Indian Patents. 234519:"PHARMACEUTICAL COMPOSITION OF KETOROLAC"

Title of Invention	"PHARMACEUTICAL COMPOSITION OF KETOROLAC"
Abstract	A synergistic pharmaceutical composition as prolonged release injectable containing ketorolac or its water soluble derivative along with at least one of hydrophilic polymer or vegetable oil or hydrophobic no polymeric compound together with optionally one or more parentally acceptable excipients for relieving pain.

Full Text	Filed of the Invention The invention relates to prolonged release injectable pharmaceutical composition of ketorolac or its water-soluble derivatives. The invention also provides compositions made of hydrophilic or hydrophobic release modifying agent that can be used to provide a low viscosity, free flowing injectable preparation for use as a sustained drug delivery system. Background of the Invention Pain is an unpleasant sensational and emotional experience elicited by the activation of specific nociceptors. Pain derived from tissue injury is exhibited in the form of local edema, inflammation and hyperalgesia (Dahl et al., Br. J. Pharmacol. 66:703-712 (2000); Dahl, Acta Anaesthesiologica Scandinavica. 44: 1-13 (1991)). The specific drugs are the commonly used analgesics for mild and moderate pain like the NSAIDs,_paracetamol (acetaminophen) and acetylacetic acid. NSAIDs by inhibiting the cyclooxygenase, modulate the arachidonic acid cascade and hence the peripheral pain. Ketorolac is a NSAID, displaying potent analgesic and modest anti¬inflammatory activity. It has been evaluated for analgesic action and has found to be comparable to opioids and is primarily, being marketed for use in postoperative conditions. Ketorolac is further finding application in acute pain states of renal, colonic, migraine headache, cancer pain (DeAndrade et al., Orthopedics 17:157-166 (1994); Gillis et al., Drugs 53:139-188 (1997). Ketorolac appears particularly useful in treatment of pain due to bone metastates and cancer patients. Though opioids remain important drugs for severe postoperative pain, their regular use has limitations of possible occurrence of excess sedation or postoperative nausea and vomiting (PONV), drowsiness, respiratory depression, gastrointestinal and bladder dysfunction, development of addiction, which can delay patient recovery and discharge. Ketorolac does not produce respiratory depression or cause drug dependence thus has clear advantages over opioids. The drug may be particularly useful when opioid therapy is contraindicated, in balanced analgesia regimens and when an opioid sparing effect or avoidance of respiratory depression is desired. The economic implications of using ketorolac versus an opioid drug as the primary analgesic in the postoperative settings has been investigated in retrospective cohort studies of hospitalized patients and have demonstrated an overall rapid recovery, shorter hospital stay and reduction in hospitalization cost (Gillis et al., Drugs 53:139-188 (1997)). Intramuscular ketorolac is indicated for short-term management (upto 5 days) of postoperative pain. The current recommendation for the use of ketorolac for postoperative pain in UK and US is at a dose of 30 mg every 4-6 hr for not more than five days. Thus the dosage regimens of intermittent administration of aqueous ketorolac tromethamine injection during the acute postoperative phase explains the requirement for a sustained release formulation which would reduce the frequency of administration, decrease the possible occurrence of side effects and thus lessen the patients agony. Ketorolac is marketed as a racemate, the S (-) enantiomer is more biologically active than the R (+) enantiomer. Ketorolac tromethamine, IH-Pyrrolizine-l-carboxylic acid, 5-benzoyl-2,3-dihydro, (±)-, compound with 2-amino-2-(hydroxymethyl)-l,3-propanediol (1:1) is a freely water soluble salt (U.S.P. 24/NF 19 United States Pharmacopoeia! Convention Inc. Rockville M.D. 946-948 (1999)). At physiological pH, the salt form dissociates to from a free anionic molecule, which is less hydrophilic. Ketorolac follows linear kinetics and has characteristics of two-compartment model (Mroszczak et al., Drug Metab. Disposition 15:618-626 (1987)). It has been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice. Parenteral preparations are generally not preferred due to their invasive nature, but in acute conditions and emergency states they prove to be essential and efficacious over other delivery routes. However, a parenteral sustained release therapy would be favored over a multiple injection schedule of a conventional parenteral dosage form. Majorly, the subcutaneous and intramuscular routes have been explored for administration of parenteral sustained release dosage form. Several pharmaceutical approaches may be applied for development of a parenteral controlled-release or sustained-release formulation. Methylcellulose and carboxymethylcellulose are safe, parenterally acceptable hydrocolloids that have been reported to achieve a sustained release preparation on the basis of viscosity enhancing phenomenon. Certain polymers form a dissociable complex with the drug hence delay its release (Leung et al., Controlled Drug Delivery (1987)). Suspensions can be utilized to control drug delivery with major rate controlling step being the dissolution of drug. The system has to be optimized in terms of stability, syringeability, and pain on injection, minimum effective concentration. Suspensions pose problem with respect to physical instability due to ostwald ripening and pain at the site of injection. Many limitations of the aqueous suspension carrier dosage form such as control of particle size, chemical instability in water, polymorphism etc. can be overcome by the use of oleaginous vehicle. Parenteral controlled release systems can be achieved by an oil system. Some of the oils acceptable for intramuscular injection are sesame oil, olive oil, arachis oil, maize oil, cottonseed oil and castor oil. Encapsulation-type depot preparations can be fabricated from biodegradable or bioabsorbable macromolecules. Typical examples of these systems are liposomes, micospheres, micro and nunoparticles The drug is suspended in a biodegradable/bioerodible polymer and then the particle size is reduced to 200 u,m in diameter (typically microspheres of 50-100 u.m in diameter are preferred for subcutaneous and intramuscular delivery. Some examples of biodegradable/bioerodible polymers are polyglactin 910, poly (isobutyl cyanoacrylate), poly(2-hydroxyethy-L-glutamine), poly(lactic acid). However, the above discussed microparticulate systems have limited application. The processes available to make parenteral microcapsules/microspheres are few and difficult to validate with respect the parameters critical for release of drug and have rigorous manufacturing requirements. Limited number of excipient acceptable for parenteral use, and the limited number of pharmaceutically acceptable solvents and other processing aids add to the hurdles. Product formulated with desired properties should be able to combat any changes that tend to occur during transport and storage (i.e. throughout its shelf life). Liposomes require considerable preparation time, have low stability, and only a small amount of drug can be encapsulated within the small particles and released with time. In addition, because liposomes are small particles, they are poorly retained at the implantation site. Non-polymeric materials have been described for use as solid drug delivery matrices. Examples include cholesterol in the form of pellets for dispensing steroids (Shimkin et al., Endocrinology 29:1020 (1941)) and phospholipids. More recently, biodegradable polymers that have been used in drug delivery devices are lactide, glycolide, epsilon-caprolactone and copolymers thereof (Yolles, U.S. Pat. No. 3,887,699; Kent, U.S. Pat. No. 4,675,189; Pitt, U.S. Pat. No. 4,148,871; Schindler, U.S. Pat. No. 4,702,917), polyorthoesters and polyanhydrides have also been used as bioerodible matrices for drug release and as medical devices (U.S. Pat. Nos. 4,093,709 and 4,138,344, Choi and Heller; U.S. Pat. No. 4,906,474, Domb and Langer, M.I.T.). These polymers are solids at room temperature and, and are inserted into the body by surgical procedures. If prepared as microparticles, microspheres, microcapsules or nanoparticles, such forms can be injected into the body using standard syringes and needles. U.S. Pat. No. 4,938,763 (Dunn) describes methods and compositions in which biodegradable polymers are combined with biocompatible solvents to form a composition that can be administered into the body, whereupon they coagulate or precipitate upon contact with aqueous body fluid to form a solid implant for use as a medical device. These systems find application in long-term therapies and are not suited for delivery over short periods like a few days. In situ gelling systems made of polymeric/non polymeric complexes can be utilized as drug delivery systems based on their ability to undergo sol-gel transformation. Thus, injectable parenteral sustained release drug delivery systems may be developed that undergo reversible phase transformations. Numerous examples of these systems have been reported as novel drug delivery systems. Poloxamers or Pluronics are poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers which exhibit phenomenon of reverse thermal gelation, inter polymeric complex of polymethacrylic acid and polyethylene glycol in hydroalcholic solvent system and graft copolymers that are temperature sensitive polymer (N-isopropyl acrylamide, NIPAAm) grafted on to pH sensitive backbone of PAAc (polyacrylic acid) (Haglund et al., J. Control. Rel. 41:229-235 (1996); Chen et al., Nature 373:49-52 (1995)). The key factors in designing an injectable microsphere delivery system is to choose an appropriate polymeric excipient. The selected polymer should be suitable in terms of tissue compatibility, biodegradation kinetics, drug compatibility, drug permeability, mechanical properties and ease of processing. Objects of the Invention The main object of the invention is to provide a prolonged release injectable preparation of ketorolac using ketorolac free acid or its salts Another object of the invention is to obtain prolonged release of ketotrolac by using poly vinyl pyrrolidone in an aqueous medium, as the rate-retarding agent. Another object of the invention is to obtain prolonged release of ketorolac by using vegetable oil - castor oil as the vehicle. Another object of the invention is to obtain prolonged release of ketorolac by using hydrophobic non-polymeric material glycerol monoleate as the rate-retarding agent. Another object of the invention is to reduce the frequency of administration of injectable ketorolac formulations per day, for analgesic treatment. Another object of the invention is to provide liquid injectable dosage forms including stabilizers, complexing agents, antoxidants, preservatives, isotonicifiers, solubilizers, viscosity modifying agents, pH modifying agents and vehicles. Another object of the invention is to decrease the side effects associated with parenteral therapy of ketorolac. Still yet another object of the invention is to provide analgesia by intra-muscular administration of the formulation. Further object of the invention is to provide analgesia by intra-muscular administration of the formulation in combination with other analgesic drugs given by parenteral or other route of administration. Summary of the Invention Accordingly, the present invention provides a synergistic intra-muscular injectable formulation containing ketorolac or its salts, a rate retarding agents such as hydrophilic polymer - polyvinyl pyrrolidone and / or vegetable oil (castor oil) as the vehicle and / or a hydrophobic non-polymeric agent glycerol monoleate and parenterall acceptable excipient and a process for the preparation of the same Brief Description of the Drawings Figure 1: In vitro release profile of K2, K3 and K4 in comparison with Kl (mean ± S.D.) across hydrophilised polytetrafluoroethylene (PTFE) filter membrane, pore size 0.45 /im. Figure 2: Comparison of percentage analgesic response in acetic acid induced writhing test in mice produced by formulations K2, K3, K4 and conventional formulation Kl after 15 min and 4 hrs of intramuscular injection (mean ± S.E.M). Figure 3: Percentage analgesic response produced by Kl and K2 in acetic acid induced writhing test in mice (mean ± S.E.M), n = 6. Figure 4: Percentage analgesic response produced by Kl and K3 in acetic acid induced writhing test in mice (mean ± S.E.M), n = 6. Figure 5: Percentage analgesic response produced by Kl and K4 in acetic acid induced writhing test in mice (mean ± S.E.M), n = 6. Figure 6: Drug blood concentration vs time profile of Kl (dose: 7.5 mg/kg) and K4 (dose: 21.25 mg/kg) after intramuscular administration (mean ± S.D.), n = 4. Figure 7: Drug blood concentration vs time profile of Kl (dose: 7.5 mg/kg) and K3 (dose: 21.25 mg/kg) after intramuscular administration (mean ± S.D.), n = 4. Brief description of the table Table 1: Comparison of the pharmacodynamic characteristics obtained from single dose administration of formulations Kl to K4. Detailed Description of the Invention Accordingly the present invention provides a synergistic formulation as prolonged release injectable for relieving pain, the said composition comprising: a a ketorolac or its water soluble derivative, b at least a rate retarding agent selected from hydrophilic polymer, vegetable oil or hydrophobic non-polymeric compound; and c optionally, one or more parentally acceptable excipient such as herein described, wherein, the ketorolac drug is in intimate association with rate retarding agent, in an amount effective to prolong the release of the drug and also substantial part of the drug is present in solubilised state. An embodiment of the invention provides a formulation, wherein the ketorolac is present as a free acid. Another embodiment, the ketorolac water-soluble derivative is ketorolac tromethamine. Still another embodiment, the hydrophilic polymer used as a rate retarding agent is selected from polyvinylpyrrolidone, povidonum, polyvidone, poly(l-vinyl-2-pyrrolidone), PVP or mixtures thereof. Still another embodiment, the polymer is present in an amount of 0.1 to 10.0 w/v % of the total formulation. Yet another embodiment, the ketorolac drug concentration is in the range of 15 mg/ml to 120 mg/ml. Still another embodiment of the invention provides a formulation in which the vegetable oil used as a rate retarding agent is selected from a group consisting of castor oil, ricinous oil, tangantangan or mixtures thereof. In yet another embodiment, the hydrophobic non-polymer compound used as release rate retardant is selected from a group consisting of glycerol monooleate (9-octadecenoic acid (Z)-monoester, 1,2,3 - propanetriol, monolein or peceol. Yet another embodiment, the parenterally acceptable pharmaceutical excipient is selected from group consisting of benzyl alcohol, benzylbenzoate, ethyl alcohol, polyethyleneglycol, glycerol, propylene glycol, sodium chloride, dextrose, mannitol, xylitol, sodium metabisulphite, sodium sulphite, ascorbic acid, cystein or mixtures thereof. Still another embodiment, the concentration of benzyl alcohol used is in the range of 0.1 to 10 w/w %, preferably 1 to 7 w/w % and more preferably 2 to 6 w/w %. In yet another embodiment, the rate-retarding agent is used in combination thereof, in an amount effective to prolong the release of drug substance. One embodiment of the invention provides wherein hydrophilic polymer used is polyvinylpyrrolidone. Another embodiment, polyvinyl pyrrolidone is used as rate-retarding agent in the range of 0.1 to 10% w/v, preferably in the range of 0.5 to 2% and still more about 0.75 to 1.25 % w/v. Another embodiment of the invention castor oil is used as rate retarding agent in the range of 90 to 99.9% w/v, preferably about 93 to 99% and still more preferably in the range of 94 to 98% w/v. Another embodiment of the invention castor oil is used in combination with benzyl alcohol in the range of 0.1 to 10% w/v, preferably about 1 to 7% and still more preferably in the range of 2 to 6% w/v. Another embodiment, glycerol monoleate is used as the rate-retarding agent in the range of 65 to 97% w/v, more preferably 80 to 96% w/v and still more preferably 90 to 96% w/v Another embodiment of this invention ketorolac - as free acid or as its water soluble derivative - is present in the concentration of 15 to 120 mg/ml, preferably 30 to 105 mg/ml and more preferably 30 to 50 mg/ml. In yet another embodiment of this invention, the ketorolac is present as a free acid and its water soluble derivative is ketorolac tromethamine. In yet another embodiment, parenterally acceptable excipients are isotonicifiers selected from sodium chloride, dextrose, mannitol, xylitol, glycerol; antoxidants from sodium metabisulfite, sodium sulphite, ascorbic acid; complexing agents from citric acid, disodium edetate; pH modifying agents from sodium hydroxide, hydrochloric acid; preservative from benzyl alcohol, phenol, ethyl alcohol; vehicles from water, glycerol, poly ethylene glycol, propylene glycol and ethyl alcohol. In yet another embodiment, the formulation may be presented in the form of an ampoule, vial, pre-filled syringe or any other presentation acceptable for parenteral administration. Yet one more embodiment of the present invention provides a process for preparation of injectable composition using different rate (release) retarding agents, the said process consisting of: a) For polyvinyl pyrrolidone as a rate-retarding agent - dissolving ketorolac tromethamine in water, adding and dissolving polyvinyl pyrrolidone, adding ethyl alcohol as the preservative, filtering through a 0.22 microns sterile membrane filter made of Nylon or cellulose acetate and aseptically filling into ampoules, vials, pre-filled syringes or any other suitable pack. b) For castor oil as a rate retarding agent - Dissolving ketorolac in benzyl alcohol by stirring; adding castor oil; aseptically filtering through 0.22-micron membrane filter and aseptically filling into ampoules, vials, pre-filled syringes or any other suitable pack. c) For glycerol monoleate as a rate-retarding agent - Dissolving ketorlac in water and slowly adding to glycerol monoleate with stirring, adding ethyl alcohol as the preservative; filtering through 0.22 micron membrane filter and aseptically filling into ampoules, vials, pre-filled syringes or any other suitable pack. In an another embodiment of the present a process for the preparation a synergistic pharmaceutical formulation as prolonged release injectable for relieving pain, the said process comprising steps of: i) dissolving ketorolac or its derivative in water, ii) adding at least a rate retarding agent selected from hydrophobic polymer or vegetable oil or hydrophobic non-polymer compound to step (i) solution to dissolve, iii) adding a parenterally acceptable excipient to step (ii) solution and filtering aseptically through 0.22 micron membrane filter, and, iv) filling the aseptically obtained solution of step (c) in ampoule, vials, pre-filled syringes or any other suitable pack. Another embodiment of the invention provides a process, the hydrophilic polymer used is selected from polyvinylpyrrolidone, povidonum, polyvidone, poly(l-vinyl-2-pyrrolidone), PVP or mixtures thereof. In an another embodiment of the present invention relates to an intramuscular "prolonged release" formulation of ketorolac for human and veterinary use. The term "prolonged release" as used herein, means that the activity of the therapeutic agent is extended beyond the time period normally achieved when the therapeutic agent is injected into a host using a conventional, prior art carrier. As conventional injectable formulations are well known in the art, a skilled practitioner could readily understand the meaning of the term. The desired system was achieved by employing hydrophilic and hydrophobic excipient with release rate retarding properties and other properties required in an injection formulation. Polyvinylpyrrolidone (Kollidon® 17 PF) BASF, Germany, glycerylmonooleate (Peceol), Gattafosse, France and castor oil (Castor oil U.S.P.) were used. In yet another embodiment of the present invention, release rate-retarding agent, include any material, which substantially reduces release of ketorolac from the injection formulation, in the biological system. The term "substantially " with respect to reducing release rate includes completely inhibiting, preventing, slowing, delaying, decreasing or restricting release of ketorolac from the formulation to a measurable degree. It will be understood that both selection of release rate retardants and its amount used in the formulation of the invention should fulfill general requirements of safety, toxicity, Theological properties, bio-compatibility and other pharmaceutical parameters prescribed for injection formulations. In still another embodiment of the present invention, a few suitable excipient that can be used as release rate retardants include, either alone or in combination, polymers like polyvinylpyrrolidine eg. Kollidone 12 PF and Kollidon 17 PF of BASF, Germany. Sodium carboxymethylcellulose (eg. Na CMC, Hi media, India), vegetable oils (eg. castor, sesame, mustard, olive, arachis, maize, cottonseed, safflower and soybean oil), acacia, tragacanth, either alone or in combination with benzyl alcohol, block copolymers of ethylene oxide and propylene oxide (eg. Poloxamers, Pluronic F), glycerol monoleate and glycerol monolinoleate. In yet another embodiment of the present invention, PVPs vary in their molecular weight and viscosity PVP used for ketorolac injection formulation should have a molecular weight of less than 25,000, preferably about 10,000 to 20,000. An example of this would be Koliidone 12 PF and Kollidon 17 PF from BASF, Germany. PVPs used in present invention are available under brandnames Kollidon (BASF, Germany and Plasdone C (ISP, U.S.A.). In still yet another embodiment of the present invention, ketorolac prolonged release injection formulations, for example ketorolac formulation containing PVP, presence of PVP in solubilised state alongwith ketorolac is believed to retard the release of the drug by interaction with drug molecules via electrostatic bonds (ion to ion, ion to dipole, dipole to dipole bonds) or vander waal forces and hydrogen bridges to form a complex and thus influence the availability of drug as well as the rate of drug transfer from aqueous drug formulation. A ketorolac-PVP formulation of this embodiment preferably comprises about 0.1 to 10 % w/v of PVP, preferably about 0.5 to 2% w/v and still more preferably about 0.75 to 1.25 % w/v of PVP. Ketorolac may be present in this formulation preferably to 1.5 mg to 120 mg/ml; more preferably about 3 mg to 105 mg and still more preferably about 30 to 50 mg/ml. In another embodiment of the present invention, the preferred vegetable oil used for ketorolac injection formulation of present invention would be castor oil, as it allows solubilisation of desired levels of ketorolac free acid. A ketorolac-castor oil formulation of this embodiment preferably comprises about 90 to 99.9 % w/v of castor oil, preferably about 93 to 99 % w/v and still more preferably about 94 to 98 % w/v of castor oil. Benzyl alcohol in the concentration of 0.1 to 10 w/w, preferably about 1 to 7% w/w and more preferably 2 to 6 % w/w can be added to aid in solubilisation of ketorolac and also to reduce local pain at the site of injection. Ketorolac may be present in this formulation preferably to 1.5 mg to 120 mg/ml; more preferably about 3 mg to 105 mg and still more preferably about 30 to 50 mg/ml. In ketorolac prolonged release injection formulations, for example ketorolac formulation containing castor oil, presence of castor oil in solubilised state along with ketorolac is believed to retard the release of the drug by partitioning of drug from the oil system into the surrounding aqueous phase. Apparent partition coefficient (k) of the drug then governs the dynamic equilibrium between oil and aqueous phase. In still another embodiment of the present invention, the preferred hydrophobic non-polymeric release rate-retarding agent for the present invention would be glycerol monooleate. A ketorolac-glycerol monooleate formulation of this embodiment preferably comprises about 65 % to 97 % w/v of glycerol monooleate, more preferably about 80 to 96 % w/v and still more preferably about 90 to 96 % w/v of glycerol monooleate. Ketorolac may be present in this formulation preferably to 1.5 mg/ml to 120 mg/ml; more preferably about 3 mg/ml to 105 mg/ml and still more preferably about 30 mg/ml to 50 mg/ml. In ketorolac prolonged release injection formulations, for example ketorolac formulation containing glycerol monooleate, presence of glycerol monooleate in solubilised state alongwith ketorolac is believed to retard the release of the drug due to spontaneous formation of a transparent and stiff gel like structure called cubic phase, when placed in aqueous medium. Glycerol monooleate undergoes phase transitions in response to changes in composition (% water content) and temperature conditions and forms a depot system which can control the release based on diffusional exchange of water from the surrounding medium into the matrix (Wyatt, Pharm. Technol. 116-122 (1992); Engstrom et al., Int. J. Pharm. 86:137-145 (1992)). Glycerol monooleate is metabolized by the lipase enzyme in the body to glycerol and oleic acid. Various works have been published on the incorporation of drugs such as lidocaine, clotrimazole, vitamin E (Ganem-Quintanar et al., Drug Dev. & Ind. Pharm. 26:809-820 (2000); Malonne et al., Bio. Pharm. Bull. 23:627-631 (2000)). In still another embodiment of the present invention, ketorolac tromethamine or ketorolac free acid and rate retarding excipient can be further formulated together with one or more pharmaceutical composition. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling, storage, stability or to permit formulation suitable for parenteral administration. Excipient include, by way of illustration and not limitation, vehicle, isotonicifier, antioxidant, solubiliser, preservative, viscosity modifying agents, pH modifying agent, complexing agent etc. Non limiting examples of excipient that can be used to prepare pharmaceutical composition of the invention comprise one or more pharmaceutically acceptable isotonicifier as excipient. Suitable isotonocifier illustratively include sodium chloride, dextrose, mannitol, xylitol, glycerol and the like. Such isotonocifiers, if present, constitute a percentage sufficient to exert osmotic pressure nearly equal to that of biological tissues. Antioxidants may include one or more pharmaceutically acceptable antioxidants like sodium metabisulphite, sodium sulphite, ascorbic acid, EDTA etc. Antioxidants may be added in concentration sufficient to prevent oxidative degradation of the drug, without causing toxicity to the biological system. pH modifying agent such as sodium hydroxide and hydrochloric acid were used to maintain the pH of the composition within the range of 6.9 to 7.9. In still yet another embodiment of the present invention, the ketorolac dosage form of the invention preferably comprise ketorolac in a daily dosage of 1.5 mg/ml to 120 mg/ml; more preferably about 3 mg/ml to 105 mg/ml and still more preferably about 30 mg/ml to 50 mg/ml. Composition of the invention comprises one or more injection dose units. Each dose unit comprises ketorolac in a therapeutically effective amount that is preferably about 15 mg to 120 mg. The term " dose unit" herein means a portion of a pharmaceutical composition that contains an amount of a therapeutic or prophylactic agent, in the present case ketorolac, suitable for a single injectable administration to provide a therapeutic effect. Administration of such doses can be repeated as required, typically at a dosage frequency of one to about four times per day. It will be understood that therapeutically effective amount of ketorolac for a subject is dependent interalia on the body weight of the subject. A "subject" herein, to which a therapeutic agent or composition thereof can be administered, includes a human patient of either sex and of any age, and also includes any non human animal, particularly a warm blooded animal. Typical dose units in a composition of the invention contain about 5,10, 15, 20, 30, 40, 50, 60, 80 or 100 mg/ml of ketorolac. Especially preferred amounts of ketorolac per dose unit, for humans would be 30 mg/ml to about 50 mg/ml. The above composition is not a mere admixture. In fact, it is a synergistic composition having unexpected properties which are not anticipated or obvious to a person skilled in the art. The properties such as prolonged release is excellent when compared with conventional compositions. The following examples illustrate aspects of the present invention but are not to be construed as limitations. EXAMPLES Conventional formulation Kl for immediate release was prepared in following manner -Ketorolac tromethamine - 30 mg/ml; Water for injection q.s. 1ml and having pH 7.2 Example 1 A formulation K2 was prepared using PVP, in the following manner- Ketorolac tromethamine- 42.5 mg per ml Polyvinylpyrrolidone (Kollidone® 17 PF) - 0.9 % w/v Water for injection q.s. to 2ml pH7.2 Accurately weighed amount of Ketorolac tromethamine was dissolved in water. Polyvinylpyrrolidone (Kollidone® 17 PF) was added and the solution was stirred and then degassed. The preparation was sterilized by filtration through 0.22 fim polyvinylidene fluoride filter membrane and collected in presterilized vessel. The preparation was then filled in ampoules in Class 100 environment and sealed under nitrogen purging. Example 2 A formulation K3 was prepared using castor oil, in the following manner-Ketorolac free acid - 28.83 mg per ml Benzyl alcohol 4 % w/v Castor oil q.s. 2 ml pH 7.2 Ketorolac was added to the benzyl alcohol in small amounts and dissolved by continuous stirring. Further presterilized castor oil was oil was added. The solution was stirred for obtaining homogenous solution and then degassed. The preparation was then filled in ampoules in Class 100 environment and sealed under nitrogen purging. Example 3 A formulation K4 was prepared using glycerol monooleate, in the following manner- Ketorolac tromethamine - 42.5 mg/ml Water for injection - 5 % w/v Glycerol monooleate (Peceol) q.s. 2 ml pH7.2 The drug was dissolved in water 5% w/v and then added slowly under continuous stirring in glycerol monooleate. The viscous solution was stirred to obtain homogenous mix and the degassed. The preparation was sterilized by filtration through 0.22 /im polyvinylidene fluoride filter membrane and collected in presterilized vessel. The preparation was then filled in ampoules in Class 100 environment and sealed under nitrogen purging In vitro release: Modified Franz diffusion cell was designed to perform in vitro release studies of the formulation Kl to K4 across hydrophilised polytetrafluroethylene (PTFE) pore size 0.45 p.m. Samples were withdrawn at predetermined time points and replaced with buffer maintained at 37 °C. Samples were analyzed UV spectrophotometrically at A.max 323 nm. Cumulative amount of drug released per cm sq. vs time across the synthetic membranes is shown in Figure 1. The release profile obtained for aqueous ketorolac tromethamine 30 mg per ml was considered, as the fastest release that can be achieved, as the support membrane was the only release-controlling factor. The release profiles were compared on the basis of cumulative amount of drug released per cm sq. in twelve hours (Mn) from the formulations. The formulations may be ranked for the drug release sustaining capacity, in which maximum retardation was shown by K3 followed by K4 and K2. Example 4 Pharmacodynamic evaluation: Performance in animal models Male Swiss Albino mice of weight 16-25 g were fasted overnight before the experiment and water was allowed ad libitum throughout the study. Acetic acid induced Writhing test was performed to determine the analgesic response of drug formulation administered intramuscularly (Domer, Eur. J. Pharmacol. 