FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"STABLE ORAL PHARMACEUTICAL COMPOSITION OF CANDESARTAN CILEXETIL"


2. APPLICANT:
(a) NAME: M/S. INDOCO REMEDIES LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956.
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East),
Mumbai - 400 098. Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:

The following specification particularly describes the invention and the manner in which it is to be performed.


TECHNICAL FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical formulations comprising candesartan cilexetil and to a process for the preparation thereof.
BACKGROUND OF THE INVENTION
Cardiovascular diseases (CVD) are the main cause of death for both males and females in the United States, Europe, Canada and other technologically advanced countries of the world. It is also in the top five causes of death in lesser-developed countries. Diseases of the cardiovascular system include those that compromise the pumping ability of the heart, hypertension, failure of the valves, inflammation of the heart muscle and/or the tissue surrounding it, or narrowing or hardening of the arteries.
Hypertension or high blood pressure occurs when the force of blood passing through blood vessels is above normal. This increase in the pressure forces the blood to hit the blood vessel walls. Consistently high blood pressure can increase no. of other complications like atherosclerosis, stroke, heart attack and may also lead to heart and kidney failure; necessitating the inclusion of drugs like Diuretics, Beta blockers, Calcium channel blockers, ACE inhibitors, Angiotensin II receptor blockers, vasodilators, centrally-acting anti-hypertensives, Alpha blockers.
Angiotensin II is formed from Angiotensin I in a reaction catalyzed by angiotensin-converting enzyme. It is a very potent chemical that causes the muscles surrounding the blood vessels to contract, which thereby narrows the blood vessels. This narrowing increases the pressure within the vessels and can cause high blood pressure (hypertension). Angiotensin receptor blockers (ARBs) block the action of angiotensin II. As a result, the blood vessels dilate and the blood pressure is reduced. The lower blood pressure makes it easier for the heart to pump blood and can improve heart failure. In addition, the progression of kidney disease due to high blood pressure is slowed.
Today, numerous angiotensin II receptor blockers are available in the market; few examples of which include Candesartan, Irbesartan, Losartan, Valsartan, Eprosartan, Olmesartan and Telmisartan.
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Candesartan Candesartan Cilexetil

Candesartan is a useful therapeutic agent approved in USA, Europe, Canada and many other countries for the treatment of hypertension and heart failure in patients with left ventricular systolic dysfunctions. Owing to its poor solubility when administered orally, it has been developed as a prodrug (i.e. candesartan cilexetil) which rapidly hydrolyzes to candesartan during absorption from the gastrointestinal tract. Even though Candesartan cilexetil is a racemic mixture containing one chiral centre; it undergoes hydrolysis at the ester link to form the active drug (i.e. candesartan) which is achiral.

Desethyl Candesartan
It has been disclosed by most of the inventors in the prior art that candesartan cilexetil alone is stable at room temperature; however, when it is formulated into the dosage form like tablet with various excipients, it degrades over time. This degradation leads to the generation of no. of impurities like methyl candesartan, ethyl candesartan, desethyl candesartan, benzimidazole, n-trityl candesartan and n-trityl cilexetil candesartan. Although the reason for this impurity generation is not exactly known; however, it is speculated that this might be due to friction, abrasion, heat and compression forces generated or exposure to moisture, humidity, elevated pressure and light during formulation. Further, it might be mentioned that Health Authorities all over the world are very concerned about the level of impurities and degradation products present either in
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the drug substance or the final dosage form. Thus, attempts have been made by the formulators to prepare a stable candesartan cilexetil composition wherein the level of degradation products is well below the permissible limit. To name a few, US Pat. No. 5,534,534 by Makino et al covers a pharmaceutical composition comprising angiotensin II blockers and oily substances having lower melting point of 20°C to 60 °C. Makino et al claims that the inclusion of the oily substance gives stable candesartan cilexetil formulation. Singh et al in patent publication no. WO 2005084648 Al covers the stable
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pharmaceutical composition comprising an effective amount of candesartan cilexetil and one or more polymers like maltodextrin, polyvinyl alcohol or xanthan gum. Additionally, Singh et al in patent publication no. WO 2005070398 A2 claims a stable pharmaceutical composition of candesartan cilexetil and one or more co-solvents like propylene glycol, polyethylene alcohol, ethanol, glycerin etc. Patent publication no. WO 2006122254 A2 by Kurgan et al discloses stable Form I of candesartan cilexetil which is of fine particle size.
Further, in their endeavor to prepare a stable Candesartan cilexetil oral pharmaceutical composition, the present inventors have surprisingly found that indeed such a stable pharmaceutical composition can be prepared by incorporation of light liquid paraffin or Polyethylene glycol 100-400 in the formulation. The formulations prepared by using the light liquid paraffin or Polyethylene glycol 100-400 were found to exhibit superior stability with the quantity of desethyl candesartan and other impurities generated much below the permissible limits even after exposure to the more stringent conditions i.e. 50 °C /75 % RH (as against 40 ° C/75 % RH, which is used in the prior art);
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to stable pharmaceutical composition by the inventors that can be prepared by incorporation of light liquid paraffin or polyethylene glycol 100-400 in the formulation.
Thus, in the first embodiment, the invention provides a novel, stable oral pharmaceutical composition of candesartan cilexetil.
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In the second embodiment, the invention provides a novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil and wherein the stability is maintained by using light liquid paraffin or polyethylene glycol 100-400 along with other suitable excipients.
In the third embodiment, the invention provides a novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil and wherein the stability is maintained even after exposure to stringent conditions during formulation like 50°C/75%, friction, abrasion, heat and compression forces by using light liquid paraffin or polyethylene glycol along with other suitable excipients.
In the fourth embodiment, the invention provides a novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil and wherein the stability is with regard to the level of impurities like methyl candesartan, ethyl candesartan, desethyl candesartan, benzimidazole, n-trityJ candesartan and n-trityl cilexetil candesartan.
In the fifth embodiment, the invention provides the process for the preparation of novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil.
Further, the light liquid paraffin which is being included in the proposed composition is a hydrocarbon with 15-40 carbon atoms and has the boiling point above 200 °C.
PEG 100, 200, 300, 400 are low molecular weight grades of Polyethylene glycol which can be used effectively for the stabilization of candesartan cilexetil in the formulation. However, more preferable is PEG. 400 (Polyethylene Glycol 400) which due to its low toxicity, as compared to higher molecular weight Polyethylene glycol (1000-6000; which are associated with the carcinogenic potential) is widely used in a variety of pharmaceutical formulations. It is strongly hydrophillic and has the melting point of 4-8 °C
Candesartan cilexetil, which is used in the present invention, is a prodrug, which rapidly hydrolyzes to candesartan during absorption from the gastrointestinal tract. The dose of candesartan cilexetil administered to the patients may be between 1-50 mgs or more particularly, it may be between about 2 mg to 40 mg. However, the exact dose to be given
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to the patient to get the intended therapeutic effect may vary depending upon the weight, age, sex of the patient.
The pharmaceutical compositions of candesartan cilexetil in combination with PEG 100-400 or light liquid paraffin along with other pharmaceutical excipients are preferably given orally in the form of tablet or capsule; however, the tablet dosage form are more preferred.
The various excipients that could be employed for the preparation of the oral dosage forms are disintegrants, fillers, binders, glidants, surfactants and lubricants.
The pharmaceutical composition of candesartan cilexetil can be prepared in tablet dosage form by the methods known in the art like direct compression, wet granulation or dry granulation.
Thus, in one aspect of the invention, the tablets are prepared by blending the candesartan cilexetil and light liquid paraffin or PEG 100-400, with all the excipients like filler, diluent, glidant, disntegrant and lubricating the blend and compressing the lubricated blend.
In another aspect of the invention, the tablets are prepared by mixing the candesartan cilexetil and light liquid paraffin or PEG 100-400, filler, diluent, disntegrant and granulating it with the binder solution; drying the granules, sizing and lubricating and compressing the lubricated granules.
In yet another aspect of the invention, the tablets are prepared by blending the candesartan cilexetil and light liquid paraffin or PEG 100-400, filler, diluent, glidant, disntegrant, passing it through roller compactors to get flakes, milling the flakes to attain granules which are then lubricated and finally compressing the granules.
The disintegrant that can be used is selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose,
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macrocrystalline cellulose, polyacrilin potassium, powdered cellulose, pregelatinized starch, sodium or calcium alginate and starch.
The filler that can be used in the present invention is selected from calcium carbonate, calcium sulfate, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil (type I), kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate.
The binder that can be used in the present invention is selected from acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcelluiose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminaum silicate, maitodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, corn starch, and zein.
The surfactant is selected from anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide).
The lubricant is selected from stearate acid metal salt (magnesium stearate or calcium stearate), stearic acid, sodium lauryl sulfate, sodium lauryl magnesium, powdered gum arabic, carnauba wax, anhydrous silicic acid, magnesium oxide, silic acid hydrate, boric acid, fatty acid sodium salt and leucine.
Optionally, the composition may further comprise a coloring agent.
Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention.
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Example 1: Candesartan Cilexetil (16 mg) Tablets prepared and stabilized using
PEG 400
S.No Ingredients Quantity
(wt/tablet) mg
1. Candesartan Cilexetil 16
2. Lactose monohydrate 37
3. Cornstarch 115
4. Hydroxy propyl cellulose 6
5. Crospovidone 14
6. PEG 400 10
7. Magnesium stearate 1.8
8. Ferric oxide 0.2
Procedure:
a. Candesartan cilexetil, lactose monohydrate and corn starch were dry mixed in
rapid mix granulator.
b. PEG 400 and hydroxyl propyl cellulose were dissolved in water.
c. Dry mix was granulated with the solution of step b in RMG.
d. The wet granules were then dried in a vacuum drier, passed through the sieve and
subjected to sizing.
e. Crosspovidone and ferric oxide were added to the granules of step d after passing
it through sieve.
f. Finally, magnesium sterate was added after passing it through sieve, mixed with
the blend of step e and compressed to get tablets.
Example 2: Candesartan Cilexetil (16 mg) Tablets prepared and stabilized using PEG 400

S.No Ingredients Quantity
(wt/tablet) mg
1. Candesartan Cilexetil 16
2. Lactose 78.4
3. Pregelatinised starch 50
4. Povidone 9
5. PEG 400 10
6. Aerosil 2
7. Ac-di-sol 14.
8. Talc 4
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9. Sodium starch glycolate 14
10. Sodium stearyl fumarate 2
11. Ferric oxide 0.6
Procedure:
a. Candesartan cilexetil and PEG 400 were dispersed in water.
b. Lactose, Pregelatmised starch and Povidone were mixed in rapid mix granulator
and granulated with dispersion of step a.
c. The wet granules were then dried in a vacuum drier, passed through the sieve and
subjected to sizing.
d. Talc, aerosil, ac-di-sol, sodium starch glycolate and ferric oxide were blended
with granules obtained from step c.
e. Finally, Sodium stearyl fumarate was added after passing it through sieve with the
blend of step d; mixed and compressed to get tablets.
Example 3: Candesartan Cilexetil (4 mg) Tablets prepared and stabilized using PEG 100

S.No Ingredients Quantity (wt/tablet) mg
1. Candesartan Cilexetil 4
2. Microcrystalline cellulose 19.6
3. Pregelatmised starch 12.5
4. Povidone 2.25
5. PEG 100 2.5
6. Aerosil 0.5
7. Ac-di-sol 3.5
8. Talc 1
9. Polycrylline Potassium 3.5
10. Sodium stearyl fumarate 0.5
11. Ferric oxide 0.15
Procedure:
f. Candesartan cilexetil and PEG 100 were dispersed in water.
g. Microcrystalline cellulose, pregelatinised starch and povidone were mixed in rapid
mix granulator and granulated with dispersion of step a.
h. The wet granules were then dried in a vacuum drier, passed through the sieve and subjected to sizing.
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i. Talc, aerosil, ac-di-sol, polycrylline potassium and ferric oxide were blended with
granules obtained from step c. j. Finally, Sodium stearyl fumarate was added after passing it through sieve with the
blend of step d; mixed and compressed to get tablets.
Example 4: Candesartan Cilexetil (8 mg) Tablets prepared and stabilized using PEG
200
S.No Ingredients Quantity
(wt/tabiet) mg
1. Candesartan Cilexetil 8
2. Microcrystalline cellulose 76
3. Povidone 3
4. PEG 200 5
5. Sodium starch glycolate 7
6. Sodium stearyl fumarate 0.9
7. Ferric oxide 0.1
Procedure:
a. Candesartan cilexetil, microcrystalline cellulose and povidone were dry mixed in
rapid mix granulator.
b. PEG 200 was dissolved in water.
c. Dry mix comprising candesartan cilexetil, microcrystalline cellulose and povidone
was granulated with the solution obtained from step b in rapid mixer granulator.
d. The wet granules were then dried in a vacuum drier, passed through the sieve and
subjected to sizing.
e. Sodium starch glycolate and ferric oxide were added to the granules of step d after
passing it through sieve.
f. Finally, sodium stearyl fumarate was added after passing it through sieve, mixed
with the blend of step e and compressed to get tablets.
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Example 5: Candesartan Cilexetil (16 mg) Tablets prepared and stabilized using Light liquid paraffin
S.No Ingredients Quantity
(wt/tablet) mg
1. Candesartan Cilexetil 16
2. Lactose monohydrate 46
3. Maize starch 115
4. Hydroxy propyl cellulose 6
5. Crospovidone 14
6. Light liquid paraffin 0.8
7. Magnesium stearate 1.8
8. Ferric oxide 0.4
Procedure:
a. Lactose monohydrate, maize starch and hydroxy propyl cellulose were dry mixed
in rapid mix granulator.
b. Dry mix was granulated with water, dried and sized.
c. Candesartan cilexetil was blended with light liquid paraffin in a stainless steel
vessel.
d. The granules obtained from step b were mixed with Candesartan cilexetil-Iight
liquid paraffin blend obtained from step c.
e. Crosspovidone and ferric oxide were added to the granules of step d after passing
it through sieve.
f. Finally, magnesium stearate was added after passing it through sieve, mixed with
the blend of step e and compressed to get tablets.
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Example 6: Candesartan Cilexetil (32mg) Tablets prepared and stabilized using Light liquid paraffin
S.No Ingredients Quantity
(wt/tablet) mg
1. Candesartan Cilexetil 32
2. Microcrystalline cellulose 100
3. Lactose 222
4. Light liquid paraffin 1.6
5. Povidone 12
6. Sodium starch glycolate 28
7. Sodium stearyl fumarate 3.6
8. Ferric oxide 0.8
Procedure:
a. Lactose monohydrate, povidone and microcrystalline cellulose were dried mixed
in rapid mix granulator.
b. Water was added to the dry mix obtained in step a and granulated.
c. Candesartan cilexetil was blended with light liquid paraffin in a stainless steel
vessel.
d. The granules obtained from step b were blended with Candesartan cilexetil-light
liquid paraffin blend obtained from step c.
e. Sodium starch glycolate and ferric oxide were added to the granules of step d after
passing it through sieve.
f. Finally, sodium stearyl fumarate was added after passing it through sieve, mixed
with the blend of step e and compressed to get tablets.
Further, using the tablets obtained from example 1 and 4, the effect in assay and the level of impurities on utilizing light liquid paraffin and polyethylene glycol 400 was studied. The results were compared with the assay and the level of impurities obtained from the formulations disclosed in the prior art. These are summarized in Table I.
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Table 1: Comparative stability data of Candesaratan Cilexetil tablets

Impurities Batch with PEG 400 (as example 1) Batch with Light liquid paraffin (as example 4) Results as disclosed in WO2005084648 which utilize maltodextrin as stabilizer Results as disclosed in WO2005070398 which utilizes cosolvents like propylene glycol as stabilizer
Initial 1 M
at
R.T 1M at
50°C/
75% Initial 1 M
at
R.T 1M
at
50°C/ 75% Initial 1M at
40°C/ 75% Initial 1M at
40°C/ 75%
Methyl candesartan 0.000 0.000 0.000 0.000 0.000 0.000 ND ND ND ND
Ethyl candesartan 0.058 0.057 0.058 0.067 0.068 0.070 ND ND ND ND
Desethyl
candesartan
cilexetil 0.122 0.124 0.202 0.028 0.030 0.040 0.152 0.398 0.073 0.238
Benzimidazole 0.000 0.000 0.000 0.000 0.000 0.000 ND ND ND ND
Methoxy
analogueof
candesartan 0.000 0.000 0.023 0.000 0.000 0.000 ND ND ND ND
N-trityl candesartan 0.000 0.000 0.000 0.000 0.000 0.000 ND ND ND ND
N-Tryetyl
candeandesartan
cilexetil 0.000 0.000 0.000 0.000 0.000 0.000 ND ND ND ND
Total unknown 0.107 0.107 0.264 0.146 0.146 0.198 ND ND ND ND
Total impurities 0.287 0.288 0.547 0.241 0.244 0.308 0.949 2.238 0.652 0.874
1 M: After 1 month R.T: Room Temperature ND: Not disclosed
The formulations prepared by using the light liquid paraffin or Polyethylene glycol 400 were found to exhibit superior stability. The quantity of desethyl candesartan and other impurities generated were much below the permissible limits even after exposure to the more stringent conditions i.e. 50 °C /75 % RH (as against 40 ° C/75 % RH, which is used in the prior art) and thus, the use of PEG 400 and light liquid paraffin clearly showed a stabilizing effect on candesartan cilexetil.
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We Claim,
1. A novel, stable pharmaceutical composition comprising an effective amount of candesartan cilexetil and a stabilizing agent selected from light liquid paraffin or polyethylene glycol 100-400.
2. A novel pharmaceutical composition of claim 1, wherein polyethylene glycol 100-400 is selected from polyethylene glycol 100, 200, 300 or 400.
3. A novel pharmaceutical composition of claim 1, wherein stabilizing agent selected from light liquid paraffin or polyethylene glycol 100-400 is used either alone or in combination with each other.
4. A novel pharmaceutical composition according to claim 1, wherein the stability is maintained even after exposure to stringent conditions during formulation like 50°C/75%, friction, abrasion, heat and compression forces by using light liquid paraffin or polyethylene glycol along with other suitable excipients.
5. A novel pharmaceutical composition according to claim 1, wherein the stability is with regard to the level of desethyl candesartan in the formulation even after exposure to stringent conditions.
6. A novel pharmaceutical composition according to claim 1, wherein the stability is further with regard to the level of impurities like methyl candesartan, ethyl candesartan, benzimidazole, n-trityl candesartan and n-trityl cilexetil candesartan in the formulation even after exposure to stringent conditions.
7. A novel pharmaceutical combination composition of claim 1, wherein the suitable dosage form is oral tablet.
8. A novel pharmaceutical combination composition of claim I; wherein the composition further contains suitable pharmaceutical excipients.
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9. A novel pharmaceutical composition according to claim 1 and 8, wherein suitable pharmaceutical excipients are selected from disintegrants, fillers, binders, surfactants and lubricants.
10. The process for the preparation of novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil.