This application is patent of addition of IN 2674/DEL/2005 filed on Oct. 5, 2005.
Field of the invention
The present invention relates to a stabilized pharmaceutical composition comprising amorphous 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 |3, 6-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.
'x,
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.
Fluvastatin is known to occur in various crystalline forms as well as amorphous forms. The various crystalline forms have been disclosed in EP 1,330,435, WO 04/113292, WO 05/037787, WO 04/096765, WO 04/113291 and WO 03/013512. Amorphous fluvastatin and process for preparation thereof has been disclosed in one of our copending application WO 06/030304.
The use of amorphous form as the active substance is advantageous over crystalline form because the amorphous form dissolves faster and better which is an important factor for bioavailability of the active substance in the body. However, it is well known that the stability of an active substance depends on a solid state form in which it exists and that an amorphous form is less stable than a crystalline form indicating that an amorphous form is even more susceptible to heat, light, moisture and low pH compared to a crystalline form.
Also, although the physical form of a drug substance is carefully selected for dosage form manufacture, the processing conditions will determine the solid state of the drug in the final product. During tablet manufacture, processing steps may include milling, granulation, drying, and compression, which may lead to change in the solid state form. These processing induced transformations may lead to change in the solid state of the drug. One solid state form may differ from other form in its stability, solubility that may lead to difference in bioavailability. In some cases it has been observed that one solid state differ from other in mechanical properties such as hardness, tensile strength, tabletting and even flow.
So it was desired to have a stabilized pharmaceutical composition comprising fluvastatin which has desired chemical stability as well as physical stability and still provides comparable release profile similar to the innovator's release profile.
We found that a stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salts thereof was obtained by dry granulation process. There was no polymorphic conversion observed during the entire shelf life of the composition. It was observed that amorphous fluvastatin particles have poor wetting properties; however pharmaceutical composition comprising amorphous fluvastatin when prepared by dry granulation provided a desired dissolution profile.
Summary of the invention
Hence, in one of the aspects, there is provided a stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salts thereof wherein the composition is prepared by dry granulation process.
In another aspect, there is provided a dry granulation process for the preparation of stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salt thereof.
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 amorphous Fluvastatin or pharmaceutically acceptable salts thereof wherein the composition is prepared by dry granulation process.
In one of the aspects, there is provided a process for the preparation of a composition comprising amorphous fluvastatin, comprising the steps of
i) optionally blending fluvastatin or pharmaceutically acceptable salt thereof and
pharmaceutically acceptable inert excipients,
ii) compacting fluvastatin / above blend to compacts in roller compacter and screening the
compacts to obtain granules,
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.
In one of the aspects, there is provided a process for the preparation of a composition comprising amorphous fluvastatin, comprising the steps of
i) optionally blending fluvastatin or pharmaceutically acceptable salt thereof and
pharmaceutically acceptable inert excipients,
ii) compressing fluvastatin / above blend to obtain slugs and screening the slugs to obtain
granules,
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.
In one of the aspects, there is provided a stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salts thereof wherein the composition is prepared by dry granulation process and the aqueous dispersion or solution of said composition provides a pH of less than 8.
In another aspect, there is provided a dry granulation process for the preparation of stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salt thereof and 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 composition is prepared by dry granulation process and the aqueous dispersion or solution of said composition provides a pH of less than 8.
In one of the aspects, there is provided a stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salts thereof wherein the composition is prepared by dry granulation process and the aqueous dispersion or solution of said composition provides a pH of 6-7.5.
In another aspect, there is provided a dry granulation process for the preparation of stabilized pharmaceutical composition comprising amorphous Fluvastatin or pharmaceutically acceptable salt thereof and 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 composition is prepared by dry granulation process and the aqueous dispersion or solution of said composition provides a pH of 6-7.5.
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 will be present in an amount within the range of from about 1 to about 60% by weight of the composition. The amorphous form as disclosed in our copending application WO 06/030304 may include amorphous Form R-6 and R-14 'of Fluvastatin sodium.
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 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 USP. As per USP, 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 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 fluvastatin alone or of a blend of fluvastatin and pharmaceutically acceptable inert excipients.
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, disintegrants, 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, polysorbate 80, eudragits,
ethyl cellulose, gelatin, gum arable, polyvinyl alcohol, pullulan, carbomer, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, microcrystalline cellulose and the like.
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. Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like in an amount within the range of from about 0.1 to about 20% by weight.
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 polyvinylpyrrolidones 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 polyvinyl alcohols. Examples of suitable waxes include fatty acids and glycerides.
The composition may be packed in the form of cold form blister pack or in HOPE bottle. The HOPE bottle may further comprise desiccant, silica or zeolite or molecular sieve.
The following examples represent the embodiments, but are not to be construed as limiting the scope of the claim
Tabele Removed
1. Fluvastatin was sifted with talc.
2. Microcrystalline cellulose, intragranular Crospovidone and pregelatinized starch were
sifted separately.
3. The materials in step 1 and 2 were blended together.
4. Intragranular magnesium Stearate was sifted and added to the above blend.
5. The blend formed in step 4 was compacted and passed through sieve.
6. Extragranular excipients were sifted and added to the granules formed in step 5 and then
the mixture blended.
7. The blend was filled in capsule shell.
A dispersion of the composition of Example 1 equivalent to 20 mg of fluvastatin in 10 ml of water had a pH of 6.78 and in 100 ml of water a pH of 6.66
A dispersion of the composition of Example 1 equivalent to 40 mg of fluvastatin in 10 ml.of water had a pH of 7.08 and in 100 ml of water a pH of 6.79
The drug release of capsules so prepared was determined by using BP apparatus II, in a 500 ml medium containing water. The results are given in table below:
(Tabele Removed)
*CFB and HOPE stands for cold form blister pack and HOPE bottle with silica gel desiccant.
Also the composition of Example 1 was monitored for any polymorphic conversion during the stability studies in which no polymorphic conversion was observed.
1. Tabele Removed
2. Fluvastatin was compacted and passed through sieve.
3. Fluvastatin granules formed in step 1 were sifted with the remaining excipients and the
mixture was blended.
3. The blend was filled in capsule shell.

(Table Removed)
The composition was prepared by same method as given in example 1.
(Table Removed)
The composition was prepared by same method as given in example 1.

WE CLAIM:
1. A stabilized pharmaceutical composition comprising amorphous Fluvastatin or
pharmaceutically acceptable salts thereof wherein the composition is prepared by dry
granulation process.
2. The pharmaceutical composition according to claim 1, wherein the aqueous dispersion
or solution of said composition provides a pH of less than 8.
3. The pharmaceutical composition according to claim 1, wherein the aqueous dispersion
or solution of said composition provides a pH of 6-7.5.
4. The pharmaceutical composition according to claim 1, wherein pharmaceutically
acceptable salts of fluvastatin include sodium, potassium or ammonium salts.
5. The pharmaceutical composition according to claim 1, wherein the composition further
comprises pharmaceutically acceptable inert excipients like fillers, binders,
disintegrants, lubricants /glidants, coloring agents, release modifying agents.
6. The pharmaceutical composition according to claim 1, wherein the composition is solid
dosage form selected from tablet, capsule or pill.
7. The pharmaceutical composition according to claim 1, wherein the composition remains
stable for atleast 3 months at 40°C and 75 % relative humidity.
8. The pharmaceutical composition according to claim 1, wherein there is no polymorphic
conversion for atleast 3 months at 40°C and 75 % relative humidity.
9. A process for the preparation of a composition according to claim 1 comprising the steps
of:
i) optionally blending amorphous fluvastatin or pharmaceutically acceptable salt
thereof and pharmaceutically acceptable inert excipients, ii) compacting fluvastatin/above blend to compacts in roller compacter and screening
the compacts to obtain granules, 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.
10. A process for the preparation of a composition according to claim 1 comprising the steps
of
i) optionally blending amorphous fluvastatin or pharmaceutically acceptable salt
thereof and pharmaceutically acceptable inert excipients, ii) compressing fluvastatin/above blend to obtain slugs and screening the slugs to
obtain granules, 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.