Title of Invention

NOVEL FORMULATIONS OF NSAID FOR RECTAL USE

Abstract

The present invention discloses a novel NSAIDS formulations in liquid or semi solid form for rectal use with pharmaceutically acceptable drug delivery system wherein, the said formulation comprises active ingredient as NSAIDS like rofecoxib, paracetamol, nimesulide and their pharmaceutical analogues with one or more pharmaceutically acceptable exipients as water miscible liquid base, co-solvent systems, thickening or gelling agent, viscosity modifier or wetting agents and stabilizer either alone or in combination with solubilizers and purified water. Further, this composition is provided with a squeezable container for convenient and better patient compliance.

Full Text

FORM 2 THE PATENTS ACT 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] Novel formulations of NSAID for rectal use (a) M/s. LYKA LABS LIMITED (b) 77, NEHRU ROAD, VILE PARLE (EAST), MUMBAI - 400 099. MAHARASHTRA, INDIA. (c) AN INDIAN COMPANY REGISTERED UNDER THE INDIAN COMPANIES ACT 1956 The following specification particularly describes the nature of this invention and the manner in which it has to be performed: ORIGINAL GRANTED 21-7-2008 26 MAY 2004 Technical field of the Invention. The present invention relates to novel formulations of non-steroidal anti-inflammatory drugs (NSAIDS) in liquid or semi solid form for rectal use with drug delivery system. More particularly this invention relates to formulations of NSAIDS like Rofecoxib, Paracetamol, Nimesulide In liquid or semisolid form for rectal use either separately or concomitantly. Background and Prior Art. Non-steroidal anti-inflammatory drugs (NSAIDS) are among the most frequently prescribed drugs worldwide due to their 'over the counter' (OTC) availability. NSAIDS agents are commonly used as anti-inflammatory, analgesic, anti-thrombotic, antipyretic and anti-rheumatic agents. Almost 1000 million people world wide are taking them on regular basis because of their analgesic effectiveness, their anti-inflammatory and anti-pyretic effect and as they do not produce the sedation, mental clouding, nausea, constipation and other side effects of opioids. They occupy a large share of the market and are available in various forms like tablets, capsules, syrups, suspensions, injections, topical creams, gels etc. However above mentioned dosage forms of NSAIDS are reasonably safe in most cases in prescribed dosages and for short duration. NSAIDS suppress the activity of both isoforms of cyclo-oxygenase (COX). Inhibition of COX-1, the constitutive isoform, is primarily responsible for the adverse gastrointestinal effects of the NSAIDS. Thus these drugs cause gastrointestinal toxicity in a large number of cases. Thus with NSAIDS treatment majority of deaths are occurred by gastrointestinal bleeding. In mouth, they cause oral ulceration, in oesophagus, they can cause ulceration and stricture formation. In stomach and duodenum, they can cause ulcers, sever bleeding, perforation and obstruction. It also causes life threatening renal and hepatic injury, especially among the elderly. In an effort to reduce the adverse effect of NSAIDS, Lager et. al. (Needleman and Isaleson in 1997) developed a new generation of NSAIDS known as cyclooxygenase 2 (COX -II) inhibitors like Rofecoxib, Valdecoxib and Celecoxib. These new class of selective COX -II inhibitors have entered the market with promise of better gastrointestinal tract (GIT) tolerance and over all safety profile compared to traditional NSAIDS. Rofecoxib is widely used drug, available in various forms like tablets, suspensions and topical gels. In case of Rofecoxib, the rate of absorption is moderate when given orally (C max: 2-3 hrs.). The mean oral bioavailability of Rofecoxib tablets is 93.0 %, the tablet and suspension forms being bioequivalent. It however exhibits poor therapeutic effect by oral route due to poor water solubility, the reason being the rate limiting step of drug dissolution into gastric fluids. An injectable dosage form is not introduced due to poor solubility. This necessitates need for developing routes of administration for better absorption. The rectal route is one such lucrative option. It alters several advantages over conventional routes of administration. Prior art on rectal dosage forms are available which are as follows. FR 2647344 describes Paracetamol pharmaceutical composition with improved bioavailabity comprising aqueous or non aqueous aerosol foams for rectal use. US 6486 204 discloses different dosage forms like rectal and vaginal in the form of suppositories, oral administration includes pharmaceutically acceptable emulsions, solutions, suspension, syrups and elixirs containing inert diluents commonly used in the art, such as water, parental composition comprises COX-2 inhibitor and the anti - cancer agent or agents in combination with pharmaceutically acceptable carrier and nasal or