% <0.06% <0.06% <0.06%
Individual unknown compounds <0.06% <0.06% <0.06% <0.06% <0.06% <0.06%
Total Related 0.09% 0.28% 0.36% 0.09% 0.20% 0.31%
*HDPE pack - 100 tablets in 150 cc HDPE bottle with 1.0 g Trisorb and induction sealed.
**Blister pack - Cold Forming blister with push-through aluminum foil.
ND - Not Detected T=O - Time Zero Analysis Comp 3 - Keto acid (Major degradation product) Comp 4 - Lactone (Major degradation product) Excellent chromatographic resolution between the main peak and its degradation products or impurities was achieved using a C18 reversed column with acidic ammonium acetate and an increasing gradient using acetonitrile and tetrahydrofuran.

Degradation products were quantified at 280 nm. The reporting limit of the degradation products was set at 0.03 %.

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 containing an HMG-CoA reductase inhibitor and free of stabilizing agents, said dosage form comp rising an HMG -CoA
reductase inhibitor combined with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.

2. The dosage form according to claim 1, wherein the colloidal silicon dioxide is present in an amount ranging from 0.5 to 2.5%, the microcrystalline cellulose is present in an amount ranging from 15 to 55% and lactose monohydrate is present in an amount ranging from 30 to 70%.

3. The dosage form according to claim 1, wherein 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%.

4. The dosage form according to any one of claims 1 to 3, wherein the HMG-CoA
reductase inhibitor is a statin.

5. The dosage form according to claim 4, wherein the statin is rosuvastatin or a pharmaceutically acceptable salt thereof.

6. The dosage form according to any one of claims 1 to 5, wherein the pharmaceutically acceptable active substance is rosuvastatin calcium.

7. The dosage form according to any one of claims 1 to 6, further comprising a lubricant and/or a disintegrant.

8. The dosage form according to claim 7, wherein the lubricant is magnesium stearate.

9. The dosage form according to claim 8, wherein the disintegrant is crospovidone.

10. The dosage form according to any one of claims 1 to 9 in the form of a capsule or a tablet.

11. The dosage form according to any one of claims 1 to 9 in the form of a tablet.

12. A process for manufacturing the dosage form according to any one of claims 1 to 11, wherein said process comprises:
- a first step of combining an HMG-CoA reductase inhibitor with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate so as to form a blend;
- a second step of compressing said blend obtained in step 1; and - optionally, a third step of applying a coating composition.

13. A novel stable pharmaceutical dosage form free of stabilizing agents, said dosage form comprising a core composition and a coating composition, wherein the core composition comprises an HMG-CoA reductase inhibitor combined with at least the following pharmaceutically acceptable excipients: colloidal silicon dioxide, microcrystalline cellulose, and lactose monohydrate.

14. The dosage form according to claim 12, wherein the coating comprises one or more of the following: a coating agent, alone or in combination with any other pharmaceutically acceptable excipient, including for example, 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 film forming polymer is Opadry ® or Opadry II®.-