FIELD OF THE INVENTION
The invention provides a prolonged release pharmaceutical composition of
Indapamide comprising one or more cellulose derivatives polymers selected from
hydroxy propyl methyl cellulose (HPMC) or sodium carboxy methyl cellulose or
both.
The invention also provides a prolonged release pharmaceutical
composition of Indapamide and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Indapamide is chemically known as 3-(Aminosulfonyl)-4-chloro-N-(2,3-
dihydro-2-methyl-lH-indol-l-yl)benzamide and its chemical structure is as
follows:
Ov NH2
Indapamide is a diuretic antihypertensive agent which involves the renal and
extrarenal actions exerts its mechanism of action in the control of hypertension. The
site of action from renal is proximal part of the distal tubule and the ascending part
of Henle's loop where Sodium and chloride ions are excreted in approximately
equivalent amounts. The increased delivery of sodium to the distal tubular exchange
site results in increased potassium excretion and hypokalemia.
Indapamide is a 2-methyl indoline derivative of 4-chloro-3-sulfamoyl
benzamide. It is referred to as a thiazide-like diuretic as its action is similar to the
thiazide diuretics. It inhibits sodium and chloride reabsorption from the distal
convoluted tubule by blocking the sodium/chloride co-transporter (symporter).
Dose based response have shown that Indapamide lowers blood pressure (BP) at
doses below that needed to elicit a diuresis, and appears to have antihypertensive
effects other than diuresis. Indapamide is rapidly absorbed from the gastrointestinal
tract and peak plasma concentrations are seen 1-2 hours after dosing. Because of its
long half-life, it is effective in once daily dosing. Indapamide is extensively
metabolised, with only about 7% of the total dose administered recovered in the
urine as unchanged drug during the first 48 hours after administration. It is
pharmaceutically compatible with most of the reported adjuvants/excipients. The
target population with uptake the dose of Indapamide is delivered to age group more
than 18 to get desired response. Targeted population to get affect from hypertension
mainly ranges more than 18 and in most of cases age range between 35-50 having
the high blood pressure. For this age range there is a need to minimise the dosing
frequency to have a less dependency on multiple dosing and also minimise the side
effects.
Indapamide was approved in India by Central Drugs Standard Control
Organisation on Jun 12, 1996 as sustained release coated tablet for the treatment of
moderate hypertension. The registered brand name available for Indapamide as
NATRILIX SR sold by Servier Laboratories.
Indapamide as new amino indoline derivatives compounds were disclosed
in GB 1,203,691 (Science Union, Laszlo Beregi Pierre et al.,1969) Pierre et al in
this disclosed the diuretic and anti-hypertensive properties of various amino
indoline compounds and their method of preparation using n-amino indoline as
starting material. Compound preparation is disclosed.
The composition disclosed by Alain Cuine et al in EP0519820 (1992) as
matrix tablets for sustained release of Indapamide. Natrilix® marketed tablets of
Indapamide were launched at Australia on December 1998 by Servier Laboratories.
The sustained release is controlled by the use of specific viscosity between 1000 to
20,000 centipoise of methylhydroxypropyl cellulose and 10,000 to 7,00,000
centipoise (cP) of polyvidone. The process for preparation of the tablet includes a
wet granulation step wherein the Indapamide, polyvidone and lactose are combined
with an aqueous-alcoholic granulation liquid to yield granules, which are then dried
and mixed with the methylhydroxypropyl cellulose. Finally, lubricant is added and
the mixture is compressed to prepare the tablets.
Josse R. Thomas et al in Suppl II Hypertension, Vol 7, No 6, Nov 1985
discloses the dose of 2.5mg of Indapamide once daily effectively reduces arterial
blood pressure in about two-thirds of patients with mild to moderate hypertension
and that this reduction is related to the severity of the hypertension. The dose
depended frequency is showing less side effects and a simple once-daily dosage
regimen. However, the dose dependent side effects during 2.5mg have been
reported. Specifically, Hypokalaemia reported in patient history of taking such dose
of2.5mg.
Katarzyna Jureczek et al in WO2004/002475 (2002) discloses the tablets
preparation process first mixing the Indapamide with lactose monohydrate and
copovidone. Then the mixture is moistened with purified water and then granulated.
The granulate thus obtained is dried, cooled, mixed with hypromellose having the
viscosity ranges between 1000 to 20,000 cP and lubricants and compressed in a
tabletting machine.Andrejka Kramar et al in WO2005/074884 (2005) discloses a
sustained release pharmaceutical composition of Indapamide in the form of a tablet
obtainable through the direct compression process using oligosaccharide or
polysaccharide with cellulose derivative with the viscosity of 1000 to 15000cps as
hydrophilic matrix former.
MireilleDebauge etalm EP1902709 (2005) and EP1669062 (2005) teaches
that it is not necessary to combine two polymers from two different chemical
families in order to achieve extended release of Indapamide from tablets. The
disclosed invention does not contain povidone but a mixture of 20 to 50% by weight
of a medium (4000 cP) or high viscosity polymer (15,000 and 100,000 cP.), and
from 0.5 to 10% by weight and of a low viscosity polymer (05 cP ), in combination
used to control the sustained release. The mixture of medium high and low viscosity
cause the dual mechanism in single tablet which results in not achieve the initial
50%) release within desired time. The release of the active ingredient is both
diffusion and erosion of the matrix, cause the initial release more than 50% in first
3 hours. Hence still a need remain to prepare the composition which capable to
maintain the linear release profile of initial 08 hours.
However, the described prior art processes result in composition with
Indapamide showing high fluctuations in terms of their drug content, release profile
and desired time interval for drug release which for pharmaceutical preparations
administering active ingredients to the human body is highly undesirable. Still need
remain to obtain a better therapeutic index at lower expenditure and to prepare such
a composition which is capable to deliver the drug as prolonged period of time in
order to produce medication for safe and economical manner. The dosing frequency
is also a motivation to formulate such a composition which can reduce the dosing
frequency and able to provide the optimum onset of action. Thus, there exists unmet
need to provide a composition, which is simple, stable and easy to manufacture and
at the same time provides a steady state plasma concentration of drug and the
composition is scalable on industrial scale with enhance release profile capable to
follow the linear release profile upto initial 08 hours.
Formulations described in prior art with the sustained release pattern also
not capable to follow the linear release profile upto initial 08 hours. Inventors of the
present invention observed contrary to the teaching of prior art that it was not
necessary to combine two polymers of different category, namely a high viscosity
HPMC and povidone or two HPMC grades with different viscosities for release of
the active prolonged release principle. Inventors of the present invention optimised
the ratio of HPMC of viscosity less than 100 cP with salts of polycarboxymethyl as
polymer mixture of cellulose derivative polymers to meet the desired linear release
profile. There is a further need to optimize the extended release pharmaceutical
dosage forms comprising Indapamide, affective for 24 hours with precise delivery
of drug to minimise the dose dependency and in order to make it convenient to
manufacture, administer, and provide the requisite daily dosage of Indapamide.
SUMMARY OF THE INVENTION
The present invention relates to prolonged release pharmaceutical
composition of Indapamide with cellulose derivatives polymer as an excipient.
In one aspect of present invention, it relates to a prolonged release
pharmaceutical composition of Indapamide comprising 0.1-2% w/w of Indapamide,
10-25%) w/w of one or more cellulose derivatives polymers with the viscosity of
ranging between 20-80 cP measured using 0.5% w/w of aqueous solution.
In another aspect of present invention, it relates a prolonged release
pharmaceutical composition, wherein the said composition provides drug release
upto 24 hours.
It yet another aspect of present invention it relates to a process of preparing
prolonged release pharmaceutical composition of Indapamide, wherein the process
comprises the steps of:
a) sifting filler, Indapamide and lubricants
b) dry mixing about l/4th amount of filler with Indapamide
c) blending the remaining quantity of filler with step b) drug mixture in
blender.
d) adding cellulose derivate polymers with glidant and blending for 5-15
min.
e) blended material of step d) wetted using aqueous media and mixed in
RMG for 10-3 Omin.
f) granulating the material of step e) in RMG using impeller rotation of 80-
120 rpm & chopper speed at 2500 to 3000 rpm for less than 2 min.
g) drying the granules for 15-20 min at 50-60°C and sifting,
h) dried the granules after sifting at 50-70 °C.
i) adding cellulose derivate polymers mixed for 5-15 min with blended
material after pass through #30-#50 sieve,
j) lubricating the mixing material for time ranging between 5 to 60 min
after sieving.
k) compressing or encapsulating the lubricated material and optionally
performing aqueous coating.
A prolonged release pharmaceutical composition of Indapamide according
to the present invention can provide up to 24-hour release profile, which may be
useful for the treatment of hypertension.
Various other specific aspects of the invention are further detailed in the
description part of the specification, wherever appropriate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides prolonged release pharmaceutical
composition of Indapamide with other suitable excipients which may be used for
the treatment of hypertension.
In one embodiment according to the present invention, it provides the
prolonged release pharmaceutical composition of Indapamide comprising 0.1-2%
w/w of indapamide, 10-25% w/w of one or more cellulose derivatives polymers
with the viscosity of 20-80 cP measured using 0.5% w/w of aqueous solution.
The term "Indapamide" as used herein, includes the compound Indapamide,
pharmaceutically acceptable salts, esters and prodrugs thereof, the active
metabolites of imatinib, and any of their polymorphs, solvates, hydrates.
Formulations can contain Indapamide in the range of 1 to 2.5 mg per dosage unit.
The release pattern of pharmaceutical composition of the present invention
may be in the form of "prolonged release" or "immediate release" or "extended
release" or "modified-release" or "sustained-release" or "delayed-released" or
"pulsatile-release". The inventors of the present invention utilize the advantages of
drug property and formulate a composition with such a release pattern which is
capable to maintain the therapeutic blood or tissue levels of the drug for prolonged
period of time.
The pharmaceutical composition of the present invention may be in the form
of oral solid dosage form preferably tablet, capsule, powder, granules, prolonged
release, sustained release, control release, immediate release composition. The
inventors of the present invention came up with the solution as oral solid
composition in the form of prolonged release profile, which is patient compliance
and easy to intake as per lowering the dosing frequency.
The cellulose polymer substances are selected from, but not limited to one
or more of cellulosic polymers copolymers or its derivatives including ester
cellulose, ether cellulose, nitrocellulose, methyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl
methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose;
polyacrylates, methyl acrylates, cellulose acetate phthalate.
The release of cellulose polymer is controlled by polymer viscosity and
concentration. Chemistry of cellulose polymer encourages a strong, tight gel
formation compared to other polymer. The cellulose polymer of different grades
with different in viscosity have selected to optimise the polymer mixture. The
present invention focusing on the aim to provide 0-8hrs zero order kinetics (linear
release profile upto initial 8 hrs), more than 50% drug should be release in 12 hrs
and more than 70% drug should be release in 24 hrs.
It was observed by the inventor of the present application that high viscosity
cellulose polymer more than 2000 cP provides the release within 12-15 hours,
cellulose polymer mixture (HPMC+CMC) with lower viscosity (20 cp in 0.5%
concentration and 50 rpm with 62 spindle) results in loose matrix formation and
100%) drug release less than 12 hrs which was not found suitable for desired release
profile. Cellulose polymer mixture (HPMC+CMC) with higher viscosity (4000 cP
in 0.5%) cone, with 61 spindle 50 rpm) results in strong matrix formation and
observed drug release not more than 60%> upto 24 hrs which was also not found
satisfactory to provide desired release profile.
To control the release up to 24 hours, inventors surprisingly found that
cellulose polymers of less than 100 cP and sodium salt of polycarboxymethyl as
second cellulose derivative have shown encouraging results as polymer mixture for
providing constant release of a drug. The optimised mixture of cellulose derivative
polymer having viscosity less than 100 cP with sodium salt of polycarboxymethyl
in the ranges between 10-50%, particularly 10-30% results in follows the zero-order
release profile. The optimised mixture surprisingly provided the required linear
release profile and inventors of the present invention found the interactions between
ionized drug molecules and polar groups on the polycarboxymethyl as (sodium
CMC) are major attributable to the rate of swelling and desired rate of erosion.
According to the present invention prolonged release pharmaceutical
composition of Indapamide with one or more cellulose derivatives polymers thereof
is provided. Employing modified drug release assays it has surprisingly been found
that the use of particular cellulose derivatives polymer mixture having a certain
optimum viscosity, notably below 100 cP. (determined according to USP35<912>
Rotational rheometer methods at 20°C) enables robust prolonged release from the
pharmaceutical composition under mechanical and chemical stress conditions as
encountered in the gastrointestinal tract. Under physiological conditions an orally
administrated dosage form undergoes considerable mechanical stress during its
passage through the gastrointestinal tract, in particular during transition through the
pylorus. In specific embodiment cellulose polymer is selected from hydroxypropyl
methylcellulose having the viscosity less than 100 cP of 0.5% solution and
polycarboxymethyl polymer as sodium carboxymethylcellulose or mixture of both.
The term "prolonged-release ", as used herein, can be used synonymously
with "extended release" or "modified-release" or "sustained-release" or "delayedreleased"
or "pulsatile-release" based on the type of release required and is
understood to mean a drug dosage system in which the rate of the API release is
more precisely controlled and is delivered from the dosage system at a predictable
and predetermined rate within the body of a patient such that a therapeutically
effective blood level, devoid of peak and trough fluctuations, over an extended
period of time. This definition excludes "immediate release" oral pharmaceutical
dosage forms, which consist of pharmaceutical dosage forms which release the
active drug immediately after oral administration.
In another embodiment according to the present invention, it provides the
process of preparing prolonged release pharmaceutical composition of Indapamide
wherein the process comprises the steps of:
a) sifting filler, Indapamide and lubricants
b) dry mixing about l/4th amount of filler with Indapamide
c) blending the remaining quantity of filler with step b) drug mixture in
blender.
d) adding cellulose derivate polymers with glidant and blending for 5-15
min.
e) blended material of step d) wetted using aqueous media and mixed in
RMG for 10-3 Omin.
f) granulating the material of step e) in RMG using impeller rotation of 80-
120 rpm & chopper speed at 2500 to 3000 rpm for less than 2 min.
g) drying the granules for 15-20 min at 50-60°C and sifting.
h) dried the granules after sifting at 50-70 °C.
i) adding cellulose derivate polymers mixed for 5-15 min with blended
material after pass through #30-#50 sieve.
j) lubricating the mixing material for time ranging between 5 to 60 min
after sieving.
k) compressing or encapsulating the lubricated material and optionally
performing aqueous coating.
The step a) of sifting the filler, Indapamide and lubricant according to the
present invention, carried out in a shifter by conventional method using mesh size
ranges between #50 to 70#, however it was optimised by the inventors of the present
invention that sifting of excipients and Active Pharmaceutical Ingredient before
mixing gives uniformity and promote the powder flow.
Furthermore, the step b) of dry mixing the sifted material with Vi amount of
filler with Indapamide by manually mixing. The mixing was performed at the
temperature ranges 30-40°C for a time period of 15 min.
The step c) of blended the mixed material of step b) in an octagonal blender
with remaining amount of filler and blend for 15-30 min at 20-30 rpm. The dried
mixing of filler using different amount at different stage provides advantage with
material handling and powder better flow of powder.
The step d) of adding cellulose derivative polymer in to the blender with
lubricant and blended for 05-15 min at 15-30 rpm. The step of adding cellulose
derivative polymer and lubricant performed as part of dry mixing in blender. The
inventors of the present invention found the advantage of blending polymer with
small amount of lubricant using dry mixing as impact on material handling.
Further granulation process of step e) carried out by slowly wetted the dry
mixed blend material of step d) using warm aqueous media of 45-50°C in RMG and
slowly mixed for 15-30 min. Addition of slowly aqueous media with slowly mixing
in RMG helpful to wet the mass properly before shearing.
Granulating the wetted mass in step f) in RMG using impeller rotation of
80-120rpm and slow down to 40-60 rpm and set the chopper at 2500-3000 rpm for
less than 02 min. Inventors have found this process of granulation at said rpm to
be most effective rotation ranges to prepare the granules of desired uniformity size
range.
Drying the prepared granules in step g) of present invention as semi-drying
using air temperature of 50-60°C for 10-20 min and sifting the granules using 5-
10# mesh size to get the uniform granules in semi-dried form.
Drying the semi-dried granules in step h) at the temperature ranges between
55-75°C for the to achieve the LOD (<2%). Shifting the dried granules using 20-
30# mesh size to get the uniform granules.
Adding remain cellulose derivative polymer as in step i) of the present
invention and mixing for 5-15 min in Octagonal blender after sifted with 30-50#
mesh size.
Inventors surprisingly observe the better intact property of composition and
improvement in release profile when Cellulose polymers are distributed in different
ratio. The addition of different ratio at different steps for preparation for
composition enhance the release profile for prolonged period of time.
Lubrication as per step j) of sifting the Magnesium stearate and colloidal
anhydrous silica using the size ranges between 50-70# and adding in blended
material as step i) by mixing for 5-10 min.
The step k) of present invention processed for lubricated mass for
compression and/or encapsulating in capsules shell followed by optional aqueous
coating.
In a particular embodiment of the present invention, it provides to prepare
prolonged release pharmaceutical compositions of Indapamide comprising 78.5-
83.6% of lactose, 8.75-12.47% of hydroxypropyl methyl cellulose, 3.35-4.34% of
sodium carboxymethyl cellulose, 0.55% of aerosil.
A prolonged release pharmaceutical composition of Indapamide described
herein can further contain one or more fillers. In general, filler is a substance
increasing the bulk volume of mixture and thus the size of final dosage form.
Preferred examples of fillers are microcrystalline cellulose, powdered cellulose,
lactose (anhydrous or monohydrate), starch (e.g., corn starch or potato starch),
pregelatinized starch, sugar and sugar alcohol like mannitol, fructose, sucrose,
dextrose, xylitol, dextrans, sorbitol, saccharose, calcium hydrogen phosphate,
calcium hydrogen phosphate dihydrate, dicalciumphosphatedihydrate,
tricalciumphophate, or mixtures thereof. The preferred filler is lactose.
Lubricants ensure that tablet formation and ejection can occur with low
friction between the dosage forms (solid) and die wall. Preferred examples of
lubricants are Sodium Stearyl Fumarate (SSF), Sucrose stearate, magnesium
stearate, stearic acid, calcium stearate, hydrogenated vegetable oil, hydrogenated
castor oil, macrogols, glycerylbehenate, talc, silicone dioxide or mixtures thereof.
The preferred lubricant is magnesium stearate.
It has been observed by present inventors that various composition
discussed in prior art suffer a disadvantage of multiple dependency of dose either
less dissolution profile or not meeting the release for desired period of time. The
present invention provides economical aqueous coating as an advantage over nonuniform
and difficult which may results as blistering, chipping, picking, blushing,
cracking (splitting) or the like.
The term "oral" administration means that the active agent is in a
formulation designed to be ingested, i.e. designed to be delivered to the
gastrointestinal system for absorption.
The term "prolonged release" or "pharmaceutical composition" comprises
capsule, tablet (film coated tablet, controlled release tablet, modified release tablet,
extended release, delayed release, immediate release etc.), micro tablet, powder,
granule and pellets. Capsules used as oral dosage form can be soft or hard capsules,
though oral dosage form of the present invention is tablet or capsule.
The term "about" is a value that can be considered ±5% of the given value.
Based on context of discussion, the term "% w/w" refers to the relative value to
total weight of granules or to total weight of pharmaceutical composition and
"%v/v" refer to volume by total volume percentage.
In one of embodiments, the application provides pharmaceutical dosage
forms of otilonium bromide having content uniformities (CU) from about 90% to
about 110% by weight, with relative standard deviations (RSD) of not more than
about 5%. In embodiments, the invention provides to pharmaceutical formulations
having friability not more than about 1 % w/w.
Usage of the terms "a" and "an" and "the" and similar referents in the context
of describing the invention (especially in the context of the following claims) are to
be construed to cover both the singular and the plural, unless otherwise indicated
herein or clearly contradicted by context. The terms "comprising" "having"
"including" and "containing" are to be construed as open-ended terms (i.e., meaning
"including, but not limited to") unless otherwise noted. Recitation of ranges of
values herein are merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range, unless otherwise
indicated herein, and each separate value is incorporated into the specification as if
it were individually recited herein. The term wt% refers to percent by weight. All
methods described herein can be performed in any suitable order unless otherwise
indicated herein or otherwise clearly contradicted by context. The use of any and
all examples or exemplary language (e.g. "such as") provided herein, is intended
merely to better illuminate the invention and does not pose a limitation on the scope
of the invention unless otherwise claimed. No language in the specification should
be construed as indicating any non-claimed element as essential to the practice of
the invention.
The terms "excipients", "adjuvant", "pharmaceutically acceptable
excipients" and "pharmaceutically compatible excipients", are used
interchangeably in this disclosure. They refer to non-API substances such as
disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical
composition. They are generally safe for administering to humans according to
established governmental standards, including those promulgated by the United
States Food and Drug Administration.
Particular embodiments of this invention are described herein, including the
best mode known to the inventors for carrying out the invention. Variations of those
particular embodiments may become apparent to those of ordinary skill in the art
upon reading the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for the invention to
be practiced otherwise than as specifically described herein. Accordingly, this
invention includes all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law. Moreover, any
combination of the above-described elements in best possible variations thereof is
encompassed by the invention unless otherwise indicated herein or otherwise
clearly contradicted by context.
While the forgoing pages provide a detailed description of the preferred
embodiments of the invention, it is being understood that the summary and
description are illustrative only of the core of the invention and non-limiting in
scope. Furthermore, as many changes can be made to the invention without
departing from the scope of the invention, it is intended that all material contained
herein be interpreted as illustrative of the invention and not in a limiting sense.
Table 01
Example 01-03 Preparation of Prolonged Release Tablet using wet
granulation:
S.No.
1.
2.
Ingredients Name Quantity per tablet (mg)
Example 01 Example 02
Dry Mixing/Intragranular
Indapamide BP*
Lactose BP**
1.5
161.50
1.5
171.5
Example 03
1.5
164.5
3.
4.
5.
6.
7.
8.
9.
10.
HPMC
Aerosil
Sodium CMC
Extragranular
HPMC
Sodium CMC
Magnesium stearate BP
Aerosil BP
Coating
Opadry03F180011
Average Weight
10.35
0.15
4.5
15.6
4.4
1.0
1.0
5
205
7.35
0.15
3.5
10.6
3.4
1.0
1.0
205
9.35
0.15
4.5
13.6
4.4
1.0
1.0
205
Manufacturing process for preparation of Indapamide prolonged release tablet
composition using wet granulation:
a) sifting filler, lubricants and Indapamide using sieve size ranges from #40 to
#70
b) dry mixing of 1/4th amount of filler with Indapamide for 10 to 20 min.
c) blending the remaining quantity of filler with Indapamide for 15 to 30 min
at 20-30 rpm.
d) adding cellulose derivate polymers with glidant and blending for 5-15 min
at 20-30 rpm
e) blended material of step d) wetted using aqueous media and mixed in RMG
for 10-30min.
f) granulating the material of step e) in RMG using impeller rotation of 80-
120 rpm & chopper speed at 2500 to 3000 rpm for less than 2 min.
g) drying the granules for 40-70 min at 45-65°C and sifting by using #5 to #15
sieve.
h) blending the dried granules after sifted through #20 to #30
i) adding cellulose derivate polymers mixed for 5-15 min with blended
material after pass through #30-#50 sieve.
j) lubricating the mixing material for 15 min after sieving with #40-#60 mesh
size.
k) compressing or capsulate the lubricated mass and optionally aqueous
coating.
Table 02
Example 04 Preparation of Prolonged Release Tablet using direct
compression:
S.No.
1.
2.
3.
4.
5.
Ingredients Name
Indapamide BP
Lactose BP
Hydroxypropyl methyl cellulose-
K15M
Magnesium stearate BP
Aerosil BP
AvgWt
Qty mg/tab
1.5
154.45
42
1.00
1.00
200.00
Manufacturing process for preparation of Indapamide prolonged release tablet
composition using direct compression:
1. Indapamide passed through # 40-50 sieve no.
2. lactose passed through #40-50 sieve no. and add in step-1 (with
geometrically mixing),
3. Then hydroxypropyl methyl cellulose-K15M passed through #40-50 sieve
no. and add in step-1,
4. Transfer blend in blender and mixed for 30-40 minutes at 22-30 RPM.
5. magnesium stearate and aerosil passing through #60-70 sieve no. add in
whole blend and mix for 5-10 minutes in blender.
6. The blended mass is compressed using suitable punch size.
Tablets prepared of Examples is packaged in closed Alu/Alu Blister or
PVC/Alu Blister and stored at three different conditions: 25°C and 60%> relative
humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and 75% RH
(Condition 3) for one month. Dissolution testing results of initial and stored samples
are shown in Table 3. The dissolution study is conducted in 900 ml of 6.5 pH
phosphate buffer using basket apparatus, while stirred at 100 rpm for 24 hours. The
temperature of the dissolution medium was maintained at 37 ± 0.5 °C.
Dissolution testing results of marketed tablet and Examples 01-03 are
shown in Table 03:
TABLE 03
Time
(hours)
0
1
2
4
8
12
24
Cumulative % Drug Dissolved
Trial 01
Avg.
0
7
13
25
51
68
99
%RSD
0
0.52
0.75
0.63
5.09
6.98
7.19
Trial 02
Avg.
0
12
19
37
70
91
98
%RSD
0
0.55
0.82
2.94
3.15
3.87
5.23
Trial 03
Avg.
0
9
15
29
60
80
95
%RSD
0
0.82
0.52
1.17
11.62
14.68
9.77
Natrilix SR
Avg.
0
4
9
22
42
63
98
%RSD
0
0.42
0.62
1.1
4.2
5.7
8.9
The abovementioned examples, which are provided by way of illustration, should
not be construed as limiting the scope of the invention with respect to parameters,
ingredients and quantities used in any manner.

We Claim:
1. A prolonged release pharmaceutical composition of Indapamide comprising
0.1-2% w/w of Indapamide, 10-25% w/w of one or more cellulose
derivatives polymers with the viscosity of 20-80 cP measured using 0.5%
w/w of aqueous solution.
2. A prolonged release pharmaceutical composition prepared according to
claim 1, wherein the said prolonged release composition provides drug
release upto 24 hours.
3. A prolonged release pharmaceutical composition according to claim 1,
wherein one or more cellulose derivative polymers are selected from
hydroxy propyl methyl cellulose (HPMC) or sodium carboxy methyl
cellulose or both present in a ratio of about 1:3.
4. A process of preparing prolonged release pharmaceutical composition of
Indapamide, wherein the process comprises the steps of:
a) sifting filler, Indapamide and lubricants
b) dry mixing about l/4th amount of filler with Indapamide
c) blending the remaining quantity of filler with step b) drug mixture in
blender.
d) adding cellulose derivate polymers with glidant and blending for 5-15
min.
e) blended material of step d) wetted using aqueous media and mixed in
RMG for 10-3 Omin.
f) granulating the material of step e) in RMG using impeller rotation of 80-
120 rpm & chopper speed at 2500 to 3000 rpm for less than 2 min.
g) drying the granules for 15-20 min at 50-60°C and sifting,
h) dried the granules after sifting at 50-70 °C.
i) adding cellulose derivate polymers mixed for 5-15 min with blended
material after pass through #30-#50 sieve.
j) lubricating the mixing material for time ranging between 5 to 60 min
after sieving,
k) compressing or encapsulating the lubricated material and optionally
performing aqueous coating.
5. A prolonged release pharmaceutical composition prepared according to
claim 4 wherein filler used in said composition selected from lactose, xylitol
or mannitol.
6. A prolonged release pharmaceutical composition prepared according to
claim 4 wherein glidant used in said composition are selected from colloidal
anhydrous silica, talc or starch.
7. A prolonged release pharmaceutical composition prepared according to
claim 4 may be used for the treatment of hypertension.