Field of the invention
The present invention relates to a stabilized pharmaceutical composition, comprising Fluvastatin or pharmaceutically acceptable salts thereof and process for preparation thereof.
Background of the invention
Fluvastatin is a member of a class of drugs commonly referred to as HMG CoA reductase inhibitors and is used to reduce blood cholesterol levels in patients in need of such treatment. Fluvastatin is [R*. S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid and is described in US 5,354,772.
Fluvastatin is particularly sensitive to an acidic environment in which hydroxy acids are degraded into a lactone. The instability of Fluvastatin is due to the extreme lability of the p, 5- hydroxy groups on the heptenoic acid chain and the presence of the double bond, such that at neutral to acidic pH, the compounds readily undergo elimination or isomerization or oxidation reactions to form conjugated unsaturated aromatic compounds, as well as the threo isomer, the corresponding lactones, and other degradation products. US 5,356,896 disclosed a stabilized Fluvastatin formulation by maintaining an alkaline environment so that the aqueous dispersion of the pharmaceutical formulation reaches a pH above 8. The composition comprises a basifying agent like calcium carbonate or sodium carbonate.
Further, the PCT application, WO 00/35425 discloses stabilization of the statins with buffers, among which are listed, for example sodium and potassium citrate, sodium phosphate, disodium phosphate, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, sodium or magnesium carbonate, sodium ascorbinate, benzoate, sodium or potassium hydrogen carbonate, sodium or potassium lauryl sulfate and mixtures thereof.
The PCT application WO 01/93860 discloses a composition comprising a homogeneous mixture of a HMG-CoA reductase inhibitor with a buffering substance or a basifying substance, obtained by co-crystallization and/or co-precipitation of said HMG-CoA reductase inhibitor and said buffering substance or basifying substance.
All these prior art suggest a pH of more than 8 is required to stabilize the formulation and the use of one or more alkaline substances. However, the local alkaline environment occurring at the site of dissolution of the pharmaceutical composition may have negative impact on the gastric mucosa with its normally acidic environment. This negative impact may be particularly evident for patients
with a damaged gastric mucous membrane where the mucosa per se is not able to create a sufficient acidic environment inside the stomach for normal digestive functioning. It is particularly important in chronic therapies as in the case of prophylaxis or treatment with HMG-CoA reductase inhibitor.
We have surprisingly found a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of less than 8 and hence would have less negative impact on the gastric mucosa than pharmaceutical compositions of prior art. We also found that it is not necessary to maintain the pH more than 8 to obtain a stabilized composition of Fluvastatin.
Summary of the invention
In one of the aspects, there is provided a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of less than 8.
In another aspect, there is provided a process for the preparation of a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of less than 8.
In another aspect, there is provided a method of treating or preventing hypercholesterolemia in a mammal in need thereof comprising administering to the mammal effective amount of a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of less than 8.
In another aspect, there is provided a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of 6-7.5.
In another aspect, there is provided a process for the preparation of a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of 6-7.5.
In another aspect, there is provided a method of treating or preventing hypercholesterolemia in a mammal in need thereof comprising administering to the mammal effective amount of a stabilized
pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof wherein the aqueous dispersion or solution of said composition provides a pH of 6-7.5.
In another aspect, there is provided a stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically acceptable salts thereof comprising mannitol or microcrystalline cellulose and pregelatinized starch wherein the aqueous dispersion or solution of said composition provides a pH of 6-7.5.
According to another aspect, there is provided a stabilized pharmaceutical composition comprising from about 5-50 % by weight of Fluvastatin,
from about 20-80 % by weight of mannitol or microcrystalline cellulose, from about 20-80 % by weight of pregelatinized starch, from about 0.1-15% by weight of lubricant/glidant.
Detailed description
The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, pill and like. It also includes conventional as well as extended release compositions.
Fluvastatin, as used herein includes Fluvastatin and their free-acid forms, their ester forms, e.g. lactone forms. The pharmaceutically acceptable salts thereof include sodium, potassium or ammonium, preferably sodium. Fluvastatin may exist in any of the solid-state forms available such as amorphous, crystalline or any other polymorphic form, preferably amorphous form. Fluvastatin will be present in an amount within the range of from about 1 to about 60% by weight of the composition.
The pH of an aqueous solution or dispersion of the composition is less than 8, preferably between 6 to 7.5. The pH may be determined by taking a unit dosage of the composition containing 20 mg fluvastatin and dispersing or dissolving the composition in 10 to 100 ml of water.
The term stabilized as used herein as used herein is meant that after storage for three months at 40°C and 75% relative humidity, the assay content of Fluvastatin is within the limit described in DSP. As per DSP, the Fluvastatin content should be not less than 90% and not more than 110% of the labeled amount.
As per USP, the content of certain impurities have to be determined such as fluvastatin anti-isomer, 3-hydroxy-5-keto-fluvastatin, fluvastatin hydroxy diene, and fluvastatin short chain aldehyde and the limits described for these impurities are 1.5%, 1.0%, 1.0% and 0.5% of the total impurities found respectively.
The pharmaceutical composition as defined herein further comprises pharmaceutically acceptable inert excipients. The term "pharmaceutical acceptable inert excipients" as used herein includes excipients such as fillers, binders, lubricants/glidants, coloring agent, release modifying agent and the like.
The composition may include one or more fillers such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose in an amount within the range of from about 5 to about 90% by weight.
The composition may include one or more binders in an amount within the range of form about 10 to about 60%. The specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, polysorhate 80, eudragits, ethyl cellulose, gelatin, gum arabic, polyvinyl alcohol, pullulan, carbomer, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, microcrystalline cellulose and the like.
The examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Release modifying polymer may be a water-soluble polymer, or a water insoluble polymer (including waxes). Examples of water-soluble polymers include polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides (such as alginate, xanthan gum, etc.), polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. Examples of water-insoluble polymers include acrylates such as methacrylates, acrylic acid copolymers; cellulose derivatives such as ethylcellulose or cellulose acetate; polyethylene, and high molecular weight polyvinylalcohols. Examples of suitable waxes include fatty acids and glycerides.
Coloring agent may be selected from FDA approved colorants and the examples are Iron oxide, Lake of Tartrazine, Allura red, Lake of Quinoline yellow, Lake of Erythrosine.
According to one of the embodiments, the pharmaceutical composition is prepared by a process, comprising the steps of
i) blending fluvastatin or pharmaceutically acceptable salt thereof with pharmaceutically
acceptable inert excipients;
ii) optionally granulating or comilling the above blend; iii) optionally blending the granules with pharmaceutically acceptable inert extragranular
excipients;
iv) lubricating the granules/blend; v) compressing the lubricated granules/blend into suitable sized tablets or filling into
capsules.
According to one of the embodiments, the pharmaceutical composition is prepared by wet granulation technique, comprising the steps of
i) blending fluvastatin or pharmaceutically acceptable salt thereof with pharmaceutically
acceptable inert excipients;
ii) granulating the above blend with a granulating fluid; iii) optionally blending the granules with pharmaceutically acceptable inert extragranular
excipients;
iv) lubricating the granules/blend; v) compressing the lubricated granules/blend into suitable sized tablets or filing into capsules.
According to one of the embodiments, the pharmaceutical composition is prepared by dry granulation technique, comprising the steps of
i) blending fluvastatin or pharmaceutically acceptable salt thereof with pharmaceutically acceptable inert excipients;
ii) granulating the above blend using slugging or roller compaction;
iii) optionally blending with pharmaceutically acceptable inert extragranular excipients;
iv) lubricating the granules/blend;
v) compressing the lubricated granules/blend into suitable sized tablets or filing into capsules.
According to one of the embodiments, the pharmaceutical composition is prepared by direct compression, comprising the steps of
i) blending fluvastatin or pharmaceutically acceptable salt thereof with pharmaceutically
acceptable inert excipients; ii) lubricating the granules/blend; iii) compressing the lubricated granules/blend into suitable sized tablets or filing into capsules.
According to one of the embodiments, capsules may be prepared by,
- Mixing Fluvastatin along with pharmaceutically acceptable inert excipients,
- Lubricating the blend,
- Filling the blend into capsule shells.
According to one of the embodiments, capsules may be prepared by,
- mixing fluvastatin along with pharmaceutically acceptable inert excipients,
- comilling the above blend,
- adding the remaining excipients and then lubricating the blend,
- filling the blend into capsule shell.
Upon subjecting the so-formed capsules to a stability study at 40°C and 75 % relative humidity for three months, it was found that the pharmaceutical composition was stable.
The following examples represent the embodiments, but are not to be construed as limiting the scope of the claims.
Examples
(Table Removed)

1. Fluvastatin was sifted along with pregelatinized starch.
2. Microcrystalline cellulose was sifted and added to the blend of step 1 and mixed.
3. Sifted magnesium stearate and talc was added to the blend of step 2 and the mixture was
blended.
4. The blend was filled into capsule shell.
A dispersion of the composition equivalent to 20 mg fluvastatin in 10 ml of water had a pH of 7.21 and in 100 ml of water a pH of 6.91.The capsules were subjected to stability studies at a temperature of 40° C at 75 % relative humidity for three months. The residual percentages of Fluvastatin in the capsules were determined as given in Table 1.
Table 1: Stability data of the composition of Example 1.

\(Table Removed)
Examples 2 and 3

\(Table Removed)
These compositions were prepared by same method as given in example 1.
A dispersion of the composition of Example 2 equivalent to 20 mg of fluvastatin in 10 ml of water had a pH of 7.18 and in 100 ml of water a pH of 7.06
The capsules of Example 2 were subjected to stability study at a temperature of 40° C at 75 % relative humidity for three months. The residual percentages of Fluvastatin in the capsules were determined. The stability data of the composition is given in Table 2.
Table 2: Stability data of the composition of Example 2.
\(Table Removed)
The stability data of Examples 1 and 2 indicate that the compositions were stable as per the limits set for impurities by USP.
Exam pie 4
Composition of Example 2 was processed by the following procedure.
1. Fluvastatin was sifted along with pregelatinized starch.
2. Microcrystalline cellulose was sifted and added to the blend of step 1 and mixed.
3. The mixture was co milled.
4. Sifted magnesium stearate and talc was added to the blend of step 2 and the mixture was
blended.
5. The blend was filled into capsule shell.

WE CLAIM:
1. A stabilized pharmaceutical composition comprising Fluvastatin or pharmaceutically salts
thereof, wherein the aqueous dispersion or solution of said composition provides a pH of
less than 8.
2. The pharmaceutical composition according to claim 1, wherein the aqueous dispersion or
solution of said composition provides a pH between 6 to 7.5
3. The pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable
salts of fluvastatin include sodium, potassium or ammonium salts.
4. The composition according to claim 1, wherein fluvastatin may exist in any of the solid state
forms selected from the group consisting of amorphous, crystalline and any other
polymorphic form.
5. The composition according to claim 1, wherein fluvastatin is present in an amount within the
range of from about 1 to 60% by weight of the composition.
6. The pharmaceutical composition according to claim 1, wherein the composition further
comprises pharmaceutically acceptable inert excipients.
7. The pharmaceutical composition according to claim 6, wherein the pharmaceutically
acceptable inert excipients are fillers, binders, lubricants /glidants, coloring agents, release
modifying agents.
8. The pharmaceutical composition according to claim 7, wherein the filler is lactose, sugar,
cornstarch, modified cornstarch, mannitol, sorbitol, wood cellulose, microcrystalline
cellulose, calcium carbonate or mixtures thereof.
9. The pharmaceutical composition according to claim 7, wherein the filler is present in an amount of within the range of from about 5 to about 90% by weight of the composition.
10. The pharmaceutical composition according to claim 7, wherein the binder is microcrystalline
cellulose, polyvinylpyrrolidone, lactose, corn starch, modified corn starch, sugars, gum
acacia, carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
11. The pharmaceutical composition according to claim 7, wherein the binder is present in an
amount of within the range of from about 10 to about 60% by weight of the composition.
12. The pharmaceutical composition according to claim 1, having the following composition:
from about 5 to about 25% by weight fluvastatin;
from about 30 to about 60% by weight of mannitol or microcrystalline cellulose; from 20 to about 40% by weight by weight of pregelatinized starch; from about 0.1 to about 15% by weight of talc and magnesium stearate.
13.The pharmaceutical composition according to claim 1, wherein the dosage form is solid.
14. The pharmaceutical composition according to claim 13, wherein the dosage form is tablet
or capsule.
15. A process for the preparation of a composition according to claim 1, comprising the steps of
i) blending fluvastatin or pharmaceutically acceptable salt thereof and pharmaceutically
acceptable inert excipients; ii) optionally granulating the above blend iii) optionally blending the granules with pharmaceutically acceptable inert
extragranular excipients; iv) lubricating the granules/blend; v) compressing the lubricated granules/blend into suitable sized tablets or filling into
capsules.
16. A process according to claim 15, wherein the granulation is by wet granulation.
17. A process according to claim 15, wherein the granulation is by dry granulation.
18. A process according to claim 17, wherein the dry granulation is by roller compactor or
slugging.
19. Use of the stabilized pharmaceutical composition according to claim 1, for the prevention or
treatment of hypercholesterolemia.
20. A pharmaceutical composition comprising fluvastatin as herein described.