FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
SUSTAINED RELEASE COMPOSITIONS OF ALFUZOSIN
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides sustained release formulations comprising more than one functional layer that contain alfuzosin or salt thereof along wherein the first layer comprises of less than 5% of at least one pharmaceutically acceptable hydrophilic rate-controlling polymer and the second layer comprises of at least one 0.5 to 95% of the hydrophilic rate-controlling polymer.
The following specification particularly describes the invention and the manner
in which it is to be performed.
The present invention provides sustained release formulations comprising more than one functional layer that contain alfuzosin or salt thereof along wherein the first layer comprises of less than 5% of at least one pharmaceutically acceptable hydrophilic rate-controlling polymer and the second layer comprises of at least
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one 0.5 to 95%; of the hydrophilic rate-controlling polymer.
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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 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 marketed for the treatment of benign prostatic hyperplasia and, more specifically, for the treatment of the symptoms associated with benign prostatic hyperplasia. Alfuzosin is indicated for the treatment of moderate to sever symptoms of benign prostatic hyperplasia.
US Patent No 6,149,940 discloses a preparation of an alfuzosin 10 mg once daily composition for oral delivery, which is based on Geomatrix technology. The three-layer tab et described in the '940 patent consists of a hydrophilic active matrix core containing alfuzosin hydrochloride in single layer supported by two inert, non-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. When the tablet comes into contact with gastric juices, it increases considerably in volume and thus remains
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in the stomach for a longer time. In this manner, most of the drug is absorbed in a controlled manner in the portion of the gastrointestinal tract having the highest
capacity for absorption. The alfuzosin is released in zero order from the dosage

form developed using this technology.
US Patent No 5,589,190 disclose a pharmaceutical composition that includes an alfuzosin core. The core is coated with a coating whose dissolution is pH dependent, which thereby enables the release of alfuzosin to be modulated over the entire length of the digestive tract.
European Patent EP 700,285 discloses drug delivery compositions of alpha
adrenoceptor blocking agents that have a biphasic drug release profile.
US Patent No 4,259, 314 disclose a dry pharmaceutical formulation containing a therapeutic agent and a dry carrier that includes hydroxypropyl methylcellulose and hydroxypropyl cellulose.
PCT Patent Application WO 2004/037228 provides sustained release dosage forms of alfuzosin or salt thereof having single functional layers and optionally
one or more non-functional layers along with one or more release retarding

ingredients.
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The present inventors have now surprisingly found that release profile of alfuzosin or salt thereof as provided in the '940 Patent and the '228 Application wherein the multi-layer composition in which only single layer is functional can be achieved by having a multi-layer composition in which more than one layer are functional, characterized by the fact that first layer comprises of alfuzosin or salt thereof along with at least one hydrophilic rate-controlling polymer in amount of
less than 5% and the second layer comprises of alfuzosin or salt thereof along
with at least one rate-controlling polymer in amount of 0.5 to 95% of the total weight of the layer.
In one of the aspects of the present invention there is provided a sustained release formulation which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer,
c) an optional third layer which comprises of hydrophilic rate controlling polymer,
wherein all the layers optionally have one or more pharmaceutically
acceptable diluent and / or lubricant.

In another aspect of the present invention there is provided a sustained release formulation of which comprises of
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a) first layer comprising alfuzosin or salt thereof and less than 5% of at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer and at least one pharmaceutically acceptable diluent and / or lubricant,
c) an optional third layer which comprises of hydrophilic rate controlling polymer.
In yet another aspect of the present invention there is provided a sustained release formulation of which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least
one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer and at least one pharmaceutically acceptable diluent and / or lubricant,
c) an optional third layer which comprises of hydrophilic rate controlling polymer.
wherein 30°/p or less amount of alfuzosin is released within first hour and 50%
or more amount of alfuzosin is released within next 19 hours when the
dissolution is measured using USP Type II apparatus at 100 rpm and using
0.01 M hydrochloric acid at 37°C±2.

