WO2006008757A2

WO2006008757A2 - Stabilized pharmaceutical compositions of pravastatin

Info

Publication number: WO2006008757A2
Application number: PCT/IN2005/000191
Authority: WO
Inventors: Jatin Desai; Keyur Patel; Daxesh Patel; Sweety Christian
Original assignee: Cadila Healthcare Limited
Priority date: 2004-05-05
Filing date: 2005-05-05
Publication date: 2006-01-26
Also published as: WO2006008757A3

Abstract

Stabilized pharmaceutical compositions containing Pravastatin or its pharmaceutically acceptable salts are disclosed. The composition comprises of pravastatin or its pharmaceutically acceptable salt, stabilized by synergistic combination of substantially low amount of alkalizing agent and nonionic surfactant, to impart a pH between 8 to 8.75 to an aqueous solution or dispersion of the said composition.

Description

STABILIZED PHARMACEUTICAL COMPOSITIONS CONTAINING

PRAVASTATIN

FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising pravastatin or its pharmaceutically acceptable salt, which is sensitive to low pH environment. The invention also relates to a novel process for making the stable pharmaceutical composition of pravastatin or its pharmaceutically acceptable salt. BACKGROUND OF THE INVENTION AND PRIORART

Statins are group of drugs used widely as hypolipidaemic agents for lowering the blood pressure or disease pertaining to cardiovascular system. Pravastatin is competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin produces lipid-lowering effect in two ways. First, as a consequence of reversible inhibition of HMG-CoA reductase activity, it effects modest reduction in intracellular pools of cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor- mediated catabolism and clearance of circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of VLDL, the LDL precursor.

Pravastatin sodium is relatively polar and hydrophilic in nature. Literature reveals that statins including pravastatin are highly susceptible to temperature, light and moisture. These compounds degrade more rapidly in presence of inert pharmaceutically acceptable excipients/additives. Moreover, statins are highly susceptible to acidic environment, for instance, in stomach (pH<3). Pravastatin gets degraded rapidly in presence of gastric fluid to form lactone and an inactive isomer primarily 3-a-hydroxy- isopravastatin (Triscari et. al., J. Clin. Pharmacol, 1995; 35:142). The inactivation and/or degradation of pravastatin in gastric fluid limits the total absorption and/or rate of absorption of pravastatin from a pharmaceutically acceptable oral dosage form such as tablets.

The chemical structure of pravastatin is shown in Figure 1. As shown in Figure 1, pravastatin has a beta (β) and delta (δ) hydroxy groups (marked in bold arrows). These beta and delta hydroxy groups of heptenoic acid present in pravastatin may undergo chemical transformation due to isomerization, oxidation etc. and may lead to formation of degradation products such as conjugated unsaturated aromatic compounds, isomers and/or lactones. However, literature citation reveals that considerable amount of work has been done in the area of preventing degradation of pravastatin in a pharmaceutically acceptable solid oral dosage form although number of demerits are associated with each of the concepts.

Figure 1

EP0336298 discloses a stable pharmaceutical formulation for pravastatin by maintaining an alkaline environment so that the aqueous dispersion of the pharmaceutical formulation reaches a pH above 9, preferably about 10 by addition of a basifying agent, such as magnesium oxide. In view of the stability of the active substance such a formulation is effective. However, relatively high amount of basifying agent may lead to disturbance of gastric pH. This negative impact may be particularly evident for patients with a damaged gastric mucous membrane.

US Patent No. 5,030,447 and 5,180,589 reveal a pharmaceutical composition which has excellent stability, when dispersed in water has a pH of at least 9, and includes a medicament which is sensitive to low pH environment such as pravastatin. While, such an approach may be suitable for enhancing the stability of the drug, however, the local alkaline environment occurring at the site of dissolution due to high amount of basifying agent may damage the gastric mucosa especially, in chronic therapies with HMG-CoA reductase inhibitors. US patent 6,531,507 discloses stabilized pharmaceutical formulation comprising HMG-CoA reductase inhibitors analogs by forming a homogeneous composition with a buffering substance or a basifying substance by co-crystallization or co-precipitation of active and buffering agent. The composition is capable of providing a pH in the range from 7 to 12. This leads to an additional processing step. Also, the co- crystallization and co-precipitation processes need the control of processing parameters. Since, it is well known to those skilled in the art that the change in crystal structure may lead to change in physico-chemical properties like crystal lattice, polymorphic form, compressibility and solubility of the active, which in turn may affect the pharmaceutical benefit of the active medicament. However, the present invention discloses a simple and industrially applicable method for preparation of Pravastatin formulation.

U.S. Pat. No. 5,225,202 discloses an enteric coated pharmaceutical composition of pravastatin in the form of tablet, beadlet, pellet or particle that is enteric coated with neutralized hydroxypropylmethyl cellulose phthalate and a plasticizer which affords protection in a low pH environment of 3 or less while release medicament at a pH of 4.5 or higher. It is well known to the formulation scientist that phthalate polymers are prone to hydrolysis. Also, due to aging, the properties of the polymer change, which could have significant effect on both ultimate dissolution behaviour and mechanical properties of the applied coating. Further, with time, under ambient conditions, the enteric coating gives an acidic residue which may degrade pravastatin within the formulation itself. Furthermore, an enteric coated formulation requires prolonged time to attain the effective serum concentration. Additionally, the application of the enteric coating is an additional operation which increases the length of the manufacturing process and thereby the cost of the product.

Therefore, it is increasingly clear that pravastatin is highly unstable in presence of environmental factors such as heat, light and moisture, in presence of pharmaceutically acceptable excipients and is also unstable at the gastric pH. Prior art reveals that pharmaceutically acceptable formulation of pravastatin can only be stabilized by imparting pH of at least 9 to the pharmaceutical composition or by enteric coating of pravastatin or pravastatin dosage forms. The present invention discloses a pharmaceutical composition containing pravastatin using embodiment of pravastatin in a dry matrix. The compositions were found to be stable upon prolonged storage and gives desired plasma profile for therapeutic efficacy following oral ingestion of pharmaceutical composition containing pravasatin. SUMMARY OF THE INVENTION

Most surprisingly, we noticed that the pharmaceutical composition containing pravastatin or its salts disclosed in this invention is stable below pH 9 with substantially low amount (well below 1%) of alkalizing agent. In addition to that, the pharmaceutical composition described in the present invention does not contain metallic oxides and hydroxides. Moreover, it contains non ionic surfactant as a stabilizer which has not- been disclosed or known in the prior art of patents disclosed above. The process is meticulously designed in order to potentiate/synergize the stabilization effect. The composition described in this invention does not uses any enteric coating polymer for coating of either pravastatin or its dosage forms. DESCRIPTION OF THE INVENTION

The present invention describes a novel method and composition for stabilization of HMG-CoA inhibitor such as pravastatin in a pharmaceutically acceptable dosage form. Pravastatin is unstable as well as it gives poor bioavailibility due to degradation by gastric fluids. However, it was noticed that pravastatin alongwith non-ionic surfactant and minute concentration of alkalizing agent (pH<9) most unexpectedly demonstrates excellent storage stability and desired plasma profile. Surprisingly, it was found that very low concentration of sodium carbonate (0.26% w/w) and cremophor EL (0.25% w/w) exhibits synergism for stabilization of pravastatin even at pH <9 (8.62). The lower pH is expected to cause less damage to the gastric mucosa. In addition to that, very low concentration of alkalizing agent is expected to cause relatively less ionic imbalance in the gastrointestinal tract. In the present invention, it was also noticed that meticulous selection of manufacturing process potentiates/synergizes the stabilization of pravastatin. The manufacturing process was designed to embed pravastatin using excipients wherein the alkalizing agents have been selectively distributed in the outer layer to provide alkaline microenvironment. Moreover, pravastatin was entrapped in a matrix using direct compaction technique and therefore, pravastatin was found stable since no hygroscopic excipient or aqueous granulation fluid was used.

We most unexpectedly noticed that, the combination of extremely low amount of alkalizing agent with surfactant in addition to meticulous selection of method for manufacturing offers superior option for stabilizaiton of pravastatin composition. The stable or stabilization means generation of less impurities/degradation products when a particular composition is subjected to accelerated temperature and humidity as described under ICH guidelines. The unknown impurity < 0.10% w/w and and total impurities equivalent to 1% or less after 12 weeks at 40°C/75% RH is referred to as stable composition hereinafter.

The present invention discloses a novel, simple and industrially applicable method for stabilization of pharmaceutical composition containing pravastatin using very low amount of alkalizing agent and non ionic surfactant. Since the pH of the formulation is below 9, the composition may be advantageous in terms of maintenance of ionic balance and expected to cause less disturbance and damage to gastrointestinal tract. It was also found that the said invention produces desired plasma profile in order to elicit therapeutic response in the body.

The present invention provides a pharmaceutical composition comprising of pravastatin or its pharmaceutically acceptable salts, stabilized by alkalizing agent and nonionic surfactant, to impart a pH between 8 to 8.75 to an aqueous solution or dispersion of the said composition.

The composition comprises the drug substance and an alkalizing agent along with other excipients. The said alkalizing agent is capable of imparting a pH of between

8.5 to 8.7 to an aqueous solution or dispersion of the said composition and thereby stabilizes the formulation against pH related degradation. The resulting composition provides an extended storage life to the pravastatin, even in the presence of potentially reactive excipients like lactose.

The pharmaceutical composition of the invention, which is in form of a tablet, comprises pravastatin sodium as the pharmaceutically acceptable salt of pravastatin. Pravastatin sodium is present in an amount within the range of between 1 and 50% and preferable 5 and 20% by weight of the composition.

Examples of alkalizing agents are alkali metal carbonates, alkali metal bicarbonates and alkaline earth metal carbonates such as sodium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, zinc carbonate, with sodium carbonate being preferred. The alkalizing agent will be present in an amount within the range of between 0.001 and 10%, preferably 0.05 and 5% and more preferably 0.1 and

1% by weight of the composition.

According to the present invention, the pharmaceutical composition contains a nonionic surfactant selected from the group consisting of polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan fatty acid ester, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylenated ricin oil, polyoxyethylenated fatty acid glyceride, poloxamer, with polyoxyl 35 castor oil (Cremophor EL) being preferred. The nonionic surfactant may be present in an amount between 0.01 and 10%, preferably 0.05 and 5%, more preferably 0.1 and 1% by weight of the composition.

Other possible adjuvants such as diluents, binders, disintegrants, lubricants may be included optionally, in the inventive formulation.

The pharmaceutical composition may contain diluent selected from, but not limited to group consisting of lactose, microcrystalline cellulose, starch, sugars, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium phosphate, dextrin, maltodextrin, with lactose being preferred. The diluent may be present in an amount between 10 and 80%, preferably 25 and 70%, more preferably 40 and 60% by weight of the composition. In the present invention, the pharmaceutical composition may contain a binder in order to prepare a cohesive and compressible powder blend. The pharmaceutical composition may contain binder selected from the group consisting of microcrystalline cellulose, polyvinyl pyrrolidone, starch, starch derivatives, gum acacia, hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose with microcrystalline cellulose being preferred. The binding agent may be present in an amount between 10 and 50%, preferable 20 and 40% by weight of the composition.

The composition of present invention may contain a disintegrant selected from but not limited to a group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, starch, with croscarmellose sodium being preferred. The disintegrant may be present in an amount between 1 and 15%, preferably 3 and 9% by weight of the composition.

In the present invention, the pharmaceutical composition may contain a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, with magnesium stearate being preferred. The lubricant may be present in an amount between 0.1 and 2% by weight of the composition.

The following examples further illustrate this invention and are not to be construed as hmiting the scope but to be read in conjunction with the description, provide deep understanding of the invention outlined here. EXAMPLE 1

A pravastatin formulation in the form of tablets having the following composition was prepared as described below.

Ingredient Percent by weight

Parit A

Pravastatin sodium 10.00

Microcrystalline cellulose 32.25

Anhydrous lactose 51.24

Croscarmellose sodium 5.00

Sodium carbonate anhydrous 0.26

Cremophor EL 0.25

Purified water q.s.

Part B

Magnesium stearate 1.00

pH of formulation = 8.62

Pravastatin sodium, Microcrystalline cellulose, anhydrous lactose and croscarmellose sodium were mixed together for 5 min in a rapid mixer granulator.

Aqueous solution of sodium carbonate and cremophor EL were prepared separately and mixed together. The dry blend of Pravastatin sodium, microcrystalline cellulose, anhydrous lactose and croscarmellose sodium was granulated with aqueous solution of sodium carbonate and cremophor EL. The resulting damp mass was dried and sifted to get granules. The dried granules (part A) were lubricated with magnesium stearate (part

B). This lubricated blend was compressed into tablets or filled into causules. The stability of formulation was not satisfactory.

EXAMPLE 2

Ingredient Percent by weight

Part A

Pravastatin sodium 10.00 Microcrystalline cellulose 32.25

Anhydrous lactose 51.24

Croscarmellose sodium , 5.00

Sodium carbonate anhydrous 0.26

CremophorEL 0.25 Part B

Magnesium stearate 1.00

pH of formulation = 8.62

Pravastatin sodium, microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, sodium carbonate and cremophor EL were mixed together for 5 min in a rapid mixer granulator. The blend was roller compacted/slugged. The granules

(part A) were lubricated with magnesium stearate (part B). This lubricated blend was compressed into tablets or filled into causules.

The stability of formulation was not satisfactory.

EXAMPLE 3 A pravastatin formulation in the form of tablets having the following composition was prepared as described below.

Ingredient Percent by weight

Microcrystalline cellulose 32.25

Anhydrous lactose 51.24

Croscarmello se sodium 5.00

Sodium carbonate anhydrous 0.26

Cremophor EL 0.25 Part B

Pravastatin sodium 10.00

Magnesium stearate 1.00

pH of formulation = 8.62

Microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, sodium carbonate and cremophor EL were mixed together for 5 min in a rapid mixer granulator. The blend was roller compacted/slugged. The granules (part A) were mixed with pravastatin sodium and magnesium stearate (part B). This lubricated blend was compressed into tablets.

The stability of formulation was not satisfactory. EXAMPLE 4

Ingredient Percent by weight

Part A

Microcrystalline cellulose 32.25

Anhydrous lactose 51.49

Croscarmellose sodium 5.00

Sodium carbonate anhydrous 0.26

Purified water q.s.

Part B

10.00

Pravastatin sodium Magnesium stearate 1.00

pH of formulation = 8.00 Microcrystalline cellulose, anhydrous lactose and croscarmellose sodium were mixed together for 5 min in a rapid mixer granulator. Aqueous solution of sodium carbonate anhydrous was prepared. The mixture of microcrystalline cellulose, anhydrous lactose and croscarmellose sodium was granulated with aqueous solution of sodium carbonate anhydrous. The resulting damp mass was dried and sifted to get granules. The dried granules (part A) were mixed with pravastatin sodium and magnesium stearate (part B). This lubricated blend was compressed into tablets or filled into causules.

Upon subjecting the so-formed tablet to stability at 40°C./75% relative humidity for 3 months, it was found that the tablet containing pravastatin did not retain their stability. Stability data for Pravastatin sodium tablets kept at 40 C and 75% relative humidity for 12 weeks

EXAMPLE 4 Pravachol SO nig

Time Single Total impurity Single Total maximum maximum impurity impurity impurity

Initial 0.07 0.97 0.09 0.21

4 week 0.07 1.20 0.09 0.26

8 week 0.08 1.40 0.09 0.22

12 week 0.09 1.60 - -

EXAMPLE 5

Ingredient Percent by weight

Microcrystalline cellulose 32.25 Anhydrous lactose 51.30 Croscarmellose sodium 5.00 Cremophor EL 0.45 Purified water q.s. Part B

Pravastatin sodium 10.00 Magnesium stearate 1.00

pH of formulation = 6.82

Microcrystalline cellulose, anhydrous lactose and croscarmellose sodium were mixed together for 5 min in a rapid mixer granulator. Aqueous solution of cremophor EL was prepared. The mixture of microcrystalline cellulose, anhydrous lactose and croscarmellose sodium was granulated with aqueous solution of cremophor EL. The resulting damp mass was dried and sifted to get granules. The dried granules (part A) were mixed with pravastatin sodium and magnesium stearate (part B). This lubricated blend was compressed into tablets or filled into capsules. Upon subjecting the so-formed tablet to stability' at 40°C./75% relative humidity for 3 months, it was found that the tablet containing pravastatin did not retain their stability.

Stability data for Pravastatin sodium tablets kept at 40 C and 75% relative humidity for 12 weeks

EXAMPLE 5 Pravachol 80 mg

Time Single Total Single Total maximum impurity maximum impurity impurity impurity

Initial 0.04 0.33 0.09 0.21

4 week 0.11 3.60 0.09 0.26

0.17 4.40 0.09 0.22

8 week

12 week 0.18 4.30 - -

EXAMPLE 6

Ingredient Percent by weight

Microcrystalline cellulose 32.25

Anhydrous lactose 51.30

5.00

Croscarmellose sodium

Sodium carbonate anhydrous 0.45

Purified water q.s.

Part B

Pravastatin sodium 10.00

Magnesium stearate 1.00

pH of formulation = 9.71 Microcrystalline cellulose, anhydrous lactose and croscarmellose sodium were mixed together for 5 min in a rapid mixer granulator. Aqueous solution of sodium carbonate anhydrous was prepared. The mixture of microcrystalline cellulose, anhydrous lactose and croscarmellose sodium was granulated with aqueous solution of sodium anhydrous. The resulting damp mass was dried and sifted to get granules. The dried granules (part A) were mixed with pravastatin sodium and magnesium stearate (part B). This lubricated blend was compressed into tablets or filled into causules.

Upon subjecting the so-formed tablet to stability at 40°C./75% relative humidity for 3 months, it was found that the tablet containing pravastatin did not retain their stability.

EXAMPLE 6 Pravachol SO nig

Initial 0.04 0.28 0.09 0.21

4 week 0.09 1.20 0.09 0.26

8 week 0.13 1.20 0.09 0.22

12 week 0.17 1.50 - -

EXAMPLE 7

Ingredient Percent by weight

Microcrystalline cellulose 32.25

Anhydrous lactose 51.24

Croscarmellose sodium 5.00

Sodium carbonate anhydrous 0.26

Cremophor EL 0.25 Purified water q.s. Part B

Pravastatin, sodium 10.00 Magnesium stearate 1.00

pH of formulation = 8.62

Microcrystalline cellulose, anhydrous lactose and croscarmellose sodium were mixed together for 5 min in a rapid mixer granulator. Aqueous solution of sodium carbonate anhydrous and cremophor EL were prepared separately and mixed together. The mixture of microcrystalline cellulose, anhydrous lactose and croscarmellose sodium was granulated with aqueous solution of sodium carbonate anhydrous and cremophor EL. The resulting damp mass was dried and sifted to get granules. The dried granules (part A) were mixed with pravastatin sodium and magnesium stearate (part B). This lubricated blend was compressed into tablets or filled into causules.

Upon subjecting the so-formed tablet to stability at 40°C./75% relative humidity for 3 months, it was found that the tablet containing pravastatin retained their statbility.

EXAMPLE 7 Pravachol 80 mg

Initial 0.08 0.28 0.09 0.21

0.09 0.51 0.09 0.26

4 week

8 week 0.08 0.77 0.09 0.22

12 week 0.09 1.00 - -

Claims

1. A pharmaceutical composition comprising of pravastatin or its pharmaceutically acceptable salt, stabilized by synergistic combination of substantially low amount of alkalizing agent and nonionic surfactant, to impart a pH between 8 to 8.75 to an aqueous solution or dispersion of the said composition.

2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of pravastatin is pravastatin sodium.

3. The pharmaceutical composition as claimed in claim lor 2, wherein the amount of pravastatin sodium is between 1 and 50% by weight of the composition, preferably,

5 and 20% by weight of the composition.

4. The pharmaceutical composition as claimed in any preceding claim, wherein the alkalizing agent is selected from the group consisting of alkali metal carbonate, alkali metal bicarbonate, alkaline earth metal carbonate and mixtures thereof.

5. The pharmaceutical composition as claimed in claim 5, wherein the alkalizing agent is sodium carbonate anhydrous.

6. The pharmaceutical composition as claimed in any preceding claim, wherein the amount of alkalizing agent is between 0.001 and 10% by weight of the composition, preferably, between 0.05 and 5%, more. preferably, between 0.1 and 1% by weight of the composition.

7. The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan fatty acid ester, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylenated ricin oil, polyoxyethylenated fatty acid glyceride, poloxamer and mixtures thereof.

8. The pharmaceutical composition as claimed in any preceding claim, wherein the nonionic surfactant is polyoxyl 35 castor oil (cremophor EL).

9. The pharmaceutical composition as claimed in any preceding claim, wherein the amount of nonionic surfactant is between 0.01 and 10% by weight, preferably 0.05 and 5%, more preferably, 0.1 and 1% by weight of the composition.

10. The pharmaceutical composition as claimed in any preceding claim in the form of a tablet or capsule.

11. The pharmaceutical composition as claimed in claim 10, further comprising pharmaceutically acceptable diluent, binder, disintegrant and lubricant.

12. The pharmaceutical composition as claimed claim 11, wherein the diluent is selected from the group consisting of lactose, microcrystalline cellulose, starch, sugars, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium phosphate, dextrin, maltodextrin and mixtures thereof.

13. The pharmaceutical composition as claimed in claim 12, wherein the amount of diluent is between 10 and 80%, preferably, 25 and 70%, most preferably, 40 and 60% by weight of the composition.

14. The pharmaceutical composition as claimed in claim 11, wherein the binder is selected from the group consisting of micrqcrystalline cellulose, polyvinyl pyrrolidone, starch, starch derivatives, gum acacia, hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose and mixtures thereof.

15. The pharmaceutical composition as claimed in claim 14, wherein the amount of binder is between 10 and 50%, preferably, 20 and 40% by weight of the composition.

16. The pharmaceutical composition as claimed in claim 12, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, starch and mixtures thereof.

17. The pharmaceutical composition as claimed in claim 12, wherein the amount of . disintegrant is between 1 and 15%, preferably 3 and 9% by weight of the composition.

18. The pharmaceutical composition as claimed in claim 12, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate., zinc stearate and mixtures thereof.

19. The pharmaceutical composition as claimed in claim 12, wherein the amount of lubricant is between 0.1 and 2% by weight of the composition.

20. An immediate release stable tablet of pravastatin sodium comprising: - 5-20% by weight pravastatin sodium

- 0.1 - 1 % by weight alkalizing agent

- 0.1 - 1 % by weight nonionic surfactant

- 40-60% by weight diluent

- 20-40% by weight binder - 3-9% by weight disintegrant

- 0.1 -2% by weight lubricant imparts a pH of at least 8 to an aqueous solution or dispersion of the composition.

21. A process for preparation of pharmaceutical composition as claimed in claim 20 wherein the process comprises of:

(a) dry mixing of diluent, binder and disintegrant

(b) preparation of aqueous solution of nonionic surfactant and alkalizing agent separately and subsequently mixing both the solutions

(c) granulating the dry blend of step (a) with the solution of step (b) (d) drying and sifting of the granules of step (c)

(e) blending dried granules of step (d) with pravasatin sodium and lubricant

(f) compressing the blend of step (e) into tablets or filling the blend of step (e) into capsules