Pharmaceutical Composition Comprising Alfuzosin and Dutasteride
Field of the Invention
The present invention relates to a pharmaceutical composition comprising alfuzosin and dutasteride and process for the preparation thereof. The compositions are useful for the treatment of patients with benign prostatic hyperplasia (BPH).
BPH, a benign, non-cancerous enlargement of the prostate, is a well-known complaint in men, which generally comes to medical attention from the age of 50 onwards. About 50% of all men aged over 50 and 95% of all men aged over 70 are affected by it. BPH is a generally progressive condition which in serious cases may endanger kidney function and require surgical intervention. The number of untreated patients runs at over 37 million worldwide. The reduced flow rate and voiding (obstructive) symptoms of BPH are generally considered to be caused by two main factors, the enlarged prostatic gland (the static component), and the tone of the smooth muscle of the stroma and urethra (the dynamic component). Storage (irritative) symptoms have been associated with bladder dysfunction secondary to outflow obstruction. The growth and tone of the prostate compresses or lengthens the urethra, causing the symptoms of urethral blockage and possibly leading to urinary retention.
Standard treatments for BPH involve surgical or pharmacological intervention. Surgical intervention involves removal of the prostate via radical prostectomy or removing the prostate adenoma via transurethral resection of the prostate. These invasive surgical procedures have limited utility because of the morbidity associated with operative procedures as well as the persistence and recurrence of obstructive and irritative symptoms. Surgical procedures are, therefore, not recommended for patients exhibiting mild to moderate symptoms.
Presently, pharmacological interventions in the treatment of BPH can be distinctly categorized into two main categories: 5-alpha-reductase inhibitors and alpha-1-adrenreceptor antagonists. The 5-alpha-reductase inhibitors such as finasteride and dutasteride reduce the size of prostate, thereby alleviating the static component of bladder outlet obstruction. The lesser efficacy associated with these inhibitors is mechanism-based, in that 5-alpha-reductase inhibitors decrease the size of prostate by reducing the amount of epithelial tissue without affecting the smooth muscle and the dynamic component of bladder outlet obstruction.
Other pharmacological therapy involves the administration of subtype non-selective alpha adrenoreceptor antagonists like alfuzosin, prazosin and doxazosin. These agents relax

prostatic urethral smooth muscle by blocking the alpha-1-mediated effects on endogenous tone and hence affecting the dynamic component of bladder outlet obstruction and relieving obstructive symptoms. In addition, these alpha-1- adrenoreceptor antagonists have also been found to relieve the irritative bladder symptoms associated with BPH.
Alfuzosin is a selective alpha-1-adrenoceptor antagonist that belongs to the chemical class of 4-amino-6, 7-dimethoxy quinazol-2-yl-alkylene diamines. Alfuzosin acts as a selective and competitive antagonist of alpha-1-adrenoceptor mediated contraction of prostatic, prostatic capsule, bladder base and proximal urethral structures and is used in the treatment of symptoms of benign prostatic hyperplasia.
Alfuzosin has a short half-life and shows the characteristic of being absorbed preferentially in the upper part of the gastrointestinal tract and, in particular, being absorbed in the duodenum and the jejunum. Sustained release compositions of alfuzosin provide various advantages over conventional multiple dosing including better patient compliance, reduced fluctuations of plasma drug levels, and reduced toxicity.
Alfuzosin is available commercially as a once daily extended release tablet.
Dutasteride, chemically defined as (5α, 17β)-N- {2,5 bis (trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide, is a 5-alpha-reductase inhibitor. Dutasteride alone is used to inhibit conversion of testosterone to dihydrotestosterone (DHT), the androgen primarily responsible for the enlargement of prostrate gland.
Dutasteride is commercially available in the form of soft gelatin capsules.
Dutasteride is not easy to dissolve. These solubility challenges can affect bioavailability, possibly resulting in reduced or unpredictable bioavailability. The choice of excipients is important in order to ensure good solubility and good bioavailability of the pharmaceutically active compound. Also, dutasteride is prone to oxidation. So, gelatin capsule formulations can be much more resistant to oxidation due to the low oxygen permeation of typical gelatin shells and further have better bioavailability.
In view of the above constraints, it would be a challenge to formulate both alfuzosin and dutasteride in a single dosage form.
U.S. Patent No. 6,149, 940 discloses a preparation of an alfuzosin 10 mg once daily composition for oral delivery. It consists of a hydrophilic active matrix core containing alfuzosin

hydrochloride and two inert, functional layers (one swellable layer and one erodible layer) whose functions are to control the hydration and swelling rate of the core, and thereby slow down and linearize the dissolution of the drug.
U. S. Patent No. 5,589,190 teaches that the sustained release of alfuzosin is dependent on the nature and thickness of the coating. Further, this patent discloses a combination of two types of tablets with different release rates that are filled into hard gelatin capsules for once-daily oral administration.
European Patent No.700285 discloses drug delivery compositions of alpha adrenoceptor blocking agents that have a biphasic drug release profile. This patent teaches matrix compositions using hydroxypropyl methylcellulose and a coating that is designed to dissolve under the conditions present in the colonic region.
PCT Application 99/08684 discloses a gelatin capsule filled with therapeutically effective amount of a pharmaceutically active aza steroid, polyethylene glycol, and propylene glycol.
PCT Applications 92/16213 and 93/19758 discloses combination of 5-α-reductase inhibitor and a- adrenergic receptor blocker for the treatment of Prostatic Hyperplasia.
U. S. Patent Application No. 20030225118 discloses the combination of tamsulosin, or an acid addition salt thereof with a 5-alpha-reductase inhibitor for treating benign prostatic hyperplasia (BPH) or for the long-term prevention of acute urinary retention.
U. S. Patent No. 5565467 discloses Dutasteride and its method of use.
U. S. Patent application No. 20050101607 discloses a combination of alpha antagonist and/or 5-alpha-reductase inhibitor and a beta-3-adrenoceptor agonist for the treatment of functional bladder disorders.
The combination of alfuzosin with dutasteride provides a synergistic effect, as compared to the monotherapy. Though alfuzosin and dutasteride are widely used individually, but there is still a need for a composition comprising alfuzosin and dutasteride, which will be safer, effective, and economical and will have better patient compliance.
Thus the present invention relates to pharmaceutical composition comprising alfuzosin, dutasteride and one or more pharmaceutically acceptable excipients. The composition is used

for the treatment of benign prostatic hyperplasia and shall offer additional benefit compared to each monotherapy leading to increased efficacy and improved patient compliance.
Summary Of The Invention
According to one embodiment there is provided a pharmaceutical composition comprising alfuzosin, dutasteride and one or more pharmaceutically acceptable excipients.
According to another embodiment there is provided a pharmaceutical composition containing alfuzosin and dutasteride, wherein the composition comprises a) one subunit comprising alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and b) a second subunit comprising dutasteride, one or more pharmaceutically acceptable excipients and optionally one or more carriers.
According to another embodiment there is provided a bilayer tablet containing alfuzosin and dutasteride, wherein the tablet comprises: a) one layer comprising alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and b) a second layer comprising dutasteride and one or more pharmaceutically acceptable excipients.
According to another embodiment there is provided a hard gelatin capsule containing alfuzosin and dutasteride, wherein the capsule comprises: a) a tablet comprising alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and b) a soft gelatin capsule comprising dutasteride, one or more carriers and one or more pharmaceutically acceptable excipients.
According to another embodiment there is provided a soft gelatin capsule containing alfuzosin and dutasteride, wherein the capsule comprises a) a tablet comprising alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and b) a dispersion comprising dutasteride, one or more carriers and one or more pharmaceutically acceptable excipients.
According to another embodiment there is provided a pharmaceutical composition containing alfuzosin and dutasteride, wherein the composition comprises a) a tablet comprising alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and b) a coating surrounding the tablet and comprising dutasteride and one or more pharmaceutically acceptable excipients.

According to another embodiment, there is provided a process for the preparation of a pharmaceutical composition containing alfuzosin and dutasteride, the process comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, followed by compression into tablets, and,
b) dispersing dutasteride in a solvent and adding one or more pharmaceutically acceptable
excipients to obtain a dispersion, and,
c) coating the tablet of step (a) with the dispersion of step (b) to obtain the pharmaceutical
composition.
According to still another embodiment, there is provided a process for the preparation of bilayer tablet containing alfuzosin and dutasteride, the process comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients to obtain granules,
b) granulating dutasteride and one or more pharmaceutically acceptable excipients to obtain
granules, and,
c) compressing the granules of step (a) and the granules of step (b) to obtain bilayered tablet.
Detailed Description of the Invention
The term "alfuzosin" as used herein refers to alfuzosin or salts thereof. The term "dutasteride" refers to dutasteride free base.
The "subunit" may be in the form of granules, tablet, capsule or dispersion/solution comprising either alfuzosin or dutasteride. The capsule may be hard gelatin capsule or soft gelatin capsule. The dispersion / solution may be either filed into a capsule or coated over a tablet. The subunits may be in the form of different layers of a bilayered tablet.
The pharmaceutical composition may be in the form of capsules or tablets containing the subunits comprising alfuzosin or dutasteride. The tablet may be bilayered, coated or uncoated tablet. The capsule may be either hard gelatin capsule or soft gelatin capsule.
Soft gelatin encapsulation provides the potential to improve the bioavailability of pharmaceutical agents. Relatively insoluble active ingredients can be dispersed in a liquid or gelled carrier to provide faster absorption upon rupture of the capsule. Further, it may be useful to include anti-oxidant in the composition so as to prevent oxidation of the pharmaceutical active in the composition. The other advantages of soft gelatin capsules include superior patient compliance/consumer preference (ease of swallowing, appealing appearance, absence of

objectionable taste, and convenience) and pharmaceutical elegance, excellent dose uniformity, better tamper evidence (tampering leads to puncturing and visible leakage) and safer handling of highly potent or cytotoxic drug compounds.
The "carrier" may be selected from one or more of oils such as corn oil, peanut oil, safflower oil, soya bean oil, miglycol 812 (neutral oil, triglycerides of medium chain fatty acids); propylene glycol mono-or-di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol caprylic-capric acid diester (Miglyol TM 840); and polyalkylene glycol such as polyethylene glycol 400-600;dimethylsolfoxide. The preffered carrier is mono-diglycerides of caprylic and capric acid (CAPMUL MCM).
The "pharmaceutically acceptable excipients" may be selected from one or more of binders, diluents, disintegrants, lubricants/glidants and antioxidants.
Suitable binders may be selected from one or more of starches such as corn starch, pregelatinized starch and maize starch; cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers such as polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; sugars such as sorbitol and mannitol.
Suitable diluents may be selected from one or more of sugars such as dextrose, glucose and lactose; sugar alcohols such as sorbitol, xylitol and mannitol; cellulose derivatives such as powdered cellulose and microcrystalline cellulose; starches such as corn starch, pregelatinized starch and maize starch.
Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal silicon dioxide.
The antioxidant may be selected from one or more of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbic acid. A particularly preferred anti-oxidant is butylated hydroxytoluene. Antioxidants may be used alone or in combination.
The present invention relates to pharmaceutical composition comprising alfuzosin and dutasteride, in which alfuzosin is present in an extended release form and dutasteride is

present in an immediate release form. The extended release form of alfuzosin comprises one or more of rate controlling agents
The rate controlling agents may be selected from one or more of hydrophilic polymers.
The hydrophilic polymers may be selected from one or more of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose or sodium carboxymethyl cellulose; gums such as xanthan gum, karaya gum, locust bean gum, alginic acid or sodium alginate; and vinyl alcohol or vinylpyrrolidone based polymers such as polyvinyl alcohol, or polyvinylpyrrolidone; polyethylene oxides. The use of hydroxypropyi methylcellulose (HPMC), hydroxypropylcellulose, carboxymethylcellulose is preferred.
The composition may be prepared by conventional processes known to a person skilled in the art. Ail the ingredients may be mixed together to obtain blend/ dispersion or the blend may be granulated further (by dry granulation or wet granulation) to obtain the granules. The blend/granules may be either directly filled into capsule or may be compressed into tablets using suitable toolings. Further, the granules may be compressed to obtain bilayered tablets. Alternatively, the granules can be compressed to form an inner core containing one active ingredient and subsequently an outer coat of dispersion containing the other active ingredient can be coated around the inner core.
The subunits may be prepared in the form of tablet and soft gelatin capsules, which may be filled into hard gelatin capsules. Alternatively, the subunits may be prepared in the form of tablet and dispersion, which may be filled into soft gelatin capsules.
The tablet may optionally be coated. The coating comprises one or more film forming polymers and optionally one or more inert pharmaceutically acceptable additives dispersed in one or more solvents. The various solvents include water, ethanol, methanol, isopropyl alcohol, dichloromethane, chloroform, acetone, ether or mixtures thereof.
The film-forming polymers may be selected from one or more hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellullose and the like.
The inert pharmaceutically acceptable additives include one or more of plasiticizers, viscosity modifiers, flow aids and colorants.

Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
Soft gelatin capsule shell can be produced according to any of the acceptable methods known in the art for production of such capsules. Such methods are disclosed, for example, at page 699 of the United States Pharmacopeia XIX (1975) and at pages 929-930 of the National Formulary XIV (1975).
The gelatin ribbons are continuously conveyed between the dies, with portions of the fill
formulation being trapped between the sheets inside the die cavities. The sheets are then
pressed together, and severed around each die so that opposed edges of the sheets - flow
together to form a continuous gelatin sheath around the entrapped medicament. The part of the
gelatin sheet that is severed from the segments forming the capsules is then collected for
recycling, and the soft capsules are dried.
The gelatin will normally have a bloom in the range of from about 150 to about 275, and may be Type A or B gelatins, or a mixture thereof. Limed bone, acid bone, fish and/or pig skin gelatins may be used. In order to provide adequate flexibility and strength to the shell, various plasticizers have been probed. Examples of suitable plasticizers include glycerin, xylitol, sorbitol, polyglycyerol, non-crystallizing solutions of sorbitol, glucose, fructose and glucose syrups with varying equivalents.
The sheath formulations may also contain other ingredients, such as taste modifiers, coloring agents, preservatives and moisture retaining agents. Taste modifiers include non reducing sugars, such as xylitol, maltitol, or Lycasin manufactured by Roquette America, Inc. and normally may be present up to about 5% by weight of the sheath composition. Suitable preservatives include methylparaben, propylparaben or mixtures thereof. Suitable moisture retaining agents include celluloses, cellulose derivatives, starches, starch derivatives, vegetable gums, non-hygroscopic, mono-, di- and oligosaccharides, and silicon dioxide. Various FD&C coloring agents may be used to impart the desired color to the capsule.
According to one embodiment, there is provided a process for the preparation of a soft gelatin capsule containing alfuzosin and dutasteride, the process comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, followed by compression into tablets, and,
b) dispersing dutasteride in a carrier and adding one or more pharmaceutically acceptable excipients to obtain a dispersion, and,
c) filling the tablet of step (a) and the dispersion of step (b) into soft gelatin capsules to obtain the pharmaceutical composition.
According to another embodiment, there is provided a process for the preparation of a pharmaceutical composition containing alfuzosin and dutasteride, the process comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, followed by compression into tablets, and,
b) dispersing dutasteride in a solvent and adding one or more pharmaceutically acceptable
excipients to obtain a dispersion, and,
c) coating the tablet of step (a) with the dispersion of step (b) to obtain the pharmaceutical
composition.
According to another embodiment, there is provided a process for the preparation of bilayer tablet containing alfuzosin and dutasteride, the process comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients to obtain granules,
b) granulating dutasteride and one or more pharmaceutically acceptable excipients to obtain
granules, and,
c) compressing the granules of step (a) and the granules of step (b) to obtain bilayered tablet.
According to another embodiment, there is provided a process for the preparation of hard gelatin capsule containing alfuzosin and dutasteride, the process comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, followed by compression into tablets, and,
b) dispersing dutasteride in one or more carriers and adding one or more pharmaceutically
acceptable excipients to obtain a dispersion, and, filling the dispersion into a soft gelatin
capsule, and,
c) filling the tablet of step (a) and the soft gelatin capsule of step (b) into a hard gelatin capsule
to obtain the pharmaceutical composition.
The following non-limiting examples illustrate the pharmaceutical composition comprising alfuzosin and dutasteride disclosed in various embodiments of the specification.
Example 1 - 3

(Table Removed)
Brief manufacturing process:
A. Preparation Of Gelatin Mass For Shell
1. Gelatin is mixed in chilled water and is allowed to swell for about 30 minutes in the
melter to obtain a viscous mass.
2. Methyl paraben, propylparaben are dissolved in glycerine followed by addition of
caramel colour to obtain a solution.
3. The solution of step 2 is added to the viscous mass obtained in step 1 to obtain a
bulk.
4. The bulk is heated under vacuum with continuous stirring to obtain a consistent
mass.
5. The consistent mass obtained in step 4 is unloaded in a holding tank, which is then
maintained at 55-60°C.
B. Alfuzosin Tablet
6. A 25% solution of povidone (part 2) is prepared in purified water.
7. Alfuzosin HCI, colloidal anhydrous silica, povidone (part 1) & lactose are sifted
together through BSS #44 to obtain a mixture.
8. The mixture of step 7 is blended in a rapid mixer granulator followed by granulation
with povidone solution of step 6 to obtain granules.
9. The granules obtained in step 8 are dried in a fluid bed drier, and then sifted through
#44BSS to obtain alfuzosin lactose granules.
10. Alfuzosin-lactose granules obtained in step 9, colloidal anhydrous silica, povidone,
lactose & hydroxypropyl methylcellulose are all mixed to obtain a blend.
11. To the blend of step 10, hydroxypropyl methylcellulose, talc and magnesium
stearate are added to obtain a final blend.
12. The final blend obtained in step 11 is then compressed to tablets followed by coating
with opadry to obtain alfuzosin tablet.
C. Dutasteride Dispersion
13. Mono-di-glycerides of caprylic/ monodiglyceroides/ monodiglycerides of capric or
caprylic/capric acid is transferred to a stainless steel vessel and heated to 60°C to
obtain a solution.
14. Butylated hydroxy toluene is added under stirring to the solution of step 13, followed
by addition of dutasteride under stirring, the stirring is further continued for 30 min to
obtain dutasteride mixture.
D. Encapsulation
15. The dutasteride mixture obtained in step 14 is encapsulated in dark brown opaque
consistent mass obtained in step 5 at a fill weight of 350 mg.
16. After setting the fill weight, alfuzosin tablet obtained in step 12 are introduced
through the feeder attached such that each soft gel capsule contains a single tablet
of alfuzosin along with 350 mg of liquid dispersion of dutasteride.
Example 4

(Table Removed)
Brief Manufacturing Process
A. Alfuzosin Layer
1. Alfuzosin HCI, lactose anhydrous, colloidal anhydrous silica and povidone are sifted
through # 44 BSS.
2. The material of step 1 is blended for 15 min.
3. Talc and magnesium stearate are sifted through #44BSS and added to the blend of step
2 and blended.
4. Blend from step 3 is roller compacted and milled using multimill to obtain Alfuzosin
lactose granules.
5. Extra granular lactose anhydrous, povidone, colloidal anhydrous silica,
hydroxypropylmethylcellulose and hydroxypropylcellulose are sifted through #30BSS
and extra granular talc and magnesium stearate are sifted through #44BSS.
6. Alfuzosin lactose granules of step 4, lactose anhydrous, povidone,
hydroxypropylcellulose and silica colloidal anhydrous are blended, followed by addition
of hydroxypropylmethylcellulose followed by further blending.
7. Finally talc and magnesium stearate are added to the blend of step 6 and blended to
obtain a final Alfuzosin lactose granule blend.
B. Dutasteride Layer
8. Dutasteride is dissolved in ethanol under stirring to obtain a solution.
9. Lactose, hydroxypropylmethyl cellulose and croscarmellose sodium are sifted through
#44BSS to obtain a blend.
10. Blend of step 9 is granulated with solution obtained in step 8 to obtain granules.
11. Granules obtained in step 10 are dried and milled through #25BSS.
12. Yellow iron oxide sifted through #60BSS and magnesium stearate sifted through
#44BSS are added to the dried granules and blended for 5 min to obtain a final blend.
C. Bilayer Tablet Compression
13. The bilayer tablets are compressed using the blend of Alfuzosin layer obtained in step 7
and the blend of dutasteride layer obtained in step 12.
Example 5

(Table Removed)
Brief Manufacturing Process
A. Alfuzosin Tablet
1. Alfuzosin HCI, lactose anhydrous, silica colloidal anhydrous and povidone are sifted
through # 44 BSS and blended.
2. Talc and magnesium stearate are sifted through #44BSS and added to blend of step 1
and further blended.
3. Blend from step 2 is roller compacted and milled using multimill to obtain Alfuzosin
lactose granules.
4. Extra granular lactose anhydrous, povidone, silica colloidal anhydrous ,
hydroxypropylmethylcellulose and hydroxypropylcellulose are sifted through #30BSS
and extra granular talc and magnesium stearate are sifted through #44BSS.
5. Alfuzosin lactose granules of step 3, lactose anhydrous, povidone,
hydroxypropylcellulose and silica colloidal anhydrous are blended, followed by addition
of hydroxypropylmethylcellulose and further blended to obtain a blend.
6. Finally talc and magnesium stearate are added to the blend of step 5 and blended to
obtain a final Alfuzosin lactose granule blend.
7. The alfuzosin lactose granule blend is compressed using the approved punch tooling to
obtain tablets.
8. Opadry is dispersed in isopropyl alcohol and then dichloromethane added to obtain a
dispersion.
9. The tablet obtained in step 7 is coated with the dispersion obtained in step 8.
B. Dutasteride Coating
10. Opadry is dispersed in isopropyl alcohol and then dichloromethane added to obtain a
dispersion.
11. Dutasteride is dissolved in dichloromethane and added to dispersion of step 1 under
continuous stirring to obtain a final dispersion.
C. Coating
12. The tablet obtained in step 9 is coated with the dispersion obtained in step 11.
Example 6

(Table Removed)
A. Alfuzosin Tablet
1. Alfuzosin HCI, lactose anhydrous, silica colloidal anhydrous and povidone are sifted
through # 44 BSS and blended.
2. Talc and magnesium stearate are sifted through #44BSS and added to blend of step 1
and further blended.
3. Blend from step 2 is roller compacted and milled using multimill to obtain Alfuzosin
lactose granules.
4. Extra granular lactose anhydrous, povidone, silica colloidal anhydrous,
hydroxypropylmethylcellulose and hydroxypropylcellulose are sifted through #30BSS
and extra granular talc and magnesium stearate are sifted through #44BSS.
5. Alfuzosin lactose granules of step 3, lactose anhydrous, povidone,
hydroxypropylcellulose and silica colloidal anhydrous are blended, followed by addition
of hydroxypropylmethylcellulose and further blended to obtain a blend.
6. Finally talc and magnesium stearate are added to the blend of step 5 and blended to
obtain a final Alfuzosin lactose granule blend.
7. The alfuzosin lactose granule blend is compressed using the approved punch tooling to
obtain tablets.
8. Opadry is dispersed in isopropyl alcohol and then dichloromethane added to obtain a
dispersion.
9. The tablet obtained in step 7 is coated with the dispersion obtained in step 8.
B. Dutasteride Soft Gels
10. Mono-di-glycerides of caprylic/ monodiglyceroides/ monodiglycerides of capric or
caprylic/capric acid is transferred to a stainless steel vessel and heated to 40-45°C to
obtain a solution.
11. Butylated hydroxy toluene is added under stirring to the solution of step 10, and cooled,
followed by addition of dutasteride under stirring, the stirring is further continued for 30
min to obtain dutasteride mixture which is filled into soft gelatin capsule.
C. Capsule Filling
12. The tablet obtained in step 8 and dutasteride soft gel capsule obtained in step 11 are filled into a hard gelatin capsule to obtain the final composition.

WE CLAIM:
1. A pharmaceutical composition containing alfuzosin and dutasteride, wherein the
composition comprises:
a) one subunit comprising alfuzosin, one or more rate controlling agents and one or
more pharmaceutically acceptable excipients, and,
b) a second subunit comprising dutasteride, one or more pharmaceutically acceptable
excipients and optionally one or more carriers.

2. The composition according to claim 1, in the form of soft gelatin capsule containing
alfuzosin and dutasteride, wherein the capsule comprises a) a tablet comprising
alfuzosin, one or more rate controlling agents and one or more pharmaceutically
acceptable excipients, and b) a dispersion comprising dutasteride, one or more carriers
and one or more pharmaceutically acceptable excipients.
3. The composition according to claim 1, in the form of a bilayer tablet containing alfuzosin
and dutasteride, wherein the tablet comprises: a) one layer comprising alfuzosin, one or
more rate controlling agents and one or more pharmaceutically acceptable excipients,
and b) a second layer comprising dutasteride and one or more pharmaceutically
acceptable excipients.
4. The composition according to claim 1, wherein the composition comprises: a) a tablet
comprising alfuzosin, one or more rate controlling agents and one or more
pharmaceutically acceptable excipients, and b) a coating surrounding the tablet and
comprising dutasteride and one or more pharmaceutically acceptable excipients.
5. The composition according to claim 1, in the form of hard gelatin capsule containing
alfuzosin and dutasteride, wherein the capsule comprises: a) a tablet comprising
alfuzosin, one or more rate controlling agents and one or more pharmaceutically
acceptable excipients, and b) a soft gelatin capsule comprising dutasteride, one or more
carriers and one or more pharmaceutically acceptable excipients.
6. The composition according to any of the preceding claims wherein, the rate controlling
agent comprises hydrophilic polymers selected from one or more of cellulose derivatives
selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, carboxymethyl cellulose or sodium carboxymethyl cellulose; gums selected
from xanthan gum, karaya gum, locust bean gum, alginic acid or sodium alginate; and
vinyl alcohol or vinylpyrrolidone based polymers selected from polyvinyl alcohol, or polyvinylpyrrolidone ; polyethylene oxides or mixtures thereof.
7. The composition according to any of the claims 1,2 or 5 wherein, the carrier is selected
from one or more of oils selected from corn oil, peanut oil, safflower oil, soya bean oil or
neutral oil; propylene glycol mono-or-di-fatty acid esters selected from propylene glycol
dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol
laurate, propylene glycol ricinoleate or propylene glycol caprylic-capric acid diester; and
polyalkylene glycol selected from polyethylene glycol 400-600 and dimethylsolfoxide.
8. A process for the preparation of the pharmaceutical composition of claim 4, the process
comprising the steps of: a) granulating alfuzosin, one or more rate controlling agents
and one or more pharmaceutically acceptable excipients, followed by compression into
tablets, and, b) dispersing dutasteride in a solvent and adding one or more
pharmaceutically acceptable excipients to obtain a dispersion, and, c) coating the tablet
of step (a) with the dispersion of step (b) to obtain the pharmaceutical composition.
9. A process for the preparation of the bilayer tablet of claim 3, the process comprising
the steps of: a) granulating alfuzosin, one or more rate controlling agents and one or
more pharmaceutically acceptable excipients to obtain granules, b) granulating
dutasteride and one or more pharmaceutically acceptable excipients to obtain granules,
and, c) compressing the granules of step (a) and the granules of step (b) to obtain
bilayered tablet.
10. A pharmaceutical composition comprising alfuzosin and dutasteride and process of
preparation thereof substantially described and exemplified herein.