Indian Patents. 222973:A PHARMACEUTICAL ORAL DOSAGE FORM COMPRISING OF A NOVEL COMBINATION OF ACECLOFENAC, PARACETAMOL AND SERRATIOPEPTIDASE

Title of Invention	A PHARMACEUTICAL ORAL DOSAGE FORM COMPRISING OF A NOVEL COMBINATION OF ACECLOFENAC, PARACETAMOL AND SERRATIOPEPTIDASE
Abstract	The present invention describes a pharmceutical oral dosage from comprising of a novel combination of aceclofenac,paracetamol and serratiopeptidase, for the treatment of acute, inflammatory condition. It also describes process of preparation of such pharmaceutical oral dosage form.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION. (See section 10] Title of the invention: A Pharmaceutical Oral Dosage Form Comprising of A Novel Combination of Aceclofenac , Paracetamol and Serratiopeptidase 2. M/S. J.B.CHEMICALS & PHARMACEUTICALS LTD., an Indian Company, having its Registered Office at Neelam Centre, "B' Wing, 4th floor, Hind Cycle Road, Worli, Mumbai 400 025, Maharashta, India. 3. The following specifications particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. 1324/MUM/2004 A Pharmaceutical Oral Dosage Form Comprising of A Novel Combination of Aceclofenac , Paracetamol and Scrratiopeptidasc BACKGROUND OF THE INVENTION 1. Field of the Invention This invention generally relates to pharmaceutical compositions for oral administration. This invention relates in particular to such compositions comprising of a novel combination of aceclofenac, paracetamol and serratiopeptidase for the treatment of acute, painful and inflammatory conditions. 2. Description of the Prior Art Various painful inflammatory conditions including those associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, postoperation state, musculoskeletal trauma, sports injuries, sinusitis etc are treated with NSAIDS. Rheumatoid arthritis is a chronic multisystem disease of unknown cause. Although there are a variety of systemic manifestations, the characteristic feature of rheumatoid arthritis is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. The potential of the synovial inflammation to cause cartilage destruction and bone erosions and subsequent changes in joint integrity is the hallmark of the disease. ( Ref: Principals of internal medicines by T.R.Harrison) Medical management of rheumatoid arthritis involves use of nonsteroidal anti¬inflammatory drugs and analgesics to control the symptoms and signs of the local inflammatory process. Osteoarthritis is the most common joint disease of humans. It is characterized by deep ache in joints. Treatment is aimed at reducing pain, maintaining mobility and minimizing disability. NSAIDs decrease joint pain and improve mobility. 1 Aceclofenac is a potent analgesic and anti-inflammatory drug and has provided relief in various inflammatory and painful conditions. Aceclofenac is highly selective COX-2 inhibitor with COX-1 : COX-2 IC50 ratio of 129.(Henrotin Y, de leval X et al. In vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators. lnflamm.Res. 2001 Aug.50(8):391-9) It acts at periphery by decreaseing proinflammatory prostaglandin synthesis by inhibiting cyclooxygenase 2 (COX 2). Not only Acelcofenac is potent analgesic and anti-inflammatory agent but in contrast to some tother NSAIDs (e.g. Diclofenac and naproxen), Aceclofenac has shown stimulatory effects on cartilage matrix synthesis. (Dingle JT. The effect of NSAIDs on human cartilage glucosaminoglycan synthesis.Eur.J. Rheumatol Inflamm ,1996:l6(l):47-52). Thus it is drug of choice in treatment of degenerative arthritis conditions.4'hydroxyaceclofenac, a major metabolite of Aceclofenac has chondroprotectibe properties attributable to suppression of IL-I-8-mediated promatrix metalloproteinase production.(Dooeley M. Spencer CM et al, Aceclofenac: A repraisal of its use in the management of pain and rheumatic disease.Drugs 2001; 61(9): 1351-1378). Aceclofenac decreases pain levels, reduces the severity of symptoms and improves the functional capacity of the affected joint in patients with osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. It has been found to be effective in post surgical dental pain, ankylosing spondylitis, rheumatoid arthritis, musculoskeletal trauma, primary dysmenorrhoea, lumbago. Metanalysis of studies involving more than 3000 patients indicated that a significantly greater proprtion of patients receiving Aceclofenac remained free from Gl symptoms after 3 to 6 months treatment than recipients of Diclofenac , naproxen, Piroxicam, lndomethancin, Tenoxican or Ketoprofen.(Peris F Bird HA et al: Treatmetn compliance and safety of aceclofeanc versus standard NSAIDs in patients with 2 common arthritic disorders: a metaanalysis, F.ur J Rhematol Inflamm lc)96;16(l):37- 45). Paracetamol is time tested, trusted, cost effective and popular analgesic and acts centrally i.e. it has selective inhibitory action on cyclooxygenase in brain. Paracetamol is administered by mouth in tablets , syrup, suspension, capsules in dose range of 125 mg -500 mg per dose .it is taken with or after food. Aceclofenac is administered by mouth as tablets in the dose range of 100 mg to 200 mg daily. Serratiopeptidase is an enzyme derived from bacteria belonging to genus Sen?, ' . A widely used anti-inflammatory enzyme, it is a stronger casenolytic or fibrinolitic agent than most other alkaline or neutral proteases. The purified enzyme has very good medicinal action in the body after absorption, especially, anti-inflammatory and sputum liquefying properties. It eliminates inflammatory oedema and swelling, accelerates liquefaction of pus and sputum, and enhances the action of antibiotics. In sharp contrast to this, NSAIDs only relieve pain. Serratiopeptidase has wide-ranging applications, which are listed below. The usual dose is 15 mg -30 mg daily. In case of analgesics, it is advantageous to have two drugs with different mechanism of action, differing or simultaneous onset and differing duration of effect to prolong their therapeutic efficacy.