Field of the invention
The present invention relates to controlled release formulation comprising an a-adrenoreceptor antagonist. More particularly, the present invention relates to controlled release formulation comprising alfuzosin hydrochloride and a mixture of hydrophilic and hydrophobic polymers.
Background of the invention
Alfuzosin is a selective α-1 adrenoceptor antagonist that belongs to the chemical class of 4-amino-6,7-dimethoxyquinazol-2-yl-alkylene diamines. Chemically, alfuzosin is (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino]propyl]tetrahydro-2-furancarboxamide hydrochloride and is disclosed in US 4,315,007.
Alfuzosin is commercially available as extended release tablets under the trade name UROXATRAL® in the US and film coated tablets as well as extended release tablets under the trade name XATRAL® in Europe. It is used orally in the symptomatic treatment of benign prostatic hypertrophy (BPH).
Controlled-release dosage forms are characterized in that they convey a markedly larger amount of medicinal product than traditional pharmaceutical preparations, so as to allow the dosage regimen to be simplified. Most of these novels therapeutic systems are capable of releasing the active substance conveyed per se, at a constant rate up to complete release of the active substance. These systems may be applied widely to administer medicinal products that are absorbed uniformly in the gastrointestinal tract.
Various patents disclose the use of pharmaceutical carriers in the preparation of controlled release formulation. US Patent No. 4,680,323 discloses a sustained release pharmaceutical carrier suitable for admixture with active ingredients comprising: (a) 5.5-98.5% by weight of hydroxypropyl methylcellulose; (b) 0.25-

4.5% by weight of hydroxypropyl cellulose; (c) 1-90% by weight of a carboxyvinyl polymer.
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 as disclosed in US patent No. 6,149,940. Controlled release compositions of alfuzosin provide various advantages over conventional multiple dosing including better patient compliance, reduced fluctuations of plasma drug levels, and reduced toxicity. US patent No. 6,149,940 further discloses the tablet composition of alfuzosin hydrochloride constituted by at least two layers, which comprise: the first, a mixture of hydrophilic polymers, 5.00 to 90.00%, and the second, a mixture of hydrophilic polymers and alfuzosin hydrochloride and optionally a third layer being primarily highly impervious to passage of the active substance. Such tablet has drawbacks that, the tablet is initially heavier than the density of the gastric fluids in which it will be immersed. The tablet composition made according to this patent may have a risk of being expelled from the stomach before having acquired sufficient flotation power. Further, the manufacture of multi-layered tablets using this technology is time consuming, complex to produce, involves special facilities, and consequently relatively expensive.
US Patent No. 5,589,190 discloses pharmaceutical compositions containing a core, namely a tablet affording immediate release or sustained release or microparticles affording immediate release of alfuzosin hydrochloride, coated with a membrane whose nature and thickness enable the release of the active principle to be controlled on the basis of pH and time.
EP 0 700 285 discloses drug delivery compositions of alpha adrenoceptor blocking agents that have a biphasic drug release profile, characterized in that the composition is adapted to release the drug in two portions, the first portion of the drug being released in the upper GIT and the second portion of the drug being

released by sustained release in the terminal ileum/ colon. This patent teaches matrix compositions using hydroxypropyl methylcellulose and a coating that is designed to dissolve under the conditions present in the colonic region.
Due to its intense absorption at the duodenum-jejenum level, Alfuzosin hydrochloride is a favourable candidate for the production of a pharmaceutical preparation with controlled release in the proximal/ upper parts of the gastrointestinal tract. The compositions according to US 5,589,190 and EP 0 700 285 have disadvantage of having the drug release mainly in the latter part of the small intestine and in the large intestine thereby decreasing the effective absorption of the drug.
US Patent No. 6,861,072 describes a gastro-retentive, controlled release two or three layered composition containing a carbon dioxide generating system that enables floatation of the dosage form.
US 2004/0115259 discloses process for the production of a homogeneous monolithic floating tablet which involves homogeneous mixing of active principle with a quantity of excipient from 50.00 to 99.90% of the total mass, the excipient being selected from at least one compound of the family of cellulosic derivatives and/or povidone derivatives and/or derivatives of polyvinyl acetate, and finally compression of this mixture to monolithic homogeneous tablet with immediate flotation in the gastric medium. This publication discloses that using specific excipients, immediate floatation can be ensured if a specific compression pressure is used. However, this method has disadvantages in commercial processing such as damaging the tablet surface if it is too friable at the low pressures used for compression to obtain a low-density tablet. Moreover, the low pressures that are normally required for quick floatation may result in altering (quickening) the dissolution such that drug release is not sustained to the required levels.
US 2006/0062845 and US 2006/0062846 discloses a composition comprising: a polymeric matrix; and alfuzosin in the polymeric matrix, wherein the composition is monolithic in form, and the polymeric matrix is adapted to release 13-33% of the

alfuzosin within 2 hours of administration, 40-60% of the alfuzosin within 7 hours of administration and greater than 80% of the alfuzosin within 20 hours of administration. It is also disclosed a polymeric matrix which is composed of hydrophilic polymer that swell upon contact with gastric fluid.
WO 2004/028503 discloses controlled release composition containing inner core comprising at least one cellulose derivative, and an amphiphilic material and an outer layer comprising polymer and plasticiser. This publication mentions the use of release retarding agents in both, the inner core as well as the outer layer. Moreover, the example mentions the use of two polymers (a core containing HPMC and outer coating of ethyl cellulose) that are completely different with respect to their properties. This makes the formulation process complicated and even more difficult to control or predict the in vitro/ in vivo release profile.
WO 2004/037228 discloses sustained release compositions comprising a single functional layer, containing drug and release retarding ingredient such as cellulose polymer, methacrylate polymer, acrylic acid polymer, block copolymer, gum and polyethylene oxide and optionally, one or more nonfunctional layers. In this case, all the examples given illustrate the usage of a combination of two different polymers for retarding drug release. Moreover, the use of hydrophilic polymers may result in a formulation that would swell and erode, resulting in a constant change in the surface area available for drug release.
WO 2006/094736 discloses solid controlled-release formulation of alfuzosin hydrochloride, hydrophilic polymers, polyvinylpyrrolidone and lactose.
WO 2006/021692 discloses a composition in the form of a gastric resident matrix tablet mainly comprising of alfuzosin hydrochloride characterized in that with the contact with a medium representative of the gastric fluid, it increases in volume, after fifteen minutes, of a rate of swelling of at least 200%. This patent publication further discloses the gastric resident matrix tablet comprises of povidone or polyvinyl acetate in proportions from 30 to 80% in weight of the phase, crospovidone in the

proportions from 5 to 25% weight of the phase and carbomer in proportions from 5 to 40% in weight of the phase.
EP 1 194 131 claims a delayed release coated core producing a timed pulse release, comprising an active substance in its core and a polymer coating comprising at least one or more ammonio methacrylate copolymers, characterized in that the core comprises at least one or more surfactants.
In view of the disadvantages/drawbacks as seen with the above prior art, there exists a need for developing controlled release formulation of alfuzosin hydrochloride. Surprisingly, inventors of the present invention have formulated controlled release formulation of alfuzosin, which releases the drug over a prolonged period of time, has very less chances of burst release, has good gastroretentive properties, and retain their initial form to a considerable extent.
Objective of the invention
Accordingly, the main objective of the present invention is to provide controlled release formulation of alfuzosin hydrochloride.
Yet another objective of the present invention is to provide controlled release formulation, comprising hydrophilic and hydrophobic matrices prepared by simple formulation process as compared to the complex tri-layer tablet disclosed in prior art.
Yet another objective of the present invention is to provide controlled release formulation of alfuzosin hydrochloride in such a way that it will comply with the reference product in terms of in vivo parameters for bioequivalence such as Cmax, AUC, Tmax and in vitro parameters like dissolution, disintegration etc.
Summary of the invention
Accordingly, the present invention provides a controlled release formulation comprising alfuzosin hydrochloride and a mixture of hydrophilic and hydrophobic polymers.

Detailed description of the invention
The most commonly used method of modulating the drug release is to include it in a matrix system. Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance. The drug release for extended duration, particularly for highly water-soluble drugs, using a hydrophilic matrix system is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. For such drugs with high water solubility, hydrophobic polymers are suitable as matrixing agents for developing sustained-release dosage forms. Hydrophobic polymers provide several advantages, ranging from good stability at varying pH values and moisture levels to well-established safe applications.
Faster release of the drug from the hydrophilic matrix was probably due to faster dissolution of the highly water-soluble drug from the core and its diffusion out of the matrix forming the pores for entry of solvent molecules. Further, incorporation of hydrophobic polymer in addition to hydrophilic polymer control the drug release to some extent, which could be attributed to the decreased penetration of the solvent molecules in the presence of hydrophobic polymer leading to decreased diffusion of the drug from the matrix.
The pharmaceutically acceptable hydrophilic polymers according to the present invention include polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, vinyl acetate copolymers, polysaccharides such as alginate, xanthum gum and the like, polyethylene oxide, acrylic acid copolymers such as carbomer; maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. Examples of hydrophobic polymers include wax materials, cellulose derivatives such ethylcellulose or cellulose acetate, copolymers of polyvinyl alcohol and high molecular weight polyvinyl alcohols.

Suitable wax materials used in accordance with the present invention are selected from hydrogenated vegetable oil, carnauba wax, candellia wax, bees wax, paraffin wax, stearic acid, glyceryl behenate, cetyl alcohol, cetosteryl alcohol, and mixtures thereof.
In another embodiment of the present invention, the controlled release formulation further comprises one or more excipients selected from diluents, binders, disintegrants, glidants and lubricants.
In another embodiment of the present invention, the controlled release formulation may be in the form of tablet or capsule.
Suitable diluents of the present invention are selected from calcium phosphate-dibasic, calcium silicate, microcrystalline cellulose, lactose, sucrose, starch, polyols such as mannitol, sorbitol, xylitol, maltitol and the like and mixtures thereof.
Suitable binders of the present invention are selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelatin, alginates, starch, povidone, copolyvidone, microcrystalline cellulose, pregelatinized starch and the like and mixtures thereof.
Suitable lubricants of the present invention are selected from sodium stearyl fumarate, magnesium stearate, hydrogenated vegetable oil, stearic acid, calcium stearate, glyceryl behenate, sodium lauryl sulfate, talc and the like and mixtures thereof.
Suitable glidant's include talc, colloidal silicon dioxide, cornstarch and the like.
The tablets may be uncoated or optionally coated with film coating
composition. The coating solution mainly comprises of film forming polymers and one or more of plasticizers, opacifier and the like.

Suitable film forming polymers used according to the present invention is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose hydroxyethyl cellulose and the like.
Suitable opacifier used according to the present invention is titanium dioxide.
In another embodiment of the present invention the controlled release formulation comprising alfuzosin hydrochloride and a mixture of hydrophilic and hydrophobic polymer, may be prepared by direct compression and or wet granulation.
The direct compression process comprises the steps of
i). blending alfuzosin hydrochloride and hydrophilic and hydrophobic polymer with one or more pharmaceutical acceptable excipient, ii). lubricating the blend of step (i), iii). compressing the lubricated blend to obtain tablets and iv). optionally coating the core tablets with film forming materials. The wet granulation process comprises the steps of i) sifting and mixing alfuzosin hydrochloride, wax, and diluent, ii) granulating the contents of step (i) using a solution of binder in a solvent iii) drying and lubricating the granules, and compressing the blend into tablets.
In yet another embodiment the controlled release formulation comprising alfuzosin hydrochloride and a mixture of hydrophilic and hydrophobic polymer may also be prepared by melt granulation, fusion and hot melt extrusion.
The following example further exemplifies the invention and is not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1
Alfuzosin tablets prepared by direct compression

The processing steps involved in manufacturing alfuzosin hydrochloride tablet are given below:
1. Alfuzosin hydrochloride, hypromellose, polyvinylpyrrolidone, hydrogenated
vegetable oil, dibasic calcium phosphate anhydrous, carbopol, colloidal silicon
dioxide were shifted and blended geometrically,
2. lubricated the blend of stage (1) with magnesium sterate,
3. compressed the blend into tablet.
4. finally coated the tablets obtained in step (3) with film coating materials.

We claim:
1. A controlled release formulation comprising alfuzosin hydrochloride and a
2. mixture of hydrophilic and hydrophobic polymers.
3. The controlled release formulation as claimed in claim 1, wherein the
4. hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone,
5. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, vinyl
6. acetate copolymers, polysaccharides, polyethylene oxide, acrylic acid copolymers
7. such as carbomer; maleic anhydride/methyl vinyl ether copolymers and derivatives
8. and mixtures thereof.
9. The controlled release formulation as claimed in claim 1, wherein the
10. hydrophobic polymer is selected from the group consisting of wax materials,
11. cellulose derivatives such ethylcellulose or cellulose acetate, copolymers of polyvinyl
12. alcohol and mixtures thereof.
4. The controlled release formulation as claimed in claim 3, wherein the wax
material is selected from the group of hydrogenated vegetable oil, carnauba wax,
candellia wax, bees wax, paraffin wax, stearic acid, glyceryl behenate, cetyl alcohol,
cetosteryl alcohol, and mixtures thereof.
5. The controlled release formulation as claimed in claim 1, further comprises
6. one or more pharmaceutically acceptable excipients such as diluents, binders,
7. lubricant and glidants.
8. The controlled release formulation as claimed in claim 5, wherein the diluent
9. is selected from the group consisting of lactose, calcium phosphate-dibasic, calcium
10. silicate, microcrystalline cellulose, sucrose, starch, polyols and mixtures thereof.
11. The controlled release formulation as claimed in claim 5, wherein the binder is
12. selected from the group of hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
13. gelatin, alginates, starch, povidone, copolyvidone, microcrystalline cellulose,
14. pregelatinized starch and mixtures thereof.

15. The controlled release formulation as claimed in claim 5, wherein the
16. lubricant is selected from sodium stearyl fumarate, magnesium stearate,
17. hydrogenated vegetable oil, stearic acid, calcium stearate, glyceryl behenate, sodium
18. lauryl sulfate, talc and mixtures thereof.
19. The controlled release formulation as claimed in claim 5, wherein the glidants
20. is selected from talc, colloidal silicon dioxide and cornstarch.
21. The controlled release formulation as claimed in claim 1, is in the form of
22. tablet or capsule.
23. A process for the preparation of controlled release formulation comprising
24. alfuzosin hydrochloride and a mixture of hydrophilic and hydrophobic polymer,
25. which comprises the steps of:
(i) blending alfuzosin hydrochloride and hydrophilic and hydrophobic polymer
with one or more pharmaceutical acceptable excipient,
(ii) lubricating the blend of step (i),
(iii) compressing the lubricated blend to obtain tablets and
(iv) optionally coating the core tablets with film forming materials.