WO2008115572A1 - Procédés et compositions d'ains - Google Patents

Procédés et compositions d'ains Download PDF

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Publication number
WO2008115572A1
WO2008115572A1 PCT/US2008/003723 US2008003723W WO2008115572A1 WO 2008115572 A1 WO2008115572 A1 WO 2008115572A1 US 2008003723 W US2008003723 W US 2008003723W WO 2008115572 A1 WO2008115572 A1 WO 2008115572A1
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Prior art keywords
less
compound
dose
pain
nsaid
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PCT/US2008/003723
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English (en)
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Najib Babul
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Theraquest Biosciences, Inc.
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Publication of WO2008115572A1 publication Critical patent/WO2008115572A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention is directed to parenteral pharmaceutical compositions of ultra-low dose of NSAIDs to provide effective analgesic, anti-inflammatory and antipyretic effects and the use thereof for treating and preventing pain, inflammation and fever.
  • the present invention is also directed to a method of administration of pharmaceutical compositions of ultra-low dose of NSAIDs to provide effective analgesic, anti-inflammatory and antipyretic effects and the use thereof for treating and preventing pain, inflammation and fever.
  • Acute pain is usually a consequence of an identifiable insult, such as surgery or other trauma, or a consequence of a disease, e.g., kidney stones, mechanical low back pain, etc.
  • an identifiable insult such as surgery or other trauma
  • a disease e.g., kidney stones, mechanical low back pain, etc.
  • public health statistics several hundred million people worldwide undergo inpatient or outpatient surgery each year.
  • several hundred million visits are made annually to the emergency room.
  • emergency room visits it is estimated by survey data that more than 20% require analgesic treatment.
  • Recent studies have shown that more than 60% of patients who undergo surgery experience moderate to severe pain despite analgesic treatment.
  • opioid analgesics e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine
  • acetaminophen nonsteroidal anti-inflammatory drugs (NSAIDs) e.g., ketoprofen, ibuprofen, naproxen, tiaprofenic acid, aceclofenac, diclofenac, piroxicam, loxaprofen, fenoprofen, flurbiprofen, tenoxicam, lomoxicam, acetylsalicylic acid, flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, diflunisal, etodolac, fenbufen, isoxicam
  • opioid analgesics e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine
  • neuro-active steroids including beta adrenergic agonists, e.g., albuterol; selective prostanoid receptor antagonists; NMDA antagonists; neuronal nicotinic receptor agonists; calcium channel antagonists; serotonin 5-HT(lB/lD) receptor agonists sodium channel blockers; cannabinoid agonists; superoxide dismutase mimetics; p38 MAP kinase inhibitors; triptans, TRPVl agonists; ketamine; NKl receptor antagonists; gabapentinoids; and glycine receptor antagonists.
  • beta adrenergic agonists e.g., albuterol
  • NMDA antagonists e.g., NMDA antagonists
  • neuronal nicotinic receptor agonists e.g., calcium channel antagonists
  • serotonin 5-HT(lB/lD) receptor agonists sodium channel blockers
  • cannabinoid agonists superoxid
  • parenteral drug formulations have become a very important component in the arsenal of available drug delivery options, particularly for drugs having analgesic, antiinflammatory or antipyretic effects.
  • Parenteral routes of administration including subcutaneous, intramuscular, intrathecal, epidural and intravenous injection, offer numerous benefits over oral delivery in particular situations, for a wide variety of drugs.
  • parenteral administration of a drug typically results in attainment of a therapeutically effective blood concentration of the drug in a shorter time than is achievable by oral administration. This is especially true of intravenous injection, whereby the drug is placed directly into the bloodstream.
  • Parenteral administration can also result in more predictable blood serum concentrations of a drug, because drug loss in the gastrointestinal tract due to absorption, distribution, metabolism, binding to food and other causes are eliminated.
  • Parenteral administration is generally the preferred method of drug delivery in emergency situations, and is also useful in treating subjects who are uncooperative, unconscious, or otherwise unable or unwilling to accept oral medication.
  • Parenteral drugs are particularly useful for treating a condition such as pain, inflammation or fever when: 1 ) the condition is of severe intensity; 2) there is a need for rapid onset of effect; 3) there is a need for rapid or frequent dose titration to keep condition under control; and/or 4) the patient is unable to receive oral medication e.g., due to nausea, vomiting, confusion, obtundation, loss of consciousness and bowel obstruction.
  • opioids exert an analgesic effect is through agonism at the various opioid receptors, e.g., mu, delta and/or kappa.
  • the opioids are well-known for their potential for physical dependence and addiction.
  • Other side effects of opioids, particularly in the acute setting and more particularly in non-opioid tolerant or opioid naive patients, include nausea, vomiting, pruritus, constipation, sedation, and potentially fatal respiratory depression.
  • opioids particularly in the acute setting and more particularly in non-opioid tolerant or opioid naive patients, include nausea, vomiting, pruritus, constipation, sedation, and potentially fatal respiratory depression.
  • increased doses are required to achieve a satisfactory analgesic effect.
  • alternative therapies for the management of acute pain are widely sought, so as to minimize the amount of opioid patients will require for pain management.
  • Compounds which serve as replacements for opioids or reduce the required opioid dose have utility in the treatment of pain.
  • the NSAIDs are highly effective as analgesics. They are used to treat both acute and chronic pain, usually by the oral route of administration.
  • the main mechanism by which NSAIDs exert an analgesic effect is through the inhibition of the synthesis of certain prostaglandin, or prostanoids.
  • the synthesis of prostanoids utilizes two distinct COX enzymes: COX-I and COX-2.
  • Traditional NSAIDs inhibit both enzymes.
  • NSAIDs may also inhibit other lipogenic enzymes, such as 5-lipooxygenase.
  • NSAIDs are not addictive, they are not without significant toxic effects, such as gastrointestinal injury, hepatotoxicity and decrease clotting ability.
  • Ketorolac is presently the only NSAID available in parenteral form in the United
  • ketorolac has been withdrawn from the market by the local health authorities, due to its high propensity to cause serious and life threatening side effects. Injectable ketorolac must be given every 4 to 6 hours to provide continuous relief of pain. In some countries, other parenteral NSAIDs such as diclofenac and lornoxicam are also available, but in most countries, ketorolac still remains by far the most frequently used injectable NSAID.
  • Parecoxib a parenteral COX-2 selective NSAID, has been approved in Europe with restrictions on its use and has been twice denied approval by the United States Food and Drug Administration for the management of acute post-surgical pain.
  • parecoxib the injectable prodrug of the now withdrawn drug, valdecoxib
  • An important early adverse postsurgical safety signal came from a CABG study included in the original U.S. NDA. In the parecoxib and valdecoxib group, 19.0% had serious adverse events, versus 9.9% in the placebo group.
  • NSAIDs When administered by the IV route, many NSAIDs are associated with one or more drawbacks, including poor solubility, pain on injection, venous irritation, thrombophlebitis, intramuscular pain and irritation, and the need to inject in a large volume of physiologic fluid and/or as a slow IV infusion (instead of as a bolus) to minimize local irritation.
  • drawbacks including poor solubility, pain on injection, venous irritation, thrombophlebitis, intramuscular pain and irritation.
  • Kostamovaara et al. (Br. J. Anaesth.
  • Benzyl alcohol has been associated with a fatal toxic syndrome in premature infants, and parenteral preparations containing the benzyl alcohol are not recommended in neonates. ⁇ See British National Formulary, No. 49, March 2005).
  • the 3 mL volume for IM administration is more that the 2 mL maximum recommended volume and therefore it may be associated with increased frequency and intensity of injection site pain.
  • Some regulatory health authorities have required the following dosing language for IM diclofenac acid (Voltarol Ampoules. U.K. Summary of Product Characteristics, March 2005):
  • Diclofenac must not be given as an intravenous bolus injection. Diclofenac must be diluted with 100-500 mL of either sodium chloride solution (0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5 mL 8.4% or 1 mL 4.2%). Only clear solutions should be used. Two alternative regimens are recommended: For the treatment of moderate to severe post-operative pain, 75 mg should be infused continuously over a period of 30 minutes to 2 hours. If necessary, treatment may be repeated after 4-6 hours, not exceeding 150 mg within any period of 24 hours. For the prevention of post-operative pain, a loading dose of 25 to 50 mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of approximately 5 mg per hour up to a maximum daily dosage of 150 mg.”
  • Pain as a consequence of administration of a drug intended to ameliorate other pains can lead to patient refusal to accept therapy and require diagnostic workup to rule out infiltration, extravasation and infection at the injection site. It can also lead to further medical complications, increased reliance on opioid analgesics for pain relief, delayed discharge from hospital and increased cost of therapy. Patients report the pain sensation as stinging, burning, soreness, tenderness, aching, throbbing, cramping, gripping and radiating. It may be localized to the injection site or it may radiate to the proximal area, e.g., the arm. It may or may not be accompanied by redness.
  • Phlebitis is an inflammation of the vein in which endothelial cells of the venous wall become irritated and cells roughen, allowing the adherence of platelets.
  • the site is tender to touch and can be very painful. Phlebitis can prolong hospitalization unless it is treated early.
  • the process of phlebitis formation involves increased capillary permeability, resulting in leakage of proteins and fluids into interstitial space.
