Technical field of the invention:
The present invention relates to novel lipid lowering composition comprising Ubidecarenone (Coenzyme Q10) and a HMG-CoA reductase inhibitor such as Atorvastatin composition used for the treatment of hypercholesterolemia, coronary heart disease, dyslipidemia and other elevated blood lipid level-related diseases. The invention further relates to reduction in side effects of statins by supplemention with Coenzyme Q10. The invention also relates to process for preparation of the said composition.
Background and prior art:
Hypercholesterolemia refers to levels of cholesterol in the blood that are higher than normal. Hypercholesterolemia increases the risk of heart disease. Elevated levels of circulating cholesterol cause deposits to form inside blood vessels. These deposits result in a disease process called atherosclerosis. The symptoms are therefore the consequences of cardiovascular disease.
Statins are widely used for the treatment of hypercholesterolemia and coronary heart disease and for the treatment and protection of stroke. Even brief exposure to atorvastatin causes a marked decrease in blood ubiquinone concentration. There have been various adverse effects, most commonly affecting muscle and ranging from myalgia to rhabdomyolysis. (Arch Neurol.2004 Jun; 61(6); 889-92)
Atorvastatin Calcium is 3- hydroxyl 3- methyl glutaryl coenzyme A. (HMG- CoA) reductase inhibitor is a lipid regulatory drug with action on plasma lipids similar to those of Simvastatin, which is used in the treatment of combined hypercholesterolemia and Hyperlipidaemia. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-b, d -dihydroxy-5- (1 -methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid, calcium salt (2:1) trihydrate. The molecular formula of atorvastatin is (C33H34 FN205)2Ca-3H20 and its molecular weight is 1209.42. Its structural formula is:


Atorvastatin is indicated as an adjunct to diet for the treatment of dyslipidaemia, specifically hypercholesterolemia. Atorvastatin shows therapeutic response in two weeks and maximum response is achieved usually in 4 weeks and maintained during chronic therapy. In two multi centered placebo controlled trials patients with hypercholesterolemia, Atorvastatin is given as a single dose over 6 weeks significantly reduced total cholesterol, LDL and triglycerides. The therapeutic dose of Atorvastatin calcium is 5 mg, 10 mg and 15 mg.
Coenzyme Q was first discovered in 1957 by Professor F. L. Crane and colleagues at the University of Wisconsin Enzyme Institute. In 1958, its chemical structure was reported by Dr. D.E. Wolf and a research group at Merck Laboratories led by Dr. Karl Folkers. The various kinds of Coenzyme Q can be distinguished by the number of isoprenoid side chains they have. The most common Coenzyme Q in human mitochondria is Q10. Ubiquinone is a fat-soluble coenzyme, also known as Ubidecarenone, is a biologically active quinone with an isoprenoid side chain, related in structure to vitamin K and vitamin E. Ubidecarenone is a naturally occurring coenzyme involved in the electron transport in the mitochondria which has given for cardiovascular disorder including mild or moderate heart failure. Because of its ability to transfer electrons and therefore act as an antioxidant, Coenzyme Q is a valued dietary supplement.


A deficiency of the antioxidant coenzyme Q10 may be associated with long-term conditions including heart disease and high blood pressure. Symptoms of deficiency also include gingivitis, and weakened immune function.
Coenzyme Q10 shares a common biosynthetic pathway with cholesterol. Isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate, are linked alternatingly in polyprenyl chains, which are also called isoprenes. The 15-carbon isoprene chain is farnesyl pyrophosphate, which is a precursor to cholesterol, while the 50-carbon isoprene chain forms the side chain of coenzyme Q10.
The synthesis of an intermediary precursor of Coenzyme Q10, mevalonate, is inhibited by some beta blockers, a blood pressure lowering medication , and statins, a class of cholesterol lowering drugs. Statins can reduce serum levels of coenzyme Q10 by up to 40%. Research suggests the logical option of supplementation with coenzyme Q10 as a routine adjunct to any treatment which may reduce endogenous production of coenzyme Q10, based on a balance of likely benefit against very small risk. HMG Co A reductase inhibitors might result in impaired antioxidant protection due to depletion of the essential nutrient coenzyme Q10 resulting in decreased plasma coenzyme Q10 levels, therefore leading to oxidative stress. Statin-induced coenzyme Q10 deficiency is preventable with supplemental coenzyme Q10 with no adverse impact on the cholesterol lowering of the statin drugs.
Ubidecarenone is also under investigation for the management of Huntington's chorea and condition associated with coenzyme deficiency. It has been reported that the potential adverse effects of statins in chronic heart failure (CHF) include reduction in levels of ubiquinone and loss of protection that lipoproteins may provide through binding
and detoxifying endotoxins entering the circulation via the gut. (J Am. Coll cardiol 2002
Mayl5; 39(10); 1567-73).
These observations may relate to two Merck & Co.., Inc. patents for combining CoQIO within statin in capsule: US patent 4929437, issued May 29, 1990 and US patent 4933165, issued June 12,1990.

US 4929437 discloses a pharmaceutical composition and method of counteracting HMG-CoA reductase inhibitor-associated elevated transaminase levels. The method comprises the adjunct administration of an effective amount of a HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q.sub.10. The compounds of the invention may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like, preferably hard-gelatin capsule comprising of 20 mg of lovastatin and 35 mg of Coenzyme Q10 formulated with pharmaceutically acceptable ingredients.
WOO 152822 discloses a composition comprising ubiquinol and an amount of a reducing agent effective to reduce or eliminate the oxidation of ubiquinol to ubiquinone. The composition comprises an amount of a surfactant or vegetable oil or mixtures, thereof and optionally, a solvent effective to solubilize ubiquinol and the reducing agent. The composition further comprises of an effective amount of a HMG CoA reductase inhibitor drug. The said compositions are in oral, parenteral or topical dosage form and preferably soft gelatin capsules.
While none of the above prior art references as discussed above claims the pharmaceutical combination of atorvastatin and ubidecarenone, our invention specifically relates to a novel pharmaceutical composition of atorvastatin and ubidecarenone and a process of preparation.
Object of the invention:
The main object of the present invention is to provide a novel pharmaceutical composition comprising ubidecarenone and atorvastatin for the treatment of hypercholesterolemia, coronary heart disease, dyslipidemia and other elevated blood lipid level-related diseases.
Further object of the present invention is to provide pharmaceutical composition with supplemental Coenzyme Q10 to overcome statin-induced Coenzyme Q10 deficiency.
It is yet another object of the present invention is to provide a process for the preparation of the film coated tablets.

Summary of the invention:
The present invention discloses novel lipid. lowering pharmaceutical composition comprising ubidecarenone (Coenzyme Q10) and HMG CoA reductase inhibitor preferably atorvastatin. The invention discloses process for preparation of the said composition using a fluid bed processor during the granulation stage which provides residual solvent level less than acceptable limit prescribed by the ICH guidelines. The novel combination is provided in the form of film coated tablets.
Detailed description of the invention:
The present invention describes novel pharmaceutical composition for the treatment of hypercholesterolemia comprising Ubidecarenone (Coenzyme Q10) and HMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitor of the said composition specifically comprises therapeutically effective amount of Atorvastatin.
Atorvastatin reduces total cholesterol, LDL, VDL and triglycerides and increases HDL in patients with hypercholesterolemia and mixed dyslipidemia.
HMG CoA reductase inhibitors leads to depletion of the essential nutrient coenzyme Q10 resulting in decreased plasma coenzyme Q10 levels. Coenzyme Q10 is essential for mitochondrial function and antioxidant activity, and since oxidative mechanisms are important in atherogenesis hence a reduction in CoQ10evel may lead to coronary atherosclerosis despite optimal reduction in cholesterol levels by the use of atorvastatin or statin drugs. Hence CoQ10eficiency can cause mitochondrial encephalomyopathies related to a primary or secondary ubidecarenone deficiencies. Ubidecarenone (coenzyme Q10) supplementation does not interfere with the cholesterol-lowering effect of statin drugs
The present invention describes composition for lowering the cholesterol and preventing depletion of ubidecarenone by atorvastatin which comprises of film coated tablets containing ubidecarenone - 10 mg and atorvastatin calcium equivalent to atorvastatin 10 formulated along with pharmaceutically acceptable excipients.

The pharmaceutically acceptable safe inert excipients and adjuvants which are used in the formulations for the manufacturing of tablets include, but are not limited to, diluents, disintegrating agents, lubricant, binder, glidant, preservatives, film coating polymers, colorants, solvents and the like.
The excipients used for tabletting purpose are selected from diluents, disintegrating agents, lubricants and glidants.
Diluents for the purpose of film coated tablet are selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, lactose, calcium sulfate, Mannitol, Sorbitol, Starch used in the range of 20 -80 %.
Non-limiting examples of disintegration agents include microcrystalline cellulose, crosscarmellose sodium, crospovidone, starch and modified starches used in the range of 2-20%.
Lubricants and glidants are selected from the group consisting of talc, magnesium stearate, colloidal silicon dioxide, stearic acid, sodium and stearyl fumarate, Hydrogenated castor oil in the art, used in the range of 0.5 - 5 %.
Binders are selected from the group povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and polymethacrylates.
Film coating polymers are selected from a group of hydrophilic polymers of different viscosity grades consisting of medium or high viscosity grade of hydroxypropyl methylcellulose.
The present invention is illustrated by way of the following non-limiting example. The example is not limited to the particular embodiment illustrated herein but include the permutations, which are obvious set forth in the description.


The pharmaceutical composition of the present invention as described above can be formulated by three procedures which provide the use of ribbon mixer for granulation or a rapid mixer granulator and by using fluid bed processor with selected processing parameters. By using fluid bed processor, the residual solvent level is less than the accepted level prescribed in ICH guide lines.

The process for the preparation of the composition comprises of the following methods: I. Conventional Method:

The process of preparing the composition comprises the following:
1. Sifting: Atorvastatin calcium, lactose, dibasic calcium phosphate, sodium starch glycolate and ubidecarenone are sieved.
2. Preparation of binder solution: povidone, methyl paraben and propyl paraben are dissolved in isopropyl alcohol.
3. Granulation: I: Atorvastatin calcium, lactose, dibasic calcium phosphate, sodium starch glycolate are charged into the ribbon mixer and mixed for 30 minutes. Binder solution is added slowly under mixing and mixed for 10 minutes.
4. Drying and sizing: Wet mass is milled through 10 mm sieve by using multi mill and dried in tray drier for 25 minutes with out applying temperature and

subsequently dried at a temperature of 50°C± 2°C for 30 minutes. The moisture content is checked using IR balance so as to keep the same below 2%. Dried granules are passed through 20 # by using sifter and the granules are collected in a storage container. (Granule I).
5. Granulation; II: Ubidecarenone is charged into the ribbon mixer and the binder solution is added slowly and mixed for 10 minutes.
6. Drying and Sizing: Wet mass is milled through 10 mm sieve by using multi mill and dried in tray drier for 25 minutes with out applying temperature and subsequently dried at a temperature of 40°C± 2°C for 30 minutes. The moisture content is checked using IR balance so as to keep the same below 2%. Dried granules are passed through 20 # by using sifter and the granules are collected in a storage container. (Granules II).
7. Lubrication: Granules I and II are loaded in to cleaned ribbon mixer and sodium starch glycolate; talc, colloidal silicon dioxide and magnesium stearate are added and mixed.
8. Compression: The lubricated granules are compressed at an average weight of 121 ± 3mg per tablet using rotary tablet press machine and the tablets are checked for the following parameters:

9. Preparation of coating solution: Hydroxy propyl methyl cellulose is dispersed in
isopropyl alcohol in a clean SS vessel. Methylene chloride is added under
mixing. Propylene glycol is added and mixed for 30 minutes.Titanium dioxide,
sunset yellow (Lake) and talc are dispersed in IPA and passed through colloid mill
and filtered through 200# and added to the HPMC solution and mixed for 15
minutes.

10. Coating: Tablets are loaded into the coating pan and the parameters are set. The tablets pre heated before spraying the coating solution. The coating solution is sprayed continuously till the solution is exhausted. The tablets are dried at low temperature subsequently.
11. Observation: Ubidecarenone has low melting point, the process of preparation of the tablets is done by non aqueous conventional method by using isopropyl alcohol as solvent and during the drying in tray dryer. The solvent remaining in the granules is above the accepted level. Mottling appearance in tablet is visible.


