Field of the invent
The present invention reiaies 10 a siaomzea sona aosage rorm, comprising (3K, fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or pharmaceutically acceptable salts thereof and process for the preparation thereof.
Background of the invention
The HMG-CoA Reductase Inhibitors, commonly referred to as "statins," are considered a first-line therapy for the treatment of high cholesterol. HMG-CoA Reductase is'an enzyme that helps liver to produce cholesterol in the body. Statins blocks this enzyme, thus reducing the amount and frequency of cholesterol being produced.
7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid is a new member of HMG CoA reductase inhibitors and is used to reduce blood cholesterol levels in patients in need of such treatment. It is disclosed in our copending PCT application published as WO 04/106299. Compound of Formula I discloses a particular enantiomer of the above said class, which is (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid.
(Figure Removed)
It is used for treatment of arteriosclerosis, atherosclerosis, ischemia, hyperlipidaemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, stroke, endothelium dysfunctions, peripheral vascular disease, peripheral arterial disease, coronary heart disease, myocardial dysfunction, cerebral infarction, myocardial microvascular disease, dementia, Alzheimer's disease, osteoporosis and/or osteopenia, angina or restenosis.
\HMG-CoA reductase inhibitors are present in the form of salts in the final pharmaceutical formulation, which are particularly sensitive to an acidic environment, under these conditions hydroxy acids are degraded into a lactone. The instability of statins is due to the extreme lability of the p, 6- hydroxy groups on the heptanoic acid chain and the presence of the double bond. 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.
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.
The inventors have now found that for optimal stability and desired shelf life of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, the environmental pH should be equal to or greater than 4.5.
Further, it was observed that it is desirable that the pH of solid dosage form is equal to or greater than 8, which is stabilized by the addition of an alkalinizing agent.
Summary of the invention
Hence, in one of the aspects, there is provided a stabilized solid dosage form comprising (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or pharmaceutically acceptable salts thereof as active ingredient and one or more of stabilizing agents, wherein the aqueous dispersion or solution of said solid dosage form provides a pH equal to or greater than 8.
In another aspect, there is provided a process for preparation of a stabilized solid dosage form comprising (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or pharmaceutically
acceptable salts thereof as active ingredient and one or more of stabilizing agents, wherein the aqueous dispersion or solution of said solid dosage form provides a pH equal to or greater 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 solid dosage form comprising (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or pharmaceutically acceptable salts thereof as active ingredient and one or more of stabilizing agents, wherein the aqueous dispersion or solution of said solid dosage form provides a pH equal to or greater than 8.
Hence, in another aspect, there is provided a stabilized solid dosage form comprising (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt as active ingredient and one or more stabilizing agents, wherein the aqueous dispersion or solution of said solid dosage form provides a pH equal to or greater than 8.
According to another aspect, there is provided a stabilized solid dosage form comprising
- from about 5-50 % by weight of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-
4-[(4-hydroxy methylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
hemi calcium salt,
- from about 0.1 to 30 % by weight of stabilizing agent
from about 20-80 % by weight of diluent
- from about 0.1-15% by weight of disintegrant
- from about 0.1 -15% by weight of lubricant/glidant
According to another aspect, there is provided a stabilized solid dosage form comprising (3R, 5R)-7-[2-(4-fluoro phenyl) -5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or pharmaceutically acceptable salts thereof as active ingredient and one or more of stabilizing agents, wherein the aqueous dispersion or solution of said solid dosage form provides a pH equal to or greater than 8 and the active ingredient is stable at pH equal to or greater than 4.5.
Detailed description
The active ingredient as well as the dosage form was subjected to stability studies. The stability of active substance was determined as solution state stability at pH 2, 4.5, 5.5, 7.5,
9, 10 and 12 for 2 weeks as given in the Table 1. It was observed that the active substance was stable at pH equal to or greater than 4.5, more particularly at pH 4.5-12.
(Table Removed)