sublingual composition. Rectal or vaginal administration in suppositories forms contain, in addition to the active substance like Rofecoxib, excipients such as cocoa butter or a suppository wax. A Cox-II inhibitor drug is disclosed as useful in treating or preventing prostate cancer either alone or in combination with other drug. US 6602520 describes non-effervescent tablet suitable for oral or rectal administration, which disintegrate fast and release rapidly even with small amount of liquids. Rectal dosage forms currently available in the market are in the form of suppositories, and find minimum patient compliance due to inconvenience and inelegance of dosage form. Keeping this in mind we have developed a unique dosage form in liquid and semisolid form for rectal use and also provided a squeezable container for convenient administration of the same. OBJECTIVES OF THE INVENTION An objective of the invention is to provide NSAIDS formulation useful for systemic and /or local treatment by the rectal route in a form, which is convenient to administer. Another objective of this invention is to overcome general reluctance to usage of rectal route by providing higher efficacy and elegancy of product, which holds high potential in therapy. Advantage of this Invention Rectal preparations are transparent or translucent or opaque liquids or semisolids containing the active substance in a suspended or solubilized state. It is a novel and unique formulation and owing to its embodiments it offers several advantages over conventional oral dosage forms as follows; Drugs administered orally must run through a series of absorption and elimination sites before it can enter the general circulation. Rectal route on the other hand is richly supplied with capillaries that drain into the inferior vena cava, thus allowing drug to be rapidly absorbed. This means a faster onset of action, a desirable feature in case of painkillers. Drugs administered via rectal route partially bypass hepatic first pass metabolism leading to better blood levels of the active. GIT side effects of NSAIDS like ulceration are avoided, improving patient compliance. The composition is so formulated so as to allow easy mixing with rectal fluids. This leads to better absorption and hence better bioavailability of the drug. The viscosity of the formulation is optimized to allow convenient administration and comfort during use. It is fluid enough to spread over a large surface area leading to better bioavailability as against a suppository formulation that has to first liquefy. At the same time it is viscous enough to be retained in the rectal cavity and not lead to embarrassing leakages. The base chosen is aqueous or water miscible base that facilitates mixing with rectal fluids. This not only leads to better bioavailability but also the comfort during use unlike the fatty base suppositories. This leads to better patient compliance to the regimen. The composition is so formulated so as to allow faster release of the medicament from base unlike fatty based suppositories. In case of solution formulations, the drug being already in the solubilised form dissolves faster in rectal fluids leading to better bioavailability. The pH of rectal fluids is around 7.4. This is a pH where most drugs exist in the unionized form and hence exhibit maximum lipid solubility and are absorbed more readily than in stomach pH, since principle method of drug absorption is diffusion through lipid regions of cell membrane. Due to its high viscosity, it remains in contact with the rectal mucosa providing longer time for absorption, maintaining blood levels for longer time and thus providing relief for longer time compared to oral, topical or injectable dosage forms. The formulation is provided packaged in a specially designed convenient and user friendly plastic rectal tube (Design Patent No 182121). It is a disposable package meant for single use. This allows self-administration while maintaining hygiene and along with other attributes thus makes for a highly elegant dosage form. Unlike a suppository that can be displaced upwards or downwards in the rectal region, leading to difference in bioavailability with difference in site of absorption, this preparation ensures spreadability over larger surface area over a given site thus giving more consistent bioavailability profiles. Components of formulation and package are compatible and do not affect bioactivity of active ingredients or physical properties of vehicle. The composition is so formulated as to contain effective amount of active in 5 ml of preparation, a volume that is easily and comfortably accommodated in the rectal cavity, another attribute towards better patient compliance. Drugs used to treat local inflammation or pain in the rectal cavity like haemmorhoidal pain, find good usage via this dosage form, due to better availability at site of action. Manufacturing procedure eliminates need for complex mechanical equipment. Requires simple equipment like jacketed S. S. tanks with stirrer Ingredients used in the formulation like Polyethylene Glycol, Propylene Glycol, Polysorbate, Polyacrylamide are known solubility enhancers which improve absorption through biological membranes. All excipients chosen are non-toxic, non-irritant have little or no physiological effect at the concentration used. In case of patients who require long-term NSAID therapy, for example in case of rheumatic pain, this dosage form avoids the GIT effects of oral NSAID therapy. Hence formulation is especially suitable for such therapy. Further objects and advantages of the present invention will become apparent from a consideration of the ensuing description of the invention. SUMMARY OF THE INVENTION: Novel formulations of NSAIDS in liquid or semi solid form for rectal use with drug delivery system wherein the said formulations comprises active ingredient, NSAIDS like Rofecoxib, Paracetamol, Nimesulide, Valdecoxib and their pharmaceutical analogues in an amount ranging from 0.05 to 25 % by weight of the total composition; one or more water miscible liquid base like pharmaceutically acceptable water miscible and non greasy solvents like purified water, propylene glycol, glycerin, ethanol, low molecular Weight polyethylene glycol and mixtures thereof in an amount ranging from 2 to 95 % by weight of the total composition; co-solvent system like polyethylene glycol 400 in the range of 5 to 95 % by weight, pharmaceuticaly acceptable thickening or gelling agent selected from non toxic hydrophilic polymers like xanthan gum, alginates, carageenan, tragacanth, sodium carboxymethyl cellulose, Methyl cellulose, Hydroxy Propyl Celluloses (HPCs), Hydroxy Propyl Methyl Celluloses (HPMCs), various starches, locust bean gum, gelatin, pectin, polyacrylamides, high molecular weight Polyethylene Glycol and the like in the range from 0.05 % to 0.50 % by weight of the total composition; viscosity modifier like high molecular weight Polyethylene Glycols at a concentration of 1.0 % to 25.0 % by weight of the total composition; solubilizers or wetting agents such as Propylene glycol, low molecular weight Polyethylene Glycol, Polysorbates and such agents at a concentration 0.1 % to 2.0 % by weight of total composition; solubiliser and stabilizer such as ethanol at a concentration 1 to 15 %; triethanolamine or sodium hydroxide solution to adjust the pH of the final formulation at 5 to 8; Preservatives like Phenoxyethanol, Sodium Benzoate, Disodium EDTA, Methyl Paraben, Propyl Paraben either alone or in combination at a percentage 0.02 % to 0.5 % by weight of the total composition and purified water 50 to 90 % by weight of the total composition. DESCRIPTION OF THE INVENTION: The present invention relates to novel formulations of NSAIDS (Non Steroidal anti¬inflammatory drugs) in liquid or semi solid form for rectal drug delivery system including a combination of a squeezable container. Each of these elements of the drug delivery system has certain characteristics so that the combination: 1) Allows easy administration of measured amount of drug. 2) Provides for comfort during administration and use. 3) Provides for better bioavailability of drug and hence better therapeutic action. 4) Provides for a highly user friendly and elegant formulation which improves patient compliance to therapy. The composition of this invention are in the form of solution, suspension or gels comprising the active medicament, water miscible vehicle, solubilizers, wetting agents, hydrophilic soluble gellant polymer, viscosity modifiers and preservative. The compositions are water miscible, thick and non greasy, easy to extrude from the tube and are well retained in the rectal cavity without causing discomfort to the user. According to the present invention the pharmaceutical composition comprises drugs useful as analgesics, antipyretics, antirheumatic, anti thrombotic agents. The actives are selected from the NSAID group and include drugs like Rofecoxib, Paracetamol, Valdecoxib, Nimesulilde, and their pharmaceutically accepted analogs. The active I ingredient may be present in an amount from 0.05 % to 25.0 % by weight, more! preferably from 0.25 % to 15.0 % by weight of the total composition. According to the present invention the pharmaceutical composition comprise one or more of a water miscible liquid base which is a pharmaceutically acceptable solvent and which has negligible physiological effect via rectal administration. The solvent may be used to either dissolve or suspend the active medicament. The liquid bases chosen are water miscible and non greasy so that they easily mix with rectal fluids allowing for better absorption of medicament with minimal discomfort to the user. Preferred solvents include Purified water, Propylene Glycol, Glycerin, Ethanol, low molecular weight Polyethylene Glycol, and mixtures thereof. Low molecular weight Polyethylene Glycol having molecular weight ranging from 200 to 1000 preferably 400 to 800 are used. They may be present in an amount 2.0 % to 95.0 % by weight of the total composition preferably 5.0 % to 80.0 % by weight of the total composition. They may be used alone or more preferably in combination to function as co-solvent system. The most preferred combination in case of rectal solution formulation is Propylene glycol 5.0 % to 95.0 % preferably 10.0 % to 80.0 % and Polyethylene Glycol 400 in a concentration from 5.0 % to 95.0 % preferably 25.0 % to 85.0 % by weight of total composition. The most preferred vehicle in case of suspension or gel formulation is Purified water preferably 50.0 % to 90.0 % by weight. The present invention may also comprise a pharmaceutically acceptable thickening or gelling agent which is compatible with other ingredients used in the formulation. It is selected from a group of non toxic hydrophilic polymers like xanthan gum, alginates, carageenan, tragacanth, sodium carboxymethyl cellulose, Methyl cellulose, Hydroxy Propyl Celluloses (HPCs), Hydroxy Propyl Methyl Celluloses (HPMCs), various starches, locust bean gum, gelatin, pectin, polyacrylamides, high molecular weight Polyethylene Glycol and the like. In the present invention preferably a polyacrylamide i.e. Carbopol is selected since it gives viscous solution at low concentration. It is used in a concentration ranging from 0.05 % to 0.50 % by weight of the total composition preferably 0.10 % by weight. The Carbopol used in the case of this patent is of the grade Carbopol 980 manufactured by B. F. Goodrich / Novion. Alternatively other grades of carbopol like Carbopol 974, 971,981, 940 and 941 may also be used. The amount of gellant used is optimized to achieve desired viscosity. The solution should be viscous enough to be retained in the rectal cavity yet easy to extrude from tube for accurate dosing. It is generally adjusted between 200 to 5000 centipoise, more preferably between 250 to 3500 centipoise, this range being most comfortable for rectal administration. Viscosity is determined using Brookfield Viscometer at 10 rpm. According to the present invention, in case of solution formulation, certain thickening agents are used to increase viscosity of the formulation to improve residence time at site of administration called viscosity modifier. Preferred viscosity modifier are high molecular weight Polyethylene Glycols having molecular weight ranging from 1500 to 15,000, preferably 1500 to 6000, most preferably Polyethylene Glycol 4000 at a concentration of 1.0 % to 25.0 %, preferably 5.0 % to 10.0 % by weight of the total composition. The present invention of rectal solution formulation contains Polyethylene Glycol 4000 at a concentration of 5.0 % as viscosity enhancer. The present invention may also comprise suitable solubilizers or wetting agents such as Propylene glycol, low molecular weight Polyethylene Glycol, Polysorbates and such agents. The most preferred solubilizer is Polyoxyethylene sorbitan monooleate (Polysorbate 80) i.e. Tween 80 at a concentration 0.1 % to 2.0 % by weight preferably 0.5 % to 1.0 % by weight of total composition. The pH of the final formulation is kept at 5 to 8 which is most comfortable for rectal administration. pH can be adjusted using triethanolamine or sodium hydroxide solution. Preferred pH range of the present invention is from 5 to 7.5. Ethanol is used as a solubiliser and stabilizer at a concentration of 1 to 15 %. This invention thus omits the need for complex mechanical equipment and expensive excipients employed in prior art such as heating equipment molds and, skilled labor as is required in the manufacture of suppositories. This provides advantages in manufacturing, distribution, waste disposal and other economies as well resulting in a more cost effective formulation. The invention further comprises a specially designed squeezable plastic container such as tube called applicator provided with a extended portion, the material preferably being polyethylene (Design Patent No 182121). The extended part of the tube can be comfortably inserted at the site of administration i.e. rectal cavity at required distance to administer the formulation. The tube is sized to hold a unit dose of 5 ml, to hold it conveniently without spilling and to be comfortable to hold and administer the dose easily and hygienically into the rectal cavity. This is a disposable type package meant for single use. The design allows for self-administration and makes for the elegance of the product. In addition to the above ingredients, preservatives (water soluble) can be added to prevent microbial contamination. Preservatives used are Phenoxyethanol, Sodium Benzoate, Disodium EDTA, Methyl Paraben, Propyl Paraben either alone or in combination at a percentage 0.02 % to 0.5 % by weight of the total composition. The therapeutically effective compositions of this invention are by conventional procedure. The base is first prepared followed by addition of medicament. The preparation is then adjusted to final concentration, viscosity and pH. According to the present invention, the said formulation may be an aqueous viscous solution based system. The most preferred gellant in such case is Carbopol 980. The vehicle comprises of Purified water in combination with Polyethylene Glycol, Propylene glycol, Ethanol or Glycerin. The present product in the solution form may be transparent, translucent or opaque in appearance depending on extent of solubilization of active. According to the present invention, Rofecoxib rectal solution comprises Rofecoxib - 0.2 % to 2.0 %, Phenoxyethanol - 0.5 % to 2.0 %, ethanol - 5 to 15 %, Carbopol 980 - 0.05 % to 0.5 % in Purified water. Triethanolamine (10 %) solution is used to adjust pH between 5 to 8. The most preferred formulation for Rofecoxib rectal solution comprises Rofecoxib - 1 %, Ethanol - 9.0 %, Phenoxyethanol - 1.0 %, Carbopol 980 - 0.1%, triethanolamine solution to adjust pH of the solution to 5.0 to 8.0 and Purified water q.s. to 100 %. According to the present invention, Rofecoxib rectal solution 1 % w/v comprises Rofecoxib 1 %, phenoxyethanol 1 %, ethanol 5%, propylene glycol 10 %, carbopol 980 0.15%, 20 % triethanol amine solution 0.16 % and purified water q.s. to 100%. Another invented formulation of Rofecoxib rectal solution 1 % w/v comprises Rofecoxib 1 %, phenoxyethanol 1 %, ethanol 7.5 %, propylene glycol 5 %, polyethylene glycol 400 (PEG 400) 5 % , carbopol 940 0.15% and 20% triethanol amine solution 0.16% and purified water q.s. to 100 %. Other formulation of Rofecoxib rectal solution 1% w/v comprises Rofecoxib 1% w/v, phenoxyethanol 1 %, ethanol 10 %, propylene glycol 5 %, carbopol 940 0.10 %, 20 % triethanol amine solution 0.12 % and purified water q.s. to 100 % Also other water miscible gellants used can be HPMC of different viscosity grade ranging from 100 to 15000 centipoise. Alternatively Methyl cellulose of different viscosity grades may be used. Preferably HPMC grade 100 cps or 4000 cps can be used in preparation of gel. According to the present invention, Nimesulide rectal solution comprises Nimesulide -0.20 % to 2.0 %, Propylene glycol - 10.0% to 25.0 %, Polyethylene Glycol 400 - 65.0% to 95.0 %, Polyethylene Glycol 4000 - 2.0 % to 20.0 %. It may also include Disodium EDTA - 0.02 % to 2.0 %, Sodium benzoate - 0.05 % t o 1.0 % as preservatives. The most preferred formulation being Nimesulide - 0.25 % to 2.0 %, Propylene glycol -15.0 % to 20.0 %, Polyethylene Glycol 400 - 75.0 % to 85.0 %, Polyethylene Glycol 4000 - 2.0 % to 10.0 % by weight of total composition. According to another formulation in the present invention, Paracetamol rectal solution comprises Paracetamol - 2.0 % to 20.0 %, Propylene glycol - 65.0 % to 95.0 %, Polyethylene Glycol 400 -10.0 % to 35.0 %, Polyethylene Glycol 4000 - 2.0 % to 20.0 % and Tween 80 - 0.5 to 1.0%. It may also include Disodium EDTA - 0.02 % to 2.0 %, Sodium benzoate - 0.05 % to 1.0 % as preservatives. The most preferred formulation being Paracetamol - 2.0 % to 15.0 %, Propylene glycol -50.0 % to 75.0 %, Polyethylene Glycol 400 - 15.0 % to 40.0 %, Polyethylene Glycol 4000 - 2.0 % to 10.0 % and Tween 80 - 0.5 % by weight of total composition. In the third embodiment of the invention the product is provided in a user friendly package i.e. in a specially designed squeezable plastic container such as tube provided with an extended nozzle, the material preferably being polyethylene. The present invention is further illustrated by the following examples :- Example 1 The following composition is that of Rofecoxib Rectal solution Table 1 Ingredient % by weight Rofecoxib 1.0 Ethanol 9.0 Carbopol 980 0.1 Phenoxyethanol 1.0 Purified water q.s. to 100 gm Triethanolamine (10%) q.s. to pH 6.5 (q.s.: - quantity sufficient) The viscosity of the final preparation is 6000 centipoise and the pH is 6.5. Example 2 The following composition is that of Rofecoxib Rectal Solution 1% w/v Table 2 Ingredient % by weight Rofecoxib 1 Phenoxyethanol 1 Ethanol 5 Propylene glycol 10 Carbopol 980 0.15 20% triethanolamine solution 0.16 Purified water q.s. to 100 Example 3 The following composition is that of Rofecoxib Rectal Solution 1% w/v Table 3 ingredient % by weight Rofecoxib 1 Phenoxyethanol 1 Ethanol 7.5 Propylene glycol 5 Polyethylene glycol 400 (PEG 400) 5 Carbopol 940 0.15 20% triethanolamine solution 0.16 Purified water q. s. to 100 Example 4 The following composition is that of Rofecoxib Rectal Solution 1% w/v Table 4 Ingredient % by weight Rofecoxib 1 Phenoxyethanol 1 Ethanol 10 Propylene glycol 5 Carbopol 940 0.10 20% Ethanolamine solution 0.12 Purified water q. s. to 100 Example 5 The following composition is that of Nimesulide Rectal Solution. Table 5 Ingredient % by weight Nimesulide 2.0 Polyethylene glycol - 400 (PEG 400) 78.0 Propylene glycol 15.0 Polyethylene glycol - 4000 (PEG 4000) 5.0 The viscosity of the final preparation is 300 centipoise and the pH is 5.0. Example 6 The following composition is that of Paracetamol Rectal Solution. Table 6 Ingredient % by weight Paracetamol 6.50 Polyethylene glycol - 400 (PEG 400) 30.0 Propylene glycol 58.0 Polyethylene glycol - 4000 (PEG 4000) 5.0 Tween 80 0.5 The viscosity of the final preparation is 300 centipoise and the pH is 7.1. The advantages of the present invention are manifold and range from ease of administration and comfort during use to faster relief from pain and more patient compliance. To summarize, our invention provides for a highly effective and elegant liquid or semisolid formulation for NSAIDS via the rectal route. The formulation and process eliminate the use of expensive equipment. The formulation is so optimized as to ensure maximum bioavailability of active and hence maximum therapeutic efficacy of the final product. The final product thus is more users friendly and more efficacious, offering great potential for the rectal route as an alternative to other routes currently in use for such medication. While the above description contains many specificities, these should not be construed as limitations in the scope of the invention, but rather as an exemplification of one preferred embodiment thereof. Many other variations are possible, for example : Alternatively other NSAIDS having systemic or local use may be used. For example Valdecoxib, Celecoxib, Aspirin, Indomethacin, Ibuprofen may be used alone or in combination. Though the present invention considers NSAIDS as active, other pharmacologically active agents useful for systemic or local action may be used. For example drugs that are used to relive pain and irritation of haemorrhoids like Cinchocaine, Benzocaine, Hamamelis and Zinc oxide may also be formulated as per present invention either alone or in combination with NSAIDS. Also water miscible gellant used can be HPMC of different viscosity grade ranging from 100 to 15000 centipoise. Alternatively Methyl cellulose of different viscosity grades may be used. We claim, 1. A Novel pharmaceutical composition of NS AIDS in liquid or semi solid form for rectal use with drug delivery system comprising at lest one NSAIDS ,selected from the group consisting of Rofecoxib, Paracetamol, Nimesulide, Valdecoxib and their pharmaceutical analogues in an amount ranging from 0.05 to 25 %;more preferably 0.25% to 15.0% by weight of the total composition and component a) as one or more water miscible liquid base like pharmaceutically acceptable water miscible and non greasy solvents like Purified Water, Ethanol, Propylene glycol, Glycerin, low molecular Weight polyethylene glycol and mixtures thereof in an amount ranging from 2 to 95 % by weight of the total composition; component b) co-solvent system like polyethylene glycol in the range of 5 to 95 % by weight and polyethylene glycol 400 in the range of 5 to 95 % by weight, component c) pharmaceutically acceptable thickening or gelling agent selected from non toxic hydrophilic polymers like xanthan gum, alginates, carageenan, tragacanth, sodium carboxymethyl cellulose, Methyl cellulose, Hydroxy Propyl Celluloses (HPCs), Hydroxy Propyl Methyl Celluloses (HPMCs), various starches, locust bean gum, gelatin, pectin, polyacrylamides and high molecular weight Polyethylene Glycol and in the range from 0.05 % to 0.50 % by weight of the total composition; component d) viscosity modifier like high molecular weight Polyethylene Glycols at a concentration of 1.0 % to 25.0 % by weight of the total composition; component e) solubilizer and stabilizer like ethanol at a concentration of 1 to 15% by weight of the final formulation; component f) solubilizers or wetting agents such as Propylene glycol, low molecular weight Polyethylene Glycol and Polysorbates at a concentration 0.1 % to 2.0 % by weight of total composition; triethanolamine or sodium hydroxide solution to adjust the pH of the final formulation at 5 to 8; component g) Preservatives like Pnenoxyethanol, Sodium Benzoate, Disodium EDTA, Methyl Paraben, Propyl Paraben either alone or in combination at a percentage 0.02 % to 0.5 % by weight of the total composition and component h) purified water 50 to 90 % by weight of the total composition. 2. Novel formulations as claimed in claim 1 wherein the preferred range of concentration of the said active ingredient is 0.25 to 15 % by weight of the total composition. 3. Novel formulations as claimed in claim 1 wherein the said lower molecular weight polyethylene glycol has molecular weight 200 to 1000, preferably 400 to 800. 4. Novel formulations as claimed in claim 1 wherein the preferred range of concentration of water miscible liquid phase is 5 to 80 % by weight of the total composition. 5. Novel formulations as claimed in claim 1 wherein preferred concentration range of polyethylene glycol is 10 to 80 % by weight of the total composition. 6. Novel formulations as claimed in claim 1 wherein the preferred concentration range of polyethylene glycol 400 is 25 to 85 % by weight of the total composition. 7. Novel formulations as claimed in claim 1 wherein thickening or gelling agent is a acrylic acid polymer selected as carbopol like carbopol 974, 971, 981, 940, 941, 980, more preferably carbopol 980. 8. Novel formulations as claimed in claim land 7 wherein preferred range of concentration of thickening or gelling agent is 0.10 % by weight of the total composition. 9. Novel formulations as claimed in claim 1 wherein the viscosity of the said formulation is 200 to 5000 centripoise, preferably 250 to 3500 centripoise. 10. Novel formulations as claimed in claim 1 wherein the said viscosity modifier is selected from polyethylene glycol with molecular weight in the range of 1500 to 15000, preferably 1500 to 6000, more preferable 4000. 11. Novel formulations as claimed in claim 1 wherein the said polyethylene glycol with molecular weight 4000 is used at the concentration 5 to 10 %, preferably 5% by weight of the total composition. 12. Novel formulations as claimed in claim 1 wherein the said solubilizer or wetting agent is polyoxyethylene sorbitan monooleate (polysorbate 80). 13. Novel formulations as claimed in claim 1 wherein the preferred concentration of the said sollubiliser / wetting agent is in the range of 0.5 to 1 % by weight of the total composition. 14. Novel formulations as claimed in claim 1 wherein the said rectal solution of Rofecoxib comprises Rofecoxib - 0.2 % to 2.0 %; Phenoxyethanol - 0.5 % to 2.0 %; Carbopol 980 - 0.05 % to 0.5 %; Ethanol 5 to 15 % , Triethanolamine (10 %) solution to adjust pH of the said solution between 5 to 8 and purified water q.s. to 100 %. 15. Novel formulations as claimed in claims 1 and 14 wherein the said rectal solution of Rofecoxib comprises Rofecoxib -1.0 %, Ethanol - 9.0 %, Phenoxyethanol - 1.0 %, Carbopol 980 - 0.1%, Triethanolamine solution (10%) to adjust the pH of the said solution to 5.0 to 8.0 and Purified water q.s. to 100. 16. Novel formulations as claimed in claims 1 and 14 wherein the said rectal solution of Rofecoxib comprises Rofecoxib - 1.0 %, Phenoxyethanol -1.0 %, Ethanol 5 %, Carbopol 980 - 0.15 %, propylene glycol 10 %, Triethanolamine (20 %) solution to adjust pH of the said solution to 5 to 8 and purified water q.s. to 100%. 17. Novel formulations as claimed in claims 1 and 14 wherein the said rectal solution of Rofecoxib comprises Rofecoxib - 1.0 %, Phenoxyethanol -1.0 %, Ethanol 7.5%, Propylene glycol 5 %, Polyethylene glycol 400 (PEG 400) 5 %, Carbopol 940 - 0.15 %, Triethanolamine (20 %) solution to adjust pH of the said solution to 5 to 8 and purified water q.s. to 100%. 18. Novel formulations as claimed in claims 1 and 14 wherein the said rectal solution of Rofecoxib comprises Rofecoxib - 1.0 %, Phenoxyethanol -1.0 %, Ethanol 10 %, Carbopol 940 - 0.10%, Propylene glycol 5 %, Triethanolamine (20 %) solution to adjust pH of the said solution to 5 to 8 and purified water q.s. to 100%. 19. Novel formulations as claimed in claim 1 wherein the said formulation of Nimesulide comprises Nimesulide - 0.20 % to 2.0 %, Propylene glycol - 10.0% to 25.0 %, Polyethylene Glycol 400 - 65.0% to 95.0 %, Polyethylene Glycol 4000 - 2.0 % to 20.0 %, Disodium EDTA - 0.02 % to 2.0 % and Sodium benzoate - 0.05 % t o 1.0 % by weight of the total composition. 20. Novel formulations as claimed in claim 19 wherein the said preferred formulation of Nimesulide comprises Nimesulide - 0.25 % to 2.0 %, Propylene glycol - 15.0 % to 20.0 %, Polyethylene Glycol 400 - 75.0 % to 85.0 %, Polyethylene Glycol 4000 - 2.0 % to 10.0 % by weight of total composition. 21. Novel formulations as claimed in claim 1 wherein the said formulation comprises Paracetamol - 2.0 % to 20.0 %, Propylene glycol - 65.0 % to 95.0 %, Polyethylene Glycol 400 - 10.0 % to 35.0 %, Polyethylene Glycol 4000 - 2.0 % to 20.0 % and Tween 80 - 0.5 to 1.0%, Disodium EDTA - 0.02 % to 2.0 % and Sodium benzoate -0.05% to 1.0%. 22. Novel formulations as claimed in claim 21 wherein the said preferred formulation comprises Paracetamol - 2.0 % to 15.0 %, Propylene glycol - 50.0 % to 75.0 %, Polyethylene Glycol 400 - 15.0 % to 40.0 %, Polyethylene Glycol 4000 - 2.0 % to 10.0 % and Tween 80 - 0.5 % by weight of total compression. 23. Novel formulations as claimed in claims 1 to 22 wherein the said formulation is used with delivery system comprises a specially designed squeezable plastic container such as tube called applicator provided with a extended portion, the material preferably being polyethylene. 24. Novel formulations of NS AIDS in liquid or semi solid form for rectal use with drug delivery system as substantially described herein with reference to foregoing examples 1 to 6. Dated this the 26 day of May 2004 Dr. Gopakumar G.Nair Agent for the Applicant

Documents:

418-mum-2003-abstract(21-07-2008).doc

418-mum-2003-abstract(21-07-2008).pdf

418-MUM-2003-ABSTRACT(26-5-2004).pdf

418-mum-2003-abstract.doc

418-mum-2003-cancelled pages(21-07-2008).pdf

418-MUM-2003-CLAIMS(26-5-2004).pdf

418-mum-2003-claims(granted)-(21-07-2008).doc

418-mum-2003-claims(granted)-(21-07-2008).pdf

418-mum-2003-claims.doc

418-mum-2003-correspondence(21-07-2008).pdf

418-MUM-2003-CORRESPONDENCE(21-7-2008).pdf

418-mum-2003-correspondence(ipo)-(30-10-2008).pdf

418-mum-2003-form 1(21-07-2008).pdf

418-MUM-2003-FORM 1(21-7-2008).pdf

418-mum-2003-form 1(28-04-2003).pdf

418-MUM-2003-FORM 1(28-4-2003).pdf

418-mum-2003-form 18(05-12-2006).pdf

418-mum-2003-form 2(granted)-(21-07-2008).doc

418-mum-2003-form 2(granted)-(21-07-2008).pdf

418-MUM-2003-FORM 2(TITLE PAGE)-(26-5-2004).pdf

418-mum-2003-form 26(17-09-2004).pdf

418-mum-2003-form 3(21-07-2004).pdf

418-MUM-2003-FORM 3(21-7-2008).pdf

418-mum-2003-form 3(28-04-2003).pdf

418-mum-2003-form 4(27-04-2004).pdf

418-mum-2003-form 5(26-05-2004).pdf

418-mum-2003-form-2.doc

418-mum-2006-abstract.pdf

418-mum-2006-claims.pdf

418-mum-2006-correspondence-received ver-260504.pdf

418-mum-2006-correspondence-received ver-301104.pdf

418-mum-2006-description (complete).pdf

418-mum-2006-form-2.pdf

418-mum-2006-form-26.pdf

418-mum-2006-form-5.pdf