Low Dose Compositions for Dutasteride
Cross Reference to Related Application
This is a patent of addition to 1627/DEL/2006 (complete specification), filed on Jul 16, 2007 and the present invention comprises a modification of the invention described in the specification of 1627/DEL/2006.
Field of the Invention
The present invention relates to a low dose composition comprising dutasteride and process for the preparation thereof. The compositions are useful for the treatment of patients with benign prostatic hyperplasia (BPH).
Dutasteride, chemically defined as (5a, 17P)-N- {2,5 bis (trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide, is a 5-alpha-reductase inhibitor. Dutasteride 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. It is sold under the brand name Adovart® in US.
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 pharmaceutical^ 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.
Adovart® is available as a soft gel capsule containing 0.50mg of dutasteride. Dutasteride is practically insoluble in water and hence has formulation challenges with respect to bioavailability. In Adovart® dutasteride is dissolved in mixture of mono-di-glycerides of caprylic/capric acid to increase bioavailability. It has to be formulated in soft gel capsule with the addition of antioxidant like butylated hydroxytoluene so as to prevent the oxidation of the steroids and to obtain increased bioavailability.

There remains a need for a new pharmaceutical composition comprising of dutasteride exhibiting sufficient or increased bioavailability. Formulation comprising higher bioavailability of dutasteride may allow a reduction in dose. In particular it is desired to obtain a tablet dosage form which is free of limitations associated with soft gel capsulation like manufacturing concerns, crosslinking and ageing. Further, use of soft gelatin capsules has the additional limitation of dealing with the mindset of strict vegetarians. Thus, there is a need to obtain a tablet dosage form which apart from being patient compliant is comparatively economical and easy to make.
Prior art does not acknowledge the use of dutasteride in a tablet dosage form.
PCT Application 99/08684 discloses a gelatin capsule filled with therapeutically effective amount of a pharmaceutical^ active aza steroid, polyethylene glycol, and propylene glycol.
Dutasteride can also be used as a combination with Alfuzosin an alpha adrenoreceptor antagonist, which as compared to the monotherapy provides a synergistic effect and is also safer, effective, and economical.
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 is available commercially as a once daily extended release tablet.
PCT Application Nos. 92/16213 and 93/19758 disclose combination of 5-a-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.
PCT Application 2006/099121 discloses nanoparticulate compositions of finasteride, dutasteride, tamsulosin, or a combination thereof. The formulations exhibit unexpectedly prolonged release and can be formulated into injectable depot dosage forms.

Thus the present invention relates to a low dose composition comprising inert tablet comprising one or more pharmaceutically acceptable excipients and a coating surrounding the inert tablet, wherein the coating comprises 0.40-0.45mg dutasteride and one or more pharmaceutically acceptable excipients.
The invention also relates to pharmaceutical composition comprising alfuzosin, 0.40-0.45mg 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 low dose composition, wherein the composition comprises: a) an inert tablet comprising one or more pharmaceutically acceptable excipients, and b) a coating surrounding the tablet and comprising 0.40-0.45mg dutasteride and one or more pharmaceutically acceptable excipients.
According to another embodiment, there is provided a process for the preparation of a low dose composition, wherein the process comprises the steps of: a) granulating/ mixing one or more pharmaceutically acceptable excipients, followed by compression into inert tablets, and, b) dispersing 0.40-0.45mg dutasteride in a solvent and adding one or more pharmaceutically acceptable excipients to obtain a dispersion, and, c) coating the inert tablet of step (a) with the dispersion of step (b) to obtain the pharmaceutical composition.
According to another embodiment, there is provided a pharmaceutical composition containing alfuzosin and dutasteride, wherein the composition comprises: a) a tablet comprising 10 mg alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and b) a coating surrounding the tablet and comprising 0.40-0.45mg of dutasteride and one or more pharmaceutically acceptable excipients.
According to further embodiment, there is provided a process for the preparation of a low dose composition, wherein the process comprises 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.
Detailed Description of the Invention
According to one embodiment there is provided a low dose composition for dutasteride, comprising 0.40-0.45mg dutasteride and one or more pharmaceutically acceptable excipients.
The term "dutasteride" refers to dutasteride free base, wherein dutasteride is present in the range of 0.40-0.45 mg.
According to another embodiment, there is provided a low dose composition comprising 10mg alfuzosin, 0.40-0.45mg dutasteride and one or more pharmaceutically acceptable excipients.
The term "alfuzosin" as used herein refers to alfuzosin or salts thereof, wherein alfuzosin is present in the amount of 10mg.
The pharmaceutical composition may be in the form of tablets. The tablet may be bilayered, coated or uncoated tablet.
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, mannitol and mixtures thereof.
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, maize starch and mixtures thereof.

Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, corn starch and mixtures thereof.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
The present invention also relates to the low dose composition comprising dutasteride and alfuzosin, 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 and mixtures thereof.
The composition may be prepared by conventional processes known to a person skilled in the art. All 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 compressed into tablets using suitable tooling.
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 of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellullose and mixtures thereof.
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.
According to another embodiment, there is provided a process for the preparation of a low dose composition containing alfuzosin and dutasteride, the process comprising the steps of:
a) granulating alfuzosin, one or more rate controlling agents and one or more
pharmaceutical^ 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.
Pharmacokinetic studies were carried out under fed condition using the composition obtained according to the embodiment of the invention against innovator formulation.
The term "innovator formulation" as used herein refers to capsule formulation of dutasteride, commercially available in U.S under the trade name Adovart® soft gel capsules, from GlaxoSmithKline and extended release tablet formulation of alfuzosin, commercially available in UK under the trade name Xatral®, from Sanofi-Synthelabo Limited.
It was observed that the composition comprising 10mg alfuzosin and 0.5mg dutasteride showed increased bioavailability in comparison with Adovart® capsule i.e., was suprabioavailable with respect to Adovart® and was bioequivalent with respect to Xatral®. The details are provided in Table 1.
Based on the above it can be concluded that a composition comprising 10mg alfuzosin and 0.40-0.45mg dutasteride would be bioequivalent with respect to both Xatral® & Adovart®.
Further, a composition containing an inert tablet coated with 0.40-0.45mg of dutasteride would be bioequivalent to Adovart® soft gel capsule.
According to one embodiment, the pharmaceutical composition containing 10mg alfuzosin and 0.40-0.45mg dutasteride is bioequivalent to the innovator formulation of Xatral® with respect to alfuzosin and bioequivalent to the innovator formulation of Adovart® with respect to dutasteride.

According to another embodiment there is provided a low dose composition of dutasteride, wherein the composition comprises a) an inert tablet comprising one or more pharmaceutically acceptable excipients, and b) a coating surrounding the tablet and comprising 0.40-0.45mg dutasteride and one or more pharmaceutical^ acceptable
excipients.
According to another embodiment, there is provided a process for the preparation of a low dose composition, wherein the process comprises the steps of: a) granulating/ mixing one or more pharmaceutically acceptable excipients, followed by compression into inert tablets, and, b) dispersing 0.40-0.45mg dutasteride in a solvent and adding one or more pharmaceutically acceptable excipients to obtain a dispersion, and, c) coating the inert tablet of step (a) with the dispersion of step (b) to obtain the pharmaceutical composition.
The following non-limiting examples illustrate the low dose composition comprising dutasteride disclosed in various embodiments of the specification.
Example 1
(Table Removed)
Brief Manufacturing Process
A. Alfuzosin Tablet
1. Alfuzosin HCI, lactose anhydrous, silica colloidal anhydrous and povidone were sifted through # 44 BSS and blended.
2. Talc and magnesium stearate were sifted through #44BSS and added to blend of step 1 and further blended.
3. Blend from step 2 was roller compacted and milled using multimill to obtain Alfuzosin lactose granules.
4. Extra granular lactose anhydrous, povidone, silica colloidal anhydrous, hydroxypropylmethylcellulose and hydroxypropylcellulose were sifted through #30BSS and extra granular talc and magnesium stearate were sifted through #44BSS.
5. Alfuzosin lactose granules of step 3, lactose anhydrous, povidone, hydroxypropylcellulose and silica colloidal anhydrous were blended, followed by addition of hydroxypropylmethylcellulose and further blended to obtain a blend.
6. Finally talc and magnesium stearate were added to the blend of step 5 and blended to obtain a final Alfuzosin lactose granule blend.
7. The alfuzosin lactose granule blend was compressed using the approved punch
tooling to obtain tablets.
8. Opadry was dispersed in isopropyl alcohol and then dichloromethane added to obtain a dispersion.
9. The tablet obtained in step 7 was coated with the dispersion obtained in step 8.
B. Dutasteride Coating
10. Opadry was dispersed in isopropyl alcohol and then dichloromethane was added to obtain a dispersion.
11. Dutasteride was dissolved in dichloromethane and added to dispersion of step 10 under continuous stirring to obtain a final dispersion.
C. Coating
12. The tablet obtained in step 9 was coated with the dispersion obtained in step 11.
Pharmacokinetic Studies under Fed Condition:
Pharmaceutical composition comprising Alfuzosin and dutasteride of Example 1 was compared with extended release marketed formulation of Alfuzosin (Xatral® tablet; marketed by Sanofi-Syntheloba in UK) and Dutasteride soft gel capsules (Adovart® soft gel capsules; marketed by GlaxoSmithKline in US) underfed condition on 37 healthy adult male subjects.
Values for various pharmacokinetic parameters, including observed Tmax, Cmax, AUCo-t, and AUC 0-a, were calculated and are provided in Table 1 & 2 below.
Reference (R):
• Xatral® XL 10 mg Tablets (Alfluzosin prolonged release 10 mg) manufactured by Sanofi Synthelabo Limited, UK; Batch No. BC333, Expiry Date: March'2009 and
• Avodart® Capsules 0.5 mg (Dutasteride 0.5 mg), manufactured by GlaxoSmithKline Inc, USA, Batch No.RP052769A , Expiry Date: March'2009.
Test (T): Alfluzosin XL 10 mg and Dutasteride 0.5 mg, (Example 1), Batch No. MSR (3230)046A, Expiry Date: June '2009

TABLE 1: Comparative pharmacokinetic data for dutasteride in tablets of Example 1
(T) and Adovart®(R) in 37 Healthy Adult Human Male Subjects:
(Table Removed)

* Log-transformed parameters, the antilog of the mean
As evident from the above data in Table 1, dutasteride in composition comprising alfuzosin and dutasteride of Example 1, is suprabioavailable to Adovart® soft gel capsules. Cmax of dutasteride in Example 1 is 1.18 times that of Adovart® soft gel capsules, while AUC (o-[) is 1.21 times that of Adovart® soft gel capsules.
TABLE 2: Comparative pharmacokinetic data for Alfuzosin in tablets of Example 1 (T) and Xatral®(R) in 37 Healthy Adult Human Male Subjects
(Table Removed)
* Log-transformed parameters, the antilog of the mean
As evident from the above data in Table 2, the alfuzosin in composition comprising alfuzosin and dutasteride of Example 1, is bioequivalent to Xatral® Tablets.
Example 2
(Table Removed)
Brief Manufacturing Process
A. Alfuzosin Tablet
1. Sift alfuzosin HCI, lactose anhydrous, silica colloidal anhydrous and povidone through #44 BSSand blended.
2. Sift Talc and magnesium stearate through #44BSS and add to blend of step 1 and further blend.
3. Roller compact the blend from step 2 was and mill using multimill to obtain Alfuzosin lactose granules.
4. Sift extra granular lactose anhydrous, povidone, silica colloidal anhydrous,
hydroxypropylmethylcellulose and hydroxypropylcellulose through #30BSS and sift extra
granular talc and magnesium stearate through #44BSS.
5. Blend alfuzosin lactose granules of step 3, lactose anhydrous, povidone, hydroxypropylcellulose and silica colloidal anhydrous, followed by addition of hydroxypropylmethylcellulose and further blend to obtain a blend.
6. Finally add talc and magnesium stearate to the blend of step 5 and blend to obtain a final Alfuzosin lactose granule blend.
7. Compress alfuzosin lactose granule blend using the approved punch tooling to obtain tablets.
8. Disperse opadry in isopropyl alcohol and then add dichloromethane to obtain a dispersion.
9. Coat the tablet obtained in step 7 with the dispersion obtained in step 8.
B. Dutasteride Coating
10. Disperse opadry in isopropyl alcohol and then add dichloromethane to obtain a dispersion.
11. Dissolve dutasteride in dichloromethane and added to dispersion of step 10 under continuous stirring to obtain a final dispersion.
C. Coating
12. Coat the tablet obtained in step 9 with the dispersion obtained in step 11.
Example 3
(Table Removed)
A. Inert Tablet
1. Sift anhydrous lactose and microcrystalline cellulose to obtain a blend. Sift magnesium stearate & lubricate the blend.
2. Compress the blend of step 1 followed by coating to obtain inert tablet
B. Dutasteride Coating
3. Disperse opadry in isopropyl alcohol and then add dichloromethane to obtain a
dispersion.
4. Dissolve dutasteride in dichloromethane and add to dispersion of step 3 under
continuous stirring to obtain a final dispersion.
C. Coating
5. Coat the tablet obtained in step 2 with the dispersion obtained in step 4.

Example 4
(Table Removed)
A. Inert Tablet
1. Sift anhydrous lactose and microcrystalline cellulose to obtain a blend. Sift magnesium stearate & lubricate the blend.
2. Compress the blend of step 1 followed by coating to obtain inert tablet
B. Dutasteride Coating
3. Disperse opadry in isopropyl alcohol and then add dichloromethane to obtain a
dispersion.
4. Dissolve dutasteride in dichloromethane and add to dispersion of step 3 under
continuous stirring to obtain a final dispersion.
C. Coating
5. Coat the tablet obtained in step 2 with the dispersion obtained in step 4.

WE CLAIM:
1. A low dose composition comprising dutasteride, wherein the composition comprises:
a) an inert tablet comprising one or more pharmaceutical^ acceptable excipients, and,
b) a coating comprising 0.40-0.45mg dutasteride and one or more pharmaceutically acceptable excipients.
2. A low dose composition containing alfuzosin and dutasteride, wherein the
composition comprises:
a) a tablet comprising 10mg alfuzosin, one or more rate controlling agents and one or more pharmaceutically acceptable excipients, and,
b) a coating comprising 0.40-0.45mg dutasteride and one or more pharmaceutically acceptable excipients.

3. The composition according to claim 2, wherein the rate controlling agent comprises hydrophilic polymers selected from 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 and polyethylene oxides.
4. The composition according to any of the claims 1 or 2, wherein the pharmaceutically acceptable excipients are selected from one or more of binders, diluents, disintegrants, and lubricants.
5. The composition according to claim 4, wherein the binders are selected from one or more of cellulose derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums selected from xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; and sugars selected from sorbitol and mannitol; the diluents are selected from one or more of sugars selected from dextrose, glucose and lactose; sugar alcohols selected from sorbitol, xylitol and mannitol; cellulose derivatives selected from powdered cellulose and microcrystalline cellulose and starches selected from corn starch, pregelatinized

starch and maize starch; the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch; and, the lubricants are selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal silicon dioxide.
6. The process for the preparation of the low dose composition according to claim 1, wherein the process comprises the steps of: a) granulating/ mixing one or more pharmaceutical^ acceptable excipients, followed by compression into inert tablets, and, b) dispersing dutasteride in a solvent and adding one or more pharmaceutical^ acceptable excipients to obtain a dispersion, and, c) coating the inert tablet of step (a) with the dispersion of step (b) to obtain the pharmaceutical composition.
7. The process for the preparation of the composition according to claim 2, wherein the process comprises 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.
8. A low dose composition comprising dutasteride and process of preparation thereof substantially described and exemplified herein.