WO2009118764A1

WO2009118764A1 - Pharmaceutical composition comprising diclofenac and paracetamol

Info

Publication number: WO2009118764A1
Application number: PCT/IN2009/000201
Authority: WO
Inventors: Rajesh Jain; Sukhjeet Singh
Original assignee: Panacea Biotec Limited
Priority date: 2008-03-28
Filing date: 2009-03-27
Publication date: 2009-10-01

Abstract

Compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, optionally in association with one or more pharmaceutically acceptable excipient(s) are provided whereby paracetamol and diclofenac are present in the combination in such amounts that the effect of the composition is more favorable than the added effects of the amounts of each drug separately. The present invention also provides process of preparing such compositions and methods of using them. The composition of the present invention are safe, effective and well-tolerated, and are useful for the management such as prophylaxis, amelioration and/or treatment of pain associated with or without inflammation and/or other associated disease(s)/disorder(s).

Description

PHARMACEUTICAL COMPOSITION COMPRISING DICLOFENAC AND

PARACETAMOL

FIELD OF THE INVENTION The invention relates to a composition comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, optionally in association with one or more pharmaceutically acceptable excipient(s), whereby paracetamol and diclofenac are present in the combination in such amounts that the effect of the composition is more favorable than the added effects of the amounts of each drug separately. Preferably the compositions of the present invention are designed in such a manner that alleviates or substantially minimizes any gastro-intestinal side effects toxicity associated with the therapy. The present invention also provides process of preparing such compositions and methods of using them. The composition of the present invention are safe, effective and well-tolerated, and are useful for the management such as prophylaxis, amelioration and/or treatment of pain associated with or without inflammation and/or other associated disease(s)/disorder(s).

BACKGROUND OF THE INVENTION ■ Pain is a biological function which signals the presence of injury, insult or disease within the body. Thus, one of the long-existing primary goals of medicine is the relief of pain. Relief is sought usually by the administration of analgesic drugs which increase the pain threshold. Analgesia can be induced by ways of several routes of administration that include intramuscular, subcutaneous, intravenous, oral, rectal, transdermal analgesics; continuous infusions of opioids and/or non-steroidal anti- inflammatory drugs (NSAIDs); patient-controlled administration of opioids and/or NSAIDs; and intermittent boluses and/or continuous infusion of epidural or intrathecal opioids. NSAIDs like ketoprofen, diclofenac or ketorolac are well known analgesic agents that provide pain relief. NSAIDs decrease levels of inflammatory mediators generated at the site of tissue injury. It is also necessary that drugs such as those listed above begin to release in the- body at predictable times, in order to avoid or reduce undesirable gastrointestinal side effects. Since peptic ulceration and gastrointestinal bleeding have been reported in patients receiving NSAIDs and many drugs used for management of pain, it is recommended that patients be maintained on the lowest dose possible, consistent with achieving a satisfactory therapeutic response and that the drug be administered with food, and not in a fasting state. Yet, the medical art previously lacked a dosage form for administering a NSAID or pain management drugs that provides therapy with a predictable delay. Further, it is difficult to satisfy this requirement with a single chemical entity, as a potent analgesic will normally cause concomitant side-effects, whereas a drug that gives rise to few or no side-effects will also generally be a less effective analgesic. Almost all analgesic drugs induce reactions other than the relief of pain. Some of these reactions are e.g. gastrointestinal disorders, dizziness, constipation, nausea, and vomiting. Thus when using analgesics in man, considerations other than achieving the primary effect (analgesia) must be borne in mind, so that novel drugs are sought which have the maximum analgesic effect accompanied by a minimum of side-reactions. There is therefore a continual search for a combination of drugs which will enable the total amount of drug to be reduced and which can be administered in such proportions that maximum analgesic effect can be produced with little or no side-effects. What is sought is, on the one hand, a potentiation of the therapeutic, i.e. analgesic, effect and, on the other, a reduction of undesirable side-effects. More active analgesic combinations are in constant demand because they offer the attractive possibility of relieving pain with reduced dosages thereby diminishing the expected side effects and toxicity that would result from the otherwise required higher dosages.

Cyclooxygenase (COX) is an enzyme that is responsible for formation of important biological mediators called prostanoids (including prostaglandins, prostacyclin and thromboxane). Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain; this is the method of action of well-known drugs such as aspirin, diclofenac and ibuprofen. Diclofenac is a Nonsteroidal anti- inflammatory drug (NSAID) which provides anti-inflammatory, analgesic, and antipyretic activity in humans. The primary mechanism responsible for its anti- inflammatory, antipyretic, analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). Diclofenac is approved in the United States for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is also considered to be useful for the short-term treatment of acute musculoskeletal injury, acute painful shoulder, postoperative pain and dysmenorrhea. A delayed release formulation of diclofenac, Voltaren™, has been developed and utilizes diclofenac sodium salt in an enteric coated tablet which acts to resist the release of diclofenac in the low pH of gastric fluid. Diclofenac sodium is useful for short-term treatment of acute musculoskeletal injury, acute painful shoulder, and postoperative pain. It is safe, tolerable, and effective for the relief of postoperative pain. Diclofenac also has shown to be highly effective and safe in pediatric population as postoperative analgesic. Diclofenac is associated with low incidence of gastrointestinal adverse effects.

Paracetamol or acetaminophen is the active metabolite of phenacetin, a so-called coal tar analgesic. It has analgesic and antipyretic properties. It is well tolerated, available over-the-counter, so it is commonly used for the relief of fever, headaches, and other minor aches and pains. Acetaminophen is a viable alternative to the NSAIDs, especially because of the low incidence of adverse effects, and should be the preferred choice in high-risk patients. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of additional NSAIDs or opioid analgesics to be used, thereby minimizing overall side-effects. It is considered safe for human use at recommended doses; however, acute overdose can cause fatal liver damage, and the number of accidental self-poisonings and suicides has grown in recent years. Paracetamol reduces the production of prostaglandins, pro-inflammatory chemicals the production of which is also inhibited by aspirin, but, unlike aspirin, paracetamol does not have much anti-inflammatory action. Paracetamol is a weak inhibitor of PG synthesis of COX-I and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 μmol/L). When the levels- of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-I and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. The addition of acetaminophen to NSAIDs may confer additional analgesia compared to acetaminophen alone.

South African Patent no. ZA79/6821 describes a pharmaceutical composition comprising as a primary agent a compound selected from diclophenac, sulindac, fenbufen, naproxen, ketoprofen, indoprofen and fenprofen, in combination with a potentiating agent which is paracetamol. South African Patent No. ZA8903422A describes a pharmaceutical composition comprising as active ingredients therapeutically effective amounts of an anti-inflammatory agent selected from diclophenac, sulindac, indomethacin, naproxen, piroxicam, ketoprofen, and tiaprofenic acid, and pharmaceutically acceptable salts thereof, and the analgesics paracetamol and codeine. Chinese patent no. CNl 104495 describes a composite diclofenac sodium injection which comprises diclofenac sodium and paracetamol as major medicine, antioxidant, and solvent, and is prepared through dissolving auxiliary materials and major medicine, regulating pH value, filtering, bottling and sterilizing. US patent no. 4234601 describes improved method of producing analgesia made possible by the discovery that a potentiation of analgesic or antinociceptive properties of 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid (Diclofenac) or its salt is produced by administration with acetaminophen in specific proportions. US Patent no. 4464376 describes analgesic and anti-inflammatory compositions which comprise caffeine together with a selected non-narcotic/non-steroidal anti-inflammatory drug (NSAID) or a selected narcotic analgesic or both. This patent discloses that the analgesic effect of the combination of a selected NSAID and a selected narcotic analgesic is greater than for either alone which analgesic effect is further enhanced by the addition of caffeine. US patent no. 4690927 describes a combination of the NSAID diclofenac and codeine in a weight ratio of diclofenac to codeine of about 1 : 1 to about 3:1. US patent no. 4948581 describes a long acting diclofenac formulation where the formulation has a rapidly dissolving component providing quick pharmaceutical action and an enteric component providing a delayed pharmaceutical action. The said patent however does not mention combination dosage form of diclofenac with paracetamol. European patent no. EPOO 12621 describes a pharmaceutical composition suitable for reducing pain, in dosage unit form, comprising diclofenac, sulindac, fenbufin, naproxen, ketoprofen, indoprofen, fenoprofen, or a salt thereof together with acetaminophen. Ukrainian Patent application no. UA24839U describes anti-inflammatory and antirheumatic drug that contains paracetamol, natrium diclofenac and additive. PCT publication no. WO9966919 describes pharmaceutical composition comprising an alkali or alkaline- earth metal salt of acetaminophen and at least one other active ingredient selected from the group consisting of analgesics, decongestants, expectorants, antitussives, antihistamines, gastrointestinal agents, diurectics, bronchodilators and mixtures thereof. PCT publication no. WO2001093680 describes conjugates of a combination of pharmacologically active agents (e.g., NSAIDs and selective COX-2 inhibitors). US patent no. 6558701 describes multilayer tablet containing the active substances Tramadol and Diclofenac and/or their in each case physiologically compatible salts, with the active substances being separated from one another by a separating layer. US patent no. 6929805 describes medicinal preparations which can be administered orally and contain a fixed combination of at least one locally acting analgesic with a rapid onset of action and at least one systemically acting analgesic with a sustained action.

No single analgesic agent is perfect and no single analgesic can treat all types of pain. Yet each agent has distinct advantages and disadvantages compared to the others. Hence, clinical outcomes might be improved under certain conditions with the use of a combination of analgesics, rather than reliance on a single agent. A combination is most effective when the individual agents act through different analgesic mechanisms and act synergistically. By activating multiple pain-inhibitory pathways, combination analgesics can provide more effective pain relief for a broader spectrum of pain, and might also reduce adverse drug reactions. Further, if an NSAID is necessary, it should be used at the lowest effective dose and for the shortest time possible to minimize the risk of adverse effects. For persistent pain with or without inflammation, adding of NSAID such as diclofenac to regular paracetamol can help to control intermittent pain, while minimizing the adverse side effects. The combination of paracetamol with diclofenac may thus help reduce the doses of NSAIDs without compromising the analgesic efficacy, and at the same time increasing the gastrointestinal tolerability. The addition of paracetamol to diclofenac may confer additional analgesia compared to paracetamol alone.

Although several prior art literature is available on combination of drugs having analgesic properties; there still exists a need for an improved and safer form of administration of drugs for pain management associated with or without inflammation. Also there is a need to provide pharmaceutical compositions comprising NSAID which eliminates or reduces the gastrointestinal side effects and is thereby not deleterious to the stomach. The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to alleviate the drawbacks existing in present art to develop dosage form compositions comprising a combination of diclofenac and paracetamol which possess increased gastrointestinal tolerability without compromising particularly the analgesic efficacy, by using different polymers alongwith other suitable excipients thus demonstrating a significant advancement over the prior art.

SUMMARY OF INVENTION

It is the objective of the present invention to provide a pharmaceutical composition comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, optionally in association with one or more pharmaceutically acceptable excipient(s), wherein the said active agents are present in the combination in such amounts that the effect of the composition is more favorable than the added effects of the amounts of each drug separately.

It is the objective of the present invention to provide compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof which possess increased gastrointestinal tolerability without compromising the efficacy, and are thereby safe and useful for pain management associated with or without inflammation and/or other associated disease(s)/disorder(s).

It is an objective of the present invention to provide bilayered pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the first layer comprises paracetamol optionally alongwith one or more pharmaceutically acceptable excipient(s), and the second layer comprises diclofenac and at least one delayed release (enteric) polymer(s) optionally alongwith one or more pharmaceutically acceptable excipient(s) characterized in that paracetamol is released almost immediately upon administration followed by a sustained or delayed release of diclofenac.

It is an objective of the present invention to provide pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises a core containing diclofenac alongwith a release rate controlling polymer(s) or an enteric material optionally alongwith one or more pharmaceutically acceptable excipient(s), and a coating comprising of paracetamol alongwith at least one film forming polymer optionally alongwith one or more pharmaceutically acceptable excipient(s).

It is an objective of the present invention to provide pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises a first layer containing diclofenac which is in the form of a compressed tablet surrounded by a second layer containing paracetamol which is compressed on to the first layer, and a third layer which is in the form of a coating such as film coating or sugar coating over the second layer and which comprises at least one coating material optionally alongwith diclofenac or paracetamol or a combination thereof.

In accordance with the present invention, the term "bilayered pharmaceutical composition" as used herein refers to a composition wherein the dosage form has two layers wherein one layer is exactly adjacent to the next layer and completely surrounded by the next layer. For example, a bilayered coated tablet-in-tablet dosage form according to the present invention comprises a first layer which is in the form of a compressed tablet surrounded by a second layer which is compressed on to the first layer, and a third layer which is in the form of a coating such as film coating or sugar coating over the second layer. Similarly the term "multilayered" refers to a composition comprising at least three or more layers. In accordance with the present invention, a layer is one which is compressed or in the form of a coat.

It is also an objective of the present invention to provide a dosage form composition which comprises diclofenac in two distinct fractions, in combination with an immediate release fraction of paracetamol, wherein the said dosage form provides an immediate release of diclofenac from the first fraction; a sustained or delayed release of diclofenac from the second fraction; and wherein the said dosage form composition provides relief from pain associated with or without inflammation and/or other associated disease(s)/disorder(s) for an extended period of time.

It is a preferred objective of the present invention to provide a dosage form composition comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises a first layer containing diclofenac which is in the form of a compressed tablet optionally surrounded by a barrier layer containing pharmaceutical acceptable excipients; an enteric coating optionally followed by a film coating which releases diclofenac in the upper part of the intestine; a second layer containing paracetamol which is compressed on to the first layer which releases paracetamol in the stomach, and optionally a third layer which is in the form of a coating such as film coating or sugar coating over the second layer.

It is another preferred objective of the present invention to provide a dosage form composition comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises a first layer containing diclofenac which is in the form of a compressed tablet optionally surrounded by a barrier layer containing pharmaceutical acceptable excipients; an enteric coating optionally followed by a film coating which releases diclofenac in the upper part of the intestine; a second layer containing paracetamol which is compressed on to the first layer, which releases paracetamol in the stomach and optionally a third layer which is in the form of a coating such as film coating or sugar coating over the second layer and which comprises at least one coating material optionally alongwith diclofenac or paracetamol or a combination thereof.

It is yet another objective of the present invention to provide process for preparation of such pharmaceutical compositions comprising diclofenac and paracetamol.

It is still another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition. The compositions of the present invention comprising paracetamol and a NSAID provide effective prophylactic or therapeutic concentrations of the NSAID analgesic active agent(s) for extended periods of time.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, optionally in association with one or more pharmaceutically acceptable excipient(s), wherein the said active agents are present in the combination in such amounts that the effect of the composition is more favorable than the added effects of the amounts of each drug separately. Preferably diclofenac is in the form of diclofenac sodium, diclofenac potassium, diclofenac calcium or diclofenac magnesium. More preferably diclofenac is in the form of diclofenac sodium. It might be appreciated that the active agent diclofenac and paracetamol wherever appears in the patent specification also covers their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives unless otherwise mentioned.

In an embodiment, the present invention provides bilayered pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the first layer comprises paracetamol optionally alongwith one or more pharmaceutically acceptable excipient(s), and the second layer comprises diclofenac and at least one delayed release polymer(s) optionally alongwith one or more pharmaceutically acceptable excipient(s) characterized in that paracetamol is released almost immediately upon administration followed by a sustained or delayed release of diclofenac.

In accordance with the present invention, the term "bilayered analgesic pharmaceutical composition" as used herein refers to a composition wherein the dosage form has two layers wherein one layer is exactly adjacent to the next layer and completely surrounded by the next layer. For example, a bilayered coated tablet-in-tablet dosage form according to the present invention comprises a first layer which is in the form of a compressed tablet surrounded by a second layer which is compressed on to the first layer, and a third layer which is in the form of a coating such as film coating or sugar coating over the second layer. Similarly the term "multilayered" refers to a composition comprising at least three or more layers. In accordance with the present invention, a layer is one which is compressed or in the form of a coat.

In an embodiment, the present invention provides pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises a core containing diclofenac alongwith a release rate controlling polymer or an enteric material optionally alongwith one or more pharmaceutically acceptable excipient(s), and a coating comprising of paracetamol alongwith at least one film forming polymer optionally alongwith one or more pharmaceutically acceptable excipient(s).

In another embodiment, the present invention provides pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises a first layer containing diclofenac which is in the form of a compressed tablet surrounded by a second layer containing paracetamol which is compressed on to the first layer, and a third layer which is in the form of a coating such as film coating or sugar coating over the second layer and which comprises at least one coating material optionally alongwith diclofenac or paracetamol or a combination thereof.

In an embodiment, the bilayered analgesic pharmaceutical compositions according to the present invention are prepared in such a manner as to affect an immediate release of the first pulse of paracetamol or its pharmaceutically acceptable salt followed by a delayed release of diclofenac or its pharmaceutically acceptable salt. The pharmaceutical compositions of the present invention provide a less frequent dosing of the medicament as is required by only a delayed release dosage form of diclofenac, and increases the resultant patient regime compliance. The compositions of the present invention can be made for twice-a-day or thrice-a-day administration. Further, such a formulation is simple to make and the manufacturing process is reproducible. The compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof possess increased gastrointestinal tolerability without compromising the efficacy, and are thereby safe and useful for pain management associated with or without inflammation and/or other associated disease(s)/disorder(s). The compositions according to the present invention provide on the one hand, a potentiation of the therapeutic, such as analgesic effect and;, on the other, a reduction of undesirable side-effects.

In an embodiment, the present invention provides a dosage form composition which comprises diclofenac in two distinct fractions, in combination with an immediate release fraction of paracetamol, wherein the said dosage form provides an immediate release of diclofenac from the first fraction; a sustained or delayed release of diclofenac

^■ from the second fraction; and wherein the said dosage form composition provides relief from pain associated with or without inflammation and/or other associated disease(s)/disorder(s) for an extended period of time.

In one of the preferred embodiments, the present invention provides dosage form compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises (a) a first layer containing diclofenac which is in the form of a compressed tablet; an enteric coating which releases diclofenac in the upper part of the intestine; (b) a second layer containing paracetamol which is compressed on to the first layer which releases paracetamol in the stomach, and optionally a third layer which is in the form of a coating such as film coating or sugar coating over the second layer; and wherein the said active agents are present in the combination in such amounts that the effect of the composition is more favorable than the added effects of the amounts of each drug separately alongwith increased gastrointestinal tolerability without compromising the analgesic efficacy.

In one of the preferred embodiments, the present invention provides dosage form compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, wherein the said composition comprises (a) a first layer containing diclofenac which is in the form of a compressed tablet; an enteric coating which releases diclofenac in the upper part of the intestine; (b) a second layer containing paracetamol which is compressed on to the first layer, which releases paracetamol in the stomach and optionally a third layer which is in the form of a coating such as film coating or sugar coating over the second layer; and which comprises at least one coating material optionally alongwith diclofenac or paracetamol or a combination thereof.

In one of the embodiments, the first layer containing diclofenac in the form of a compressed tablet is optionally surrounded by a barrier layer containing pharmaceutical acceptable excipients and the enteric coating is optionally followed by a film, coating.

In an embodiment, the release of the active agent from the compositions of the present invention is predominantly by erosion mechanism or combination of erosion and diffusion mechanisms. Particularly the release of paracetamol which is formulated for immediate release is predominantly by rapid disintegration of the composition comprising paracetamol. The release of diclofenac is predominantly by erosion mechanism, diffusion mechanism or combination of erosion and diffusion mechanisms.

In an embodiment of the present invention, the composition is in the form of a tablet comprising an inner core tablet which is enteric coated so as to delay the release and thus releasing the drug diclofenac particularly in the intestinal region of the GlT. Alternatively the diclofenac is present as granules which are enteric coated. The said granules may be compressed or compacted to form the layer containing diclofenac. The enteric coating applied to the core tablet is formed from a coating composition comprising a major proportion of a methacrylic acid-methyl rαethacrylate copolymer, a glycerin fatty acid ester mainly as a plasticizer, and talc mainly as an anti-adhesion agent Any other additives including coloring agents, flavors and extenders may be added if desired. Suitable coating materials according to the present invention comprise one or more agents selected from but not limited to enteric polymer /film former such as Eudragit® L-100, Eudragit® L-100 55, Eudragit® SlOO, Eudragit® L30D 55; plasticizer such as Methyl citrate, propylene glycol; anti-adherants/lubricants such as colloidal silicon dioxide, talc; and solvents such as isopropyl alcohol, dichloromethane, purified water, and the like or mixtures thereof. In a further embodiment, a second layer containing paracetamol alongwith one or more pharmaceutical excipient(s) is compressed on to the enteric-coated tablet containing diclofenac to prepare a bilayered tablet (tablet-in-tablet).

In a further embodiment, a film coating is applied on the bilayered tablet according to the present invention which may be a protective seal coat which is applied by means of a conventional sugar or polymeric film coating solution. For example, a composition of Opadry® Yellow and sodium chloride (90%- 10% to 10%-90%) which is applied from a water based system may be used to coat the tablets of the invention. Opadry® yellow contains hydroxypropylmethyl cellulose; titanium dioxide; polyethylene glycol 4000; polysorbate 80; D&C yellow No.10 aluminum lake; and FD&C red #40 aluminum lake. These coatings may also contain a minor amount e.g. 2-5% of a water swellable polymer such as hydroxypropylmethyl cellulose or a polyethylene oxide polymer having a molecular weight of 200,000 to 1,000,000 (wt.av.). Other Opadry® coating products such as Opadry® Clear or Opadry® with various pigment lakes may also be used in the invention to change the appearance of the tablets. Tabcoat® TC as an alternative can be used as film coating agent. Other aqueous film-forming polymers may also be employed in place of hydroxypropyl methylcellulose. These coatings may be applied in the form of a suspension by using a perforated coating pan.

In another embodiment of the present invention, the composition of the present invention is formulated as tablets/minitablets filled into a capsule. For example, in one embodiment the capsule comprises one tablet containing paracetamol in an immediate release form and one tablet containing diclofenac in a delayed or sustained release form. In another embodiment, the capsule comprises bilayered minitablets wherein the innermost layer contains diclofenac in a delayed or sustained release form and the outer layer comprises paracetamol in an immediate release form.

In another embodiment, the release rate controlling polymers of the present invention comprises a polymeric material selected from but not limited to the group comprising pH dependent polymers; pH independent polymers; swellable polymers; non-swellable polymers; hydrophilic polymers; hydrophobic polymers and/or one or more other hydrophobic materials; ionic polymers such as sodium alginate, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose; non-ionic polymers' 'luέh.% ' hydroxypropyl methylcellulose; synthetic or natural polysaccharide selected from the group comprising alkylcelluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch and starch derivative, and mixtures thereof. The polymeric material used in the present invention is selected from but not limited to a group comprising cellulosic polymer, methacrylate polymer, methacrylate copolymer such as Eudragit® EPO, Eudragit® ElOO, Eudragit® E12,5 and the like or mixtures thereof, Polyvinylpyrollidone (PVP), alginate, polyvinylpyrrolidone-polyvinyl acetate (PVP-PVA) copolymer, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(alkyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(alkyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(alkylene), poly(alkylene oxide), poly(alkylene terephthalate), poly( vinyl isobutyl ether), poly( vinyl acetate), poly(vinyl chloride) and polyurethane or a mixture thereof used either alone or in combination thereof. In a further embodiment, the dosage form composition additionally comprises a gum selected from but not limited to a group comprising xanthan gum, guar gum, gum arabic, carrageenan gum, karaya gum, locust bean gum, acacia gum, tragacanth gum, agar and the like or mixtures thereof.

In an embodiment, the enteric polymer used to make the delayed release fraction comprising diclofenac is preferably a polyacrylate or a polymethacrylate such as Eudragit® L-IOO, Eudragit® L-IOO 55, Eudragit® SlOO, Eudragit® LlOO, Eudragit® L30D 55, and the like or mixtures thereof.

In a further embodiment, the release rate controlling polymers for formulating diclofenac into a sustained release form according to the present invention is preferably selected from but not limited to a group comprising carbopol; cellulosic polymers such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose; copolymers of methyl vinyl ether and maleic anhydride such as Gantrez®; enteric polymers; sodium hyaluronate; gums; alginates; polycarbophil; polyvinyl pyrrolidone, mixture of polyvinyl pyrrolidone and polyvinyl alcohol^' polyethylene oxide; starch; dextran; chitosan; and the like or mixtures thereof. In an embodiment of the present invention, the pH independent polymer is selected from but not limited to a group comprising alkyl celluloses such as methyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxypropyl methyl cellulose (HPMC, Methocel®), hydroxy alkyl celluloses such as hydroxypropyl cellulose (HPC, Klucel®) and hydroxy ethyl cellulose (HEC, Natrosol®), polyethylene glycols (PEG®, Lutrol®), copolymers of ethylene oxide with propylene oxide (Poloxamer®), gelatin, polyvinylpyrrolidones (PVP, Kollidon®), vinylpyrrolidones, vinyl acetates, polyvinylimidazoles, polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long-chained alpha. -olefins, copolymers of vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl methacrylates), copolymers of vinylpyrrolidone/dimethylaminopropyl methacrylamides, copolymers of vinylpyrrolidone/ dimethylarninopropyl acrylamides, quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates, terpolymers of vinylcaprolactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride, terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polycarboxylic acids, polyacrylamides, polyvinyl alcohols (PVA, Mowiol®), optionally hydrolysed polyvinyl acetate, copolymers of ethyl acrylate with methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide gums, both natural and modified (semi-synthetic), including but not limited to xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, alginic acid, other alginates (e.g. sodium alginate, propyleneglycol alginate), benitonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, and the like, or mixtures thereof.

In another preferred embodiment, the pharmaceutical compositions deliver diclofenac in two substantially distinct pulses, wherein one pulse is released in vivo almost immediately after ingestion and a second pulse is released after a gap of at least 3 hours, preferably after 5 hours. The total daily dose of diclofenac is therefore divided into two fractions for release separately so as to avoid a high concentration of the active agent at any given point of time which can synergize or potentiate or add to the effect of paracetamol. In an embodiment, the dosage form compositions according to the present invention are designed in the following manner: i) A coating or a compressed layer of paracetamol (upon the layer of diclofenac) that is released almost immediately (first pulse) after the tablet is exposed to medium either in-vivo or vitro, and wherein the diclofenac is release almost immediately in the intestinal region of the GIT, ii) A layer of diclofenac sodium beneath the coating or compressed layer (containing paracetamol in the immediate release form) that provides a sustained release of diclofenac for an extended period of time, or iii) An inner tablet of diclofenac sodium that disintegrates to provide an immediate release of the drug (second pulse) once the sustained release layer of diclofenac sodium has been substantially eroded allowing the passage of in vivo fluids, wherein the paracetamol is present as immediate release multiparticulates (granules) in the layer containing diclofenac in a sustained release form or the paracetamol is present in a separate outermost layer which is released almost immediately upon administration of the dosage form

In an embodiment according to the present invention, the composition comprises an inner core (one layer) containing one part of paracetamol in a fast release form on which a sustained release layer is formulated comprising diclofenac alongwith a hydrophilic swelling polymer such as hydroxypropyl methylcellulose (HPMC) as the release rate controlling polymer (second layer). On the second layer is provided a third layer which comprises another part of paracetamol in a fast release form. When the said composition is exposed to aqueous fluids in vivo, first the uppermost layer containing paracetamol disintegrates to release a first pulse of the said drug. Subsequently the aqueous fluids contact the second sustained release layer containing diclofenac whereupon the release rate controlling polymer in the said second layer swells forming a gel or a gel-like mass which prevents the entry of the fluid into the inner tablet (first layer) for at least 3-5 hours. Subsequently the said gel or gel-like mass erodes gradually thus leading to the contact of the in vivo fluids with the inner layer (first layer) and its disintegration to release the second pulse of paracetamol.

In an embodiment, the composition of the present invention comprises one or more pharmaceutically acceptable excipient(s) selected from but not limited to a group comprising diluents; disintegrants; binders; fillers; bulking agent; organic acid(s); colorants; stabilizers; preservatives; lubricants; glidants; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents such as glycerine, various grades of polyethylene oxides, transcutol and glycofurol; tonicity adjusting agents; local anesthetics; pH adjusting agents; antioxidants; osmotic agents; chelating agents; viscosifying agents; acids; sugar alcohol; reducing sugars; non-reducing sugars and the like used either alone or in combination thereof. Certain excipients used in the present composition can serve more than one purpose. Suitable binders include for example starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, pregelatinised starch, hydroxypropylcellulose, or mixtures thereof. The disintegrants useful in the present invention include but not limited to a group comprising croscarmellose sodium (e.g. Primellose®), sodium starch glycollate, cross-linked sodium carboxymethyl cellulose (e.g. Ac-di-sol®), Solutab®, Vivasol®, starches, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, clays, alginates, gums and the like used either alone or in combination thereof. The diluents or fillers useful in the present invention are selected from but not limited to a group comprising lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate, calcium lactate, dextrose, dextran, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, cellulose powder, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, glycine, or bentonites, and the like, or mixtures thereof. The lubricants useful in the present invention are selected from but not limited to a group comprising talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, waxes and the like used either alone or in combination thereof. The anti-adherents or glidants are selected from but not limited to a group comprising talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, colloidal silicon dioxide, and the like, or mixtures thereof. In an embodiment of the present invention, the composition may additionally comprise a conventionally known antioxidant such as ascorbyl palmirate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate, α-tocopherol, and the like or mixtures thereof. In another embodiment, the dosage form of the present invention additionally comprises at least one surfactant selected from a group comprising anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants or mixtures thereof.

In a further embodiment, the composition of the present invention is preferably formulated as a solid dosage form such as layered tablets (coated or uncoated), bilayer tablets, tablet in tablet, or layered minitablets (coated or uncoated) filled into capsules. The tablets can be prepared by either wet granulation, direct compression, or by dry compression (slugging). The granulation technique is either aqueous or non-aqueous. The non-aqueous solvent used is selected from a group comprising acetone, ethanol, isopropyl alcohol or methylene chloride. In an embodiment, the compositions of the present invention are in the form of compressed tablets, moulded tablets, mini-tablets, compacts, pellets, granules or the like.

In another embodiment, the present invention provides process for preparation of such pharmaceutical compositions according to the present invention comprising diclofenac and paracetamol. La a further embodiment of the present invention is provided a process for the preparation of such bilayered pharmaceutical compositions according to the present invention.

In another embodiment, the preparation of such composition comprises the following steps: i) treating diclofenac alongwith one or more pharmaceutically acceptable ' excipient(s), ii) compressing the material of step (i) into tablet, iii) coating the tablet of step (ii) with at least one enteric polymer(s) optionally with one or more pharmaceutically acceptable excipient(s), iv) treating paracetamol with one or more pharmaceutically acceptable excipient(s), v) compressing the material of step (iv) on to the tablet of step (iii) to obtain a bilayered tablet, and vi) optionally film coating or sugar coating the tablet obtained in step (v). In another embodiment, the preparation of such composition comprises the following steps: i) treating diclofenac with at least one release rate controlling polymer(s) optionally alongwith one or more pharmaceutically acceptable excipient(s), ii) compressing the material of step (i) into tablet, iii) treating paracetamol with one or more pharmaceutically acceptable excipient(s), iv) compressing the material of step (iii) on to the tablet of step (ii) to obtain a bilayered tablet, and v) optionally film coating or sugar coating the tablet obtained in step (iv).

In still another embodiment, the preparation of such composition comprises the following steps: i) treating one part of paracetamol with one or more pharmaceutically acceptable excipient(s) and compressing it into a tablet, ii) treating diclofenac with an enteric polymer and/or a release rate controlling polymer alongwith one or more pharmaceutically acceptable excipient(s), iii) compressing the material of step (ii) on to the tablet of step (i) to obtain a bilayered tablet, iv) treating the other part of paracetamol with one or more pharmaceutically acceptable excipient(s) and compressing it on to the tablet of step (iii) to obtain a trilayered tablet, and v) optionally film coating or sugar coating the tablet obtained in step (iv).

In still another embodiment, the preparation of such composition comprises the following steps: i) treating diclofenac with one or more pharmaceutically acceptable excipient(s) and compressing it into a tablet, ii) coating diclofenac tablet in step (i) with one or more pharmaceutically acceptable excipient(s), iii) coating diclofenac tablet in step (ii) with enteric polymer(s), iv) treating paracetamol with one or more pharmaceutically acceptable excipient(s) and compressing it on to the tablet of step (iii) to obtain a tablet in tablet, and v) optionally film coating or sugar coating the tablet obtained in step (iv). In yet another embodiment of the present invention is provided a method of using such composition according to the present invention which comprises administering to a subject in need thereof an effective amount of the composition. The compositions of the present invention comprising paracetamol and a NSAID particularly diclofenac provide effective prophylactic or therapeutic concentrations of the NSAID analgesic active agent(s) for extended periods of time.

In still another embodiment of the present invention is provided a use of the dosage form composition comprising diclofenac and paracetamol for the preparation of a medicament for treating pain associated with inflammation or without inflammation and/or other associated disease(s)/disorder(s).

In a further embodiment of the present invention, is provided an use of the dosage form, for the management of one or more disease(s)/disorder(s) which includes prophylaxis, amelioration and/or treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, acute musculoskeletal injury, acute painful shoulder, postoperative pain, dysmenorrhea, relief of fever, headaches, and other aches and pains.

The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention in any manner whatsoever.

Example-1:

Part A: Diclofenac sodium (Delayed release)

S. No . Ingredient Quantity (mg)

Core tablet composition

1. Diclofenac sodium (equivalent to diclofenac) 25

2. Microcrystalline cellulose 25

3. Lactose 31.73

4. Povidone K-30 1.47

5. Purified water q.s. (lost in processing)

6. Croscarmellose sodium 4.5

7. Talc 0.85

8. Magnesium stearate 0.85 9. Sodium lauryl sulfate 0.6 Barrier coating composition

10. . Hydroxypropyl methylcellulose ^PMC E-lS) . 1.4

11. Triethyl citrate 0.4

12. Purified water q.s. (lost in processing) Enteric coating composition

13. Methacrylic Acid Copolymer Dispersion 10.32 (Eudragit® L30D 55)

14. Triethyl citrate 3.1

15. Talc 2.95

16. Simethicone emulsion (30%) 0.03

17. Purified water q.s. (lost in processing)

Outer film coating composition

18. Tabcoat® TC 3.1

19. Purified water q.s. (lost in processing)

Part B: Paracetamol (Immediate release)

S. No. Ingredient Quantity (mg)

1. Paracetamol 500

2. Pregelatinized starch 283.74

3. Lactose 309.6

4. Microcrystalline cellulose 34

5. Maize starch 24

6. ,, Sodium methylparaben 0.6

7. Sodium propylparaben 0.06

8. Purified water q.s. (lost in processing)

9. Talc 24

10. Stearic acid 18

11. - Colloidal silicon dioxide 6

Procedure:

Preparation of Diclofenac sodium delayed release tablet (Part A) i)- Diclofenac sodium, microcrystalline cellulose and lactose were sifted with a sieve of mesh size 40. ii). The material of step (i) was mixed for 10 minutes. iii). Povidone (K-30) was dissolved in Purified water with continuous stirring to form a clear solution using a mechanical stirrer. iv). The binder of step (iii) was mixed with the mass of step (ii) to form the granules. v). The granules of step (iv) were dried. vi). Croscaraiellose sodium, talc, magnesium stearate and sodium lauryl sulphate were sifted together with sieve of mesh size 60 followed by blending of the material. vii). The blend of step (vi) was compressed into tablets. Preparation of Barrier coating solution: viii). Hydroxypropyl methylcellulose was dissolved in purified water to form a uniform solution followed by addition of triethyl citrate with constant stirring. ix). The tablets of step (vii) were coated with the coating solution of step (viii). Preparation of Enteric coating dispersion: x). Talc was dispersed in Purified water by stirring it with the help of mechanical stirrer. Triethyl citrate was added into the abovesaid dispersion with continuous stirring. Methacrylic acid copolymer dispersion and Simethicone were added into the abovesaid material with uniform mixing using a mechanical stirrer for 40-45 minutes. The coating dispersion was filtered through sieve of mesh size 80. xi). The tablets of step (ix) were coated with the coating solution of step (x). Preparation of Film coating dispersion: xii). Tabcoat TC was added in Purified water and stirred for 45 minutes without incurring flotation to form uniform slurry followed by reducing the stirrer speed to eliminate vortex formation. xiii). The tablets of step (xi) were coated with the coating solution of step (xii). Preparation of Paracetamol immediate release tablet (Part B) xiv). Paracetamol, pregelatinized starch, lactose and microcrystalline cellulose were sifted together, xv). Maize starch was sifted with sieve of mesh size 40. xvi). The material of step (xiv) was mixed for 10 minutes. xvii). Maize starch of step (xv) was dispersed in purified water followed by addition of sodium methylparaben and sodium propylparaben with constant stirring, xviii). The binder material of step (xvii) was mixed with the material of step (xvi) for 3-5 minutes to obtain granules, xix). The granules of step (xviii) were dried and passed through sifter cum multimill. xx). Talc, stearic acid and colloidal silicon dioxide were sifted together through sieve of mesh size 60. xxi). The dried granules of step (xix) and (xx) were blended together for 8-10 minutes, xxii). Compress the blend of step (xxi) into tablet in tablet in such a way that each tablet contains one diclofenac sodium enteric coated tablet 25mg surrounded by layer of paracetamol.

ExampIe-2:

Part A: Diclofenac sodium (Delayed release)

S. No. Ingredient Quantity (mg)

Con i tablet composition

1. Diclofenac sodium (equivalent to diclofenac) 50

2. Microcrystalline cellulose 4.5

3. Lactose 27.23

4. Povidone K-30 1.47

5. Purified water q.s. (lost in processing)

6. Croscarmellose sodium 4.5

7. Talc 0.85

8. Magnesium stearate 0.85

9. Sodium lauryl sulfate 0.6

Barrier coating composition

10. Hydroxypropyl methylcellulose (HPMC E-15) 1.4

11. Triethyl citrate 0.4

12. •Purified water q.s. (lost in processing) Enteric coating composition

13. Methacrylic Acid Copolymer Dispersion 10.32 (Eudragit® L30D 55)

14. Triethyl citrate 3.1

15. Talc 2.95

16. Simethicone emulsion (30%) 0.03

17. Purified water q.s. (lost in processing)

Outer film coating composition

18. Tabcoat® TC 3.1

19. Purified water q.s. (lost in processing)

Part B: Paracetamol (Immediate release) S. No. Ingredient Quantity (mg)

1. Paracetamol 500

22.. PPrreeggeellaattiinniizzeedd ssttaarrcchh 283.74

3. Lactose 309.6

4. Microcrystalline cellulose 34

5. Maize starch 24

6. Sodium methylparaben 0.6

77.. SSooddiiuumm pprrooppyyllppaarraabbeenn 0.06

8. Purified water q.s. (lost in processing)

9. Talc 24

10. Stearic acid 18

11. Colloidal silicon dioxide 6

Procedure:

Preparation of Diclofenac sodium delayed release tablet (Part A) i). Diclofenac sodium, microcrystalline cellulose and lactose were sifted with a sieve of mesh size 40. ii). The material of step (i) was mixed for 10 minutes. in). Povidone (K-30) was dissolved in Purified water with continuous stirring to form a clear solution using a mechanical stirrer. iv). The binder of step (iii) was mixed with the mass of step (ii) to form the granules. v). The granules of step (iv) were dried. vi). Croscarmellose sodium, talc, magnesium stearate and sodium lauryl sulphate were sifted together with sieve of mesh size 60 followed by blending of the material. vii). The blend of step (vi) was compressed into tablets. Preparation of Barrier coating solution: viii). Hydroxypropyl methylcellulose was dissolved in purified water to form a uniform solution followed by addition of triethyl citrate with constant stirring. ix). The tablets of step (vii) were coated with the coating solution of step (viii). Preparation of Enteric coating dispersion: x). Talc was dispersed in Purified water by stirring it with the help of mechanical stirrer. Triethyl citrate was added into the abovesaid dispersion with continuous stirring. Methacrylic acid copolymer dispersion and Simethicone were added into the abovesaid material with uniform mixing using a mechanical stirrer for 40-45 minutes. The coating dispersion was filtered through sieve of mesh size 80. xi). The tablets of step (ix) were coated with the coating solution of step (x). Preparation of Film coating dispersion: xii). Tabcoat TC was added in Purified water and stirred for 45 minutes without incurring flotation to form uniform slurry followed by reducing the stirrer speed to eliminate vortex formation, xiii). The tablets of step (xi) were coated with the coating solution of step (xii).

Preparation of Paracetamol immediate release tablet (Part B) xiv). Paracetamol, pregelatinized starch, lactose and microcrystalline cellulose were sifted together. xv). Maize starch was sifted with sieve of mesh size 40. xvi). The material of step (xiv) was mixed for 10 minutes. xvii). Maize starch of step (xv) was dispersed in purified water followed by addition of sodium methylparaben and sodium propylparaben with constant stirring. xviii). The binder material of step (xvii) was mixed with the material of step (xvi) for 3-5 minutes to obtain granules, xix). The granules of step (xviii) were dried and passed through sifter cum multimill. xx). Talc, stearic acid and colloidal silicon dioxide were sifted together through sieve of mesh size 60. xxi). The dried granules of step (xix) and (xx) were blended together for 8-10 minutes, xxii). Compress the blend of step (xxi) into tablet in tablet in such a way that each tablet contains one diclofenac sodium enteric coated tablet 25mg surrounded by layer of paracetamol.

Example-3:

Part A: Diclofenac sodium (Delayed release)

S. No. Ingredient Quantity (mg)

Core tablet composition

1. Diclofenac sodium (equivalent to diclofenac) 75

2. Microcrystalline cellulose 10

3. Lactose 26.23

4. Povidone K-30 1.47

5. Purified water q.s. (lost in processing)

6. Croscarmellose sodium 5

7. Talc 0.85

8. Magnesium stearate 0.85

9. Sodium lauryl sulfate 0.6

Barrier coating composition

10. Hydroxypropyl methylcellulose (HPMC E- 15) 1.8

11. Triethyl citrate 0.6

12. Purified water q.s. (lost in processing)

Enteric coating composition

13. Methacrylic Acid Copolymer Dispersion 12.4

(Eudragit® L30D 55)

14. Triethyl citrate 3.71 15. Talc 3.52

16. Simethicone emulsion (30%) 0.035

17. Purified water q.s. (lost in processing)

Outer film coating composition

18. Tabcoat® TC 4.1

19. Purified water q.s. (lost in processing)

Part B: Paracetamol (Immediate release) S. No. Ingredient Quantity (mg) 1. Paracetamol 500

2. Pregelatinized starch 283.74

3. Lactose 309.6

4. Macrocrystalline cellulose 34

5. Maize starch 24

6. Sodium methylparaben 0.6

7. Sodium propylparaben 0.06

8. Purified water q.s. (lost in processing)

9. Talc 24

10. . Stearic acid 18

11. Colloidal silicon dioxide 6

Procedure: Preparation of Diclofenac sodium delayed release tablet (Part A) i). Diclofenac sodium, microcrystalline cellulose and lactose were sifted with a sieve of mesh size 40. ii). The material of step (i) was mixed for 10 minutes, iii). Povidone (K-30) was dissolved in Purified water with continuous stirring to form a clear solution using a mechanical stirrer, iv). The binder of step (iii) was mixed with the mass of step (ii) to form the granules. v). The granules of step (iv) were dried, vi). Croscarmellose sodium, talc, magnesium stearate and sodium lauryl sulphate were sifted together with sieve of mesh size 60 followed by blending of the material. vii). The blend of step (vi) was compressed into tablets.

Preparation of Barrier coating solution: viii). Hydroxypropyl methylcellulose was dissolved in purified water to form a uniform solution followed by addition of triethyl citrate with constant stirring. ix). The tablets of step (vii) were coated with the coating solution of step (viii).

Preparation of Enteric coating dispersion: x). Talc was dispersed in Purified water by stirring it with the help of mechanical stirrer. Triethyl citrate was added into the abovesaid dispersion with continuous stirring. Methacrylic acid copolymer dispersion and

Simethicone were added into the abovesaid material with uniform mixing using a mechanical stirrer for 40-45 minutes. The coating dispersion was filtered through sieve of mesh size 80. xi). The tablets of step (ix) were coated with the coating solution of step (x). Preparation of Film coating dispersion: xii). Tabcoat TC was added in Purified water and stirred for 45 minutes without incurring flotation to form uniform slurry followed by reducing the stirrer speed to eliminate vortex formation. xiii). The tablets of step (xi) were coated with the coating solution of step (xii). Preparation of Paracetamol immediate release tablet (Part B) xiv). Paracetamol, pregelatinized starch, lactose and macrocrystalline cellulose were sifted together. xv). Maize starch was sifted with sieve of mesh size 40. xvi). The material of step (xiv) was mixed for 10 minutes. xvii). Maize starch of step (xv) was dispersed in purified water followed by addition of sodium methylparaben and sodium propylparaben with constant stirring, xviii). The binder material of step (xvii) was mixed with the material of step (xvi) for 3-5 minutes to obtain granules. xix). The granules of step (xviii) were dried and passed through sifter cum multimill. xx). Talc, stearic acid and colloidal silicon dioxide were sifted together through sieve of mesh size 60. xxi). The dried granules of step (xix) and (xx) were blended together for 8-10 minutes, xxii). Compress the blend of step (xxi) into tablet in tablet in such a way that each tablet contains one diclofenac sodium enteric coated tablet 25mg surrounded by layer of paracetamol.

ExampIe-4: Part A: Diclofenac sodium (Delayed release) S. No. Ingredient Quantity (mg) Core tablet composition

1. Diclofenac sodium (equivalent to diclofenac) 50

2. Lactose 100 3. Crospovidbne (Kollidon® CL) 17

4. Zinc stearate 2

5. Talc 1 Enteric coating composition

6. Eudragit® SlOO 10 7. Triethyl citrate 2

8. Talc 1

9. Isopropyl alcohol (IPA) q.s. (lost in processing)

10. Dichloromethane (DCM) q.s. (lost in processing) Procedure: i) Diclofenac sodium, zinc stearate and talc mixture were compacted by means of roller compaction followed by breaking of the compacts, ii) The material of step (i) was mixed with lactose, microcrystalline cellulose & crospovidone and lubricated with magnesium stearate and talc, iii) The material of step (ii) was compressed into tablets. iv) A coating solution was prepared by dispersing Eudragit® SlOO, triethyl citrate and talc in a mixture of isopropyl alcohol and dichloromethane. v) The tablets were finally coated with the material of step (iv) and dried. Part B: Paracetamol (Immediate release)

S. No. Ingredient Quantity (mg)

1. Paracetamol 500

2. Microcrystalline cellulose . 75 3. Croscarmellose sodium 20

4. Stearic acid 5

5. Talc 5 Procedure: i) Paracetamol, microcrystalline cellulose, croscarmellose sodium, stearic acid and talc were mixed together. ii) The material of step (i) (Part B) is compressed on to the enteric coated diclofenac sodium tablets of step (v) (Part A) to obtain a bilayer tablet.

Part C: Film Coating Composition S. No. Ingredients Quantity/ tablet (mg)

1. Opadry® White 2

2. Isopropyl alcohol q.s. (lost in processing)

3. Dichloromethane q.s. (lost in processing) Procedure: i) Opadry® white was weighed. ii) Necessary quantity of isopropyl alcohol and dichloromethane was added into the mixing vessel, iii) Opadry® white of step (i) was steadily added in isopropyl alcohol and dichloromethane of step (ii) with continuous stirring. iv) The tablets of step (ii) (Part B) are coated with the material of step (iii).

Example-5:

Part A: Diclofenac Tablets (Delayed release)

S. No. Ingredient Quantity (mg) Core tablet composition

1. Diclofenac potassium (equivalent to diclofenac) 50

2. Mannitol 80

3. Crospovidone (Kollidon® CL) 27

4. Magnesium stearate 2 5. Colloidal silicon dioxide 1 Enteric coating composition

6. Eudragit® L-IOO 55 10

7. Triethyl citrate 2 8. Talc 1

9. Isopropyl alcohol q.s. (lost in processing)

10. Dichloromethane q.s. (lost in processing) Procedure: i) Diclofenac sodium, magnesium stearate and colloidal silicon dioxide mixture were compacted by means of roller compaction followed by breaking of the compacts, ii) The material of step (i) was mixed with mannitol and crospovidone, followed by mixing with Magnesium stearate and Talc, iii) The material of step (ii) was compressed into tablets. iv) A coating solution was prepared by dispersing Eudragit® L-100 55, triethyl citrate and talc in a mixture of isopropyl alcohol and Dichloromethane. v) The tablets were finally coated with the material of step (iv) and dried.

Part B: Paracetamol film coated (Immediate release)

S. No. Ingredient Quantity (mg)

1. Paracetamol 500

2. Lactose 75

3. Croscarmellose sodium 20

4. Magnesium stearate 5

5. Talc 5

FiIn i coating formula

6. Hydroxypropyl methylcellulose 3

7. Polyethylene glycol 0.1

8. Purified water q.s. (lost in processing)

Procedure: i) Paracetamol, lactose, croscarmellose sodium, magnesium stearate and talc were mixed together and compressed into tablets, ii) A coating solution was prepared by dissolving hydroxypropyl methylcellulose and polyethylene glycol in purified water, iii) The tablets of step (i) were coated with the material of step (ii).

Part C: Preparation of capsule One enteric coated tablet of diclofenac sodium and one film coated tablet of paracetamol was filled into each hard gelatin capsule.

Claims

1. Pharmaceutical compositions comprising a combination of diclofenac and paracetamol, or pharmaceutically acceptable salts, wherein the said composition comprises (a) a first layer containing diclofenac which is in the form of a compressed tablet; an enteric coating which releases diclofenac in the upper part of the intestine; (b) a second layer containing paracetamol which is compressed on to the first layer which releases paracetamol in the stomach, and optionally a third layer which is in the form of a coating such as film coating or sugar coating over the second layer; and wherein the said active agents are present in the combination in such amounts that the effect of the composition is more favorable than the added effects of the amounts of each drug separately alongwith increased gastrointestinal tolerability without compromising the analgesic efficacy.

2. Compositions according to claim 1, wherein the said composition comprises (a) a first layer containing diclofenac which is in the form of a compressed tablet; an enteric coating which releases diclofenac in the upper part of the intestine; (b) a second layer containing paracetamol which is compressed on to the first layer, which releases paracetamol in the stomach and optionally a third layer which is in the form of a coating such as film coating or sugar coating over the second layer; and which comprises at least one coating material optionally alongwith diclofenac or paracetamol or a combination thereof.

3. Compositions according to claim 1 or 2, wherein the first layer containing diclofenac in the form of a compressed tablet is optionally surrounded by a barrier layer containing pharmaceutical acceptable excipients and the enteric coating is optionally followed by a film coating.

4. Compositions according any one of the preceding claims, wherein the diclofenac is diclofenac sodium or diclofenac potassium.

5. Compositions according any one of the preceding claims, wherein the composition is in the form of a tablet comprising an inner core tablet which is enteric coated so as to delay the release and thus releasing the drug diclofenac particularly in the intestinal region of the GIT.

6. The composition according to claim 5, wherein the enteric coating is selected from enteric polymer/film former such as Eudragit® L-IOO, Eudragit® L-IOO 55, Eudragit® SlOO, Eudragit® L30D 55 and the like or mixtures thereof.

7. The compositions according to any one of the preceding claims, wherein the composition of the present invention comprises one or more pharmaceutically acceptable exciρient(s) selected from a group comprising diluents; disintegrants; binders; fillers; bulking agent; organic acid(s); colorants; stabilizers; preservatives; lubricants; glidants; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents such as glycerine, various grades of polyethylene oxides, transcutol and glycofurol; tonicity adjusting agents; local anesthetics; pH adjusting agents; antioxidants; osmotic agents; chelating agents; viscosifying agents; acids; sugar alcohol; reducing sugars; non- reducing sugars and the like used either alone or in combination thereof.

8. The compositions according to any one of the preceding claims, wherein the composition of the present invention is preferably formulated as a solid dosage form such as layered tablets (coated or uncoated), bilayer tablets, tablet in tablet, or layered minitablets (coated or uncoated) filled into capsules.

9. The compositions according to claim 8, wherein the compositions of the present invention are in the form of compressed tablets, moulded tablets, mini-tablets, compacts, pellets, granules or the like.

10. The process of preparation of pharmaceutical compositions according to claim 1, comprising diclofenac and paracetamol.

11. The process of preparation of pharmaceutical compositions according to claim 10, wherein the preparation of composition comprises the following steps: i). treating diclofenac with one or more pharmaceutically acceptable excipient(s) and compressing it into a tablet, ii). coating diclofenac tablet in step (i) with one or more pharmaceutically acceptable eχcipient(s), iii). coating diclofenac tablet in step (ii) with enteric polymer(s), iv). treating paracetamol with one or more pharmaceutically acceptable excipient(s) and compressing it on to the tablet of step (iii) to obtain a tablet in tablet, and v). optionally film coating or sugar coating the tablet obtained in step (iv).

12. Method of using such composition according to claim 1, which comprises administering to a subject in need thereof an effective amount of the composition.

13. Use of the dosage form composition according to claim 1, comprising diclofenac and paracetamol for the preparation of a medicament for treating pain associated with inflammation or without inflammation and/or other associated disease(s)/disorder(s) .

14. Use of the dosage form according to claim 13, for the management of one or more disease(s)/disorder(s) which includes prophylaxis, amelioration and/or treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, acute musculoskeletal injury, acute painful shoulder, postoperative pain, dysmenorrhea, relief of fever, headaches, and other aches and pains.

15. The pharmaceutical compositions and processes for the preparation of pharmaceutical compositions substantially as herein described and illustrated by the examples.