FORM-2
THE PATENTS ACT, 1970
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COMPLETE SPECIFICATION
[SECTION10]
1. EFFERVESCENT ACECLOFENAC FORMULATIONS AND
METHOD FOR PREPARATION THEREOF.
2. (a) Astron Research Ltd.
(b) 2nd Floor Premier House l,
Bodakdev, Ahmedabad-380054.
Gujarat State, India.
(c) Nationality: ïndian.
The following specification particularly describes and ascertains the nature of
the invention and the manner in which it is to be performed.


The present invention relates to effervescent aceclofenac formulations
and method for preparalion thereof.
More particularly in the present invention effervescent formulations is
prepared in the form of tablet, granules, powder containing aceclofenac as a
therapeutic agent,
The formulations dissolves in water to yield an effervescent solution
containing dissolved therapeutic agent.

Prior Art:
Effervescent formulations present several advantages over conventional

oral drug delivery systems like swallowing tablets and capsules. Effervescent
formulations are most liked by patients who find difficulty in swallowing tablets
and/or capsules. Higher bioavailability of the drug present in effervescent
formulations, as the drug reaches gastrointestinal tract in ready-to absorb state;
reduced localized contact into upper gastrointestinal tract resulting into less
irritation and greater tolerability.
Korean patent 1020030003500 describes cost effective formulation for
oral administration containing aceclofenac and production thereóf. The

formulation contains the mixture of 4/56 to 84 parts by weight of aceclofenac, 56

to.84 parts by weight of a surfactant is milled and added 10 to 168 'parts by

weight of a polymer base selected from the group consis'ting of
polyvinylpyrrolidone, methyl cellulose, ethyl cellulose,
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hydroxypropylmethylcellulose, carboxymethylceüulose, glycerol monóstearate,
carbomer and poloxamer.
Patent WO 03/004060 discloses compositions and preparation methods
for bioavailable oral aceclofenac dosage forms. A pharmaceutical preparation for
oral administration, comprising aceclofenac, a polymeric base selected from the

group consisting of Polyvinylpyrrolidone, methylcellulose, ethylcellulose,
hydroxypropylemethyl-cellulose, carboxymethyl-cellulose,
glycerolmonostearate, carbamer and poloxamer and surfactant. Wherein the
preparation is formulated into solid powder, compressed particles, granules or tablets,, capsules or semisolid form. The composition comprises aceclofenac in
an amount of 56 to 84 parts by weight.
US patent 5,853,759 discloses effervescent alendronate formulation. The
effervescent formulation comprising of alendronate sodium, citric acidj sodium
bicarbonate, sodium carbonate, sodium benzoate, xylitol, sweetener, flavoring
agent.
US patent 4,942,039 describes an effervescent analgesic antacid
composition having reduced sodium content. It produced from a mixture of an
analgesic, such as acetylsalicylic acid, acetaminophen, ketoprofen or a mixture
thereof, citric acid, sodium bicarbonate, calcium carbonate, potassium

bicarbonate, glycine, lubricants and minor amounts of flavors and sweeteners.
US patent 5,762,951 describes direc'tly tabletable effervescent

composition consisting essentially of an acidic component which is a spray dried
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acidic salt in the form of substantially spheriqal particles and an alkaline
component. Here the solution/suspension of acidic salts in a suitable solvent or
solvent mixture is initially prepared as a feed liquid. This feed liquid is then
dried in a customary spray dryer. The acidic effervescent having essentially
spherical particles obtained in this way can be direetly tableted.
Aceclofenac is a nonsteroidal antiinflamatory & analgesic agent. It is used
in the symptomatic treatment of pain and inflammation in osteoarthritis,
rheumatoid arthritis and ankylosing spondylitis. lts usual adult dose is 200 mg
daily taken as two separate 100 mg doses. Aceclofenc is rapidly absorbed & the
bioavailability is almost 100%. The side effects of aceclofenac are
gastrointestinal (e.g. dyspepsia, abdominal pain, nausea and diarrhea).
Aceclofenac is practically insoluble in water and in acidic media. The gastric

media being acidic, dissolution of the aceclofenac after administration of oral
tablet is very slow. This prolongs the residence time of the drug in stomach.
Prolonged stay of the drug in stomach results in accentuation of the above-
mentioned side effects. Further, the absorption of the aceclofenac gets delayed as

evident from the higher value of Tmax (1.25 hours to 3 hours).
None of the above prior art disclosures specifically disclose or suggest the
novel composition of the present invention.

To come over and control the side effects occur in presently available

aceclofenac formulations, the present invention is made to produce effervescent
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aceclofenac formulations using other pharmaceutical excipients in the form of

ready-to-absorb aceclofenac for oral administration.
The field of Invention:
The present invention relates to the formulation of pharmaceutical

composition that contains atleast one therapeutic agent alongwith other
pharmaceutical excipients. The pharmaceutical composition, when added to a
suitable quantity of water, produces effervescence solution and intake of it gives
therapeutic effect of the medicament present in the solution.

The therapeutic agent (i.e. the medicament) present in the efférvescent
formulations is aceclofenac or a salt thereof.

The pharmaceutical excipients present in the formulations comprises an
efférvescent system that produces CO2 and other ingredients, but is not limited
to, one or more of following: diluents, binders, lubricants, glidants, colorants and

flavouring agents.
The effervescent system is the main component of the formulation. It

results in the evolution of CO2 as soon as the formulation is added into a suitable
quantity of water. The effervescence chiefly due to the reaction between an acid
and CO2 producing agent present in the formulations.

Acid used in the formulation are any of pharmaceutically acceptable acid.
Various acids used are tartaric acid, citric acid, maleic acid, fumaric acid, adipic
acid, succinic acid and their alkali hydrogen acid salts. The preferable acid in
present case is citric acid in anhydrous form.
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Single or combination of various CO2 (effervescence) producing agent
exemplified in the present inventioh are sodium bicarbonate, sodium carbonate,
potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium

glycine carbonate and mixtures thereof. The preferable CO2 producing agent in
present invention is sodium glycine carbonate.
The ratio of the acid and CO2 producing agent (referred henceforth
carbonate component) is an important factor for producing a clear solution of
aceclofenac after addition of the formulation to the water. As the aceclofenac is
practically insoluble in water, the pH of the system maintained is in alkaline
range for the complete dissolution of the aeclofenac. The pH of 5% aqueous
solution of sodium glycine carbonate is 7-9. The ratio of the acid and carbonate

component ranges from 1:1.5 to 1:20 and more preferably between 1:8 & 1:13.
A binder is required to formulate granules or tablets of aceclofenac. The
binder is added directly to the powder blend for direct compression or during
granu/ation. One or more suitable binder is incliided are not limited 'to: non-
reducing sugar, such as mannitol, compressible lactose, dextrose or sorbitol and
more preferably polyvinylpyrrolidone. Other binders such as sodium chloride,
sodium benzoate and sodium sulfate are also used in preparing the aceclofenac
formulations. The binder is usually present upto 10% of the tablet weight and
preferably about 1% to 2% based on wt/wt.
The formulations includes incorporation of one or more lubricant and
glidant. Lubricants used are: stearic acid salts, powdered sodium benzoate, L-
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leucine, sodium lauryl sulfate, polyethylene glycol (PEG) and silicon dioxide.
Preferable lubricants used are sodium benzoate and polyethylene glycol
(micronized, molecular weight 6000 to 10,000) due to higher aqueous solubility.

Aceclofenac is bitter in taste. To make the solution (produced after
addition of the effervescent formulation to the water) pleasing in taste, one or
more flavouring and sweetening agents used in preparation process are: xylitol,
sucrose, aspartame, cyclamic acid salts, acesulfame-K, saccharin acid or its salts,
and mixtures thereof.
The effervescent formulation is prepared in the form of effervescent
powder, granules or tablets. The effervescent formulation of Aceclofenac gives
synergistic effect in symptomatic treatment of pain inflammation in

osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
. The effervescent powder is prepared by simple admixture of the
therapeutic moiety and various pharmaceutical excipients. Example l describes
composition and method for formulations of a effervescent powder containing
aceclofenac.
Example 1:
Aceclofenac 14.28% w/w (preferable 14.28% w/wj
Sodium glycine carbonate 14 - 80% w/w (preferable 66.00% w/w)
Citric acid (anhydrous) 1.4 - 10% w/w (preferable 5.00% w/w)
Pharmatose 10 - 50% w/w (preferable 10% w/w)
Aspartame 1-3% w/w (preferable 1.5% w/w)
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Sodium Saccharin l - 3% w/w (preferable 1.5% w/w)
Orange flavour 0.5 - 2% w/w (preferable 1.28% w/w)
Active pharmaceutical substance aceclofenac and other pharmaceutical

excipients as mentioned above are sifted through 30# mesh sieve. All the
ingredients are mixed in a twin blender or a doublé cone blender. The process
needs an area of controlled humidity. Finally effervescent aceclofenac powder is
prepared.
The effervescent aceclofenac granules are prepared by wet granulation
method using a suitable solvent for binder.

Example 2 illustrates the composition of effervescent aceclofenac
granules and method of its preparation.
Example 2:

Aceclofenac 14.28% w/w (preferable 14.28% w/w)
Sodium glycine carbonate 14 - 80% w/w (preferable 66.00% w/w)
Citric acid (anhydrous) 1.4 - 10% w/w (preferable 5.00% w/w)
Polyvinylpyrrolidone 0.5 - 5% w/w (preferable 1.00% w/w)
Aspartame 1-3% w/w (preferable 1.50% w/w)
Sodium Saccharin 1-3% w/w (preferable 1.50% w/w)
Orange flavour 0.5 - 2% w/w (preferable 1.50% w/w

Isopropyl Alcohol 0.5 - 3% w/w (preferable 1.28% w/w)
Binder Polyvinylpyrrolidone is dissolved in solvent isopropyl alcohol.
Active pharmaceutical ingrediënt aceclofenac, other pharmaceutical excipients
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such as sodium glycine carbonate and anhydrous citric acid are passeo through

30# mesh sieve, the powder mixture is blended in a doublé cone blender or twin
blender. The powder blend is passed through Wet granulation after adding
binding solution. Wet granules are dried at 50° C - 60° C till the moisture content
of the dry mass is in the range of 1-2%. Dry, free flowing granules are filled
immediately in sachets, which prevent the absorption of moisture by the

granules.
Free flowing granules are also prepared using mannitol as both sweetener
and diluent.
Example 3:
Aceclofenac 15.62% w/w (preferable 15.62% w/w)
Sodium glycine carbonate 14 - 80% w/w (preferable 41.03% w/w)

Citric acid (anhydrous) 1.4 - 10% w/w (preferable 5.46% w/w)
mannitol 10 - 50% w/w (preferable 31.24% w/w)

Polyvinylpyrrolidone 0.5 - 5% w/w (preferable 0.15% w/w)
Aspartame 1-3% w/w (preferable 1.50% w/w)

Sodium Saccharin l - 3% w/w (preferable 1.50% w/w)
Orange flavour 0.5-2% w/w (preferable 1.50% w/w)
Isopropyl Alcohol 0.5 - 3% w/w (preferable 2.00% w/w)
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The method of preparation of the granules is same as describe'd in the
example 2 except that the mannitol sifted through 30# mesh sieve is mixed with
initial powder blend before the granulation.
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Effervescent tablets are prepared by directly compressing the effervescent
powder or by compressing the effervescent granules. Lubricants and/or
antiadherents augment smooth tabletting during compression stage under
controlled humidity (preferably below 25% R.H.)
Example 4:
Effervescent granules obtained in example 3
Sodium Benzoate 2-5% w/w (preferable 3.00 % w/w)
Polyethylene Glycol 0.5-5.0 % w/w (preferable 1.00 % w/w
(PEG 8000, micronized)
Effervescent granules obtained in example 3 are mixed with above
components for 3-5 minutes and this blend is compressed under controlled
humidity, where humidity is below less than 40% R.H. and preferably below
30% R.H.
Compressed tablets are packed in aluminurh foil or plastic tubes without
putting the tablets available to the atmospheric condition for longer time in order
to avoid the moisture absorption.
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We claim,
1. Effervescent aceclofenac formulations and method for preparation thereof
comprising the mixture of therapeutic agent aceclofenac 14.28% w/w or

salt thereof and other pharmaceutical excipients such as effervescence
producing agent sodium glycine carbonate 14-80% w/w, acid-anhydrous
citric acid 1.4-10% w/w, sweetener pharmatose 10-50% w/w & aspartame
1-3% w/w, sodium saccharine 1-3% w/w, orange flavour 0.5-2% w/w,
binder polyvinylpyrrolidone 0.5-5% w/w, solvent isopropyl alcohol 0.5-
3% w/w, sweetener & diluent mannitol 10-50% w/w.

2. Method for preparation of effervescent aceclofenac formulations as
claimed in claim l comprising the steps of:
(a) active .pharmaceutical substance aceclofenac and other
pharmaceutical excipients sodium glycine carbonate, citric acid
(anhydrous), pharmatose, aspartame, sodium saccharin orange
flavour are passed through 30# mesh sieve and further mixing in a

twin blender or doublé cone blender under controlled humidity to
préparé effervescent aceclofenac powder;

(b) preparing binder solution using polyvinylpyrrolidone in solvent
ïsopropyl alcohol;
(c) mannitol is passing through 30# mesh sieve and mixing with
effervescent aceclofenac powder as prepared in step-a, is blended
with binder solution and passing through wet granulation;
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(d) wet granules obtained from step-c are drying at 50 C - 60 C till
the moisture content of dry mass is 1-2%;

(e) lubricants sodium benzoate 2-5% w/w and polyethylerie glycol
0.5-5.0% w/w are admixing with the aceclofenac effervescent
granules for 3-5 minutes obtained from step-d;
(f) compressing the granules into tablet form under cóntrolled
humidity below 25% R.H.
3. Effervescent aceclofenac formulations and method for preparation thereof
as claimed in claim l wherein formulation is comprising an preferable
amount of aceclofenac is 14.28% w/w, sodium glycine carbonate is
66.00% w/w, anhydrous citric acid is 5.00% w/w, pharmatose is 10%
w/w, aspartame is 1.5% w/w, sodium saccharin is 1.5% w/w, orange
flavour is 1.28% w/w, polyvinylpyrrolidone is 1.00% w/w, isopiopyl
alcohol is 1.28% w/w, sodium benzoate is 3.00% w/w, polyethylene
glycol 1.00% w/w.
4. Effervescent aceclofenac formulations as claimed in claim l wherein
formulation is prepared in powder, granules and tablet form.
5. Effervescent aceclofenac formulations and method for preparation thereof
as claimed in claim l wherein acid is selected from the group consisting
of tartaric acid, citric acid, maleic acid, rumaric acid, adipic acid, succinic

acid and their alkali hydrogen acid salts.
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6. Effervescent aceclofenac formulations and ihethod for preparation thereof
as claimed in claim l wherein effervescence producing agent isiselected
from the group consisting of sodium bicarbonate, sodiurn carbonate,
potassium bicarbonate, potassium carbonate, sodium sesquicarbonate,

sodium glycine carbonate and mixtures thereof.
7. Effervescent aceclofenac formulations and method for preparatioh thereof
as claimed in claim 5 & 6 wherein the ratio of acid and Carbonate
component is 1:1.5 to 1:20 and preferably between 1:8 & 1:13.

8. Effervescent aceclofenac formulations and method for preparatioh thereof
as claimed in claim l wherein the binder is selected from the group

consisting of mannitol, compressible lactose, dextrose, sorbitol,
preferably polyvinylpyrrolidone, sodium chloride, sodium benzoate,
sodium sulfate.

9. Effervescent aceclofenac formulations and method for preparation thereof
as claimed in claim l wherein the lubricant is selected form the group

consisting of stearic acid salts, powdered sodium benzoate, L-leucine,

sodium lauryl sulfate, polyethylene glycol, silicon dioxide.
10. Effervescent aceclofenac formulations and method for preparation thereof

as claimed in claim l wherein flavouring and sweetening agents are

selected from the group consisting of xylitol, sucrose, aspartame,

cyclamic acid salts, acesulfame-K, saccharin acid or its salts and mixtures
thereof.
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ll.Effervescent aceclofenac formulations and method for preparation thereof
as substantially herein described with foregoing description and
examples.
Dated this on 10th day of August 2004.

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