FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
SUSTAINED RELEASE DOSAGE FORM OF INDAPAMIDE
Applicant
Name : Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed.

SUSTAINED RELEASE DOSAGE FORM OF INDAPAMIDE
FIELD OF INVENTION
The present invention relates to sustained release pharmaceutical composition of indapamide in a solid oral dosage form prepared by wet granulation comprising high viscosity hydroxypropyl methylcellulose alone as release controlling agent. Further the said composition is free from povidone, copovidone or any other combination of release controlling agents.
The present invention also relates to process of preparation of sustained release pharmaceutical composition of indapamide in a solid oral dosage form by wet granulation comprising high viscosity hydroxypropyl methylcellulose alone as release controlling agent.
BACKGROUND OF THE INVENTION
Indapamide, a nonthiazide diuretic is used alone or in combination with other drugs for the treatment of hypertension and congestive heart failure and to prevent salt and fluid retention associated with heart failure. It differs from thiazides in that it doesn't contain a thiazide ring system and contains only one sulfonamide group. The chemical name of Indapamide is 4-chloro-N-(2-methyl-l-indolinyl)-3-sulfamoylbenzamide. The antihypertensive action of it is thought to be due to the inhibition of transmembrane ionic flux essentially calcic and stimulation of the synthesis of vasodilatory hypotensive prostaglandins.
Indapamide has been known to be present as immediate or controlled release dosage form to be given as oral route. The immediate release dosage form has been found to give varied plasma concentration (peak effect), which may lead to overdosing or underdosing, which in turn may lead to various adverse effects. To maintain the
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concentration of drug in therapeutic window many controlled release formulation of Indapamide are available in the prior art, which intend to provide desired release profile and a better therapeutic index.
Sustained release dosage forms available in the prior art may provide a good release profile under ideal conditions. It's very difficult to maintain ideal body conditions for getting a controlled release profile. Moreover some of these formulations are bulky and have a lengthy manufacturing process. The simplest kind of controlled release dosage forms are matrix based formulations and these matrices may use different kind of polymers to control the rate of drug release. The various techniques to make modified release as described in prior art are as follows:
US 6500459 Bl discloses about controlled onset and sustained release drug delivery systems, where there is a core, which contains an active ingredient, a hydrophilic carrier, a hydrodynamic diffusion enhancer and optionally other pharmaceutical excipients and this core is surrounded by three coating membranes. This type of formulation provides a very bulky formulation and has a lengthy and complicated manufacturing process. In this formulation drug release is also controlled by functional coating, there are chances of dose dumping, due to accidental bursting of the functional coating membrane. Sudden dose dumping may lead to various side effects on the patients.
EP 0519820 Bl discloses method of prolonging the release of indapamide tablets. Matrix tablets described in this invention essentially requires two polymers from different chemical family's i. e HPMC and Polyvidone for obtaining a controlled release of the active constituent. As per EP 0519820 Bl, polyvidone having molecular weight between 10,000 and 700,000 in an amount between 2% to 10% of the mass of tablet and hypromellose having viscosity between 1,000 and 20,000 cps in an amount between 30% to 50% of the total mass of the tablet are required for controlling the release of indapamide. The examples (Example 1-5) disclosed in EP
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0519820 Bl contains polyvidone in an amount of less than 5% (3.3%, 3.1%, 3.1%, 4.3%, 4.64%) of the total mass of the tablet. In "Handbook of Pharmaceutical Excipients", Fourth Edition, page no: 508, the concentration of polyvidone is disclosed and the concentration of polyvidone as disclosed in examples of EP 0519820 Bl falls in the same limit.
Moreover, this prior art doesn't discloses formulation which protects the drug against the effect of light as there is no film coating while the drug has been reported to be photosensitive in the literature (Ref: The complete drug reference pp 913, 33rd edition Martindale). Also, Alcohol used in wet granulation is problematic from safety reasons and should be limited by GMP and other quality-based requirements. For example, special equipment (explosion- resistant apparatuses) used in the stages where alcohol is used as a solvent must be available. Secondly, alcohol has to be recycled for environmental protection and safety reasons. A process where alcohol is used is not the first choice also from an economical point of view.
WO2004/002475 Al discloses sustained release tablet containing indapamide require copovidone and hypromellose for better control of the drug release. The disclosed formulation also requires two different families of polymers for sustained release formulation of indapamide.
WO 2005/ 074884 A2 discloses sustained release compositions of indapamide which can be prepared by a direct compression mixture. The general disadvantages of direct compression process are as under:
1. Need for commensurate particle size or particle size distribution between drug and excipients.
2. Low blend density.
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WO 2006/061502 Al discloses formulation of indapamide, essentially comprising a mixture of at least two hydrophilic cellulosic polymers with different viscosities, such as hydroxypropylmethylcelluloses, to manufacture control release formulation of Indapamide.
In all prior art, there is requirement of the additional component other than Hydroxypropyl Methylcellulose for controlling the release of indapamide from the dosage form.
Surprisingly we have found that sustained release formulation of indapamide can be made using high viscosity HPMC alone as release controlling agent. The instant invention is devoid of limitation of use of povidone or copovidone or combination of different viscosities of hydroxypropyl methyl cellulose and has following features:
a) Simple manufacturing process.
b) Acceptable dissolution profile.
c) Acceptable economics of excipients.
d) Acceptable economics of manufacturing process.
e) Acceptable bioavailabilty.
SUMMARY OF THE INVENTION
The first aspect of the present invention is to provide a sustained release solid oral dosage form of indapamide comprising high viscosity hydroxypropyl methylcellulose alone as release controlling agent.
Another aspect of the present invention is to provide a sustained release solid oral dosage form of indapamide comprising high viscosity hydroxypropyl methylcellulose alone as release controlling agent, wherein the said composition is free from povidone or copovidone or combination of release controlling agents.
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Another aspect of the present invention is to provide a sustained release solid oral dosage form of indapamide in an amount of 0.6 to 0.9% by weight of dosage form comprising high viscosity hydroxypropyl methylcellulose alone as release controlling agent in an amount less than 28 % by weight of dosage form, wherein the said composition is free from povidone or copovidone or combination of release controlling agents.
