WO2005070398A2

WO2005070398A2 - Pharmaceutical compositions of candesartan cilexetil stabilized with co-solvents

Info

Publication number: WO2005070398A2
Application number: PCT/IB2005/000156
Authority: WO
Inventors: Romi Barat Singh; Girish K. Karanth; Vishnubhotla Naga Prasad
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-01-23
Filing date: 2005-01-21
Publication date: 2005-08-04
Also published as: WO2005070398A8; WO2005070398A3

Abstract

The present invention relates to stable pharmaceutical compositions that include candesartan cilexetil and one or more co-solvents.

Description

PHARMACEUTICAL COMPOSITIONS OF CANDESARTAN CILEXETIL STABILIZED WITH CO-SOLVENTS Technical Field of the Invention The present invention relates to stable pharmaceutical compositions of candesartan cilexetil. Background of the invention In the field of therapy of hypertension, angiotensin II receptor antagonists have attracted attention as an effective agent for the therapy of hypertension following administration of angiotensm I converting enzyme (ACE) inhibitors. Candesartan is a selective ATi subtype angiotensin II receptor antagonist. Candesartan cilexetil is a prodrug and is hydrolyzed to candesartan during absorption from the gastrointestinal tract. It falls in the class of benzimidazole -7- carboxylic acid and its derivatives. These agents exhibit a strong and more effective hypotensive action and are less likely to cause coughing as a side effect as compared to other classes of ACE inhibitors. Candesartan cilexetil has low aqueous solubility because it is hydrophobic in nature.

The low bio availability of hydrophobic drags with extremely low water solubility can be a serious problem. Different approaches have been taken to achieve a desired level of drug solubility and dissolution rate. These approaches have been based on preparations with increased surface area (micronised powders), molecular inclusion complexes (cyclodextrines and derivatives), co-precipitates with water-soluble polymers (PEG, poloxamers, PNP, HPMC) and non-electrolytes (urea, mannitol, sugars, etc.), micellar solutions in surfactant systems (Cremophor™, Tween™, Gellucires™), and multilayer vesicles (liposomes and niosomes). Dispersed colloidal vehicles, such as oil-in-water, water-in-oil and multiple (O/W/O or W/O/W) emulsions, microemulsions and self-emulsifying compositions also have been used to improve bio availability of poorly soluble molecules. None of these approaches has provided the efficiency for selected cases for bioavailability improvement of immediate drug release formulations. Candesartan is stable against temperature, moisture and light when it is alone in the solid state. However, when candesartan is prepared into tablets with other ingredients it has been observed that the content of the active ingredient diminishes over time. U.S. Patent No. 5,534,534 discloses that the reduction in the content of the candesartan cilexetil with the lapse of time in pharmaceutical compositions can be reduced by incorporating oily substances having a low melting point in these compositions. This oily substance is incorporated into the active component to form a stable composition in which decomposition with time caused by compression can be suppressed. Thus is described as resulting in a stable composition in which the crystalline disorder is minimized. Summary of the Invention In one general aspect there is provided a stable pharmaceutical composition for oral administration. The pharmaceutical composition includes a therapeutically effective amount of candesartan cilexetil and one or more co-solvents. Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the co-solvent may include one or more of propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, polyethylene glycol esters and mixtures thereof. The concentration of co-solvent maybe between 1% to 10% w/w of the total weight of the composition. The pharmaceutical composition may further include one or more fatty acid esters, one or more surfactants and other pharmaceutically acceptable excipients. The fatty acid ester be one or more of glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glycerol oleate, glycerol linoleate, glyceryl lauropalmitoleate and mixtures thereof. The surfactant may be one or more of sodium lauryl sulphate, poloxamer, and Polysorbate 80. The other pharmaceutically acceptable excipients may be one or more of filler, binder, disintegrant, lubricant, coloring and flavoring agent. The filler may be one or more of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose, and mixtures thereof. The binder may be one or more of methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof. The disintegrant may be one or more of calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof. The lubricant may be one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof. The stable pharmaceutical composition may include one or more fatty acid esters present in the range of 0.5% to 5% w/w and one or more surfactants present in the range of 0.1%) to 2% w/w of the total weight of the composition. The stable pharmaceutical composition may be a tablet coated with one or more functional and/or non-functional layers that include a coating composition. The coating composition may be a film forming polymer and polyethylene glycol. The film forming polymer may be present in a concentration of 25-90% by weight of the coating composition. The polyethylene glycol may be present in a concentration of 10-75% by weight of the coating composition. The coating composition may further include other coating additives including plasticizers, coloring agents, gloss producers and lubricants/glidants. In another general aspect there is provided a process for the preparation of a stable pharmaceutical composition of candesartan cilexetil. The process includes the steps of: a) dispersing candesartan cilexetil in a solution comprising a co-solvent in water to form a dispersion; b) granulating a blend of diluents and disintegrant with the dispersion; c) optionally further granulating with a binder solution; d) lubricating the granules of step b) or step c); and e) compressing the lubricated granules into tablets. Embodiments of the process may include one or more of the features described above or the following. For example, the process may further include coating the tablets with a coating composition that includes a film forming polymer and polyethylene glycol. In another general aspect there is provided a method of treating a condition for which candesartan cilexetil is indicated. The method includes administering a pharmaceutical composition comprising a therapeutically effective amount of candesartan cilexetil and one or more co-solvents. Embodiments of the method may include one or more of the features described above. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention The present invention is directed to candesartan cilexetil pharmaceutical compositions that include a mixture of fatty acid glycerides with a surfactant and a co-solvent. The present invention provide pharmaceutical compositions of candesartan cilexetil which are not only stable but also achieve the same rate (Cmax) and extent of absorption (AUC) from the gastrointestinal tract as that achieved by the commercially available formulation of candesartan sold under the trade name "ATACAND". The pharmaceutical compositions can be administered for treatment of hypertension or any other condition for which candesartan cilexetil is indicated (i.e., beneficial). Since candesartan cilexetil has low water solubility the use of a co-solvent improves its bioavailability by increasing its solubility and dissolution rate in aqueous solutions. The co-solvent can be selected from, for example, propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, polyethylene glycol esters and mixtures thereof. Polyethylene glycol in the formulation serves the dual purpose of acting as enhancer for the absorption of candesartan and as plasticizer in the coating layer. Various authors have described the enhancement mechanism of polyethylene glycol. For example, according to Hugger et al (Hugger, E. D., Kenneth L. A., Ronald T. B., Journal of Pharmaceutical Sciences, Vol. 91, No. 9, September 2002, pp. 1980-1990) PEG 300 is capable of inhibiting efflux transporter activity mediated by p-glycoprotein. Similarly, Johnson et al (Johnson, B. M., Charman, W. N., and Porter, C. J. H., AAPS PharmSci 2002; 4(4), pp. 1-13) studied the effect of PEG 400 and other excipients on p-glycoprotein mediated efflux of certain drugs. Thereby the formulation is stable due to stabilizer present in the core and bioequivalent due to the polyethylene glycol present in the coating layer. Polyethylene glycol may be present alone or in combination with one or more other plasticizers and it may be present in a concentration of 10-75%) by weight of the coating composition. The term "candesartan cilexetil" used herein refers to a prodrug that is hydrolyzed to candesartan during absorption from the gastrointestinal tract. The term "therapeutically effective amount" used herein refers to a nontoxic but sufficient amount of the agent to provide the desired effect. The term "co-solvent" relates to a substance that is miscible with water and gastrointestinal fluid and increases the solubility and dissolution rate of candesartan cilexetil in aqueous solutions and gastrointestinal fluids. Examples of co-solvents include propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, polyethylene glycol esters and mixtures thereof. The term "stable" as used herein refers to a negligible reduction in the content of active ingredient with the lapse of time. Examples of fatty acid esters include glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glyceryl caprylate/caprate, glycerol oleate, glycerol linoleate, glyceryl lauropalmitoleate or mixtures thereof. Examples of surfactants include sodium lauryl sulphate, poloxamer, Polysorbate 80 Cremophor and the like. The composition may contain one or more pharmaceutically acceptable excipients in addition to candesartan cilexetil, the fatty substance, the surfactant and the co-solvent. The term "other pharmaceutically acceptable excipient" refers to ingredients of the composition, excluding the active drug substance. Examples of other pharmaceutically acceptable excipients as used herein include fillers, binders, disintegrants, lubricants, glidants, colors and the like. The fillers can be selected from one or more of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized and the like. Examples of binders include one or more of methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like. Examples of dismtegrants include one or more of calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like. Examples of lubricants and glidants include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like. The coloring agents of the present invention may be selected from any FDA approved colors for oral use. Candesartan cilexetil can be present in the range of 2% to 35% w/w and most particularly about 3% to about 30% w/w, based on the total weight of the composition. The co-solvent can be present in the range of 1 to 10% w/w. Propylene glycol can be present in the range of 1% to 10% w/w and more particularly from about 1% to about 5% w/w, based on the total weight of the composition. The fatty acid esters can be present in the range of 0.5% to 10% w/w and more particularly from about 1% to about 5% w/w, based on the total weight of the composition. The surfactant can be present in the range of 0.1% to 2% w/w and more particularly from about 0.2% to about 1% w/w, based on the total weight of the composition. The pharmaceutical composition can be prepared by processes known in the art such as wet granulation, dry granulation or direct compression and the final dosage form may be in the form of tablets, capsules, or other suitable dosage form. In one of the embodiments candesartan cilexetil tablet may be prepared by dispersing candesartan cilexetil, Polysorbate 80 and Glyceryl caprate in a solution of propylene glycol in water; adding this drug dispersion to lactose, microcrystalline cellulose and calcium carboxymethyl cellulose by spraying and making granules; drying the granules; sizing the granules; lubricating the granules; and compressing the lubricated granules. The tablets prepared by the present invention may be coated with one or more additional layers using a coating composition that include film forming agents and/or pharmaceutically acceptable excipients. The coating composition may further include other coating additives such as plasticizers, coloring agents, gloss producers and lubricants/glidants. The coating composition may include another plasticizer in combination with polyethylene glycol. The plasticizer may be selected, for example, from one or more of diethyl phthalate, dibutyl phthalate, triethyl citrate, and other suitable plasticizers. The coating layers over the tablet may be applied as a solution/dispersion of coating ingredients using any conventional technique known in the art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, and the like. Examples of solvents used for preparing a solution/dispersion of the coating ingredients include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof. Example of film forming agents include ethyl cellulose, hydroxypropyl rnethylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate, waxes such as polyethylene glycol, methacrylic acid polymers such as Eudragit ® RL and RS, and the like and mixture thereof. Alternatively, commercially available coating compositions comprising film- forming polymers marketed under various trade names, such as Opadry®, may also be used for coating. hi one of the embodiments candesartan cilexetil tablet may be prepared by dispersing candesartan cilexetil, Polysorbate 80 and Glyceryl caprate in a solution of propylene glycol in water; adding this drug dispersion to lactose, microcrystalline cellulose and calcium carboxymethyl cellulose by spraying and making granules; drying the granules; sizing the granules; lubricating the granules; compressing the lubricated granules into tablets; coating the tablets with a dispersion of a film forming polymer, polyethylene glycol, titanium dioxide and talc. In one embodiment, the stable pharmaceutical composition includes a therapeutically effective amount of candesartan cilexetil, fatty acid esters, surfactant and a co-solvent. The concentration of candesartan cilexetil is in the range of 2% to 35% w/w, fatty acid ester is in the range of 0.5% to 5% w/w, surfactant is in the range of 0.1% to 2% w/w and propylene glycol is in the range of 1% to 10% w/w of the total weight of the composition. In another embodiment, the stable pharmaceutical composition includes a therapeutically effective amount of candesartan cilexetil and propylene glycol. The composition achieves the same rate (Cmax) and extent of absorption (AUC) from the gastrointestinal tract as that achieved by its commercially available formulation of candesartan sold under the trade name "ATACAND" by AstraZeneca. In another embodiment, the stable pharmaceutical composition for oral administration includes a therapeutically effective amount of candesartan cilexetil, fatty acid esters, surfactant and a co-solvent. The composition achieves the same rate (Cmax) and extent of absorption (AUC) from the gastrointestinal tract as that achieved by its commercially available formulation of candesartan sold under the trade name "ATACAND" by AstraZeneca. The following examples are illustrative of the invention, and are not intended to be construed as limiting the invention.

EXAMPLE 1

PROCEDURE: 1. Candesartan cilexetil, Polysorbate 80 and Glyceryl caprate are dispersed in a solution of propylene glycol in water. 2. Povidone K-30 is dissolved in water separately. 3. Lactose, microcrystalline cellulose, and calcium carboxymethyl cellulose are mixed in a high shear mixer and granulated with the dispersion of Step 1 and Step 2. 4. The wet granules are dried in a fluid bed drier, passed through a screen, and sized. 5. The extragranular calcium carboxymethyl cellulose is passed through a screen and blended with the granules of step 4. 6. The magnesium stearate is passed through a screen, blended with the blend of step 5 and compressed into tablets. EXAMPLE 2

PROCEDURE: 1. Candesartan cilexetil and Glyceryl caprylate are dispersed in a solution of propylene glycol in water. 2. Povidone K 30 is dissolved in water separately. 3. Lactose, microcrystalline cellulose, and calcium carboxymethyl cellulose are mixed in a high shear mixer and granulated with the dispersion of Step 1 and Step 2. 4. The wet granules are dried in a fluid bed drier, passed through a screen, and sized. 5. The extragranular calcium carboxymethyl cellulose is passed through a screen and blended with the granules of step 4. 6. The magnesium stearate is passed through a screen, blended with the blend of step 5, and compressed into tablets.

In vitro dissolution study In vitro release of candesartan cilexetil from tablets as per the compositions of Examples 1 and 2 were studied in 900 ml, pH 6.8 Phosphate buffer and 0.35% polysorbate- 20, using USP apparatus - II, at 50 rpm. The results are listed in Table 1. Table 1. In vitro release of candesartan cilexetil from tablets

In Vivo Bioavailability Study In vivo performance of candesartan cilexetil from tablets prepared as per the composition of Example 1 were evaluated with respect to the ATACAND in 15 healthy male volunteers under fasting condition. The study protocol followed was open randomized, three treatment, three period, three sequence and single dose crossover study on candesartan cilexetil under fasting condition with a wash out period of at least 4 days. Pharmacokinetic parameters C_max (Maximum plasma concentration), AUCo-_t (Area under the plasma concentration vs. time curve from 0 hours to the time of last sample collected) and AUCo-oc (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. The results of the study are given in Table 2.

Table 2. Comparative pharmacokinetic data for tablets of candesartan cilexetil tablet and ATACAND® tablet

The tablets of Example 1 demonstrate a comparable extent of absorption when compared to the reference ATACAND. The use of a co-solvent shows a stabilizing effect on candesartan cilexetil. Table 3 shows comparative stability data at various intervals (40°C/75%RH) with reference to the amount of desethyl candesartan and total related substances found. Table 3. Comparative stability data at various intervals (40°C/75%RH) with reference to the amount of desethyl candesartan and total related substances

Table 3 clearly indicates that the use of a co-solvent stabilizes the candesartan cilexetil compositions. EXAMPLE 3

PROCEDURE:

1. Propylene glycol and Polysorbate 80 are mixed with a part of the purified water to form a clear solution.

2. Candesartan cilexetil and Glyceryl caprate are dispersed in the above solution. 3. Povidone K 30 is dissolved in water separately and mixed with the above drug dispersion.

4. Lactose, microcrystalline cellulose, and calcium carboxymethyl cellulose are mixed in a high shear mixer and granulated with the above dispersion.

5. The wet granules are dried in a fluid bed drier, passed through a screen, and then sized.

6. The extragranular calcium carboxymethyl cellulose is passed through a screen and blended with the granules of step 5.

7. The magnesium stearate is passed through a screen, blended with the blend of step 6, and compressed into tablets. 8. Ingredients of the coating composition are dispersed in water and coated on the above tablets.

In vitro dissolution study In vitro release of candesartan cilexetil from tablets as per the composition of Example 3 were studied in 900 ml, pH 6.8 Phosphate buffer and 0.35% polysorbate-20, using USP apparatus - II, at 25 and 50 rpm. The results are provided in Table 4.

Table 4. In vitro release of candesartan cilexetil from tablets

While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

Claims

WE CLAIM: 1. A stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of candesartan cilexetil and one or more co-solvents. 2. The stable pharmaceutical composition according to claim 1 wherein the co-solvent comprises one or more of propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, polyethylene glycol esters and mixtures thereof. 3. The stable pharmaceutical composition according to claim 1 wherein the concentration of co-solvent comprises between 1% to 10% w/w of the total weight of the composition. 4. The stable pharmaceutical composition according to claim 1 wherein the pharmaceutical composition further comprises one or more fatty acid esters, one or more surfactants and other pharmaceutically acceptable excipients. 5. The stable pharmaceutical composition according to claim 4 wherein the fatty acid ester comprises one or more of glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glycerol oleate, glycerol linoleate, glyceryl lauropalmitoleate and mixtures thereof. 6. The stable pharmaceutical composition according to claim 4 wherein the surfactant comprises one or more of sodium lauryl sulphate, poloxamer, and Polysorbate 80. 7. The stable pharmaceutical composition according to claim 4 wherein the other pharmaceutically acceptable excipients comprises one or more of filler, binder, disintegrant, lubricant, coloring and flavoring agent. 8. The stable pharmaceutical composition according to claim 7 wherein the filler comprises one or more of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose, and mixtures thereof. 9. The stable pharmaceutical composition according to claim 7 wherein the binder comprises one or more of methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof. 10. The stable pharmaceutical composition according to claim 7 wherein the disintegrant comprises one or more of calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof. 11. The stable pharmaceutical composition according to claim 7 wherein the lubricant comprises one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof. 12. The stable pharmaceutical composition according to claim 4 comprising one or more fatty acid esters present in the range of 0.5% to 5% w/w and one or more surfactants present in the range of 0.1 % to 2% w/w of the total weight of the composition. 13. The stable pharmaceutical composition according to claim 1 wherein the pharmaceutical composition comprises a tablet, the tablet being coated with one or more functional and/or non-functional layers comprising a coating composition. 14. The stable pharmaceutical composition according to claim 13 wherein the coating composition comprises a film forming polymer and polyethylene glycol. 15. The stable pharmaceutical composition according to claim 14 wherein the film forming polymer comprises a concentration of 25-90% by weight of the coating composition. 16. The stable pharmaceutical composition according to claim 14 wherein the polyethylene glycol comprises as a concentration of 10-75% by weight of the coating composition. 17. The stable tablet according to claim 14 wherein the coating composition further comprises other coating additives comprising plasticizers, coloring agents, gloss producers and lubricants/glidants. 18. A process for the preparation of a stable pharmaceutical composition of candesartan cilexetil, the process comprising the steps of: a) dispersing candesartan cilexetil in a solution comprising a co-solvent in water to form a dispersion; b) granulating a blend of diluents and disintegrant with the dispersion; c) optionally further granulating with a binder solution; d) lubricating the granules of step b) or step c); and e) compressing the lubricated granules into tablets. 19. The process according to claim 18 further comprising coating the tablets with a coating composition comprising a film forming polymer and polyethylene glycol. 20. A method of treating a condition for which candesartan cilexetil is indicated, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of candesartan cilexetil and one or more co-solvents..