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1. WO2012064306 - EFFERVESCENT FORMULATIONS OF ROSUVASTATIN

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[ EN ]

EFFERVESCENT FORMULATIONS OF ROSUVASTATIN

The present invention relates to effervescent formulations comprising rosuvastatin and/or a pharmaceutically acceptable salt thereof as active agent.

The Prior Art

Rosuvastatin, which was first disclosed in the patent numbered US5260440 (A), is an HMG Co A enzyme inhibitor having the chemical name (3i?,5S,6E)-7-[4-(4-fluorophenyl)-6-(l-methylethyl)-2[methyl(methylsulphonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid illustrated in formula (I):


(I)

It is indicated that rosuvastatin, which is displayed in formula (I) in the patent numbered US 5260440, prevents cholesterol formation by inhibiting the activation of the enzyme named HMG-CoA reductase that is responsible for cholesterol synthesis in the body and it is effective in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

Rosuvastatin formulations in the prior art are in tablet form. Rosuvastatin formulations marketed under the trade name "Crestor®" are in tablet forms of 5, 10, 20 and 40 mg comprising rosuvastatin calcium. However, these formulations hold some disadvantages that tablet dosage form brings along.

The first and the most significant disadvantage of tablet dosage form is its low bioavailability compared with suspension dosage forms. As it is known, highest bioavailability is obtained from oral solutions.

At the same time, dosage forms such as tablet and capsule pose swallowing difficulty for particularly elderly and physically handicapped patients as they are hard to swallow even when taken with liquid and have unpleasant taste. In parallel with this, these patients do not take their medication regularly and this substantially affects the efficiency of the treatment.

Suspension dosage forms, on the other hand, are not preferred because of their short shelf life.

Effervescent dosage forms developed as an alternative to the dosage forms listed above are more advantageous compared with the conventional forms due to fast dissolving. Effervescent formulations are dissolved fast, release the active agent/agents into the aqueous liquid simultaneously and fast. The time spent between addition of the formulation into water or its dissolution or intake of the solution is relatively short. Consumption of the formulations in a short time impedes the degradation of the active agent with water; therefore, this type of formulations consumed in a short time do not require high amounts of stabilizing agent.

In addition, pharmaceutical formulations in effervescent form are particularly preferred by patients in terms of ease of use and carrying. This type of formulations are more advantageous for use of elderly and physically handicapped patients. Formulation is rapidly dispersed in aqueous liquid and can be administered by the oral route, with a spoon or as a drop when necessary.

However, the problem about effervescent dosage forms comprising rosuvastatin and/or pharmaceutically acceptable salts thereof is their insufficient dissolution and failure to create a clear solution when mixed with water.

Insufficient dissolution impedes administration of required amount of the active agent to the patient and thus lead to decrease in efficiency of the treatment.

At the same time, patients do not want to drink the solution blurred due to the particles suspended in water.

To this respect, the active agent rosuvastatin has not been formulated in effervescent form so far.

In the prior art, effervescent dosage forms comprising rosuvastatin and/or pharmaceutically acceptable salts thereof and the problems they hold have not been referred to.

As a result of research and development studies they conducted on effervescent rosuvastatin formulations, the inventors have found that sufficient dissolution is surprisingly ensured and a clear solution is obtained when an organic salt with divalent cation is used.

Detailed Description of The Invention

The first embodiment of the invention relates to advanced pharmaceutical formulations comprising rosuvastatin in therapeutically effective amounts.

A characteristic feature of the formulations of the present invention is that said formulations are in effervescent form.

Another characteristic feature of the present invention is that said formulations comprise a pharmaceutically acceptable organic salt with divalent cation in order to provide sufficient dissolution.

Another characteristic feature of the present invention is that said organic salt is selected from a group comprising calcium bicarbonate and magnesium carbonate.

The organic salt with divalent cation used in the formulations of the present invention is preferably calcium carbonate.

Another characteristic feature of the formulations of the present invention is that amount of the organic salt which is used in order to ensure sufficient dissolution and have divalent cation is in the range of 1% to 10%, preferably in the range of 1% to 5% by weight.

Another characteristic feature of the formulations of the present invention is that effervescent formulations comprise at least one effervescent acid, at least one effervescent base and at least one other pharmaceutically acceptable excipient in addition to these.

Another characteristic feature of the formulations of the present invention is that the effervescent base is selected from a group excluding calcium carbonate.

Another characteristic feature of the formulations of the present invention is that said formulation comprises at least two effervescent acids which are chemically different.

Effervescent formulations produced according to the present invention can easily form clear solutions in water and do not require use of high amounts of stabilizing agent. These

formulations are dissolved in a particular amount of water and/or a similar liquid regardless of temperature of the liquid.

Effervescent formulations can be produced in water soluble tablet, granule or powder form.

Effervescent formulations of the present invention can comprise at least one antihypertensive substance in an effective amount, preferably one or more sterol absorption inhibitor as a second active agent. The sterol absorption inhibitor used in rosuvastatin formulations of the present invention is preferably ezetimibe and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or combinations thereof.

The term "pharmaceutically acceptable derivatives" used throughout the text refers to salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms of the active agent and/or combinations thereof.

Effervescent pharmaceutical formulations of the present invention comprise other pharmaceutically acceptable components such as additives and excipients selected from disintegrants, viscosity enhancing agents, filling agents, drying agents, stabilizing agents, lubricants, diluents, binders, glidants, anti-foam agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.

The effervescent mixtures comprised in the effervescent formulations of the present invention are composed of at least one pharmaceutically acceptable effervescent base and at least one effervescent acid.

The effervescent bases to be used in the effervescent formulations of the present invention can be selected from a group comprising sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.

The effervescent base used in the effervescent formulations of the present invention is selected from a group excluding calcium carbonate though it is preferably sodium hydrogen carbonate.

The effervescent acids to be used in the effervescent formulations of the present invention can be a pharmaceutically acceptable anhydrous organic or inorganic acid, especially citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid and/or their pharmaceutically acceptable salts, hydrates, anhydrates or preferably a combination thereof.

Effervescent formulations of the present invention comprise at least two effervescent acids selected from the group listed above.

In other terms, the effervescent acid comprised in the effervescent formulations of the present invention is a mixture of at least two effervescent acids which are chemically different.

The diluents that can be used in the effervescent formulations of the present invention comprises one or more components selected from the group comprising alkaline metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmito stearate, lactitol, lactose, directly compressible lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates thereof and/or derivatives thereof.

In the effervescent formulations of the present invention; antioxidants, chelating agents, alkalinizing agents and photoprotective agents can be used as stabilizing agent.

The stabilizing agents that can be used in the effervescent formulations of the present invention can be selected from alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline-earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; organic components such as primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzyl ethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate and/or pharmaceutically acceptable hydrates and/or derivatives thereof.

The disintegrants that can be used in the effervescent formulations of the present invention can be selected from highly dispersive polymers, for instance cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate.

The binders that can be used in the effervescent formulations of the present invention comprise one or more components selected from the group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hypromellose and polyvinylpyrrolidone.

The filling agents that can be used in the effervescent formulations of the present invention comprises one or more components selected from the group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol.

The lubricants that can be used in the effervescent formulations of the present invention comprise one or more components selected from the group comprising highly metallic stearates (magnesium stearate, calcium stearate, aluminium stearate etc), fatty acid esters (sodium stearyl fumarate etc), fatty acids (stearic acid etc), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.

The sweeteners that can be used in the effervescent formulations of the present invention comprise one or more components selected from the group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, saccharine and/or pharmaceutically acceptable salts thereof.

The effervescent formulations of the present invention can comprise at least one taste regulating agent in addition to one or more sweeteners.

The flavouring agents that can be used in the effervescent formulations of the present invention can be banana, strawberry, lemon, orange, peach, vanilla or similar natural fruit or aromatic plant flavours.

The effervescent formulations of the present invention comprise;

• Rosuvastatin calcium in the range of 0.1 % to 5%

• An organic salt with divalent cation in the range of 1 % to 10%

• At least two different effervescent acid in the range of 40% to 70%

· At least one effervescent base in the range of 10% to 40%

• One or more pharmaceutical excipient in the range of 1% to 20%

Effervescent formulations of the present invention can be produced using the techniques in the prior art such as wet or dry granulation techniques.

Another characteristic feature of the formulations of the present invention is that said formulations are used in prophylaxis and/or treatment of atherosclerosis,

hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, myocardial infarction, stroke.

The examples below are given so as to clarify the invention. These examples does not limit the scope of the invention and are considered with the explanation part given in detail above.

Example 1. Effervescent formulation comprising rosuvastatin calcium


The method for the effervescent tablet of rosuvastatin to be produced according to the formulation given above is as follows:

1. An effective amount of rosuvastatin calcium, calcium carbonate and at least one other pharmaceutically acceptable excipient are mixed.

2. The active agent mixture obtained is preferably granulated wet with deionized water.

3. The rosuvastatin granules obtained are dried and sieved.

4. Other pharmaceutically acceptable excipients are added into the dry mixture and the end mixture is sent to tablet compression machine.