(Analgesic, antipyretic and anti-inflammatory agents.Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th Edn, 687 - 729). 3 Pharmacokinetics of paracetamol and aceclofcnac: Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. The concentration in plasma reaches peak in 30 minutes and half life in plasma is about 2 hours after the therapeutic dose. Aceclofenac has a favourable pharmacokinetic profile, which favors its combination with Paracetamol. The time to peak plasma concentration of aceclofenac is 1.08 -1.37 hrs whereas that with paracetamol is 30 -60 min. The efficacy of the combination will be more since the pharmacokinetic profile of the drugs is similar. Aceclofenac also has half life of 4 hrs which makes its administration twice a day. Lower doses of the combination will be required for the analgesic action. Pharmacokinetic profile of paracetamol and aceclofenac: Parameters Aceclofenac Paracetampl Tmax 1.08-1.37 hrs 30 -60 minutes Elimination half life 4 hrs 2 hrs. Thus taking into consideration the limitations associated with the existing anti¬inflammatory , analgesic pharmaceutical compositions, the inventor has come out with a unique composition comprising of aceclofenac, paracetamol and serratiopeptidase in a dosage form suitable for oral administration having anti¬inflammatory, analgesic and antiedemic , healing property. This combination has been found to be therapeutically better over either aceclofenac, paracetamol ,serratiopeptidase individually. Accordingly, it is among the objects of the present invention to provide oral dosage formulation containing aceclofenac, paracetamol and serratiopeptidase. 4 SUMMARY OF THE INVENTION It is an object of this invention to provide a novel solid pharmaceutical composition for oral administration that comprises of aceclofenac, paracetamol and serratiopeptidase. It is another object of the present invention to provide the process of preparation of oral solid dosage form. DETAILED DESCRIPTION OF THE INVENTION This invention generally relates to pharmaceutical compositions for oral administration. This invention relates in particular to such compositions comprisi- ~ of a novel combination of aceclofenac, paracetamol and serratiopeptidase for the treatment of acute, painful and inflammatory conditions. The present invention comprises of a)Aceclofenac in an amount of about 50 to 200 mg, preferably 100 mg. b)Serratiopeptidase in an amount of about 5 mg to 50 mg, preferably from 5-20 mg and most preferably 15 mg. c)ParacetamoI is incorporated in the oral solid dosage form of the present invention in an amount of about 125 mg to 1000 mg , preferably from 125 mg to 500 mg and most preferably 500 mg. The novel composition comprising of aceclofenac, paracetamol and serratiopeptidase in a dosage form suitable for oral administration alleviates pain, relieves inflammation and promotes healing. Indications: The present invention is indicated 1) Acute exacerbation of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis. 5 2) Trauma: sports injurities, sprains, laceration, fractures and dislocation 3) Post operative state: to reduce post operative swelling . pain, 4) Carpel tunnel syndrome 5) Respiratory medicine: bronchitis, lung abscess, sinusitis and bronchitis. 6) Dermatology: Acute painful inflamed dermatoses 7) Dentistry: Pericoronitis of the wisdom tooth and alveolar abscess. 8) Opthalmology: Hyphaema, uveitis, oedema due to injury and operation , long standing opacity of the vitreous body. 9) Urology: Cystitis, epididymitis. The preferred oral dosage form is tablets or capsules. It can also be administered in liquid oral dosage forms like syrup, suspension. The excipients for tablet dosage form may comprise of tablet diluents, binder, disintegrant, lubricant, antiadherant, jjlv,ant, coating agent, solvents, antioxidants, colorants, flavorants, sweetening agents, direct compression excipients, polishing agents. Tablets are prepared by either wet granulation or dry mix process. In wet granulation process, typical binder used are maize starch, pregelatinized cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose. Diluent is selected from maize starch, lactose, dicalcium phosphate, microcrystalline cellulose. Disintegrant used is selected from croscarmellose sodium, colloidal silicon dioxide, sodium lauryl sulfate ,sodium starch glycollate, starch, microcrystalline cellulose . Lubricants most commonly used in tablets are stearates such as magnesium stearate and calcium stearate. The lubricant most frequently used is magnesium stearate , usually at a level of from about 1 percent to about 2 percent by weight. Antiadherants is selected from talc, colloidal silicon dioxide . For dry mix process, typical binder used is selected from methyl cellulose, spray dried lactose, microcrystalline cellulose. Capsules are prepared by conventional method .i.e. all active ingredients are individually sieved through 40# and mixed along with excipients in a mixer such as planetary mixer. The blend is then filled into capsules on capsule filling machine . 6 Furthermore the present invention provides the process for preparation of composition of the preferred embodiment which may be coated with a polymeric film merely to provide protection from moisture. The said coating polymer is selected from a group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol or methacrylic acid polymer, the most preferred being hydroxypropyl methyl cellulose. The said coating is soluble in fluid of the environment i.e. soluble in acidic pH and does not retard the release of active agent. The coating imparts moisture barrier properties to increase stability. The present invention provides the process for preparation of composition of the preferred embodiment is as described below: Preparation of coated tablets: a) The active agent, microcrystalline cellulose, colloidal anhydrous silica, colon- are sifted through 40# sieve and mixed in a suitable mixer for 10 minutes. b) The blend is granulated with warm water, starch paste by mechanical means. c) Granules are dried at 45-50°C till LOD is between 2-3%w/w. d) Dried granules are mechanically sifted through 30# sieve. e) The granules are lubricated with mixture of sodium starch glycolate, colloidal anhydrous silica, colour, magnesium stearate (presifted through 40#) by mechanical mixing. f) The lubricated granules are then compressed on tablet compression machine. Q) Coating: Appropriate quantity of hydroxypropyl methylcellulose, polyethylene glycol is dissolved in blend of Isopropyl alcohol, dichloromethane under stirring to get clear solution. The solution is strained through 100# & used for film coating of tablets The granules can be prepared either by wet granulation, dry granulation, slugging and compaction. The most preferred process being wet granulation. 7 The invention will be more fully understood from the following examples. These examples are to be constructed as illustrative of the invention and not limitative thereof: Example 1 - Example 1 discloses a process for preparation by wet granulation of coated tablets according to the present invention 1. Granulation % w/w Aceclofenac 14.2 Paracetamol 71.0 Serratiopeptidase 2.1 Microcrystalline cellulose 1.8 Croscarmellose Sodium 1.0 Maize Starch 3.5 Lubrication Sodium starch glycolate 1.0 Colloidal Silicon Dioxide 1.0 Magnesium stearate 0.5 Talc 0.7 2. Coating % w/w Hydroxypropyl methylcellulose 2.0 Polyethylene Glycol 0.8 Isopropyl Alcohol 15.0 Dichloromethane 15.0 Colour 0.2 Titanium Dioxide 0.2 The process for preparation of composition of Example I is as follows: 8 a)Aceclofcnac, Serratiopeptidase, Paracetamol, microcrystallinc cellulose, Croscarmellose Sodium are sifted through 40# sieve and mixed in a suitable mixer for 10 minutes. b) The blend is granulated with warm water and starch paste by mechanical means. c) Granules are dried at 45-50°C till LOD is between 2-3%w/w. d) Dried granules are mechanically sifted through 30# sieve. e) The granules are lubricated with mixture of sodium starch glycolate, colloidal anhydrous silica, talc, magnesium stearate (presifted through 40#) by mechanical Compression: Lubricated granules are compressed on tablet compression machine. Coating: Appropriate quantity of hydroxyporpyl methyl cellulose, polyethylene glycol, colour is dissolved in solution of Isopropyl alcohol, Dichloromethane under stirring to get clear solution. The solution is strained through 100# & used for film coating of tablets Example 2 Example 2 discloses a process for preparation by dry mix or direct compression of according to the present invention 1. Dry mix % w/w Aceclofenac 11.0 Paracetamol 55.0 Serratiopeptidase 1.6 Calcium carbonate 7.5 Microcrystalline cellulose (Avicel) 18 Croscarmellose Sodium 1.0 Magnesium stearate 0.5 Talc 0.7 Lubrication 9 Magnesium stearate 0.7 laic 0.8 Coating % w/w Hydroxypropyl methylcellulose 2.0 Polyethylene Glycol 0.8 Isopropyl Alcohol 15.0 Dichloromethane 15.0 Colour 0.2 Titanium Dioxide 0.2 The process for preparation of composition of Example 2 is as follows: Preparation of Immediate release granule 1: a) Aceclofenac, Serratiopeptidase, Paracetamol, microcrystalline celluiose,calcium carbonate, croscarmellose sodium, magnesium stearate, talc are sifted through 40# sieve and mixed in a suitable mixer for 15 minutes. b) The blend is compressed into slugs by mechanical means. c) Slugs are then milled through multimill. d) Dried granules are mechanically sifted through 30# sieve. e) The granules are lubricated with a mixture of magnesium stearate, talc (presifted through 40#) by mechanical mixing. f) Lubricated granules are then compressed on compression machine. Coating: Appropriate quantity of hydroxyporpyl methyl cellulose, colour, polyethylene glycol is dissolved in solution of Isopropyl alcohol, Dichloromethane under stirring to get clear solution. The solution is strained through I00# & used for film coating of tablets. It is to be understood that the examples and embodiments described hereinabove are for the purposes of providing a description of the present invention by way of 10 examples and are not to be viewed as limiting the present invention in any way. Modification that may be made to that described in above examples by those of ordinary skill in the art is also contemplated by the present invention and is to be included within the spirit. Example 3 Example 3 discloses a process for preparation of capsules according to the present invention 1. Ingredients % w/w Aceclofenac 14.0 Paracetamol 70.0 Serratiopeptidase 3.0 Maize Starch 10.0 Colloidal Anhydrous Silica 2.0 Magnesium stearate 1 -0 The process for preparation of composition of Example 3 is as follows: Preparation of blend: a) Aceclofenac, Serratiopeptidase, Paracetamol, maize starch, are sifted through 40# sieve and mixed in a suitable mixer for 15 minutes. b) Added colloidal anhydrous silica, magnesium stearate presifted to above blend and mixed for 10 minutes. c) The blend is filled into capsules on capsule filling machine. Clinical trials: To investigate the effectiveness of the present invention in relieving pain, inflammation in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, postoperation state, musculoskeletal trauma, sports injuries, sinusitis clinical trials were carried out at five different centers all over India. Number of patients of different age groups were included in the trial. This study is not disclosed to the 11 public and the trials were done in confidence. The results of clinical study in India is given beiow. 1. In this study 100 patients having pain due to various degenerative and inflammatory rheumatic diseases like (Post traumatic pain. Low back pain. Cervical pain. Ankylosing spondylitis, Rheumatoid arthritis and Osteoarthritis) were considered and divided into 2 groups of 25 each. One group received aceclofenac tablets and the other group received present invention, twice a day for seven days .40% of the patients scored pain as severe in the beginning of the therapy. On first follow up it was found that in patients maintained on present invention the percentage was reduced to 5% at the first follow up visit while in patients receiving only aceclofenac the percentage was 12%.On second follow-up it was observed fl rt 28% of the patients receiving the present invention were fully relieved and 60% of the patients reported light pain whereas those receiving aceclofenac tablets 13% of the patients were relieved of pain and 45% reported light pain. This indicates that present formulation is superior than aceclofenac tablets alone in inflammatory rheumatic diseases. 2. 40 patients suffering from acute dental pain were included in the trial and they were divided into two groups. Group one received combination tablet of aceclofenac and paracetamol and group two received tablet of the present invention twice daily. The group of the present formulation showed improvement much faster as compared to the group combination of aceclofeanc and paracetamol tablets. There was noticeable reduction in inflammation in group receiving tablets of the present invention. This clearly indicates that present formulation is better choice than combination of aceclofenac and paracetamol. 3. 30 patients suffering from trauma such as sports injuries, sprains, laceration, fractures were included in the trial and divided into 2 groups of 15 each. One group received The results demonstrated that at visit 2,87% of patients were satisfied with the tablets of the present invention and by visit 3, 90% of patients were satisfied with the tablets of the present invention. 12 4. In this study effectiveness of tablets of the present invention in 40 patients with carpal tunnel syndrome was evaluated clinically. After baseline electrophysiological studies, these patients were divided in two groups. Group one was given tablets of the present invention and group two was given serratiopeptidase tablets. Clinical and electrophysiological reassessment was done after 6 weeks. In group one 72% cases showed significant clinical improvement as against 50% cases in group two .No significant side effect was observed. 5. In this study 70 patients having pain due to trauma due to sports injuries, sprains, laceration, fractures and dislocation, were considered and divided into 2 groups of 35 each. Treatment lasted 7-8 days. Group one received tablets of the present invention and group two received aceclofenac tablets. The tablets were given two times a day. After 3-4 days treatment ^nificant symptoms regression was observed in group one . The intensity of pain and severity of inflammation, swelling was reduced faster in patients in group one as compared to group two. Tolerance was found to be good and similar in both groups. Statistical comparison between the two groups confirmed the greater efficacy and rapid action of the present invention against all symptoms examined. Above clinical trials confirm the efficacy of the solid oral dosage form of the present invention in treatment of acute, painful and inflammatory conditions. It is to be understood that the example and embodiments described hereinabove are for the purpose of providing a description of present invention by way of example and are not be viewed as limiting the present invention in any way. Those who are skilled in the art can made various modifications or changes that may be made to the described invention and are also contemplated by it which can be included within the spirit and purview of this application. 13 We claim: 1. A pharmaceutical oral dosage form comprising of Aceclofenac in amount from 50 mg to 200 mg, preferably from 100 to 200 mg and most preferably 100 mg; Paracetamol in amount from 125 mg to 750 mg, preferably 500 mg and Serratiopeptidase in amount from 5 mg to 30 mg, preferably 15 mg. 2. A pharmaceutical oral dosage form as in claim 1 wherein the dosage form is tablet, capsule, syrup, suspension. 3. A pharmaceutical oral dosage form as in claim 2 wherein the preferred solid oral dosage form is tablet. Dated this 25th day of September 2007 For J.B. CHEMICALS & PHARMACEUTICALS LIMITED SHRI. SHIRISH BHAGWANLAL MODY DIRECTOR

Full Text

FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See section 10]
Title of the invention: A Pharmaceutical Oral Dosage Form Comprising of A Novel Combination of Aceclofenac , Paracetamol and Serratiopeptidase
2. M/S. J.B.CHEMICALS & PHARMACEUTICALS LTD., an Indian Company, having its Registered Office at Neelam Centre, "B' Wing, 4th floor, Hind Cycle Road, Worli, Mumbai 400 025, Maharashta, India.
3. The following specifications particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
1324/MUM/2004

A Pharmaceutical Oral Dosage Form Comprising of A Novel Combination of Aceclofenac , Paracetamol and Scrratiopeptidasc
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention generally relates to pharmaceutical compositions for oral administration. This invention relates in particular to such compositions comprising of a novel combination of aceclofenac, paracetamol and serratiopeptidase for the treatment of acute, painful and inflammatory conditions.
2. Description of the Prior Art
Various painful inflammatory conditions including those associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, postoperation state, musculoskeletal trauma, sports injuries, sinusitis etc are treated with NSAIDS.
Rheumatoid arthritis is a chronic multisystem disease of unknown cause. Although there are a variety of systemic manifestations, the characteristic feature of rheumatoid arthritis is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. The potential of the synovial inflammation to cause cartilage destruction and bone erosions and subsequent changes in joint integrity is the hallmark of the disease. ( Ref: Principals of internal medicines by T.R.Harrison)
Medical management of rheumatoid arthritis involves use of nonsteroidal anti¬inflammatory drugs and analgesics to control the symptoms and signs of the local inflammatory process.
Osteoarthritis is the most common joint disease of humans. It is characterized by deep ache in joints. Treatment is aimed at reducing pain, maintaining mobility and minimizing disability. NSAIDs decrease joint pain and improve mobility.
1

Aceclofenac is a potent analgesic and anti-inflammatory drug and has provided relief in various inflammatory and painful conditions. Aceclofenac is highly selective COX-2 inhibitor with COX-1 : COX-2 IC50 ratio of 129.(Henrotin Y, de leval X et al. In vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators. lnflamm.Res. 2001 Aug.50(8):391-9)
It acts at periphery by decreaseing proinflammatory prostaglandin synthesis by inhibiting cyclooxygenase 2 (COX 2).
Not only Acelcofenac is potent analgesic and anti-inflammatory agent but in contrast to some tother NSAIDs (e.g. Diclofenac and naproxen), Aceclofenac has shown stimulatory effects on cartilage matrix synthesis. (Dingle JT. The effect of NSAIDs on human cartilage glucosaminoglycan synthesis.Eur.J. Rheumatol Inflamm ,1996:l6(l):47-52).
Thus it is drug of choice in treatment of degenerative arthritis conditions.4'hydroxyaceclofenac, a major metabolite of Aceclofenac has chondroprotectibe properties attributable to suppression of IL-I-8-mediated promatrix metalloproteinase production.(Dooeley M. Spencer CM et al, Aceclofenac: A repraisal of its use in the management of pain and rheumatic disease.Drugs 2001; 61(9): 1351-1378).
Aceclofenac decreases pain levels, reduces the severity of symptoms and improves the functional capacity of the affected joint in patients with osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. It has been found to be effective in post surgical dental pain, ankylosing spondylitis, rheumatoid arthritis, musculoskeletal trauma, primary dysmenorrhoea, lumbago.
Metanalysis of studies involving more than 3000 patients indicated that a significantly greater proprtion of patients receiving Aceclofenac remained free from Gl symptoms after 3 to 6 months treatment than recipients of Diclofenac , naproxen, Piroxicam, lndomethancin, Tenoxican or Ketoprofen.(Peris F Bird HA et al: Treatmetn compliance and safety of aceclofeanc versus standard NSAIDs in patients with
2

common arthritic disorders: a metaanalysis, F.ur J Rhematol Inflamm lc)96;16(l):37-
45).
Paracetamol is time tested, trusted, cost effective and popular analgesic and acts centrally i.e. it has selective inhibitory action on cyclooxygenase in brain. Paracetamol is administered by mouth in tablets , syrup, suspension, capsules in dose range of 125 mg -500 mg per dose .it is taken with or after food.
Aceclofenac is administered by mouth as tablets in the dose range of 100 mg to 200 mg daily.
Serratiopeptidase is an enzyme derived from bacteria belonging to genus Sen?, ' . A
widely used anti-inflammatory enzyme, it is a stronger casenolytic or fibrinolitic
agent than most other alkaline or neutral proteases.
The purified enzyme has very good medicinal action in the body after absorption, especially, anti-inflammatory and sputum liquefying properties.
It eliminates inflammatory oedema and swelling, accelerates liquefaction of pus and sputum, and enhances the action of antibiotics. In sharp contrast to this, NSAIDs only relieve pain. Serratiopeptidase has wide-ranging applications, which are listed below. The usual dose is 15 mg -30 mg daily.
In case of analgesics, it is advantageous to have two drugs with different mechanism of action, differing or simultaneous onset and differing duration of effect to prolong their therapeutic efficacy.(Analgesic, antipyretic and anti-inflammatory agents.Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th Edn, 687 - 729).
3

Pharmacokinetics of paracetamol and aceclofcnac:
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. The concentration in plasma reaches peak in 30 minutes and half life in plasma is about 2 hours after the therapeutic dose. Aceclofenac has a favourable pharmacokinetic profile, which favors its combination with Paracetamol. The time to peak plasma concentration of aceclofenac is 1.08 -1.37 hrs whereas that with paracetamol is 30 -60 min. The efficacy of the combination will be more since the pharmacokinetic profile of the drugs is similar. Aceclofenac also has half life of 4 hrs which makes its administration twice a day. Lower doses of the combination will be required for the analgesic action.
Pharmacokinetic profile of paracetamol and aceclofenac:

Parameters Aceclofenac Paracetampl
Tmax 1.08-1.37 hrs 30 -60 minutes
Elimination half life 4 hrs 2 hrs.
Thus taking into consideration the limitations associated with the existing anti¬inflammatory , analgesic pharmaceutical compositions, the inventor has come out with a unique composition comprising of aceclofenac, paracetamol and serratiopeptidase in a dosage form suitable for oral administration having anti¬inflammatory, analgesic and antiedemic , healing property. This combination has been found to be therapeutically better over either aceclofenac, paracetamol ,serratiopeptidase individually.
Accordingly, it is among the objects of the present invention to provide oral dosage formulation containing aceclofenac, paracetamol and serratiopeptidase.
4

SUMMARY OF THE INVENTION
It is an object of this invention to provide a novel solid pharmaceutical composition for oral administration that comprises of aceclofenac, paracetamol and serratiopeptidase.
It is another object of the present invention to provide the process of preparation of oral solid dosage form.
DETAILED DESCRIPTION OF THE INVENTION
This invention generally relates to pharmaceutical compositions for oral administration. This invention relates in particular to such compositions comprisi- ~ of a novel combination of aceclofenac, paracetamol and serratiopeptidase for the treatment of acute, painful and inflammatory conditions.
The present invention comprises of
a)Aceclofenac in an amount of about 50 to 200 mg, preferably 100 mg.
b)Serratiopeptidase in an amount of about 5 mg to 50 mg, preferably from 5-20 mg
and most preferably 15 mg. c)ParacetamoI is incorporated in the oral solid dosage form of the present invention in
an amount of about 125 mg to 1000 mg , preferably from 125 mg to 500 mg and
most preferably 500 mg.
The novel composition comprising of aceclofenac, paracetamol and serratiopeptidase in a dosage form suitable for oral administration alleviates pain, relieves inflammation and promotes healing.
Indications:
The present invention is indicated
1) Acute exacerbation of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis.
5

2) Trauma: sports injurities, sprains, laceration, fractures and dislocation
3) Post operative state: to reduce post operative swelling . pain,
4) Carpel tunnel syndrome
5) Respiratory medicine: bronchitis, lung abscess, sinusitis and bronchitis.
6) Dermatology: Acute painful inflamed dermatoses
7) Dentistry: Pericoronitis of the wisdom tooth and alveolar abscess.
8) Opthalmology: Hyphaema, uveitis, oedema due to injury and operation , long standing opacity of the vitreous body.
9) Urology: Cystitis, epididymitis.
The preferred oral dosage form is tablets or capsules. It can also be administered in liquid oral dosage forms like syrup, suspension. The excipients for tablet dosage form may comprise of tablet diluents, binder, disintegrant, lubricant, antiadherant, jjlv,ant, coating agent, solvents, antioxidants, colorants, flavorants, sweetening agents, direct compression excipients, polishing agents.
Tablets are prepared by either wet granulation or dry mix process. In wet granulation process, typical binder used are maize starch, pregelatinized cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose. Diluent is selected from maize starch, lactose, dicalcium phosphate, microcrystalline cellulose. Disintegrant used is selected from croscarmellose sodium, colloidal silicon dioxide, sodium lauryl sulfate ,sodium starch glycollate, starch, microcrystalline cellulose . Lubricants most commonly used in tablets are stearates such as magnesium stearate and calcium stearate. The lubricant most frequently used is magnesium stearate , usually at a level of from about 1 percent to about 2 percent by weight. Antiadherants is selected from talc, colloidal silicon dioxide .
For dry mix process, typical binder used is selected from methyl cellulose, spray dried lactose, microcrystalline cellulose.
Capsules are prepared by conventional method .i.e. all active ingredients are individually sieved through 40# and mixed along with excipients in a mixer such as planetary mixer. The blend is then filled into capsules on capsule filling machine .
6

Furthermore the present invention provides the process for preparation of composition of the preferred embodiment which may be coated with a polymeric film merely to provide protection from moisture. The said coating polymer is selected from a group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol or methacrylic acid polymer, the most preferred being hydroxypropyl methyl cellulose. The said coating is soluble in fluid of the environment i.e. soluble in acidic pH and does not retard the release of active agent. The coating imparts moisture barrier properties to increase stability.
The present invention provides the process for preparation of composition of the preferred embodiment is as described below: Preparation of coated tablets:
a) The active agent, microcrystalline cellulose, colloidal anhydrous silica, colon- are
sifted through 40# sieve and mixed in a suitable mixer for 10 minutes.
b) The blend is granulated with warm water, starch paste by mechanical means.
c) Granules are dried at 45-50°C till LOD is between 2-3%w/w.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of sodium starch glycolate, colloidal
anhydrous silica, colour, magnesium stearate (presifted through 40#) by mechanical
mixing.
f) The lubricated granules are then compressed on tablet compression machine.
Q) Coating:
Appropriate quantity of hydroxypropyl methylcellulose, polyethylene glycol is dissolved in blend of Isopropyl alcohol, dichloromethane under stirring to get clear solution. The solution is strained through 100# & used for film coating of tablets
The granules can be prepared either by wet granulation, dry granulation, slugging and compaction. The most preferred process being wet granulation.
7

The invention will be more fully understood from the following examples. These examples are to be constructed as illustrative of the invention and not limitative thereof:
Example 1 -
Example 1 discloses a process for preparation by wet granulation of coated tablets according to the present invention
1. Granulation % w/w
Aceclofenac 14.2
Paracetamol 71.0
Serratiopeptidase 2.1
Microcrystalline cellulose 1.8
Croscarmellose Sodium 1.0
Maize Starch 3.5
Lubrication
Sodium starch glycolate 1.0
Colloidal Silicon Dioxide 1.0
Magnesium stearate 0.5
Talc 0.7
2. Coating % w/w
Hydroxypropyl methylcellulose 2.0
Polyethylene Glycol 0.8
Isopropyl Alcohol 15.0
Dichloromethane 15.0
Colour 0.2
Titanium Dioxide 0.2
The process for preparation of composition of Example I is as follows:
8

a)Aceclofcnac, Serratiopeptidase, Paracetamol, microcrystallinc cellulose, Croscarmellose Sodium are sifted through 40# sieve and mixed in a suitable mixer for 10 minutes.
b) The blend is granulated with warm water and starch paste by mechanical means.
c) Granules are dried at 45-50°C till LOD is between 2-3%w/w.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of sodium starch glycolate, colloidal
anhydrous silica, talc, magnesium stearate (presifted through 40#) by mechanical
Compression:
Lubricated granules are compressed on tablet compression machine.
Coating:
Appropriate quantity of hydroxyporpyl methyl cellulose, polyethylene glycol, colour
is dissolved in solution of Isopropyl alcohol, Dichloromethane under stirring to get
clear solution. The solution is strained through 100# & used for film coating of
tablets
Example 2
Example 2 discloses a process for preparation by dry mix or direct compression of
according to the present invention
1. Dry mix % w/w
Aceclofenac 11.0
Paracetamol 55.0
Serratiopeptidase 1.6
Calcium carbonate 7.5
Microcrystalline cellulose (Avicel) 18
Croscarmellose Sodium 1.0
Magnesium stearate 0.5
Talc 0.7
Lubrication
9

Magnesium stearate 0.7
laic 0.8
Coating % w/w
Hydroxypropyl methylcellulose 2.0
Polyethylene Glycol 0.8
Isopropyl Alcohol 15.0
Dichloromethane 15.0
Colour 0.2
Titanium Dioxide 0.2
The process for preparation of composition of Example 2 is as follows:
Preparation of Immediate release granule 1:
a) Aceclofenac, Serratiopeptidase, Paracetamol, microcrystalline celluiose,calcium
carbonate, croscarmellose sodium, magnesium stearate, talc are sifted through 40#
sieve and mixed in a suitable mixer for 15 minutes.
b) The blend is compressed into slugs by mechanical means.
c) Slugs are then milled through multimill.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with a mixture of magnesium stearate, talc (presifted through 40#) by mechanical mixing.
f) Lubricated granules are then compressed on compression machine.
Coating:
Appropriate quantity of hydroxyporpyl methyl cellulose, colour, polyethylene glycol
is dissolved in solution of Isopropyl alcohol, Dichloromethane under stirring to get
clear solution. The solution is strained through I00# & used for film coating of
tablets.
It is to be understood that the examples and embodiments described hereinabove are for the purposes of providing a description of the present invention by way of
10

examples and are not to be viewed as limiting the present invention in any way. Modification that may be made to that described in above examples by those of ordinary skill in the art is also contemplated by the present invention and is to be included within the spirit.
Example 3
Example 3 discloses a process for preparation of capsules according to the present
invention
1. Ingredients % w/w
Aceclofenac 14.0
Paracetamol 70.0
Serratiopeptidase 3.0
Maize Starch 10.0
Colloidal Anhydrous Silica 2.0
Magnesium stearate 1 -0
The process for preparation of composition of Example 3 is as follows: Preparation of blend:
a) Aceclofenac, Serratiopeptidase, Paracetamol, maize starch, are sifted through 40# sieve and mixed in a suitable mixer for 15 minutes.
b) Added colloidal anhydrous silica, magnesium stearate presifted to above blend and mixed for 10 minutes.
c) The blend is filled into capsules on capsule filling machine.
Clinical trials:
To investigate the effectiveness of the present invention in relieving pain, inflammation in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, postoperation state, musculoskeletal trauma, sports injuries, sinusitis clinical trials were carried out at five different centers all over India. Number of patients of different age groups were included in the trial. This study is not disclosed to the
11

public and the trials were done in confidence. The results of clinical study in India is given beiow.
1. In this study 100 patients having pain due to various degenerative and inflammatory rheumatic diseases like (Post traumatic pain. Low back pain. Cervical pain. Ankylosing spondylitis, Rheumatoid arthritis and Osteoarthritis) were considered and divided into 2 groups of 25 each. One group received aceclofenac tablets and the other group received present invention, twice a day for seven days .40% of the patients scored pain as severe in the beginning of the therapy. On first follow up it was found that in patients maintained on present invention the percentage was reduced to 5% at the first follow up visit while in patients receiving only aceclofenac the percentage was 12%.On second follow-up it was observed fl rt 28% of the patients receiving the present invention were fully relieved and 60% of the patients reported light pain whereas those receiving aceclofenac tablets 13% of the patients were relieved of pain and 45% reported light pain. This indicates that present formulation is superior than aceclofenac tablets alone in inflammatory rheumatic diseases.
2. 40 patients suffering from acute dental pain were included in the trial and they were divided into two groups. Group one received combination tablet of aceclofenac and paracetamol and group two received tablet of the present invention twice daily. The group of the present formulation showed improvement much faster as compared to the group combination of aceclofeanc and paracetamol tablets. There was noticeable reduction in inflammation in group receiving tablets of the present invention. This clearly indicates that present formulation is better choice than combination of aceclofenac and paracetamol.
3. 30 patients suffering from trauma such as sports injuries, sprains, laceration, fractures were included in the trial and divided into 2 groups of 15 each. One group received The results demonstrated that at visit 2,87% of patients were satisfied with the tablets of the present invention and by visit 3, 90% of patients were satisfied with the tablets of the present invention.
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4. In this study effectiveness of tablets of the present invention in 40 patients with carpal tunnel syndrome was evaluated clinically. After baseline electrophysiological studies, these patients were divided in two groups. Group one was given tablets of the present invention and group two was given serratiopeptidase tablets. Clinical and electrophysiological reassessment was done after 6 weeks. In group one 72% cases showed significant clinical improvement as against 50% cases in group two .No significant side effect was observed.
5. In this study 70 patients having pain due to trauma due to sports injuries, sprains, laceration, fractures and dislocation, were considered and divided into 2 groups of 35 each. Treatment lasted 7-8 days. Group one received tablets of the present invention and group two received aceclofenac tablets. The tablets were given two times a day. After 3-4 days treatment ^nificant symptoms regression was observed in group one . The intensity of pain and severity of inflammation, swelling was reduced faster in patients in group one as compared to group two. Tolerance was found to be good and similar in both groups. Statistical comparison between the two groups confirmed the greater efficacy and rapid action of the present invention against all symptoms examined.
Above clinical trials confirm the efficacy of the solid oral dosage form of the present invention in treatment of acute, painful and inflammatory conditions. It is to be understood that the example and embodiments described hereinabove are for the purpose of providing a description of present invention by way of example and are not be viewed as limiting the present invention in any way. Those who are skilled in the art can made various modifications or changes that may be made to the described invention and are also contemplated by it which can be included within the spirit and purview of this application.
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We claim:
1. A pharmaceutical oral dosage form comprising of Aceclofenac in amount from 50 mg to 200 mg, preferably from 100 to 200 mg and most preferably 100 mg; Paracetamol in amount from 125 mg to 750 mg, preferably 500 mg and Serratiopeptidase in amount from 5 mg to 30 mg, preferably 15 mg.
2. A pharmaceutical oral dosage form as in claim 1 wherein the dosage form is tablet, capsule, syrup, suspension.
3. A pharmaceutical oral dosage form as in claim 2 wherein the preferred solid oral dosage form is tablet.
Dated this 25th day of September 2007
For J.B. CHEMICALS & PHARMACEUTICALS LIMITED
SHRI. SHIRISH BHAGWANLAL MODY DIRECTOR

Documents:

1324-mum-2004-cancelled pages(13-12-2004).pdf

1324-mum-2004-claims(granted)-(13-12-2004).doc

1324-mum-2004-claims(granted)-(13-12-2004).pdf

1324-mum-2004-correspondence(26-9-2007).pdf

1324-mum-2004-correspondence(ipo)-(11-8-2008).pdf

1324-mum-2004-form 1(13-12-2004).pdf

1324-mum-2004-form 19(13-12-2004).pdf

1324-mum-2004-form 2(granted)-(13-12-2004).doc

1324-mum-2004-form 2(granted)-(13-12-2004).pdf

1324-mum-2004-form 3(10-12-2004).pdf

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Patent Number

222973

Indian Patent Application Number

1324/MUM/2004

PG Journal Number

06/2009

Publication Date

06-Feb-2009

Grant Date

29-Aug-2008

Date of Filing

13-Dec-2004

Name of Patentee

M/S. J. B. CHEMICALS & PHARMACEUTICALS LTD.

Applicant Address

Neelam Centre,'B'Wing, 4th Floor,Hind Cycle Road, Worli,Mumbai-

Inventors:

#	Inventor's Name	Inventor's Address
1	SHRI SHIRISH B. MODY	232 Kshitij Apartments, Nepean Sea Road, Mumbai-400 036.
2	DOSHI MADHUKANT MANSUKHLAL	9 Chhabal,Hansoti Lane, Ghatkopar(W),Mumbai-400 077
3	JOSHI MILIND DATTATRAYA	B-402 Prakriti Apts; K.K.Mill Compound, Mohan Sunderji Road, Raghunath Nagar,Thane(W)

PCT International Classification Number

A61P5/44

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA