DESC:The present invention relates to a stable, multi-particulate pharmaceutical composition of rosuvastatin and its pharmaceutically acceptable salt.

BACKGROUND
Rosuvastatin is marketed as rosuvastatin calcium in the form of tablets containing 5, 10, 20 and 40 mg of rosuvastatin calcium under the brand name of Crestor®. It is indicated in patients with primary hyperlipidemia as an adjunct to diet to reduce elevated total cholesterol, low density lipoprotein and triglyceride levels and to increase high density lipoprotein. Prevalence of hyperlipidemia increases with age and needs chronic therapy and thus HMG-CoA inhibitors such as rosuvastatin calcium are generally prescribed to patients life-long. Further, geriatric population need to take more than one medication.

Solid unit oral dosage forms are available in a variety of sizes, shapes. It is always preferable to design a dosage form that is patient compliant in terms of adhering to the therapy. Sometimes such solid dosage forms pose a problem while swallowing due the size, stickiness, taste, aftertaste or frequency of administration. Particularly in patients suffering from dysphagia, swallowing solid oral dosage forms may be very painful, if not impossible. Thus there is always a need for a dosage form that eases the oral administration.

The present inventors have discovered a novel pharmaceutical composition having multiple pellets, each pellet having a higher percentage of rosuvastatin loaded into it. The high percentage loading makes the single unit dosage form a compact one with less of excipients. The multiparticulate composition is found to be not only patient compliant but also chemically stable throughout the shelf life of the product.

SUMMARY OF THE INVENTION
The present invention provides a stable multi-particulate pharmaceutical composition comprising pellets filled in capsule, sachet, pouch or a device for administration of pellets, the pellets comprising a mixture of rosuvastatin or its pharmaceutically acceptable salts, one or more osmotic release modifiers and one or more stabilizers. The present inventors have found that osmotic release modifiers accelerate release of rosuvastatin from the pellets. Such a stable multi-particulate pharmaceutical composition of rosuvastatin calcium is particularly advantageous as it can be administered by sprinkling on soft food such as applesauce, pudding, custard, oatmeal or yoghurt. The pellets are such that they escape chewing or mastification and are palatable. Thus a stable, multi-particulate pharmaceutical composition of rosuvastatin calcium that is very patient compliant is presented. Alternatively, the pellets can also be administered via nasogastric tubing for hospitalized patients.

DETAILED DESCRIPTION OF THE INVENTION
The term ‘pellet’ as used herein means any particle that is prepared by process of agglomeration which is achieved by granulation, compaction, extrusion, slugging, drug loading or the like. Such a pellet has good flow, with an aspect ratio of about 1 to 2. Further the pellets may be spherical, oval in regular shape with a smooth surface and density higher than the powder.

The term ‘stable’ as used herein means that when the multi-particulate pharmaceutical composition of the present invention is stored at accelerated conditions such as 40°C/ 75% relative humidity, the rosuvastatin lactone impurity is less than 0.5%, preferably less than 0.1%. Further the multi-particulate pharmaceutical composition is said to be stable when the total impurities, which include anti-isomer (impurity A), 5-keto rosuvastatin, rosuvastatin lactone (impurity B), dehydro rosuvastatin acid, 5-keto rosuvastatin, dehydro lactone, dehydro triene, and highest unknown impurity are less than 1.5%, preferably less than 1% by weight.

The average particle size of the individual pellets of the stable multi-particulate pharmaceutical composition of rosuvastatin calcium is determined by sieve analysis using ASTM sieve. The sieve analysis is a practice or procedure used to assess the particle size distribution of a granular material, wherein the sieve mesh size is represented by a micrometer average particle size through which the particles pass.

The term ‘sprinkle’ as used herein means that the stable multi-particulate pharmaceutical composition is to be added onto food or any edible material or liquid such as water, juices etc. before administration. The stable multi-particulate pharmaceutical composition may be in the form of sachets or filled into capsules which may be sprinkled on food or edible material or in the form of a dispersible tablet which is dispersed in a liquid to yield a dispersion of the individual particles before drinking. The multi-particulate pharmaceutical composition may be administered by initially opening the contents of the sachet or pouch or capsule filled with the stable multi-particulate pharmaceutical composition and transferring it onto soft food such as applesauce, pudding, custard, oatmeal and yoghurt and swallowed immediately. Alternatively geriatric patients who have difficulty swallowing may be administered the stable multi-particulate pharmaceutical composition by mixing the contents of the sachet or pouch or capsule filled with stable multi-particulate pharmaceutical composition, into liquid medium such as water. The solution may be then orally administered through a nasogastric tube into the stomach.

