FIELD OF THE INVENTION
The present invention relates to candesartan cilexetil particles having d(0.9) value of less than about 15 microns and d(0.5) value of less than about 6 microns. It, further, relates to a pharmaceutical composition comprising the said particles.
BACKGROUND OF THE INVENTION
Many orally-administered drugs display poor bioavailability when administrated in conventional dosage forms. With several drugs, absorption may be as little as 30% or less of the orally administered dose. To compensate for this effect, a very large dose is often administered so that absorption of the therapeutically required quantity of the drug can occur. This technique may prove costly with expensive drugs, and the non-absorbed drug may also have undesirable side effects within the gastrointestinal tract. In addition, the poorly absorbed drugs often display a great deal of variability between patients in bioavailability, and this can create dosing problems. This poor bioavailability is often associated with poor solubility of drugs. There are various techniques available to overcome solubility and bioavailability problem, and one such viable technique is particle size reduction.
Candesartan is commercially available for oral administration in two forms - candesartan alone and in combination with hydrochlorothiazide and is indicated for the treatment of hypertension. EP0750982 discloses candesartan generically as well as specifically. EP0782852 or EP0546358 disclose 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.
SUMMARY OF THE INVENTION
In the present invention, we have found out that the particle size of candesartan cilexetil is an important parameter to achieve the desired bioavailability. The present invention relates to candesartan cilexetil particles having d(0.9) value of less than about 15 microns and d(0.5) value of less than about 6 microns and pharmaceutical composition thereof.
Hence, according to one of the aspects, there is provided candesartan cilexetil particles having d(0.9) value of less than about 15 microns.
In another aspect, there is provided candesartan cilexetil particles having d(0.9) value of less than about 15 microns and d(0.5) value of less than about 6 microns.
In another aspect, there is provided a process of preparation of candesartan cilexetil particles by wet milling or dry milling technique wherein the particles have d(0.9) value of less than about 15 microns and d(0.5) value of less than about 6 microns.
In another aspect, there is provided a pharmaceutical composition comprising candesartan cilexetil particles wherein the particles have d(0.9) value of less than about 15 microns and d(0.5) value of less than about 6 microns.
In another aspect, there is provided a pharmaceutical composition comprising candesartan cilexetil particles and hydrochlorothiazide wherein the candesartan cilexetil particles have d(0.9) value of less than about 15 microns.
In another aspect, there is provided a pharmaceutical composition comprising candesartan cilexetil particles and hydrochlorothiazide wherein the candesartan cilexetil particles have d(0.9) value of less than about 15 microns and d(0.5) value of less than about 6 microns.
DETAILED DESCRIPTION
The term 'Candesartan Cilexetil' used herein refers to a prodrug that is hydrolyzed to Candesartan during absorption from the gastrointestinal tract. Candesartan may be present alone or in combination with compounds having diuretic or calcium antagonistic activity.
The compounds having diuretic activity may be selected from amiloride, chlorothiazide,
hydrochlorothiazide, benzthiazide, ticrynafen, acetazolamide, aminophylline, cyclothiazide,
trichloromethiazide, cyclopenthiazide, cyclothiazide, methyclothiazide,
benzylhydrochlorothiazide, penfluthiazide, ethiazide, hydroflumethiazide, polythiazide, clofenamide, chlorthalidone, cyclothiazide, bendroflumethiazide, meticrane, tripamide, methrazone, indapamide, quinethazone, furosemide, bumetanide, mefruside, azosemide, ethacrynic acid, sodium ethacrynate, piretanide, spironolactone, potassium cancrenaote and triamterene, or mixtures thereof.
The compounds having calcium antagonistic activity may be selected from diltiazem hydrochloride, terodiline hydrochloride, nicardipine hydrochloride, valnidipine hydrochloride, flunarizine hydrochloride, verapamil hydrochloride, manidipine hydrochloride, cinnarizine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, nildipine, nimodipine, penidipine and benidipine or mixtures thereof.
The term "d(0.9 value)" as used herein means atleast 90% of candesartan cilexetil particles have volume diameter less than specified value when measured by a light scattering method, for example Malvern Mastersizer. Candesartan cilexetil particles have d(0.9) value less than about 15 urn, in particular d(0.9) value between about 5 -12 urn.
The term "d(0.5 value)" as used herein means atleast 50% of candesartan cilexetil particles have volume diameter less than specified value when measured by a light scattering method for example Malvern Mastersizer. Candesartan cilexetil particles have d(0.5) value less than about 6 urn, in particular d(0.5) value between about 2 - 5 urn.
Particle size reduction may be carried out using various conventionally available mills such as ball mill, an attritor mill, air jet mill and media mills such as a sand mill and a bead mill. Air jet mill can be used only for dry milling process whereas all the other mills may be used for both dry as well as wet milling. The milling may be carried out using candesartan alone or with other pharmaceutically acceptable excipients such as surfactants or binding agents or a diluent. During wet milling, water may be used as medium for particle size reduction.
Pharmaceutical composition as used herein includes solid dosage forms such as tablets, capsules, or liquid dosage forms such as solution or a suspension.
The liquid dosage form should have suitable properties such as viscosity, taste and flavor. The pharmaceutically acceptable excipients in liquid dosage form may be selected from suspending agent, solvents, preservative, coloring agents, flavoring agents and sweeteners.
The pharmaceutically acceptable excipients for solid dosage form may be selected from surfactants, diluents, binders, disintegrants, lubricants, glidants and coloring agents.
The surfactant may be selected from sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates, sodium stearate, potassium stearate, sodium oleate, benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, macrogols , polyoxyethylene sorbitan fatty acid esters, fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols, polyglycolized glycerides such as Gelucire; polyoxyethylene-polyoxypropylene block copolymer such as Poloxamer, polyethoxylated castor oil such as cremophor and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol. The amount of surfactant may range from about 0.5 to about 20% based on the total weight of pharmaceutical composition.
Diluents may be selected from the group consisting of sugars (including lactose, sucrose, and dextrose), polyols (including mannitol, xylitol, and sorbitol), microcrystalline cellulose, starch, powdered cellulose and combinations thereof. The amount of diluent may range from about 40 to about 60% based on the total weight of the pharmaceutical composition.
Binders may be selected from polyvinylpyrrolidone (povidone), polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, and alginates),
starches, gelatin and cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose) or combinations thereof. The amount of binder may range from about 2 to about 20% based on the total weight of the pharmaceutical composition.
Disintegrants may be selected from starch, clays, cellulose and derivatives, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, and soy polysaccharides. The amount of disintegrant may range from about 2 to about 10% based on the total weight of the pharmaceutical composition.
Lubricants/glidants may be selected from talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, and hydrogenated vegetable oils. The amount of lubricant may range from about 0.1 to about 1.0% based on the total weight of the pharmaceutical composition.
The composition may further comprise oily substance as disclosed in EP0782852 or EP0546358. The oily substances may be selected from hydrocarbon, higher fatty acid, higher alcohol, fatty acid ester of polyhydric alcohol, higher alcohol ether of polyhydric alcohol, and polymer or copolymer of alkylene oxide.
The coloring agents of the present invention may be selected from any FDA approved colors for oral use.
The pharmaceutical composition may be prepared by wet granulation, dry granulation, or direct compression.
The pharmaceutical composition may be coated with one or more functional/non-functional coatings comprising film forming agents and/or pharmaceutically acceptable excipients.
The coating layers over the pharmaceutical composition may be applied as solution/ dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like.
Example 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 methylcellulose, 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.
The following examples are provided to enable one of the ordinary skill in art to prepare dosage forms of the invention and should not be construed as limiting the scope of invention.
EXAMPLES
Example-1
Three batches of candesartan cilexetil having a particle size distribution (when measured by Malvern) as given below were obtained.

(Table Removed)

Example- 2

(Table Removed)
Procedure:
1. Hydrochlorothiazide, lactose monohydrate, carmellose calcium and maize starch were transferred to a fluid bed processor and blended to obtain uniform blend.
2. Iron oxide red (for 16+12.5mg tablet) was added to blend of step 1 and mixed till uniform blend was obtained.
3. Macrogol 8000 and Hydroxypropyl Cellulose (low viscosity) were dissolved in purified water.
4 Candesartan cilexetil was dispersed in the solution of step 3.
5. Blend of step 2 was granulated with the dispersion of step 4 using top spray granulation process in fluidized bed processor to obtain drug coated granules.
6. Lactose monohydrate and carmellose calcium were blended with granules of step 5.
7. The blend of step 6 was lubricated with magnesium stearate and compressed into suitable size tablets.
Example - 3
The pharmaceutical composition of Candesartan cilexetil and Hydrochlorothiazide tablets comprising candesartan cilexetil particles [d(0.9) value=6.4um] was prepared as per procedure given in Example 2.

WE CLAIM:
1. Candesartan cilexetil particles having d(0.9) value of less than about 15 microns.
2. The candesartan cilexetil particles according to claim 1 wherein the particles have d(0.9) value between about 5 -12 microns.
3. The candesartan cilexetil particles according to claim 1 wherein the particles have d(0.5) value of less than about 6 microns.
4. The candesartan cilexetil particles according to claim 1 wherein the particles have d(0.5) value between about 2 - 5 microns.
5. The process of preparation of candesartan cilexetil particles according to claim 1 wherein the particles are prepared by wet milling or dry milling technique
6. The pharmaceutical composition of candesartan cilexetil particles according to claim 1 wherein the composition is a tablet.
7. The pharmaceutical composition according to claim 6 wherein the tablet comprises pharmaceutical^ acceptable excipients selected from the group consisting of surfactants, diluents, binders, disintegrants, lubricants, glidants and coloring agents.
8. The candesartan cilexetil particles according to claim 6 wherein the tablet further comprises an oily substance of melting point in the range of 20 to 90° C.
9. The pharmaceutical composition according to claim 6 wherein the tablet further comprises hydrochlorothiazide.
10. The candesartan cilexetil particles as used and exemplified herein.