FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
COMPLETE SPECIFICATION
"BILAYERED SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING
ALFUZOSIN"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at B/2, Mahalaxmi Chambers 22, Bhulabhai Desai Road
Post Box No. 26511 Mumbai- 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

"BILAYERED SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING ALFUZOSIN"
This application claims the benefit under Indian Provisional Application 1419/MUM/2005, filed on November 14, 2005, and entitled "BILAYERED SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING ALFUZOSIN", the contents of which are incorporated by reference herein.
FIELD OF INVENTION:
Present field of invention relates to bilayered sustained release tablet comprising Alfuzosin ((R, S)-N-[3-[(4-amino-6, 7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide) or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof, and method of manufacturing the same.
BACKGROUND OF INVENTION:
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 15 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 exclusively for the treatment of benign prostatic hyperplasia and, more specifically, for the treatment of the symptoms associated with benign prostatic
2

hyperplasia. Alfuzosin is indicated for the treatment of moderate to sever symptoms of benign prostatic hyperplasia.
Amongst the various dosage forms that have been submitted and approved by regulatory agencies in Europe, the USA, and other countries there are various administration regimens. For example, the 2.5 mg immediate release tablet dosage form is generally administered three times per day. The 5 mg modified release tablet may be administered once or twice per day depending on the age of the patient and the condition to be treated. A once daily formulation of alfuzosin, Xatral- XL (available in Europe) and Uroxatral (recently approved in the USA), provides equivalent systemic exposure when compared to the 2.5 mg immediate release tablet dosage form of alfuzosin administered 30 thrice daily. These once daily formulations were developed to provide a controlled release of alfuzosin over an extended period of time for 24 hours.
U.S. Patent No. 6,149,940 discloses a preparation of an alfuzosin 10 mg once daily composition for oral delivery using a technology termed Geomatrix that has been developed by Jagotec-AG. The three-layer Geomatrix tablet described in the '940 patent 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. 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 capacity for absorption. The alfuzosin is released 1 in zero order from the dosage form developed using this technology. However, the manufacture of multi- layered tablets by this technology involves special facilities, is time consuming, complex to produce, and consequently relatively expensive.
U.S. Patent No. 5,589,190 discloses a pharmaceutical composition that includes an alfuzosin core. The core is coated with a coating whose dissolution is pH dependent, 20
3

which thereby enables the release of alfuzosin to be modulated over the entire length of the digestive tract. The '190 patent teaches that the sustained release of alfuzosin is dependent on the nature and thickness of the coating. Further, the '190 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. These coated formulations, however, have disadvantages including the possibility of leakage of active ingredient from the coating and the need for strict process controls during their manufacture.
WO2004037228 discloses a pharmaceutical composition of alfuzosin or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof, which release the active ingredient over an extended period of time. The pharmaceutical composition can be a sustained release oral dosage form that includes a single functional layer and, optionally, one or more nonfunctional layers adjacent to the single functional layer. The single functional layer includes alfuzosin or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof and one or more release retarding ingredients.
OBJECTIVE OF THE INVENTION:
Objective of the present invention is directed to a bilayered sustained release tablet comprising Alfuzosin or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof, and method of manufacturing the same. One of the layers of the bilayered tablet would include drug along with a hydrophilic polymer and the second layer would include hydrophobic polymer with or without drug.
DETAILED DESCRIPTION OF INVENTION:
The present invention provides a bilayered sustained release tablet comprising Alfuzosin or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof and one or more release retarding ingredients and one or more pharmaceutically acceptable excipients. One of the layers of the bilayered tablet would include drug along with a hydrophilic polymer and the second layer would include hydrophobic polymer with or without drug.
4

The release retarding agents described herein in this specification could be hydrophilic polymer or a hydrophobic polymer.
The term "release retarding ingredients" as used herein refers to any suitable polymer capable of retarding the release of active ingredient for about 12 to about 24 hours. Suitable release retarding ingredients include one or more of cellulose derivatives, acrylic acid or methacrylate polymers/copolymers, gums, vinyl alcohol or vinyl pyrrolidone based polymers, block copolymers, polyethylene oxide, lipids and waxes.
Suitable cellulose polymers include, for example, one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and ethyl cellulose. Suitable gums include, for example, one or more of xanthum gum, caraya gum, locust bean gum, alginic acid, gaur gum and sodium alginate. The acrylic acid or methacrylic acid/methacrylate based polymers may include one or more of Eudragit polymers, such as Eudragit L- 100, L 30 D- 55, L-100 55, S-100 and Carbomers or Carbopols. Suitable waxes include paraffin, carnauba, beeswax, or equivalents. Suitable lipids include hydrogenated vegetable oil, long chain fatty acid esters, and derivatives thereof.
The release retarding agents such as hydrophilic polymers may include ,but are not limited to cellulose derivatives include hydroxy CI-4 alkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. For example, the hydrophilic agent may be a mixture of two different types or two different grades of the hydroxy CI-4 alkyl celluloses Carboxyalkyl celluloses like carboxymethyl cellulose and its alkali salts, and d embodiments of the present invention crosslinked carboxyalkyl celluloses like crosslinked carboxymethyl cellulose, commonly known as croscarmellose, and its alkali salts may also be used as the hydrophilic polymers.
5

The release retarding agents such as hydrophobic polymers may include ,but are not limited to acrylic acid or methacrylic acid/methacrylate based polymers may include one or more of Eudragit polymers, such as Eudragit L- 100, L 30 D- 55, L-100 55, S-100 and Carbomers or Carbopols. Suitable waxes include paraffin, carnauba, beeswax, or equivalents. Suitable lipids include hydrogenated vegetable oil, long chain fatty acid esters, and derivatives thereof.
The amount of release retarding ingredient in the composition ranges from about 10% to about 90%, preferably between about 30% to about 80%, and more preferably between about 50% to about 75% by weight of the composition. The amount of lubricants/glidants in the composition ranges from about 0.5% to about 5%, and more preferably between about 1.0% to about 3. 0% by weight of the composition. The amount of binders in the composition ranges from about 2% to about 10%, and more preferably about 3.5% to 6%. The amount of filler varies from about 10% to about 60%, and more preferably from about 12% to about 30%. These amounts (i.e., release retarding ingredient, lubricant/glidant, and binder) are based on the weight of the composition. The pharmaceutically acceptable excipients may be selected, for example, from binders such as polyvinyl pyrrolidone, pregelatinized starch and gelatin; diluents such as lactose, mannitol and microcrystalline cellulose; and lubricants/glidants such as magnesium stearate, zinc stearate, talc and colloidal silicon dioxide. In one preferred embodiment, the sustained release dosage form includes hydroxypropyl methylcellulose in amounts ranging from about 10% to about 90% w/w, hydroxypropyl methylcellulose in amounts ranging from about 15% to about 50% w/w, hydroxypropyl cellulose in amounts ranging from about 10% to about 90% w/w, hydroxypropyl cellulose in amounts ranging from about 15% to 50% w/w, Eudragit L-100 55 in amounts ranging from about 1% to about 20% w/w, Eudragit L-100 55 in amounts ranging from about 4% to about 12% w/w, lactose in amounts ranging from about 10% to; about 60% w/w, polyvinyl pyrrolidone in amounts ranging from about 2% to about 10% w/w, magnesium stearate in amounts ranging from about 0.1% to about 5% w/w, talc in amounts ranging from about 0.1% to about 5% w/w, and colloidal silicon dioxide in amounts ranging from about 0.1% to 5% w/w.
6

The sustained release composition may be ultimately processed in the form of tablets, capsules, pellets, granules or other dosage form suitable for oral administration. The tablets may be prepared by various techniques such as direct compression, wet granulation or dry granulation. The tablets may be optionally coated with a nonfunctional coating to form a nonfunctional layer. The tablet/minitablets may be optionally filed into 10 capsules.
The following examples are provided to further exemplify the invention, and are not intended to limit the scope of the invention.
EXAMPLE 1
Preparation of the granulate constituting the first layer comprising of Hydrophilic swellable polymers

Sr.No Ingredients mg/tab
1. Alfuzosin Hydrochloride 0-10
2. Gaur gum 87.5
3. Xanthan Gum 87.5
4. Lactose 158-168
5. Talc 1.75
6. Colloidal silicon dioxide 1.75
7. Magnesium stearate 3.5
Total weight of first layer 350.00
All the ingredients are sifted and mixed by geometric dilution and passed through roll compactor. The roll compacted mass was then milled through 30 mesh.
7

(B) Preparation of granulate constituting the second layer comprising of nonswellable polymers

Sr.No Ingredients mg/tab
Alfuzosin Hydrochloride 0-10
Ethyl cellulose 75.00
Mannitol 63.5-73.5
Talc 0.75
Magnesium stearate 0.75
Total weight of second layer 150.00
All the ingredients are sifted and mixed by geometric dilution.
(C) Preparation of the two layer tablets (By compression)
Bilayered tablet was prepared by using suitable tablet compression machine.
EXAMPLE 2
(A) Preparation of the granulate constituting the first layer comprising of Hydrophilic swellable polymers

Sr.No Ingredients mg/tab
1. Alfuzosin Hydrochloride 0-10
2. Carbopol 74G NF 105 -140
3. Lactose 193-228
4. Talc 1.75
5. Colloidal silicon dioxide 1.75
6. Magnesium stearate 3.5
Total weight of first Layer 350.00
All ingredients are sifted and mixed by geometric dilution and passed through roll compactor. The roll compacted mass was then milled through 30 mesh.
(B) Preparation of granulate constituting the second layer comprising of nonswellable polymers
Sr. No Ingredients mg/tab

8
1. Alfuzosin Hydrochloride 0-10
2. Ethyl cellulose 75.00
3. Mannitol 63.5-73.5
4. Talc 0.75
5. Magnesium stearate 0.75
Total weight of second layer 150.00
All the ingredients are sifted and mixed by geometric dilution.
(C) Preparation of the two layer tablets (By compression)
Bilayered tablet was prepared by using suitable tablet compression machine

9

Claims:
1. A pharmaceutical composition in the form of a bilayered sustained release tablet
comprising Alfuzosin or pharmaceutically acceptable salt, solvates, enantiomers or
mixtures thereof and one or more release retarding ingredients in both the layers and one
or more pharmaceutically acceptable excipients
2. A pharmaceutical composition as claimed in claim 1 wherein the release retarding
agent comprises hydrophilic polymer or hydrophobic polymer.
3. A pharmaceutical composition in the form of a bilayered sustained release tablet as claimed in claim 1 and claim 2 comprising drug along with a hydrophilic polymer in one layer and the second layer would include hydrophobic polymer with or without drug
4. A pharmaceutical composition according to claim 1 wherein the concentration of the compression aid in the at least one non-steroidal anti-inflammatory phase is between 10% and 90% (by wt).
5. A pharmaceutical composition according to claim 1 wherein the release retarding ingredient in the composition ranges from about 10% to about 90%, preferably between about 30% to about 80%, and more preferably between about 50% to about 75% by weight of the composition
6. A pharmaceutical composition in the form of a bilayered sustained release tablet as claimed in claim 1 comprising two separate layers that are prepared by wet granulation technique or dry granulation technique or using slugging technique.
7. A sustained release pharmaceutical composition comprising Alfuzosine may be
ultimately processed in the form of capsules, pellets, granules or other dosage form
suitable for oral administration
10

8. A pharmaceutical composition according to claim 1 wherein tablets may be optionally coated with a nonfunctional coating to form a nonfunctional layer.
9. The process of making a bilayered sustained release tablet comprising Alfiizosin or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof and one or more release retarding ingredients in both the layers and one or more pharmaceutically acceptable excipients as depicted in examples of the specification.

11

ABSTRACT
The present invention is directed to a bilayered sustained release tablet comprising Alfuzosin or pharmaceutically acceptable salt, solvates, enantiomers or mixtures thereof, and method of manufacturing the same. One of the layers of the bilayered tablet would include drug along with a hydrophilic polymer and the second layer would include hydrophobic polymer with or without drug.
Dated this fourteenth (14th) day of November, 2006

1