Field of the invention
The present invention relates to pharmaceutical composition comprising atorvastatin or pharmaceutically acceptable salt thereof, and losartan or pharmaceutically acceptable salt thereof, process for the preparation thereof.
Background of the invention
Atherosclerotic cardiovascular disease and its complications are a major health problem in most countries of the world and continue to rank among the leading causes of mortality and morbidity. They result in huge health care expenditures and economic losses and are source of great suffering for those affected and their families. Hypertension and hyperlipidaemia are independent risk factors for atherosclerotic cardiovascular disease, however, hypertension commonly co-exists with hyperlipidaemia.
Considering the fact that hypertension commonly co-exists with hyperlipidaemia, a large number of patients would require concomitant therapy for both the diseases. This concomitant therapy would be more effective, if a combination therapy is used. Moreover, combination therapy affords the physician and the patient the opportunity to more effectively treat diseases that may stem from more than one cause. When used correctly and appropriately, combination therapy leads to better outcomes than monotherapy by treating more than one cause of the disease and/or by synergistically enhancing the action of one of the component drugs. Combination therapy also leads to better outcome by reducing noncompliance by the patient to a particular regimen.
HMG-CoA reductase inhibitors are effective lipid lowering drugs, of these atorvastatin is considered to be most effective and is indicated as an adjunct to diet to reduce lipid levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types lla and lib). It is also indicated as an adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels. Atorvastatin is additionally indicated for the treatment of patients with primary dysbetalipoproteinemia who do not respond adequately to diet. Atorvastatin is also indicated to reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Angiotensin II receptor antagonists are commonly used antihypertensive. Angiotensin II (A-ll) is a potent vasoconstrictor, which causes aldosterone secretion and sympathetic activation contributing to the development of hypertension. Angiotensin-ll receptor antagonists are effective and safe in
the treatment of hypertension with or without left ventricular hypertrophy. They are also approved for treatment of diabetic nephropathy.
HMG CoA reductase inhibitors and angiotensin II receptor antagonists being effective lipid lowering and antihypertensive drugs, respectively, would be indicated concomitantly in a large number of patients with co-existing risk factors of hypertension and hyperlipidaemia. Hence, this combination can be used for the treatment and prevention of atherosclerosis and hypertension.
WO 99/11260 disclosed pharmaceutical combinations of Atorvastatin or a pharmaceutically acceptable salt thereof and antihypertensive agents and methods of such combinations to treat subjects suffering of angina pectoris, atherosclerosis, and to treat subjects with symptoms of cardiac risk, including humans.
Inventors have now found out that it is advantageous to combine atorvastatin and losartan in a single dosage form as both losartan and atorvastatin can be dosed once daily and both can be dosed at any time of the day without regard to the timing of meals. The inventors have developed a once a day composition comprising atorvastatin and losartan wherein both the components are present in unit dosage form.
Summary of the invention
According to one of the aspect, there is provided a once a day pharmaceutical composition, comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof.
According to another aspect, there is provided a process for preparation of once a day pharmaceutical composition, comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof.
In yet another aspect, there is provided a method of treating or preventing atherosclerosis and/or hypertension wherein said method comprises administering once a day pharmaceutical composition, comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof.
According to one of the aspect, there is provided a once a day pharmaceutical composition, comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a single dosage form.
According to one of the aspects, there is provided a once a daily bilayer tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof wherein one layer comprises atorvastatin and other layer comprises losartan.
According to one of the aspects, there is provided process for preparation of a once a daily bilayer tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof wherein one layer comprises atorvastatin and other layer comprises losartan.
According to one of the aspects, there is provided process for preparation of a once a daily bilayer tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof comprising the steps of i) preparation of atorvastatin blend or granules
a) blending atorvastatin, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend of step a) or granules of step b),
ii) preparation of losartan blend or granules

a) blending losartan and one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend of step a) or granules of step b),
iii) compressing the blend or granules of step i) and step ii) to form a bilayer tablet.
Detailed description
The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, minitablet, pill and alike. It also includes conventional as well as modified release compositions.
As used herein the term "atorvastatin" refers to atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin iron, atorvastatin zinc, and other suitable salts of atorvastatin. Atorvastatin may exist in any of the solid state forms available such as amorphous or crystalline form.
As used herein "Losartan" refers to losartan as well as salts such as potassium, sodium, calcium and ammonium salts. Losartan may exist in any of the solid-state forms available such as
amorphous or crystalline form. The various crystalline forms of Losartan are described in US 5,608,075 and WO 03/048135.
Therapeutically effective amount of atorvastatin or pharmaceutically acceptable salt thereof ranges from 10-80 mg equivalent to atorvastatin. Therapeutically effective amount of losartan or pharmaceutically acceptable salt thereof ranges from 25-100 mg equivalent to losartan. The combination may comprise strengths such as atorvastatin and losartan - 10 mg and 50 mg, 10 mg and 25 mg equivalent to the drug amount, respectively.
The particle size of atorvastatin may be used with dgo of less than approximately 200 jam. This size may be obtained either directly by the synthesis or by using conventional milling techniques, such as air jet milling, ball milling, cad milling, multi milling and other suitable size reduction techniques.
In an acidic environment, atorvastatin degrades into corresponding lactone. It is further destabilized on contact with excipients such as binders, diluents, and surfactants, when formulated in the form of tablets, powders or other dosage forms. So, the atorvastatin component may comprise stabilizing alkali metal salt additive selected from amongst one or more of sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate and other suitable alkali metal salts. In particular, the stabilizing alkali metal salt additive may be selected from amongst sodium carbonate and disodium hydrogen orthophosphate, although the other alkali metal salt additives may also be selected. The alkali metal salt additive is present at a concentration of between approximately 1.2 % to less than about 5% by weight of the composition.
Suitable alkaline metal salt additives such as calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide may also be used.
The pharmaceutical composition may be provided in the form of capsules wherein the capsule comprises beads comprising atorvastatin and losartan.
In one of the embodiment, there is provided a once a daily pharmaceutical composition comprising a atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of
a) coating inert core with a drug layer comprising atorvastatin,
b) coating the said core of step a) with a seal coat,
c) coating cores of step b) with a drug layer comprising losartan,
d) coating the cores of step c) with a seal coat,
e) filling the beads of step d) into capsules.
The pharmaceutical composition may be provided in the form of capsules wherein the capsule comprises two beads viz. one of atorvastatin and another of losartan.
In another embodiment, there is provided a once a daily pharmaceutical composition comprising atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of
a) coating inert core with a drug layer comprising losartan and
b) coating separate inert cores with a drug layer comprising atorvastatin,
c) filling the beads of step a) and b) into capsules.
The inert core described here can be water insoluble, soluble or swellable.
The pharmaceutical composition may be provided in the form of capsules or tablets wherein the capsule or tablet comprises spheroids.
In another embodiment, there is provided a once a daily pharmaceutical composition comprising atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of:
a) extruding atorvastatin with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) optionally, seal coating the spheroids of step b)
d) coating the spheroid of step b) or c) with drug layer comprising losartan,
e) filing these spheroids into capsules or compressing them into tablets.
In another embodiment, there is provided a pharmaceutical composition comprising atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of:
a) extruding losartan with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) optionally, seal coating the spheroids of step b)
d) coating the spheroid of step b) or c) with drug layer comprising atorvastatin
e) filing these spheroids into capsules or compressing them into tablets.
The pharmaceutical composition may be provided in the form of tablets wherein atorvastatin and losartan are separated by a layer or a membrane of a physiologically acceptable inert material.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of
a) blending atorvastatin with one or more pharmaceutically inert excipients;
b) optionally granulating the blend,
c) lubricating the blend or granules,
d) compressing the lubricated blend of step c) into tablet,
e) optionally coating the core with suitable inert excipients,
f) dispersing or dissolving losartan and other inert excipients in a suitable solvent system.
g) coating the tablet of step d) or e) with drug layer of losartan.
The pharmaceutical composition may be provided in the form of tablets wherein atorvastatin and losartan are processed to form a bilayer/multilayer tablet or inlay tablet.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of i) preparation of atorvastatin tablets
a) blending atorvastatin, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
ii) preparation of losartan granules

a) blending losartan and one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
d) compressing the blend of step c) into tablet
iii) compressing the granules of step i) and the tablets of step ii) to form an inlay tablet.
The pharmaceutical composition may be provided in the form of capsules wherein atorvastatin composition in the form of tablets, minitablets, granules or pellets and losartan in the form of the powder, granules, minitablets or pellets.
In another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising atorvastatin and losartan or pharmaceutically acceptable salts thereof comprising the steps of
a) blending atorvastatin, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a,
c) lubricating the blend or granules of step b,
d) compressing the lubricated blend of step c into suitable size tablet,
e) blending losartan and one or more pharmaceutically inert excipients;
f) filling the tablet and losartan powder blend into a capsule.
The beads or tablets as described above may have an additional non-functional coating such as polyethylene glycol for protection or to improve the aesthetic appeal of the product. Non functional coating may also help in overcoming a common problem of the rupturing or cracking of release controlling layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores to tablet or filling into capsule/sachet.
Tablets may be prepared by conventional methods like direct compression, wet granulation or dry granulation.
The pharmaceutical composition as defined herein further comprises pharmaceutically inert excipients. The term pharmaceutically inert excipients includes substances known in the art such as diluents, surfactants, binders, disintegrants, coloring agents, stabilizers, release modifying agents, surfactants, lubricants, plasticizers required for preparation of pharmaceutical compositions.
Examples of diluents include powdered cellulose, microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, dicalcium phosphate and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, copovidone and the like.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of modified release polymer include water-soluble polymers or water insoluble polymers. Specific example of water-soluble polymers includes polyvinylpyrrolidone, hydroxy propyl cellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides (such as alginate, xanthum gum), polyethylene oxide, maleic anhydride, methyl vinyl ether copolymers and derivatives and mixtures thereof.
Specific example of water-insoluble polymers include acrylates such as methacrylates, methacrylic acid copolymers, acrylic acid copolymers; cellulose derivatives such ethylcellulose or cellulose acetate; polyethylene, and high molecular weight polyvinyl alcohols.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Examples of lubricants or glidants include magnesium stearate, sodium stearyl fumarate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, zinc stearate, silicon dioxide, sodium chloride and the like.
Examples of plasticizers include polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate and the like.
Besides the above-mentioned excipients, other ancillary substances, in particular, coloring agents, alkalizing agents and other additives are used. Coloring agent of the may be selected from FDA approved colorants and may be selected from Iron oxide, Lake of Tartrazine, Allura red, Lake of Quinoline yellow, Lake of Erythrosine.
Examples of stabilizers include antioxidants, buffers, alkalizers, chelating agents and the like.
The pharmaceutically acceptable antioxidants may be selected from butylated hydroxy anisole (BHA), carotenoids, sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, citric acid, malic acid, and ascorbic acid.
The chelating agents may be selected from amongst one or more of those suitable chelating agents known in the art. Example of suitable chelating agent includes, but is not limited to disodium edetate (EDTA). The chelating agents are present at a concentration of up to approximately 5% by weight of the compositions.
Water insoluble core includes silicon dioxide, small particles of glass, or plastic resin particles such as polypropylene or polyethylene. Water-soluble core includes sugar spheres such as glucose, mannitol, lactose, xylitol, dextrose, sucrose and salt cores such as sodium chloride, potassium chloride. Water swellable core may be made up of hydroxypropyl methylcellulose, microcrystalline cellulose or starch. Inert core may have a diameter ranging from about 150-600 urn, preferably about 250-425 urn.
Polymer solution or dispersion may be prepared in various solvents such as water, ethanol, methanol, isopropyl alcohol, chloroform, acetone, ether or mixture thereof. Different methods like spray coating in conventional pan, fluidized bed processor, dip coating can be used for coating process.
The following example represents preferred embodiments, but is not to be construed as limiting the scope of the claims.
Example
(Table Removed)
PROCESS ATORVASTATIN BLEND
1. Atorvastatin Calcium, a part of croscarmellose sodium & colloidal anhydrous silica, a part of
microcrystalline cellulose, sodium lauryl sulphate and Hydroxypropyl cellulose were sifted
through sieve.
2. Sodium carbonate & the remaining quantity of microcrystalline cellulose were passed
separately through multimill.
3. Butylated hydroxyanisole & Butylated hydroxytoluene were dissolved in Isopropyl alcohol.
4. A part of quantity of lactose was sifted through sieve and granulated with solution of step 3.
5. Remaining quantity of croscarmellose sodium and colloidal anhydrous silica were sifted
with remaining quantity of lactose.
6. The materials of step 1 and 2 were blended and the material of step 4 and 5 were added to
it and the resultant was mixed properly.
7. The blend of step 6 was lubricated with blend of step 6.
LOSARTAN POTASSIUM BLEND
1. Losartan potassium, lactose anhydrous, intragranular microcrystalline cellulose &
pregelatinized starch were sifted together.
2. Intragranular magnesium stearate was mixed with the blend of step 1.
3. The above blend was granulated using roller compacter.
4. Extragranular microcrystalline cellulose, pregelatinized starch & colloidal anhydrous silica
were sifted and mixed with the granules.
5. Talc & magnesium stearate were sifted and mixed with the above material.
BILAYER TABLET
1. Blends of the Losartan potassium layer and Atorvastatin layer were compressed into bilayer
tablet.
2. The tablets were film coated with aqueous dispersion of Opadry.

WE CLAIMS :
1. Once a day pharmaceutical composition comprising atorvastatin or a pharmaceutically
acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable
salts of atorvastatin include atorvastatin calcium, atorvastatin magnesium, atorvastatin
aluminum, atorvastatin iron, and atorvastatin zinc.
3. The pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable
salts of losartan include losartan potassium, losartan sodium, losartan calcium and losartan
ammonium salts.
4. The composition according to claim 1, wherein atorvastatin or losartan may exist in any of
the solid state forms such as amorphous or crystalline.
5. The pharmaceutical composition according to claim 1, wherein atorvastatin is present in
range of 10-80 mg equivalent to atorvastatin and losartan is present in the range from 25-
100 mg equivalent to losartan.
6. The pharmaceutical composition according to claim 5, wherein the combination may
comprise strengths such as atorvastatin and losartan - 10 mg and 50 mg, 10 mg and 25
mg, respectively.
7. The composition according to claim 1, wherein composition further comprises one or more
pharmaceutically inert excipients selected from the group consisting of metal salt additive,
buffers, diluents, surfactants, antioxidants, disintegrants, binders, lubricants, glidants and
chelating agents.
8. The composition according to claim 7, wherein metal salt additive is selected from alkali or
alkaline metal salt additive selected from the group consisting sodium carbonate, sodium
hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; and
calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide,
magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide, respectively.
9. The pharmaceutical composition according to claim 1, wherein the composition is tablet.
10. The pharmaceutical composition according to claim 9, wherein tablet is inlay tablet.
11. The pharmaceutical composition according to claim 9, wherein tablet is bilayer tablet.
12. The pharmaceutical composition according to claim 9, wherein tablet is compression coated
tablet.
13. The pharmaceutical composition according to claim 1, wherein the composition is capsule.
14. The pharmaceutical composition according claim 13, wherein atorvastatin or losartan is in
the form of granules, powder, beads, tablets, and minitablets.
15. A process for the preparation of the composition of claim 1, comprising the steps of:
i) preparation of atorvastatin blend or granules.

a) blending atorvastatin, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a),
c) lubricating the blend or granules of step a) or step b),
ii) preparation of losartan blend or granules.
d) blending losartan and one or more pharmaceutically inert excipients;
e) optionally granulating the blend of step a),
f) lubricating the blend or granules of step a) or step b),
iii) compressing the blend or granules of step i) and step ii) to form a bilayer tablet.
16. A process for the preparation of pharmaceutical composition of claim 1, comprising the
steps of
a) coating inert core with a drug layer comprising atorvastatin,
b) coating cores of step a) with a drug layer comprising losartan,
c) filing the beads of step b) into capsules.
17. The process according to claim 16, wherein core of step a) or b) are further coated with a
seal coat.
18. The process according to claim 16, wherein coating is applied using techniques such as
spray coating or fluidized bed processor or dip coating.
19. The process according to claim 16, wherein inert core is selected from water insoluble,
soluble and swellable cores.
20. A process for preparation of a pharmaceutical composition of claim 1, comprising the steps
of:
a) extruding atorvastatin with suitable excipients,
b) breaking the extruded cylinders into appropriate length and transforming them into
spheroids,
c) optionally, seal coating the spheroids of step b),
d) coating the spheroid of step b) or c) with drug layer comprising losartan,
e) filing these spheroids into capsules or compressing them into tablets.
21. Use of the composition according to claim 1, for the treatment or prevention of hypertension
or atherosclerosis.
22. A pharmaceutical composition comprising atorvastatin and losartan as herein described.