FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
"A NOVEL PHARMACEUTICAL TABLET 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 TABLET COMPOSITION CONTAINING DEXIBUPROFEN AND PARACETAMOL.»
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates generally to a novel pharmaceutical composition containing Dexibuprofen and paracetamol in the form of solid oral tablet 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 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 mechanism of action. All of the
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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.
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.
Some reports suggest that receptor mechanisms are involved in the mechanism of action of acetaminophen. These studies involved administration of acetaminophen to mice by three routes: (1) directly into the brain (intracerebroventricular), (2) directly into the spinal cord (intrathecal), or (3) into brain and spinal cord simultaneously. Following the administration of acetaminophen, antinociception (analgesia) was assessed using a standard abdominal constriction test in which a chemical irritant (acetylcholine) was injected into the peritoneum and inhibition of the behavioral response was equated with antinociception.
Administration of acetaminophen only into the brain produced minimal antinociception, whereas administration of acetaminophen only into the spinal cord produced dose-related antinociception but only to about 60% of the maximum effect. In contrast, administration of acetaminophen simultaneously into brain and spinal cord produced a dose-related and full analgesic effect, demonstrating enhanced potency and antinociceptive effect. Mathematical
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analysis revealed a statistically significant synergistic analgesic interaction between spinal and supraspinal administration. These findings and subsequent work suggest that acetaminophen has a direct action at the level of the spinal cord and it stimulates a supraspinal system that releases neurotransmitters at the level of the spinal cord.
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 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 propacetamol 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
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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.
Safety: Less dose of individual drugs required. Hence, less chance of adverse effects of both the drugs.
Better GI tolerability: Dexibuprofen has got good GI tolerability. Paracetamol is also a well tolerated drug with a good GI safety. Improved compliance of the patient.
US 6,663,893 patent assigned to Bristol-Myers Squibb Co. claims an invention for that masks the undesirable taste of a pharmaceutically active ingredient, i.e. drug or medicine, that is taken orally. The coating composition is comprised of dimethylaminoethyl methacrylate and neutral methacrylic acid ester, a cellulose ester polymer, and an alkaline modifier. This patent claims an invention using single drug dexibuprofen and not combination product. Whereas the invention disclosed herein in this invention is for combination product of S-ibuprofen and paracetamol.
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
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combination product , but claims use of sole ingredient Dexibuprofen 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 100 mg-500 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 solid oral dosage form, to provide compliance to the patients who can not easily swallow capsule dosage form.
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 tablet 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 tablet oral dosage form.
According further aspect of this invention the both the drugs dexibuprofen and paracetamol are granulated separately.
Further aspect of the invention is dexibuprofen granules are prepared by dry granulation technique e.g. slugging and paracetamol granules are prepared by wet granulation method.
Yet another aspect of the invention is the said tablets are stable and the combination drug therapy results into a synergestic effect.
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In yet another aspect of the invention the process of making the tablet 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.
In yet another aspect the tablets are film coated in nature.
The intelligent selection of the ingredients is resulting into a cost effective combination product in the form of tablet 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
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compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local ,oral or by systemic administration of the active ingredient to the host.
Compositions may take the form of solid dose forms, for example, tablets prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e. g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art.
"Diluents" is intended to mean substances that acts as a filler in the formulation .Microcrystalline cellulose,lactose,sucrose,Mannitol,starch, Lactose monohydrate, dicalcium phosphate, starch etc. can be used as diluents in this composition, or combinations thereof and other material known to those of ordinary skill in the art.
The term "disintegrant as used herein intended to mean a substance that helps in breaking the tablet into granules in stipulated period of time.Crosscarmellose sodium, sodium starch glycolate, pregelatinized starch, crosspovidone, Eudragit EPO can be used as disintegrants in this composition or combinations thereof and other material known to those of ordinary skill in the art.
The term lubricants used herein is used are selected from the group stearic acid,Colloidal silicon dioxide,polyethylene glycol,hydrogenated vegetable oil,sodium steryl fumarate , magnesium stearate, etc.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention discloses an oral pharmaceutical composition in the form of tablet having combination of one drug selected as acetaminophen and the other therapeutically effective component selected from the group of NSAID'S e.g. Dexibuprofen.
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.

STEP NAME OF INGREDIENTS Rationale forUsingexcipients
(1) Dexibuprofen Granulation
Dexibuprofen Active Drug
Microcrystalline Cellulose (AvicelPHlOl) Diluent
Hydroxypropylmethylcellulose 6 cps Lubricant
Hydrogenated Castor Oil (Boricin Pharma) Binding agent
Colloidal Silicon Dioxide Glidant
Talc Lubricant
(H) Paracetamol Granulation
Paracetamol Active Drug
Microcrystalline Cellulose Diluent
Pregelatinised Starch (Starch 1500) Binder
Povidone (K-30) Binder
Methylparaben Preservative
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Propylparaben Preservative
Sodium Metabisulphite Anti -oxidant
(Ill) Lubrication
Microcrystalline Cellulose (Avicel PH 102) Binder
Colloidal Silicon Dioxide Glidant
Talc Disintegrant
Carmellose Calcium (Carboxymethylcellulose -Calcium) Lubricant
Hydrogenated Castor Oil (Boricin Pharma) Lubricant
Magnesium Stearate Glidant
TENTATIVE FORMULATION SHEET FOR COATING

SR. NO. INGREDIENTS QTY. PER BATCH IN KG
1 Hydroxypropylmethylcellulose E5 LV 0.993
2 Triacetin 0.099
3 Talc 0.261
4 Titanium Dioxide 1.047
5 Isopropyl Alcohol 15.600
6 Dichloromethane 62.200
Manufacturing Process:
I Dexibuprofen granules:-
Sifting & Dry Mixing
Sift using mechanical sifter through 80 # sieve.
Dexibuprofen
Sift using mechanical sifter through 60 # sieve.
Microcrystalline cellulose.(Avicel PH 102)
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Dry Mixing : l0min.
II Slugging
After Dry mixing all ingredients with Active Drug added in a hopper and slugged using 16 mm Round FFBE punch. Granule passed through 10 # ,16 # and finally through 30 #.
III Diminution
Diminution through 30 # sieve.
II Paracetamol granules
I Sifting & Dry Mixing
Sifting of active drug and other Raw material through, Paracetamol (through 40# sieve) Microcrystalline cellulose. (through 60# sieve) Starch( through 60# sieve) Dry Mixing :10min.
II Preparation of granulating Solution (Starch Paste)
Purified water
Povidone K -30 Boiling water in this dissolve Methyl paraben Propyl paraben to this add Purified water in this dissolve , Sodium metabisulphite. Ill Wet mixing
Mixing Time : 15 Min.
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Speed : 2 & 3
IV Wet sifting
Sifting of wet material through 10 #
V Drying
In Rapid Dryer
Temp. : 45°c-55°c
Drying Time : 30 min.
VI Diminution
Diminution through 30 # sieve. HI Mixing both granules
Mix part 1 & part 11 thoroughly with respect to the yields obtained and then remove the fines through 40#.
VII Lubrication
Fines from above step were lubricated with
Microcrystailine cellulose.(Avicel PH 102),
Boricin Pharma,
Calcium CMC,
Croscarmallose sodium,
Talc,
Magnessium striate, &
Colloidal silicon Dioxide
Dated this twenty third (23rd )day of May,2006

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