COMPLETE AFTER PROVISIONAL LEFT ON 22/05/2006
FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - GASTRORETENTIVE SUSTAINED RELEASE
PHARMACEUTICAL COMPOSITIONS OF ALFUZOSIN
2. Applicant(s)
(a) NAME : TORRENT PHARMACEUTICALS LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Torrent Research Centre, P.O. Bhat - 382 428,
Dist. Gandhinagar, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a gastroretentive sustained release dosage form comprising alfuzosin or pharmaceutically acceptable salt, solvate, enantiomer or mixtures thereof, which is devoid of a risk of premature burst release and hydrophilic rate controlling polymer.
BACKGROUND AND PRIOR ART
Alfuzosin is a selective alpha-1 adrenoceptor antagonist, which is used for the treatment of the signs and symptoms of benign prostatic hyperplasia. Alfuzosin has a short elimination half-life and shows the characteristic of being absorbed preferentially in the proximal part of the gastrointestinal tract. According to a conventional oral dosage form, this compound must hence be administered several times daily.
Thus, the sustained release dosage form of alfuzosin provides various advantages that are not achieved with the corresponding conventional dosage form including improved patient compliance, reduced fluctuations of plasma drug levels, as well as minimizing side effects.
US 6149940 discloses a controlled release pharmaceutical tablet of alfuzosin hydrochloride, which essentially consists of two layers and may optionally contain a third layer also. First layer has the property of swelling after coming in contact with aqueous biological fluids and the second layer contains a mixture of hydrophilic polymers and alfuzosin hydrochloride with other auxiliary substances. This second layer is compressed in a suitable manner and comprises auxiliary substances such that the alfuzosin hydrochloride will be released over a predetermined interval of time. It has been proposed to control this release by addition of a third layer constituted also of hydrophilic polymers so as to protect the layer containing the alfuzosin hydrochloride and to slow the release, at least at the outset.
Such type of formulations has drawbacks. The tablet is initially heavier than the density of the gastric fluids in which it will be immersed. A risk remains that the tablet might be expelled before acquiring sufficient flotation power. The kinetics of
2

swelling of hydrophilic polymers is slow, of the order of a half hour, and this delay is sufficient that they could be expelled. A sufficient swelling, which would avoid passage through the pylorus, is achieved several hours after ingestion so that the dimensional characteristics and eventually mechanical retention cannot overcome the problem of lack of initial flotation. The gastric dwell time also depends on the anatomy of the individual, the size of the pylorus, the rhythm of opening and closing, so that all these parameters give rise to wide variations to controlled release pattern of the drug. Moreover, the manufacturing of multi-layered tablets is complex and requires special facilities, and also time consuming, which ultimately proves expensive. There are also possibilities of layers getting separated during shelf life or after administration, which in turn would affect the quality/efficacy of the product.
French patent application 2784583 discloses a multi-layer tablet, improved in that it comprises an effervescent couple, which generates carbon dioxide while it comes in contact with gastric fluids. These bubbles of carbon dioxide provide flotation properties to this tablet. This flotation is completed by the presence of hydrophilic polymers in the dosage form, which swell and increase the volume of the tablet over time.
However, such type of compositions remains complicated to produce industrially because it is necessary to work in an atmosphere of controlled humidity because of the effervescent couple. Precautions are also required to store the obtained products, given the presence of this effervescent couple, so eventually it leads to an increase in production cost. The effervescent couple used contains sodium whose content is not desirable particularly in the case of a low sodium diet.
WO 2004/037228 discloses a sustained release dosage form comprising a single functional layer and optionally, one or more non-functional layer wherein the single functional layer comprises active pharmaceutical ingredient and one or more release retarding ingredients.
In such type of formulation, due to small size of the tablet with swelling makes tablet core soft and thus increases the risk of tablet being expelled from the
3

stomach due to peristaltic movements. Insufficient wetting may also lead to the expulsion of tablet from stomach. Also, single layer tablet does not assure floating of the tablet in stomach, which may accelerate expulsion of tablet from stomach. Since alfuzosin has absorption window of proximal part of small intestine, early expulsion of tablet from stomach may hamper the absorption of the drug.
US Patent Application 20040115259 discloses a tablet containing Alfuzosin Hydrochloride permits guaranteeing optimum dwell time in the stomach of the individual by immediate flotation, a controlled release following a profile whose kinetics can vary and be adapted particularly between kinetics of the order of 0 and 1, and to complete retention by flotation the excipient being selected from at least one compound of the family of cellulose derivatives and/or derivatives of povidone and/or derivatives of polyvinyl acetate, and compression of this mixture with a force permitting obtaining a monolithic homogenous tablet.
The invention claimed here is of immediate flotation. However, the flotation time of tablet would highly depend upon other physiological properties of GIT e.g. food effect and wetting properties of GIT, and amount of liquid in the stomach after administration. Since these parameters are variable gastric retention of these tablets remains unpredictable.
Thus, there exists a need for sustained release dosage form of alfuzosin and process for making such dosage form that overcomes the problems discussed above.
OBJECTS OF THE PRESENT INVENTION
It is an object of the present invention to provide a gastroretentive sustained release dosage form of alfuzosin or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, which gives predictable drug release over an extended period of time.
A further object of the present invention is to offer a gastroretentive dosage form, wherein gastric retention is ensured by size of the dosage form and hence no
4

other parameter e.g. wetting time, food, and physiological state of GIT would alter the gastric retention of the dosage form.
Another object is to provide gastroretentive dosage form wherein drug release mechanism is achieved by surface erosion by employing hydrophobic polymers to avoid prerequisites for controlled release like wetting time, swelling time of the formulation and avoid premature burst release of drug.
A further object is to provide a simple and cost effective process of manufacturing sustained release dosage form of alfuzosin or pharmaceutical^ acceptable salt, solvate, enantiomers or mixtures thereof.
SUMMARY OF THE INVENTION
The present invention according to one aspect relates to gastroretentive sustained release dosage form comprising alfuzosin or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, which gives predictable drug release over an extended period of time.
The present invention provides gastroretentive formulation, wherein gastric retention is ensured by size of the dosage form and hence no other parameter e.g. wetting time, food, and physiological state of GIT would alter the gastric retention of the dosage form.
The present invention employs hydrophobic release controlling agents and the drug release mechanism is by surface erosion hence wetting time, swelling time are not the pre-requisites for controlled release and it would be devoid of premature burst release of drug.
The present invention according to another aspect further relates to a simple and cost effective process of manufacturing sustained release dosage form of alfuzosin or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
5

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides gastroretentive sustained release dosage form comprising alfuzosin or pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, which gives predictable drug release over an extended period of time. Gastroretentive dosage form of the present invention do not swell or float in the contents of stomach but remain there for extended period of time due to the size and hence other parameters such as wetting time, food, and physiological state of GIT would not affect the release profile of the drug. Pharmaceutical dosage form of the instant invention are prepared without mixing with hydrophilic rate controlling polymers and the drug release mechanism is by surface erosion hence wetting time, swelling time are not the pre-requisites for controlled release thereby is devoid of a risk of premature burst release.
In one preferred embodiment, alfuzosin hydrochloride is mixed with pharmaceutically acceptable excipients and resultant mixture is compressed in to tablets. The compressed tablets are than coated with release controlling agents to achieve sustained release.
In another embodiment, the sustained release dosage form is characterized in that pharmaceutically acceptable excipients are mixed and compressed in to tablet. The compressed tablets are than coated with alfuzosin hydrochloride and followed by release controlling agents to achieve sustained release.
The term "Sustained release" as used herein refers to the release of an active ingredient such as a drug from a composition or dosage form in which the active ingredient is released according to a desired profile over an extended period of time and is taken to encompass controlled release, modified release, prolonged release, pulsatile release, and delayed release and the like.
Such release rates can provide therapeutically effective levels of active ingredient for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response offers many inherent benefits
6

that are not achieved with the corresponding short acting, immediate release preparations.
A sustained release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bio-availability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.
The term "dosage form" denotes any form of the formulation that contains an amount sufficient to achieve a therapeutic effect with a single administration.
The term "proximal part of the gastrointestinal tract" as used herein refers to stomach, duodenum, and jejunum.
The dosage form of the present invention includes the active ingredient in a range of about 1 mg to about 30 mg. More preferably dosage forms contain either 5 mg or 10 mg of active ingredient.
The term "active ingredient" as used herein refers to alfuzosin or its salt, solvate, hydrates, enantiomer or mixtures thereof.
The sustained release dosage form of the present invention may be administered either twice daily or once daily.
The sustained release dosage form according to the instant invention comprises at least one release controlling agent and other pharmaceutically acceptable excipient(s). These pharmaceutically acceptable excipients are selected from the following categories but not limited to diluents, fillers, binders, antiadherents, glidants, lubricants, and/or plasticizers.
The term "release controlling agents" as used herein refers to any suitable agents, capable of retarding the release of active ingredient present in the dosage form. As per present invention "Suitable release controlling agent" is
7

intended to mean hydrophobic substances, which can control the release of drug from the dosage form. Such compounds comprise, Eudragit RL, Eudragit RS, Ethylcellulose, hydrogenated castor oil and other materials known to one of ordinary skill in the art.
The amount of release controlling agent(s) to be used will be determined based on various parameters such as the desired gastric retention period, size of the tablet, drug release rate etc.
As used herein, the term "diluents" or "fillers" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds comprise, dibasic calcium phosphate, lactose, mannitol, microcrystalline cellulose, precipitated calcium carbonate, sorbitol and starch and other materials known to one of ordinary skill in the art. The diluent or filler may be present in an amount ranging from 10% to 90% by weight of the composition.
As used herein, the term "binders" is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds comprise, acacia, compressible sugar (e.g. NuTab), gelatin, liquid gluclose, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch and other materials known to one of ordinary skill in the art. The binder may be present in an amount ranging from 0.5% to 15% by weight of the composition.
As used herein, the term "antiadherents" is intended to mean agents, which prevent the sticking of tablet formulation ingredients to punches and dies in a tableting machine during production. Such compounds comprise, magnesium stearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to one or ordinary skill in the art. The anti adherent may be present in an amount ranging from 0.5% to 5% by weight of the composition.
As used herein, the term "glidants" is intended to mean agents used in tablet and capsule formulations to reduce friction during tablet compression. Such
8

compounds comprise, colloidal silica, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to one of ordinary skill in the art. The glidant may be present in an amount ranging from about 0.5% to about 5% by weight of the composition.
As used herein, the term "lubricants" is intended to mean substances used in tablet formulations is reduce friction during tablet compression. Such compounds comprise, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate and other materials known to one of ordinary skill in the art. The lubricant may be present in an amount ranging from about 0.5% to about 5% by weight of the composition.
Plasticizers are optionally included in the tablets to modify the properties and characteristics of the polymers used in the coats or core of the tablets. As used herein, the term 'plasticizer' comprises all the compounds capable of plasticizing of softening of polymer or binder used in invention. The plasticizer should be able to lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder. Plasticizers, such as low molecular weight PEG, generally broaden the average molecular weight of a polymer in which they are included thereby lowering its glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of a polymer.
Plasticizers useful in the invention comprise, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene • glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol, monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetylributycitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl
9

glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. The PEG based plasticizers are available commercially or can be made by a variety of methods such as disclosed in Poly(ethylene glycol) Chemistry : Biotechnical and Biomedical Applications (J.M. Harris, ed.: Plenum Press, NY) the disclosure of which is hereby incorporated by reference. The plasticizer may be present in an amount ranging from about 0.5% to about 20% by weight with respect to coating polymers.
The following examples are provided to further illustrate the invention, and are not intended to limit the scope of invention.
Process for the preparation of the formulation is as under:
1. Sift diluents and binder through ASTM 40# mesh and mix them in a suitable mixer, Drug previously sifted through ASTM 40# mesh can be optionally mixed with the above sifted diluents.
2. Sift the lubricants through ASTM 60# mesh.
3. Lubricate the blend from step 1 with the sifted lubricants using suitable blender.
4. Compress the lubricated blend from step 3 into tablets using suitable compression machine.
5. Coat the compressed tablets from step 4 first optionally with drug and finally with release controlling agents using suitable coating machine.
10

EXAMPLES Example 1

S.No Ingredient Mg/tab % w/w
1. Alfuzosin Hydrochloride 10.00 1.25
2. Lactose 353.00 44.13
3. Microcrystalline Cellulose 248.00 31.00
4. Starch 129.00 16.12
5. Polyvinyl pyrrolidone K-30 32.00 4.00
6. Talc 16.00 2.00
7. Mg. Stearate 8.00 1.00
8. Colloidal silicon dioxide 4.00 0.50
800.00
Sustained release Coating Ethylcellulose and HPMC / Eudragit RL and RS 2 - 5%

Alfuzosin and colloidal silicon dioxide are mixed with lactose geometrically, and passed through ASTM 40# mesh, Microcrystalline cellulose, starch, Polyvinyl pyrrolidone (PVP K30) are sifted through ASTM 40# and mixed with the alfuzosin blend. The resulting mixture was lubricated with Talc and magnesium stearate, which were previously sifted through 40# mesh. The resulting mixture was compressed to tablets. The compressed tablets were coated with release controlling agents to achieve sustained release.
The dissolution rate of the novel dosage form was determined in 0.01 N HCI using a USP Type II apparatus with a paddle speed of 100rpm, at 37±2°C. The results of these studies are shown in Table 1.
Table 1. Dissolution profile of the Example 1 and comparative dissolution with innovator formulation

Time (hrs) Percent drug released 0.01 N HCI, (Torrent formulation) Percent drug released 0.01 N HCI, (innovator formulation)
2 20 16.4
8 54 56.4
12 83 72.2
24 102 98
11

Example 2

S.No Ingredient Mg/tab % w/w
1. Lactose 68.15 13.63
2. Microcrystalline Cellulose 225.00 45.00
3. Hypromellose 2208 (Methocel K 100M) 140.00 28.00
4. Polyvinyl pyrrolidone K-30 45.00 9.00
5. Talc 12.50 2.50
6. Mg. Stearate 6.25 1.25
7. Colloidal silicon dioxide 3.10 0.625
500.00
Drug coating(Alfuzosin hydrochloride and Filmforming agent)
Sustained release Coating Eudragit RL/RS 2-4%
Lactose, Microcrystalline cellulose, Hypromellose and polyvinyl pyrrolidoene K 30 passed through ASTM 40# mesh, The resulting mixture was lubricated with Talc and magnesium stearate which were previously sifted through 40# mesh. The resulting mixture was compressed to tablets. The compressed tablets were coated with Alfuzosin hydrochloride and followed by release controlling agents to achieve sustained release.
The dissolution rate of the novel dosage form was determined in 0.01 N HCI using a USP Type II apparatus with a paddle speed of 100rpm, at 37+2°C. The results of these studies are shown in Table 2.
Table 2. Dissolution profile of the Example 2

Time (hrs) Percent drug released 0.01 N HCI
2 31
8 62
12 89
24 101
12

WE CLAIM:
1. A gastroretentive sustained release pharmaceutical dosage form comprising an alfuzosin or a pharmaceutically acceptable salt, solvate, enantiomer or a mixture thereof, and one or more hydrophobic release controlling agent which may further include one or more pharmaceutically acceptable excipient.
2. A sustained release dosage form as claimed in claim 1, wherein release controlling agent is selected from the group comprising of eudragit, ethylcellulose, or hydrogenated castor oil.
3. A sustained release dosage form as claimed in claim 1, which is in the form of a tablet.
4. A sustained release dosage form as claimed in claim 1, which is administered either once or twice daily.
5. A process for the preparation of gastroretentive sustained release pharmaceutical dosage form comprising an alfuzosin or a pharmaceutically acceptable salt, solvate, enantiomer or a mixture thereof comprises the steps of;

a) blending one or more pharmaceutically acceptable excipient with or without active ingredient;
b) optionally granulating the blend;
c) lubricating the blend of step a) or granules obtained from step b);
d) compressing into a suitable size solid oral dosage form;
e) the inert core is further coated with active ingredient with or without pharmaceutically acceptable excipient;
f) solid dosage form obtained in step d) or step e) is finally coated with suitable release controlling agent.
6. A gastroretentive sustained release pharmaceutical dosage form as defined
herein, substantially described particularly with reference to the example.
Dated this 18th day of May 2006

ABSTRACT
GASTRORETENTIVE SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS OF ALFUZOSIN
A gastroretentive sustained release dosage form of Alfuzosin or pharmaceutically acceptable salt, solvate, enantiomer or mixtures thereof, which gives predictable drug release over an extended period of time. Gastric retention of the present invention is ensured by size of the tablet and hence other parameters such as wetting time, food, and physiological state of GIT would not affect the release profile of the drug. Instant invention employ hydrophobic polymers and the drug release mechanism is by surface erosion hence wetting time, swelling time are not the pre-requisites for controlled release hence it would be devoid of premature burst release of. drug. Furthermore, present invention also relates to a method for producing such dosage form.
14