Title of Invention	A PROCESS FOR PREPARING SYNERGISTIC FIXED DOSE PHARMACEUTICAL COMPOSITION
Abstract	The present invention relates to a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, a method of alleviating pain, and also, a process thereof.

Title of Invention

A PROCESS FOR PREPARING SYNERGISTIC FIXED DOSE PHARMACEUTICAL COMPOSITION

Abstract

The present invention relates to a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, a method of alleviating pain, and also, a process thereof.

Full Text	A process for preparing synergistic fixed dose pharmaceuticai composition Fieid of the Present Invention The present invention relates to a synergistic pharmaceutical composition useful in alleviating pain. It relates to the composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives. Background and prior art references Commercially Ibuprofen is available as a conventional tablet and has been reformulated and presented as a melt in the mouth tablet. Similarly Paracetamol is also available as a conventional tablet and it has been improved by use of pharmaceutically acceptable additives upon to Paracetamol actifast or PANADOL actifast tablets. PANADOL is improved by addition of GRAS (Generally regarded as safe) additives. Ibex is improved by changing physical characteristics. Paracetamol has antipyretic and mild analgesic actions together with some antiinflammatory activity. These effects are related to inhibition of prostaglandin synthesis. The absolute oral bioavailability is about 80 % and is independent of dose in the range 5-20 mg/kg. It is indicated for the relief of mild to moderate pain of diverse etiology. It is less effective when pain is associated with acute inflammation. Ibuprofen has prominent anti-inflammatory effects in addition to having analgesic and antipyretic actions. The analgesic effects of ibuprofen are the result of both a peripheral and a central effect and are distinct from its property as an antiinflammatory drug. It inhibits prostaglandin synthesis in tissues by inhibiting the enzyme cyclooxygenase. Ibuprofen is effective in relieving pain and reducing the temperature in febrile patients. It is also a useful anti-inflammatory drug in the treatment of inflammatory disorders. Caffeine has analgesic, CNS stimulant, diuretic and bronchodilator effects. The analgesic activity of caffeine results from several mechanisms: 1) blockade of peripheral pronociceptive actions of adenosine 2) activation of central nonadrenergic pathways that constitute an endogenous pain suppressing system 3) CNS stimulation with a consequent modulation of the affective component of pain. Caffeine is rapidly and completely absorbed after oral administration. Since paracetamol has only mild anti-inflammatory activity and since it is less effective when pain is associated with acute inflammation, ibuprofen, which has prominent anti-inflammatory effect, is combined with paracetamol to make the formulation effective in the treatment of painful / inflammatory conditions. GENERAL PRINCIPLES OF COMBINATION THERAPY 1. When two or more drugs produce synergistic effect because of different modes of action. 2. When toxicity or side effects of two or more drugs are better tolerated than maximum doses of individual drugs due to lesser doses of individual drugs in the combination. 3. When a single drug does not result in complete response, minimum effective dose of another drug can be added. 4. When treatment is aimed at conditions involving more than one causes. JUSTIFICATION IN SUPPORT OF COMBINATION THERAPY: 1 There is sufficient ground for all drugs being given together. 2 Combination produces efficacy that is not achievable with the individual drugs. 3 Combination results in some synergistic effect due to different modes of action. 4 Combination is better tolerated due to avoidance of maximum doses of individual drugs. 5 Individual drugs are compatible in terms of their pharmacokinetic characteristics. 6 There is no drug-drug interaction resulting in blockade of response of one by the other drug. 7 Drug interactions from combination therapy do not result in any significant adverse consequences. 8 Doses of individual drugs are such that flexibility is not compromised due to fixed dose combination. RELATIVE ADVANTAGES OF FIXED DOSE COMBINATION: 1 Fixed dose combination (FDC) results in better patient compliance due to less number of tablet a patient has to take and lesser side effects. 2 FDC is convenient for a patient to carry to work place as compared to different packs of individual drugs. 3 Cost-effective for the patient compared to cost of individual drugs. Objects of the present Invention The main object of the present invention is to develop a synergistic pharmaceutical composition useful in treating pain. Yet another object of the present invention is to develop a method alleviating pain. Still another object of the present invention is to develop a process for the preparation of a synergistic pharmaceutical composition. Summary of the present Invention The present invention relates to a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60 %, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, a method of treating pain, and also, a process thereof. Detailed description of the present Invention Accordingly, the present invention relates to a synergistic pharmaceutical composition useful in alleviating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60%, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, a method of treating pain, and also, a process thereof. in still another embodiment of the present invention, wherein the invention relates to a synergistic pharmaceutical composition useful in alleviating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60%, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives which are generally regarded as safe (GRAS). In still another embodiment of the present invention, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%. in still another embodiment of the present invention, wherein the concentration of the Ibuprofen is preferably about 32%. In still another embodiment of the present invention, wherein the concentration of paracetamol is preferably about 52%. In still another embodiment of the present invention, wherein the concentration of caffeine is preferably about 4.8%. In still another embodiment of the present invention, wherein the comppsition is in a form selected from a group comprising tablet, pellet, mircotablet, capsule. (In still another embodiment of the present invention, wherein the caffeine is about 150% more active in the composition. In still another embodiment of the present invention, wherein the paracetamol is about 100% more active in the composition. In still another embodiment of the present invention, wherein the ibuprofen is about 30% more active in the composition. In still another embodiment of the present invention, wherein the said method comprising step of administering a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 30 to 40%, paracetamol of concentration ranging between 50 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives to the subject. In still another embodiment of the present invention, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%. In still another embodiment of the present invention, wherein the concentration of the Ibuprofen is preferably about 32%. In still another embodiment of the present invention, wherein the concentration of paracetamol is preferably about 52%. In still another embodiment of the present invention, wherein the concentration of caffeine is preferably about 4.8%. In still another embodiment of the present invention, wherein the administration of the composition is through oral route. In still another embodiment of the present invention, wherein the composition is released immediately into bloodstream, leading to faster action. In still another embodiment of the present invention, wherein the method (process) is useful in treating rheumatoid arthritis ankylosing spondylitis, osteoarthritis, non-rheumatoid (seronegative) arthropathies, non-articular rheumatoid, periarticular conditions such as capsulitis, bursitis, tendonitis, tenosynovitis, sprains, strains, dysmenorrhoea, dental pain, post-operative pain, headache including migraine headache, infective inflammatory conditions such as tonsillitis, pharyngitis, otitis media, pharyngitis, inflammatory conditions in gynecology, urology and ophthalmology, accidental injuries including fracture, and post operative wounds. In still another embodiment of the present invention, wherein the composition is to be administered about three times in a day. In still another embodiment of the present invention, wherein the invention relates to a process of preparing a synergistic pharmaceutical composition in a compressed form, useful in effectively treating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, said process comprising steps of: • meshing paracetamol, ibuprofen, and caffeine in the range of 12 to 80 mesh, • meshing additives of excipient nature in the range of 20 to 200 mesh, • blending the aforementioned excipients of to uniformity using additive(s) of binder nature, • adding treated maize starch slurry to the blend to obtain the synergistic composition. • granulating the synergistic composition, • lubricating the granules using additive(s) of lubricant nature, and • compressing the lubricated granules to obtain compressed synergistic pharmaceutical composition useful in effectively treating pain. • The composition is then filled into capsules. In still another embodiment of the present invention, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%. In still another embodiment of the present invention, wherein the binders are selected from a group comprising PVP, Starch, HPMC, HPC, polysorbate, Polyethylene glycol, Gelatin, and various natural gums. 1 still another embodiment of the present invention, wherein the binding is for the time duration ranging between 10 to 45 minutes. In still another embodiment of the present invention, wherein the binder is prepared at temperature ranging between 30 to 75^C. The Present invention relates to a composition particularly adapted to oral administration wherein the actives are immediately released upon administration. The composition is comprised of cores containing actives Paracetamol, Ibuprofen and caffeine in tablet, pellet or microtablet form. It is characterized in such a form that the actives are immediately released into the bloodstream leading to faster action and relief. A process for preparing the composition is disclosed. Invitro dissolution profile of Capsules versus Capsules containing Microtablets conducted in different time intervals is described in the detailed prior-art. This invention relates to the immediate release of combination of actives like Ibuprofen, Paracetamol and Caffeine that are in tablet, pellet or microtablet form for the treatment of pain. These Combinations are used as orally administrable pharmaceutical preparation that releases the actives immediately into the bloodstream on administration to provide faster action and immediate relief in the treatment of pain. The invention also relates to a process for preparing this composition. The present invention provides a method for treatment of pain comprising the concurrent administration of Ibuprofen, Paracetamol and caffeine in a microtablet, which results in immediate release of the actives for the treatment of pain. In our case by altering the product into microtablets, we have increased the surface area of the product exponentially thereby increasing the dissolution and hence absorption and thus action. The analgesia produced by the concurrent administration of Ibuprofen, Paracetamol and caffeine provides a rapid onset, providing greater pain relief and maintaining the analgesic effect for a longer time. This combination also provides an Anti-inflammatory and Antipyretic effect. In the state of pain and trauma there is fatigue and lack of coordination in the body, Caffeine acts as a stimulant and stimulates the central-nervous-system and increases energy metabolism throughout the brain. It also enhances the performance of an individual upon administration. This effect of increase in performance is propagated to Improved patient performance. The Invitro dissolution profile of Ibuprofen, Paracetamol and Caffeine Composition in conventional tablet form, powder in hard gelatin capsule form and in microtablet filled in capsule form is mentioned in the chart 1. CHART1 : Invitro Dissolution profile of Ibuprofen, Paracetamol and Caffeine from three different dosage forms : Note: — The above-mentioned data Indicates samples not analyzed as 100% drug has been released at the previous time interval. Chart 1 provides the dissolution profile of active in different dosage form. This chart substantiates the immediate release of our combination drug in Microtablet form. The actives in Microtablet form are dissolved in Gl track in less than 20 minutes i.e. --150 times much faster than other dosage forms. This immediate release facilitates faster action of the combination drug there by providing faster relief. The present invention comprises pharmaceutical compositions as Tablets, Pellets or Microtablets containing Ibuprofen, Paracetamol and Caffeine for combination therapy. In this preferred embodiment, the composition is in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule. For this, any gelatin capsule conventionally employed in the pharmaceutical formulation field can be used. The compositions of this invention are particularly suitable for oral administration of the active principles and are particularly suitable for alleviate pain. Rationale for Combination of Ibuprofen 200mg, Paracetamol 325mg and Caffeine 30mg. When treatment is aimed at conditions involving unknown / more than one cause there is sufficient ground for three drugs being given together. Paracetamol in the presence of Caffeine was approximately 1.4 times more potent (synergistic activity) than the analgesic without caffeine. A recent series of studies on postoperative oral surgery pain demonstrated significant adjuvant activity (synergistic activity) for caffeine in combination with Ibuprofen. The potency ratios for analgesic combinations containing caffeine range from 1.29 to 1.92 for paracetamol and 1 to 1.29 for ibuprofen. Ibuprofen and caffeine administered together provided significantly shorter times to meaningful improvement in headache relief than ibuprofen or placebo; and significantly greater total analgesia than ibuprofen alone, caffeine alone or placebo. Significantly more subjects obtained meaningful headache relief with ibuprofen and caffeine administered together than with ibuprofen alone, caffeine alone or placebo. One of the adverse reactions of ibuprofen is that it can precipitate bronchospasm in patients hypersensitive to NSAIDs particularly in patients with a past history of asthma when used alone\ Caffeine has bronchodilator effectV When ibuprofen and caffeine are administered together there are less chances of bronchospasm being precipitated in asthma patients since caffeine has bronchodilator effect. Studies document the analgesic efficacy of Paracetamol in dosage of 325 - 650 mg. A recent study showed that doses of IBUPROFEN, PARACETAMOL, AND CAFFEINE 200mg, 400mg are equally effective in the treatment of migraine. Section-1 RATIONALE FOR IBUPROFEN 200 MG + PARACETAMOL 325 MG AND CAFFEINE 30 MG WHEN TREATMENT IS AIMED AT CONDITIONS INVOLVING MORE THAN ONE CAUSES THERE IS SUFFICIENT GROUND FOR THREE DRUGS BEING GIVEN TOGETHER The response to nociceptor sensory input is a multifactorial process, with both central and pehpheral mechanisms involved Several neurotransmitters participate in the transmission and modulation of this multifaceted process and thus, it is often difficult to achieve complete pain control using a single pharmacological agent without significant adverse events. Ibuprofen is a propionic acid derivative with anti-inflammatory / analgesic activity. It has clinically useful anti-inflammatory properties that result from its inhibition of prostaglandin synthesis and other effects on the immune system. Paracetamol (acetaminophen) is an analgesic and antipyretic. Paracetamol is effective in treating mild to moderate pain such as headache, neuralgia and musculoskeletal pain. Caffeine is a member of the group of chemically related alkaloids known as methylxanthines. Almost all organ systems can be influenced by the methylxanthines, although the predominant site of activity involves the central nervous system and the cardiovascular system. Caffeine acts as a mild stimulant to the nervous system, blocking the neurotransmitter adenosine and resulting in a feeling of well being and alertness. Caffeine also alters perception of pain. Section-ll COMBINATION PRODUCES EFFICACY THAT IS NOT ACHIEVABLE WITH THE INDIVIDUAL DRUGS. Ibuprofen is a good anti-inflammatory drug. However, pain relief with doses of Ibuprofen that can be easily tolerated by patients (200 mg three times daily) is not adequate. Paracetamol is an analgesic / antipyretic but has very little antiinflammatory activity. Its analgesic effect can be complemented by caffeine. For patients with migraine, long-term management can be difficult due to the complex nature of the condition. But new clinical guidelines, developed by the American Academy of Family Physicians and the American College of Physicians-American Society of Internal l\/ledicine, stress the importance of step care and patient education in the treatment and prevention of migraine. Step care should begin with the use of non-steroidal anti-inflammatory drugs (NSAIDs)"particularly aspirin, ibuprofen, naproxen sodium, and the combination agent acetaminophen plus aspirin (or any other NSAIDs) plus caffeine as first-line treatment for acute attacks of any degree of severity. If the patient does not respond to NSAIDs, migraine-specific drugs should then be tried. Various studies have shown the effectiveness of the addition of caffeine to Ibuprofen and / or Paracetamol for acute pain. Ibuprofen and caffeine administered together provided significantly greater analgesic activity than ibuprofen alone, caffeine alone, and placebo. Ibuprofen and caffeine administered together demonstrated significantly shorter times to meaningful improvement in headache relief than ibuprofen or placebo; significantly greater total analgesia than ibuprofen alone, caffeine alone, or placebo; and significantly greater peak relief than ibuprofen alone, caffeine alone, or placebo. Significantly more subjects obtained meaningful headache relief with ibuprofen and caffeine administered together than with ibuprofen alone or placebo. More patients reported complete headache relief with ibuprofen and caffeine administered together than with ibuprofen alone, caffeine alone, or placebo. Ibuprofen and caffeine administered together was rated significantly better by patients than either ibuprofen alone, caffeine alone, or placebo. No subjects ended participation in the study early because of adverse events. Pooled data also demonstrated that a combination of NSAID like aspirin, acetaminophen and caffeine (Excedrin) was significantly better than placebo for nausea, photophobia, phonophobia, functional disability and pain relief in the treatment of migraine. Combination of Ibuprofen, paracetamol and caffeine is an effective antiinflammatory and analgesic in the treatment of inflammatory / painful conditions like rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies; in the treatment of non-articular rheumatic conditions, in periarticular conditions such as frozen shoulder (capsulitis), bursitis, tendonitis, tenosynovitis and low back pain; Ibuprofen can also be used in soft tissue injuries such as sprains and strains. Ibuprofen is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhoea, dental and postoperative pain and for symptomatic relief of headache, including migraine headache. Section-Ill COMBINATION RESULTS IN SYNERGISTIC EFFECT DUE TO DIFFERENT MODES OF ACTION Nonsteroidal anti-inflammatory drugs like ibuprofen reduce inflammation by inhibition of prostaglandin synthesis at the site of inflammation. NSAID's may also act to a limited extent in reducing prostaglandin formation centrally and thus provide certain amount of relief from pain. Paracetamol acts on the CNS to produce analgesia and antipyretic effect. It has got negligible anti-inflammatory action in therapeutic doses. Caffeine produces intrinsic antinociceptive actions in animal models and adjunctive analgesic properties in humans. These properties are due to multiple actions of adenosine on the transmission of noxious sensory information. Inflammation is one of the body's prime responses when the body is in a state of disease. Inflammatory response of the body could be due to any insult or injury that could have occurred. Of the five classical symptoms of inflammation (redness, heat, pain, edema and functional limitations), the most common one would be pain. A physician treating inflammatory disorders is primarily concerned with treating inflammation while the patient's main need is quicl This is the rationale behind the combination of an anti-inflammatory like Ibuprofen, an analgesic like paracetamol and a mood-elevating agent like caffeine. Since inflammation and pain co-exist in many situations, the scope exists across specialties for the use of fixed dose combination of ibuprofen, paracetamol and caffeine. ALL THE DRUGS ARE COMPATIBLE IN TERMS OF THEIR PHARMACOKINETIC CHARACTERISTICS The usually recommended adult dosage of ibuprofen is 200-400 mg in 3 times daily doses. The usually recommended adult dosage of paracetamol is 325-650 mg three times daily. The usually recommended adult dosage of Caffeine in oral analgesic preparation is 15-65 mg three times daily. Both ibuprofen and paracetamol are rapidly and completely absorbed following oral administration. Peak serum concentrations are achieved between 15 min and 2 hour for paracetamol and between 1 hour and 2 hours for ibuprofen. Oral administration of caffeine results in very good bioavailability. There is little evidence that food delays absorption of caffeine. Section-IV Rationale for addition of caffeine to Ibuprofen and Paracetamol One major rationale for combination is to add minimum effective dose of another drug wlien adequate dose of initial drug has not produced complete/ sufficient response or when the patients do not tolerate the maximum therapeutic doses of the individual drugs. Patients who are not getting adequate pain relief from the available combination of Ibuprofen 200 mg and Paracetamol 325 mg can shift to Ibex. (All drugs are within therapeutic dose range). Some patients may not very well tolerate higher doses of Ibuprofen. The analgesic effect of Paracetamol is seen with 1500mg to 4000mg/ days, which may not be very well tolerated by patients. Addition of caffeine reduces the requirement for higher doses both Ibuprofen and Paracetamol for the analgesic effect i.e., in-patients suffering from moderate to severe painful conditions. There is no increased toxicity as the total intakes of all the drugs are well within the recommended therapeutic doses of individual drugs. Indications Fixed dose combination tablet of ibuprofen 200mg, Paracetamol 325mg plus caffeine 30 mg (Ibex) is indicated for the treatment of migraine and tension type headache. Ibex is also indicated for the treatment of painful / inflammatory conditions like rheumatoid arthritis, oesteoarthritis, cervical spondolosis, ankylosing spondylitis and other sero-negative arthropathies; soft tissue rheumatic conditions such as tendinitis, fibrosistitis, myositis, bursitis, capsulitis and low back pain; infective inflammatory conditions such as tonsillitis, pharyngitis, otitis media, pharyngitis, and inflammatory conditions in gynecology, urology and ophthalmology; soft tissue injuries such as sprains, strains, sports injuries, lacerated wounds and other accidental injuries including fracture and post operative wounds; dental inflammatory conditions such as alveolar abscesses, periodontitis, following dental extractions and maxillofacial surgeries; and dysmenorrhoea in adults. Dosage and administration The recommended dosage of Ibex is one to two tablet 3 times daily. The daily intake of all ingredients (ibuprofen, paracetamol and caffeine) is well within the maximum daily recommended doses. Section-V Regulatory status in other countries Fixed dose combinations of an NSAID, acetaminophen (paracetamol) and caffeine are in regular clinical use abroad for decades and there is no serious adverse events reported with these combinations. Absence of untoward drug-drug interactions No untoward drug-drug interactions or adverse clinical consequence are observed between the components of this formulation (ibuprofen, paracetamol and caffeine). Also, no adverse physicochemical interaction has been observed between the active components of the formulation. They are found to be physico-chemically compatible. According to one particular embodiment, the composition according to this invention takes the form of a capsule containing 10 to 70 micro-tablets, having the following composition, expressed in mg/ per capsule, starting from the core: Paracetamol: 200 to 500, Ibuprofen: 100 to 200, Caffeine: 10 to 60, Maize Starch: 10 to 30, PVPK 30: 5 to 30, Aerosil: 1 to 10, Stearic acid: 2 to 10, HPMC E5: 5 to 30, Titanium Dioxide: 0.1 to 3, Polyethylene Glycol: 0.5 to 5, Talc: 0,5 to 5, Colors: 0 to 2 This process is not only limited to Ibuprofen, Paracetamol and Caffeine combination as tablets, pellets or Microtablets but can also include any other NSAID's like Diclofenac, Carisoprodol, chlormezanone, Tizanidine hydrochloride any muscle relaxants and neutraceuticals. The invention will now be described in more detail on the basis of the following examples, which are only provided by way of illustrative example. The examples should not be construed to limit the scope of the invention. EXAMPLE 1 Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg was prepared. The examples provided have a total composition of 620mg per capsule and this can be increased upto 650mg per capsule. To achieve the foregoing objective with its purpose, the present system provides for the immediate release of the combination of active agents to an environment of use. In this process of preparing this composition the actives are swifted through 12 to 80 mesh and the excipieints are passed through 20 to 200 mesh. Any retention on the mesh is milled using suitable milling devices and the actives and excipients are swifted through a desired mesh. After this the actives and excipients are dry blended till content uniformity is attained (10-45 minutes). The binders normally used are PVP, Starch, HPMC, HPC, Sarbutol, and Poly ethylene glycol, Gelatin or various natural gums. The suitable binder is prepared at temperature range of 30-75 degree centigrade and then dissolved in water. Then the maize starch slurry is added to the actives, suitable vessels are made use for the binder preparation. For wet granulation the dry mixing powder is added to the binder preparation in a suitable fluid bed processor. The wet screening is done using suitable screening methods. The whole wet mass is loaded to the fluid bed process and fluid bed dryer. The inlet temperature is maintained at a suitable temperature and dried till Loss on Drying (LOD) of less than 4% is achieved. The dry granules are milled using suitable meshes and techniques, here a suitable granulator is used .The dry granules are blended with lubricated excipients in a suitable blender till proper lubrication and content uniformity of the actives are achieved. The lubricated granules ready for compression are compressed using 2.0mm to 4mm punches. EXAMPLE 2 Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration. A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared. The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of polyvinyl pyrolidone in water. The granules were dried, sized, lubricated with Maize starch, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 3: Preparation, of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared. The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with Starch Paste. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 4: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared. The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of polyvinyl pyrolidonePVPK-30 and PVPK-90 in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 5: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared. The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of HPMC E5 in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 6: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared. The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of HPC LF 21 in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Talc, Stearic acid and compressed to microtablets The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 7: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared. The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of gelatine in water and Starch paste. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 8: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared The pharmaceutical composition was prepared using the method described in example 1, Paracetamoljbuprofen ,Caffeine were blended with the Maize Starch and granulated with a solution of PVPK-30 and Polysorbate 80 in water. The granules were dried, sized, lubricated with Sodium starch glycollate ,Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 9: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of Veegum in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 10: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a Maize Starch Paste. The granules were dried, sized, lubricated with Crosspovidone, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 11: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a Maize starch Paste and Polysorbate 80 in water. The granules were dried, sized, lubricated with Cross povidone, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. EXAMPLE 12: Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration. A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution Acacia in water. The granules were dried, sized, lubricated with cross povidone, Aerosil, Stearic acid and compressed to microtablets. The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1. The foregoing description and examples have been set forth merely to illustrate invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations falling within the scope of the appended claims and equivalents thereof. Claims 1. A synergistic pharmaceutical composition useful in alleviating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives. 2. A synergistic composition as claimed in claim 1, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%. 3. A synergistic composition as claimed in claim 1, wherein the concentration of the Ibuprofen is preferably about 32%. 4. A synergistic composition as claimed in claim 1, wherein the concentration of paracetamol is preferably about 52%. 5. A synergistic composition as claimed in claim 1, wherein the concentration of caffeine is preferably about 4.8%. 6. A synergistic composition as claimed in claim 1, wherein the composition is in a form selected from a group comprising tablet, pellet, mircotablet, capsule. 7. A synergistic composition as claimed in claim 1, wherein the caffeine is about 150% more active in the composition. 8. A synergistic composition as claimed in claim 1, wherein the paracetamol is about 100% more active in the composition. 9. A synergistic composition as claimed in claim 1, wherein the ibuprofen is about 30% more active in the composition. 10. A method of alleviating pain in a subject in need thereof, said method comprising step of administering a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 30 to 40%, paracetamol of concentration ranging between 50 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives to the subject. 11. A method of alleviating as claimed in claim 10, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%. 12. A method of alleviating as claimed in claim 10, wherein the concentration of the Ibuprofen is preferably about 32%. 13. A method of alleviating as claimed in claim 10, wherein the concentration of paracetamol is preferably about 52%. 14. A method of alleviating as claimed in claim 10, wherein the concentration of caffeine is preferably about 4.8%. 15. A method of alleviating as claimed in claim 10, wherein the administration of the composition is through oral route. 16. A method of alleviating as claimed in claim 10, wherein the composition is released immediately into bloodstream, leading to faster action. 17.A method of alleviating as claimed in claim 10, wherein the method is useful in treating rheumatoid arthritis ankylosing spondylitis, osteoarthritis, non-rheumatoid (seronegative) arthropathies, non-articular rheumatoid, periarticular conditions such as capsulitis, bursitis, tendonitis, tenosynovitis, sprains, strains, dysmenorrhoea, dental pain, post-operative pain, headache including migraine headache, infective inflammatory conditions such as tonsillitis, pharyngitis, otitis media, pharyngitis, inflammatory conditions in gynecology, urology and ophthalmology, accidental injuries including fracture, and post operative wounds. 18. A method of alleviating as claimed in claim 10, wherein the method the composition is to be administered about three times in a day. 19.A process of preparing a synergistic pharmaceutical composition in a compressed form, useful in effectively treating pain, said composition comprises ibuprofen of concentration ranging between 30 to 40%, paracetamol of concentration ranging between 50 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, said process comprising steps of: a. meshing paracetamol, ibuprofen, and caffeine in the range of 12 to 80 mesh, b. meshing additives of excipient nature in the range of 20 to 200 mesh, c. blending the mesh of step (a) and (b) to uniformity using additive(s) of binder nature, d. adding maize starch slurry to the blend to obtain the synergistic composition. e. granulating the synergistic composition, f. lubricating the granules using additive(s) of lubricant nature, g. compressing the lubricated granules to obtain compressed synergistic pharmaceutical composition useful in effectively treating pain, and h. optionally, filing the compressed composition into capsules. 20.A process as claimed in claim 19, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%. 21. A process as claimed in claim 19, wherein the binders are selected from a group comprising PVR, Starch, HPMC, HPC, Sarbutol, Polyethylene glycol. Gelatin, and various natural gums. 22. A process as claimed in claim 19, wherein the binding is for the time duration ranging between 10 to 45 minutes. 23. A process as claimed in claim 19, wherein the binder is prepared at temperature ranging between 30 to 75°C. 24. A synergistic pharmaceutical composition substantially as herein described with reference to the foregoing examples 25. A process of preparing a synergistic pharmaceutical composition substantially as herein described with reference to the foregoing examples

Full Text

A process for preparing synergistic fixed dose pharmaceuticai composition
Fieid of the Present Invention
The present invention relates to a synergistic pharmaceutical composition useful in alleviating pain. It relates to the composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives.
Background and prior art references
Commercially Ibuprofen is available as a conventional tablet and has been reformulated and presented as a melt in the mouth tablet. Similarly Paracetamol is also available as a conventional tablet and it has been improved by use of pharmaceutically acceptable additives upon to Paracetamol actifast or PANADOL actifast tablets. PANADOL is improved by addition of GRAS (Generally regarded as safe) additives. Ibex is improved by changing physical characteristics.
Paracetamol has antipyretic and mild analgesic actions together with some antiinflammatory activity. These effects are related to inhibition of prostaglandin synthesis. The absolute oral bioavailability is about 80 % and is independent of dose in the range 5-20 mg/kg. It is indicated for the relief of mild to moderate pain of diverse etiology. It is less effective when pain is associated with acute inflammation.
Ibuprofen has prominent anti-inflammatory effects in addition to having analgesic and antipyretic actions. The analgesic effects of ibuprofen are the result of both a peripheral and a central effect and are distinct from its property as an antiinflammatory drug. It inhibits prostaglandin synthesis in tissues by inhibiting the enzyme cyclooxygenase. Ibuprofen is effective in relieving pain and reducing the

temperature in febrile patients. It is also a useful anti-inflammatory drug in the treatment of inflammatory disorders.
Caffeine has analgesic, CNS stimulant, diuretic and bronchodilator effects. The analgesic activity of caffeine results from several mechanisms: 1) blockade of peripheral pronociceptive actions of adenosine 2) activation of central nonadrenergic pathways that constitute an endogenous pain suppressing system 3) CNS stimulation with a consequent modulation of the affective component of pain. Caffeine is rapidly and completely absorbed after oral administration.
Since paracetamol has only mild anti-inflammatory activity and since it is less effective when pain is associated with acute inflammation, ibuprofen, which has prominent anti-inflammatory effect, is combined with paracetamol to make the formulation effective in the treatment of painful / inflammatory conditions.
GENERAL PRINCIPLES OF COMBINATION THERAPY
1. When two or more drugs produce synergistic effect because of different modes of action.
2. When toxicity or side effects of two or more drugs are better tolerated than maximum doses of individual drugs due to lesser doses of individual drugs in the combination.
3. When a single drug does not result in complete response, minimum effective dose of another drug can be added.
4. When treatment is aimed at conditions involving more than one causes.
JUSTIFICATION IN SUPPORT OF COMBINATION THERAPY:
1 There is sufficient ground for all drugs being given together.

2 Combination produces efficacy that is not achievable with the individual drugs.
3 Combination results in some synergistic effect due to different modes of action.
4 Combination is better tolerated due to avoidance of maximum doses of individual drugs.
5 Individual drugs are compatible in terms of their pharmacokinetic characteristics.
6 There is no drug-drug interaction resulting in blockade of response of one by the other drug.
7 Drug interactions from combination therapy do not result in any significant adverse consequences.
8 Doses of individual drugs are such that flexibility is not compromised due to fixed dose combination.
RELATIVE ADVANTAGES OF FIXED DOSE COMBINATION:
1 Fixed dose combination (FDC) results in better patient compliance due to less number of tablet a patient has to take and lesser side effects.
2 FDC is convenient for a patient to carry to work place as compared to different packs of individual drugs.
3 Cost-effective for the patient compared to cost of individual drugs.

Objects of the present Invention
The main object of the present invention is to develop a synergistic pharmaceutical composition useful in treating pain.
Yet another object of the present invention is to develop a method alleviating pain.
Still another object of the present invention is to develop a process for the preparation of a synergistic pharmaceutical composition.
Summary of the present Invention
The present invention relates to a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60 %, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, a method of treating pain, and also, a process thereof.
Detailed description of the present Invention
Accordingly, the present invention relates to a synergistic pharmaceutical composition useful in alleviating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60%, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, a method of treating pain, and also, a process thereof.
in still another embodiment of the present invention, wherein the invention relates to a synergistic pharmaceutical composition useful in alleviating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60%, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives which are generally regarded as safe (GRAS).

In still another embodiment of the present invention, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%.
in still another embodiment of the present invention, wherein the concentration of the Ibuprofen is preferably about 32%.
In still another embodiment of the present invention, wherein the concentration of paracetamol is preferably about 52%.
In still another embodiment of the present invention, wherein the concentration of caffeine is preferably about 4.8%.
In still another embodiment of the present invention, wherein the comppsition is in a form selected from a group comprising tablet, pellet, mircotablet, capsule.
(In still another embodiment of the present invention, wherein the caffeine is about 150% more active in the composition.
In still another embodiment of the present invention, wherein the paracetamol is about 100% more active in the composition.

In still another embodiment of the present invention, wherein the ibuprofen is about 30% more active in the composition.
In still another embodiment of the present invention, wherein the said method comprising step of administering a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 30 to 40%, paracetamol of concentration ranging between 50 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives to the subject.
In still another embodiment of the present invention, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%.
In still another embodiment of the present invention, wherein the concentration of the Ibuprofen is preferably about 32%.
In still another embodiment of the present invention, wherein the concentration of paracetamol is preferably about 52%.
In still another embodiment of the present invention, wherein the concentration of caffeine is preferably about 4.8%.

In still another embodiment of the present invention, wherein the administration of the composition is through oral route.
In still another embodiment of the present invention, wherein the composition is released immediately into bloodstream, leading to faster action.
In still another embodiment of the present invention, wherein the method (process) is useful in treating rheumatoid arthritis ankylosing spondylitis, osteoarthritis, non-rheumatoid (seronegative) arthropathies, non-articular rheumatoid, periarticular conditions such as capsulitis, bursitis, tendonitis, tenosynovitis, sprains, strains, dysmenorrhoea, dental pain, post-operative pain, headache including migraine headache, infective inflammatory conditions such as tonsillitis, pharyngitis, otitis media, pharyngitis, inflammatory conditions in gynecology, urology and ophthalmology, accidental injuries including fracture, and post operative wounds.
In still another embodiment of the present invention, wherein the composition is to be administered about three times in a day.
In still another embodiment of the present invention, wherein the invention relates to a process of preparing a synergistic pharmaceutical composition in a compressed form, useful in effectively treating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, said process comprising steps of:
• meshing paracetamol, ibuprofen, and caffeine in the range of 12 to 80 mesh,
• meshing additives of excipient nature in the range of 20 to 200 mesh,

• blending the aforementioned excipients of to uniformity using additive(s) of binder nature,
• adding treated maize starch slurry to the blend to obtain the synergistic composition.
• granulating the synergistic composition,
• lubricating the granules using additive(s) of lubricant nature, and
• compressing the lubricated granules to obtain compressed synergistic pharmaceutical composition useful in effectively treating pain.
• The composition is then filled into capsules.
In still another embodiment of the present invention, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%.
In still another embodiment of the present invention, wherein the binders are selected from a group comprising PVP, Starch, HPMC, HPC, polysorbate, Polyethylene glycol, Gelatin, and various natural gums.

1 still another embodiment of the present invention, wherein the binding is for the time duration ranging between 10 to 45 minutes.
In still another embodiment of the present invention, wherein the binder is prepared at temperature ranging between 30 to 75^C.
The Present invention relates to a composition particularly adapted to oral administration wherein the actives are immediately released upon administration. The composition is comprised of cores containing actives Paracetamol, Ibuprofen and caffeine in tablet, pellet or microtablet form. It is characterized in such a form that the actives are immediately released into the bloodstream leading to faster action and relief. A process for preparing the composition is disclosed. Invitro dissolution profile of Capsules versus Capsules containing Microtablets conducted in different time intervals is described in the detailed prior-art.
This invention relates to the immediate release of combination of actives like Ibuprofen, Paracetamol and Caffeine that are in tablet, pellet or microtablet form for the treatment of pain. These Combinations are used as orally administrable pharmaceutical preparation that releases the actives immediately into the bloodstream on administration to provide faster action and immediate relief in the treatment of pain. The invention also relates to a process for preparing this composition.
The present invention provides a method for treatment of pain comprising the concurrent administration of Ibuprofen, Paracetamol and caffeine in a microtablet, which results in immediate release of the actives for the treatment of pain. In our case by altering the product into microtablets, we have increased the surface area of the product exponentially thereby increasing the dissolution and hence absorption and thus action. The analgesia produced by the concurrent administration of Ibuprofen, Paracetamol and caffeine provides a rapid onset, providing greater pain relief and maintaining the analgesic effect for a longer

time. This combination also provides an Anti-inflammatory and Antipyretic effect. In the state of pain and trauma there is fatigue and lack of coordination in the body, Caffeine acts as a stimulant and stimulates the central-nervous-system and increases energy metabolism throughout the brain. It also enhances the performance of an individual upon administration. This effect of increase in performance is propagated to Improved patient performance. The Invitro dissolution profile of Ibuprofen, Paracetamol and Caffeine Composition in conventional tablet form, powder in hard gelatin capsule form and in microtablet filled in capsule form is mentioned in the chart 1.
CHART1 : Invitro Dissolution profile of Ibuprofen, Paracetamol and Caffeine from three different dosage forms :

Note: — The above-mentioned data Indicates samples not analyzed as 100% drug has been released at the previous time interval.
Chart 1 provides the dissolution profile of active in different dosage form. This chart substantiates the immediate release of our combination drug in Microtablet form. The actives in Microtablet form are dissolved in Gl track in less than 20 minutes i.e. --150 times much faster than other dosage forms. This immediate release facilitates faster action of the combination drug there by providing faster relief.
The present invention comprises pharmaceutical compositions as Tablets, Pellets or Microtablets containing Ibuprofen, Paracetamol and Caffeine for combination therapy.
In this preferred embodiment, the composition is in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule. For this, any gelatin capsule conventionally employed in the pharmaceutical formulation field can be used. The compositions of this invention are particularly suitable for oral administration of the active principles and are particularly suitable for alleviate pain.
Rationale for Combination of Ibuprofen 200mg, Paracetamol 325mg and Caffeine 30mg.
When treatment is aimed at conditions involving unknown / more than one cause there is sufficient ground for three drugs being given together.
Paracetamol in the presence of Caffeine was approximately 1.4 times more potent (synergistic activity) than the analgesic without caffeine.

A recent series of studies on postoperative oral surgery pain demonstrated significant adjuvant activity (synergistic activity) for caffeine in combination with Ibuprofen.
The potency ratios for analgesic combinations containing caffeine range from 1.29 to 1.92 for paracetamol and 1 to 1.29 for ibuprofen.
Ibuprofen and caffeine administered together provided significantly shorter times to meaningful improvement in headache relief than ibuprofen or placebo; and significantly greater total analgesia than ibuprofen alone, caffeine alone or placebo. Significantly more subjects obtained meaningful headache relief with ibuprofen and caffeine administered together than with ibuprofen alone, caffeine alone or placebo.
One of the adverse reactions of ibuprofen is that it can precipitate bronchospasm in patients hypersensitive to NSAIDs particularly in patients with a past history of asthma when used alone\ Caffeine has bronchodilator effectV When ibuprofen and caffeine are administered together there are less chances of bronchospasm being precipitated in asthma patients since caffeine has bronchodilator effect.
Studies document the analgesic efficacy of Paracetamol in dosage of 325 - 650 mg.
A recent study showed that doses of IBUPROFEN, PARACETAMOL, AND CAFFEINE 200mg, 400mg are equally effective in the treatment of migraine.
Section-1
RATIONALE FOR IBUPROFEN 200 MG + PARACETAMOL 325 MG AND CAFFEINE 30 MG

WHEN TREATMENT IS AIMED AT CONDITIONS INVOLVING MORE THAN ONE CAUSES THERE IS SUFFICIENT GROUND FOR THREE DRUGS BEING GIVEN TOGETHER
The response to nociceptor sensory input is a multifactorial process, with both central and pehpheral mechanisms involved Several neurotransmitters participate in the transmission and modulation of this multifaceted process and thus, it is often difficult to achieve complete pain control using a single pharmacological agent without significant adverse events.
Ibuprofen is a propionic acid derivative with anti-inflammatory / analgesic activity. It has clinically useful anti-inflammatory properties that result from its inhibition of prostaglandin synthesis and other effects on the immune system.
Paracetamol (acetaminophen) is an analgesic and antipyretic.
Paracetamol is effective in treating mild to moderate pain such as headache,
neuralgia and musculoskeletal pain.
Caffeine is a member of the group of chemically related alkaloids known as methylxanthines. Almost all organ systems can be influenced by the methylxanthines, although the predominant site of activity involves the central nervous system and the cardiovascular system. Caffeine acts as a mild stimulant to the nervous system, blocking the neurotransmitter adenosine and resulting in a feeling of well being and alertness. Caffeine also alters perception of pain.
Section-ll
COMBINATION PRODUCES EFFICACY THAT IS NOT ACHIEVABLE WITH THE INDIVIDUAL DRUGS.

Ibuprofen is a good anti-inflammatory drug. However, pain relief with doses of Ibuprofen that can be easily tolerated by patients (200 mg three times daily) is not adequate. Paracetamol is an analgesic / antipyretic but has very little antiinflammatory activity. Its analgesic effect can be complemented by caffeine.
For patients with migraine, long-term management can be difficult due to the complex nature of the condition. But new clinical guidelines, developed by the American Academy of Family Physicians and the American College of Physicians-American Society of Internal l\/ledicine, stress the importance of step care and patient education in the treatment and prevention of migraine.
Step care should begin with the use of non-steroidal anti-inflammatory drugs (NSAIDs)"particularly aspirin, ibuprofen, naproxen sodium, and the combination agent acetaminophen plus aspirin (or any other NSAIDs) plus caffeine as first-line treatment for acute attacks of any degree of severity. If the patient does not respond to NSAIDs, migraine-specific drugs should then be tried.
Various studies have shown the effectiveness of the addition of caffeine to Ibuprofen and / or Paracetamol for acute pain.
Ibuprofen and caffeine administered together provided significantly greater analgesic activity than ibuprofen alone, caffeine alone, and placebo. Ibuprofen and caffeine administered together demonstrated significantly shorter times to meaningful improvement in headache relief than ibuprofen or placebo; significantly greater total analgesia than ibuprofen alone, caffeine alone, or placebo; and significantly greater peak relief than ibuprofen alone, caffeine alone, or placebo. Significantly more subjects obtained meaningful headache relief with ibuprofen and caffeine administered together than with ibuprofen alone or placebo. More patients reported complete headache relief with ibuprofen and caffeine administered together than with ibuprofen alone, caffeine alone, or placebo. Ibuprofen and caffeine administered together was rated significantly

better by patients than either ibuprofen alone, caffeine alone, or placebo. No subjects ended participation in the study early because of adverse events.
Pooled data also demonstrated that a combination of NSAID like aspirin, acetaminophen and caffeine (Excedrin) was significantly better than placebo for nausea, photophobia, phonophobia, functional disability and pain relief in the treatment of migraine.
Combination of Ibuprofen, paracetamol and caffeine is an effective antiinflammatory and analgesic in the treatment of inflammatory / painful conditions like rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies; in the treatment of non-articular rheumatic conditions, in periarticular conditions such as frozen shoulder (capsulitis), bursitis, tendonitis, tenosynovitis and low back pain; Ibuprofen can also be used in soft tissue injuries such as sprains and strains. Ibuprofen is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhoea, dental and postoperative pain and for symptomatic relief of headache, including migraine headache.
Section-Ill
COMBINATION RESULTS IN SYNERGISTIC EFFECT DUE TO DIFFERENT MODES OF ACTION
Nonsteroidal anti-inflammatory drugs like ibuprofen reduce inflammation by inhibition of prostaglandin synthesis at the site of inflammation. NSAID's may also act to a limited extent in reducing prostaglandin formation centrally and thus provide certain amount of relief from pain.
Paracetamol acts on the CNS to produce analgesia and antipyretic effect. It has got negligible anti-inflammatory action in therapeutic doses.

Caffeine produces intrinsic antinociceptive actions in animal models and adjunctive analgesic properties in humans. These properties are due to multiple actions of adenosine on the transmission of noxious sensory information.
Inflammation is one of the body's prime responses when the body is in a state of disease. Inflammatory response of the body could be due to any insult or injury that could have occurred. Of the five classical symptoms of inflammation (redness, heat, pain, edema and functional limitations), the most common one would be pain.
A physician treating inflammatory disorders is primarily concerned with treating inflammation while the patient's main need is quicl This is the rationale behind the combination of an anti-inflammatory like Ibuprofen, an analgesic like paracetamol and a mood-elevating agent like caffeine.
Since inflammation and pain co-exist in many situations, the scope exists across specialties for the use of fixed dose combination of ibuprofen, paracetamol and caffeine.
ALL THE DRUGS ARE COMPATIBLE IN TERMS OF THEIR PHARMACOKINETIC CHARACTERISTICS
The usually recommended adult dosage of ibuprofen is 200-400 mg in 3 times
daily doses.
The usually recommended adult dosage of paracetamol is 325-650 mg three
times daily.
The usually recommended adult dosage of Caffeine in oral analgesic preparation
is 15-65 mg three times daily.

Both ibuprofen and paracetamol are rapidly and completely absorbed following oral administration. Peak serum concentrations are achieved between 15 min and 2 hour for paracetamol and between 1 hour and 2 hours for ibuprofen. Oral administration of caffeine results in very good bioavailability. There is little evidence that food delays absorption of caffeine.
Section-IV
Rationale for addition of caffeine to Ibuprofen and Paracetamol
One major rationale for combination is to add minimum effective dose of another drug wlien adequate dose of initial drug has not produced complete/ sufficient response or when the patients do not tolerate the maximum therapeutic doses of the individual drugs.
Patients who are not getting adequate pain relief from the available combination of Ibuprofen 200 mg and Paracetamol 325 mg can shift to Ibex. (All drugs are within therapeutic dose range).
Some patients may not very well tolerate higher doses of Ibuprofen. The analgesic effect of Paracetamol is seen with 1500mg to 4000mg/ days, which may not be very well tolerated by patients. Addition of caffeine reduces the requirement for higher doses both Ibuprofen and Paracetamol for the analgesic effect i.e., in-patients suffering from moderate to severe painful conditions.
There is no increased toxicity as the total intakes of all the drugs are well within the recommended therapeutic doses of individual drugs.
Indications

Fixed dose combination tablet of ibuprofen 200mg, Paracetamol 325mg plus caffeine 30 mg (Ibex) is indicated for the treatment of migraine and tension type headache.
Ibex is also indicated for the treatment of painful / inflammatory conditions like rheumatoid arthritis, oesteoarthritis, cervical spondolosis, ankylosing spondylitis and other sero-negative arthropathies; soft tissue rheumatic conditions such as tendinitis, fibrosistitis, myositis, bursitis, capsulitis and low back pain; infective inflammatory conditions such as tonsillitis, pharyngitis, otitis media, pharyngitis, and inflammatory conditions in gynecology, urology and ophthalmology; soft tissue injuries such as sprains, strains, sports injuries, lacerated wounds and other accidental injuries including fracture and post operative wounds; dental inflammatory conditions such as alveolar abscesses, periodontitis, following dental extractions and maxillofacial surgeries; and dysmenorrhoea in adults.
Dosage and administration
The recommended dosage of Ibex is one to two tablet 3 times daily. The daily intake of all ingredients (ibuprofen, paracetamol and caffeine) is well within the maximum daily recommended doses. Section-V
Regulatory status in other countries
Fixed dose combinations of an NSAID, acetaminophen (paracetamol) and caffeine are in regular clinical use abroad for decades and there is no serious adverse events reported with these combinations.
Absence of untoward drug-drug interactions
No untoward drug-drug interactions or adverse clinical consequence are

observed between the components of this formulation (ibuprofen, paracetamol and caffeine).
Also, no adverse physicochemical interaction has been observed between the active components of the formulation. They are found to be physico-chemically compatible.
According to one particular embodiment, the composition according to this invention takes the form of a capsule containing 10 to 70 micro-tablets, having the following composition, expressed in mg/ per capsule, starting from the core: Paracetamol: 200 to 500, Ibuprofen: 100 to 200, Caffeine: 10 to 60, Maize Starch: 10 to 30, PVPK 30: 5 to 30, Aerosil: 1 to 10, Stearic acid: 2 to 10, HPMC E5: 5 to 30, Titanium Dioxide: 0.1 to 3, Polyethylene Glycol: 0.5 to 5, Talc: 0,5 to 5, Colors: 0 to 2
This process is not only limited to Ibuprofen, Paracetamol and Caffeine combination as tablets, pellets or Microtablets but can also include any other NSAID's like Diclofenac, Carisoprodol, chlormezanone, Tizanidine hydrochloride any muscle relaxants and neutraceuticals.
The invention will now be described in more detail on the basis of the following examples, which are only provided by way of illustrative example. The examples should not be construed to limit the scope of the invention.
EXAMPLE 1
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following

composition expressed in mg was prepared. The examples provided have a total composition of 620mg per capsule and this can be increased upto 650mg per capsule.

To achieve the foregoing objective with its purpose, the present system provides for the immediate release of the combination of active agents to an environment of use. In this process of preparing this composition the actives are swifted through 12 to 80 mesh and the excipieints are passed through 20 to 200 mesh. Any retention on the mesh is milled using suitable milling devices and the actives and excipients are swifted through a desired mesh.
After this the actives and excipients are dry blended till content uniformity is attained (10-45 minutes). The binders normally used are PVP, Starch, HPMC, HPC, Sarbutol, and Poly ethylene glycol, Gelatin or various natural gums. The suitable binder is prepared at temperature range of 30-75 degree centigrade and then dissolved in water. Then the maize starch slurry is added to the actives, suitable vessels are made use for the binder preparation.
For wet granulation the dry mixing powder is added to the binder preparation in a suitable fluid bed processor. The wet screening is done using suitable screening

methods. The whole wet mass is loaded to the fluid bed process and fluid bed dryer. The inlet temperature is maintained at a suitable temperature and dried till Loss on Drying (LOD) of less than 4% is achieved.
The dry granules are milled using suitable meshes and techniques, here a suitable granulator is used .The dry granules are blended with lubricated excipients in a suitable blender till proper lubrication and content uniformity of the actives are achieved. The lubricated granules ready for compression are compressed using 2.0mm to 4mm punches.
EXAMPLE 2
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration.
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared.

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of polyvinyl pyrolidone in water. The granules

were dried, sized, lubricated with Maize starch, Aerosil, Stearic acid and compressed to microtablets.
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 3:
Preparation, of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared.

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with Starch Paste. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets.

The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 4:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared.

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of polyvinyl pyrolidonePVPK-30 and PVPK-90 in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets.
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.

EXAMPLE 5:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared.

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of HPMC E5 in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets.
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 6:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration

A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared.

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of HPC LF 21 in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Talc, Stearic acid and compressed to microtablets
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 7:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration

A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared.

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of gelatine in water and Starch paste. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 8:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared

The pharmaceutical composition was prepared using the method described in example 1, Paracetamoljbuprofen ,Caffeine were blended with the Maize Starch and granulated with a solution of PVPK-30 and Polysorbate 80 in water. The granules were dried, sized, lubricated with Sodium starch glycollate ,Aerosil, Stearic acid and compressed to microtablets.
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 9:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution of Veegum in water. The granules were dried, sized, lubricated with Sodium starch glycollate, Aerosil, Stearic acid and compressed to microtablets
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 10:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a Maize Starch Paste. The granules were dried, sized, lubricated with Crosspovidone, Aerosil, Stearic acid and compressed to microtablets.
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 11:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a Maize starch Paste and Polysorbate 80 in water. The

granules were dried, sized, lubricated with Cross povidone, Aerosil, Stearic acid and compressed to microtablets.
The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
EXAMPLE 12:
Preparation of a Pharmaceutical Composition of Ibuprofen, Paracetamol and Caffeine Intended for Oral Administration.
A pharmaceutical composition according to the present invention in the form of dispersible Microtablets contained in a gelatin capsule having the following composition expressed in mg/ percentage was prepared

The pharmaceutical composition was prepared using the method described in example 1, Paracetamol, Ibuprofen, Caffeine were blended with the Maize Starch and granulated with a solution Acacia in water. The granules were dried, sized, lubricated with cross povidone, Aerosil, Stearic acid and compressed to microtablets.

The stability of the Paracetamol + Ibuprofen and Caffeine Microtablets obtained was evaluated by the method described in example 1. The results obtained confirm those obtained for the composition according to example 1.
The foregoing description and examples have been set forth merely to illustrate invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations falling within the scope of the appended claims and equivalents thereof.

Claims
1. A synergistic pharmaceutical composition useful in alleviating pain, said composition comprises ibuprofen of concentration ranging between 25 to 40%, paracetamol of concentration ranging between 40 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives.
2. A synergistic composition as claimed in claim 1, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%.
3. A synergistic composition as claimed in claim 1, wherein the concentration of the Ibuprofen is preferably about 32%.
4. A synergistic composition as claimed in claim 1, wherein the concentration of paracetamol is preferably about 52%.
5. A synergistic composition as claimed in claim 1, wherein the concentration of caffeine is preferably about 4.8%.

6. A synergistic composition as claimed in claim 1, wherein the composition is in a form selected from a group comprising tablet, pellet, mircotablet, capsule.
7. A synergistic composition as claimed in claim 1, wherein the caffeine is about 150% more active in the composition.
8. A synergistic composition as claimed in claim 1, wherein the paracetamol is about 100% more active in the composition.
9. A synergistic composition as claimed in claim 1, wherein the ibuprofen is about 30% more active in the composition.
10. A method of alleviating pain in a subject in need thereof, said method comprising step of administering a synergistic pharmaceutical composition useful in treating pain, said composition comprises ibuprofen of concentration ranging between 30 to 40%, paracetamol of concentration ranging between 50 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives to the subject.
11. A method of alleviating as claimed in claim 10, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration

ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%.
12. A method of alleviating as claimed in claim 10, wherein the concentration of the Ibuprofen is preferably about 32%.
13. A method of alleviating as claimed in claim 10, wherein the concentration of paracetamol is preferably about 52%.
14. A method of alleviating as claimed in claim 10, wherein the concentration of caffeine is preferably about 4.8%.
15. A method of alleviating as claimed in claim 10, wherein the administration of the composition is through oral route.
16. A method of alleviating as claimed in claim 10, wherein the composition is released immediately into bloodstream, leading to faster action.
17.A method of alleviating as claimed in claim 10, wherein the method is useful in treating rheumatoid arthritis ankylosing spondylitis, osteoarthritis, non-rheumatoid (seronegative) arthropathies, non-articular rheumatoid, periarticular conditions such as capsulitis, bursitis, tendonitis, tenosynovitis, sprains, strains, dysmenorrhoea, dental pain, post-operative pain, headache including migraine headache, infective inflammatory conditions such as tonsillitis, pharyngitis, otitis media, pharyngitis, inflammatory conditions in gynecology, urology and ophthalmology, accidental injuries including fracture, and post operative wounds.
18. A method of alleviating as claimed in claim 10, wherein the method the composition is to be administered about three times in a day.

19.A process of preparing a synergistic pharmaceutical composition in a compressed form, useful in effectively treating pain, said composition comprises ibuprofen of concentration ranging between 30 to 40%, paracetamol of concentration ranging between 50 to 60, and caffeine of concentration ranging between 2 to 10%, optionally along with pharmaceutically acceptable additives, said process comprising steps of:
a. meshing paracetamol, ibuprofen, and caffeine in the range of 12 to
80 mesh,
b. meshing additives of excipient nature in the range of 20 to 200
mesh,
c. blending the mesh of step (a) and (b) to uniformity using additive(s)
of binder nature,
d. adding maize starch slurry to the blend to obtain the synergistic
composition.
e. granulating the synergistic composition,
f. lubricating the granules using additive(s) of lubricant nature,
g. compressing the lubricated granules to obtain compressed
synergistic pharmaceutical composition useful in effectively treating
pain, and
h. optionally, filing the compressed composition into capsules.
20.A process as claimed in claim 19, wherein the additives are selected from a group comprising Maize starch of concentration ranging between 2 to 10%, Sodium Starch glycolate of concentration ranging between 0.5 to 9%, PVPK of concentration ranging between 1 to 5%, Aerosil of

concentration ranging between 0.2 to 0.4%, Stearic acid of concentration ranging between 0.3 to 0.8%, HPMC of concentration ranging between 1.5 to 3.0%, Titanium Dioxide of concentration ranging between 0.15 to 0.30%, Polyethylene Glycol of concentration ranging between 0.15 to 0.30%, Talc of concentration ranging between 0.1 to 0.2%, color of concentration ranging between 0.001-005%, gelatin of concentration ranging between 0.3 to 0.6%, polysorbate of concentration ranging between 0.3 to 0.6%, veegum of concentration ranging between 2 to 4%, crosspovidone of concentration ranging between 0.4 to 0.7%, and acacia of concentration ranging between 2 to 4%.
21. A process as claimed in claim 19, wherein the binders are selected from a group
comprising PVR, Starch, HPMC, HPC, Sarbutol, Polyethylene glycol. Gelatin,
and various natural gums.
22. A process as claimed in claim 19, wherein the binding is for the time duration
ranging between 10 to 45 minutes.
23. A process as claimed in claim 19, wherein the binder is prepared at temperature
ranging between 30 to 75°C.
24. A synergistic pharmaceutical composition substantially as herein described with
reference to the foregoing examples
25. A process of preparing a synergistic pharmaceutical composition substantially as
herein described with reference to the foregoing examples

Documents:

0421-che-2004 abstract duplicate.pdf

0421-che-2004 claims duplicate.pdf

0421-che-2004 description (complete) duplicate.pdf

421-che-2004 claims granted.pdf

421-che-2004-abstract.pdf

421-che-2004-claims.pdf

421-che-2004-correspondnece-others.pdf

421-che-2004-correspondnece-po.pdf

421-che-2004-description(complete).pdf

421-che-2004-form 1.pdf

421-che-2004-form 19.pdf

421-che-2004-form 26.pdf

421-che-2004-form 3.pdf

421-che-2004-form 5.pdf

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Patent Number

221305

Indian Patent Application Number

421/CHE/2004

PG Journal Number

37/2008

Publication Date

12-Sep-2008

Grant Date

20-Jun-2008

Date of Filing

07-May-2004

Name of Patentee

MEDREICH STERILAB LIMITED

Applicant Address

MEDREICH HOUSE, NO. 12/8, SARASWATI AMMAL STREET, M.S. NAGAR, BANGALORE 560 033,

Inventors:

#	Inventor's Name	Inventor's Address
1	RAJENDRA G. LALA	272, TEACHERS COLONY, 3RD AVENUE, 4TH MAIN, KORAMANGALA, BANGALORE,
2	C.P. BOTHRA	NO. 14, 7TH CROSS, JAIBHARATHNAGAR, BANGALORE 560 033,

PCT International Classification Number

A 61 K 9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA