FIELD OF THE INVENTION
The present invention relates to a dry granulation process for the preparation of a pharmaceutical composition of Rosuvastatin or pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Rosuvastatin is a synthetic lipid-lowering agent. Rosuvastatin, (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid, is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. It is commercially marketed in United States under the trade name CRESTOR ® by AstraZeneca UK Limited and is available as 5, 10, 20 and 40 mg tablet.
US 5,260,440 (US RE37314) discloses compound Rosuvastatin and process for preparation thereof. The use of Rosuvastatin for the treatment of heterozygous familial hypercholesterolemia is disclosed in US 6,858,618.
There have been various attempts to stabilize pharmaceutical composition comprising Rosuvastatin.
US 6,316,460 discloses a pharmaceutical composition of Rosuvastatin, comprising tribasic phosphate salt having a multivalent cation, tribasic calcium phosphate is specifically disclosed as stabilizer.
WO 08/062476 discloses a direct compression process for preparation of a pharmaceutical composition comprising a therapeutically effective amount of a HMG-CoA reductase inhibitor and an inorganic salt of a monovalent cation.
SUMMARY OF THE INVENTION
Hence, we have now developed an alternative process for the preparation of a pharmaceutical composition of Rosuvastatin or pharmaceutically acceptable salts thereof.
According to one aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of Rosuvastatin or pharmaceutically acceptable salts thereof and an alkaline stabilizer selected from a group consisting sodium citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium bicarbonate wherein the pH of the composition is between 6-8 and the composition is prepared by a dry granulation process.
According to one aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of Rosuvastatin or pharmaceutically acceptable salts thereof comprising:
(a) from about 5 to about 20% by weight Rosuvastatin;
(b) from about 70 to about 90% by weight of diluent;
(c) from about 0.5 to about 5% by weight of an alkaline stabilizer selected from a group consisting sodium citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium bicarbonate; and
(d) from 1 to about 10% by weight by weight of disintegrant;
wherein the pH of the composition is between 6-8 and the composition is prepared by a dry granulation process.
According to one aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of Rosuvastatin or pharmaceutically acceptable salts thereof comprising:
(a) from about 5 to about 20% by weight Rosuvastatin;
(b) from about 70 to about 90% by weight of lactose and microcrystalline cellulose;
(c) from about 0.5 to about 5% by weight of sodium citrate; and
(d) from 1 to about 10% by weight by weight of crospovidone;
wherein the pH of the composition is between 6-8 and the composition is prepared by a dry granulation process.
According to another aspect, there is provided a process for the preparation of pharmaceutical composition comprising the steps of:
(a) Blending Rosuvastatin with an alkaline stabilizer selected from a group consisting sodium
citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium
bicarbonate;
(b) Compacting the blend of step (a) to compacts in roller compacter and screening the compacts to obtain granules;
(c) optionally blending the granules with pharmaceutically acceptable inert extragranular excipients;
(d) lubricating the granules of step (b) or blend of step (c); and
(e) compressing the lubricated granules/blend into suitable sized tablets or filling into capsules; wherein the pH of the composition is between 6-8.
According to another aspect, there is provided a process for the preparation of pharmaceutical composition comprising the steps of:
(a) Blending Rosuvastatin with an alkaline stabilizer selected from a group consisting sodium citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium bicarbonate;
(b) Compressing the blend of step (a) to obtain slugs and screening the slugs to obtain granules;
(c) optionally blending the granules with pharmaceutically acceptable inert extragranular excipients;
(d) lubricating the granules of step (b) or blend of step (c); and
(e) compressing the lubricated granules/blend into suitable sized tablets or filling into capsules; wherein the pH of the composition is between 6-8.
In another aspect, there is provided a method for the treatment of hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) or slowing of the progression of atherosclerosis comprising administering to a subject a pharmaceutical composition comprising Rosuvastatin or pharmaceutically acceptable salts thereof and an alkaline stabilizer selected from a group consisting sodium citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium bicarbonate wherein the pH of the composition is between 6-8 and the composition is prepared by dry granulation process.
DETAILED DESCRIPTION
The term "pharmaceutically acceptable salts" of Rosuvastatin refers to the pharmaceutical acceptable include 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.
Rosuvastatin or its pharmaceutically acceptable salts may exist in any polymorphic forms such as crystalline or amorphous. The particle size of Rosuvastatin is D0.9 less than 160 urn and DO.5 less than 50 mµ.
The pharmaceutical compositions of the present invention are prepared by dry granulation method. Dry granulation method as described herein includes compaction and slugging. Dry granulation may be carried out of Rosuvastatin alone or of a blend of Rosuvastatin and pharmaceutically acceptable inert excipients. The dry granulation provides benefit over direct compression as well as wet granulation. Dry granulation process also provides a benefit that the likelihood of polymorphic conversion is reduced with this process.
Suitable alkaline stabilizers include sodium citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium bicarbonate. The concentration of stabilizer may vary from about 0.5-5% by weight of the pharmaceutical composition.
The pH of the composition was determined by taking a unit composition and dispersing or dissolving the composition in 10 to 100 ml of water.
The term "pharmaceutical composition" may include solid dosage forms such as tablets, caplets, pills and the like. The composition in addition to Rosuvastatin and alkaline stabilizer may comprise pharmaceutically acceptable inert excipients.
The term 'pharmaceutically acceptable inert excipients' as used herein includes diluents, binders, disintegrants, lubricants, glidants, plasticizers, opacifiers, coloring agents and the like.
Suitable diluents include microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose, sugar compressible, sugar confectioners, and the like. The concentration of diluent may vary from about 70-90% by weight of the pharmaceutical composition.
Suitable binders include alginic acid or sodium alginate, cellulose or cellulose derivatives such as carboxy methyl cellulose sodium, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, or methylcellulose, gelatin, povidone, starch, pregelatinized starch and the like. The concentration of binder may vary from about 1-10% by weight of the pharmaceutical composition.
Suitable disintegrants include croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch and low substituted hydroxypropyl cellulose and the like. The concentration of disintegrants may vary from about 1-10% by weight of the pharmaceutical composition.
Suitable lubricants include fatty acids or fatty acid derivatives such as calcium stearate, magnesium stearate, sodium stearyl fumarate, zinc stearate or stearic acid, hydrogenated vegetable oil, polyalkylene glycols such as polyethylene glycol, talc and the like. The concentration of lubricants may vary from about 0.01-5% by weight of the pharmaceutical composition.
The pharmaceutical composition may be further coated with a functional or non functional coating. The coating composition may comprise of pharmaceutically acceptable excipients such as binders, plasticizers, coloring agents and opacifiers.
Suitable plasticizers include propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, and mixtures thereof.
Suitable opacifiers include titanium dioxide, talc, calcium carbonate, behenic acid and cetyl alcohol and the like.
Suitable coloring agents include FDA approved colorants such as iron oxide, lake of tartrazine, allura red, lake of quinoline yellow, lake of erythrosine, titanium dioxide and the like.
Suitable solvents for the coating include water, ethanol, methanol, isopropyl alcohol, dichloromethane, acetone or mixture thereof.
According to one embodiment, there is provided a process for the preparation of pharmaceutical composition comprising the steps of:
(a) Blending Rosuvastatin with an alkaline stabilizer and a part of diluent;
(b) Compacting the blend of step (a) to compacts in roller compacter and screening the compacts to obtain granules;
(c) blending the granules with disintegrant and remaining part of diluent;
(d) lubricating the blend of step (c);
(e) compressing the lubricated blend into suitable sized; and
(f) coating the pharmaceutical composition obtained from step (e).
In one of the embodiments, the particle size of amorphous Rosuvastatin was D0.9 - 15µm; D0.5-5µm.
In one of the embodiments, the particle size of amorphous Rosuvastatin was D0.9 - 49 µm; D0.5-13µm.
The following examples are representative of the invention, but are not to be construed as limiting the scope of the claims.
EXAMPLS Example 1

(Table Removed)
BRIEF MANUFACTURING PROCESS
1. Rosuvastatin calcium, microcrystalline cellulose, lactose monohydrate and sodium citrate were blended;
2. The blend obtained from step (1) was lubricated with magnesium stearate and compacted;
3. The compacts are screened through suitable size sieve to obtain granules of desired size;
4. The granules obtained from step (3) were blended with microcrystalline cellulose and crospovidone;
5. The blend of step (4) was lubricated with magnesium stearate and compressed to suitable size tablets;
6. Tablets obtained from step (5) were coated with dispersion of Opadry to obtain the final composition.
The pH of the formulation, when dispersed in 10 ml of water was found to be 6.8.
No polymorphic conversion was observed in the tablets when subjected to stability studies at
40°C and 75% RH after 3 months.
Example 2

(Table Removed)
BRIEF MANUFACTURING PROCESS
1. Rosuvastatin calcium, microcrystalline cellulose, lactose monohydrate, crospovidone and sodium citrate were blended;
2. The blend obtained from step (1) was lubricated with magnesium stearate and compacted;
3. The compacts are screened through suitable size sieve to obtain granules of desired size;
4. The granules obtained from step (3) were blended with microcrystalline cellulose and crospovidone;
5. The blend of step (4) was lubricated with magnesium stearate and compressed to suitable size tablets;
6. Tablets obtained from step (5) were coated with dispersion of Opadry to obtain the final composition.

WE CLAIM:
1. A dry granulation process for the preparation of pharmaceutical composition of Rosuvastatin comprising Rosuvastatin or pharmaceutically acceptable salts thereof and an alkaline stabilizer selected from a group consisting sodium citrate, sodium borate, sodium carbonate, sodium phosphate monobasic and sodium bicarbonate wherein the pH of the composition is between 6-8.
2. The process according to claim 1, wherein Rosuvastatin is present in amorphous form.
3. The process according to claim 1, wherein the composition is a tablet.
4. The process according to claim 1, wherein the composition further comprises pharmaceutically acceptable excipients selected from the group consisting diluents, binders, disintegrants, lubricants, glidants, plasticizers, opacifiers and coloring agents.
5. The process according to claim 1, wherein the composition comprises:

(a) from about 5 to about 20% by weight Rosuvastatin;
(b) from about 70 to about 90% by weight of diluent;
(c) from about 0.5 to about 5% by weight of an alkaline stabilizer; and
(d) from 1 to about 10% by weight by weight of disintegrant.
6. The process according to claim 1, wherein the composition comprises:
(a) from about 5 to about 20% by weight Rosuvastatin;
(b) from about 70 to about 90% by weight of lactose and microcrystalline cellulose;
(c) from about 0.5 to about 5% by weight of sodium citrate; and
(d) from 1 to about 10% by weight by weight of crospovidone.
7. The process according to claim 1, wherein the dry granulation process comprises the
steps of:
a) Blending Rosuvastatin with an alkaline stabilizer;
b) Compacting the blend of step (a) to compacts in roller compacter and screening the compacts to obtain granules;
c) optionally blending the granules with pharmaceutically acceptable inert extragranular excipients;
d) lubricating the granules of step (b) or blend of step (c); and
e) compressing the lubricated granules/blend into suitable sized tablets or filling into capsules
8. The process according to claim 1, wherein the dry granulation process comprises the
steps of:
a) Blending Rosuvastatin with an alkaline stabilizer;
b) Compressing the blend of step (a) to obtain slugs and screening the slugs to obtain granules;
c) optionally blending the granules with pharmaceutically acceptable inert extragranular excipients;
d) lubricating the granules of step (b) or blend of step (c); and
e) compressing the lubricated granules/blend into suitable sized tablets or filling into capsules.

9. The process according to claim 7 or 8, wherein a disintegrant is blended with granules of step b).
10. The process for preparation of pharmaceutical composition of Rosuvastatin as used and exemplified herein.