FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"CHRONOTHERAPEUTIC DOSAGE FORM OF ATORVASTATIN"
2. APPLICANT:
(a)NAME:FDC LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, ' Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to oral floating gastroretentive controlled release dosage form of Atorvastatin which releases the medication based on chronotherapy; and the process for preparation thereof.
BACKGROUND OF THE INVENTION:
Statins are popular cholesterol-lowering drugs which are used in the management of hypercholesterolemia and are shown to be significantly effective in decreasing the risk of heart attacks, strokes, death and other coronary artery diseases related to high cholesterol levels. However, there is a raising concern about the safety of statin drugs.
In August 2001, statin drug 'Cerivastatin' was withdrawn from the market, worldwide due to its high-bioavailability associated side-effect of fatal rhabdomyolysis'(breakdown of muscle fibers) which damages the kidney and leads to kidney failure.
Also, recently in February 2012, US Food and Drug Administration (FDA) has added new safety alerts to the labels of widely-used statin drugs stating that use of statin medications can lead to memory loss & confusion and may increase the risk of developing diabetes. Hence, the safety of statin drugs has become a matter of great concern in recent times.
Atorvastatin is one of statins which significantly reduces both cholesterol and triglycerides in the blood and in turn helps in decreasing the risk of heart attacks, strokes, death and other coronary artery diseases related to high cholesterol levels.
Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, which reduces production of cholesterol by inhibiting HMG-CoA reductase enzyme that plays a key role in synthesis of cholesterol in the liver.


Atorvastatin is capable of reducing levels of Total Cholesterol (TC), low density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol and triglycerides (TG) within the blood, and achieves greater cholesterol reductions than other statins such as lovastatin, pravastatin or simvastatin.
Atorvastatin has rare but severe adverse effects such. as muscle pain/weakness known as myopathy, serious breakdown of muscle known as rhabdomyolysis, liver damage, fever, abdominal pain, diarrhea, jaundice, urinary tract infection and kidney problems. Less serious adverse effects associated with Atorvastatin includes headache, nausea, constipation and allergic reaction such as skin rash, itching. Moreover, as atorvastain is prescribed on a long-term basis, atorvastain in high doses or in combination with certain drugs (e.g. fibrate, niacin) received for concomitant conditions during the course of statin therapy can lead to fatal adverse effects. Hence, it is desirable to have safer as well as efficacious atorvastatin dosage forms.
Atorvastatin blocks the pathway for synthesizing cholesterol in the liver by inhibiting HMG-CoA reductase enzyme present in the liver. As atorvastatin effect is confined to the liver, atorvastatin is required to have high drug concentration in the liver to'exhibit enhanced efficacy, and low systemic bioavailability in order to reduce the risk of systemic adverse effects.
Further, cardiovascular system along with metabolism is heavily dependant on the biological clock and follows the circadian rhythm, and hence major fraction of cholesterol in human body is synthesized in liver at night time. So, it is desirable to have

atorvastatin dosage forms which exhibit high hepatic bioavailability and low systemic bioavailability, preferably during the night time.
US patent application 20060003001 discloses chronotherapeutjc formulations of cardiovascular drugs, that achieve a specific therapeutic blood level profile and particularly suitable for use as once-daily, wherein said cardiovascular formulation is co-administered with statins selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, resuvastatin or simvastatin. However, said US application discloses instant-release multiparticulate which are coated with polymeric material comprising gastro-resistant and enterosoluble polymer(s). Moreover, said US application does not disclose the gastroretentive dosage form of any statin drug, and also does not discuss about the hepatic and systemic bioavailability of the dosage form.
US patent application 20110003837 discloses modified release formulations of HMG CoA reductase inhibitors, such as lovastatin, pravastatin, atorvastatin, nivastatin, rosuvastatin, cerivastatin, pitvastatin, and particularly rosuvastain, or its salts, polymorphs, solvates, hydrates, prodrug or metabolite; wherein the modified release formulation provides reduced incidence of adverse effects and improved efficacy when compared to the immediate release formulation upon oral administration. However, the modified release formulations of said US patent application, does not describe chronotherapeutic drug delivery of Atorvastatin which increases hepatic bioavailability and decreases systemic availability upon oral administration.
US patent application 2009/0099151 discloses modified release pharmaceutical composition comprising active ingredient including HMG CoA reductase inhibitors; a polymer system in an amount less than about 80% w/w of the composition comprising at least two swellable pH independent polymers wherein at least one is hydrophilic; optionally other pharmaceutically acceptable excipients is provided. The said US application does not teach floating gastroretentive formulation.
US patent 7887841 discloses chronotherapeutic pharmaceutical formulation having a core containing an active ingredient such as atorvastatin, and a delayed-release compression coating comprising a natural or synthetic gum applied onto the surface of

the core. Even though, said US patent discloses delayed-release technology as well as chronotherapeutic technology for said pharmaceutical formulation, natural or synthetic gum is an essential component required for said chronotherapeutic formulation. Also, said US patent does not discuss about the improved hepatic bioavailability or reduced systemic bioavailability upon oral administration of the chronotherapeutic formulation.
None of the aforementioned prior art, discloses an atorvastatin dosage form that exhibits improved hepatic bioavailability and reduced systemic bioavailability, preferably at the night time. The present inventors have attempted to improve the safety and efficacy of Atorvastatin dosage form, and have developed a safer and efficacious chronotherapeutic dosage form of Atorvastatin which exhibits improved liver targetability and reduced systemic drug transformation, preferably at night time.
SUMMARY OF INVENTION:
The present invention relates to oral floating gastroretentive controlled release dosage form of Atorvastatin which releases the medication based on chronotherapy; and the process for preparation thereof. The oral dosage form of present invention comprises atorvastatin or its pharmaceutically acceptable salts, esters or derivatives, along with hydrophilic and/or hydrophobic rate-controlling agents, solubilizers, gas-generating agent(s), superdisintegrants(s) and other pharmaceutically acceptable excipients. The said dosage form of Atorvastatin further comprises one or more cardiovascular agents.
The present invention provides safe and efficacious dosage form of Atorvastatin which exhibits improved liver targetability and reduced systemic drug transformation, preferably at the night time. Thus, the present invention provides Atorvastatin dosage form that exhibits improved therapeutic efficacy while minimizing the adverse effects such as muscle pain/weakness known as myopathy, serious breakdown of muscle known as rhabdomyolysis, liver damage, fever, abdominal pain, diarrhea, jaundice, urinary tract infection, kidney problems, memory loss/confusion, risk of developing diabetes, headache, nausea, constipation and allergic reactions such as skin rash and itching.

The Atorvastatin dosage form of the present invention also provides reduced interactions with the other drugs received for concomitant conditions during the course of statin therapy and thus reduces adverse effects.
DETAILED DESCRIPTION:
The present invention relates to oral floating gastroretentive controlled release dosage form of Atorvastatin which releases the medication based on chronotherapy; and'the process for preparation thereof. The oral dosage form of present invention comprises atorvastatin or its pharmaceutically acceptable salts, esters or derivatives, along with hydrophilic and/or hydrophobic rate-controlling agents, solubilizers, gas-generating agent(s), superdisintegrants(s) and other pharmaceutically acceptable excipients. The present invention provides a safer and efficacious chronotherapeutic dosage form of Atorvastatin.
Atorvastatin is a BCS class-II drug, which has poor solubility and high permeability. Poor/ erratic solubility and dissolution of Atorvastatin leads to partial/incomplete absorption and inconsistency in release profile of Atorvastatin. Hence, it is very difficult to develop controlled release formulation.
Atorvastatin has pH dependent solubility, with maximum solubility at alkaline pH, and absorption of drug is required at proximal part of gastro-intestinal tract (stomach and small intestine). Hence, it is desirable to formulate gastroretentive controlled release formulation which slowly releases drug over period of time and simultaneously gets retained in upper part of gastro-intestinal tract for a prolonged period.
Atorvastatin used in the present invention is in the range of 0.5% to 40% w/w of total weight of formulation
In order to improve the solubility of the Atorvastatin, solublizers are added" in the present invention to obtain a predictable drug release profile. The solubility enhancement of the Atorvastatin is achieved by incorporating alkalizers as solublizers. Alkalizers improve the solubility of the drug by providing the optimum

microenvirnmental pH, which enhances the solubilization of the drug in the dosage form.
The solubilizer(s) used in the present invention are selected from but not limited to sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate or aluminum carbonate. However, calcium carbonate due to its gas generating tendency in presence of acidic pH, has also been used in present invention as a gel forming agent for certain polymers and for high mechanical strength of the dosage form. The sblubilizer(s) used in the present invention are present in the range of 2% to 45% w/w of total weight of formulation.
The present invention provides a novel floating gastroretentive delivery system for controlled release of Atorvastatin in upper part of gastro-intestinal tract. The dosage form floats on the surface of the gastric contents with controlled release of the Atorvastatin, wherein the drug is delivered over a period of time which is similar to the transit time of the dosage form in the absorptive region of the proximal part of gastrointestinal tract.
Floating gastroretentive drug delivery systems are designed to improve the-gastric residence time of drug and/or dosage form. Due to the floating gastroretentive nature of the present invention dosage form, atorvastatin is delivered in a controlled release manner which minimizes access of Atorvatatin to systemic circulation and thus lowers the drug concentration. This reduced systemic drug exposure of atorvastatin translates into reduced inhibition of HMG-CoA in non-hepatic tissue, leading to normal functioning of non-hepatic tissue and fewer associated adverse effects. Thus, the gastroretentive drug delivery of Atorvastatin offers low systemic availability and reduces the incidence of side effects, enhancing the safety profile of Atorvastatin dosage form. Moreover,.the gastroretention of the Atorvastatin dosage form provides high drug concentration of atorvastatin in the liver, leading to improved hepatic bioavailability which enhances the therapeutic efficacy of Atorvastatin dosage form.
In chronotherapeutic drug-delivery system, in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. It

is based on the observation that there is an interdependent relationship between peak to trough rhythmic activity in disease symptoms and risk factors, pharmacologic sensitivity and pharmacokinetics of many drugs. The specific time that patients take their medication is very important as it has significant impact on treatment success. Optimal clinical outcome cannot be achieved if drug plasma concentration is constant. If symptoms of a disease display circadian variation, drug release should be modified over the period of time in accordance with circadian variation. Drug pharmacokinetics can also be time-dependent; therefore, variations both in a disease state and in drug plasma concentration needs to be taken into consideration in developing drug delivery systems intended for the treatment of disease with adequate dose at appropriate time.
Due to chronotherapeutic nature of the present dosage form, peak drug concentration of atorvastatin in liver is attained at midnight when administered at bed time, thus offering improved hepatic bioavailability and reduced systemic availability of the gastroretentive dosage form at the night time. As a result the present invention provides improved therapeutic efficacy of Atorvastatin dosage form while minimizing its adverse effects, at the desired time.
Hydrophillic and/of hydrophobic agents used in the present invention, control the drug release rate of atorvastatin from dosage form. Hydrophillic agents are a network of polymeric chains which are insoluble in water, and sometimes form a colloidal gel when water is used as dispersion medium. These agents swell when incorporated in solid dosage forms, and creates a rigid gel structure in presence of dissolution media. This rigid gel structure provides rate-controlling barrier for drug release and drug dissolution. Hydrophobic agents are waxy materials which are erodible and control the release of drug through pore diffusion and erosion.
The hydrophilic rate-controlling agent(s) used in the present invention are selected from but not limited to polyvinyl pyrrolidone, crospovidone, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methyl cellulose, polyethylene oxide, polysaccharides such as alginic acid and its salt, xanthan gum or mixtures thereof, and are present in the range of 5% to 80% w/w of total weight of formulation.

The hydrophobic rate-controlling agent(s) used in the present invention are selected from but not limited to cellulose derivatives; zein; acrylic resins; higher aliphatic alcohols; polylactic acid; polyglycolic acid; oils such as vegetable oil, mineral oil, hydrogenous vegetable oil; waxes such ascarnauba wax; low-melting hydrophobic materials such as glyceryl behenate, fatty alcohols, fatty acids or fatty esters; and are present in the range of 5% to 80% w/w of total weight of formulation.
Gas generating agent(s) are used in the formulation to increase porosity, which further improves drug release profile. Gas generating agents increase the channels and hence it assures maximum drug release from the dosage form, especially for poorly soluble drugs. Moreover, the gas generating agents reduce the density of the dosage form and thus offer prolonged floating and gastroretention.
The gas-generating agent(s) used in the present invention are selected from but not limited to carbonates such as calcium carbonate, sodium carbonate or sodium glycine carbonate; and bicarbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate. The gas generating component interacts with an acid source triggered by contact with water or simply gastric fluid to generate gas. The gas generating agent(s) are used alone or in combination with an acid source such as organic acid. The organic acids are selected from citric acid or its salts such as sodium or calcium citrate; malic acid; tartaric acid; succinic acid; fumaric acid; maleic acid or their salts; ascorbic acid and its salts such as sodium or calcium ascorbate; or mono or bi-alkali salts of organic acids having one or more than one carboxylic groups. The gas-generating agent(s) are present in the range of 2 to 45% w/w of total weight of formulation.
Superdisintegrants are used in the formulation to increase the swellability of the dosage form, and offer increased size of dosage form that is not affected by gastric emptying. Superdisintegrants also increase the wettability of dosage forms which allows penetration of gastric fluid inside the dosage form. Gastric fluid is absorbed by the superdisintegrants that lead to gellation of hydrophillic agent, and form a viscous gel layer. The intimate contact of gastric fluid with hydrophilic agent increases the gel strength of the dosage form. The formed gel layer maintains the integrity of the tablet

dosage form and acts as a barrier for drug release, thus offering controlled mode of drug release from the dosage form.
The superd is integrants used in the present invention are selected from but not limited to croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone, or polyvinylpyrrolidone-vinyl acetate copolymer, and are present in the range of 1% to 10% w/w of total weight of formulation.
The other pharmaceutically acceptable excipients used in the present invention comprise one or more diluents, binders, lubricants and glidants.
The diluents used in the present invention are selected from a group consisting "of lactose such as spray-dried lactose monohydrate, alpha-lactose monohydrate, anhydrous alpha-lactose, anhydrous beta-lactose and agglomerated lactose; sugars; dextrose; polyols such as mannitol, sorbitol or xylitol; organic acids such as tartaric acid; and inorganic salts such as dibasic calcium phosphate, tribasic calcium phosphate and calcium sulfate.
The diluents used in the present invention optionally include adsorbent diluents. Adsorbent diluents are solid materials or combination of solid materials that are capable of adsorbing and carrying an oily or fluid material such as simethicone, while retaining sufficient flowability to assure content uniformity and sufficient compatibility to be processed into tablets using direct compression methods.
The adsorbent diluents used in the present invention, are selected from a group consisting of silicified microcrystalline cellulose, silicone dioxide, activated charcoal, talc, calcium silicate, maltodextrin, magnesium aluminum silicate, clay, natural starches, starch derivatives or cyclodextrin.
The lubricants used in the present invention are selected from but not limited to stearic acid, palmitic acid, glyceryl behenate, talc, magnesium stearate, castor oil, hydrogenated castor oil or mineral oil.

The glidants used in the present invention are selected from but not limited to colloidal silicone dioxide, talc, magnesium carbonate.
The Atorvastatin dosage form of present invention further comprises one or more cardiovascular agents.
The chronotherapeutic dosage form of Atorvastatin of present invention, exhibits improved liver targetability and reduced systemic drug transformation, preferably at the night time, thus improving the efficacy of atorvastatin dosage form while minimizing its adverse effects such as muscle pain/weakness known as myopathy, serious breakdown of muscle known as rhabdomyolysis, liver damage, fever, abdominal pain, diarrhea, jaundice, urinary tract infection, kidney problems, memory loss/confusion, risk of developing diabetes, headache, nausea, constipation and allergic reactions such as skin rash and itching.
The Atorvastatin dosage form of present invention also provides reduced interactions with the other drugs received for concomitant conditions during the course of statin therapy and thus reduces fatal adverse effects.
The dosage form of present invention exists in the form of monolithic system such as single layered or multi-layered tablets, pellets or capsules, or in the form of multiparticulate system such as mini pellets, mini tablets or beads contained in capsule, pouch or sachet; as a oral unit dosage form.
The present invention is exemplified by the following examples which are provided for illustration only and should not be construed to limit the scope of the invention.
Examples Example 1

Sr.No Ingredient . mg/ tablet
1 Atorvastatin (calcium trihydrate) 80
2 Calcium carbonate 30

3 Sodium bicarbonate 30
4 Crospovidone 15
5 Anhydrous lactose 34
6 Hydroxypropyl methyl cellulose 60
7 Glyceryl behenate 20
8 Colloidal silicone dioxide 2
9 Magnesium stearate 4
Example 2

Sr.No Ingredient mg/ tablet
1 Atorvastatin (calcium trihydrate) 40
2 Calcium carbonate 15
3 Sodium bicarbonate 15
4 Crospovidone 7.5
5 Anhydrous lactose 17
6 Hydroxypropyl methyl cellulose 30
7 Glyceryl behenate 10
8 Silicon dioxide 1
9 Magnesium stearate 2
Preparation for example 1 and 2:
Atoravastatin calcium, calcium carbonate, lactose, glyceryl behenate, hydroxypropyl methyl cellulose we're sifted and mixed. This blend was granulated using purified water as aqueous wet granulation. The wet granules were milled. These granules were, initially air-dried and then dried at about 55°C. Dried granules were sifted and mixed with sodium bicarbonate and crospovidone as extragranular materials, which were further lubricated with magnesium stearate and colloidal silicone dioxide, and finally compressed by conventional pressing procedure.
Example 3

Sr.No Ingredient mg/ tablet
1 Atorvastatin (calcium trihydrate) 80

2 Calcium carbonate 30
3 Sodium bicarbonate 30
4 Crospovidone 15
5 Anhydrous lactose 32
6 Hydroxypropyl methyl cellulose 50
7 Polyvinylpyrrolidone 15
8 Carbopol 971 P 20
9 Colloidal silicone dioxide 2
10 Magnesium stearate 4
Example 4

Sr. No Ingredient mg/ tablet
1 Atorvastatin (calcium trihydrate) 20.0
2 Calcium carbonate 7.5
3 Sodium carbonate 7.5
4 Crospovidone 3.75
5 Anhydrous lactose 8.0
6 Hydroxypropyl methyl cellulose 15.0
7 Polyvinylpyrrolidone 3.75
8 Carbopol 971 P 5.0
9 Silicon dioxide 0.5
10 Magnesium stearate 1.0
Preparation for example 3 and 4:
Atoravastatin calcium, calcium carbonate, lactose, glyceryl behenate, hydroxypropyl methyl cellulose, carbopol 971 P, sodium carbonate and crospovidone sifted and mixed geometrically, further silicon dioxide and magnesium stearate were added as glidant and lubricant, and finally compressed by direct compression method using conventional pressing procedure.

Example 5

Sr.No Ingredient mg/ tablet
1 Atorvastatin (calcium trihydrate) 80.0
2 Sodium bicarbonate 30.0
3 Croscarmellose sodium 14.0
4 Dibasic calcium phosphate 40.0
5 Microcrystalline cellulose 30.0
6 Hydroxypropylcellulose 50.0
7 Sodium alginate 30.0
8 Talc 2.0
9 Magnesium stearate 4.0
Preparation:
Atoravastatin calcium, dibasic calcium phosphate, microcrystalline cellulose, sodium alginate and croscarmellose sodium were sifted and mixed geometrically. This blend was granulated using roller compaction method. The compacts formed were milled. These granules were sifted and mixed with sodium bicarbonate as extragranular materials which were further lubricated with talc and magnesium stearate, and finally compressed by conventional pressing procedure.
Example 6

Sr.No Ingredient mg/ tablet
1 Atorvastatin (calcium trihydrate) 80
2 Calcium carbonate 30
3 Sodium bicarbonate 30
4 Microcrystalline cellulose 50
5 Hydroxypropyl methyl cellulose 45
6 Polyvinyl pyrrolidone 15
7 Polyethylene oxide 35
8 Crospovidone 20
9 Colloidal silicone dioxide 2
10 Magnesium stearate 6

Preparation:
Atoravastatin calcium, calcium carbonate, microcrystalline cellulose, polyethylene oxide, hydroxypropyl methyl cellulose were sifted and mixed. This blend was granulated using polyvinylpyrrolidone with purified water as aqueous wet granulation. The wet granules were milled. These granules were initially air-dried and then dried at about 55°C. Dried granules were sifted and mixed with sodium bicarbonate and crospovidone. as extragranular materials, which were further lubricated with magnesium stearate and colloidal silicone dioxide, and finally compressed by conventional pressing procedure.
Example 7

Sr.No Ingredient mg/ tablet
1 Magnesium aluminometasilicate 100.0
2 Silicone oil 120.0
3 Microcrystalline cellulose 250.0
4 Polyvinylpyrrolidone 15.0
5 Sodium starch glycolate 11.0
6 Magnesium stearate 4.0
Preparation of first layer:
Magnesium aluminometasilicate and microcrystalline cellulose were sifted. In glass mortar and pestle, silicone oil was levigated into the magnesium aluminometasilicate; further microcrystalline cellulose was added and mixed. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled. These granules were initially air-dried and then at about 55°C. Dried granules were sifted and lubricated magnesium stearate and sodium starch glycolate.

Sr.No Ingredient mg/ tablet ''
1 Atorvastatin (calcium trihydrate) 80
2 Calcium carbonate 30
3 Sodium bicarbonate 30
4 Crospovidone 15

5 Anhydrous lactose 27.5
6 Hydroxypropyl methyl cellulose 50
7 Colloidal silicone dioxide 1
8 Glyceryl behenate 1.5
Preparation of second layer:
Atoravastatin calcium, calcium carbonate, sodium bicarbonate, lactose, hydroxypropyl
methyl cellulose, were sifted and mixed geometrically. This blend was granulated with
purified water using aqueous wet granulation. The wet granules were milled. These
granules were initially air-dried and then at about 55°C. Dried granules were sifted and
mixed with crospovidone which were further lubricated with colloidal silicone dioxide
and glyceryl behenate.
Bilayer compression:
First and second tablet layer compositions were compressed into bilayer tablets.
Dissolution Profile:

Sr. No. Time (hr) % Cumulative Release
1 2 30-60%
2 6 60%-85%
3 8 NLT 85%
Drug release profile:

Sr.
No. Time
(hr) % Cumulative Release

Example
1 Example 2 Example 3 Example
4 Example
5 Example 6 Example 7
1 0 0 0 0 0 0 0 0
2 0.5 14.5. 14.1 14.1 14.4 11.2 10.2 14.8
3 1 24.9 24.0 24.2 25.0 19.8 18.4 25.4
4 2 41.2 39.9 40.9 41.3 35.6 31.6 ■ 40'.0
5 4 63.2 62.9 65.4 66.2 53.3 45.0 61.9
6 6 78.6 77.7 77.1 77.8 66.2 59.6 79.2
7 8 95.3 94.6 94.6 95.2 84.0 74.4 96.3

WE CLAIM:
1. A chronotherapeutic, oral floating gastroretentive controlled release dosage form of Atorvastatin or pharmaceutically acceptable salts, esters or derivatives thereof, comprising rate-controlling agents, solubilizers, gas-generating agent(s), superdisintegrants(s) and other pharmaceutically acceptable excipients and process of preparation thereof.
2. The chronotherapeutic oral dosage form of Atorvastatin as claimed in claim 1, wherein Atorvastatin is present in the range of 0.5% to 40% w/w of total weight of formulation.
3. The chronothapeutic oral dosage form of Atorvastatin as claimed in claim 1, wherein the rate-controlling agents comprises hydrophilic and/or hydrophobic agents for controlling the release rate of atorvastatin.
4. The chronotherapeutic oral dosage form as claimed in claim 1, wherein the hydrophilic rate-controlling agent(s) are selected from a group consisting of polyvinyl pyrrolidone, crospovidone, hydroxymethylcellulose, hydroxyethyf- cellulose, hydroxylpropylceflulose, hydroxylpropylmethylcellulose, methyl cellulose, polyethylene oxide, polysaccharides including alginic acid and its salt, and xanthan gum, and are present in the range of 5% to 80% w/w of total weight of formulation.
5. The chronotherapeutic oral dosage form as claimed in claim 1, wherein the hydrophobic rate-controlling agent(s) are selected from a group consisting of cellulose derivatives, zein, acrylic resins, higher aliphatic alcohols, polylactic acid, polyglycolic acid, oils including vegetable oil, mineral oil, hydrogenous vegetable oil, waxes includeing carnauba wax, and low-melting hydrophobic materials including glyceryl behenate, fatty alcohols, fatty acids and fatty esters, and are present in the range of 5% to 80% w/w of total weight of formulation.
6. The chronotherapeutic oral dosage form as claimed in claim 1, wherein the solublizers are selected from a group consisting of calcium carbonate, sodium carbonate,

potassium carbonate, aluminum carbonate and sodium bicarbonate, and are present in the range of 2 to 45% w/w of total weight of formulation.
7. The chronotherapeutic oral dosage form as claimed in claim 1, wherein the gas-generating agent(s) include carbonates and bicarbonates, selected from calcium carbonate, sodium carbonate, sodium glycine carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, and are present in the range of 2 to 45% w/w of total weight of formulation.
8. The chronotherapeutic oral dosage form as claimed in claim 6, wherein the gas generating agent(s) are used alone or in combination with an acid source comprising organic acids selected from a group consisting of citric acid, rnalic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, ascorbic acid and their salts, and mono/bi-alkali salts of organic acids.
9. The chronotherapeutic oral dosage form as claimed in claim l, wherein the superdisintegrants are selected from a group consisting of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate copolymer, and are present in the range of l% to 10% w/w of total weight of formulation.

10. The chronotherapeutic oral dosage form as claimed in claim 1, wherein the other pharmaceutically acceptable excipients comprise diluents, binders, lubricants and glidants.
11. The chronotherapeutic oral dosage form as claimed in claim 1, further comprises one or more cardiovascular agents.