In another embodiment, there is provided composition of a sustained release tablet of indapamide, characterized in that the tablet contains indapamide in the amount 0.6% to 0.9% by the weight of tablet, Lactose monohydrate in an amount of 40% to 80% by the weight of tablet, pregelatinized starch in an amount of 2% to 5% by the weight of tablet, high viscosity hypromellose in an amount less than 28% by the weight of tablet, and the lubricants in an amount of 0.1% to 3% by the weight of tablet.
In yet another embodiment, process of preparation of sustained release pharmaceutical composition of indapamide in a solid oral dosage form by wet granulation comprises of following steps:
a) Mixing of indapamide and diluent(s) then wetting of this mixture by purified water. The wet mass prepared is then granulated, dried and then graded, so as to obtain the granules.
b) Mixing of the granules obtained in step a) with hydroxypropyl methylcellulose.
c) Lubrication of the mixture obtained in step b) with colloidal silicondioxide and magnesium stearate.
d) Compression of the lubricated mixture obtained in step c) in a rotary tableting machine.
e) Film coating the compressed tablets from step d).
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DETAILED DESCRIPTION OF THE INVENTION
Hydroxypropyl methylcellulose (HPMC, hypromellose) have been widely studied for their applications in oral sustained release systems. When in contact with water, HPMC hydrates rapidly and forms a gelatinous barrier layer around the tablet. The rate of drug release from HPMC matrix is dependent on various factors such as type of polymer, drug, polymer/drug ratio, particle size of drug and polymer, and the type and amount of excipients used in the formulation.
The present invention relates to a sustained release dosage form comprising Indapamide a nonthiazide antihypertensive drug, prepared by wet granulation and using high viscosity hydroxypropyl methylcellulose alone to control the drug release.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "sustained" as used herein in relation to the composition according to the invention or a rate controlling polymer or used in any other context means release, which is not immediate release and is taken to encompass controlled release, modified release, prolonged release, timed release, retarded release, extended release and delayed release, The term "sustained release dosage form" as used herein can be described as dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form.
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The instant invention use high viscosity hydroxypropyl methylcellulose alone as release controlling agent, to control the release of indapamide formulation. Contrary to prior art, the instant invention does not require copovidone or povidone or combination of different release controlling polymers to control the drug release. The instant invention also doesn't use the combination of release controlling polymers from same chemical family and having different viscosities to control the release of indapamide. The instant invention is simple, economic, and efficient process to manufacture sustained release solid oral dosage form of Indapamide.
Indapamide, which is a photosensitive drug, requires specially formulated dosage forms that not only provide better release characteristics but also protect the drug from degradation and thereby provides a better shelf life to the final product. The term photosensitive here denotes something that degrades in the presence of light.
The amount of indapamide in the pharmaceutical formulation is from 0.1 to 10 mg. In a preferred embodiment, the amount of indapamide is 0.5 to 5 mg.
The pharmaceutically acceptable excipients are selected from the following categories but not limited to diluents, fillers, glidants, lubricants, and /or plasticizers.
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 dosage form. If desired, more than one diluent or fillers can be used. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, lactose anhydrous, lactose monohydrate, pregelatinized starch, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol and starch and other materials known to one of ordinary skill in the art. The "diluent" or "filler" is present in the composition in the range of 40% to 80% by weight of dosage form.
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As used herein, the term "glidants" is intended to mean agents used in formulation to improve flow of powder or pellets. Such compounds include, by way of example and without limitation, colloidal silica, talc, calcium silicate, magnesium silicate, colloidal silicondioxide and other materials known to one of ordinary skill in the art.
A used herein, the term "lubricants" is intended to mean Lubricant can be selected from the group comprising of Stearic acid, Polyethylene glycol, Magnesium stearate, Calcium stearate, Zinc stearate, Talc or Silica, Hydrogenated caster oil, etc.
As used herein, the term 'plasticizer' should be able to provide the desired plasticity to the coating. Plasticizers, such as PEG 6000, Glyceryl monopalmetostearate / Glyceryl monostearate, Dibutyl phthalate, Triethyl citrate, Macrogol are included.
The polymer coating can be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and their mixture thereof.
The release controlling agent is responsible for controlling the drug release from the formulation and any one high viscosity hydroxypropyl Methylcellulose selected from Hydroxypropyl Methylcellulose K100M (Methocel KIOOMCR) and Hydroxypropyl Methylcellulose K15M, can be used as release controlling agent in the instant invention. The preffered high viscosity hydroxypropyl Methylcellulose is Hydroxypropyl Methylcellulose K100M (Methocel KIOOMCR). The viscosity of high viscosity hydroxypropyl methylcellulose (2% in water), is in the range of 11,000 to 120,000 cP. The release controlling agent is present in an amount less than 28% by weight of dosage form.
The term bioavailability herein relates to a measure of the amount of active ingredient that is absorbed via the gastrointestinal tract into the bloodstream. The term relative bioavailability herein denotes the ratio, expressed as a percentage, of the AUC's of two specific orally administered formulations at the same dosage.
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The term AUCo-t herein means the area under the plasma concentration-time curve in the sampling period from time 0 to time tk (time of last quantifiable concentration), as determined using the trapezoidal rule and expressed in ug/mL*h. The term AUC herein means the area under the plasma concentration-time curve from time 0 to infinity as calculated according to: AUC=AUCCM+ Ck/B, where Ck means the last quantifiable concentration and B means the terminal phase first order elimination rate constant, which is obtained from the In concentration-time plot and is equal to the opposite value of its terminal slope calculated by least squares linear regression and is expressed in units ug/mL*h.
The term Cmax denotes the peak plasma concentration and is estimated directly from the plasma concentrations.
The instant invention can be prepared by the process given below:
a) Mixing of indapamide, diluent then wetting of this mixture by purified water. The wet mass prepared is then granulated, dried and then graded, so as to obtain the granules.
b) Mixing of the granules obtained in step a) with hydroxypropyl methylcellulose.
c) Lubrication of the mixture obtained in step b) using suitable glident and lubricant.
d) Compression of the lubricated mixture obtained in step c) in a rotary tableting machine.
e) Film coating the compressed tablets from step d).
Examples
Indapamide Sustained Release Tablets 1.5mg:
The invention is illustrated by (but not limited to) the following examples:
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Table 1

S.No Ingredients 1 2
Core Tablet Mg / Tablet
1. Indapamide 1.50 1.50
2. Lactose Monohydrate 144.22 143.10
3. Pregelatinized Starch 6.88 -
4. Purified Water q.s q.s
5. Hypromellose (Methocel K100M CR) 50.00 -
6. Hypromellose (Methocel K15M) - 54.00
7. Colloidal Silicondioxide 0.40 0.40
8. Magnesium Stearate 1.00 1.00
Core Weight 204.00 200.00
Coatin g
1. Hypromellose (6cps) 2.80 2.80
2. Polyethylene Glycol 6000 0.43 0.43
3. Titanium Dioxide 0.85 0.85
4. Purified Water q.s q.s
Coated Tablet Weight 208.08 204.08
Indapamide and lactose monohydrate were mixed optionally in presence of pregelatinised starch and granulated by adding purified water in a suitable granulator. The granules were dried and these dried granules were sized through 1.00 mm screen. Now hypromellose was sifted through 40# and mixed with dried granules. Colloidal silicone dioxide and magnesium stearate were sifted through 60 # and mixed with the blend. These lubricated granules were compressed to tablets using suitable round standard concave punches. The tablets were filmcoated in perforated coating pan.
The dissolution of the present invention was determined by following method:
Instrument : Apparatus IUSP
RPM : 100
Dissolution Medium : 900mL, pH 6.8 buffer
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The dissolution profiles of the tablets prepared as per examples 1 to 2 and of Fludex LP Market Sample of Indapamide prolonged release (Mfgr: Servier Lab) are given in the table below:
Table 2

Example -> 1 2 Fludex LP B.No: 3L9030
Time (Hours) % drug dissolved
1 2.8 6.1 4.1
2 5.9 9.2 9.2
4 13.8 20.7 18.9
8 33.5 35.2 37.2
12 50.6 54.4 54.1
16 62.9 62.9 66.8
20 72.0 72.0 77.5
24 79.1 79.3 84.1
The relative bioavailabilities of solid pharmaceutical composition of example 1 of the present invention in comparison to the formulation currently on the market (Fludex LP) were evaluated. The bioavailability of sustained release Indapamide Tablets 1.5 mg was evaluated in fasted state and fed state in a group of 36 healthy subjects. The study was two period, two sequence, cross over single dose administration. Blood samples were collected before dose and at predetermined intervals after dose. It was found that the relative bioavailability of the solid pharmaceutical compositions of the present invention is comparable to the formulation currently on the market. The derived Cmax and AUC of the two studies are given in table below:
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Table 3

S.No Study Design Product ID Mean of pharmacokinetic parameters
*-max AUCo-, AUCo-inf
(ng/mL) (jig*h/mL) (ng*h/mL)
1. Two period, Indapamide SR
two sequence, cross over, controlled, block Tablet 1.5 mg(TorrentPharmaceuticals) 6.279 226.578 241.481
Fludex LP Tablet
randomized, 1.5mg
single dose study in Fasted condition (ServierLaboratories,B.No:3L9030) 6.523 217.624 232.429
2. Two period, Indapamide SR
two sequence, cross over, controlled, block Tablet 1.5 mg(TorrentPharmaceuticals,) 7.728 208.769 223.280
Fludex LP Tablet
randomized, 1.5mg
single dose study in Fed condition (ServierLaboratories,B.No:3L9030) 8.197 206.326 221.365
Thus from the above data, it can be concluded that the relative bioavailability of the two formulations are comparable.
Dated this 4th day of September, 2006
^_
Praveen Hand Gandhi,
Torrent Pharmaceuticals Limited, Torrent Research Centre P.O. Bhat - 382428, Gandhinagar Gujarat, India

Claims:
1. A solid oral sustained release tableted dosage form comprising indapamide in the amount 0.6% to 0.9% by the weight of tablet, Lactose monohydrate in an amount of 40% to 80% by the weight of tablet, pregelatinized starch in an amount of less than 5% by the weight of tablet, high viscosity hypromellose in an amount less than 28% by the weight of tablet, and the lubricants in an amount of 0.1% to 3% by the weight of tablet, wherein the sustained release tablet dosage form is prepared by wet granulation, wherein the solid oral sustained release dosage form is free from povidone, copovidone, and combination of release controlling agents.
2. A solid oral sustained release tablet dosage form of indapamide according to claim 1, is optionally film coated.
3. A solid oral sustained release tablet dosage form of indapamide according to claim 1, wherein high viscosity hypromellose has viscosity in the range of 11,000 to 120,000 cP.
4. The process for preparing solid oral sustained release tablet dosage form of indapamide according to claim 1, comprises of the following steps:

a) Mixing of indapamide and diluent then wetting of this mixture by purified water. The wet mass prepared is then granulated, dried and then graded, so as to obtain the granules.
b) Mixing of the granules obtained in step a) with hydroxypropyl methyl cellulose.
c) Lubrication of the mixture obtained in step b) with colloidal silicondioxide and magnesium stearate.
d) Compression of the lubricated mixture obtained in step c) in a rotary tableting machine.
e) Film coating the compressed tablets from step d).
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5. A solid oral sustained release dosage form comprising:

Core Tablet
Indapamide Lactose Monohydrate Pregelatinized Starch Hypromellose (Kl OOMCR) Colloidal Silicondioxide Magnesium Stearate Film Coat Hypromellose (6cps) Polyethylene Glycol 6000 Titanium Dioxide

in an amount of about 1.50mg in an amount of about 144.22mg in an amount of about 6.88mg in an amount of about 50.00mg in an amount of about 0.40mg in an amount of about l.Omg
in an amount of about 2.80mg in an amount of about 0.43mg in an amount of about 0.85mg

6. A solid oral sustained release dosage form comprising:

Core Tablet
Indapamide Lactose Monohydrate Hypromellose (K15M) Colloidal Silicondioxide Magnesium Stearate Film Coat Hypromellose (6cps) Polyethylene Glycol 6000 Titanium Dioxide

in an amount of about 1.50mg in an amount of about 143.10mg in an amount of about 54.00mg in an amount of about 0.40mg in an amount of about l.Omg
in an amount of about 2.80mg in an amount of about 0.43mg in an amount of about 0.85mg

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ABSTRACT
The present invention relates to solid oral sustained release tablet dosage form of indapamide by wet granulation, comprising high viscosity hydroxypropyl methylcellulose alone as release controlling agent, further the said composition is free from povidone or copovidone or combination of release controlling agents. The present invention also relates to a process for preparing said dosage form.