FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
ORAL CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed

The present invention relates to an oral controlled release pharmaceutical composition comprising alfuzosin or its pharmaceutical^ acceptable salts.
More particularly, the present invention relates to an oral controlled release pharmaceutical composition comprising alfuzosin or its pharmaceutically acceptable salt, wherein the composition is suitable for once daily administration.
BACKGROUND OF THE INVENTION
Alfuzosin hydrochloride disclosed in Japanese Examined Patent Application Publication Number 60-23114 is known to be an antagonist of a, -adrenergic receptor, and is in the symptomatic treatment of benign prostatic hypertrophy. It displays an absorption whose intensity decreases along the digestive tract, absorption being low in the ileum and colon.
United States Patent Number US 6,149,940 ('940 patent) disclosed a system that was designed for drugs such as alfuzosin hydrochloride which are more intensely absorbed at the duodenum-jejunum than the subsequent portions of the gastrointestinal tract. The system of '940 patent discloses a pharmaceutical tablet for oral administration and for the controlled release of alfuzosin hydrochloride into the proximal segments of the gastrointestinal track, the tablet comprising: a) a first layer having the property of swelling considerably and quickly on contact with aqueous biological fluids, the first layer being produced by compression of a mixture or of a granulate comprising a hydrophilic polymer constituting from 5.0 to 90% of the weight of the first layer, b) a second layer adjacent to the first layer containing the alfuzosin hydrochloride, the second layer being formulated with a hydrophilic polymer and with an auxiliary substance to give the preparation suitable properties of compressibility and in order to allow the release of alfuzosin hydrochloride within a predetermined time period, c) and optionally a third layer adjacent to the second layer comprising a hydrophilic polymer which gels and/or swells and which may optionally be broken down and has a barrier function whit.n modifies the release of the alfuzosin hydrochloride from the second layer, the third layer being primarily highly impervious to passage of the active substance. The system of the '940 patent is available in the United States under the trade name of UROXATRAL® and under the trade name XATRAL® XL in Europe. Although the system of the '940 provides alfuzosin controlled release tablets, the system requires compression of two >r more different compositions as two or more compressed layers resulting in bilayer or trilayer tablets rather the i the compression of a single composition into one tablet. This requirement makes the manufacturing proce s slower, resulting in lower production output and higher costs to manufacture the product. Also during large scale manufacturing of multilayered tablets, it is sometimes observed that a small percent of tablets show separation of layers. This may occur during manufacturing, during storage or transport of the final product or also after oral administration. Thus there is a potential risk for failure of such a composition to deliver the desired amount of alfuzosin at the desired rate. Therefore, there is a need to provide a single composition in the
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form of tablets that can be manufactured at a faster output and yet address the problem of alfuzosin preferential absorption in the duodenum-jejunum region and relatively poor absorption thereafter i.e the solution to the problem should not compromise the bioavailability of alfuzosin hydrochloride in the fed as well as the fasted state as compared to system of the '940 patent such as UROXATRAL®.
Several attempts have been made to make such matrix controlled release systems comprising alfuzosin. For example, United States Patent Application Number US20060062845A1 ('845 patent application) discloses a pharmaceutical composition having a polymeric matrix composition comprising alfuzosin hydrochloride.
United States patent application number US20060147530 ('530 patent application) discloses a sustained release oral dosage form comprising a single functional layer and optionally, one or more nonfunctional layers adjacent to the single functional layer, wherein the single functional layer comprises alfuzosin or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and one or more release retarding ingredients.
PCT publication number WO2006094736 ('736 publication) discloses a solid composition in the form of tablet containing alfuzosin hydrochloride, hydrophilic polymers, polyvinylpyrrolidone and lactose.
We have now surprisingly found an easy to manufacture oral controlled release pharmaceutical composition in the form of a simple matrix comprising alfuzosin or its pharmaceutically acceptable salt, hydrogel polymers and pH dependent polymer having the same bioavailability of alfuzosin hydrochloride in the fed as well as the fasted state as compared to the system of the '940 patent.
More particularly, when the composition of the present invention is compared to the system of '940 patent, by administering them in a cross-over bioavailability study to a group of volunteers, the composition of the present invention showed the same bioavailability as compared to the system of the '940 patent. The system of the '940 patent, commercially marketed under the trade name of UROXATRAL® and holds a New Drug Approv :1 Number 021287 (approved by United States Food and Drug Administration) and shows different bioavailability when administered to human subjects who are fasted versus those who have had a standard mea). Surprisingl), the simple and easy to manufacture composition of the present invention has the same bioavailability as the system of the '940 patent, both in fasted subjects and in the fed subjects. It is surprising that the system had the same level of food effect as that of the system of '940 patent even though the '940 patent system was designed to be retained in the stomach for longer durations.
OBJECTS OF THE INVENTION
It is the object of the present invention to provide an oral controlled release pharmaceutical composition comprising therapeutically effective amounts of alfuzosin or its pharmaceutically acceptable salt.
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It is another object of the invention to provide a once daily controlled release pharmaceutical composition comprising therapeutically effective amounts of alfuzosin or its pharmaceutically acceptable salt.
SUMMARY OF THE INVENTION
The present invention provides an oral controlled release pharmaceutical composition comprising therapeutically effective amount of the alfuzosin or its pharmaceutically acceptable salt, hydrogel polymer and pH dependent polymer that is soluble in water at a pH below about 5.
DESCRIPTION OF THE FIGURES
Figure I presents in vitro dissolution of the alfuzosin tablets prepared according to the present invention versus the system of the '940 patent, dissolution media 0.01 N HC1, pH 2.0
Figure 2 presents in vitro dissolution of the alfuzosin tablets prepared according to the present invention versus the system of the '940 patent, dissolution media, acetate buffer pH 4.5
Figure 3 presents in vitro dissolution of the alfuzosin tablets prepared according to the present invention versus the system of the '940 patent, dissolution media, phosphate buffer pH 6.8
Figure 4 presents in vitro dissolution of the alfuzosin tablets according to the present invention in various dissolution media
Figure 5 presents comparative mean plasma alfuzosin profile following oral administration of alfuzosin 10 ing in fed state versus the system of the '940 patent
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DETAILED DESCRIPTION OF THE INVENTION
The term "pharmaceutically inert" as used herein means those salts/ excipients which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without any pharmacological action, undue toxicity, irritation, allergic response, and the like and are effective for their intended use.
As used herein, the term "pH dependent" polymer that is soluble below pH 5.0 refer to a polymer that is rendered soluble in aqueous medium by decreasing the pH to just below about 5.0.
The term "controlled release" as used herein means that the composition upon oral administration releases the drug in a controlled manner for at least about 8 hours, preferably at least 12 hours.
The term 'bioavailability' as used herein means the rate and extent of drug absorption upon administration. The extent of absorption is related to the area under the curve when the plasma concentration is plotted against time in hours; whereas the rate of absorption may be related to the time required to reach the maximum plasma concentration (Tmax).
The term 'bioequivalent' as used herein means that the 90 % confidential interval of the ratios of the logarithmically transformed mean values of the pharmacokinetic parameters i.e AUCo-inf,„ AUC0.T and peak plasma concentration Cmax obtained upon oral administration of the composition of the present invention, to the logarithmically transformed mean values achieved upon oral administration of equal doses of the system of '940 patent commercially available under the trade name of UROXATRAL®, is within the range of 0.80 to 1.25.
In one preferred embodiment, the oral controlled release pharmaceutical composition is in the form of a matrix composition. The term "matrix" as used herein means that the drug is blended uniformly with the excipients. The term "monolithic" is not intended to require that the composition be formed from a single material or comprise a completely homogenous mixture. The matrix composition may be monolithic or in more than o: j phase.
The amount of alfuzosin or its pharmaceutically acceptable salt that may be used in the controlled release composition of the present invention ranges from about 1 mg to about 30 mg, preferably from about 5 mg to about 15 mg per unit dosage form. One preferred embodiment of the present invention uses alfuzosin hydrochloride in amount of about 10 mg per unit dosage form.
According to the present invention, the oral controlled release pharmaceutical composition comprises one or
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more pH dependent polymers that are soluble in water at a pH below about 5. Preferably, the pH dependent polymer is soluble in water at a pH below about 5 and swellable and permeable at pH above about 5.0.
The oral controlled release pharmaceutical composition of the present invention provides controlled release of alfusozin or its pharmaceutically acceptable salt. Particularly, the oral controlled release pharmaceutical composition of the present invention when tested using USP type II apparatus with a paddle speed of 50 rpm in 900 ml of dissolution medium at 37 °C ± 5 °C, provides a release as specified in table below.
Table 1

Time in hours pH 6.8 buffer pH 4.5 buffer 0.01 N HC1
3 10-30 20-40 25-45
6 20-40 35-55 40-60
10 30-50 55-75 60-80
16 50-60 70-90 80-95
24 60-80 85-100 >95
More particularly, the alfuzosin or its pharmaceutically acceptable salt is released more slowly at a pH above 5 than at apH below 5.
A wide variety of polymer materials soluble in water at a pH below about 5 can be used pH dependent
polymers according to the present invention. Several such polymers are discussed in the United States Patent
Number US 4,486,471. Examples of such polymer material include dialkylaminoalkyl-cellulose (e.g.,
diethylaminomethylcellulose), benzylaminoalkyl-cellulose (e.g., benzylaminomethylcellulose),
carboxyalkyl(benzylamino)cellulose (e.g., carboxymethyl(benzylamino) cellulose),
dialkylaminoacetate. cellulose. acetate (e.g., diethylaminoacetate.cellulose.acetate), cellulose.acetate, dialkylamino. hydroxyalkyl ether (e.g., cellulose.acetate.N,N-di-n-butylamino. hydroxypropyl ether), piperidyl.alkyl.hydroxyalkylcellulose (e.g., piperidyl.ethyl.hydroxypropylcellulose, piperidyl.ethyl. hydroxyethylcellulose), carboxyalkyl.piperidyl.starch (e.g., carboxymethyl.piperidyl.starch), poly-dialkylaminoalkylstyrene (e.g., poly-diethylaminomethylstyrene), poly-vinylacetacetal. dialkylaminoacetate (e.g., poly-vinylacetacetal.dimethylaminoacetate, poly-vinylacetacetal.diethylaminoacetate), 2-(p-vinylphenyl)glycine. vinyl acetate copolymer, N-vinylglycine.styrene copolymer, a copolymer of (/,) dialkylaminoalkyl methacrylate and (B) one or two alkyl methacrylates (e. g., dimethylaminoethyl methacrylate.methyl methacrylate copolymer, butyl methacrylate.2-dimethylaminoethyl methacrylate-methyl methacrylate copolymer), a copolymer of (A) 2-alkyl-5-vinylpyridine, (B) alkyl acrylate or acrylonitrile and (C) methacrylic acid (e.g., 2-methyl-5-vinylpyridine.methyl acrylate.methacrylic acid copolymer, 2-methyl-5-vinylpyridine.acrylonitrile.methacrylic acid copolymer), a copolymer of 2-vinyl-5-alkylpyridine and styrene (e.g., 2-vinyl-5-ethylpyridine. styrene copolymer), and a copolymer of 2-vinylpyridine and alkyl methacrylc e (e. g., 2-vinylpyridine.methyl methacrylate copolymer).
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According to one preferred embodiment, the pH dependent polymer may be any pharmaceutical^ acceptable inert polymer synthesized by polymerizing basic monomer that will ionize significantly at pH below about 5, The basic monomer may be polymerized with other neutral non-ionizable monomers. Generally the ratio of tne basic monomer to neutral monomer will be such that there are sufficient proportions of basic ionizable group incorporated in the polymer so as to render it soluble below about pH 5.
In one preferred embodiment, the pH dependent polymer is soluble below about pH 5 and is swellable and permeable above pH 5. Preferably the pH dependent polymer is an aery late polymer obtained by polymerizing dimethylamino ethyl methacrylate with neutral methacrylate esters. In a more preferred embodiment of the present invention the pH dependent polymer is a polymer obtained by polymerization of the monomers namely, butyl methacrylate, 2-dimethyl amionethyl methacrylate and methyl methacrylate. This polymer, poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate) may be prepared from different molar ratios of the monomers, however, preferably, the butyl methacrylate, 2-dimethyl amionethyl methacrylate and methyl methacrylate molar ratio is about 1:2:1. This preferred polymer butyl methacrylate, 2-dimethyl amionethyl methacrylate and methyl methacrylate with a molar ratio of about 1:2:1 is available in different physical forms under the trade names Eudragit E 100, Eudragit E 12.5 and Eudragit EPO. Eudragit E 100 is in the form of granules, Eudragit E 12.5 is available in the form of 12.5 % w/v solution in an organic solvent and Eudragit E PO is available in powder form. These grades of the pH dependent polymers are described in the "Handbook of Pharmaceutical Excipients, 3rd edition, Ed by Arthur H. Kibbe, American Pharmaceutical Association, Washington DC, 2000" page number 401-404. It is to be noted that the pH dependent polymers such as anionic copolymerization products of methacrylic acid and methyl methacrylate, for example, Eudragit L and S, Eastacryl 30D, Kollicoat MAE 30 D and the like; ammoniomethacrylate copolymers for example, Eudragit RL and RS and the like, neutral copolymer of polymethacrylic acid esters for example, Eudragit NE and the like, described in the literature are not the pH dependent polymers according to the present invention.
According to one embodiment of the present invention, the pH dependent polymer may be used in amoun.s ranging from about 1 % by dry weight of the composition to about 50 % by weight of the composition, preferably from about 3 % by dry weight of the composition to about 25 % by dry weight of the composition, most preferably from about 5 % by dry weight to about 10 % by dry weight of the composition.
In a preferred embodiment of the present invention, the pH dependent polymer is poly (butyl methacrylate, (,.?-dimethyl aminoethyl) methacrylate, methyl methacrylate) present in amounts ranging from about 5 to about 10 % by weight of the composition.
Examples of hydrogel polymers that may be used in the present invention include, but are not limited to,
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cellulose derivatives, alginic acid and its derivatives, starch and its derivatives, gums, polyacrylic acid and the like and mixture thereof.
The hydrogel polymer may be used in an amount ranging from about 2 % to about 99 % by weight of the composition, preferably about 10 % to about 75 % and most preferably about 20 % to about 50 % by weight of composition.
Cellulose ethers and esters are available in different viscosity grades. The grades may be expressed in terms of viscosity and/or in terms of number average molecular weight. The viscosity and number average molecular weight are related to each other. Such grades of the cellulose ethers are described in terms of number average molecular weight, degree of polymerization. The cellulose derivatives described in United States Patent Number US 4,871,548 may also be used as hydrogel polymers according to the present invention.
The cellulose derivatives that may be used include, but are not limited to, cellulose ethers, cellulose esters and the like. Examples of suitable cellulose ethers include hydroxypropyl methyl cellulose, available from Dow Chemicals under the trade name Methocel, hydroxypropyl cellulose low substituted, hydroxypropyl cellulose, available from Aqualon under the trade name Klucel, hydroxyethyl cellulose, available from Aqualon under the trade name Natrosol and Cellosize available from Amerchol Corporation, carboxymethylcellulose sodium, available under the trade name Akucell.
Methocel is available in various viscosity grades. The typical viscosities, unless specified, are expressed for a 2 % w/v aqueous solution measured at 20°C. For example, K100 LVP having viscosity ranging from about 80 to about 120, K4MP having medium viscosity ranging from about 3000 to about 5600, kl5 M having high viscosity ranging from about 12,000 to about 21,000; K100 MP having high viscosity ranging from about 80, 000 to about 120,000.
Low viscosity grades of Methocel include, but are not limited to, E3 PREM.LV having viscosity ranging fron about 2.4 to about 3.6, E5 PREM.LV having viscosity ranging from about 4 to about 6, E6 PREM.LV havii.g viscosity ranging from about 5 to about 7, E15 PREM.LV having viscosity ranging from about 12 to about 18, E50 PREM.LV having viscosity ranging from about 40 to about 60 and K3 PREM.LV having viscosity ranging from about 2.4 to about 3.6.
Klucel is available in different viscosity grades. For example, Klucel HF (1 % w/v) solution shows a viscosity ranging from about 1500 to about 3000. Klucel MF (2 % w/v) solution shows a viscosity ranging from about 4000 to about 6500. Klucel GF (2 % w/v) solution shows a viscosity ranging from about 150 to about 400. Klucel JF (5 % w/v) solution shows a viscosity ranging from about 150 to about 400. Klucel LF (5 % w/v)
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solution shows a viscosity ranging from about 75 to about 150 and Klucel EF (10 % w/v) solution shows a viscosity ranging from about 200 to about 600.
Different types of viscosity grades of Natrosol 250 are available such as HHR having 1 % w/v solution 3400 to about 5000, H4R having viscosity ranging from about 2600 to about 3300, HR having viscosity ranging from about 1500 to about 2500 and MHR having viscosity ranging from about 800 to about 1500. Low viscosity grades of Natrosol include, but are not limited to, MR, KR, GR, ER, JR and LR.
Carboxymethyl cellulose is available as low viscosity Akucell AF 0303 (1 % w/v showing a viscosity ranging from about 10 to about 15 mPas. The medium viscosity grade of Akucell AF2785 shows a viscosity ranging from about 1500 to about 2500. The 1 % w/v solution of high viscosity grade of Akucell AF3085 shows a viseosity ranging from about 8000 to about 1200.
One embodiment of the present invention uses hydroxypropyl methyl cellulose (HPMC) having viscosity of about 100,000 cps. The percentage of the hydroxypropyl methylcellulose that may be used ranges from about I % to about 80 % by weight of the total weight of the composition, preferably from about 5 % to about 75 %, most preferably from about 10 % to about 50 % by weight of the composition.
"Another embodiment of the present invention uses a mixture of high viscosity grade hydroxyl propyl methyl cellulose, low viscosity grade hydroxyl propyl methyl cellulose and high viscosity grade hydroxyl propyl cellulose.
In one embodiment, the amount of high viscosity grade hydroxyl propyl cellulose ranges from about 0.1 % to about 50 %, preferably from about 2 % to about 25 % and most preferably from about 5 % to about 15 % by weight of the composition.
In one embodiment of the present invention, the amount of low viscosity grade hydroxypropyl methyl cellulose that may be used ranges from about 1 % to about 10 % of the composition. In a specific embodiment, the low viscosity grade hydroxypropyl methyl cellulose used is viscosity grade hydroxypropyl methyl cellulose E3 LV. It may be used in the dry form or may be suspended in water and used as the granulating fluid.
Alginic acid is available in different viscosity grades. The viscosities depend on the molecular weight. Typically, 0.5 % w/w aqueous dispersion shows a viscosity of approximately 10 mPas while a 2 % w/w aqueous dispersion shows a viscosity of approximately 2000 mPas.
Sodium alginate is also available in different viscosity grades. Typically, a 1 % w/v aqueous solution shows i
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viscosity of 20 to about 400 mPas.
Examples of polyacrylic acid that may be used in the present invention, includes, acrylic acid polymer, available under the brand name Carbomer. Various grades of carbomer depending upon the viscosity are available, for example, Carbomer 910 (1.0 % w/v) viscosity ranging from about 3000 to about 7000, Carbomer 934 (0.5 % w/v) viscosity ranging from about 30,500 to about 39,400, Carbomer 934P (0.5 % w/v) viscosity ranging from about 29,400 to about 39,400, Carbomer 940 (0.5 % w/v) viscosity ranging from about 40,000 to about 60,000, Carbomer 941 (0.5 % w/v) viscosity ranging from about 4,000 to about 11,000 and Carbomer 1342 (1.0 % w/v) viscosity ranging from about 9500 to about 26,500.
Examples of gums that may be used in the present invention include, tragacanth, guar gum, acacia, xanthan gum and the like and mixture thereof. Tragacanth is available in various grades depending upon the grade and the source of material. Typically, 1 % w/v aqueous dispersions may range in viscosity from about 100 to about 4000 mPas. 1 % w/v dispersion of guar gum shows a viscosity of about 4.86 Pas. 1 % w/v dispersion of xanthan gum shows a viscosity of about 1200 to about 1600 mPas.
Examples of starches that may be used as hydrogel polymers include, but are not limited to, starch, pregelatinized starch and the like and mixtures thereof. Typical viscosity of about 2 % w/v aqueous dispersion at 25° C is about 8 to about 10 mPas. Typical viscosity of 2 % w/v aqueous dispersion at 25° C is about 13.0 mPas.
The oral controlled release pharmaceutical composition of the present invention may also are conventional pharmaceutically acceptable excipients such as diluents, disintegrants, the lubricants known in the art. Examples of diluent include, but are not limited to, mannitol, lactose, dextrose and the like and mixtures thereof. Examples of lubricants include, but are not limited to, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talcum and the like, and mixtures thereof.
The oral controlled release pharmaceutical composition of the present invention may be in the form of granules, powder filled in capsules, compressed tablets, microparticles, extrudates and the like.
When the oral controlled release pharmaceutical composition of the present invention is in the form of granules, the composition may be prepared by wet granulation, dry granulation or direct compression. One specific embodiment of the present invention uses the process of wet granulation.
In one embodiment of the present invention, the oral controlled release pharmaceutical composition is in the form of tablets. Accordingly, the present invention provides a process for preparation of an oral controlled
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release pharmaceutical composition in the form of tablet comprising therapeutically effective amount of alfuzosin or its pharmaceutically acceptable salt, hydrogel polymer and a pH dependent polymer that is soluble in water at a pH below about 5; said process comprising
(i) granulating alfuzosin or its pharmaceutically acceptable salt with a first part of hydrogel polymers
optionally along with a pharmaceutically acceptable excipient
(ii) Drying the granules and applying a pH dependent polymer
(iii) mixing the dried granules with the remaining part of hydrogel polymers, optionally with a
pharmaceutically acceptable excipient, and
(iv) compressing the mixture into a tablet.
According to this preferred embodiment of the present invention, the first part of hydrogel polymer comprises a mixture of hydroxypropyl methyl cellulose and hydroxyl propyl cellulose. In the preferred embodiments, the hydroxypropyl methyl cellulose is a mixture of high viscosity and low viscosity grades of hydroxypropyl methyl cellulose. In another embodiment, the remaining portion of the hydrogel polymer is a high viscosity grade of hydroxypropyl methyl cellulose. In a preferred embodiment, the hydroxypropyl methyl cellulose used in the remaining part is a high viscosity grade of hydroxypropyl methyl cellulose wherein the 2 % aqueous solution viscosity ranges from about 80,000 to about 120,000 mPas.
According to this embodiment of the process of the present invention, alfuzosin or its pharmaceutically acceptable salt is present intragranularly and the pH dependent polymer is present extragranularly. Alfuzosin or its pharmaceutically acceptable salt may be dry mixed with the excipients or it may be dissolved in aqueous medium and used as a granulating fluid. The pH dependent polymer may be applied on the dried granules by spraying a solution of the pH dependent polymer in a suitable solvent or by dry blending the dried granules with the pH dependent polymer.
The present invention also provides a process comprising;
(i) granulating alfuzosin or its pharmaceutically acceptable salt, a part of the hydrogel polymer and
pH dependent polymer, optionally, other excipients and drying the granules (ii) mixing the dried granules with the remaining part of the hydrogel polymers, optionally with
other pharmaceutical excipients (iii) compressing the mixture into tablets.
According to another embodiment of the present invention, the pH dependent polymer may be partly added in the granulating fluid and partly the dried granules may be coated with the remaining amount. The granulating fluid may contain alfuzosin hydrochloride, low viscosity hydrogel polymer and the pH dependent polymer, -i one embodiment of the present invention, the granules are spray coated in a suitable spray granulator such -.s
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fluid bed granulator. According to one specific embodiment of the present invention, the coated granules are dried in a fluid bed granulator till a residual moisture content reaches between about 3.5 % to about 4.5 % by weight of the granules.
The examples that follow are provided as illustrations and do not limit the scope of the present invention.

EXAMPLE 1
Table 2
ingredients mg per tablet % by weight of the tablet
Alfuzosin hydrochloride 10.0 2.94
Pregelatinized starch 114.00 33.52
Hydroxypropyl methyl cellulose K100 M 87.5 Hydroxypropyl methyl cellulose E3 LV 18.0 25.73
5.29
Hydroxypropyl cellulose HF-fine grade i 35 10.29
Purified water q.s q.s
Isopropyl alcohol q.s q.s
EudragitEPO i 25.0 7.35
Hydroxypropyl methyl cellulose K100 M 35.0 10.29
Colloidal Silicon dioxide 3.5 1.02
Magnesium stearate 5.0 1.47
Talc 7.0 2.05
Total weight of the core tablet 340 -
Pregelatinized starch, part of hydroxypropyl methylcellulose K100, part of hydroxypropyl methyl cellulose E3 LV and hydroxypropyl cellulose were sifted together through 40 mesh to obtain an excipient blend. The granulating fluid was prepared by dissolving alfuzosin hydrochloride, hydroxypropyl methylcellulose E3 LV in sufficient amount of purified water. The solution was stirred using overhead stirrer until a clear solution was formed. The excipient blend was loaded in a fluid bed granulator and granulated with the granulating fluid comprising alfuzosin hydrochloride. The granules thus obtained were dried and were further spray coated with a solution of Eudragit EPO in water and isopropyl alcohol, followed by drying of the coated granules. The dried granules were mixed with the hydroxypropyl methylcellulose (high viscosity) and colloidal silicon dioxide. The blend was lubricated with magnesium stearate, talc and compressed using a rotary tablet compression machine
EXAMPLE 2
The pH of the gastrointestinal fluids is known to change across the length of the gastrointestinal tract. Stomach shows high variability particularly the pH may be as low as 1 to 3.5 in the fasted state whereas in the fed sta s the pH may be higher. The pH of the fluids in the distal ileum and colon is near about neutral.
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The dissolution test was carried out in USP Type II apparatus with a paddle speed of 50 rpm in 900 ml of dissolution media at 37 C ± 0.5 ° C. The tablets prepared according to the present invention were tested for in vitro drug release in a range of dissolution media having different acidic to neutral pH. The dissolution profiles were compared with the system of the '940 patent namely UROXATRAL®.
The in vitro dissolution profiles of the tablet of the present invention versus the system of the '940 patent, are depicted in figures 1, 2 and 3. The dissolution profile of the composition of the present invention in acidic and neutral dissolution media is presented in Figure 4.
It may be seen that the composition of the Example 1 released alfuzosin hydrochloride at a faster rate at a pH below 5 as compared to a pH above 5. It is also evident from the composition of present invention showed similar behaviour in dissolution media at different pH, compared to the system of the '940 patent.
EXAMPLE 3
A randomized, single dose, open label, comparative and 2 way crossover bioavailability study on the Alfuzosin controlled release tablets according to the present invention versus system of the '940 patent namely Uroxatral® Tablets was carried out, both under fed and fasted conditions on 69 and 56 volunteers, respectively. The T/R ratios of the Ln Cmax , Ln AUC (0-t) and Ln AUC ((0-oo) and the Tmax values are tabulated in Table 3.

The plasma concentration profile Vs time in hours in fasted state and fed state is given in Figure 5. It was surprisingly found that the bioavailability of the easy to manufacture oral controlled release pharmaceutic d composition of the present invention even though not designed to be gastro retentive had the san e bioavailability as the gastro-retentive system of the '940 patent, namely UROXATRAL ® tablets, in both the
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fed as well as the fasted state. The oral controlled release pharmaceutical composition of the present invention showed the problem of non-uniform absorption of alfuzosin or its pharmaceutical salt across the length of trie gastro intestinal tract. The data shows that the alfuzosin tablets, 10 mg prepared according to the present invention is bioequivalent to the system of '940 patent NDA Number 021287, in both fed and fasted state.
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We claim
1. An oral controlled release pharmaceutical composition comprising therapeutically effective amount of the alfuzosin or its pharmaceutical^ acceptable salt, hydrogel polymer and pH dependent polymer that is soluble in water at a pH below about 5.
2. An oral controlled release pharmaceutical composition as claimed in claim 1 wherein the pH dependent polymer is a polymer prepared by polymerization of basic monomers with neutral monomers.
3. An oral controlled release pharmaceutical composition as claimed in claim 2 wherein the basic monomer is dimethyl aminoethyl methacrylate.
4. An oral controlled release pharmaceutical composition as claimed in claim 3 wherein the neutral monomer is a neutral methacrylate ester.
5. An oral controlled release pharmaceutical composition as claimed in 4 wherein the polymer is poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate), 1:2:1.
6. An oral controlled release pharmaceutical composition as claimed in claim 1 wherein the hydrogel polymer is selected from the group comprising of cellulose derivatives, gums, alginic acid and its derivatives, polyacrylic acid, starch and its derivatives and mixtures thereof.
7. An oral controlled release pharmaceutical composition as claimed in claim 6 wherein the cellulose derivative is selected from the group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose and mixtures thereof.

8. An oral controlled release pharmaceutical composition as claimed in claim 7 wherein the cellulose derivatives comprises a mixture of hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
9. An oral controlled release pharmaceutical composition as claimed in claim 8 wherein the hydroxypropyl methyl cellulose is a mixture of high viscosity and low viscosity grades of hydroxypropyl methyl cellulose ai.J hydroxypropyl cellulose is a high viscosity grade of hydroxypropyl cellulose.

10. An oral controlled release pharmaceutical composition as claimed in 9 wherein viscosity of 2 % aqueous dispersion of hydroxypropyl methyl cellulose ranges from about 80,000 to about 120,000 cps.
11. An oral controlled release pharmaceutical composition as claimed in 9 wherein viscosity of 1 % aqueous dispersion of hydroxypropyl cellulose ranges from about 1500 to about 3000 mPas.
12. An oral controlled release pharmaceutical composition as claimed in claim 10 wherein the high viscosity grade of hydroxypropyl methyl cellulose is present in amounts ranging from about 10 % to about 50 % by weight of the composition.
13. An oral controlled release pharmaceutical composition as claimed in claim 11 wherein the high viscosity grade of hydroxypropyl cellulose is present in amounts ranging from about 5 % to about 15 % by weight of the composition.
14. An oral controlled release pharmaceutical composition as claimed in claim 5 wherein the amount of the poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate) ranges from about 5 to about 15 % by weight of the composition.
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15. A process for preparation of an oral controlled release pharmaceutical composition in the form of tablet
comprising therapeutically effective amount of alfuzosin or its pharmaceutically acceptable salt, hydrogel
polymer and a pH dependent polymer that is soluble in water at a pH below about 5; said process comprising
(i) granulating alfuzosin or its pharmaceutically acceptable salt with a first part of hydrogel polymers,
optionally along with a pharmaceutically acceptable excipient
(ii) drying the granules and applying a pH dependent polymer
(iii) mixing the dried granules with the remaining part of hydrogel polymers, optionally with a
pharmaceutically acceptable excipient, and
(iv) compressing the mixture into a tablet.
16. An oral controlled release pharmaceutical composition in the form of tablets prepared by process of claim 15.
17. A process for preparation of an oral controlled release pharmaceutical composition of claim 15 wherein tl> first part of hydrogel polymer comprises a mixture of hydroxypropyl methyl cellulose and hydroxyl prop.I cellulose.
18. A process for the preparation of an oral controlled release pharmaceutical composition of claim 17 where;n the hydroxypropyl methyl cellulose is a mixture of high viscosity and low viscosity grades of hydroxyprop'. 1 methyl cellulose.
19. A process for the preparation of an oral controlled release pharmaceutical composition as claimed in clai.n 15 wherein the remaining part of the hydrogel polymer is a high viscosity grade of hydroxypropyl meth.. i cellulose.
20. A process for the preparation of an oral controlled release pharmaceutical composition as claimed in claim 18 wherein the viscosity of 2 % aqueous dispersion of the high viscosity grade of hydroxypropyl methyl cellulose ranges from about 80,000 to about 120,000.



ABSTRACT
The present invention relates to an oral controlled release pharmaceutical composition comprising therapeutically effective amount of the alfuzosin or its pharmaceutically acceptable salt, hydrogel polymer and pH dependent polymer that is soluble in water at a pH below about 5.
To
The Controller of Patents, Patent Office, Mumbai - 400037