FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
"A NOVEL PHARMACEUTICAL SOFT GEL COMPOSITION CONTAINING DEXIBUPROFEN AND PARACETAMOL "
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
Glenmark Pharmaceuticals Limited,Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East),
Mumbai - 400 099, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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"A NOVEL PHARMACEUTICAL SOFT GEL COMPOSITION CONTAINING DEXIBUPROFEN AND PARACETAMOL/'
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention of this application generally relates to a novel pharmaceutical composition containing Dexibuprofen and paracetamol in the form of soft gelatin capsule dosage form and process for making the same.
2. Description of the Related Art
Pain has been defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. This definition is particularly relevant because it takes into account the emotional component of pain, which can modify the pain signal, and recognizes that tissue damage encompasses potential as well as actual damage.
As the population ages and the prevalence of musculoskeletal disorders increases, treatment of the pain associated with these disorders will assume an even greater importance. Pain is both a societal and a patient problem. Patients want to have their pain eradicated, whereas the societal goal of pain management is, according to the American pain society, "to advance the treatment of people in pain by ensuring access to treatment, removing regulatory barriers, and educating practitioners." Pain treatment is constantly changing, and physicians must keep abreast to be able to offer their patients optimal care.
NSAID's(non-steroidal antiinflammatory) have good analgesic efficacy, a relatively rapid onset, and well-known adverse events including potentially fatal gastrointestinal (GIT) bleeding and disturbance of salt and water balance. They also have a relatively well-defined
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mechanism of action. All of the effects of NSAID's analgesic, anti-inflammatory, antipyretic, and antiplatelet are believed to be caused, directly or indirectly, by inhibition of the biosynthesis of prostanoids such as pge2, which induce inflammation and sensitize nociceptors.
Ibuprofen, an NSAID is marketed commercially and used clinically as a racemic mixture of S(+)- and R(-)-enantiomers, which exist in equal amounts. Dexibuprofen is the S(+) (dextrorotatory)-enantiomer of ibuprofen and accounts for virtually all pharmacodynamic (analgesic, anti-inflammatory, antipyretic) activities of the racemic compound. In vitro, dexibuprofen is over 100 times as potent as the R(-)-enantiomer as an inhibitor of prostaglandin biosynthesis; it has been suggested that any observable in vitro effect of R(-)-ibuprofen is secondary to small amounts of dexibuprofen present as an impurity.
In vivo, the R(-)-enantiomer of racemic ibuprofen undergoes unidirectional enzymatic chiral inversion to S(+)-enantiomer (dexibuprofen). This occurs to the extent about 65%, whereas there is no bioinversion of S(+)- to R(-)-ibuprofen. Although this would favor use of racemic ibuprofen, since most of its inactive enantiomer is converted to active form, proponents of dexibuprofen suggest disadvantages of the racemic drug. It is argued that conversion of racemic ibuprofen to S(+)-ibuprofen results in variability of clinical response, including delayed onset of activity, and difficulty in achieving an optimal dose; it is also felt that the formation of coenzyme A (CoA) thioester during bioinversion of R(-)- to S(+)-ibuprofen may result in toxic effects (e.g., interference of lipid anabolism/catabolism), and that R(-)-ibuprofen bioactivation is susceptible to biological factors and certain drugs. There are some preclinical/clinical data to support these contentions.
204/MAS/2001 application filed by Dr. Reddy's Laboratories Ltd. discloses that the potential advantages of dexibuprofen over racemic ibuprofen include lesser toxicity, greater clinical efficacy and/or less variability in therapeutic effects achieved, and easier dose optimization, all at half the dose of ibuprofen. A more rapid onset is also claimed for dexibuprofen, and this was demonstrated in one well-conducted comparison of dexibuprofen and ibuprofen in dental surgery patients; greater peak analgesia was also seen with dexibuprofen.
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Oral dexibuprofen in usual doses of 900 to 1200 mg daily has shown efficacy in the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and other rheumatic diseases in uncontrolled studies and randomized comparisons with ibuprofen or diclofenac. The efficacy of dexibuprofen and ibuprofen has been comparable with 50% lower doses of dexibuprofen. Dexibuprofen has been shown to be as effective as Diclofenac and celecoxib in the treatment of osteoarthritis.
Acetaminophen, chemically known as 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.
The analgesic efficacy of acetaminophen is essentially equivalent to that of NSAIDs, but acetaminophen is not anti-inflammatory. Both drugs have a comparably rapid onset of action. There are generally few AEs of acetaminophen at therapeutic doses, but if it is consumed in excess of recommended doses hepatic toxicity can result, particularly in a compromised liver. The mechanism of action of acetaminophen is unknown, but prevailing evidence suggests that it involves a central component. Acetaminophen inhibits COX-1, but in the brain rather than in the periphery.
Analgesic combinations offer a potential benefit over individual agents. Such benefits include increased compliance and reduced side effects if the same level of analgesia can be achieved with the lower doses of each component in the combination. Combining analgesics that have different mechanisms of action offers the additional potential advantage of being able to treat a broader spectrum of pain. Such an approach has been recommended by the World Health Organization and the American College of Rheumatology.
Paracetamol is frequently used as a non-opioid analgesic in postoperative pain. Its mechanism of action is not fully understood, but it is generally accepted that paracetamol is a centrally acting drug. The analgesic effect of paracetamol is probably dependent on the rate and amount of active drug reaching the CNS, where its analgesic effect takes place. When pain relief is insufficient with paracetamol alone, an NSAID may be added in combination. NSAIDs inhibit prostaglandin synthesis in peripheral tissues. Some suggest a peripheral- central synergistic
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action of NSAIDs that varies depending on the particular NSAID and on the presence of an inflammatory process. Concomitant administration of two analgesics with presumably different mechanisms of action may be more effective than the use of either drug alone. The combination of paracetamol and NSAIDs is widely used clinically.
In the most robust trial, the combination of paracetamol with ketoprofen 50 mg reduced pain scores at rest and on movement compared with ketoprofen alone after disc surgery. Oral diclofenac 100 mg combined with paracetamol 1000 mg reduced pain intensity scores, improved pain relief scores and reduced the need for rescue analgesia compared with diclofenac alone after dental surgery. Further evidence of this is seen in non-surgical studies of patients with rheumatoid arthritis, in whom indometacin (150 mg/ day) alone and the combination of indometacin (50 mg/ day) with paracetamol (4 g/ day) had the same analgesic effect, but the combination had fewer and milder side-effects. In two other studies, treatment with a combination of naproxen with paracetamol had a greater analgesic effect than treatment with higher naproxen doses alone. A review concerning paracetamol in rheumatoid arthritis suggests that there is increasing evidence that combined paracetamol and NSAID treatment is more effective than treatment with NSAIDs alone. No adverse effects attributed to the combination of paracetamol and NSAIDs were reported.
In summary, the available data suggest that standard doses of paracetamol do enhance analgesic efficacy when added to NSAIDs compared with NSAIDs alone.
Mechanism of action: Both the drugs (dexibuprofen and paracetamol) produce analgesic effects by different mechanisms. NSAIDs like dexibuprofen inhibit prostaglandin synthesis in peripheral tissues. Acetaminophen's mechanism of action appears to be due to inhibition of prostaglandin synthetase centrally. Specifically, it is a potent inhibitor of cyclo-oxygenase in the central nervous system. Hence, their actions can be complementary to each other.
Since less dose of individual drugs is required. Hence, less chance of adverse effects of both the drugs.
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Further it is known that GI tolerability Dexibuprofen has got better GI tolerability. And paracetamol is also a well tolerated drug with a good GI safety which improves compliance of the patient.
909/DELNP/2004 patent assigned to strides arcolab limited dexibuprofen containing soft gelatin capsule and process for preparing same .This patent does not discloses about the combination product , but claims use of sole ingredient Dexibuprofen in the form of soft gelatin capsule.
204/MAS/2001 application assigned to Dr.Reddys Laboratories discloses an invention for the soft gelatin capsule containing (s)(+)-ibuprofen.This patent does not discuss about the combination of paracetamol and (s)(+) ibuprofen combination in the form of soft gelatin capsule.
The daily dose of Ibuprofen alone is around 150 mg/day and for paracetamol it is 4 gms/day. Due to the synergestic combination this dose is reduced to Dexibuprofen 50 mg-100 mg and paracetamol dose to 1.5 gms daily
So, there remains the need for formulating a combination product that gives a synergestic effect, and manufactured specifically in soft gelatin capsule dosage form , to provide compliance to the patients .Due to the drug present in the composition in soluble form , this soft gel dosage form will result into quick dissolution and satisfactory bioavailability of the composition.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, is to make a novel pharmaceutical combination product in the form of soft gel capsule containing therapeutically effective amount of dexibuprofen and paracetamol.
Yet another aspect of the invention is to provide a process for making the above mentioned combination product of dexibuprofen nd paracetamol in the form of soft gelatin capsule.
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According further aspect of this invention the both the drugs dexibuprofen and paracetamol are dissolve /disperse in suitable solvent.
Yet another aspect of the invention is the to prepare a soft gel combination product that stable and the combination drug therapy results into a synergestic effect.
In yet another aspect of the invention the process of making the soft gelatin capsule that is simple and cost effective.
In further aspect of the invention the daily dose of Ibuprofen alone is around 150 mg/day and for paracetamol it is 4 gms/day. Due to the synergestic combination this dose is reduced to Dexibuprofen 100 mg-500 mg and paracetamol dose to 1.5 gms daily.
The intelligent selection of the ingredients is resulting into a cost effective combination product in the form of soft gel capsule dosage form.
DEFINITIONS
The term "treating" or "treatment" of a state, disorder or condition as used herein means (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
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The term "Surfactant" used herein are the substances that helps in reducing the surface tension between the two surfaces and helps in dissolving/dispersing the one phase into other. The compounds used as surfactants are glycerol monostearate, polysorbates, sodium laurylsulfate and sucross esters of fatty acids, polyoxyl hydrogenated castor oil (of various grades) and combination thereof.
"Solvent /vehicle" is the term used herein are the substaces that helps in dissolving or dispersing the active pharmaceutical compound or drug in the selected solvent. Solvents used herein in this invention are selected from the group but are not limited to benzyl alcohol, ethylene glycol phenyl ether, propylene glycol, propylene glycol phenyl ether, propylene carbonate, phenoxyethanol, dimethyl malonate, dimethyl succinate, diethyl succinate, dibutyl succinate, dimethyl glutarate, diethyl glutarate, dibutyl glutarate, dimethyl adipate, diethyl adipate, dibutyl adipate, various grades of polyethylene glycol or mixtures thereof.
This invention is not limited to the inactive excipients disclosed herein in this specification , but all those excipients that can be use to prepare soft gelatin capsule and is known to the person skilled in the art can be used to make the said Dexibuprofen and paracetamol soft gelatin capsule.
DETAILED DESCRIPTION
The present invention discloses an oral pharmaceutical composition in the form of soft gelatin capsule having combination of one drug selected as acetaminophen and the other therapeutically effective component selected from the group of NSAID'S e.g. Dexibuprofen. This invention is to limited to the inactive excipients disclosed herein, but all those excipients known to the person skilled in the art can be used to make the said Dexibuprofen and paracetamol soft gelatin capsule.
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The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of this invention.
Example 1. DEXIBUPROFEN AND PARACETAMOL SOFT GELATIN CAPSULE

SR. NO. INGREDIENTS QTY. PER TABLET IN MG
1 Polyethylene Glycol 400 (Macrogol 400) 400.00
2 Cremophor RH 40(Polyoxyl 40 Hydrogenated Castor Oil) 50.00
3 Dexibuprofen 300.00
4 Paracetamol 500.00
Fill Weight 1250.0
Manufacturing of Gelatin Mass (batch quantity)

SR. NO. INGREDIENTS QTY. PER BATCH IN KG
I Gelatin Mass Manufacturing
1 Gelatin (Powder) 50.000
2 Glycerin 20.000
3 Sorbitol Solution 70 % 5.000
4 Sodium Methylparaben 0.160
5 Sodium Propylparaben 0.040
6 Purified Water 45.000
7 Sunset Yellow FCF 0.132
8 Ponceau 4R 0.022
9 Titanium Dioxide 0.350

Manufacturing of Gelatin Mass
Glycerin addition:
Transfer in a reactor, filtering through 100 # Nylon cloth Glycerin, Sorbitol Solution 70 % & Purified Water
Start heating & stirring of reactor at 65 ± 5°C. Maintain temperature at 65 ± 5°C.
Manufacturing & addition of Preservative Solution
Transfer in a 5 kg SS container, filtering through 200 # Nylon cloth; Glycerin. Heat up to 65 ± 5°C
And dissolve Sodium Methylparaben and Sodium Propylparaben until a clear solution is obtained
Add this to the above glycerin and sorbitol solution.
Manufacturing of Final Gelatin Mass
Transfer gradually in a 400 litre reactor Gelatin (Powder) . After complete addition of material, close top lid tightly. Stir continuously contents of reactor for 30 minutes, maintaining the temperature at 70 ± 5°C
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Check and ensure the complete melting of gelatin powder. Remove some sample from bottom valves in glass beaker/Petri dish and check visually.
Apply vacuum upto 25 mm Hg for 30 minutes while stirring to remove air bubbles from gelatin mass.
Release vacuum & observe the sample for absence of air bubble. Transfer the gelatin mass through 20 # sieve to the holding tank.
Colour Solution Preparation
In 2 kg SS container add filtering through 100# nylon cloth Purified Water, add & dissolve Sunset Yellow FCF and Ponceau 4R. Add this solution to the above gelatin solution.
In SS container add filtering through 100# nylon cloth take purified Water, add & disperse titanium dioxide to this . Add this solution also to above gelatin solution. Stir for 15 minutes with continuous stirring.
Maintain holding tank at 55 ± 5°C. Record the temperature.
Medicament Manufacturing
In 380 litre SS bowl of mixer add Polyethylene Glycol 400 & Cremophor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) . Heat the mixture to 50 to 55°C. Add & dissolve dexibuprofen to the above material under mechnical stirringa and continue stirring until a clear solution is obtained.
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Add & disperse Paracetamol to the above solution under mechnical stirring and stir for 30 to 45 minutes until a homogeneous slurry is formed. Pass it through Tripple roller grinder mill with 80 # SS sieve & collect material in SS bowl. De-aerate by applying Vacuum up to 25 Hg for 30 minutes.
Encapsulation
Encapsulate using Encapsulation machine having die roll size 23.20 minim with oblong shape using gelatin orange colored ribbon .
Polishing
The encapsulated capsules are polished with absorbent cloth through 3 semi dryers in series.
Drying
Dry the capsules using tray dryer maintaining the temperature Condition 25±5 C & % Relative Humiditv 25±5 %.
Dated this Eighteenth (18th )day of September ,2006

Taranpreet Lamba. (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited
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