The solid dosage form was found to be stable at pH equal to or greater than 8, particularly 8-12, more particularly at pH 9-12. This may be due to the presence of pharmaceutically acceptable inert excipients, which would be affecting the stability of the dosage form, or due to various unit operations followed during the manufacturing.
The term 'solid dosage form' as used herein includes tablet, capsule, pill and like and it may be present as conventional or extended release composition.
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid as used herein includes their pharmaceutically acceptable salts, solvates, tautomers, racemates, diastereomers, metabolites, prodrugs, N-oxides their ester forms, e.g. lactone forms.
The term pharmaceutically acceptable salts refer to a salt prepared from pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metal or organic base. Examples of such metal salts include, but are not limited to sodium, calcium, potassium or ammonium, lithium, magnesium, zinc, aluminum, amino acid, monoalkyl ammonium, dialkyl ammonium, trialkyl ammonium, N-methyl glucamine, preferably hemi calcium. The compound of invention may exist in any of the solid-state forms available such as amorphous, crystalline or any other polymorphic form, preferably amorphous form. The compound of invention will be present in an amount within the range of from about 1 to about 60%, preferably 5 to 50 % by weight of the dosage form.
The pH of the dosage form was determined by taking a unit dosage of the composition containing the compound of invention and dispersing or dissolving the composition in 10 to 100 ml of water.
The term 'stabilized' as used herein means that the assay content of the compound of invention is not less than 90% w/w throughout the shelf life.
Dosage form provided herein, may contain the compound of invention either alone or in combination with other therapeutically active ingredients. It further comprises pharmaceutically acceptable inert excipients. The term "pharmaceutical acceptable inert excipients" as used herein includes excipients such as stabilizing agent, diluents, binders, lubricants/glidants, coloring agent and release modifying agent.
The term "stabilizing agent" as used herein includes alkanizing agent, buffers, antioxidant and chelating agent.
The alkanizing agent includes alkali metal salts and alkaline earth metal salts. The stabilizing alkali metal salt additive is selected from amongst one or more of sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate and other suitable alkali metal salts. Suitable alkaline metal salt additives include calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide. More particularly, calcium carbonate, potassium bicarbonate, calcium hydroxide, sodium carbonate are used as alkanizing agent to obtain the desired pH. The concentration of the alkanizing agent may be selected to obtain the desired pH levels. The concentration of alkanizing agent may vary form 0.1 to 30 % by weight, more preferably 12.5 to 30% by weight of the total weight of the dosage form.
The pharmaceutically acceptable antioxidants may be selected from amongst one or more of suitable antioxidants known in the art. Examples of suitable pharmaceutically acceptable antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, citric acid, malic acid, and ascorbic acid. The antioxidants are present at a concentration of 0.001-5 % by weight of the dosage form.
The chelating agents may be selected from amongst one or more of those suitable chelating agents known in the art. Examples of suitable chelating agents include, but are not limited to disodium edetate (EDTA). The chelating agents are present at a concentration of 0.001-5 % by weight of the dosage form.
The dosage form may include one or more diluents such as lactose, sugar, cornstarch, modified cornstarch, mannitol, sorbitol, and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose in an amount within the range of from about 20 to about 80% by weight.
The dosage form may include one or more binders in an amount of up to about 60% w/w. 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.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like. The concentration may vary from 0.1 to 15 % by weight of the dosage form.
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. The concentration may vary from 0.1 to 15 % by weight of the dosage form.
Release modifying polymer may be a water-soluble polymer, or a water insoluble polymer. Examples of water-soluble polymers include polyvinylpyrrolidone, hydroxy propylcellulose, hydroxypropyl methylcellulose, vinyl acetate copolymers, polyethylene oxide, polysaccharides (such as alginate, xanthan gum etc), methylcellulose, 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.
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 solid dosage form is prepared by a process, comprising the steps of
i) blending the compound of invention 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 solid dosage form is prepared by wet granulation technique, comprising the steps of
i) blending the compound of invention 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 into suitable sized tablets or filing into capsules.
According to one of the embodiments, the solid dosage form is prepared by dry granulation technique, comprising the steps of
i) blending the compound of invention 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 into suitable sized tablets or filling into capsules.
According to one of the embodiments, the solid dosage form is prepared by direct compression, comprising the steps of
i) blending the compound of invention or pharmaceutically acceptable salt thereof with pharmaceutically acceptable inert excipients;
ii) lubricating the blend;
iii) compressing the blend into suitable sized tablets.
According to one of the embodiments, capsules may be prepared by,
i) mixing the compound of invention or pharmaceutically acceptable salt thereof along
with pharmaceutically acceptable inert excipients, ii) lubricating the blend, iii) filling the blend into capsule shells.
According to one of the embodiments, capsules may be prepared by,
i) mixing the compound of invention or pharmaceutically acceptable salt thereof along
with pharmaceutically acceptable inert excipients, ii) comilling the above blend,
iii) adding the remaining excipients and then lubricating the blend, iv) filling the blend into capsule shell.
The following examples represent the embodiments, but are not to be construed as limiting the scope of the claims.
(Table Removed)

Process
1. Microcrystalline cellulose, Croscarmellose sodium, Calcium hydroxide and L -
Hydroxy propyl cellulose were sifted along with Hemi Calcium salt of Formula I.
2. Sifted magnesium stearate and talc was added to the blend of step 1 and the mixture
was blended.
3. The blend of step 2 was compressed.
4. The tablet was film coated with aqueous dispersion of Opadry.
The pH value for the solution of the dosage form was
a) pH value for 0.25 % w/v solution: 10.0
b) pH value for 0.50 % w/v solution: 10.01
c) pH value for 1.0% w/v solution: 10.06
(Table Removed)

Process
1. Hemi calcium salt of Formula I was blended with microcrystalline cellulose,
Croscarmellose sodium, potassium bicarbonate.
2. The blend in step 1 was granulated using L- hydroxypropylcellulose binder solution
and granules so obtained were dried.
3. The extragranular excipients were added to the granules in step 2 and blended.
4. The blend in step 3 was lubricated using magnesium stearate.
5. The blend of step 4 was compressed.
6. The tablet was film coated with aqueous dispersion of Opadry.
The pH value for the solution of the dosage form was
a) pH value for 0.25 % w/v solution: 12.00
b) pH value for 0.50 % w/v solution: 12.06
c) pH value for 1.0% w/v solution: 12.10
1. Hemi calcium salt of Formula I was blended with microcrystalline cellulose,
Croscarmellose sodium, calcium carbonate.
2. The blend in step 1 was granulated using L- hydroxypropylcellulose binder solution
and granules so obtained were dried.
3. The extragranular excipients were added to the granules in step 2 and the resultant
blended.
4. The blend in step 3 was lubricated using magnesium stearate.
5. The blend of step 4 was compressed.
(Table Removed)

The drug release of tablets so prepared was determined by using USP apparatus 2, in a 900 ml medium-containing pH 6.8 tri sodium phosphate buffer at 37± 0.5° C and 75 rpm agitation. The results are given in table 2.
(Table Removed)

Process
1. Hemi calcium salt of Formula I was blended with microcrystalline cellulose,
croscarmellose sodium, calcium carbonate.
2. The blend in step 1 was granulated using L- hydroxypropylcellulose and granules so
obtained were dried.
3. The extragranular excipients were added to the granules in step 2 and blended.
4. The blend in step 3 was lubricated using magnesium stearate.
5. The blend of step 4 was compressed.
6. The tablet was film coated with aqueous dispersion of Opadry.
The pH value for the solution of the dosage form in example 4C was
a) pH value for 0.25 % w/v solution: 9.08
b) pH value for 0.50 % w/v solution: 9.10
c) pH value for 1.0 % w/v solution: 9.21
STABILITY DATA FOR TABLETS
The tablets of the example 4 were subjected to the stability studies at different conditions. The residual percentages of Hemi calcium salt of Formula I in the tablets were determined as given in table 3.
(Table Removed)

WE CLAIM:
1. A stabilized solid dosage form comprising (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-
3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-
heptanoic acid or pharmaceutically salts thereof as active ingredient and one or more
stabilizing agent; wherein the dosage form is capable of providing a pH equal to or
greater than 8.
2. The stabilized solid dosage form according to claim 1, wherein the dosage form is
capable of providing a pH 9-12.
3. The stabilized solid dosage form according to claim 1, wherein the active ingredient
is stable at pH equal to or greater than 4.5.
4. The stabilized solid dosage form according to claim 1, wherein the dosage form
further comprises pharmaceutically acceptable inert excipients selected from
diluents, binders, disintegrants, lubricants /glidants, coloring agents and release
modifying agents.
5. The stabilized solid dosage form according to claim 1, wherein stabilizing agent
includes alkanizing agent, buffers, chelating agents and antioxidants.
6. The stabilized solid dosage form according to claim 5, wherein the alkanizing agent
is alkali or alkaline earth metal additive.
7. The stabilized solid dosage form according to claim 6, wherein alkanizing agent is
present in the concentration range of 12.5 to 30% by weight of the dosage form.
8. The stabilized solid dosage form according to claim 5, wherein chelating agent is
disodium edetate.
9. The stabilized solid dosage form according to claim 8, wherein the chelating agent is
present in the concentration range of 0.001-5 % by weight of the dosage form.

10. The stabilized solid dosage form according to claim 5, wherein the antioxidants
include butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene
(BHT), sodium sulfite, citric acid, malic acid, and ascorbic acid.
11. The stabilized solid dosage form according to claim 10, wherein the antioxidant is
present in the concentration range of 0.001-5 % by weight of the dosage form.
12. The stabilized dosage form according to claim 1 , wherein the dosage form is tablet or
capsule.
13. A process for the preparation of stabilized solid dosage form according to preceding
claims, comprising the steps of
i) blending active ingredient 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.
14. The process according to claim 13, wherein the granulation is by wet granulation or
dry granulation.
1 5. A method of treating or preventing hypercholesterolemia in a mammal in need thereof comprising administering to the mammal effective amount of stabilized solid dosage form according to claim 1 .
16. A stabilized solid dosage form comprising (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt as herein described.