II. Conventional Method:

The following steps are involved in the manufacturing of the said compositions:
1. Sifting: Atorvastatin calcium, lactose, dibasic calcium phosphate, sodium starch glycolate and ubidecarenone are sieved.
2. Preparation of binder solution: povidone, methyl paraben and propyl paraben are dissolved in isopropyl alcohol
3. Granulation: I: Atorvastatin calcium, lactose, dibasic calcium phosphate, sodium starch glycolate are loaded into the rapid mixer granulator and mixed for 10 minutes. Binder solution is added slowly under slow mixing and mixed for 2 mints and mixed at high speed for 5 minutes with chopper on.
4. Drying and sizing: Wet mass dried in fluid bed drier for 25 minutes with out applying temperature and subsequently dried at a temperature of 50°C± 2°C for 30 minutes. The moisture content is checked using IR balance so as to

keep the same below 2%. Dried granules passed are through 20 # by using sifter and the granules are collected in a storage container.(Granules I)
5. Granulation: II: Sifted ubidecarenone is charged into the rapid mixer
granulator and mixed for 5 minutes. Binder solution is added slowly under
slow mixing and mixed for 2 minutes and mixed at high speed for 5 minutes
6. Drying and Sizing: Wet mass dried in fluid bed drier for 25 minutes with out
applying temperature and subsequently dried at a temperature of 40°C± 2°C
for 30 minutes. The moisture content is checked using IR balance so as to
keep the same below 2%. Dried granules passed are through 20 # by using
sifter and the granules are collected in a storage container (Granules II).
7. Lubrication: Granules I and II are loaded into cleaned ribbon mixer and
sodium starch glycolate; talc, colloidal silicon dioxide and magnesium stearate
are added and mixed.
8. Compression: The lubricated granules are compressed at an average weight of
121 ± 3mg per tablet using rotary tablet press machine and the tablets are
checked for the following parameters.

9. Preparation of coating solution and process of coating is similar to method I.
10. Observation: Ubidecarenone has low melting point, the process of preparation
of the tablets was done by non aqueous conventional method by using
isopropyl alcohol as solvent and drying process done by fluid bed dryer.
Residual solvent level in the granules was above the accepted level. Mottling
appearance in tablet is visible.

III. Method using Fluid Bed Processor:

The following steps are involved in the manufacturing of the said compositions:
1. Sifting: Atorvastatin calcium, lactose, dibasic calcium phosphate, sodium starch glycolate and ubidecarenone are sieved.

2. Preparation of binder solution: povidone, methyl paraben and propyl paraben are dissolved in isopropyl alcohol
3. Granulation I: Sifted Atorvastatin calcium, lactose, dibasic calcium phosphate, sodium starch glycolate are charged into the product container of fluid bed processor.
The Fluid bed drier is set for the following parameters:
Fluidization level of powder is set to the level of spray nozzle, atomizing air pressure is 3.0 - 4.0 Kg/cm2, RPM of spray pump of about 40 to 50, inlet temperature of preferably 60°C, product temperature of preferably 32°C and flap opening of 40 to 50 % wherein the binder solution is sprayed continuously with intermittent stirring. After completion of spray, the atomizing air pressure is reduced to 0.5 Kg/cm2 and dried the product by setting product temperature at 45°C. The granules moisture content is kept below 2%.
4. Sizing: Dried granules passed through 20 # by using sifter and the granules are collected in a storage container (Granules I).
5. Granulation: II: Ubidecarenone is charged into the product container of fluid bed processor.
The Fluid bed drier is set for the following parameters:
Fluidization level of powder is set to the level of spray nozzle and chiller valve is kept under open position so as to avoid any melting of ubiquinone, atomizing air pressure is 3.0 - 4.0 Kg/cm2, RPM of spray pump of about 30 to 40, inlet temperature of 30°C, product temperature of preferably 30°C and flap opening of 25 to 30 % wherein the binder solution is sprayed continuously with intermittent stirring. After completion of spray, the atomizing air pressure is reduced to 0.5 Kg/cm2 and the product dried by setting product temperature at 30°C. The granules moisture content is kept below 2 %.
6. Sizing: Dried granules passed through 20 # by using sifter and the granules are collected in a storage container (Granules II).
7. Lubrication: Sifted granules I and II are charged into the clean bowl of fluid bed processor. To the granules sodium starch glycolate, talc, colloidal silicon dioxide and magnesium stearate are added. Mixed for 5 minutes, by keeping

varied flap opening cycle, to get air flow of 2-3 m/sec. for 40 seconds and 7 to 8 m/sec for 20 seconds.
8. Compression: The lubricated granules are compressed at an average weight of
121 ± 3mg per tablet using rotary tablet press machine and the tablets are
checked for the following parameters:

9. Preparation of coating solution and process of coating is similar to method I.
10. Observation: Ubidecarenone having low melting point, the process of
preparation of the tablets was done by fluid bed processor technology using
isopropyl alcohol as solvent. In dried granules the residual solvent was with in
the accepted level. The flow properties of the granules and physical
parameters of the tablets are satisfactory. The tablet surface is uniform
without mottling appearance.


It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative example and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We claim,
1. A novel pharmaceutical composition comprising 10mg Ubidecarenone (coenzyme Q10) and a HMG CoA reductase inhibitor preferably atorvastatin calcium equivalent to atorvastatin 10mg as active ingredients with pharmaceutically acceptable excipients formulated as a film coated tablet, used for the treatment of elevated blood-lipid level associated disorders and conditions associated with coenzyme Q10 deficiency.
2. The pharmaceutical composition according to claim 1 wherein the excipients are selected from the group comprising such as lubricants, diluents, binders, preservatives, glidants, disintegrants, film coating polymers, colorants and solvents.
3. The pharmaceutical composition according to claim 1 & 2, wherein the said composition comprises ubidecarenone 8.23%w/w and atorvastatin calcium 8.53 % w/w, Dicalcium Phosphate (anhydrous) 47.31 %w/w, Lactose 18.57%w/w, Sodium starch glycolate10.00 %w/w, Povidone K-30 3.27 %w/w, Methyl paraben 0.12%w/w, Propyl paraben 0.06 %w/w, Magnesium stearate 0.48 %w/w Colloidal silicon dioxide 0.20 %w/w, Talc 0.65 %w/w and isopropyl alcohol as solvent.
4. The pharmaceutical composition according to claim 1 & 2, wherein the film coating composition comprises of HPMC El 5 1.51%w/w, propylene glycol 0.23% w/w, titanium dioxide 0.34%w/w, colorant 0.50%w/w in a solvent preferably isopropyl alcohol.
5. A process for preparing a pharmaceutical composition according to claim 1 comprising:
a. sifting atorvastatin calcium, lactose, dibasic calcium phosphate, sodium
starch glycolate and ubidecarenone;
b. preparing binder solution by dissolving povidone, methyl paraben and
propyl paraben in isopropyl alcohol;
c. charging sifted Atorvastatin calcium, lactose, dibasic calcium phosphate
and sodium starch glycolate in the product container of fluid bed processor
wherein the binder solution is sprayed continuously with intermittent
stirring and drying the product by setting temperature at 45°C;
d. sizing dried granules by passing through 20 # by using sifter and collecting
the granules (Granules I) in a container;

e. charging ubidecarenone in the product container of fluid bed processor
wherein the binder solution is sprayed continuously with intermittent
stirring and drying the product by setting temperature at 30°C;
f. sizing dried granules by passing through 20 # by using sifter and the
granules and collecting in a storage container (Granules II);
g. charging sifted granules I and II in the clean bowl of fluid bed processor,
adding sodium starch glycolate, talc, colloidal silicon dioxide and
magnesium stearate and mixing for 5 minutes;
h. compressing the granules by using rotary tablet press machine; and
i. coating of the tablet by loading of the pre-heated tablets in the coating pan
and spraying the coating solution continuously till the solution is
exhausted and finally drying the tablets.
Dated this the 21st day of August 2006