FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
SUSTAINED RELEASE
PHARMACEUTICAL COMPOSITIONS OF
ALFUZOSIN AND PROCESS FOR
PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the invention:
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FIELD OF THE INVENTION
The present invention relates to sustained release pharmaceutical compositions of alfuzosin, process for preparing such compositions and method of using such compositions.
BACKGROUND OF THE INVENTION
Alfuzosin is a selective oc1 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 oq-adrenoceptor mediated contraction of prostatic, prostatic capsule, bladder base and proximal urethral structures and is used in the treatment of signs and 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 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.
U. S. Patent No. 6,149,940 discloses a preparation of an alfuzosin once daily composition for oral delivery using a Geomatrix technology that has been developed by Jagotec-AG. The three-layer Geomatrix tablet described in this patent consists of a hydrophilic active matrix core containing alfuzosin hydrochloride and two inert, functional layers (one swellable layer and one erodible layer) whose function is 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 better absorption window. The alfuzosin is released in zero order from the dosage form developed using this technology.
The WO 97/18814 patent application assigned to Pfizer discloses a controlled-release pharmaceutical formulation of doxazosin with low molecular weight polyethylene oxide and hydroxypropylmethyl cellulose.
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U.S. Patent Applications No. 2006/0062846 and 2006/0062845 assigned to Cimex disclose a monolithic composition of alfuzosin which does not float in gastric fluid. The applications disclose compositions which show desired dissolution profile with more than 70% by weight of hydroxypropyl methylcellulose based on the weight of the total composition. The applications also disclose use of polyvinylpyrrolidone as a dry binder in the composition.
The WO 04/37228 patent application assigned to Ranbaxy discloses 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, solvate, enantiomers or mixtures thereof and one or more release retarding ingredients. The release retarding ingredient may be one or more of cellulose polymer, methacrylate polymer, acrylic acid polymer, block copolymer, gum or polyethylene oxide. It discloses use of polyvinylpyrrolidone as a dry binder.
It was observed that preparation of sustained release alfuzosin formulation which is bioequivalent to the reference product available in various countries, specifically UroXatral® marketed by Sanofi in United States, is difficult due to unique nature of the formulation and specific absorption window of the drug in Gl tract. The efforts to prepare bioequivalent composition using teachings of the prior art resulted in failure and most of the times undue experimentation.
We have surprisingly found that the sustained release pharmaceutical composition of alfuzosin, can be prepared by incorporating a mixture of two or more polymers only in the specific concentration in the composition.
SUMMARY OF THE INVENTION
In one aspect, the invention discloses a sustained release pharmaceutical composition comprising:
(i) alfuzosin,
(ii) a rate controlling polymer, and
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(iii) optionally one or more pharmaceutical^ acceptable excipients.
In another aspect, the invention discloses a sustained release pharmaceutical composition comprising:
(i) alfuzosin,
(ii) a rate controlling polymer, and
(iii) optionally one or more pharmaceutical^ acceptable excipients, wherein rate controlling polymer is present extragranularly.
In another aspect, the invention discloses a process for preparation of a sustained release pharmaceutical composition, wherein the process comprising:
(i) mixing alfuzosin, a rate controlling polymer and optionally one or more
pharmaceutically acceptable excipients, (ii) granulating the mixture of step (i) with a granulating solvent or a solution, (iii) drying the granules of step (ii), (iv) mixing the granules of step (iii) with a rate controlling polymer and optionally
one or more pharmaceutically acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.
In another aspect, the invention discloses a process for preparation of a sustained release pharmaceutical composition, wherein the process comprising:
(i) mixing alfuzosin with optionally one or more pharmaceutically acceptable
excipients, (ii) granulating the mixture of step (i) with a granulating solvent or a solution, (iii) drying the granules of step (ii), (iv) mixing the granules of step (iii) with a rate controlling polymer and optionally
one or more pharmaceutically acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.
In another aspect, the invention discloses a process for preparation of a sustained release pharmaceutical composition, wherein the process comprises:
(i) mixing alfuzosin, a rate controlling polymer and optionally one or more pharmaceutically acceptable excipients,
(ii) granulating the mixture of step (i) with a granulating solvent or a solution,
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(iii) drying the granules of step (ii),
(iv) mixing the granules of step (iii) with optionally one or more phamnaceutically
acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.
In yet another aspect, the invention discloses sustained release pharmaceutical composition consisting essentially of:
(i) 1-15% by weight alfuzosin,
(ii) 35-69% by weight hydroxypropyl methylcellulose,
(iii) 30% by weight polyvinylpyrrolidone, and
(iv) 5-30% by weight lactose.
In further aspect, the invention discloses a method for the treatment of the signs and symptoms of benign prostatic hyperplasia, wherein the method comprises administering to a patient in need thereof a sustained release pharmaceutical composition of alfuzosin.
DETAILED DESCRIPTION OF THE INVENTION
The term "alfuzosin" as used herein refers to alfuzosin free base or phamnaceutically acceptable salts, hydrates, solvates and enantiomers thereof or mixtures thereof. The preferred salt of alfuzosin is alfuzosin hydrochloride. Alfuzosin may be present in an amount ranging from 1 % to 20 % by weight of the composition.
The term "sustained release pharmaceutical composition" as used herein is intended for a composition which provides the desired therapeutic effect of alfuzosin for a period of more than 12 hours, preferably for a period of 24 hours.
The term "rate controlling polymer" as used herein and appended claims refers to a mixture of polyvinylpyrrolidone and one or more hydrophilic polymers other than polyvinylpyrrolidone such that polyvinylpyrrolidone is present in an amount of more than 8 % by weight of the composition and the hydrophilic polymer is present in an amount ranging from 35 to 69 % by weight of the composition. Suitable hydrophilic polymers may be hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methyl cellulose, carboxymethylcellulose, sodium alginate,
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xanthan gum, locust bean gum, alginic acid, methacrylate copolymer or mixtures thereof. The rate controlling polymer may be present intragranularly, extragranularly or both. The rate controlling polymer provides the sustained release of alfuzosin for a period of more than 12 hours, preferably 24 hours. Preferably, rate controlling polymer comprises polyvinylpyrrolidone in an amount ranging from 10% to 20% by weight of the composition. Polyvinylpyrrolidone (PVP) may be present intragranularly, extragranularly or both. Preferably, polyvinylpyrrolidone may be present in an amount of less than 5% by weight intragranularly, and more than 5% by weight extragranularly. Polyvinylpyrrolidone may be selected from different grades available such as low molecular weight PVP (molecular weight less than or equal to 50,000 daltons) and high molecular weight PVP (molecular weight more than 50,000 daltons). Preferably, low molecular weight PVP may be present intragranularly and high molecular weight PVP may be present extragranularly. PVP may act as a binder and/or a rate controlling polymer depending on its concentration. For example, when compositions contain intragranular polyvinylpyrrolidone in an amount of less than 5% by weight of the composition and extragranular polyvinylpyrrolidone in an amount of more than 5% by weight of the composition, the intragranular PVP may act as a binder and extragranular PVP may act as a rate controlling polymer. Similarly for example, when compositions contain intragranular polyvinylpyrrolidone in an amount of 4.5% by weight of the composition and extragranular polyvinylpyrrolidone in an amount of 4.5% by weight of the composition, the intragranular PVP may act as a binder and extragranular PVP may act as a rate controlling polymer.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, lubricant and mixtures thereof.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. The diluent may be present in an amount ranging from 5 % to 80 % by weight of the composition.
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Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.
Lubricant / glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate; and mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.
Granulating solvent may be selected from water, isopropyl alcohol, ethanol, methanol, acetone, methylene chloride or mixtures thereof. Granulating solution may be a mixture of any binder in the granulating solvent.
The sustained release pharmaceutical composition of alfuzosin as described herein exhibits a dissolution of not more than 30 % in 4 hour, not more than 45 % in 8 hours, not more than 60 % in 12 hours, not more than 75 % in 20 hours, as measured in 900 ml of 0.01 N HCI using USP Type II apparatus with a paddle speed of 50 rpm at 37 ± 0.5°C.
The composition may be optionally coated.
In one embodiment, the invention provides the process for preparing a sustained release pharmaceutical composition wherein the process comprises the steps of:
mixing alfuzosin, a rate controlling polymer and optionally one or more
pharmaceutically acceptable excipients,
granulating the mixture to obtain granules,
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drying the granules,
mixing the dried granules with a rate controlling polymer and optionally one or more
pharmaceutically acceptable excipients, and
compressing the mixture into a tablet.
In another embodiment, the invention provides the process for preparing a sustained release pharmaceutical composition wherein the process comprises the steps of:
mixing alfuzosin, a rate controlling polymer and optionally one or more
pharmaceutically acceptable excipients,
granulating the mixture to obtain granules,
drying the granules,
mixing the dried granules with optionally one or more pharmaceutically acceptable
excipients, and
compressing the mixture into a tablet.
In another embodiment, the invention provides the process for preparing a sustained release pharmaceutical composition wherein the process comprises the steps of:
mixing alfuzosin, a rate controlling polymer and optionally one or more
pharmaceutically acceptable excipients, and
compressing the mixture into a tablet.
In one preferred embodiment, the sustained release composition includes hydroxypropyl methylcellulose in an amount ranging from 10% to 69% by weight, preferably from 50% to 69% by weight; polyvinylpyrrolidone in an amount ranging from 1% to 25% by weight, preferably from 10% to 15% by weight, lactose in an amount ranging from 5% to 50% by weight, preferably from 10% to 35% by weight, magnesium stearate in an amount ranging from 0.1% to 5% by weight, talc in an amount ranging from 0.1% to 5% by weight and colloidal silicon dioxide in an amount ranging from 0.1% to 5% by weight.
The term "bio-equivalent" means Cmax, AUC (W) or AUC (0-a) are in the range of 80-125% with respect to the reference product.
"Cmax" as used herein, means the maximum plasma concentration of the active ingredient, produced by the ingestion of the composition of alfuzosin or the reference
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product. "AUC" as used herein, means the area under the plasma concentration- time curve over the specified time interval, produced by the ingestion of the composition of alfuzosin or the reference product.
The term"reference product"as used herein refers to the compositions containing alfuzosin hydrochloride, which release alfuzosin for an extended period of time of about 12 hours or about 24 hours. The preferred reference product is 10 mg Xatral-XL tablet marketed in Europe, or the 10 mg UroXatral tablet marketed in USA.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
COMPARATIVE EXAMPLE 1

Ingredients Functionality Quantity (mg/tablet) % w/w
Alfuzosin hydrochloride Active ingredient 10.14 2.89
Colloidal silicon dioxide Glidant 1.33 0.38
Hydroxypropyl methylcellulose K 100MCR Rate-controlling polymer 139.00 39.71
Polyoxyethylene oxide Rate-controlling polymer 45.00 12.85
Lactose Diluent 112.86 32.24
Dibasic calcium phosphate anhydrous Diluent 20.00 5.71
Polyvinylpyrrolidone K30 Binder 15.00 4.28
Isopropyl alcohol Granulating solvent q.s. -
Talc Glidant 2.00 0.57
Colloidal silicon dioxide Glidant 0.67 0.19
Magnesium stearate Lubricant 4.00 1.14
Total weight 349.50 100.00
Alfuzosin hydrochloride, colloidal silicon dioxide, hydroxypropyl methylcellulose, polyoxyethylene oxide and lactose were sifted and mixed. A solution of polyvinylpyrrolidone was prepared in isopropyl alcohol and the mixture was granulated to obtain granules. The granules were dried, sized, ad mixed with talc, colloidal silicon dioxide and magnesium stearate. The mixture was compressed into the tablets using appropriate tooling.
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COMPARATIVE EXAMPLE 2

Ingredients Functionality Quantity (Mg/tablet) % w/w
Alfuzosin hydrochloride Active ingredient 10.14 2.89
Colloidal silicon dioxide Glidant 1.00 0.29
Hydroxypropyl methylcellulose K 100 MCR Rate-controlling polymer 245.00 70.00
Lactose monohydrate Diluent 73.36 20.96
Polyvinylpyrrolidone K30 Binder 15.00 5.00
Isopropyl alcohol Granulating solvent q.s. -
Talc Glidant 1.00 0.28
Magnesium stearate Lubricant 3.50 1.00
Colloidal Silicon dioxide Glidant 1.00 0.28
Total weight 349.50 100.00
Alfuzosin hydrochloride, colloidal silicon dioxide, hydroxypropyl methylcellulose and lactose were sifted and mixed. A solution of polyvinylpyrrolidone was prepared in isopropyl alcohol and the mixture was granulated to obtain granules. The granules were dried, sized, and mixed with talc, colloidal silicon dioxide and magnesium stearate. The mixture was compressed into the tablets using appropriate tooling.
EXAMPLE 3

Ingredients Functionality Quantity (Mg/tablet) % w/w
Alfuzosin hydrochloride Active ingredient 10.20 2.91
Colloidal Silicon dioxide Glidant 1.00 0.29
Hydroxypropyl methylcellulose K 100 MCR Rate-controlling polymer 139.00 39.71
Lactose monohydrate Diluent 36.30 10.37
Polyvinylpyrrolidone K30 Binder 12.00 3.43
Isopropyl alcohol Granulating solvent q.s. -
Hydroxypropyl methylcellulose K 100 MCR Rate-controlling polymer 102.50 29.29
Polyvinylpyrrolidone K90 Rate-controlling polymer 38.50 11.00
Talc Glidant 2.00 0.57
Magnesium stearate Lubricant 5.00 1.43
Colloidal Silicon dioxide Glidant 3.50 1.00
Total weight 349.50 100.00
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Alfuzosin hydrochloride, colloidal silicon dioxide, hydroxypropyl methylcellulose and lactose were sifted and mixed. A solution of polyvinylpyrrolidone was prepared in isopropyl alcohol and the mixture was granulated to obtain granules. The granules were dried, sized, and mixed with hydroxypropyl methylcellulose, polyvinylpyrrolidone, talc, colloidal silicon dioxide and magnesium stearate. The mixture was compressed into the tablets using appropriate tooling.
EXAMPLE 4

Ingredients Functionality Quantity (Mg/tablet) % w/w
Alfuzosin hydrochloride Active ingredient 10.20 2.91
Colloidal Silicon dioxide Glidant 1.00 0.29
Hydroxypropyl cellulose Rate-controlling polymer 139.00 39.71
Lactose Diluent 36.30 10.37
Polyvinylpyrrolidone K30 Rate-controlling polymer 21.00 6.00
Isopropyl alcohol Granulating solvent q.s. -
Sodium alginate Rate-controlling polymer 102.50 29.29
Polyvinylpyrrolidone K90 Rate-controlling polymer 29.50 8.43
Talc Glidant 2.00 0.57
Magnesium stearate Lubricant 5.00 1.43
Colloidal Silicon dioxide Glidant 3.50 1.00
Total weight 349.50 100.00
Alfuzosin hydrochloride, colloidal silicon dioxide, hydroxypropylcellulose and lactose are sifted and mixed. A solution of polyvinylpyrrolidone is prepared in isopropyl alcohol and the mixture is granulated to obtain granules. The granules are dried, sized, and mixed with sodium alginate, polyvinylpyrrolidone, talc, colloidal silicon dioxide and magnesium stearate. The mixture is compressed into tablets using appropriate tooling. The dissolution studies of the compositions as described herein in comparison to the reference product are depicted in Table 1.
TABLE 1: Comparative Dissolution in 900 ml of 0.01 N HCI using USP Type II Apparatus with a paddle speed of 50 rpm at 37 ± 0.5 °C:
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TIME IN HRS COMPARATIVE EXAMPLE 1 COMPARATIVE EXAMPLE 2 EXAMPLE 3 REFERENCE PRODUCT
0 0 0 0 0
1 14.70 12.7 11.3 15.3
3 29.40 25.8 21.8 26.7
4 35.50 30.9 26 31.3
6 46.40 39.5 34 39.9
8 56.30 47.1 41.1 50.3
10 64.20 54 47.4 59.1
12 71.50 59.9 53.3 66.9
16 81.90 71 63.8 83.4
20 88.40 78.9 72.2 92
24 91.80 86.1 80.5 94.7
The dissolution data indicates that compositions of Comparative Examples 1 and 2 can be expected to be bioequivalent to the reference product. However, as is evident from Tables 2, 3, 4 and 5, when compositions of Comparative Examples 1 and Example 3 were subjected to bioequivalence study with UroXatral as reference product, composition of Comparative Example 1 was not bio-equivalent whereas composition of Example 3 was bio-equivalent to the reference product. Tables 2, 3, 4 and 5 depict the comparison of the pharmacokinetic parameters measured in the bio-equivalent studies. The composition of Example 3 showed Cmax and Area Under the Curve (AUCt and AUC000,) at 90 % confidence interval to be between 80-125.
TABLE 2: Comparative Pharmacokinetic Data of Comparative Example 1 and Reference product.