177:127-135 (1992)). Saline or the formulation K2 to K4 was injected intramuscularly at predetermined time points before administration of 3% v/v acetic acid (0.01 ml/g) i.p. The number of writhing displayed by each mouse was counted for 20 minutes after the administration of acetic acid. Percentage response for the formulations was calculated considering the peak response by conventional formulation Kl as the maximal possible effect (Vogel et al., Drug Discovery and Evaluation 360-420 (1997)). Control and standard response was determined by injecting saline and conventional formulation Kl intramuscularly respectively at different time points. Further formulations K2 to K4 were administered and percentage response was calculated at different time points. The pharmacodynamic percentage response vs time profile for Kl formulation (dose 7.5 mg/kg) was generated. Maximum response is produced after approximately 15 min of administration and reduces to less than 50 % after 4 hrs. The formulations K2 to K4 were injected to mice at the same dose level (dose 7.5 mg/kg) and response was measured at two time points i.e. 15 min and 4 hrs after administration. Figure 2 shows the comparative percentage response produced for the test formulations. For achieving a therapeutically optimum formulation, it is essential that the formulation produced early onset (within 15-30 min) and a prolonged action. Subsequently, K2 to K4 were given at dose level of 21.25 mg/kg for the pharmacodynamic and pharmacokinetic evaluation of prolonged activity the formulations. Pharmacodynamic response obtained for K2, K3 and K4 (dose: 21.25 mg/kg) was compared to that of Kl (dose: 7.5 mg/kg), as showed in Figure 3, 4 and 5 respectively. The dotted line in the figures is the cut off for desired analgesic response i.e. 70 % response of peak analgesia. The slow release formulations can be assessed by characteristics such as half value duration (HVD, plasma level for classical HVD), plateau time or T 70% peak response (Cmax for classical T 70%). The T 70% response, i.e. the time interval for which the analgesic level is superior to or equal to T 70% of peak analgesia produced by aqueous drug solution, was calculated. The ratio of T 70% response of test and aqueous solution was calculated and listed in Table 2. The values suggested that K3 and K4 were most efficient in drug release retardation. The drug blood concentration at the T 70% analgesic response was determined from the pharmacokinetic plot of formulation Kl. Hence correlating the pharmacodynamic response with the pharmacokinetic profile, the desired drug blood concentration range Css max and Css „„„ to be attained were taken as C^ ± 25%, which were 51.39 meg/ml and 30.0 meg/ml respectively (shown as dotted lines in figure 6 & 7). The drug blood concentration vs time profile of formulations, K3 and K4 was compared with that of Kl. Example 5 Pharmacokinetic evaluation For evaluation of each formulation, three groups, of four mice each, were taken. Zero hour blood sample was collected by intraocular route and then formulation was injected intramuscularly. At each time point sample was collected from one group and from each group blood was collected at three time points. From a mice. 0.25 ml of blood was collected at each sampling time point and then 0.25 ml saline was administered i.p. Blood was collected in heparinised micro centrifugation tube, plasma was immediately separated and stored at - 22° C until analyzed. It was extracted with 0.9 ml methanol by vortex mixing for 3-4 min and then centrifuged at 13,000 rpm for 30 min. 0.8 ml of supernatant was separated and evaporated to dryness and reconstituted in mobile phase, vortex mixed for 3-4 min and then centrifuged at 13,000 rpm for 15 min. Aliquots of 100 ul. were injected into the HPLC with UV spectrophotometeric detection at 313 nm. A Shimadzu HPLC (SPD-10 AVP, Japan) was used. Chromatographic column used was Lichrosphere 100 RP-18e (250 x 4, 5u,m, Merck, Germany) and mobile phase constituted of acetonitrilerwater adjusted to pH 3.0 + 0.01 with 85% orthophosphoric acid in ratio 40:60 with flow rate 1 ml/min. The method was linear over the range of 2.5 meg/ml to 100 meg/ml. Single dose of Kl (7.5 mg/kg) was administered intramuscularly to mice and it was observed (Figure 6) that Cmax was attained in approximately 15 minutes and the concentration reduced significantly between 2nd and 4th hour. Similar trend was observed in the pharmacodynamic response where peak analgesic effect was seen at 15 minutes, which then dropped to less than 50% at the 4th hour (Figure 3). The reported terminal half-life of ketorolac in mice is 3.8 hrs. Here formulation K4 (Figure 6) produced drug blood levels higher than the desired drug blood levels in the initial period (0-2nd hr) and then further generated prolonged plateau drug blood levels for approximately 9 hrs (2nd to 11th hr) and beyond that concentration falls below the C min desired. K3 (Figure 7) produced higher drug blood levels (> Cmax des) and maintained the drug concentration levels above Cmin for time periods (7-8 hrs). The pharmacokinetic characteristic, T 80% of Cmax, was calculated for formulations to assess the slow release behavior on the basis of single dose studies. K4 maintained drug blood concentration above the desired C min for 12 hrs and K3 maintained drug blood concentration above the desired C mjn for 8 hrs.The formulation K4 behaved in the most favorable manner proving the sustaining property of the formulation. Glycerol monooleate can form a depot system, which can control the release based on diffusional exchange of water from the surrounding medium into the matrix that follows square root of time dependent drug release kinetics. However, it is essential that the cubic phase formed remains in equilibrium and the drug incorporated does not disrupt the formation of cubic lattice system in vivo. This could be a possible explanation for the fast release observed in the early period of formulation administered. Example 6: Utility of composition of invention Ketorolac, a non anti-inflammatory drug is primarily used for its analgesic activity. The trometamol salt is used for short-term management of broad-spectrum pain that requires analgesia at the opioid level, usually in postpartum and postoperative pain, cancer pain, pain of dental extraction. It has been employed in pain relief from major and minor surgery such as abdominal, orthopedic, gynecological surgeries. Ophthalmic ketorolac tromethamine is used to relieve ocular itching associated with seasonal allergic conjunctivitis. Used for topical treatment of cytoid macular edema and for prevention of ocular inflammation associated with cataract surgery. Indicated for the short-term ( Example 7 Method of treatment The present invention is further directed to a therapeutic method of treating a condition or disorder where treatment with NSAIDs is indicated, the method comprising intramuscular administration of a composition of the invention to a subject in need thereof. The dosage regimen to prevent, give relief from, or ameliorate the condition or disorder preferably corresponds to once-a-day or twice-a-day treatment, but can be modified in accordance with a variety of factors. These include the type, age, weight, sex, diet and medical condition of the subject and the nature and severity of the disorder. Thus, the dosage regimen actually employed can vary widely and can therefore deviate from the preferred dosage regimens set forth above. Initial treatment can begin with a dose regimen as indicated above. Subjects undergoing treatment with a composition of the invention can be routinely monitored by any of the methods well known in the art to determine effectiveness of therapy. Continuous analysis of data from such monitoring permits modification of the treatment regimen during therapy so those optimally effective doses are administered at any point in time, and so that the duration of treatment can be determined. In this way, the treatment regimen and dosing schedule can be rationally modified over the course of therapy so that the lowest amount of the composition exhibiting satisfactory effectiveness is administered, and so that administration is continued only for so long as is necessary to successfully treat the condition or disorder. The present compositions can be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i. e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others. Preferred combination therapies comprise use of a composition of the invention with one or more compounds selected from aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis (acetylsalicylate), amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate, antrafenine, apazone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, bezitramide, a-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butophanol, calcium acetylsalicylate, carbamazepine, carbiphene, carprofen, carsalam, chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin, clopirac, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cropropamide, crotethamide, desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium, difenamizole, difenpiramide, diflunisal, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epirizole, eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunoxaprofen, fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid, glafenine, glucametacin, glycol salicylate, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, p-lactophenetide, lefetamine, levorphanol, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine, metazocine, methadone hydrochloride, methotrimeprazine, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, piprofen, pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalte, salverine, simetride, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen. Table 1: Comparison of the pharmacodynamic characteristics obtained from single dose administration of test formulation. (Table Remove) Burke, J. P., Pestotnik, S. L., Classen, D. C. et al. Evaluaiton of the financial impact of ketorolac tromethamine therapy in hospitalized patients. Clin. Ther. 18, 197 (1996) Trotter, D. M., Warson, J. S., Wirt, T. C. et al. The use of ketorolac in lumbar spine surgery: a cost benefit analysis. J. Spinal Disord. 8, 206 (1995) Trotter, J. P., Reinhart, S. P., Kart, R. M. et al. Economic assessment of ketorolac vs narcotic analgesics in post operative pain management. Clin. Ther. 15, 938 (1993) United States Pharmacopeia 247 National Formulary 19. United States Pharmacopeia! Convention, Rockville, M.D. 946 (1999) Vogel, H. G., Vogel, W. H., Analgesia, anti-inflammatory and antipyretic activity. In: Drug discovery and evaluation, Springer, 360 (1997) Wyatt, D. M., A cubic-phase delivery system composed of glyceryl monooleate and water for sustained release of water-soluble drugs. Pharm. Technol. 16,116 (1992) We Claim: 1. A pharmaceutical composition for the treatment of postoperative pains comprising of ketorolac or its water soluble derivative in the range of 15 mg/ml to 120 mg/ml and rate retarding agent selected from hydrophilic polymer, vegetable oil or hydrophobic non-polymeric compound in the range of 0.1 to 10.0 w/v % of the total composition and optionally, one or more parenterally acceptable excipients in the range of 0.1 to 10 w/w % such as herein described. 2. A pharmaceutical composition as claimed in claim 1, wherein the ketorolac is present as a free acid. 3. A pharmaceutical composition as claimed in claim 1, wherein the ketorolac water soluble derivative is ketorolac tromethamine. 4. A pharmaceutical composition as claimed in claim 1, wherein the hydrophilic polymer used as a rate retarding agent is selected from the group of polyvinyl pyrrolidone, povidonum, polyvidone, poly(l-vinyl-2pyrrolidone), PVP or mixtures thereof. 5. A pharmaceutical composition as claimed in claim 1, wherein the vegetable oil used as a rate retarding agent is selected from a group of castor oil recinous oil, tengantangan or mixtures thereof. 6. A pharmaceutical composition as claimed in claim 1, wherein the hydrophobic non-polymer compound used as release rate retardant is selected from a group of glycerol monooleate, monolein or peceol. 7. A pharmaceutical composition as claimed in claim 1, wherein the parenterally acceptable pharmaceutical excipients is selected from the group of benzyl alcohol, benzyl benzoate, ethyl alcohol, polyethyleneglycol, glycerol, propylene glycol, sodium chloride, dextrose, mannitolxylitol, sodium metabisulphite, sodium sulphite, ascorbic acid, cystein or mixtures thereof. 8. A pharmaceutical composition as claimed in claim 7, wherein the concentration of benzyl alcohol used preferably is in the range of 1 to 7 w/v % and more preferably 2 to 6 w/v%. 9. A pharmaceutical composition as claimed in claim 1, wherein rate retarding agent is used in combination thereof. 10. A process for preparing the pharmaceutical composition as claimed in claim 1, wherein the said process comprising the following steps: a) dissolving ketorolac or its derivative in water, b) adding rate retarding agent selected from hydrophillic polymer or vegetable oil or hydrophobic non-polymer compound to step (a) solution to dissolve, c) adding a parentrally acceptable excipient to step (b) solution and filtering aseptically through 0.22 micron membrane filter, and, d) filling the aseptically obtained solution of step (c) in ampoule, vials, prefilled syringes or any other suitable pack. 11. A synergistic pharmaceutical composition and process for the preparation of said pharmaceutical composition substantially as herein described with reference to forgoing examples and drawings