In one embodiment, the stable multi-particulate pharmaceutical composition filled into capsule may be opened by a sprinkle opening device to avoid spillage of the contents of the capsule while opening the capsule. This is particularly helpful for the geriatric patients who have difficulty in opening the capsules to empty the contents on to soft food. Also the absence of fines avoids loss of dosage form due to blowing of the fine powder, while being emptied from the capsule or pouch on the carrier solid or liquid food contents. Alternatively, the pellets can be administered from a device which will dispense the pellets directly onto the soft food.

The term “mixture” as used herein means that the rosuvastatin calcium or salts thereof are mixed uniformly with excipients of various categories such as stabilizers, alkalizing agents, buffering agents, disintegrant, diluents etc. and filled into hard gelatin capsules, sachets or device.

According to the present invention, there is provided a stable multi-particulate pharmaceutical composition comprising pellets comprising rosuvastatin or its pharmaceutically acceptable salts, one or more osmotic release modifier and one or more stabilizers, wherein the composition is stable and is administered with or without food.

The present inventors have found that osmotic release modifiers accelerate release of rosuvastatin from the pellets. Such osmotic release modifiers are meant to include, agents that have good affinity for water, and dissolve quickly when in contact with aqueous medium. For the purpose of this invention, the osmotic release modifiers do not include the large molecular weight carbohydrates such as for instance, microcrystalline celluloses or sugars of the sugar spheres. The osmotic release modifiers are rather than the ones that may be low molecular weight carbohydrates that are soluble in water or the salts of the monovalent metal ions. According to one embodiment, the osmotic release modifiers are salts of monovalent metal ion such as sodium or potassium. The osmotic release modifiers are selected from the group consisting of, but are not limited to, sodium citrate, sodium phosphate, sodium bicarbonate, sodium chloride, potassium nitrate, potassium sulfate and mixture thereof. It may range from about 1% by to 20% by weight, preferably 2% by weight to 10% and most preferably 3% by weight to 8% by weight of the stable multi-particulate pharmaceutical composition. The osmotic release modifier used causes the pellets to grow in size by imbibition of water and then swell, disintegrate or burst allowing the release of the drug in the gastrointestinal tract. This phenomenon enables the pellets to release the drug when a large quantity of aqueous medium such as in gastrointestinal tract is available. The release does not occur when the pellets are sprinkled on soft food and ingested. In embodiments where pellets are harder because they are made by extrusion and spheronization, the osmotic release modifier amounts in the range of 3% to 8% are preferred. In one preferred embodiment of the present invention, the osmotic release modifier is sodium citrate which is present in the amount from about 1% by to 20% by weight, preferably 2% by weight to 10% and most preferably 3% by weight to 8% by weight of the stable multi-particulate pharmaceutical composition.

In one embodiment, the rosuvastatin may be present in different salt form like alkali metal salts such as lithium, sodium, potassium, and cesium and the like; and alkaline earth metal salts such as beryllium, magnesium, and calcium salts and the like.

In one preferred embodiment rosuvastatin is present in the form of its calcium salt. The rosuvastatin calcium present in the stable multi-particulate pharmaceutical composition ranges from about 1% by weight to 30% by weight, preferably 2% by weight to 20% and most preferably 3% by weight to 15% by weight of the stable multi-particulate pharmaceutical composition. The single unit dosage form of the stable multi-particulate pharmaceutical composition may have rosuvastatin calcium in amounts of 5, 10, 20 and 40 mg.

In one embodiment the pellets have an average particle size in the range from about 0.1 mm to 0.9 mm, preferably from 0.2 mm to 0.8 mm, and most preferably from 0.4 mm to 0.7 mm.

The stable multi-particulate pharmaceutical composition comprises one or more stabilizers which are preferably alkaline earth metal salts. In specific embodiment, the stabilizer is a salt of an alkaline earth metal. In such specific embodiment, the stabilizer is not an inorganic substance such as for example, titanium oxide or iron oxide, any other tar-based pigment. When the stabilizer used is an alkaline earth metal, it is selected from the group consisting of, but are not limited to, magnesium hydroxide, magnesium oxide, magnesium acetate, calcium acetate, calcium gluconate, calcium glycerophosphate and aluminum hydroxide and mixtures thereof. The stabilizer present in the multi-particulate pharmaceutical composition ranges from about 1% to 20% by weight, preferably 2% to 10% by weight and most preferably 3% to 8% by weight of the stable multi-particulate pharmaceutical composition. In one preferred embodiment of the present invention, the stabilizer is magnesium oxide which is present in the amount from about 1% to 20% by weight, preferably 2% to 10% by weight and most preferably 3% to 8% by weight of the stable multi-particulate pharmaceutical composition.

Apart from the osmotic release modifiers and stabilizers the pellets may further comprise conventional excipients such as disintegrants, diluents and lubricants. Examples of the disintegrants that may be used in the pellets include, but are not limited, to crospovidone, sodium starch glycolate, sodium croscarmellose, carboxymethylcellulose, low viscosity hydroxypropylcellulose, potassium polacrilin. It may be present in an amount ranging from about 15% to 50% by weight, preferably 20% to 35% by weight and most preferably 25% to 30% by weight of the stable multi-particulate pharmaceutical composition. Examples of the diluents that may be used in the pellets include, but are not limited, to microcrystalline cellulose, lactose, starch, magnesium carbonate, maltose, kaolin. It may be present in an amount ranging from 15% to 50% by weight, preferably 20% to 35% by weight and most preferably 25% to 30% by weight of the stable multi-particulate pharmaceutical composition.

In one embodiment, the pellets of the stable multi-particulate pharmaceutical composition may be prepared by extrusion and/or spheronization. In one specific embodiment, the stable multi-particulate pharmaceutical composition may be prepared by initially mixing rosuvastatin calcium, stabilizer, osmotic release modifier and other excipients and passing this powder blend through a suitable sieve. The blend is then granulated with a suitable granulating agent for example, purified water or any binder solution. The wet granules may be extruded and spheronized.

The extrudates formed are sieved to achieve the average diameter of pellets wherein 95% pellets passed through 20 mesh and 100 % pellets retained on 40 mesh. Typically, in one specific embodiment, the pellets have an average diameter of about 0.1 mm to 0.9 mm, preferably about 0.2 mm to 0.8 mm and most preferably of about 0.4-0.7 microns. The size range of the pellets provides a stable multi-particulate pharmaceutical composition which does not have a gritty feeling when sprinkled on food, which is otherwise not acceptable and may deter the user from administering as a sprinkle multi-particulate pharmaceutical composition. The rosuvastatin calcium containing pellets may be optionally coated with a taste masking coating composition. Examples of the polymers used in the taste masking coating are, dimethylaminoethyl methacrylate (Eudragit EPO), polyvinyl alcohol, low viscosity cellulose derivatives and the like and mixtures thereof. The coated pellets are then lubricated and may be filled into a capsule or a sachet or a pouch. In one specific embodiment, the present invention provides pellets comprising an admixture of rosuvastatin calcium, magnesium oxide and sodium citrate and other excipients. The pellets are further coated with a taste masking coating comprising low molecular weight hydroxypropyl methyl cellulose and low molecular weight polyethylene glycol.
In one aspect, the present invention also provides a method of treating hypercholesterolemia, particularly in subjects having difficulty swallowing. In one particular aspect, there is provided a method of treatment o f hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, homozygous familial hypercholesterolemia, comprising administering to a subject the multiparticulate pharmaceutical composition comprising pellets filled in capsule, sachet or pouch, the pellets comprising a mixture of rosuvastatin or its pharmaceutically acceptable salts, one or more osmotic release modifiers and one or more stabilizers.

The following examples illustrate the scope of the present invention without any limitation thereto.

COMPARATIVE EXAMPLE 1
Rosuvastatin calcium, microcrystalline cellulose, part of the mannitol and crospovidone were mixed in a polybag and sifted through suitable sieve. Other part of the mannitol was dissolved in purified water and used as granulating solution. The blend was granulated with mannitol solution. The wet granules were passed through an extruder. The extrudates were passed through the spheronizer to form pellets. The wet pellets were dried and dried pellets were suitable sized. A solution of Cellulose acetate and polyethylene glycol was prepared in acetone and water mixture The dried pellets were coated with the above solution. The coated pellets were dried and lubricated with silicon dioxide. The lubricated pellets were filled into hard gelatin capsules.

Table 1: In-vitro dissolution data of Comparative example 1 in various dissolution media
Time min 0.01N HCL pH 1.2 Acetate buffer pH 4.5
10 29 41
20 46 60
30 58 71
45 70 82

From Table 2, it is evident that the comparative example 1 provided poor dissolution in multimedia dissolution. For instance, in 0.01 N HCl and acetate buffer only 60 to about 70% was released at the end of 30 minutes.

The filled capsules of comparative Example 1 were subjected to accelerated stability studies and the results are provided below.
Table 2: Results of the Stability study of the comparative example 1
Anti-isomer (IMP A) 5-keto Lactone
(IMP B) Dehydro Acid 3-keto Dehydro lactone Dehydro triene Highest Unknown impurity Total impurities
Initial ND 0.35 0.03 0.01 ND ND ND 0.05 0.47
2M 40°C/75%RH 0.01 0.49 0.46 0.01 ND 0.01 ND 0.06 1.3
ND: not detectable

From the data given in Table 3, it is evident that the multiparticulate pharmaceutical composition showed very high total impurity. For example the impurities increased from 0.01 % to 1.3% at the end of just two months under accelerated temperature and humidity conditions. Further the in vitro dissolution was not satisfactory in that merely, 50% - 60% of rosuvastatin dissolved at the end of 30 minutes.

COMPARATIVE EXAMPLE 2
Trisodium citrate dihydrate was dissolved in water. Rosuvastatin calcium, microcrystalline cellulose, mannitol and crospovidone were mixed and sifted through a suitable sieve. This blend was granulated with the sodium citrate solution. The wet granules were extruded through an extruder. The extrudates were passed through a spheronizer to form pellets. The pellets were dried in fluid bed drier and suitable sized to have mean size ranging 0.4 mm to 0.8 mm.
A solution of Hydroxypropyl methyl cellulose low viscosity and polyethylene glycol was prepared in isopropyl alcohol and water .The dried pellets were coated with this solution. the coated pellets were lubricated with silicon dioxide and filled into hard gelatin capsule shells.

Table 3: In-vitro dissolution data of Comparative Example 2 in various dissolution media
Time min 0.01N HCL pH 1.2 Acetate buffer pH 4.5
10 66 75
20 81 91
30 89 96
45 93 98

The filled capsules of comparative Example 2 were subjected to accelerated and long term stability conditions for three months and the results are provided below.

Table 4: Results of the Stability study of the comparative example 2
Anti-isomer 5-keto Lactone
(IMP B) Dehydro Acid 3-keto Dehydro lactone Dehydro triene Highest unknown
impurity Total impurities
Initial 0.01 0.39 0.07 0.01 ND ND ND 0.05 0.60
3M 40°C/75%RH ND 0.11 1.06 ND ND 0.06 ND 0.33 2.66
3M 30°C/65%RH ND 0.17 0.51 ND ND 0.01 ND 0.21 1.23
3M 25°C/60%RH 0.01 0.28 0.29 ND ND ND ND 0.15 0.91
ND: not detectable

From the results of the dissolution tabulated in Table 5 above, it is apparent that capsules of comparative example 2 provided satisfactory dissolution. For instance complete dissolution of rosuvastatin calcium was observed in 0.01N HCL and acetate buffer. However, from the results of the stability studies, given in Table 6, indicated that there is sharp increase in rosuvastatin lactone impurity content, unknown impurity and total related substances with time and temperature and relative humidity. For instance, at the end of three months, at 40°C/75% relative humidity the total impurities increased from initial of 0.01 % to 2.66% by weight.

EXAMPLE 1
Trisodium citrate dihydrate was dissolved in water. Rosuvastatin calcium, microcrystalline cellulose, mannitol, crospovidone and magnesium oxide were mixed well and sifted through a suitable sieve and granulated with the sodium citrate solution. The wet granules were extruded through an extruder and spheronized in a spheronizer. The pellets were dried and suitable sized to have mean particle size ranging from 0.4mm to 0.8mm.
A solution of Hydroxypropyl methyl cellulose low viscosity and polyethylene glycol was prepared in isopropyl alcohol and water mixture. The rosuvastatin calcium pellets were coated with the solution and dried.The coated pellets were mixed with silicon dioxide. The lubricated pellets were filled into hard gelatin capsule shells.

Table 5: In-vitro dissolution data of the Example 1 in various dissolution media
Time in mins 0.01N HCL pH 1.2 Acetate buffer pH 4.5
5 70 67
10 90 91
20 96 98
30 96 99
45 97 100

The above capsules filled with pellets were subjected to accelerated, intermediate and long term stability conditions and the chemical analysis in terms of assay, known and unknown impurities was determined.

Table 6: Results of the Stability study of the pharmaceutical composition of the present invention
Anti-isomer 5-keto Lactone Dehydro Acid 3-keto Dehydro lactone Dehydro triene Highest unknown impurity Total impurities
Initial ND 0.39 ND 0.01 ND 0.01 ND 0.05 0.61
6M 40°C/75%RH ND 0.06 0.02 0.01 ND ND ND 0.18 0.67
6M 30°C/65%RH ND 0.25 0.06 0.01 ND ND ND 0.21 0.77
6M 25°C/60%RH 0.01 0.32 0.05 0.01 ND ND ND 0.13 0.71
ND: not detectable

It can be observed from the above table that the multi-particulate pharmaceutical composition of the present invention showed complete dissolution in all media. It is evident from the above Table 9, that rosuvastatin lactone impurity content remained substantially unchanged as compared to the initial concentration. This is remarkable, compared to the results of comparative example 1 and 2.
EXAMPLE 1
A single dose randomized, open label, two treatment, two period, two sequence, crossover, comparative bioavailability study was carried out in healthy volunteers under fed and fasted conditions using Crestor® Tablet, 40 mg as the reference product. In fasting study, test product was administered by sprinkling the capsule contents on a spoonful of apple sauce, while in the fed state the capsules were administered. The stable multi-particulate pharmaceutical composition was found to be bioequivalent to the reference product in fed and fasted state.

EXAMPLE 2
The multi-particulate pharmaceutical composition of Example 1 was evaluated for its physical and chemical stability during administration by mean such as sprinkling on soft food or suspending in a liquid for administration via nasogastric tube. In order to evaluate this, the pellets of Example 1 were sprinkled on applesauce and the mixture was kept for 60 minutes. After that, the mixture was analyzed for dissolution, assay and related substances. The results showed that the multi-particulate pharmaceutical composition of the present invention when sprinkled on applesauce provided same dissolution as intact capsules in 60 minutes and the drug remained unchanged.

For evaluating the chemical stability and dissolution when the multi-particulate pharmaceutical composition was administered by a nasogastric tube, the contents of one capsule of the multi-particulate pharmaceutical composition were emptied into 40 mL water, and the suspended pellets were kept aside for 60 minutes. Thereafter the suspended pellets were passed through a nasogastric tube and then analyzed for dissolution, assay and related substances. It was found that the multi-particulate pharmaceutical composition when passed through a nasogastric tube provided same dissolution as intact capsules in 60 minutes and the drug content remained unchanged, that is rosuvastatin calcium did not show any signs of chemical degradation.
,CLAIMS:1. A stable multi-particulate pharmaceutical composition comprising pellets filled in capsule, sachet or pouch, the pellets comprising a mixture of rosuvastatin or its pharmaceutically acceptable salts, one or more osmotic release modifiers and one or more stabilizers.

2. A stable multi-particulate pharmaceutical composition as claimed in claim 1, wherein the pellets are obtained by extrusion and spheronization and the average particle size of the pellets is in the range from about 0.1 mm to 0.9 mm filled into capsules or sachet or a pouch and is suitable for administration to patients by sprinkling on soft food.

3. A stable multi-particulate pharmaceutical composition as claimed in claim 2, wherein average particle size of the pellets is from about 0.4 mm to 0.8 mm.

4. A stable multi-particulate pharmaceutical composition as claimed in claim 1, wherein rosuvastatin is present in the form of its calcium salt.

5. A stable multi-particulate pharmaceutical composition as claimed in claim 1, wherein the osmotic release modifier is a salt of a monovalent metal ion.

6. A stable multi-particulate pharmaceutical composition as claimed in claim 1, wherein the stabilizer is selected from a group consisting of magnesium hydroxide, magnesium oxide, magnesium acetate, calcium acetate, calcium gluconate, calcium glycerophosphate and mixtures thereof.

7. A stable multi-particulate pharmaceutical composition as claimed in claim 6, wherein the stabilizer is magnesium oxide.

8. A stable multi-particulate pharmaceutical composition as claimed in claim 1, wherein average particle size of the pellets is from about 0.4 mm to 0.8mm, rosuvastatin is rosuvastatin calcium, stabilizer is an alkaline earth metal salt and the osmotic release modifier is inorganic salt of monovalent cation.

9. A stable multi-particulate pharmaceutical composition as claimed in claim 8, wherein the alkaline earth metal salt is magnesium oxide and the inorganic salt of monovalent cation is sodium citrate.

10. A stable multi-particulate pharmaceutical composition as in claim 2, wherein rosuvastatin calcium is present at a concentration of 10 % by weight of the each unit dosage form of the composition.