Pharmacokinetic Parameters Comparative Example 1 Reference T/R of Mean
Mean S.D. Mean S.D.
Cmax 14.544 8.78 7.365 2.44 1.97
AUC,o.« 168.814 90.53 96.052 58.89 1.76
AUCfo-mn 180.195 86.85 92.984 32.09 1.94
Table 3: Logarithmic values of pharmacokinetic parameters at 90% Confidence Interval of comparative Example 1

Pharmacokinetic Parameters 90% CI for Comparative Example 1
Lower | Upper
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Ln(Cmax) 126.1 236.04
Ln(AUCt) 119.56 249.62
Ln(AUCo^) 120.06 250.25
TABLE 4: Comparative Pharmacokinetic Data of Example 3 and Reference product.

Pharmacokinetic Parameters Example 3 Reference T/R of Mean
Mean S.D. Mean S.D.
>*max 15.300 8.501 15.202 7.889 1.0064
AUC(o-« 306.591 171.709 274.841 138.200 1.1155
AUC,0.|nf) 328.738 170.068 289.139 133.192 1.1370
Table 5: Logarithmic values of pharmacokinetic parameters at 90% Confidence Interval of Example 3

Pharmacokinetic Parameters 90% CI for Example 3
Lower Upper
LnfCnax) 87.7400 115.7300
Ln(AUQ) 95.9100 122.2000
Ln(AUCo^) 96.3600 124.7900
The characteristics of the rate-controlling polymer may be evaluated in the compositions as described herein by measurement of the swelling (S) to erosion (E) ratio (S/E) of the compositions. Not intending to be limited by any theory, the sustained release of alfuzosin from the compositions as described herein is by the diffusion of alfuzosin through the matrix formed by swelling of the rate controlling polymer in contact with the dissolution media or gastro-intestinal fluid, followed by the release of alfuzosin by gradual erosion of the matrix. The comparison between the S/E ratios is given in Table 6:
TABLE 6: Comparative S/E ratios

Time (in Hours) S/E ratio
Comparative Example 1 Example 3 Reference product
0 1.0 1.0 2.1
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1 1.3 - 1.7
2 1.4 1.2 2.2
4 2.2 1.7 2.4
24 15.0 2.8 2.1
Dated This 20th Day of October, 2006

for Torrent Pharmaceuticals Ltd, Dr. Chaitanya Dutt
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ABSTRACT
The present invention relates to sustained release pharmaceutical compositions of alfuzosin, process for preparing such compositions and method of using such compositions. More particularly, the present invention relates to a sustained release pharmaceutical composition comprising alfuzosin, a rate-controlling polymer and optionally one or more pharmaceutically acceptable excipients, wherein the rate-controlling polymer is a mixture of polyvinylpyrrolidone and one or more hydrophilic polymers other than polyvinylpyrrolidone.