DESC:TECHNICAL FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition comprising aceclofenac, paracetamol and a solubilising agent that includes surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof. The invention further relates to a process of preparation of such composition.
BACKGROUND OF THE INVENTION
Aceclofenac is a non steroidal anti inflammatory drug (NSAID) indicated for the treatment of painful rheumatic conditions such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Chemically it is a 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, carboxymethyl ester of formula I.

Aceclofenac is soluble in the alkaline environment (pH 7-7.5) and it is practically insoluble in gastric pH of 1-1.5. Since the drug dissolution in the physiological environment of the gastro- intestinal (GI) tract is the primary step in the oral absorption process, only dissolved drug can permeate the mucosa at the absorptive sites in the GI tract. Therefore for aceclofenac, relief from pain would be unlikely until the drug traverses the intestinal part (pH 6 and above) which takes about 2-4 hours.
Also administration of aceclofenac can lead to the development of gastro-duodenal lesions, e.g., ulcers and erosions, in susceptible individuals. It appears that a major factor contributing to the development of these lesions is the presence of acid in the stomach and upper small intestine of patients.
Paracetamol, also known as acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic. Chemically, it is N-(4-hydroxyphenyl)ethanamide N-(4-hydroxyphenyl)acetamide of Formula II.

Formula II
In combination with paracetamol, aceclofenac is used to ease pain and to reduce inflammation and fever. This combination is available in the market as tablets, injections, drops, suspensions etc. Since the severe pain caused in the above conditions demands immediate relief, there is a need for a composition which provides rapid dissolution after swallowing thus undergoing quick systemic absorption leading to instant relief.
Further NSAIDs are recommended to be administered with food and/or antacid to protect from the well known GI side effects. A novel increased-solubility, fast dissolving oral formulation is presented which provides quick relief from pain and appropriate local gastric acid neutralization in situ without the presence of antacid.
Indian Patent Application No. 1778/DEL/2010 discloses effervescent dosage form comprising aceclofenac, paracetamol and effervescent couple comprising an acid component & an alkaline component.
U.S. Patent No. 6,926,907 discloses pharmaceutical compositions in unit dose form for oral administration comprising an acid inhibitor present in an amount effective to raise the gastric pH to at least 3.5 upon the administration of one or more of said unit dosage forms; and a non-steroidal anti-inflammatory drug (NSAID).
PCT Publication No. WO2007129178 discloses composition comprising NSAID drug (Aceclofenac), anti-pyretic-analgesic drug (Paracetamol) and Rabeprazole along with conventional pharmaceutical excipients.
PCT Publication No. WO2005076987 discloses composition comprising NSAID and buffering agent. Buffering agents are selected from sodium bicarbonate, calcium carbonate and magnesium hydroxide.
However, despite the therapeutic benefits of NSAIDs, their use is often limited by slow dissolution from stomach and an increased risk of gastrointestinal side effects, in particular upper gastrointestinal side effects such as peptic ulceration and dyspeptic symptoms.
Thus, there exists a need for an improved formulation wherein immediate relief from pain can be attained if both the drugs in the composition dissolve rapidly and gives maximum drug dissolution in shorter duration of time. Also to offset these GI side effects of NSAIDS, there is need to develop formulation which provides local acid neutralization effect.
SUMMARY OF THE INVENTION
In one general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to about 1:2.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent that includes surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof.

In another general aspect of the invention, there is provided a fast dissolving pharmaceutical composition comprising aceclofenac, paracetamol and a solubilising agent; wherein the solubilising agent comprises surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof.
In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising (i) about 50 mg to about 100 mg of aceclofenac, (ii) about 200 mg to about 500 mg of paracetamol, (iii) about 30 mg to about 70 mg of surface modified sodium bicarbonate, (iv) about 25 mg to about 75 mg of superdisintegrant, (v) about 120 mg to about 210 mg of buffer salt, and (vi) one or more pharmaceutically acceptable excipient

In another general aspect of the invention, there is provided a pharmaceutical composition comprising aceclofenac, paracetamol and a solubilising agent; which provides quick relief from pain and appropriate local gastric acid neutralization.

In another general aspect of the invention, there is provided a simple process for preparing such pharmaceutical composition comprising aceclofenac, paracetamol and a solubilising agent.

In another general aspect of the invention, there is provided a process for preparation of pharmaceutical composition comprising about 50 mg to about 150 mg of aceclofenac, about 200 mg to about 500 mg of paracetamol and a solubilising agent, wherein the solubilising agent comprises surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof; wherein the process comprises the step of:
a) dry mixing of aceclofenac and paracetamol with pregelatinized starch
b) granulation and drying of granules,
c) sizing of dried granules through 18 mesh sieve,
d) pre-lubrication blend with surface modified sodium bicarbonate, microcrystalline cellulose, croscarmellose sodium, buffer salts and colloidal silicon dioxide,
e) lubrication with magnesium stearate for 5 minutes,
f) compression of granules of step e) into tablet,
g) film coating of tablet prepared in step f.

In another general aspect of the invention, there is provided a rapid dissolution after swallowing thus undergoing quick systemic absorption from the absorptive sites leading to instant relief.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph illustrating the cumulative release of Aceclofenac of Example 1 and commercial products mention on table 4 at pH 4.5 Acetate buffer media.

Figure 2 is a graph illustrating cumulative release of Paracetamol of Example 1 and commercial products mention on table 4 at pH 4.5 Acetate buffer media.

Figure 3 is a graph illustrating cumulative release of Aceclofenac of Example 1 and commercial products mention on table 4 at pH 7.5 Phosphate buffer media.

Figure 4 is a graph illustrating cumulative release of Paracetamol of Example 1 and commercial products mention on table 4 at pH 7.5 Phosphate buffer media.

Figure 5 is a graph illustrating cumulative release of Aceclofenac of Example 1 and Comparative Example A.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent and one or more pharmaceutically acceptable excipient. This composition provides rapid dissolution of active drug substances and also reduces gastric side effects and enhances the patient's compliance.
“Pharmaceutical composition” or “pharmaceutical formulation” or “pharmaceutical dosage form” can be used interchangeably and refers to the combination of one or more active ingredients and one or more excipients.
“Pharmaceutically acceptable excipient” refers to non-active pharmaceutical ingredient substances which are within the scope of sound medical judgment suitable for use in formulating pharmaceutical products.
The term “buffer” or “buffer salt” refers to a pharmaceutically acceptable excipient or its salt, which stabilizes the pH of a pharmaceutical preparation.
The term “solubilising agent” refers to a substance that increases the solubility in water of another material that is only partially water soluble.
In one general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent that includes surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to about 1:2.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to about 1:2.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to about 1:1.8.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration, wherein the weight ratio of paracetamol to the solubilising agent is about 1:0.1 to about 1:1.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to 1:2.6.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising (i) about 50 mg to about 150 mg of aceclofenac, (ii) about 200 mg to about 500 mg of paracetamol, (iii) about 30 mg to about 70 mg of surface modified sodium bicarbonate, (iv) about 25 mg to about 75 mg of superdisintegrant, (v) about 120 mg to about 210 mg of buffer salt, and (vi) one or more pharmaceutically acceptable excipient.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising (i) about 80 mg to about 100 mg of aceclofenac, (ii) about 200 mg to about 500 mg of paracetamol, (iii) about 30 mg to about 70 mg of surface modified sodium bicarbonate, (iv) about 25 mg to about 75 mg of superdisintegrant, (v) about 120 mg to about 210 mg of buffer salt, and (vi) one or more pharmaceutically acceptable excipient, wherein the composition releases not less than about 60% of aceclofenac at 15 minutes when tested in pH 4.5 acetate buffer, USP Apparatus-II, at 50 rpm, 37 °C ± 0.5.

In another general aspect of the invention, there is provided a pharmaceutical composition for oral administration comprising (i) about 50 mg to about 100 mg of aceclofenac, (ii) about 200 mg to about 500 mg of paracetamol, (iii) about 30 mg to about 70 mg of surface modified sodium bicarbonate, (iv) about 25 mg to about 75 mg of superdisintegrant, (v) about 120 mg to about 210 mg of buffer salt, and (vi) one or more pharmaceutically acceptable excipient, wherein the composition releases not less than about 80% of paracetamol at 15 minutes when tested in pH 4.5 acetate buffer, USP Apparatus-II, at 50 rpm, 37 °C ± 0.5.
In an embodiment, a pharmaceutical dosage form comprising about 50 mg to about 150 mg of aceclofenac, about 200 mg to about 500 mg of paracetamol and a solubilising agent, wherein the solubilising agent comprises an effersoda, a superdisintegrant, buffer salt or mixtures thereof.
In another embodiment, the aceclofenac is present in amount from about 50 mg to about 150 mg, preferably about 75 mg to about 125 mg, more preferably about 100 mg in pharmaceutical composition.
In another embodiment, the paracetamol is present in amount from about 200 mg to about 500 mg, preferably about 250 mg to about 400 mg, more preferably about 325 mg in pharmaceutical composition.
In another embodiment, the solubilising agent comprises effersoda, a superdisintegrant, buffer salt or mixtures thereof. Effersoda comprises preferably effersoda 12 which is surface modified, sodium bicarbonate powder. It may be present in an amount from about 10 mg to about 100 mg, preferably from about 30 mg to about 70 mg, more preferably about 50 mg.
Superdisintegrant is typically incorporated into pharmaceutical solid dosage forms in order to provide improved disintegration of the dosage form. Examples of pharmaceutically acceptable superdisintegrant comprises, but are not limited to, modified celluloses, e.g. croscarmellose sodium or low substituted hydroxypropyl cellulose, cross-linked polymers, e.g. crospovidone, or modified starches, e.g. sodium starch glycolate. Preferably it is croscarmellose sodium. The composition comprises superdisintegrant in an amount from about 10 mg to about 70 mg, preferably about 25 mg to about 50 mg, more preferably about 35 mg.
In another embodiment, the composition comprises of buffer salt. Buffer is pharmaceutically acceptable excipient, which stabilizes the pH of a pharmaceutical preparation. Examples of pharmaceutically acceptable buffers comprise, but are not limited to, acetic acid, citric acid, sodium acetate, citrate and phosphate, potassium phosphate, dibasic sodium phosphate heptahydrate or salts thereof. Preferably, the buffer salt comprises combination of sodium dihydrogen phosphate and trisodium citrate. In one embodiment sodium dihydrogen phosphate and trisodium citrate are present in a weight ratio of about 1:10, preferably about 1:7, more preferably about 1:4.
The amount of buffer salt in oral solid dosage form is critical since it provides a pH micro-environment suitable enough to increase the solubility of aceclofenac. The composition comprises buffer salt in an amount from about 100 mg to about 200 mg, preferably about 125 mg to about 175 mg, more preferably about 155 mg, 156 mg, 157 mg, 158 mg, 159 mg or 160 mg.
In another embodiment, the aceclofenac and the solubilising agent are present in a weight ratio of about 1:1 to about 1:5, preferably about 1:1 to about 1:3, more preferably about 1:2.4. In one embodiment paracetamol and the solubilising agent are present in a weight ratio of about 1:0.1 to about 1:1, preferably about 1:0.5 to about 1:1, more preferably about 1:0.8. The amount of solubilising agent is critical for the rapid dissolution of active ingredients in gastric pH, preferably for aceclofenac since it is practically insoluble in gastric pH of 1-1.5. Solubilising agent in an optimum amount provides favourable microenvironment which increases the pH and provides rapid dissolution of aceclofenac.
In another embodiment, about 60% to about 70%, preferably about 65 % to about 70% is released within 15 minutes from the dosage form, and about 75% to about 95%, preferably about 80% to about 90%, more preferably about 85% of paracetamol is released within 10 minutes from the dosage form when tested in pH 4.5 acetate buffer, apparatus 2, at 50 rpm, 37 °C ± 0.5.
In another embodiment, the pharmaceutical composition comprising about 100 mg of aceclofenac, about 325 mg of paracetamol, about 30 mg to about 70 mg of effersoda, about 25 mg to about 75 mg of superdisintegrant, about 120 mg to about 210 mg of buffer salt and one or more pharmaceutically acceptable excipient.
In another embodiment, the pharmaceutical composition comprises about 50 mg to 150 mg of aceclofenac, about 200 mg to 500 mg of paracetamol and an acid neutralizing agent, wherein the composition exhibits a pH of about 6 to 7 when dispersed in 50 ml of 0.1N HCl.
In another embodiment, the pharmaceutical composition comprising about 100 mg of aceclofenac, about 325 mg of paracetamol, about 30 mg to about 70 mg of effersoda, about 25 mg to about 75 mg of superdisintegrant, about 120 mg to about 210 mg of buffer salt, wherein the composition exhibits a pH of about 6 to 7 when dispersed in 50 ml of 0.1N HCl.
In another embodiment, the pharmaceutical composition for oral administration is preferably prepared in the form of tablets, capsules, lozenges, a liquid solution or suspension or powders. Preferred composition is solid dosage form which is a tablet. The tablet may be film coated or uncoated.
In another embodiment, the oral pharmaceutical composition comprises one or more pharmaceutical excipients selected from, but not limited to one or more of bulking agents or fillers, binders, disintegrants, and lubricants.
The bulking agents or fillers may be present in the core in an amount within the range from about 1 to about 95% w/w and preferably from about 10 to about 85% w/w of the composition. Examples of bulking agents or fillers suitable for use herein include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salt such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, compressible sugars, and other known bulking agents or fillers, and/or mixtures thereof, preferably microcrystalline cellulose.
The binder may be present in the core in an amount within the range from about 0 to about 30% w/w, preferably from about 10 to about 20% w/w of the composition. Examples of binders suitable for use herein include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP) (molecular weight ranging from about 5,000 to about 1,000,000, preferably about 40,000), hydroxypropyl methylcellulose (HPMC), lactose, gum acacia, ethyl cellulose, cellulose acetate, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose.
The disintegrant may be present in the core in an amount within the range from about 0.15 to about 20% w/w, preferably from about 0.25 to about 10% w/w of the composition. Examples of disintegrants suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose or other known disintegrant, preferably croscarmellose sodium.
The lubricant may be present in the core in an amount within the range from about 0.1 to about 5% w/w, preferably from about 0.2 to about 2% w/w of the composition. Examples of tabletting lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate or hydrogenated vegetable oils and fats, or mixtures thereof, preferably magnesium stearate.
In another embodiment, the pharmaceutical composition comprising about 50 mg to about 150 mg of aceclofenac, about 200 mg to about 500 mg of paracetamol and a solubilising agent, wherein the solubilising agent comprises an effersoda, a superdisintegrant, buffer salt or mixtures thereof.

In another embodiment, the pharmaceutical composition comprising aceclofenac, paracetamol and a solubilising agent, wherein the composition exhibits a pH of about 6 to 7 when dispersed in 50 ml of 0.1N HCl.

In another embodiment, the pharmaceutical composition comprising about 100 mg of aceclofenac, about 325 mg of paracetamol, about 30 mg to about 70 mg of effersoda, about 25 mg to about 75 mg of superdisintegrant, about 120 mg to about 210 mg of buffer salt and one or more pharmaceutically acceptable excipient.

In another embodiment, the pharmaceutical composition comprising:
(i) about 100 mg of aceclofenac,
(ii) about 325 mg of paracetamol,
(iii) about 150 mg of pregelatinized starch,
(iv) about 20 mg of sodium starch glycolate,
(v) about 5 mg of polyvinylpyrrolidone K 30,
(vi) about 30 mg of maize starch,
(vii) about 50 mg of surface modified sodium bicarbonate,
(viii) about 150 mg of microcrystalline cellulose,
(ix) about 29.8 mg of sodium dihydrogen phosphate,
(x) about 127 mg of trisodium citrate,
(xi) about 20 mg of croscarmellose sodium,
(xii) about 5 mg of colloidal silicon dioxide and
(xiii) about 10 mg of magensium stearate.

In another embodiment, the pharmaceutical composition comprising:
(i) about 100 mg of aceclofenac,
(ii) about 325 mg of paracetamol,
(iii) about 150 mg of pregelatinized starch,
(iv) about 30 mg of sodium starch glycolate,
(v) about 5 mg of polyvinylpyrrolidone K 30,
(vi) about 30 mg of maize starch,
(vii) about 50 mg of surface modified sodium bicarbonate,
(viii) about 30 mg of sodium dihydrogen phosphate,
(ix) about 120 mg of trisodium citrate,
(x) about 150 mg of microcrystalline cellulose,
(xi) about 35 mg of croscarmellose sodium,
(xii) about 5 mg of colloidal silicon dioxide, and
(xiii) about 10 mg of magensium stearate.

In another embodiment, the process for preparation of pharmaceutical composition comprising about 50 mg to about 150 mg of aceclofenac, about 200 mg to about 500 mg of paracetamol and a solubilising agent, wherein the solubilising agent comprises an effersoda, a superdisintegrant, buffer salt or mixtures thereof.

The process of preparation may comprise steps of dry mixing, granulation, sizing, pre-lubrication, lubrication, compression and film coating.

In another embodiment, the process for preparation of pharmaceutical oral composition comprising about 50 mg to about 150 mg aceclofenac, about 200 mg to about 500 mg paracetamol and solubilising agent, wherein the solubilising agent comprises an surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof; comprising steps of:
a) dry mixing of aceclofenac and paracetamol with pregelatinized starch,
b) granulation and drying of granules,
c) sizing of dried granules through 18 mesh sieve,
d) pre-lubrication blend with surface modified sodium bicarbonate, microcrystalline cellulose, croscarmellose sodium, buffer salts and colloidal silicon dioxide,
e) lubrication with magnesium stearate for 5 minutes,
f) compression of granules of step e) into tablet,
g) film coating of tablet prepared in step f.

In another embodiment, the aceclofenac and the solubilising agent is present in a weight ratio of about 1:1 to about 1:5, preferably about 1:1 to about 1:3.

In another embodiment, the paracetamol and the solubilising agent is present in a weight ratio of about 1:0.1 to about 1:1, preferably about 1:0.5 to about 1:1.

In another embodiment, the buffer salt comprises sodium dihydrogen phosphate, trisodium citrate or mixtures thereof.

In another embodiment, the sodium dihydrogen phosphate and trisodium citrate are present in weight ratio of about 1:1 to about 1:10.

In another embodiment, the superdisintegrant comprises croscarmellose sodium, sodium starch glycolate or mixture thereof.

In another embodiment, the composition exhibits a pH of about 6 to 7 when dispersed in 50 ml of 0.1N HCl.

It is desirable for a pharmaceutical composition to be stable during shelf life and before its ultimate use by the person in need thereof. In this regard, it is advantageous for the composition to be stable at standard conditions, in particular the standard condition means a temperature ranging for 20°C to 40°C and a relative humidity ranging for 50% to 75%.

In the description of this invention, the term "stable" means that the quantitative composition does not significantly change over the time, during the entire shelf-life of the composition for at least 3 months, advantageously for at least 6 months, more advantageously for 12 months, even more advantageously for at least 36 months, under standard conditions.

In another embodiment, the pharmaceutical composition of pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent remains stable at least 6 months under standard condition.

In another embodiment, the composition is advantageously stable for at least 6 months at a temperature of 40°C and a relative humidity of 75%. Table 6 illustrates the stability results of the pharmaceutical composition.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Composition of Aceclofenac and Paracetamol
Table 1
Sr. No Ingredients Unit quantity (in mg)
Dry Mixing
1 Aceclofenac IP 100.0
2 Paracetamol IP 325.0
3 Lycatab C (Pregelatinized starch) 150.0
4 Sodium starch glycollate 20.0
Binding Solution
5 Polyvinyl pyrrolidone K30 5
6 Maize Starch 30
7 Purified water qs
Lubrication
8 Surface modified sodium bicarbonate 50
9 Chemicel PH 102 (Microcrystalline cellulose) 150
10 Sodium dihydrogen phosphate (monohydrate) 29.8
11 Trisodium citrate (dehydrate) 127
12 Cell-o-sol (Croscarmellose Sodium) 20
13 Colloidal silicon dioxide 5
14 Magensium stearate 10
Film Coating
15 Colorezy white 31.2
16 Isopropyl Alcohol qs
17 Methylene chloride qs

Manufacturing Process:
Paracetamol and Aceclofenac was accurately weighed and passed through #20 mesh size sieves. Pregelatinized starch was weighed and passed through 40 mesh sieve and further blended with above mixture. Binder solution of polyvinyl pyrrolidone and Maize Starch was prepared in water. Paracetamol and Aceclofenac mixture was granulated with the binder solution in rapid mixer granulator. The granules was dried and passed through 18 mesh sieve. Surface modified sodium bicarbonate, microcrystalline cellulose, croscarmellose sodium, buffer salts and colloidal silicon dioxide were weighed, sieved and mixed with above dried granules for pre-lubrication using a double cone blender. The granules were further lubricated with magnesium stearate before compression. The lubricated granules were compressed into tablets and further film coated.

Example 2: Composition of Aceclofenac and Paracetamol

Table 2
Sr. No Ingredients Unit quantity (in mg)
Dry Mixing
1 Aceclofenac IP 100.0
2 Paracetamol IP 325.0
3 Lycatab C (Pregelatinized starch) 155.0
4 Sodium starch glycollate 25.0
Binding Solution
5 Polyvinyl pyrrolidone K30 5
6 Maize Starch 30
7 Purified water qs
Lubrication
8 Surface modified sodium bicarbonate 45
9 Chemicel PH 102 (Microcrystalline cellulose) 155
10 Sodium dihydrogen phosphate (monohydrate) 30
12 Trisodium citrate (dehydrate) 120
13 Cell-o-sol (Croscarmellose Sodium) 30
14 Colloidal silicon dioxide 10
15 Magensium stearate 10
Film Coating
16 Colorezy white 31.2
17 Isopropyl Alcohol qs
18 Methylene chloride qs

Manufacturing Process: Manufacturing process was similar as described for Example 1.

Example 3: Composition of Aceclofenac and Paracetamol

Table 3
Sr. No Ingredients Unit quantity (in mg)
Dry Mixing
1 Aceclofenac IP 100.0
2 Paracetamol IP 325.0
3 Lycatab C (Pregelatinized starch) 155.0
4 Sodium starch glycollate 15.0
Binding Solution
5 Polyvinyl pyrrolidone K30 5
6 Maize Starch 30
7 Purified water qs
Lubrication
8 Surface modified sodium bicarbonate 35
9 Chemicel PH 102 (Microcrystalline cellulose) 160
10 Sodium dihydrogen phosphate (monohydrate) 30
12 Trisodium citrate (dehydrate) 120
13 Cell-o-sol (Croscarmellose Sodium) 40
14 Colloidal silicon dioxide 5
15 Magensium stearate 10
Film Coating
16 Colorezy white 31.2
17 Isopropyl Alcohol qs
18 Methylene chloride qs

Manufacturing Process: Manufacturing process was similar as described for Example 1.

Table 4: Comparative data between Example 1 and some commercial products in India.

Parameter Example 1 Zerodol P Hifenac P
Label claim Each film coated tablet contains:
Aceclofenac IP….100 mg
Paracetamol IP….325 mg
Excipients…………. Q.S Each film-coated tablet contains:
Aceclofenac IP.100 mg
Paracetamol IP.325 mg
Excipients: Q.S. Each uncoated tablet contains:
Aceclofenac IP.100 mg
Paracetamol IP..325 mg
Excipients: Q.S.
Dissolution (n=6) in pH 4.5 acetate buffer simulating fed state stomach Aceclofenac: 60% in 15 mins Aceclofenac: 30% in 15 mins Aceclofenac: 30% in 15 mins
Paracetamol: 80% in 10 mins Paracetamol: 76% in 10 mins Paracetamol: 72% in 10 mins
Disintegration (n=6) 5 min 30 sec 8 min 40 sec 13 min 46 sec

Comparative Example A: Composition of Aceclofenac and Paracetamol

Table 5
Sr. No Ingredients Unit quantity (in mg)
Dry Mixing
1 Aceclofenac IP 100.0
2 Paracetamol IP 325.0
3 Lycatab C (Pregelatinized starch) 155.0
4 Sodium starch glycollate 10.0
Binding Solution
5 Polyvinyl pyrrolidone K30 5
6 Maize Starch 30
7 Purified water qs
Lubrication
8 Surface modified sodium bicarbonate 10
9 Chemicel PH 102 (Microcrystalline cellulose) 160
10 Sodium dihydrogen phosphate (monohydrate) 30
12 Trisodium citrate (dehydrate) 20
13 Cell-o-sol (Croscarmellose Sodium) 5
14 Colloidal silicon dioxide 5
15 Magensium stearate 10
Film Coating
16 Colorezy white 31.2
17 Isopropyl Alcohol qs
18 Methylene chloride qs

Manufacturing Process: Manufacturing process was similar as described for Example 1.

Table 6: Example 1 stability data

Test Month/Storage Condition 40°C/75% RH
Initial 1M 2M 3M 6M
Paracetamol assay
(% w/w) 102.7 98.8 99.1 99.5 99.9
Aceclofenac
assay
(% w/w) 103.3 97.2 96.0 94.7 92.4
Water by Karl Fischer (% w/w) 4.5 5.65 5.69 5.63 4.88

,CLAIMS:1. A pharmaceutical composition for oral administration comprising aceclofenac, paracetamol and a solubilising agent that includes surface modified sodium bicarbonate, a superdisintegrant, buffer salt or mixtures thereof, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to about 1:2.
2. The pharmaceutical composition of claim 1, wherein the weight ratio of aceclofenac to the solubilising agent is about 1:1 to about 1:1.6.
3. The pharmaceutical composition of claim 1, wherein the weight ratio of paracetamol to the solubilising agent is about 1:0.1 to about 1:1.
4. The pharmaceutical composition of any one of claims 1-3, wherein the composition releases not less than about 60% of aceclofenac at 15 minutes when tested in pH 4.5 acetate buffer, USP apparatus-II, at 50 rpm, 37 °C ± 0.5.
5. The pharmaceutical composition of any one of claims 1-3, wherein the composition releases not less than about 80% of paracetamol at 10 minutes when tested in pH 4.5 acetate buffer, USP apparatus-II, at 50 rpm, 37 °C ± 0.5.
6. The pharmaceutical composition of claim 1, wherein the surface modified sodium bicarbonate is present in an amount about 30 mg to about 70 mg.
7. The pharmaceutical composition of claim 1, wherein the superdisintegrant comprises croscarmellose sodium, sodium starch glycolate or mixture thereof
8. The pharmaceutical composition of claim 1, wherein the superdisintegrant is present in an amount of about 25 mg to about 75 mg.
9. The pharmaceutical composition of claim 1, wherein the buffer salt comprises sodium dihydrogen phosphate, trisodium citrate or mixtures thereof.
10. A pharmaceutical composition for oral administration comprising (i) about 50 mg to about 100 mg of aceclofenac, (ii) about 200 mg to about 500 mg of paracetamol, (iii) about 30 mg to about 70 mg of surface modified sodium bicarbonate, (iv) about 25 mg to about 75 mg of superdisintegrant, (v) about 120 mg to about 210 mg of buffer salt, and (vi) one or more pharmaceutically acceptable excipient.