Full Text

Filed of the Invention
The invention relates to prolonged release injectable pharmaceutical composition of ketorolac or its water-soluble derivatives. The invention also provides compositions made of hydrophilic or hydrophobic release modifying agent that can be used to provide a low viscosity, free flowing injectable preparation for use as a sustained drug delivery system.
Background of the Invention
Pain is an unpleasant sensational and emotional experience elicited by the activation of specific nociceptors. Pain derived from tissue injury is exhibited in the form of local edema, inflammation and hyperalgesia (Dahl et al., Br. J. Pharmacol. 66:703-712 (2000); Dahl, Acta Anaesthesiologica Scandinavica. 44: 1-13 (1991)). The specific drugs are the commonly used analgesics for mild and moderate pain like the NSAIDs,_paracetamol (acetaminophen) and acetylacetic acid.
NSAIDs by inhibiting the cyclooxygenase, modulate the arachidonic acid cascade and hence the peripheral pain. Ketorolac is a NSAID, displaying potent analgesic and modest anti¬inflammatory activity. It has been evaluated for analgesic action and has found to be comparable to opioids and is primarily, being marketed for use in postoperative conditions. Ketorolac is further finding application in acute pain states of renal, colonic, migraine headache, cancer pain (DeAndrade et al., Orthopedics 17:157-166 (1994); Gillis et al., Drugs 53:139-188 (1997). Ketorolac appears particularly useful in treatment of pain due to bone metastates and cancer patients.
Though opioids remain important drugs for severe postoperative pain, their regular use has limitations of possible occurrence of excess sedation or postoperative nausea and vomiting (PONV), drowsiness, respiratory depression, gastrointestinal and bladder dysfunction, development of addiction, which can delay patient recovery and discharge. Ketorolac does not produce respiratory depression or cause drug dependence thus has clear advantages over opioids. The drug may be particularly useful when opioid therapy is contraindicated, in balanced analgesia regimens and when an opioid sparing effect or avoidance of respiratory depression is desired. The economic implications of using ketorolac versus an opioid drug as the primary analgesic in the postoperative settings has been investigated in retrospective cohort studies of

hospitalized patients and have demonstrated an overall rapid recovery, shorter hospital stay and reduction in hospitalization cost (Gillis et al., Drugs 53:139-188 (1997)).
Intramuscular ketorolac is indicated for short-term management (upto 5 days) of postoperative pain. The current recommendation for the use of ketorolac for postoperative pain in UK and US is at a dose of 30 mg every 4-6 hr for not more than five days. Thus the dosage regimens of intermittent administration of aqueous ketorolac tromethamine injection during the acute postoperative phase explains the requirement for a sustained release formulation which would reduce the frequency of administration, decrease the possible occurrence of side effects and thus lessen the patients agony.
Ketorolac is marketed as a racemate, the S (-) enantiomer is more biologically active than the R (+) enantiomer. Ketorolac tromethamine, IH-Pyrrolizine-l-carboxylic acid, 5-benzoyl-2,3-dihydro, (±)-, compound with 2-amino-2-(hydroxymethyl)-l,3-propanediol (1:1) is a freely water soluble salt (U.S.P. 24/NF 19 United States Pharmacopoeia! Convention Inc. Rockville M.D. 946-948 (1999)). At physiological pH, the salt form dissociates to from a free anionic molecule, which is less hydrophilic. Ketorolac follows linear kinetics and has characteristics of two-compartment model (Mroszczak et al., Drug Metab. Disposition 15:618-626 (1987)).
It has been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice. Parenteral preparations are generally not preferred due to their invasive nature, but in acute conditions and emergency states they prove to be essential and efficacious over other delivery routes. However, a parenteral sustained release therapy would be favored over a multiple injection schedule of a conventional parenteral dosage form. Majorly, the subcutaneous and intramuscular routes have been explored for administration of parenteral sustained release dosage form.
Several pharmaceutical approaches may be applied for development of a parenteral controlled-release or sustained-release formulation. Methylcellulose and carboxymethylcellulose are safe, parenterally acceptable hydrocolloids that have been reported to achieve a sustained release preparation on the basis of viscosity enhancing phenomenon. Certain polymers form a dissociable complex with the drug hence delay its release (Leung et al., Controlled Drug Delivery (1987)).
Suspensions can be utilized to control drug delivery with major rate controlling step being the dissolution of drug. The system has to be optimized in terms of stability, syringeability,

and pain on injection, minimum effective concentration. Suspensions pose problem with respect to physical instability due to ostwald ripening and pain at the site of injection. Many limitations of the aqueous suspension carrier dosage form such as control of particle size, chemical instability in water, polymorphism etc. can be overcome by the use of oleaginous vehicle. Parenteral controlled release systems can be achieved by an oil system. Some of the oils acceptable for intramuscular injection are sesame oil, olive oil, arachis oil, maize oil, cottonseed oil and castor oil.
Encapsulation-type depot preparations can be fabricated from biodegradable or bioabsorbable macromolecules. Typical examples of these systems are liposomes, micospheres, micro and nunoparticles The drug is suspended in a biodegradable/bioerodible polymer and then the particle size is reduced to 200 u,m in diameter (typically microspheres of 50-100 u.m in diameter are preferred for subcutaneous and intramuscular delivery. Some examples of biodegradable/bioerodible polymers are polyglactin 910, poly (isobutyl cyanoacrylate), poly(2-hydroxyethy-L-glutamine), poly(lactic acid).
However, the above discussed microparticulate systems have limited application. The processes available to make parenteral microcapsules/microspheres are few and difficult to validate with respect the parameters critical for release of drug and have rigorous manufacturing requirements. Limited number of excipient acceptable for parenteral use, and the limited number of pharmaceutically acceptable solvents and other processing aids add to the hurdles. Product formulated with desired properties should be able to combat any changes that tend to occur during transport and storage (i.e. throughout its shelf life). Liposomes require considerable preparation time, have low stability, and only a small amount of drug can be encapsulated within the small particles and released with time. In addition, because liposomes are small particles, they are poorly retained at the implantation site.
Non-polymeric materials have been described for use as solid drug delivery matrices. Examples include cholesterol in the form of pellets for dispensing steroids (Shimkin et al., Endocrinology 29:1020 (1941)) and phospholipids. More recently, biodegradable polymers that have been used in drug delivery devices are lactide, glycolide, epsilon-caprolactone and copolymers thereof (Yolles, U.S. Pat. No. 3,887,699; Kent, U.S. Pat. No. 4,675,189; Pitt, U.S. Pat. No. 4,148,871; Schindler, U.S. Pat. No. 4,702,917), polyorthoesters and polyanhydrides have also been used as bioerodible matrices for drug release and as medical devices (U.S. Pat. Nos. 4,093,709 and 4,138,344, Choi and Heller; U.S. Pat. No. 4,906,474, Domb and Langer,

M.I.T.). These polymers are solids at room temperature and, and are inserted into the body by surgical procedures. If prepared as microparticles, microspheres, microcapsules or nanoparticles, such forms can be injected into the body using standard syringes and needles. U.S. Pat. No. 4,938,763 (Dunn) describes methods and compositions in which biodegradable polymers are combined with biocompatible solvents to form a composition that can be administered into the body, whereupon they coagulate or precipitate upon contact with aqueous body fluid to form a solid implant for use as a medical device. These systems find application in long-term therapies and are not suited for delivery over short periods like a few days.
In situ gelling systems made of polymeric/non polymeric complexes can be utilized as drug delivery systems based on their ability to undergo sol-gel transformation. Thus, injectable parenteral sustained release drug delivery systems may be developed that undergo reversible phase transformations. Numerous examples of these systems have been reported as novel drug delivery systems. Poloxamers or Pluronics are poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers which exhibit phenomenon of reverse thermal gelation, inter polymeric complex of polymethacrylic acid and polyethylene glycol in hydroalcholic solvent system and graft copolymers that are temperature sensitive polymer (N-isopropyl acrylamide, NIPAAm) grafted on to pH sensitive backbone of PAAc (polyacrylic acid) (Haglund et al., J. Control. Rel. 41:229-235 (1996); Chen et al., Nature 373:49-52 (1995)). The key factors in designing an injectable microsphere delivery system is to choose an appropriate polymeric excipient. The selected polymer should be suitable in terms of tissue compatibility, biodegradation kinetics, drug compatibility, drug permeability, mechanical properties and ease of processing.
Objects of the Invention
The main object of the invention is to provide a prolonged release injectable preparation of ketorolac using ketorolac free acid or its salts
Another object of the invention is to obtain prolonged release of ketotrolac by using poly vinyl pyrrolidone in an aqueous medium, as the rate-retarding agent.
Another object of the invention is to obtain prolonged release of ketorolac by using vegetable oil - castor oil as the vehicle.
Another object of the invention is to obtain prolonged release of ketorolac by using hydrophobic non-polymeric material glycerol monoleate as the rate-retarding agent.

Another object of the invention is to reduce the frequency of administration of injectable ketorolac formulations per day, for analgesic treatment.
Another object of the invention is to provide liquid injectable dosage forms including stabilizers, complexing agents, antoxidants, preservatives, isotonicifiers, solubilizers, viscosity modifying agents, pH modifying agents and vehicles.
Another object of the invention is to decrease the side effects associated with parenteral therapy of ketorolac.
Still yet another object of the invention is to provide analgesia by intra-muscular administration of the formulation.
Further object of the invention is to provide analgesia by intra-muscular administration of the formulation in combination with other analgesic drugs given by parenteral or other route of administration.
Summary of the Invention
Accordingly, the present invention provides a synergistic intra-muscular injectable formulation containing ketorolac or its salts, a rate retarding agents such as hydrophilic polymer - polyvinyl pyrrolidone and / or vegetable oil (castor oil) as the vehicle and / or a hydrophobic non-polymeric agent glycerol monoleate and parenterall acceptable excipient and a process for the preparation of the same
Brief Description of the Drawings
Figure 1: In vitro release profile of K2, K3 and K4 in comparison with Kl (mean ± S.D.) across
hydrophilised polytetrafluoroethylene (PTFE) filter membrane, pore size 0.45 /im.
Figure 2: Comparison of percentage analgesic response in acetic acid induced writhing test in
mice produced by formulations K2, K3, K4 and conventional formulation Kl after 15 min and 4
hrs of intramuscular injection (mean ± S.E.M).
Figure 3: Percentage analgesic response produced by Kl and K2 in acetic acid induced writhing
test in mice (mean ± S.E.M), n = 6.
Figure 4: Percentage analgesic response produced by Kl and K3 in acetic acid induced writhing
test in mice (mean ± S.E.M), n = 6.
Figure 5: Percentage analgesic response produced by Kl and K4 in acetic acid induced writhing
test in mice (mean ± S.E.M), n = 6.

Figure 6: Drug blood concentration vs time profile of Kl (dose: 7.5 mg/kg) and K4 (dose: 21.25 mg/kg) after intramuscular administration (mean ± S.D.), n = 4.
Figure 7: Drug blood concentration vs time profile of Kl (dose: 7.5 mg/kg) and K3 (dose: 21.25 mg/kg) after intramuscular administration (mean ± S.D.), n = 4.
Brief description of the table
Table 1: Comparison of the pharmacodynamic characteristics obtained from single dose administration of formulations Kl to K4.
Detailed Description of the Invention
Accordingly the present invention provides a synergistic formulation as prolonged release injectable for relieving pain, the said composition comprising:
a a ketorolac or its water soluble derivative,
b at least a rate retarding agent selected from hydrophilic polymer, vegetable oil or hydrophobic non-polymeric compound; and
c optionally, one or more parentally acceptable excipient such as herein described,
wherein, the ketorolac drug is in intimate association with rate retarding agent, in an amount effective to prolong the release of the drug and also substantial part of the drug is present in solubilised state.
An embodiment of the invention provides a formulation, wherein the ketorolac is present as a free acid.
Another embodiment, the ketorolac water-soluble derivative is ketorolac tromethamine.
Still another embodiment, the hydrophilic polymer used as a rate retarding agent is selected from polyvinylpyrrolidone, povidonum, polyvidone, poly(l-vinyl-2-pyrrolidone), PVP or mixtures thereof.
Still another embodiment, the polymer is present in an amount of 0.1 to 10.0 w/v % of the total formulation.
Yet another embodiment, the ketorolac drug concentration is in the range of 15 mg/ml to 120 mg/ml.
Still another embodiment of the invention provides a formulation in which the vegetable oil used as a rate retarding agent is selected from a group consisting of castor oil, ricinous oil, tangantangan or mixtures thereof.

In yet another embodiment, the hydrophobic non-polymer compound used as release rate retardant is selected from a group consisting of glycerol monooleate (9-octadecenoic acid (Z)-monoester, 1,2,3 - propanetriol, monolein or peceol.
Yet another embodiment, the parenterally acceptable pharmaceutical excipient is selected from group consisting of benzyl alcohol, benzylbenzoate, ethyl alcohol, polyethyleneglycol, glycerol, propylene glycol, sodium chloride, dextrose, mannitol, xylitol, sodium metabisulphite, sodium sulphite, ascorbic acid, cystein or mixtures thereof.
Still another embodiment, the concentration of benzyl alcohol used is in the range of 0.1 to 10 w/w %, preferably 1 to 7 w/w % and more preferably 2 to 6 w/w %.
In yet another embodiment, the rate-retarding agent is used in combination thereof, in an amount effective to prolong the release of drug substance.
One embodiment of the invention provides wherein hydrophilic polymer used is polyvinylpyrrolidone.
Another embodiment, polyvinyl pyrrolidone is used as rate-retarding agent in the range of 0.1 to 10% w/v, preferably in the range of 0.5 to 2% and still more about 0.75 to 1.25 % w/v.
Another embodiment of the invention castor oil is used as rate retarding agent in the range of 90 to 99.9% w/v, preferably about 93 to 99% and still more preferably in the range of 94 to 98% w/v.
Another embodiment of the invention castor oil is used in combination with benzyl alcohol in the range of 0.1 to 10% w/v, preferably about 1 to 7% and still more preferably in the range of 2 to 6% w/v.
Another embodiment, glycerol monoleate is used as the rate-retarding agent in the range of 65 to 97% w/v, more preferably 80 to 96% w/v and still more preferably 90 to 96% w/v
Another embodiment of this invention ketorolac - as free acid or as its water soluble derivative - is present in the concentration of 15 to 120 mg/ml, preferably 30 to 105 mg/ml and more preferably 30 to 50 mg/ml.
In yet another embodiment of this invention, the ketorolac is present as a free acid and its water soluble derivative is ketorolac tromethamine.
In yet another embodiment, parenterally acceptable excipients are isotonicifiers selected from sodium chloride, dextrose, mannitol, xylitol, glycerol; antoxidants from sodium metabisulfite, sodium sulphite, ascorbic acid; complexing agents from citric acid, disodium edetate; pH modifying agents from sodium hydroxide, hydrochloric acid; preservative from

benzyl alcohol, phenol, ethyl alcohol; vehicles from water, glycerol, poly ethylene glycol, propylene glycol and ethyl alcohol.
In yet another embodiment, the formulation may be presented in the form of an ampoule, vial, pre-filled syringe or any other presentation acceptable for parenteral administration.
Yet one more embodiment of the present invention provides a process for preparation of injectable composition using different rate (release) retarding agents, the said process consisting of:
a) For polyvinyl pyrrolidone as a rate-retarding agent - dissolving ketorolac tromethamine
in water, adding and dissolving polyvinyl pyrrolidone, adding ethyl alcohol as the
preservative, filtering through a 0.22 microns sterile membrane filter made of Nylon or
cellulose acetate and aseptically filling into ampoules, vials, pre-filled syringes or any
other suitable pack.
b) For castor oil as a rate retarding agent - Dissolving ketorolac in benzyl alcohol by
stirring; adding castor oil; aseptically filtering through 0.22-micron membrane filter and
aseptically filling into ampoules, vials, pre-filled syringes or any other suitable pack.
c) For glycerol monoleate as a rate-retarding agent - Dissolving ketorlac in water and
slowly adding to glycerol monoleate with stirring, adding ethyl alcohol as the
preservative; filtering through 0.22 micron membrane filter and aseptically filling into
ampoules, vials, pre-filled syringes or any other suitable pack.
In an another embodiment of the present a process for the preparation a synergistic pharmaceutical formulation as prolonged release injectable for relieving pain, the said process comprising steps of:
i) dissolving ketorolac or its derivative in water,
ii) adding at least a rate retarding agent selected from hydrophobic polymer or vegetable oil or hydrophobic non-polymer compound to step (i) solution to dissolve, iii) adding a parenterally acceptable excipient to step (ii) solution and filtering
aseptically through 0.22 micron membrane filter, and,
iv) filling the aseptically obtained solution of step (c) in ampoule, vials, pre-filled syringes or any other suitable pack.

Another embodiment of the invention provides a process, the hydrophilic polymer used is selected from polyvinylpyrrolidone, povidonum, polyvidone, poly(l-vinyl-2-pyrrolidone), PVP or mixtures thereof.
In an another embodiment of the present invention relates to an intramuscular "prolonged release" formulation of ketorolac for human and veterinary use. The term "prolonged release" as used herein, means that the activity of the therapeutic agent is extended beyond the time period normally achieved when the therapeutic agent is injected into a host using a conventional, prior art carrier. As conventional injectable formulations are well known in the art, a skilled practitioner could readily understand the meaning of the term. The desired system was achieved by employing hydrophilic and hydrophobic excipient with release rate retarding properties and other properties required in an injection formulation. Polyvinylpyrrolidone (Kollidon® 17 PF) BASF, Germany, glycerylmonooleate (Peceol), Gattafosse, France and castor oil (Castor oil U.S.P.) were used.
In yet another embodiment of the present invention, release rate-retarding agent, include any material, which substantially reduces release of ketorolac from the injection formulation, in the biological system. The term "substantially " with respect to reducing release rate includes completely inhibiting, preventing, slowing, delaying, decreasing or restricting release of ketorolac from the formulation to a measurable degree. It will be understood that both selection of release rate retardants and its amount used in the formulation of the invention should fulfill general requirements of safety, toxicity, Theological properties, bio-compatibility and other pharmaceutical parameters prescribed for injection formulations.
In still another embodiment of the present invention, a few suitable excipient that can be used as release rate retardants include, either alone or in combination, polymers like polyvinylpyrrolidine eg. Kollidone 12 PF and Kollidon 17 PF of BASF, Germany. Sodium carboxymethylcellulose (eg. Na CMC, Hi media, India), vegetable oils (eg. castor, sesame, mustard, olive, arachis, maize, cottonseed, safflower and soybean oil), acacia, tragacanth, either alone or in combination with benzyl alcohol, block copolymers of ethylene oxide and propylene oxide (eg. Poloxamers, Pluronic F), glycerol monoleate and glycerol monolinoleate.
In yet another embodiment of the present invention, PVPs vary in their molecular weight and viscosity PVP used for ketorolac injection formulation should have a molecular weight of less than 25,000, preferably about 10,000 to 20,000. An example of this would be Koliidone 12

PF and Kollidon 17 PF from BASF, Germany. PVPs used in present invention are available under brandnames Kollidon (BASF, Germany and Plasdone C (ISP, U.S.A.).
In still yet another embodiment of the present invention, ketorolac prolonged release injection formulations, for example ketorolac formulation containing PVP, presence of PVP in solubilised state alongwith ketorolac is believed to retard the release of the drug by interaction with drug molecules via electrostatic bonds (ion to ion, ion to dipole, dipole to dipole bonds) or vander waal forces and hydrogen bridges to form a complex and thus influence the availability of drug as well as the rate of drug transfer from aqueous drug formulation. A ketorolac-PVP formulation of this embodiment preferably comprises about 0.1 to 10 % w/v of PVP, preferably about 0.5 to 2% w/v and still more preferably about 0.75 to 1.25 % w/v of PVP. Ketorolac may be present in this formulation preferably to 1.5 mg to 120 mg/ml; more preferably about 3 mg to 105 mg and still more preferably about 30 to 50 mg/ml.
In another embodiment of the present invention, the preferred vegetable oil used for ketorolac injection formulation of present invention would be castor oil, as it allows solubilisation of desired levels of ketorolac free acid. A ketorolac-castor oil formulation of this embodiment preferably comprises about 90 to 99.9 % w/v of castor oil, preferably about 93 to 99 % w/v and still more preferably about 94 to 98 % w/v of castor oil. Benzyl alcohol in the concentration of 0.1 to 10 w/w, preferably about 1 to 7% w/w and more preferably 2 to 6 % w/w can be added to aid in solubilisation of ketorolac and also to reduce local pain at the site of injection. Ketorolac may be present in this formulation preferably to 1.5 mg to 120 mg/ml; more preferably about 3 mg to 105 mg and still more preferably about 30 to 50 mg/ml. In ketorolac prolonged release injection formulations, for example ketorolac formulation containing castor oil, presence of castor oil in solubilised state along with ketorolac is believed to retard the release of the drug by partitioning of drug from the oil system into the surrounding aqueous phase. Apparent partition coefficient (k) of the drug then governs the dynamic equilibrium between oil and aqueous phase.
In still another embodiment of the present invention, the preferred hydrophobic non-polymeric release rate-retarding agent for the present invention would be glycerol monooleate. A ketorolac-glycerol monooleate formulation of this embodiment preferably comprises about 65 % to 97 % w/v of glycerol monooleate, more preferably about 80 to 96 % w/v and still more preferably about 90 to 96 % w/v of glycerol monooleate. Ketorolac may be present in this formulation preferably to 1.5 mg/ml to 120 mg/ml; more preferably about 3 mg/ml to 105 mg/ml

and still more preferably about 30 mg/ml to 50 mg/ml. In ketorolac prolonged release injection formulations, for example ketorolac formulation containing glycerol monooleate, presence of glycerol monooleate in solubilised state alongwith ketorolac is believed to retard the release of the drug due to spontaneous formation of a transparent and stiff gel like structure called cubic phase, when placed in aqueous medium. Glycerol monooleate undergoes phase transitions in response to changes in composition (% water content) and temperature conditions and forms a depot system which can control the release based on diffusional exchange of water from the surrounding medium into the matrix (Wyatt, Pharm. Technol. 116-122 (1992); Engstrom et al., Int. J. Pharm. 86:137-145 (1992)). Glycerol monooleate is metabolized by the lipase enzyme in the body to glycerol and oleic acid. Various works have been published on the incorporation of drugs such as lidocaine, clotrimazole, vitamin E (Ganem-Quintanar et al., Drug Dev. & Ind. Pharm. 26:809-820 (2000); Malonne et al., Bio. Pharm. Bull. 23:627-631 (2000)).
In still another embodiment of the present invention, ketorolac tromethamine or ketorolac free acid and rate retarding excipient can be further formulated together with one or more pharmaceutical composition. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling, storage, stability or to permit formulation suitable for parenteral administration. Excipient include, by way of illustration and not limitation, vehicle, isotonicifier, antioxidant, solubiliser, preservative, viscosity modifying agents, pH modifying agent, complexing agent etc. Non limiting examples of excipient that can be used to prepare pharmaceutical composition of the invention comprise one or more pharmaceutically acceptable isotonicifier as excipient. Suitable isotonocifier illustratively include sodium chloride, dextrose, mannitol, xylitol, glycerol and the like. Such isotonocifiers, if present, constitute a percentage sufficient to exert osmotic pressure nearly equal to that of biological tissues. Antioxidants may include one or more pharmaceutically acceptable antioxidants like sodium metabisulphite, sodium sulphite, ascorbic acid, EDTA etc. Antioxidants may be added in concentration sufficient to prevent oxidative degradation of the drug, without causing toxicity to the biological system. pH modifying agent such as sodium hydroxide and hydrochloric acid were used to maintain the pH of the composition within the range of 6.9 to 7.9.
In still yet another embodiment of the present invention, the ketorolac dosage form of the invention preferably comprise ketorolac in a daily dosage of 1.5 mg/ml to 120 mg/ml; more preferably about 3 mg/ml to 105 mg/ml and still more preferably about 30 mg/ml to 50 mg/ml.

Composition of the invention comprises one or more injection dose units. Each dose unit comprises ketorolac in a therapeutically effective amount that is preferably about 15 mg to 120 mg. The term " dose unit" herein means a portion of a pharmaceutical composition that contains an amount of a therapeutic or prophylactic agent, in the present case ketorolac, suitable for a single injectable administration to provide a therapeutic effect. Administration of such doses can be repeated as required, typically at a dosage frequency of one to about four times per day. It will be understood that therapeutically effective amount of ketorolac for a subject is dependent interalia on the body weight of the subject. A "subject" herein, to which a therapeutic agent or composition thereof can be administered, includes a human patient of either sex and of any age, and also includes any non human animal, particularly a warm blooded animal. Typical dose units in a composition of the invention contain about 5,10, 15, 20, 30, 40, 50, 60, 80 or 100 mg/ml of ketorolac. Especially preferred amounts of ketorolac per dose unit, for humans would be 30 mg/ml to about 50 mg/ml.
The above composition is not a mere admixture. In fact, it is a synergistic composition having unexpected properties which are not anticipated or obvious to a person skilled in the art. The properties such as prolonged release is excellent when compared with conventional compositions.
The following examples illustrate aspects of the present invention but are not to be construed as limitations.
EXAMPLES
Conventional formulation Kl for immediate release was prepared in following manner -Ketorolac tromethamine - 30 mg/ml; Water for injection q.s. 1ml and having pH 7.2
Example 1
A formulation K2 was prepared using PVP, in the following manner-
Ketorolac tromethamine- 42.5 mg per ml
Polyvinylpyrrolidone (Kollidone® 17 PF) - 0.9 % w/v
Water for injection q.s. to 2ml
pH7.2
Accurately weighed amount of Ketorolac tromethamine was dissolved in water. Polyvinylpyrrolidone (Kollidone® 17 PF) was added and the solution was stirred and then degassed. The preparation was sterilized by filtration through 0.22 fim polyvinylidene fluoride filter membrane and collected in presterilized vessel. The preparation was then filled in ampoules in Class 100 environment and sealed under nitrogen purging.
Example 2
A formulation K3 was prepared using castor oil, in the following manner-Ketorolac free acid - 28.83 mg per ml Benzyl alcohol 4 % w/v Castor oil q.s. 2 ml pH 7.2
Ketorolac was added to the benzyl alcohol in small amounts and dissolved by continuous stirring. Further presterilized castor oil was oil was added. The solution was stirred for obtaining homogenous solution and then degassed. The preparation was then filled in ampoules in Class 100 environment and sealed under nitrogen purging.
Example 3
A formulation K4 was prepared using glycerol monooleate, in the following manner-
Ketorolac tromethamine - 42.5 mg/ml
Water for injection - 5 % w/v
Glycerol monooleate (Peceol) q.s. 2 ml
pH7.2
The drug was dissolved in water 5% w/v and then added slowly under continuous stirring in glycerol monooleate. The viscous solution was stirred to obtain homogenous mix and the degassed. The preparation was sterilized by filtration through 0.22 /im polyvinylidene fluoride
filter membrane and collected in presterilized vessel. The preparation was then filled in ampoules in Class 100 environment and sealed under nitrogen purging
In vitro release: Modified Franz diffusion cell was designed to perform in vitro release studies of the formulation Kl to K4 across hydrophilised polytetrafluroethylene (PTFE) pore size 0.45 p.m. Samples were withdrawn at predetermined time points and replaced with buffer maintained at 37 °C. Samples were analyzed UV spectrophotometrically at A.max 323 nm. Cumulative amount of drug released per cm sq. vs time across the synthetic membranes is shown in Figure 1. The release profile obtained for aqueous ketorolac tromethamine 30 mg per ml was considered, as the fastest release that can be achieved, as the support membrane was the only release-controlling factor. The release profiles were compared on the basis of cumulative amount of drug released per cm sq. in twelve hours (Mn) from the formulations. The formulations may be ranked for the drug release sustaining capacity, in which maximum retardation was shown by K3 followed by K4 and K2.
Example 4
Pharmacodynamic evaluation: Performance in animal models
Male Swiss Albino mice of weight 16-25 g were fasted overnight before the experiment and water was allowed ad libitum throughout the study. Acetic acid induced Writhing test was performed to determine the analgesic response of drug formulation administered intramuscularly (Domer, Eur. J. Pharmacol. 177:127-135 (1992)). Saline or the formulation K2 to K4 was injected intramuscularly at predetermined time points before administration of 3% v/v acetic acid (0.01 ml/g) i.p. The number of writhing displayed by each mouse was counted for 20 minutes after the administration of acetic acid. Percentage response for the formulations was calculated considering the peak response by conventional formulation Kl as the maximal possible effect (Vogel et al., Drug Discovery and Evaluation 360-420 (1997)). Control and standard response was determined by injecting saline and conventional formulation Kl intramuscularly respectively at different time points. Further formulations K2 to K4 were administered and percentage response was calculated at different time points.
The pharmacodynamic percentage response vs time profile for Kl formulation (dose 7.5 mg/kg) was generated. Maximum response is produced after approximately 15 min of administration and reduces to less than 50 % after 4 hrs. The formulations K2 to K4 were injected to mice at the same dose level (dose 7.5 mg/kg) and response was measured at two time
points i.e. 15 min and 4 hrs after administration. Figure 2 shows the comparative percentage response produced for the test formulations. For achieving a therapeutically optimum formulation, it is essential that the formulation produced early onset (within 15-30 min) and a prolonged action.
Subsequently, K2 to K4 were given at dose level of 21.25 mg/kg for the pharmacodynamic and pharmacokinetic evaluation of prolonged activity the formulations. Pharmacodynamic response obtained for K2, K3 and K4 (dose: 21.25 mg/kg) was compared to that of Kl (dose: 7.5 mg/kg), as showed in Figure 3, 4 and 5 respectively. The dotted line in the figures is the cut off for desired analgesic response i.e. 70 % response of peak analgesia. The slow release formulations can be assessed by characteristics such as half value duration (HVD, plasma level for classical HVD), plateau time or T 70% peak response (Cmax for classical T 70%). The T 70% response, i.e. the time interval for which the analgesic level is superior to or equal to T 70% of peak analgesia produced by aqueous drug solution, was calculated. The ratio of T 70% response of test and aqueous solution was calculated and listed in Table 2. The values suggested that K3 and K4 were most efficient in drug release retardation.
The drug blood concentration at the T 70% analgesic response was determined from the pharmacokinetic plot of formulation Kl. Hence correlating the pharmacodynamic response with the pharmacokinetic profile, the desired drug blood concentration range Css max and Css „„„ to be attained were taken as C^ ± 25%, which were 51.39 meg/ml and 30.0 meg/ml respectively (shown as dotted lines in figure 6 & 7). The drug blood concentration vs time profile of formulations, K3 and K4 was compared with that of Kl.
Example 5
Pharmacokinetic evaluation
For evaluation of each formulation, three groups, of four mice each, were taken. Zero hour blood sample was collected by intraocular route and then formulation was injected intramuscularly. At each time point sample was collected from one group and from each group blood was collected at three time points. From a mice. 0.25 ml of blood was collected at each sampling time point and then 0.25 ml saline was administered i.p. Blood was collected in heparinised micro centrifugation tube, plasma was immediately separated and stored at - 22° C until analyzed. It was extracted with 0.9 ml methanol by vortex mixing for 3-4 min and then centrifuged at 13,000 rpm for 30 min. 0.8 ml of supernatant was separated and evaporated to
dryness and reconstituted in mobile phase, vortex mixed for 3-4 min and then centrifuged at 13,000 rpm for 15 min. Aliquots of 100 ul. were injected into the HPLC with UV spectrophotometeric detection at 313 nm. A Shimadzu HPLC (SPD-10 AVP, Japan) was used. Chromatographic column used was Lichrosphere 100 RP-18e (250 x 4, 5u,m, Merck, Germany) and mobile phase constituted of acetonitrilerwater adjusted to pH 3.0 + 0.01 with 85% orthophosphoric acid in ratio 40:60 with flow rate 1 ml/min. The method was linear over the range of 2.5 meg/ml to 100 meg/ml.
Single dose of Kl (7.5 mg/kg) was administered intramuscularly to mice and it was observed (Figure 6) that Cmax was attained in approximately 15 minutes and the concentration reduced significantly between 2nd and 4th hour. Similar trend was observed in the pharmacodynamic response where peak analgesic effect was seen at 15 minutes, which then dropped to less than 50% at the 4th hour (Figure 3). The reported terminal half-life of ketorolac in mice is 3.8 hrs.
Here formulation K4 (Figure 6) produced drug blood levels higher than the desired drug blood levels in the initial period (0-2nd hr) and then further generated prolonged plateau drug blood levels for approximately 9 hrs (2nd to 11th hr) and beyond that concentration falls below the C min desired. K3 (Figure 7) produced higher drug blood levels (> Cmax des) and maintained the drug concentration levels above Cmin for time periods (7-8 hrs). The pharmacokinetic characteristic, T 80% of Cmax, was calculated for formulations to assess the slow release behavior on the basis of single dose studies. K4 maintained drug blood concentration above the desired C min for 12 hrs and K3 maintained drug blood concentration above the desired C mjn for 8 hrs.The formulation K4 behaved in the most favorable manner proving the sustaining property of the formulation. Glycerol monooleate can form a depot system, which can control the release based on diffusional exchange of water from the surrounding medium into the matrix that follows square root of time dependent drug release kinetics. However, it is essential that the cubic phase formed remains in equilibrium and the drug incorporated does not disrupt the formation of cubic lattice system in vivo. This could be a possible explanation for the fast release observed in the early period of formulation administered.
Example 6:
Utility of composition of invention
Ketorolac, a non anti-inflammatory drug is primarily used for its analgesic activity. The trometamol salt is used for short-term management of broad-spectrum pain that requires analgesia at the opioid level, usually in postpartum and postoperative pain, cancer pain, pain of dental extraction. It has been employed in pain relief from major and minor surgery such as abdominal, orthopedic, gynecological surgeries. Ophthalmic ketorolac tromethamine is used to relieve ocular itching associated with seasonal allergic conjunctivitis. Used for topical treatment of cytoid macular edema and for prevention of ocular inflammation associated with cataract surgery.
Indicated for the short-term ( Example 7
Method of treatment
The present invention is further directed to a therapeutic method of treating a condition or disorder where treatment with NSAIDs is indicated, the method comprising intramuscular administration of a composition of the invention to a subject in need thereof. The dosage regimen to prevent, give relief from, or ameliorate the condition or disorder preferably corresponds to once-a-day or twice-a-day treatment, but can be modified in accordance with a variety of factors. These include the type, age, weight, sex, diet and medical condition of the subject and the nature
and severity of the disorder. Thus, the dosage regimen actually employed can vary widely and can therefore deviate from the preferred dosage regimens set forth above.
Initial treatment can begin with a dose regimen as indicated above. Subjects undergoing treatment with a composition of the invention can be routinely monitored by any of the methods well known in the art to determine effectiveness of therapy. Continuous analysis of data from such monitoring permits modification of the treatment regimen during therapy so those optimally effective doses are administered at any point in time, and so that the duration of treatment can be determined. In this way, the treatment regimen and dosing schedule can be rationally modified over the course of therapy so that the lowest amount of the composition exhibiting satisfactory effectiveness is administered, and so that administration is continued only for so long as is necessary to successfully treat the condition or disorder.
The present compositions can be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i. e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others. Preferred combination therapies comprise use of a composition of the invention with one or more compounds selected from aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis (acetylsalicylate), amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate, antrafenine, apazone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, bezitramide, a-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butophanol, calcium acetylsalicylate, carbamazepine, carbiphene, carprofen, carsalam, chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin, clopirac, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cropropamide, crotethamide, desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium, difenamizole, difenpiramide, diflunisal,
dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epirizole, eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunoxaprofen, fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid, glafenine, glucametacin, glycol salicylate, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, p-lactophenetide, lefetamine, levorphanol, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine, metazocine, methadone hydrochloride, methotrimeprazine, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, piprofen, pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalte, salverine, simetride, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen.
Table 1: Comparison of the pharmacodynamic characteristics obtained from single dose administration of test formulation.

(Table Remove)

Burke, J. P., Pestotnik, S. L., Classen, D. C. et al. Evaluaiton of the financial impact of ketorolac
tromethamine therapy in hospitalized patients. Clin. Ther. 18, 197 (1996)
Trotter, D. M., Warson, J. S., Wirt, T. C. et al. The use of ketorolac in lumbar spine surgery: a
cost benefit analysis. J. Spinal Disord. 8, 206 (1995)
Trotter, J. P., Reinhart, S. P., Kart, R. M. et al. Economic assessment of ketorolac vs narcotic
analgesics in post operative pain management. Clin. Ther. 15, 938 (1993)
United States Pharmacopeia 247 National Formulary 19. United States Pharmacopeia!
Convention, Rockville, M.D. 946 (1999)
Vogel, H. G., Vogel, W. H., Analgesia, anti-inflammatory and antipyretic activity. In: Drug
discovery and evaluation, Springer, 360 (1997)
Wyatt, D. M., A cubic-phase delivery system composed of glyceryl monooleate and water for
sustained release of water-soluble drugs. Pharm. Technol. 16,116 (1992)

We Claim:
1. A pharmaceutical composition for the treatment of postoperative pains
comprising of ketorolac or its water soluble derivative in the range of 15
mg/ml to 120 mg/ml and rate retarding agent selected from hydrophilic
polymer, vegetable oil or hydrophobic non-polymeric compound in the
range of 0.1 to 10.0 w/v % of the total composition and optionally, one or
more parenterally acceptable excipients in the range of 0.1 to 10 w/w % such
as herein described.
2. A pharmaceutical composition as claimed in claim 1, wherein the ketorolac is present as a free acid.
3. A pharmaceutical composition as claimed in claim 1, wherein the ketorolac water soluble derivative is ketorolac tromethamine.
4. A pharmaceutical composition as claimed in claim 1, wherein the hydrophilic polymer used as a rate retarding agent is selected from the group of polyvinyl pyrrolidone, povidonum, polyvidone, poly(l-vinyl-2pyrrolidone), PVP or mixtures thereof.
5. A pharmaceutical composition as claimed in claim 1, wherein the vegetable oil used as a rate retarding agent is selected from a group of castor oil recinous oil, tengantangan or mixtures thereof.
6. A pharmaceutical composition as claimed in claim 1, wherein the hydrophobic non-polymer compound used as release rate retardant is selected from a group of glycerol monooleate, monolein or peceol.
7. A pharmaceutical composition as claimed in claim 1, wherein the parenterally acceptable pharmaceutical excipients is selected from the group of benzyl alcohol, benzyl benzoate, ethyl alcohol, polyethyleneglycol, glycerol, propylene glycol, sodium chloride, dextrose, mannitolxylitol, sodium metabisulphite, sodium sulphite, ascorbic acid, cystein or mixtures thereof.
8. A pharmaceutical composition as claimed in claim 7, wherein the
concentration of benzyl alcohol used preferably is in the range of 1 to 7 w/v
% and more preferably 2 to 6 w/v%.

9. A pharmaceutical composition as claimed in claim 1, wherein rate retarding agent is used in combination thereof.
10. A process for preparing the pharmaceutical composition as claimed in claim 1, wherein the said process comprising the following steps:

a) dissolving ketorolac or its derivative in water,
b) adding rate retarding agent selected from hydrophillic polymer or vegetable oil or hydrophobic non-polymer compound to step (a) solution to dissolve,
c) adding a parentrally acceptable excipient to step (b) solution and filtering aseptically through 0.22 micron membrane filter, and,
d) filling the aseptically obtained solution of step (c) in ampoule, vials, prefilled syringes or any other suitable pack.
11. A synergistic pharmaceutical composition and process for the preparation of
said pharmaceutical composition substantially as herein described with
reference to forgoing examples and drawings

Documents:

1032-DEL-2002-Abstract-(04-07-2008).pdf

1032-del-2002-abstract-(24-07-2008).pdf

1032-DEL-2002-Abstract.pdf

1032-DEL-2002-Claims-(04-07-2008).pdf

1032-del-2002-claims-(24-07-2008).pdf

1032-DEL-2002-Claims.pdf

1032-DEL-2002-Correspondence-Other.pdf

1032-DEL-2002-Correspondence-Others-(04-07-2008).pdf

1032-del-2002-correspondence-others-(24-07-2008).pdf

1032-del-2002-correspondence-others.pdf

1032-del-2002-correspondence-po.pdf

1032-DEL-2002-Description (Complete)-04-07-2008.pdf

1032-del-2002-description (complete)-24-07-2008.pdf

1032-DEL-2002-Description (Complete).pdf

1032-DEL-2002-Drawings-(04-07-2008).pdf

1032-DEL-2002-Drawings.pdf

1032-DEL-2002-Form-1-(04-07-2008).pdf

1032-del-2002-form-1-(24-07-2008).pdf

1032-DEL-2002-Form-1.pdf

1032-DEL-2002-Form-18.pdf

1032-DEL-2002-Form-2-(04-07-2008).pdf

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Patent Number

234519

Indian Patent Application Number

1032/DEL/2002

PG Journal Number

26/2009

Publication Date

26-Jun-2009

Grant Date

04-Jun-2009

Date of Filing

11-Oct-2002

Name of Patentee

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)

Applicant Address

SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	ARVIND K. BANSAL	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
2	VIBHA PURI	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
3	HARMANDER PAL SINGH CHAWLA	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
4	CHAMAN LAL KAUL	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.

PCT International Classification Number

A61K 31/407

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA