FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
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 with at least one pharmaceutically acceptable hydrophilic rate-controlling polymer and at least one other pharmaceutically acceptable excipient.
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 with at least one pharmaceutically acceptable hydrophilic rate-controlling polymer and at least one other pharmaceutically acceptable excipient.
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 tablet 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 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
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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.
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
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achieved by having a multi-layer composition in which more than one layer are functional.
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 at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 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 pharmaceutical^ acceptable diluent and / or lubricant.
In 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 5 to 95% of at least one hydrophilic rate controlling polymer,
b) second layer comprising alfuzosin or salt thereof and 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.
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In yet another aspect of the present invention there is provided a sustained release formulation of which comprises of
a) an immediate release layer comprising alfuzosin or salt thereof along with at least one pharmaceutically acceptable excipient,
b) a sustained release layer comprising alfuzosin or salt thereof along with at least one hydrophilic rate controlling polymer and one or more pharmaceutically acceptable excipient,
wherein 30% 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.
In yet another aspect of the present invention there is provided a sustained release formulation of which comprises of
a) an immediate release layer comprising alfuzosin or salt thereof along with at least one pharmaceutically acceptable excipient,
b) a sustained release layer comprising alfuzosin or salt thereof along with at least one hydrophilic rate controlling polymer and one or more pharmaceutically acceptable excipient,
wherein 20% 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
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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. In case of immediate release layer the rate-controlling polymer can be optional. The percentage of hydrophilic rate controlling polymer can vary between 5% to 95% w/w of the total weight of the individual layer. Optionally, each functional layer comprises of at least one pharmaceutically 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 20% 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.
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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.
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.
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The multi-layer composition prepared by dry as well as
having more than one functional layer can be a wet granulation.

The dry granulation functional layer, which layer composition .The
Such coating can contain
comprises of preparation of granules corresponding to each are then suitably lubricated and compressed to form multi-composition can be coated to have aesthetic appeal,
a colorant, plasticizer and a polymer.

In turn, the granules mixing alfuzosin or and pharmaceuticall suitable lubricant and
corresponding to each functional layer can be prepared by salt thereof along with hydrophilic rate-controlling polymer acceptable excipients. The blend is compacted along with 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 immediate release layer can have about 0.1 to 7 mg of alfuzosin or salt thereof and the sustained release layer can have about 3 mg or more of alfuzosin or salt thereof.

The capsule dosage empty capsule shell excipient can be filled
form can contain a composition mentioned above placed in or granules of drug along with rate controlling polymer and in the capsule.
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While the present embodiments, certain skilled in the art and
invention has been described in terms of its specific
modifications and equivalents will be apparent to those
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, hydroxypropyl cellulose, 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 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.
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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.
Table 1:

Ingredient Example 1 Example 2
Layer I Layer II Layer I Layer II

Mg/tab Mg/tab Mg/tab Mg/tab
Alfuzosin HCI 5.0 5.0 2 8
HPMC-K100MCR 37.5 37.5 - 60
HPMC -K4 M CR - - 8.0 -
HPC-M 60.0 60.0 8 -
Povidone 30 7.5 7.5 10 96
Microcrystalline cellulose 26.5 26.5 31.69 42.4
Talc 0.5 0.5 0.25 0.8
Magnesium stearat e 1.0 1.0 0.5 1.6
Aerosil 2.0 2.0 0.5 3.2
Lactose DCL-21 10 10 0.5 16
Iron oxide yellow - - 0.06 ~
Layer weight (mg) 150 150 60.0 240
Tablet weight (mg) 3( )0.0 30 0.0

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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 14 17
2.0 24 22 26
4.0 35 34 39
6.0 45 45 51
8.0 57 54 61
10.0 67 62 69
12.0 77 68 76
14.0 86 75 82
16.0 93 81 86
18.0 100 84 89
20.0 105 88 92
Table 3: Dissolution data in pH 6.8 Phosphate Buffer

Duration (hrs) Uroxatral® % release Example 1 % release Example 2 % release
0.0 0 0 0
1.0 14 8 14
2.0 20 14 22
4.0 28 22 32
6.0 34 30 42
8.0 40 37 49
10.0 46 44 57
12.0 50 49 63
14.0 57 54 69
16.0 61 59 75
18.0 65 63 79
20.0 70 67 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 at least one hydrophilic rate controlling polymer,
b) second layer
hydrophilic rate
c) an optional polymer,
wherein all the acceptable diluen
comprising alfuzosin or salt thereof and at least one controlling polymer,
third layer which comprises of hydrophilic rate controlling
layers optionally have one or more pharmaceutically
t and / or lubricant.

2. A sustained release formulation of which comprises of
a) first layer comprising alfuzosin or salt thereof and 5 to 95% of at least one hydrophilic rate controlling polymer,
b) second layer hydrophilic r
comprising alfuzosin or salt thereof and at least one ate 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) an immediate at least one
d release layer comprising alfuzosin or salt thereof along with
pharmaceutically acceptable excipient,
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b) a sustained re ease layer comprising alfuzosin or salt thereof along with at least one hydrophilic rate controlling polymer and one or more pharmaceutically acceptable excipient,
wherein 30% 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.
4. A sustained release formulation of which comprises of
a) an immediate release layer comprising alfuzosin or salt thereof along with at least one pharmaceutically acceptable excipient,
b) a sustained release layer comprising alfuzosin or salt thereof along with at least one hydrophilic rate controlling polymer and one or more pharmaceutically acceptable excipient,
wherein 20% 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.
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.
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6. A sustained release formulation of claims 3 and 4 wherein immediate release layer comprises about 0.1 to 7 mg of alfuzosin or salt thereof.
7. A sustained release formulation of claims 3 and 4 wherein the sustained release layer comprises 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.

acceptable exci disintegrant,
9. A sustained release formulation of claims 1 to 7 wherein pharmaceutically pient is selected from diluent, binder, filler, lubricant, colorant or antioxidant.
10. A sustained release formulation of claims 1 to 9 in form of tablet, capsule,

granules, pellets

meant for oral administration.


Dated this k™ day of

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