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In yet another aspect of the present invention there is provided a sustained release formulation of which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer and at least one pharmaceutically acceptable diluent and / or lubricant,
c) an optional third layer which comprises of hydrophilic rate controlling polymer
wherein 25% or less amount of alfuzosin is released within first hour and 50% or more amount of alfuzosin is released within next 19 hours when the dissolution is measured using USP Type II apparatus at 100 rpm and using pH 6.8 phosphate buffer at 37°C±2.
The sustained release dosage form containing alfuzosin or salt thereof includes
solid oral dosage forms such as tablets, capsules, granules and pellets.
The multi-layer composition has at least two functional layers, which comprises of alfuzosin or salt thereof. Each functional layer further comprises of at least one rate-controlling polymer. The percentage of hydrophilic rate controlling polymer in the first layer can vary between 0.1 to 5% w/w of the total weight of the individual layer. The percentage of hydrophilic rate controlling polymer in the second layer
can vary between 0.5% to 95% w/w of the total weight of the individual layer.
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Optionally, each functional layer comprises of at least one pharmaceutical^ acceptable excipient selected from diluent, disintegrant, lubricant, binder, filler or glidant.
The sustained release dosage form may have a dissolution of about 30% or less in about first hour, about 50% or more in next 19 hours when measured in a USP Type II apparatus at 100 rpm and using 0.01 M hydrochloric acid at 37°C ±2. Alternatively, the sustained release dosage form may have a dissolution of about 25% or less in about first hour, about 50% or more in next 19 hours when measured in a USP Type II apparatus at 100 rpm and using pH 6.8 phosphate buffer at 37°C±2.
The pharmaceutical^ acceptable rate controlling polymers can be selected from
a group comprising of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers and mixtures thereof. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid! salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. Suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.
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Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant,
sweetener, coloring and flavoring agent, glidant and the like. The binders may be
one or more of starch, sugars, gums, low molecular weight hydroxypropyl
methylcellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose. The lubricants
may be one or! more of talc, magnesium stearate, calcium stearate, polyethylene
glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and
sodium benzoate. The glidants may be one or both of colloidal silicon dioxide and
talc. Suitable coloring or flavoring agents include those approved for use by the
United States Food and Drug Administration (FDA) and are well known to those
skilled in the art.

The multi-layer composition having more than one functional layer can be
prepared by dry as well as wet granulation.
The dry granulation comprises of preparation of granules corresponding to each functional layer,: which are then suitably lubricated and compressed to form multilayer composition. The composition can be coated to have aesthetic appeal.
Such coating can contain a colorant, plasticizer and a polymer.
In turn, the granules corresponding to each functional layer can be prepared by
mixing alfuzosin or salt thereof along with hydrophilic rate-controlling polymer
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and pharmaceutically acceptable excipients. The blend is compacted along with suitable lubricant and sized to provide granules of desired dimensions.

The individual]functional layer can have about 0.1 mg to 30 mg of alfuzosin or
salt thereof. The first layer can have about 0.1 to 7 mg of alfuzosin or salt thereof
and the second layer can have about 3 mg or more of alfuzosin or salt thereof.
The capsule dosage form can contain a composition mentioned above placed in
empty capsule shell or granules of drug along with rate controlling polymer and
excipient can be filled in the capsule.
While the present invention has been described in terms of its specific

embodiments, certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.

Examples
The composition of the batches is provided in Table 1.
Layer 1: Alfuzosin hydrochloride ranging from 0.1 mg to 7 mg, hydroxypropyl
methylcellulose, lactose, microcrystalline cellulose, aerosil, magnesium stearate,
colorant and povidone were passed through ASTM mesh #60 and mixed in
suitable blender. The blend is compacted to get flakes of suitable hardness. The

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flakes are further sized to get granules of desired dimensions. Lubricant was
passed through ASTM mesh #40 and mixed with the granules.
Layer 2: Alfuzosin hydrochloride about 3 mg or more, hydroxypropyl
methylcellulose, lactose, hydroxypropyl cellulose, microcrystalline cellulose,
aerosil, magnesium stearate and povidone were passed through ASTM mesh
#60 and mixed in suitable blender. The blend is compacted to get flakes of
suitable hardness. The flakes are further sized to get granules of desired
dimensions. Lubricant was passed through ASTM mesh #40 and mixed with the
granules.

Blends of layer 1 and 2 were compressed using suitable tooling to get the bi-layered tablet.
Table 1 provides compositions of present invention.
Table 2 provides the dissolution data of the tablets prepared as per the Formula
provided in Table 1. For determination of drug release rate, 0.01 M hydrochloric
acid buffer in 500 ml of medium using USP Type 2 Apparatus (rpm 100) was
used.
Table 3 provides the dissolution data of the tablets prepared as per the Formula
provided in Table 1. For determination of drug release rate, pH 6.8 phosphate
buffer in 500 ml of medium using USP Type 2 Apparatus (rpm 100) was used.
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Table 1:

Ingredient Example 1 Example 2
I Layer I Layer III _Layer I Layer II

I Mg/tab Mg/tab Mg/tab Mg/tab
Alfuzosin HCI 1.0 9.0 1.0 9.0
HPMC-K100MCR 3.0 55.0 - 50.0
HPMC -K4 M| CR - - 3.5 0
HPC -M - 90.0 - 80.0
Povidone 30 - 12 - 10
Microcrystalline cellulose 67.61 23.55 57.4 31.5
Talc i 0.5 0.75 0.5 0.5
Magnesium stearate 1.0 1.5 1.0 1.0
Aerosil 1.8 3.2 1.5 3.0
Lactose DCL-21i 15 15 35 15
Iron oxide yellow 0.09 - 0.1 -
Layer weight (ring) 90.0 210.0 100.0 200.0
Tablet weight (mg) 300.0 300.0
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Table 2: Dissolution data in 0.01 M HCI Buffer

Duration (hrs) Uroxatral ® % release Example 1 % release Example 2 % release
0.0 0 0 0
1.0 17 22 26
2.0 24 29 36
4.0 35 42 51
6.0 45 52 63
8.0 57 61 73
10.0 ! 67 69 80
12.0 I 77 74 86
14.0 86 79 90
16.0 93 82 93
18.0 ! 100 84 94
20.0 ! 105 86 95
Table 3: Dissolution data in pH 6.8 Phosphate Buffer

Duration(hrs) |i Uroxatral® % release Example 1 % release Example 2 % release
0.0 I 0 0 0
1.0 ! 14 16 19
2.0 ! 20 23 26
4.0 ! 28 31 37
6.0 ! 34 38 46
8.0 40 46 54
10.0 46 52 63
12.0 ! 50 58 67
14.0 ! 57 62 75
16.0 ! 61 66 79
18.0 ! 65 71 82
20.0 ! 70 73 83
Figure 1 and Figure 2 provides comparative drug release profile against Uroxatral® Tablets in acidic and basic media respectively.
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WE CLAIM:
1. A sustained release formulation, which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer,
c) an optional third layer which comprises of hydrophilic rate controlling
i
polymer, wherein a I the layers optionally have one or more pharmaceutically acceptable; diluent and / or lubricant.
2. A sustained release formulation of which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least
one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at
least one hydrophilic rate controlling polymer and at least one
pharmaceutically acceptable diluent and / or lubricant,

c) an optional third layer which comprises of hydrophilic rate controlling
polymer.
3. A sustained release formulation of which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least one hydrophilic rate controlling polymer,
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b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer and at least one pharmaceutically acceptable diluent and / or lubricant,
c) an optional third layer which comprises of hydrophilic rate controlling polymer.
wherein 30% or less amount of alfuzosin is released within first hour and 50%
l
or more amount of alfuzosin is released within next 19 hours when the dissolution is measured using USP Type II apparatus at 100 rpm and using 0.01 M hydrochloric acid at 37°C ±2.

4. A sustained release formulation of which comprises of
a) first layer comprising alfuzosin or salt thereof and less than 5% of at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 0.5 to 95% of at least one hydrophilic rate controlling polymer and at least one pharmaceutically acceptable diluent and / or lubricant,
c) an optional third layer which comprises of hydrophilic rate controlling
polymer i
wherein 25% or less amount of alfuzosin is released within first hour and 50%
or more amount of alfuzosin is released within next 19 hours when the
dissolution' is measured using USP Type II apparatus at 100 rpm and using
pH 6.8 phosphate buffer at 37°C±2.
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5. A sustained release formulation of claims 1 to 4 wherein about 0.1 mg to 30 mg of alfuzosin or salt thereof is present in individual layer.
6. A sustained release formulation of claims 1 to 5 wherein first layer comprises

of about 0.1 to! 7 mg of alfuzosin or salt thereof.
7. A sustained release formulation of claims 1 to 5 wherein the second layer comprises of about 3 mg or more of alfuzosin or salt thereof.
8. A sustained release formulation of claims 1 to 7 wherein hydrophilic rate controlling polymer is cellulose ether derivative.
9. A sustained release formulation of claims 1 to 7 wherein pharmaceutically acceptable excipient is selected from diluent, binder, filler, lubricant, disintegrant, colorant or antioxidant.

10. A sustained granules, pellets release formulation of claims 1 to 9 in form of tablet, capsule, lets meant for oral administration.

Dated this 12 TH day of January 2006

For Wockhardt Limited

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