FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
PROVISOINAL SPECIFICATION (SECTION 10)
"ALFUZOSIN EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS"

UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER
THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE
LOCATED AT MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAI DESAI ROAD, MUMBAI-400 026.
MAHARASTRA. INDIA


The following specification describes the invention.
"ALFUZOSIN EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS"
FIELD OF INVENTION
The present invention relates to the field of pharmaceutical technology and describes a novel and advantageous method of manufacturing of extended release matrix tablets comprising alfuzosin or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, an oc,-Adrenoceptor antagonist for the treatment of urinary disorders associated with benign prostatic hyperplasia, and method of preparing the same
BACKGROUND OF THE INVENTION
Alfuzosin hydrochloride is a quinazoline derivative, selective and competitive alpha-adrenoreceptor antagonist that belongs to the chemical class of 4-amino-6, 7-dimethoxy quinazol-2-yl-alkylene diamines. It distributes preferentially in the prostate compared with plasma, and decreases the sympathetically controlled tone of prostatic smooth muscle. As a result lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH) are improved. Alfuzosin has a relatively short -half life and shows the characteristic of being absorbed preferentially in the upper part of gastrointestinal tract and, in particular, more intensely absorbed at the duodenum and jejunum. Extended release drug delivery systems have the advantages such as patient compliance, reduced toxicity and also provide a desired therapeutic effect throughout the day.
Presently, Alfuzosin is commercially available as 2.5 mg of immediate release tablets; 5 mg and 10 mg controlled release tablets. Controlled release formulations are available commercially under the brand name XATRAL-XL in Europe and as UROXATRAL in USA.
U.S. Patent 6,149,940 (Maggi L. et al, 2000) discloses the preparation of alfuzosin 10 mg once daily composition for oral delivery using Geomatrix technology. This multi-
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layer tablet, comprising hydrophilic active matrix core containing Alfuzosin and two inert, functional layers, which controls the hydration and swelling rate of the core, there by retard the release of the active ingredient. Manufacturing of this multi layered tablets require special facilities, and the technique is time consuming and relatively expensive.
International Application Publication WO 2004/037228 Al (Viswanathan. et al, 2004) describes the pharmaceutical composition containing Alfuzosin, and the composition can be a sustained release oral dosage form that includes a single functional layer, and optionally one or more non functional layers adjacent to the single functional layer. The '228 covered composition is also layered tablet composition which involves more manufacturing steps and also requires special technology for manufacturing.
US Patent Application Publication 20060062846 A1 (Mathias S. et al, 2006) discloses the controlled release of Alfuzosin in the monolithic polymeric matrix which releases the drug over a period of time by using release retarding agents (ike hvdroxypropylmethyl cellulose and Povidone. Under '846 direct compression or dry granulation or wet granulation is covered as a method of manufacturing of tablets. However, as concentration of alfuzosin in the formulation is very low (10 mg /unit), there is possibility of segregation of active or non-uniformity of drug across the dosage form can be observed, particularly with direct compression strategy. Present invention is cost effective and involves simple manufacturing procedure, and wherein there is no possibility of segregation or non-uniformity of drug across the dosage i.e. the drug is uniformly distributed across the dosage form-Abstract of WO/2006/021692 (Aiaux, et al, 2006) which describes about pharmaceutical composition in the form of a gastric resident matrix tablet, comprising an active principle, characterized in that when contacted with an environment representing a gastric fluid, it increases after fifteen minutes in volume by swelling rate of at least 200%. Drawbacks of this system that there can be dose dumping accidentally due to more swelling as well as patients may feel stomach fullness, which causes the discomfort.
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Even though many technologies are available, which allows to flexibly of modulate the release kinetics, has however problems such as high production costs and difficulty in reproducing the release kinetics. Therefore there is a need of, simple and effective composition which eliminates all these disadvantages.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved, simple and cost effective composition and process of preparation of the extended release matrix system, comprising alfuzosin or pharmaceutically acceptable its salt, solvate, enantiomers or mixtures thereof, by using drug release retarding agents.
SUMMARY OF THE INVENTION
The present invention relates to the composition and process of preparation of an extended release oral pharmaceutical composition comprising, Alfuzosin or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
The present invention provides a cost effective and simple manufacturing process, which is independent of particle size of active ingredient. Moreover, present invention discloses the composition, where there is no possibility of dose dumping as drug is uniformly adsorbed on pharmaceutically acceptable excipients.
An extended release pharmaceutical composition is in the form of matrix system, containing active ingredient, which is adsorbed or dispersed on one or more release retarding agents along with pharmaceutically acceptable excipients. Release retarding agents may comprises one or more of cellulose derivatives, gums, carboxyvinyl polymers, chitosans, carrageenans, methacrylates and copolymers, polyanhydrides, polyvinyl alcohol, glucans, dextran, waxes and vegetable oils. The cellulose derivative may be one or more of ethyl cellulose, hydroxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropylceiiulose, carboxy methyl cellulose,
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and methyl cellulose. Gum comprises one or more of xanthan gum. veegurn, guar gum, karaya gum, locust bean gum, gellan gum, hupu gum, carob gum, caramania, sodium alginate and alginic acid. Glucans may be one or more of lichenin, nigeran and glycogens.
The extended release matrix system further includes one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may include one or more of binders, diluents, glidants, and lubricants.
The binder may be one or more of polyvinyl pyrrolidone, magnesium aluminum silicate, co-povidone, acacia, agar, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate pthalate, ceratonia, chitosan, sugar, dextrin, ethyl cellulose, glyceryl behenate, guar gum, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, lactose, methylcellulose, microcrystalline cellulose, poloxamer, polyethylene oxide, sodium alginate, sorbitol and pregelatinized starch.
The diluent may be one or more of lactose, starch, dibasic calcium phosphate dihydrate, tnanrtitol, sorbitol, calcium sulphate dihydrate, dextrose, cellulose acetate, compressible sugar, ehylceliulose, polymethacryiates, sodium alginate, tragacanth, xylitol and microcrystalline cellulose.
The lubricant may be one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fiimerate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium lauryl sulfate, palmitic acid, poloxamer, sodium benzoate, sodium lauryl sulfate, and calcium stearate.
The glidant may be one or more colloidal silicon dioxide, calcium phosphate tribasic, calcium silicate, magnesium silicate, silicon dioxide, talc and starch.
The extended release formulation may contain 1-10% of Alfuzosin hydrochloride, 1-95% of one or more grades of the hydroxypropyl methylcellulose, 1-30% of the povidone, 1-50% of lactose, 0.1-5% of the magnesium stearate, and 0.1-5% of the colloidal silicon dioxide
The extended release formulation may also coma in 1-10% of Alfuzosin hydrochloride, 1-95% of one or more grades of the hydroxypropylmethyl cellulose. I-50 % of one or more types of gums, 1-30%) of the povidone, 1-50% of lactose, 0.1-5% ofthe magnesium stearate, and 0.1-5%) of the colloidal silicon dioxide.
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The matrix composition of the present invention may include the active ingredient in a range of about 1 mg to about 20 mg. Preferred dosage form contain either 5 mg or 10 mg of the active ingredient. The term 'active ingredient' refers to alfuzosin or pharmaceutical!}' acceptable salt, solvate, enantiomers or mixtures thereof.
The formulation may contain 1-10% of the active ingredient. Preferably formulation may contain 1-5% of the active ingredient. The active ingredient may be alfuzosin or pharmaceutical ly acceptable salt, solvate, enantiomers or mixtures thereof.
The formulation may contain 1-95% of the release modifying agents. Preferably formulation may contain in between 5-85% of the release modifying agents.
The formulation may contain 1-80% of the binders. Preferably formulation may contain in between 1-50% of the binders.
The formulation may contain 1-90% of the diluents. Preferably formulation may contain 1-85% of the diluents.
The formulation may contain 0.1-5% of the glidants. Preferably formulation may contain 0.1-3% of the glidants.
The formulation may contain 0.1-5%o of the lubricants. Preferably formulation may contain 0.1-3% of the lubricants.
In one preferred embodiment, the extended release matrix system may include Alfuzosin or pharmaceutical ly acceptable salt, solvate, enantiomers or mixtures thereof in amounts ranging from about 1% to about 10% w/w, hydroxypropylmethyl cellulose grades in amounts ranging from about 1% to about 95% w/w, povidone in amounts ranging from about 1% to about 30% w/w, lactose in amounts ranging from about 1% to about 50% w/w, magnesium stearate in amounts ranging from about 0.1%) to about 3% w/w, and colloidal silicon dioxide in amounts ranging from about 0.1%toabout3% w/w.
The extended release matrix system may be in the form of one or more of tablets, capsules, pellets, granules and other dosage forms suitable for oral administration
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The extended release matrix system release the drug less than about 25% in about 1 hour, less than about 75 % in about 8 hourse as measured in O.OIN HCL using USP type 11 apparatus, at 37±2°C.
The extended release matrix system release the drug less than about 50% in about 4 hours, less than about 85% in about 12 hours, as measured in 0.01N HCL using USP type 11 apparatus, at 37±2°C.
The extended release matrix system release the drug less than about 50% in about 4 hours, more than about 90% in about 24 hours, as measured in a O.OIN HCL using USP type II apparatus, at 37±2°C.
The extended release pharmaceutical composition may be used for the treatment of benign prostatic hyperplasia (BPH).
The extended release pharmaceutical composition may be administered orally either twice daily or once daily as per the requirement.
The extended release matrix system may be prepared by adsorption method or spray drying method.
In another aspect there is provided a process for forming an extended release matrix system in oral dosage form. The process includes:
• Prepare the aqueous solution containing active ingredient.
. • Spray the active ingredient solution on the mixture of pharmaceutically acceptable excipients in fluidized bed processor and dry the sprayed granules
• Mix the spray-dried granules with extra granulate excipients and lubricate with pharmaceutically acceptable Lubricants.
• Compress the lubricated granules to form a extended release matrix tablet.
In another aspect, the process for preparing an extended release matrix system may be done by adsorption method. The process includes:
• Prepare the aqueous or hydro alcoholic or non-aqueous solution containing active ingredient.
• Adsorb the active ingredient solution on the mixture of pharmaceutically acceptable excipients using rapid mixture granulator and dry the wet granules using fluidized bed drier or processor
• Mix the dried granules with extra granulate excipients and lubricate with pharmaceutically acceptable lubricants.
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• Compress the lubricated granules to form a extended release matrix tablet.
The matrix system may include esthetic coating. The esthetic coating may or may not include colorant.
Forming matrix system may be in the form of tablets, capsules, pellets, granules or other dosage forms suitable for oral administration.
According to the present invention provides a pharmaceutical composition is in the form of tablets or capsuies, which relates to extended release matrix system of Alfuzosin that may substantially reduce the adverse events, which are present in the art of conventional tablets. Alfuzosin absorbed greatly in upper parts of the GI tract, especially absorbed in duodenum and jejunum. The present composition is a matrix system containing Alfuzosin, which releases the drug in a controlled fashion over an extended period of time.
Although the invention has been described with reference to specific embodiments,
this description is not meant to be construed in a limiting sense. Various modifications
of the disclosed embodiments, as well as alternate embodiments of the invention, will
become
apparent to persons skilled in the art upon reference to the description of the
invention. It is therefore contemplated that such modifications can be made without
departing from the spirit or scope of the present invention as defined.
EXAMPLES
The following different trials performed to manufacturing of Alfuzosin HCI ER Tablets 10 mg for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example 1
Table 1: Formulation of example 1

Sr. No Ingredients Quantity per Tablet in mg
1 Alfuzosin HCL EP/BP 10.0
2 Hydroxypropyl methyl cellulose 5 cps USP 50.0
i 333 Lactose USP 50.0
4 Povidone K-29/32 USP 24.0
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:> Hydroxypropyl methyl cellulose K100M USP 160.0
6 Colloidal silicon dioxide USP 3.0
7 Magnesium stearate USP 3.0
8 Purified water USP qs
Tablet weight 300.0
Manufacturing process:
Alfuzosin HCl was dissolved in purified water and sprayed on the mixture of Hydroxypropyl methyl cellulose 5 cps, lactose and povidone K-29/32 using Fluid bed processor. Wet granules were dried till the LOD reach to 2-3% w/w and dried granules were sifted.through the mesh # 30 ASTM. These dried granules were mixed with Hydroxypropyl methyl cellulose KlOO M (#40 mesh) and finally lubricated with Colloidal silicon dioxide and Magnesium stearate (#40 mesh). The above mixture was compressed into tablets by using 8.0 mm round flat face beveled edge punches.
Example 2
Table 2 formulation of example 2

Sr.No Ingredients Quantity per Tablet in mg
1 Aifuzosin HCL EP/BP 10.0
2 Hydroxypropyl methyl cellulose 5 cps USP 50.0
3 Lactose USP 50.0
4 Povidone K-29/32 USP 24.0
5 Xanthan gum 20.0
6 Hydroxypropyl methyl cellulose K100M USP 140.0
7 Colloidal silicon dioxide USP 3.0
8 Magnesium stearate USP 3.0
9 Purified water USP qs
Tablet weight 300.0
Manufacturing process:
Aifuzosin HCl was dissolved in purified water and sprayed on the mixture of Hydroxypropyl methyl celiulose 5 cps, lactose and povidone K-29/32 using Fluid bed processor. Wet granules were dried till the LOD reach to 2-3% w/w and dried granules were sifted through the mesh # 30 ASTM. These dried granules were mixed with Hydroxypropyl methyl cellulose KlOO M and Xanthan gum (#40 mesh) and finally lubricated with Colloidal silicon dioxide and Magnesium stearate (#40 mesh). The
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above mixture was compressed into tablets by using 8.0 mm round flat face beveled edge punches.
Example 3
Table 3 formulation of example 3

Sr. No Ingredients Quantity per Tablet in mg
1 Alfuzosin HCLEP/BP 10.0
2 Hydroxypropyl methyl cellulose 5 cps USP 50.0
3 Lactose USP 50.0
4 Povidone K-29/32 USP 24.0
5 Hydroxypropyl methyl cellulose K100M USP 160.0
6 Colloidal silicon dioxide USP 3.0
7 Magnesium stearate USP 3.0
8 Purified water USP qs
Tablet weight 300.0
Manufacturing process:
Alfuzosin HCI was dissolved in purified water and adsorbed on the mixture of Hydroxypropyl methyl cellulose 5 cps, lactose and povidone K-29/32 using rapid mixer granulator. Wet granules were dried till the LOD reach to 2-3% w/w and dried granules were sifted through the mesh # 30 ASTM. These dried granules were mixed with Hydroxypropyl methyl cellulose K100 M (#40 mesh) and finally lubricated with Colloidal silicon dioxide and Magnesium stearate (#40 mesh). The above mixture was compressed into tablets by using 8.0 mm round flat face beveled edge punches.
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Dated this 16th day of July, 2008