  • the traumatized tissue continues to be irritated chemically. This in turn provokes an immune reaction, resulting in mobilization of leukocytes release of inflammatory mediators [Phillips, LD, Manual of I.V. Therapeutics, 3 rd Edition (2001), p.
  • Intravenous administration of NSAIDs in racemic or enantiomeric form including aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, ca ⁇ rofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indobufen, indomethacin, isonixin, isoxicam, ketorolac, ketoprofen,
  • Phlebitis occurs when a vein becomes inflamed by irritation or vesicant solutions or drugs. Although the use of a 0.5 to 1.0 micron inline filter can remove particulate matter not visible to the naked eye, it cannot eliminate the precipitation that occurs when the drug comes in contact with blood. Precipitation is considered to be a major cause of injection site pain, venous irritation and phlebitis.
  • Solvents, acids and bases, and some drugs can damage living tissue.
  • some dissolved drugs can produce undesirable pharmacological effects by reacting with specific receptors on the vein walls.
  • the undesirable effects caused pharmacologically and chemically are worsened by direct cellular contact with the highly concentrated precipitate.
  • precipitation of the drug within the vein upon dilution significantly exacerbates the irritation and is a key factor in determining the duration and severity of the irritation.
  • One approach to reducing mechanical, chemical and idiopathic IV NSAID irritation is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
  • One approach to reducing pain, irritation and muscular or subcutaneous toxicity after IM or SC (SQ) administration is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
  • One approach to reducing pain, irritation and muscular or subcutaneous toxicity after IM or SC (SQ) administration is to drastically reduce the volume of NSAID administered to the patient, while still providing an effective analgesic, anti-inflammatory and/or antipyretic effect.
  • One approach to reducing and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration is to drastically reduce the dose of NSAID administered to the patient, while still providing an effective analgesic or anti-inflammatory effect.
  • NSAIDS, epidural and intrathecal administration are contraindicated.
  • the volume is commensurately reduced, thereby providing the option of epidural and intrathecal NSAID administration.
  • One approach to improving the tolerability of NSAIDS after parenteral administration is to drastically reduce the dose of NSAID administered to the patient, thereby reducing the need for irritating and otherwise toxic or disagreeable pharmaceutical excipients such as benzyl alcohol.
  • the parenteral route of NSAID administration is usually used in the post-surgical pain, post-traumatic pain or intensive or critical care setting, where the patient is particularly predisposed metabolic stress, gastrointestinal perforation, ulcers and bleeding, and bleeding from the site of surgery or trauma.
  • These adverse effects, along with the aforementioned injection site effects are particularly important with the use of parenteral NSAIDS. Most of the adverse effects of NSAIDS are dose related. Consequently the lowest possible dose of an NSAID associated therapeutic effectiveness is usually suggested.
  • NSAID side effects can occur in all patients, some patient groups are at particular risk.
  • Patients are particular risk include those who: (i) are elderly; (ii) are cachectic' (iii) are immunocompromised; (iv) have a malignancy; (iv) are receiving corticosteroids; (v) with a history of significant alcohol consumption; (vi) are smokers; (vii) are receiving long-term NSAID therapy; (viii) are receiving high doses of NSAID's; (ix) have prior history of peptic ulcer disease, perforations and GI bleeding; (x) have ischemic heart disease; (xi) are undergoing CABD surgery; (xii) have a history of stroke; (xiii) are anticoagulated; (xiv) have a history of renal impairment and renovascular disease; (xv) have hepatic impairment; and (xvi) have a history of hypertension. Additional information on risk factors for NSAID toxicity may be found in the scientific and
  • NSAIDs for parenteral administration (e.g., intravenous [IM], intramuscular [IM], subcutaneous [SC], intrathecal [IT], epidural], particularly IV administration, there is a need for new therapeutic methods and pharmaceutical compositions that have analgesic, anti-inflammatory and antipyretic activity.
  • parenteral administration e.g., intravenous [IM], intramuscular [IM], subcutaneous [SC], intrathecal [IT], epidural]
  • analgesic, anti-inflammatory and antipyretic methods and pharmaceutical compositions that are: (i) readily soluble; (ii) have a reduced injection volume; (iii) have a rapid onset of effect; (iv) have a robust peak effect; (v) have a long duration of action; (vi) have a reduced incidence and severity of injection site pain, venous irritation and phlebitis; (vii) have a reduced propensity for gastrointestinal side effects, including dyspepsia, ulceration, perforation and bleeding; (viii) have a reduced frequency and severity of bleeding from or near the site of surgery or trauma; (ix) have a reduced frequency and severity of cardiovascular side effects; (x) have a reduced frequency and severity of injection site pain and irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration; and (xi) have a reduced frequency and severity of other NSAID side effects.
  • An ideal parenteral NSAID formulation should provide robust analgesic, antiinflammatory, and antipyretic effects (rapid onset and high efficacy), as well as good tolerability at and around the injection site. Further, an ideal parenteral NSAID formulation should be safe for administration by the IM, IV, SC, IT and epidural routes. Additionally, an ideal parenteral NSAID formulation should be safe for administration by the IM, IV, SC, IT and epidural routes by avoiding the use of large quantities of potentially toxic solubilizing agents, e.g., benzyl alcohol and by avoiding or minimizing the risk of precipitation following injection.
  • potentially toxic solubilizing agents e.g., benzyl alcohol
  • One approach of the invention to encourage clinicians to liberally utilize parenteral NSAIDs and optimize pain control, especially in the setting of acute pain is to reduce the frequency and severity of NSAID associated side effects while providing an effective therapeutic intervention.
  • acute pain e.g., acute postsurgical pain, trauma, renal colic, burn pain, etc
  • clinicians are forced either manage pain, inflammation and fever sub- optimally or provide adequate analgesia while risking patient safety.
  • One approach of the invention to reducing the various know toxicities of parenteral NSAID therapy while providing robust analgesic, anti-inflammatory and antipyretic is to utilize ultra-low doses of parenteral NSAID 's not previously described in the art, while still providing therapeutically effective analgesic, anti-inflammatory and antipyretic effects.
  • ultra-low dose parenteral NSAIDS can reduce the know toxicities of parenteral NSAIDS though a significant reduction in the single, individual or unit dose of the administered NSAID and the total daily administered dose of the NSAID, each individual dose provides a shorter duration of action. This in turn requires a more frequent dosing and adversely impacts on: (i) nursing, pharmacy and other institutional resources; (ii) the cost of drug and supplies (syringes, alcohol swabs, sterile solution, infusion devices, etc); (iii) sterility and the risk of infection.
  • One approach of the invention to mitigate against the adverse consequences of increased dosing frequency is to administer the ultra-low doses of parenteral NSAID using patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • Current standard of care does not recommend administration of NSAIDS by patient controlled analgesia.
  • the standard of care recommends against administration of NSAIDS by patient controlled analgesia and for a majority of NSAIDS of the invention, there are no recommendations or working examples of NSAID administration by patient controlled analgesia.
  • the present invention stems, in part from the surprising discovery that usual recommended doses of parenteral NSAIDS, with their associated adverse safety profile are not required to provide effective analgesic, anti-inflammatory and antipyretic effects. Such effects may be achieved with ultra-low dose NSAIDS, which have a reduced propensity for the known side effects of NSAIDS.
  • the present invention stems, in part from the surprising discovery that usual recommended doses of parenteral NSAIDS given by IV infusion (e.g., over 5, 10, 15, 20 or 30 minutes), with their associated adverse safety profile are not required to provide effective analgesic, anti-inflammatory and antipyretic effects. Said effects may be achieved with ultra-low dose NSAIDS given by IV bolus, which have a reduced propensity for the known side effects of NSAIDS.
  • ultra-low dose NSAIDS can provide robust analgesic, anti-inflammatory and antipyretic effects, with reduced NSAID toxicity and without the inconvenience associated with frequent administration.
  • the ultra-low dose NSAID is preceded by one or more loading doses of the same NSAID by he same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said NSAID by said route.
  • the present invention involves the use of ultra-low dose
  • the present invention involves the use of ULD of parenteral NSAIDs to provide effective anti-inflammatory effects.
  • the present invention involves the use of ULD of parenteral NSAIDs to provide effective antipyretic effects.
  • the present invention involves the use of ULD of parenteral NSAIDs to provide effective analgesic, anti-inflammatory and/or antipyretic effects while reducing the frequency and intensity of NSAID associated side effects.
  • the present invention involves the use of ULD of parenteral NSAIDS given by bolus injection to provide effective analgesic, antiinflammatory and/or antipyretic effects while reducing the frequency and intensity of NSAID associated side effects.
  • the present invention involves the use of ULD of parenteral NSAIDS given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) to provide effective analgesic, anti-inflammatory and/or antipyretic effects while reducing the frequency and intensity of NSAID associated side effects.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • a first aspect of the present invention is directed to a method for eliciting a rapid analgesic, anti-inflammatory and antipyretic response after parenteral administration of a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a second aspect of the present invention is directed to a method for eliciting a robust peak analgesic, anti-inflammatory, and/or antipyretic response after parenteral administration of a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a third aspect of the present invention is directed to a method for improving the
  • IV tolerability of a selected NSAID e.g., reduced venous irritation, injection site pain, and phlebitis after IV bolus injection, slow IV injections, short term infusions and continuous infusions, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a fourth aspect of the present invention is directed to a novel method for improving the intramuscular tolerability of a selected NSAID, e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a selected NSAID e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage after IM injection, e.g., into the gluteus, deltoid, vastus lateralis
  • a fifth aspect of the present invention is directed to a novel method for improving the SC tolerability of a selected NSAID, e.g., reduced injection site pain, subcutaneous irritation, inflammation and abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a selected NSAID e.g., reduced injection site pain, subcutaneous irritation, inflammation and abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions
  • a sixth aspect of the present invention is directed to a method for directly administering a selected NSAID by the intravenous route without the need for prior dilution and/or administration through automated or gravity feed volume control devices, e.g., volutrol, minibag, large volume parenteral bag, syringe driver, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • automated or gravity feed volume control devices e.g., volutrol, minibag, large volume parenteral bag, syringe driver
  • a seventh aspect of the present invention is directed to a method for safely administering a selected NSAID into soft tissue at the site of, or in close proximity to the pain and inflammation, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • An eighth aspect of the present invention is directed to a method for improving the tolerability and safety of intrathecal and epidural administration of a selected NSAID, e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas after epidural or intrathecal administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • NSAID e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas after epidural or intrathecal administration
  • a ninth aspect of the present invention is directed to a method reducing the frequency and severity of injection site pain, venous irritation and phlebitis of a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a tenth aspect of the present invention is directed to a method reducing the frequency and severity of gastrointestinal side effects, including dyspepsia, ulceration, perforation and bleeding from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • An eleventh aspect of the present invention is directed to a method reducing the frequency and severity of bleeding from or near the site of surgery from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a twelfth aspect of the present invention is directed to a method reducing the frequency and severity of cardiovascular side effects (e.g., hypertension, peripheral edema, fluid retention, congestive heart failure and myocardial infarction) from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • cardiovascular side effects e.g., hypertension, peripheral edema, fluid retention, congestive heart failure and myocardial infarction
  • a thirteenth aspect of the present invention is directed to a method reducing the frequency and severity of postsurgical wound complications (e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling) from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • postsurgical wound complications e.g., poor wound healing, wound closure, wound infection, edema, abscess, or swelling
  • a fourteenth aspect of the present invention is directed to a method reducing the frequency and severity of postsurgical blood loss from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a fifteenth aspect of the present invention is directed to a method reducing the frequency and amount of blood transfusion from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a sixteenth aspect of the present invention is directed to a method reducing the frequency and severity of renal complications from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a fifteenth aspect of the present invention is directed to a method reducing the frequency and severity of hepatic complications from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a sixteenth aspect of the present invention is directed to a method reducing the frequency and severity of surgical complications from orthopedic surgery or bone manipulation (e.g., non-union, malunion, avascular necrosis) from a selected NSAID, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • orthopedic surgery or bone manipulation e.g., non-union, malunion, avascular necrosis
  • a seventeenth aspect of the present invention is directed to a method reducing the frequency and severity of other NSAID side effects, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • An eighteenth aspect of the present invention is directed to a method reducing the frequency and severity of drug-drug interactions, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID.
  • a nineteenth aspect of the present invention is directed to a method reducing pain, irritation, epidural hematoma, abscess, inflammatory lesions and granulomas after epidural or intrathecal administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID, said NSAID administered in reduced injection volume.
  • a twentieth aspect of the present invention is directed to a method reducing pain, irritation, nerve damage, sterile abscess, and muscular or subcutaneous toxicity after IM or SC (SQ) administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID, said NSAID administered in reduced injection volume.
  • a twenty first aspect of the present invention is directed to a method for improving the safety and tolerability of NSAIDS after parenteral administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID, said NSAID administered with a reduced need for irritating and otherwise toxic or disagreeable pharmaceutical excipients and solubilizing agents.
  • a twenty second aspect of the present invention is directed to a method for improving the efficiency of pain management after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • a twenty third aspect of the present invention is directed to a method for reducing pharmacy, nursing and/or institutional resources for pain management after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • a twenty fourth aspect of the present invention is directed to a method for reducing drug and ancillary supply costs (e.g., sterile infusion containers, sterile swabs, syringes, etc) associated with parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • a twenty fifth aspect of the present invention is directed to a method for reducing the risk of infection after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), preferably with a closed loop system.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • a twenty sixth aspect of the present invention is directed to a method for providing effective pain relief after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said ULD of NSAID having an improved safety profile compared with usual doses of NSAIDS.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • a twenty seventh aspect of the present invention is directed to a method for providing pain relief with reduced side effects after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID given by bolus injection.
  • a twenty eighth aspect of the present invention is directed to a method for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral NSAID administration, said method comprising administering one or more loading dose(s) of said NSAID, followed by a therapeutically effective amount of ULD of a selected NSAID given by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of NSAID by the specified route of administration.
  • a twenty ninth aspect of the present invention is directed to a method for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID complexed to or in conjunction with ethylenediamine and/or piperazine.
  • a thirtieth aspect of the present invention is directed to a method for providing analgesia, anti-inflammatory and/or antipyretic effects after parenteral NSAID administration, said method comprising administering a therapeutically effective amount of ULD of a selected NSAID in conjunction with glycine.
  • a thirty first aspect of the present invention is directed to pharmaceutical compositions comprising ULD of a selected NSAID.
  • the selected NSAID is chosen from the group comprising celecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lumiracoxib, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam.
  • FIG. 1 illustrates a simulated plasma NSAID concentration after administration of drug as a rapid IV injection (IV bolus or IV push), as a slow IV infusion over 30 to 120 minutes, and after IM administration.
  • FIG. 2 illustrates the dynamic in vitro apparatus used for predicting mechanical phlebitis.
  • a Harvard Apparatus Precision Syringe Pump 22 was used to direct ISPB (which is used as a blood surrogate in this experiment), at pH 7.4 and 25 C, through a 40- cm length of flexible Tygon ® plastic tubing (type R-3603, inner diameter of 3mm), then through a Hellma QS quartz flow-through cell with a 1-cm path length at a 5 mL/min flow rate.
  • FIG. 3 illustrates a UV wavelength-scan for ketoprofen-ethylenediamine (50 mg/mL) demonstrating absence of absorbance at 540 run.
  • FIG. 4 illustrates dynamic dilution test profile for ketoprofen-ethylenediamine (50 mg/mL) formulation at 540 nm.
  • FIG. 5 illustrates a UV wavelength-scan for ketoprofen-piperazine (50 mg/mL) demonstrating absence of absorbance at 540 nm.
  • FIG. 6 illustrates dynamic dilution test profile for ketoprofen-piperazine (50 mg/mL) formulation at 540 nm.
  • FIG. 7 illustrates a UV wavelength-scan for ketoprofen-piperazine (50 mg/mL) demonstrating absence of absorbance in a 1 : 1 ratio at 540 nm.
  • FIG. 8 illustrates dynamic dilution test profile for ketoprofen-piperazine (50 mg/mL) formulation in a 1 : 1 ratio at 540 nm
  • FIG 9 illustrates a UV wavelength-scan for phenytoin sodium (50 mg/mL), a drug with high phlebitis potential, demonstrating absence of absorbance at 540 nm.
  • FIG 10 illustrates dynamic dilution test profile for phenytoin sodium (50 mg/mL).
  • the Y axis is 10 times higher for phenytoin sodium compared to all other formulations.
  • FIG. 1 1 illustrates dynamic dilution test profile for unsalified ketoprofen suspension (50 mg/mL) adjusted to pH 6.50 and filtered through a 0.45 micron filter before injection at 540 nm, showing approximately 80 and 440-fold greater propensity for precipitation relative to ketoprofen ethylenediamine and ketoprofen piperazine without pH adjustment, respectively.
  • FIG 12 shows pain relief over time on a five point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (• star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • FIG 13 shows total pain relief or TOTPAR over 0-2, 0-4, 0-6 and 0-8 hours derived from a five point categorical pain relief scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( * star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • FIG 14 shows pain intensity difference or change in pain intensity from baseline over time on a four point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (» star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • FIG 15 shows the sum of pain intensity difference (SPID) over time derived using a four point categorical scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( * star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • SPID pain intensity difference
  • FIG 16 shows pain intensity difference or change in pain intensity from baseline over time on 0-100 mm visual analog scale (VAS) in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( ⁇ star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • VAS visual analog scale
  • FIG 17 shows the sum of pain intensity difference derived using a 0-100 mm visual analog scale (VAS) in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg ( ⁇ star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • VAS visual analog scale
  • FIG 18 shows the sum of pain intensity and pain relief (SPRID) derived using the four point categorical pain intensity and the five point categorical pain relief scale in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg (D); 50% of the minimum approved dose of ketoprofen, 50 mg ( ⁇ ); 150% of the maximum approved dose of tramadol, 150 mg ( ⁇ ); maximum approved dose of tramadol, 100 mg (» star symbol); and maximum recommended bolus dose of morphine, 4 mg (•).
  • SPRID pain intensity and pain relief
  • FIG 19 shows the patient's global evaluation of treatment in patients with postsurgical pain following intravenous bolus administration of the minimum approved dose of ketoprofen, 100 mg; 50% of the minimum approved dose of ketoprofen, 50 mg; 150% of the maximum approved dose of tramadol, 150 mg; maximum approved dose of tramadol, 100 mg); and maximum recommended bolus dose of morphine, 4 mg; represented as percent of patients and collected using the following descriptors, from left to right: Poor, Fair, Good, Very Good and Excellent. Patients with Good, Very Good and Excellent are considered to have a positive or favorable treatment outcome.
  • the present invention provides a method of treating pain, inflammation or fever comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more selected ultra-low dose (ULD) NSAIDs, in racemic, enantiomeric excess or enantiomeric form.
  • ULD ultra-low dose
  • the present invention provides a method of treating pain, inflammation, or fever comprising administering to a subject in need of such treatment or prevention one or more selected NSAID analgesics, racemic, enantiomeric excess, or enantiomeric form, selected from the group comprising aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, celecoxib, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprof
  • the NSAID is selected from the group comprising celecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lumiracoxib, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam.
  • Nonsteroidal anti-inflammatory drugs typically have analgesic, anti-inflammatory, and antipyretic properties. Their mode of action appears to involve inhibition of cyclooxygenases (COX-2 and/or COX-I), leukotriene biosynthesis, and antibradykinin activity.
  • COX-2 and/or COX-I cyclooxygenases
  • NSAIDs may be non-selective (inhibit COX-I and COX-2 isozymes) or COX-2 selective (preferentially inhibit the COX-2 isozymes). NSAIDs can produce a wide variety of adverse effects.
  • NSAID For each selected NSAID, standard of care, randomized clinical trials, evidence based medicine, anecdotal evidence, medical practice, tradition guide the selection of the range of doses utilized for the analgesic, anti-inflammatory and antipyretic effects in order to provide analgesia with the fewest possible side effects. Most NSAID analgesic use is by the oral route and for a majority of NSAIDs there are no data on efficacy or safety on their use by the parenteral route of administration. Although the exact mechanisms of adverse effects have not been clearly established, at least some appear related to COX-I inhibition, while at least some of the cardiovascular complications appear to be related to COX-2 inhibition. In addition to their gastrointestinal adverse effects, NSAIDs produce dose related inhibition of platelet aggregation, prolongation of bleeding time, renal impairment, and hepatotoxicity. Parenteral administration can produce injection site burning and pain.
  • NSAID refers to one or more COX-2 and/or COX-I inhibitors, including, without limittaion, compounds selected from the group comprising aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, celecoxib, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen
  • selected NSAID refers to one or more compounds selected from the group comprising celecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)- flurbiprofen), dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lumiracoxib, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam.
  • the selected NSAID is given as an ultra-low dose (ULD) and is chosen from the group comprising celecoxib, dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lumiracoxib, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam.
  • ULD ultra-low dose
  • Ultra-low dose refers to ultra-low doses of NSAIDS or selected NSAIDS.
  • Ultra-low dose of NSAIDS or selected NSAIDS are doses of NSAIDS given by a specified route of administration which are lower than the minimum approved or recommended unit dose, individual dose, and/or daily dose of said NSAID, where said "approved” or “recommended” is approval or recommendation with respect to a parenteral NSAID dose by a supranational, national, federal, regional, state, provincial and/or territorial health authority or drug regulatory authority, a major pharmacopeia (e.g., US Pharmacopeia, British Pharmacopeia, European Pharmacopeia, Japanese Pharmacopeia and the like), Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 11th ed., McGraw Hill (2005); or Remington: The Science and Practice of Pharmacy, 21s
  • approved or “recommended” refers to a recommended or suggested parenteral dose of NSAID by a specified route of administration in a peer review journal cited in MEDLINETM or EMBASETM, or in its absence, the approved or recommended oral doses of the NSAID.
  • ULD of a specified NSAID refers to not more than 1 , 2, 3,
  • ULD of a specified NSAID refers to a dose of said NSAID given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID given by the same route of administration.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 18, 20, 22,
  • ULD of a specified NSAID refers to a dose of said NSAID given by bouls injection, said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID given by the same route of administration.
  • ULD of a specified NSAID refers to a dose of said NSAID given by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration), said dose not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 25, 28, 30, 32, 35, 40, 45, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID given by the same route of administration, wherein said ULD of the NSAID is preceded by one or more loading dose of said NSAID by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said NSAID by said route.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesi
  • ULD of a specified NSAID refers to a dose of said NSAID which is not more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the usual or minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID given by the same route of administration, wherein said ULD of the NSAID is preceded by one or more loading dose of said NSAID by the same route of administration, said loading dose at least equal to the minimum approved or recommended dose of said NSAID by the specified route of administration.
  • Ketoprofen ( ⁇ )-2-(3-benzoylphenyl)propionic acid) or (R,5>2-(3-benzoylphenyl) propionic acid), is a NSAID with analgesic, anti-inflammatory and antipyretic properties. These properties of ketoprofen have been demonstrated in classical animal models and in vitro test systems. Its mode of action appears to be similar to that of other NSAIDs and includes inhibition of prostaglandin (COX-I and COX-2 inhibition) and leukotriene biosynthesis, antibradykinin activity, and lysosome membrane-stabilizing activity. Chemically, ketoprofen belongs to the group of substituted 2-phenylpropionic acids.
  • Ketoprofen as a racemate, or as the analgesically active enantiomer (+)-(S)-2-
  • ketoprofen (3-benzoylphenyl)propionic acid (dexketoprofen), is marketed in a number of countries in a variety of forms, including oral solids, suppositories, and a topical gel.
  • Ketoprofen is soluble in benzene, ethanol, chloroform, acetone, ether, and alkaline solutions, but it is practically insoluble in water.
  • Ketoprofen is marketed as an IM 100 mg/2 mL formulation (Profenid ® , France, Aventis, Oruvail ® , Hawgreen, UK) and as a lyophilized powder for intravenous use.
  • the maximum daily dose by this route is 300 mg.
  • the IM formulation containing benzyl alcohol
  • This formulation is approved for deep intramuscular injection into the gluteal muscle, 50- 100 mg every 4 hours (max. 200 mg in 24 hours) for up to 3 days.
  • an intramuscular (IM) form of ketoprofen is also available for deep intramuscular injection into the gluteus muscle.
  • IM intramuscular
  • IM solution containing arginine, benzyl alcohol, citric acid, and water for injection
  • its use by the IV route is prohibited due to toxicity of the formulation.
  • IM administration does not provide a very rapid onset of effect, and it is painful, especially with repeated administration or with a large injection volume.
  • Most clinicians and hospitals discourage the repeated IM administration of drugs and the use of IM injection volumes greater than 1 mL.
  • IM injection volumes greater than 2 mL are generally strongly discouraged or prohibited from routine use.
  • IM administration is not appropriate in many patients due to an absence of adequate muscle mass and the possibility of bleeding and hematoma formation, especially if anticoagulated with drugs like heparin or warfarin.
  • IM administration of the acid formulation of NSAIDs has also been associated with sever nerve damage, muscle tissue necrosis, and even death.
  • a separate IV formulation of racemic ketoprofen is available in a few countries as a lyophilized powder containing sodium hydroxide, glycine, and citric acid. It is recommended by the manufacturer that IV ketoprofen be diluted in 100 to 150 mL of 5% dextrose in water or 0.9% saline and administered over approximately 20 minutes.
  • IV ketoprofen be diluted in 100 to 150 mL of 5% dextrose in water or 0.9% saline and administered over approximately 20 minutes.
  • an infusion of ketoprofen over 20 minutes means that the onset of analgesia is delayed and the peak pain relief is lower, owing to lower maximal blood concentrations.
  • ketoprofen can cause significant side effects, including venous irritation.
  • side effects including venous irritation.
  • venous irritation e.g., Castagnera, L., et al., Sem Hop Paris 64(32):2179- 2182 (1988); Semaine des hospitaux (Paris) 32:2179-88 (1988)).
  • ketoprofen by the intravenous route has been limited by the porr solubility of the drug, the need to administer it in a large volume of solution (100 to 150 mL), the need to infuse the dose over 15 to 20 minutes and the need to use solubilizers that can be toxic and that can result in drug precipitation upon injection.
  • PCT Patent application number PCT/US2006/016078 discloses novel formulations of ketoprofen, dexketoprofen, piroxicam and tenoxicam, with ethylenediamine and/or piperazine.
  • Piroxicam is an N-heterocyclic carboxamide of 1,2 benzothiazine 1,1 dioxide with analgesic and anti-inflammatory activity. It has an extended half-life of about 40 hours and is suitable for once daily administration. It is primarily biotransformed in the liver to inactive metabolites; less than 10% of a dose appears unchanged in the urine. Evidence from clinical trials indicates that piroxicam 20 mg per day is comparable to daily doses of aspirin 3 to 6 g, indomethacin 75 to 150 mg, naproxen 500 mg, ibuprofen 1200 to 2400 mg, diclofenac 75 mg and fenbufen 600 mg.
  • Piroxicam has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, acute gouty arthritis, ankylosing spondylitis, acute musculoskeletal disorders, dysmenorrhea, renal colic and acute postsurgical pain.
  • the usual adult dose of oral piroxicam is 20 to 40 mg given once a day.
  • 1,1 -dioxide is an NSAID with an oxicam structure, is entirely ionized at physiological pH, has minimal lipophilic properties, high plasma protein binding, does not accumulate in fatty tissue and skin and thus has a small volume of distribution. It is completely absorbed via the oral route and is about 99% protein bound in human plasma. Food consumption delays its rate of absorption without affecting its bioavailability. An elimination half-life of 50 to 80 hours has been estimated. Tenoxicam demonstrates linear pharmacokinetics over the 10 to 100 mg dose range. As a consequence of its low lipophilicity and high percent ionization, tenoxicam is poorly distributed into body tissues. Tenoxicam is primarily biotransformed in the liver.
  • tenoxicam demonstrates linear pharmacokinetics during multiple- dosing. As a result of its long half-life, tenoxicam can be administered once daily. Clinical trials in patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout suggest that tenoxicam 20 mg daily is an effective anti-inflammatory and analgesic agent. Gastrointestinal symptoms are the most frequently reported side effects. Compared with many other NSAIDs, tenoxicam offers certain advantages in that it is conveniently administered once daily and dosage adjustment is not required in the elderly or in patients with renal or hepatic.
  • Ketorolac ( ⁇ )-5-Benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid) is a chiral NSAID which is marketed for analgesia as the racemate. It is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular and intravenous injection. The absorption of ketorolac is rapid, with peak plasma concentrations occurring between 20 to 60 minutes post-dose. The oral bioavailability of ketorolac is estimated to range from 80 to 100%. The drug is extensively bound to plasma proteins and has a volume of distribution comparable to other NSAIDs. The elimination half-life is between 4 and 6h.
  • Ketorolac is extensively metabolized through glucuronidation and oxidation and very little is excreted unchanged. Most of the dose of ketorolac is recovered in the urine as conjugate. Ketorolac is the only nonsteroidal antiinflammatory drug (NSAID) in widespread clinical use that is available in an injectable form. Ketorolac is presently the only NSAID available in parenteral form in the United States.
  • NSAID nonsteroidal antiinflammatory drug
  • ketorolac provides efficacy comparable to that standard doses of opioid analgesics.
  • parenteral ketorolac has demonstrated efficacy in patients with renal colic, migraine headache and musculoskeletal pain.
  • the utility of ketorolac in acute pain is somewhat limited due to a prolonged time to onset of analgesia.
  • the clinical utility of parenteral ketorolac is limited due to its adverse effect profile and a restriction on duration of use. In a number of countries, injectable ketorolac has been withdrawn from the market by the local health authorities, due to its high propensity to cause serious and life threatening side effects.
  • Diclofenac (2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid) is an effective analgesic, antipyretic, and anti-inflammatory. It is rapidly absorbed after oral administration, undergoes extensive protein binding and has a short half-life. It undergoes significant first-pass metabolism, with approximately 50% of the dose biotransformed upon first pass through the liver. Diclofenac is metabolized in the liver by CYP2C to 4-hydroxydiclofenac, its primary metabolite, and to other hydroxylated forms. Following glucuronidation and sulfation the metabolites are excreted in the urine and bile.
  • Diclofenac is approved in the United States for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Diclofenac has also been extensively studied in the short-term treatment of acute musculoskeletal pain, postsurgical pain and dysmenorrhea. The major adverse events with diclofenac are gastrointestinal (approximately 20%). Elevations in hepatic transaminases occur in a significant number of patients. In some patients, transaminase levels may increase more than 3-fold. Other side effects of diclofenac include rashes, allergic reactions, fluid retention and edema. Among available NSAIDs, diclofenac appears to have the greatest risk of adverse cardiovascular outcomes.
  • Ibuprofen ( ⁇ -Methyl-4-(isobutyl)phenylacetic acid), the most commonly used
  • NSAID in the United States was the first member of the propionic acid class of NSAIDs to become commercially available.
  • Naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin are other drugs in the propionic acid class of NSAIDs that have been widely commercialized.
  • Naproxen has a longer half-life than ibuprofen.
  • Oxaprozin also has a long half-life and may be given once daily.
  • Propionic acid derivatives are approved for use in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain (e.g., postsurgical pain, musculoskeletal pain, primary dysmenorrhea).
  • the pharmacodynamics of the propionic acid derivatives do not differ greatly.
  • Ibuprofen has a half-life of approximately 2 hours. It is rapidly absorbed and undergoes significant hepatic biotransformation, followed by renal excretion of metabolites. Gastrointestinal adverse events are common with ibuprofen. Other side effects include rashes, headache, dizziness, fluid retention, and edema.
  • Ibuprofen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
  • Naproxen ((iS)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid) is almost completely absorbed upon oral administration. Food delays the rate of absorption. Peak naproxen concentrations in plasma occur within 2 to 4 hours. Naproxen is about 99% protein bound. The half-life of naproxen in plasma is about 14 hours in the young, with a 2-fold increase observed in elderly patients. Approximately one-third of the dose of naproxen undergoes 6-demethylation. This metabolite, along with naproxen is excreted as conjugated products. Gastrointestinal side effects are common. Other side effects include drowsiness, headache, dizziness and fatigue. Naproxen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
  • Flurbiprofen (2-Fluoro- ⁇ -methyl-4-biphenylacetic acid ) is a chiral NSAlD of the
  • Flurbiprofen has demonstrated efficacy in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and acute pain.
  • Side effects include hypertension, congestive heart failure, gastrointestinal ulceration, bleeding and perforation, renal and hepatic impairment.
  • Lornoxicam (6-Choloro-4-Hydroxy-2-methyl-N-2-pyridinyl-2H-thieno(2,3-e)- l,2-thiazine-3-carboxamide 1,1 -dioxide or chlorotenoxicam) is a nonsteroidal antiinflammatory drug of the oxicam class. Unlike other oxicams, lornoxicam has a relatively short plasma half-life (of approximately 3 to 5 hours. Lornoxicam is eliminated through hepatic metabolism to 5'-hydroxylornoxicam. Lornoxicam' s metabolites are excreted in urine and feces. Lornoxicam and its major metabolites bind extensively to plasma proteins. Lornoxicam has been shown to be effective in the treatment of acute and chronic pain, including postsurgical pain and osteoarthritis. Lornoxicam's side effects are consistent with its NDAIS pharmacology.
  • the rate of absorption of celecoxib is moderate when given orally, with a Cmax of approximately 2 to 4 hours.
  • Celecoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455 ⁇ 166 L.
  • the extent of absorption of celecoxib increases in proportion to increasing oral doses between 100 and 800 mg. It is eliminated following biotransformation to carboxylic acid and glucuronic acid metabolites that are excreted in urine and feces.
  • Celecoxib has an elimination half-life of approximately 11 hours in healthy individuals. In randomized clinical trials, celecoxib is superior to placebo and similar in efficacy as conventional NSAIDS for osteoarthritis and rheumatoid arthritis.
  • celecoxib 100 and 200 mg and naproxen 500 mg twice daily provide similarly efficacy.
  • celecoxib 200 mg twice daily shows efficacy comparable to twice daily slow-release diclofenac 75 mg over a 24-week period.
  • Parecoxib a prodrug of valdecoxib is the only parenterally administered cyclooxygenase-2-selective inhibitor available. The recommended dose is 40 mg administered IV or IM, followed every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. Clinical trials of parecoxib demonstrate compareable efficacy with ketorolac in a variety of postsurgical pain states. However, parecoxib has significant adverse cardiovascular risk (Babul et al, Anesthesia and Analgesia 2006; 102:644-56; Babul et al., Anesthesiology 2006;104:375).
  • Lumiracoxib is a selective COX-2 inhibitor with an oral bioavailability of 74%. It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. It has a short elimination half-life from plasma of approximately 4 hours and demonstrates dose-proportional plasma pharmacokinetics. Lumiracoxib is extensively metabolized prior to excretion, with only a small amount excreted unchanged in urine or feces. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen.
  • lumiracoxib 100 to 200 mg per day has been shown to be superior to placebo in patients with osteoarthritis, with clinical efficacy comparable to diclofenac 150 mg/day, celecoxib 200 mg/day and rofecoxib 25 mg/day.
  • lumiracoxib 400 mg/day is as effective as standard doses of NSAIDs and other coxibs. Liver function test abnormalities were more frequent with lumiracoxib than with the comparator NSAIDS. There are no data on the efficcay of parenterally administered lumiracoxib. Lumiracoxib has been withdrawn from the market in a number of countries due to serious hepatic adverse effects.
  • Etoricoxib is a selective inhibitor of COX-2. Extensive clinical trials have confirmed its analgesic and antiinflammatory efficacy to be comparable to nonselective NSAIDS. Like other COX-2 selective NSAIDS, etoricoxib displays improved gastrointestinal safety compared with nonselective NSAIDS. It is rapidly and completely absorbed following oral administration providing a rapid onset of action. Its long plasma half-life allows for once-daily dosing. Etoricoxib is currently approved in a number of countries for various indications including the treatment of acute pain, acute gouty arthritis, chronic back pain, dysmenorrhea, osteoarthritis and rheumatoid arthritis.
  • etoricoxib is 30 mg once daily (maximum daily dose, 60 mg) for OA, 90 mg once daily for RA (maximum daily dose, 90 mg) and 120 mg once daily for acute gouty arthritis (maximum daily dose, 120 mg for up to 8 days).
  • the aforementioned selected NSAIDs including the preferred NSAIDs have one or more of the drawbacks associated with administering the NSAIDs.
  • a majority of NSAIDs have never been administered parenterally. Whether administered parenterally or orally, the prior art provides guidance on the effective dose range that may be safely administered (i.e., that achieve a balance between the attainment of the desired therapeutic effects and an "acceptable” or “tolerable” level of adverse effects.
  • the present invention involves ULD administration of one or more selected
  • NSAIDs as defined herein, preferably chosen from the group consisting of dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam, and mixtures thereof, in racemic, enantiomeric excess, or enantiomeric form; said administration providing an improved method of treating pain (e.g., reduced frequency and intensity of venous irritation, injection site pain, and/or phlebitis; reduced frequency and intensity of muscle pain or nerve irritation after IM injection; reduced frequency and intensity of gastrointestinal side effects; reduced cardiovascular side effects; reduced surgical complications; reduced frequency and intensity of interactions between
  • selected NSAIDs as defined above, and preferably dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam.
  • the pharmaceutical composition is administered IV,
  • the pharmaceutical composition when given by the intravenous route, may be administered by rapid IV injection, e.g., IV bolus, IV push, or slow 2 minute IV injection for rapid onset of effect and a more robust peak effect, or alternatively by longer duration infusions.
  • the pharmaceutical composition when administered by intravenous route, the pharmaceutical composition produces little to substantially no precipitation of the NSAID in the subject's vein.
  • the pharmaceutical composition when given by the intravenous route, may be administered by slow IV infusion.
  • the pharmaceutical composition can be administered directly into epidurally or into the intrathecal space.
  • the dose of ULD of the selected NSAID is less than about 1% of the usual dose of the selected NSAID by the specified parenteral route of administration. In other embodiments, the ULD of the selected NSAID is less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID by the same parenteral route of administration. [00147] In certain preferred embodiments, the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • subcutaneous tolerability e.g., reduced injection site pain, subcutaneous irritation, subcutaneous inflammation, injection site redness, or sterile or nonsterile abscesses after subcutaneous injection, short term subcutaneous infusions and continuous subcutaneous infusions, compared to administration of usual doses of the selected NSAIDs.
  • the method of the invention will produce about
  • intrathecal and epidural tolerability e.g., reduced injection site pain and irritation, reduced epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions or intrathecal granulomas after epidural or intrathecal administration, compared to administration of usual doses of the selected NSAIDs.
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • liver function tests e.g., AST, ALT, ALP, GGT, bilirubin and albumin
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the method of the invention will produce about
  • the ULD of the selected NSAID obtains total pain relief (TOTPAR), sum of pain intensity difference (SPID) or sum of pain relief intensity difference (SPRID) at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected NSAID after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID.
  • TOTPAR total pain relief
  • SPID sum of pain intensity difference
  • SPRID sum of pain relief intensity difference
  • the ultra-low dose (ULD) of the selected NSAID after first administration by the specified parenteral route of administration obtains a TOTPAR, SPID or SPRID at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected NSAID after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains pain intensity difference (PID) and pain relief (PR) at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected NSAID after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID.
  • PID pain intensity difference
  • PR pain relief
  • the ultra-low dose (ULD) of the selected NSAID after first administration by the specified parenteral route of administration obtains a PID and PR at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose for the selected NSAID which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains peak pain relief (PPR) or peak pain intensity difference (PPID) for the selected NSAID after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID.
  • PPR peak pain relief
  • PPID peak pain intensity difference
  • the ultra-low dose (ULD) of the selected NSAID obtains a PPR or PPID for the selected NSAID after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains a
  • NNT number of patients with pain who need to be treated to obtain > 50% pain relief in one patient
  • NNT number needed to treat or NNT
  • the usual analgesic dose of the selected NSAID by the intravenous route is Ax
  • this dose obtains an NNT of Ay
  • the dose of the ULD NSAID is 2x
  • this dose obtains an NNT of not less than 3y.
  • the ultra-low dose (ULD) of the selected NSAID obtains an NNT for the selected NSAID after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains a percentage of patients who have a 30% postbaseline reduction in pain (Responded 0%) at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours post-dose for the selected NSAID after first administration by the specified parenteral route of administration which is not more than one percentage (1%) lower for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID.
  • the usual analgesic dose of the selected NSAID by the intravenous route is Ax
  • this dose obtains a Responder3o% of 4y
  • the dose of the ULD NSAID is 2x
  • this dose obtains an NNT of not less than 3y.
  • the ultra-low dose (ULD) of the selected NSAID obtains a Responder 3 o % for the selected NSAID after first administration by the specified parenteral route of administration which is not more than 1.1% lower, or not more than 1.2% lower, or not more than 1.3% lower, or not more than 1.4% lower, or not more than 1.4% lower, or not more than 1.5% lower, or not more that 1.6% lower, or not more that 1.7% lower, or not more than 1.8% lower, or not more than 0.9% lower, or not more than 0.8% lower, or not more than 0.7% lower, or not more than 0.6% lower, or not more than 0.5% lower, or not more than 0.4% lower for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains a time to confirmed perceptible pain relief using a double stopwatch method after first administration for the selected NSAID after first administration by the specified parenteral route of administration which is not more than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID.
  • the usual analgesic dose of the selected NSAID by the intravenous route is 4x, and this dose obtains a time to confirmed perceptible pain relief using a double stopwatch method of 40 minutes, and the dose of the ULD NSAID is 2x, than this dose obtains a time to confirmed perceptible pain relief of not less than 30 minutes.
  • the ultra-low dose (ULD) of the selected NSAID after first administration by the specified parenteral route of administration obtains a time to confirmed perceptible pain relief using a double stopwatch method for the selected NSAID which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains a time to meaningful pain relief using a double stopwatch method for the selected NSAID after first administration by the specified parenteral route of administration which is not less than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID.
  • the usual analgesic dose of the selected NSAID by the intravenous route is 4x, and this dose obtains a time to meaningful pain relief using a double stopwatch method of 80 minutes, and the dose of the ULD NSAID is 2x, than this dose obtains a time to meaningful pain relief of not less than 60 minutes.
  • the ultra-low dose (ULD) of the selected NSAID after first administration by the specified parenteral route of administration obtains a time to meaningful pain relief using a double stopwatch method for the selected NSAID which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected NSAID.
  • the ULD of the selected NSAID obtains a median time to rescue analgesic use for the selected NSAID after first administration by the specified parenteral route of administration which is not more than one percentage (1%) shorter (i.e., earlier) for every two percentage (2%) decrease in dose from the usual dose of the selected NSAID. For example, if the usual analgesic dose of the selected NSAID by the intravenous route is 4x, and this dose obtains a median time to rescue analgesic use of 100 minutes, and the dose of the ULD NSAID is Ix, than this dose obtains a median time to rescue analgesic use of not less than 75 minutes.
  • the ultra-low dose (ULD) of the selected NSAID after first administration by the specified parenteral route of administration obtains a median time to rescue analgesic use for the selected NSAID which is not less than 1.1% shorter, or not less than 1.2% shorter, or not less than 1.3% shorter, or not less than 1.4% shorter, or not less than 1.4% shorter, or not less than 1.5% shorter, or not more that 1.6% shorter, or not more that 1.7% shorter, or not less than 1.8% shorter, or not less than 0.9% shorter, or not less than 0.8% shorter, or not less than 0.7% shorter, or not less than 0.6% shorter, or not less than 0.5% shorter, or not less than 0.4% shorter for every 2% decrease in dose from the usual dose of the selected NSAID.
  • Analgesic efficacy measures including PID, PR, PPID, PPR, SPID, SPRID,
  • TOTPAR time to confirmed perceptible pain relief, time to meaningful pain relief, NNT and Responder 3 o % can be measured using known methods.
  • NSAID associated toxicity including intravenous tolerability (e.g., venous irritation, injection site pain and reduced phlebitis), intramuscular tolerability, (e.g., reduced injection site pain, muscular irritation, abscesses, nerve irritation and nerve damage), subcutaneous tolerability (e.g., injection site pain, subcutaneous irritation and abscesses), intrathecal and epidural tolerability (e.g., injection site pain and irritation, epidural hematoma and abscess, sterile abscesses, inflammatory mass lesions and intrathecal granulomas), cardiovascular side effects (e.g., hypertension, peripheral edema, fluid retention, congestive heart failure and myocardial infarction), renal and hepatic complications, complications from orthopedic surgery or bone manipulation (e.g., nonunion, malunion, avascular necrosis), gastrointestinal side effects (e.g., including dyspepsia, ulceration, perforation and bleeding), postsurgical wound complications
  • the selected NSAID given as a
  • the ULD NSAID is for the treatment of pain. In other embodiments, the ULD NSAID is for the treatment of acute pain. In other embodiments, the ULD NSAID is for the treatment of chronic pain. In other embodiments, the ULD NSAID is for the treatment of acute exacerbations of chronic pain. In other embodiments, the ULD NSAID is for the treatment of breakthrough pain. In other embodiments, the ULD NSAID is for the treatment of acute postsurgical pain. In other embodiments, the ULD NSAID is for the treatment of renal colic. In other embodiments, the ULD NSAID is for the treatment of signs and symptoms of migraine, including pain, phonophobia, photophobia and nausea.
  • the ULD NSAID is for the treatment of burn pain. In other embodiments, the ULD NSAID is for the treatment of burn dressing change pain. In other embodiments, the ULD NSAID is for the treatment of posttraumatic pain. In other embodiments, the ULD NSAID is for the treatment of acute musculoskeletal pain. In certain preferred embodiments, the ULD NSAID is for the treatment of acute postsurgical pain. In certain preferred embodiments, the ULD NSAID is for the treatment of acute postsurgical pain following major surgery.
  • the ULD NSAID is for the treatment of acute postsurgical pain for use in the inpatient setting (i.e., a medically supervised setting where the patient has been admitted into the hospital, clinic or medical facility, usually involving an overnight stay).
  • the ULD NSAID is for the treatment of acute postsurgical pain for use in the day surgery or outpatient surgery setting (i.e., a medically supervised setting where the patient is expected to be rapidly discharged, usually not involving an overnight stay).
  • the ULD NSAID is for the treatment of acute headache (e.g., migraine) or acute renal colic, or acute posttraumatic pain in the emergency room.
  • the ULD NSAID is for the treatment of pain for conditions under which the standard of care or the usual standard of care involves the presence of or insertion of an indwelling sterile catheter for subcutaneous, venous, epidural or intrathecal access.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of mild pain.
  • the selected NSAID given as a ULD NSAID is for the treatment of pain of at least moderate severity (i.e., moderate intensity).
  • the selected NSAID given as a ULD NSAID is for the treatment of pain of moderately severe intensity.
  • the selected NSAID given as a ULD NSAID is for the treatment of pain of that is of severe intensity. [00187]
  • ULD NSAID is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends parenteral analgesics. [00189] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends intravenous analgesics.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends subcutaneous analgesics. [00191] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends intramuscular analgesics.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of acute postsurgical pain in a medically supervised facility in patients with moderate or severe pain where the standard of care recommends epidural or intrathecal analgesics. [00193] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of pain excluding the pain of dysmenorrhea. [00194] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of pain excluding the pain of headache (e.g., migraine or tension headache).
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding dental pain.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding pain following third-molar extractions. [00197] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of pain excluding the pain associated with metatarsophalangeal surgery (e.g., bunionectomy, hammer toe repair).
  • metatarsophalangeal surgery e.g., bunionectomy, hammer toe repair.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain excluding the pain associated with podiatric surgery. [00199] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of pain excluding the pain associated with sore throat or mucositis. [00200] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of pain by administration by the infiltration route in proximity to the field of surgical incision. [00201] In certain preferred embodiments of the invention, the selected NSAID given as a
  • ULD NSAID is for the treatment of pain by administration by the infiltration route in proximity to source of pain.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding renal colic.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain by intraarticular administration.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding mild pain (i.e., pain of mild intensity).
  • mild pain i.e., pain of mild intensity.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding moderate pain (i.e., pain of moderate intensity).
  • moderate pain i.e., pain of moderate intensity.
  • ULD NSAID is for the treatment of pain excluding pain treated by intravenous infusions of the ULD NSAID (i.e., intravenous administration lasting longer than about 5 minutes).
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding chronic pain.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding neuropathic pain.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding cancer pain.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain in patients receiving concomitant opioid analgesics.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain, excluding concomitant use with opioid analgesics.
  • the selected NSAID given as a
  • ULD NSAID pharmaceutical composition for the treatment of pain, said composition devoid of opioid analgesics.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain by the parenteral route, said parenteral route excluding intra-articular administration.
  • the selected NSAID given as a
  • ULD NSAID is for the treatment of pain by the parenteral route, said parenteral route excluding administration by local tissue infiltration.
  • both the dose and the total daily dose of the selected NSAID given as ULD NSAID is significantly lower than the usual dose and daily dose of selected NSAID; said lower dose of the selected NSAID given as a ULD
  • the NSAID resulting in a shorter duration of analgesia for each administered dose compared with the usual dose of the selected NSAID; said lower dose of the ULD NSAID providing about the same overall or total analgesic or pain relieving effect by virtue of being given more frequently than the usual dose of the selected NSAID given at its usual dosing frequency; said invention still providing a significantly lower total daily dose despite about the same analgesic or pain relieving effect as the usual dose of the selected NSAID.
  • NSAID is not significantly lower than the usual dose; however, the daily dose of selected NSAID given as ULD NSAID is significantly lower than the usual daily dose of selected NSAID; said composition still providing some or all of the benefits of the present invention.
  • the dose of the selected NSAID given as ULD is the dose of the selected NSAID given as ULD
  • NSAID preferably chosen from the group consisting of dexibuprofen (S(+)-ibuprofen), dexflurbiprofen (S(+)-flurbiprofen), dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, parecoxib, piroxicam, rofecoxib, tenoxicam, valdecoxib and lornoxicam, and mixtures thereof, in racemic, enantiomeric excess, or enantiomeric form is less than about 1% of the usual dose of the selected NSAID by the specified parenteral route of administration.
  • the ULD of the selected NSAID is less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID by the same parenteral route of administration.
  • the doses of the specified ULD NSAID by the parenteral route are for the treatment of pain of mild intensity. In other said doses are for the treatment of pain of moderate intensity, moderately severe intensity or severe intensity.
  • the specified ULD NSAID by the parenteral route is for the treatment of pain in children, in which case the adult dose may be multiplied by the weight of the child (in kilograms) and then divided by 70 kilograms to provide the dose for the child in milligrams (e.g., if the adult dose in a particular embodiment is 5 mg and the child weighs 35 kg, then the dose for the child for the said embodiments is 2.5 mg)
  • the dose of ULD of the selected NSAID is less than about 1% of the usual dose of the selected NSAID by the specified parenteral route of administration, said dose administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
  • the ULD of the selected NSAID is less than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended unit dose, individual dose and/or daily dose of the same NSAID by the same parenteral route of administration.
  • the dose of ULD of the selected NSAID is administered by the specified parenteral route of administration in a volume that is less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% the minimum approved or recommended dose by the same route of administration.
  • the dose of ULD of the selected NSAID is administered at a rate that is at least about 10, 20, 30, 40, 50, 60, 70, 80, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 1000% faster than the minimum approved or recommended rate of administration for the minimum approved or recommended dose by the same route of administration.
  • the dose of ULD of the selected NSAID specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, individual dose, demand dose or daily dose is administered or solely administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
  • the dose of ULD of the selected NSAID specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose comprises the demand dose to be administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration.
  • the patient controlled analgesia is by the intravenous route (PCA).
  • said demand dose is preceded by one or more loading doses, preferably one loading dose, with the same drug by the same route of administration, said loading dose at least equal to the minimum recommended or approved dose for the intended route of administration or for oral administration.
  • the demand dose must be preceded by one or more loading doses, preferably one loading dose, with the same drug by the same route of administration, said loading dose at least equal to the minimum recommended or approved dose for the intended route of administration or for oral administration.
  • the dose of ULD of the selected NSAID specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose comprises the demand dose, said demand dose administered by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration, said demand dose to be administered at a frequency not to exceed a prespecified dosing frequency (the lockout period), said lockout period determined by a qualified clinician or medical practitioner.
  • the lockout period for patient controlled analgesia is programmed or preprogrammed into the patient controlled analgesia device or pump.
  • the demand dose by patient controlled analgesia must be associated with a lockout period.
  • the lockout period for administration of a demand dose by patient controlled analgesia is at least about 5, 6, 7, 8, 10, 12, 15, 18, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 240, 270, 300, 330 or 360 minutes.
  • the lockout period is not more than about 15, 30, 45, 60, 90, or 120 minutes.
  • the lockout period for administration of a demand dose by patient controlled analgesia is not more than 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended dosing frequency of the unit dose or individual dose of the NSAID by the same route of administration or by the oral route of administration.
  • the dose of ULD of the selected NSAID specified in the embodiments herein in mg or mg/kg or as a percentage of the minimum, usual or maximum approved or recommended unit dose, or individual dose is: (1) preceded by a loading dose; (ii) given as a demand dose by patient controlled analgesia using the intravenous, epidural, intrathecal or subcutaneous route of administration, preferably by the intravenous route (PCA); (iii) administered not more frequently then the lockout period; (iv) administered at a cumulative daily or 24 hour dose not to exceed 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70 of the minimum approved or recommended daily dose of the said NSAID by the same route of administration or by the oral route of administration.
  • the dose of ULD of the selected NSAID may be adjusted upwards or downwards based on the patients efficacy and safety response, tolerability of therapy, desired outcome and speed of outcome, provided that the each individual, unit or demand dose does not exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended dose by the same route of administration or by the oral route of administration.
  • the dose of ULD of the selected NSAID may be adjusted upwards or downwards based on the patients efficacy and safety response, tolerability of therapy, desired outcome and speed of outcome, provided that the daily or 24 hour dose does not exceed 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 28, 30, 32, 35, 37, 40,42, 45, 47, 50, 55, 60, 65, or 70% of the minimum approved or recommended daily or 24 hour dose by the same route of administration or by the oral route of administration.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketoprofen adult dose of the invention (i.e., the adult dose of the ULD ketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20.5 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 1 1 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketoprofen adult dose of the invention (i.e., the adult dose of the ULD ketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.4 mg/kg, or less than about 0.38 mg/kg, or less than about 0.36 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.32 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexketoprofen adult dose of the invention (i.e., the adult dose of the ULD dexketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 1 1.5 mg, or less than about 1 1 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 12.5 mg, or less than about 12 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexketoprofen dose of the invention (i.e., the dose of the ULD dexketoprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.1 1 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural diclofenac adult dose of the invention (i.e., the adult dose of the ULD diclofenac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 20 mg, or less than about 18 mg, or less than about 16 mg or less than about 15 mg, or less than about 12 mg, or less than about 1 1 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4.75 mg, or less than about 4.5 mg, or less than about 4.25 mg, or less than about 4 mg, or less than about 3.75 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural diclofenac dose of the invention (i.e., the dose of the ULD diclofenac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.3 mg/kg, or less than about 0.29 mg/kg, or less than about 0.28 mg/kg, or less than about 0.25 mg/kg, or less than about 0.22 mg/kg, or less than about 0.20 mg/kg, or less than about 0.18 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg, or
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural piroxicam adult dose of the invention (i.e., the adult dose of the ULD piroxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less
  • the aforementioned doses of the ULD piroxicam by the parenteral route are for the treatment of pain of mild intensity. In certain preferred embodiments the aforementioned doses of the ULD piroxicam by the parenteral route are for the treatment of pain of moderate intensity.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural piroxicam dose of the invention (i.e., the dose of the ULD piroxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.0714 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.067 mg/kg, or less than about 0.066 mg/kg, or less than about 0.065 mg/kg, or less than about 0.064 mg/kg, or less than about 0.063 mg/kg, or less than about 0.062 mg/kg, or less than about 0.061 mg/kg, or less than about 0.06 mg/kg, or less than about 0.059 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ibuprofen adult dose of the invention (i.e., the adult dose of the ULD ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 48 mg, or less than about 46 mg, or less than about 44 mg, or less than about 42 mg, or less than about 40 mg, less than about 38 mg, or less than about 36 mg, or less than about 35 mg, or less than about 34 mg, or less than about 32 mg, or less than about 30 mg, or less than about 28 mg, or less than about 26 mg, or less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ibuprofen dose of the invention (i.e., the dose of the ULD ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(+)-ibuprofen (dexibuprofen) adult dose of the invention i.e., the adult dose of the ULD S(+)-ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route is less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20.5 mg, or less than about 20 mg, less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(+)-ibuprofen (dexibuprofen) dose of the invention i.e., the dose of the ULD S(+)-ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the dose of the ULD S(+)-ibuprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route is less than about 0.357 mg/kg, or less than about 0.35 mg/kg, or about 0.34 mg/kg, or about 0.32 mg/kg, or less than about 0.30 mg/kg, less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketorolac adult dose of the invention (i.e., the adult dose of the ULD ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 5 mg, or less than about 4.9 mg, or less than about 4.8 mg, or less than about 4.7 mg, or less than about 4.6 mg, or less than about 4.5 mg, or less than about 4.4 mg, or less than about 4.3 mg, or less than about 4.2 mg, or less than about 4.1 mg, or less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than
  • the aforementioned doses of the ULD ketorolac by the parenteral route are for the treatment of pain of mild intensity. In certain preferred embodiments the aforementioned doses of the ULD ketorolac by the parenteral route are for the treatment of pain of moderate intensity.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural ketorolac dose of the invention (i.e., the dose of the ULD ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain is or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.07 mg/kg, or less than about 0.069 mg/kg, or less than about 0.068 mg/kg, or less than about 0.067 mg/kg, or less than about 0.066 mg/kg, or less than about 0.065 mg/kg, or less than about 0.064 mg/kg, or less than about 0.063 mg/kg, or less than about 0.062 mg/kg, or less than about 0.061 mg/kg, or less than about 0.06 mg/kg, or less than about 0.059 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(-)-ketorolac adult dose of the invention (i.e., the adult dose of the ULD S(-)-ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 2.5 mg, less than about 2.45 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or less than about 2.1 mg, or less than about 2 mg, or less than about 1.9 mg, or less than about 1.8 mg, or less than about 1.7 mg, or less than about 1.6 mg, or less than about 1.5 mg, or less than about 1.4 mg, or less than about 1.3 mg, or less than about 1.2 mg, or less than about 1.1 mg, or less than about 1 mg, or less than about 0.9 mg, or less
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural S(-)-ketorolac dose of the invention (i.e., the dose of the ULD S(-)-ketorolac by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.039 mg/kg, or less than about 0.038 mg/kg, or less than about 0.037 mg/kg, or less than about 0.036 mg/kg, or less than about 0.035 mg/kg, or less than about 0.034 mg/kg, or less than about 0.033 mg/kg, or less than about 0.032 mg/kg, or less than about 0.031 mg/kg, or less than about 0.03 mg/kg, or less than about 0.029 mg/kg, or less than about 0.028 mg/kg, or less than about 0.027 mg/kg, or
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural naproxen adult dose of the invention (i.e., the adult dose of the ULD naproxen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 100 mg, or less than about 98 mg, or less than about 96 mg, or less than about 95 mg, or less than about 94 mg, or less than about 92 mg, or less than about 90 mg, or less than about 88 mg, or less than about 86 mg, or less than about 85 mg, or less than about 84 mg, or less than about 82 mg, or less than about 80 mg, or less than about 79 mg, or less than about 78 mg, or less than about 76 mg or less than about 75 mg, or less than about 74 mg, or less than about 72 mg, or less than about 70 mg, or less
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural naproxen dose of the invention (i.e., the dose of the ULD naproxen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 1.428 mg/kg, or less than about 1.4 mg/kg, or less than about 1.39 mg/kg, or less than about 1.38 mg/kg, or less than about 1.37 mg/kg, less than about 1.36 mg/kg, or less than about 1.35 mg/kg, or less than about 1.34 mg/kg, or less than about 1.32 mg/kg, or less than about 1.31 mg/kg, or less than about 1.3 mg/kg, or less than about 1.28 mg/kg, less than about 1.26 mg/kg, or less than about 1.24 mg/kg, or less than about 1.22 mg/kg, or less than about 1.2 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tenoxicam adult dose of the invention (i.e., the adult dose of the ULD tenoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15.5 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12.5 mg, or less than about 12 mg, or less than about 1 1 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural tenoxicam dose of the invention (i.e., the dose of the ULD tenoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2857 mg/kg, or less than about 0.28 mg/kg, or less than about 0.27 mg/kg, or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg, or less than about 0.21 mg/kg, or less than about 0.20 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, less than about 0.2857 mg/kg, or less than about 0.
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural flurbiprofen adult dose of the invention (i.e., the adult dose of the ULD flurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12 mg, or less than about 11 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural flurbiprofen dose of the invention (i.e., the dose of the ULD flurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.3571 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.33 mg/kg, or less than about 0.32 mg/kg, or less than about 0.31 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg or less than about 0.28 mg/kg or less than about 0.27 mg/kg or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg, or less than about 0.23 mg/kg, or less than about 0.22 mg/kg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexflurbiprofen (S(+)- flurbiprofen)adult dose of the invention i.e., the adult dose of the ULD dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route
  • the adult dose of the ULD dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route is less than about 25 mg, or less than about 24 mg, or less than about 23 mg, or less than about 22 mg, or less than about 21 mg, or less than about 20 mg, or less than about 19 mg, or less than about 18 mg, or less than about 17 mg, or less than about 16 mg, or less than about 15.5 mg, or less than about 15 mg, or less than about 14 mg, or less than about 13 mg, or less than about 12.5 mg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural dexflurbiprofen dose of the invention (i.e., the dose of the ULD dexflurbiprofen by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.3571 mg/kg, or less than about 0.35 mg/kg, or less than about 0.34 mg/kg, or less than about 0.33 mg/kg, or less than about 0.32 mg/kg, or less than about 0.31 mg/kg, or less than about 0.30 mg/kg, or less than about 0.29 mg/kg, or less than about 0.2857mg/kg, or less than about 0.28 mg/kg, or less than about 0.27 mg/kg, or less than about 0.26 mg/kg, or less than about 0.25 mg/kg, or less than about 0.24 mg/kg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lornoxicam adult dose of the invention (i.e., the adult dose of the ULD lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 4 mg, or less than about 3.9 mg, or less than about 3.8 mg, or less than about 3.7 mg or less than about 3.6 mg, or less than about 3.5 mg, or less than about 3.4 mg, or less than about 3.3 mg, or less than about 3.2 mg, or less than about 3.1 mg, or less than about 3 mg, or less than about 2.9 mg, or less than about 2.8 mg, or less than about 2.7 mg, or less than about 2.6 mg, or less than about 2.5 mg, or less than about 2.4 mg, or less than about 2.3 mg, or less than about 2.2 mg, or
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lomoxicam dose of the invention (i.e., the dose of the ULD lornoxicam by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/kg, or less than about 0.052 mg/kg, or less than about 0.051 mg/kg, or less than about 0.05 mg/kg, or less than about 0.049 mg/kg, or less than about 0.048 mg/kg, or less than about 0.047 mg/kg, or less than about 0.046 mg/kg, or less than about 0.045 mg/kg, or less than about 0.044 mg/kg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural celecoxib adult dose of the invention is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg or less than about 30 mg, or less than about 28 mg, or less than about 25 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural celecoxib dose of the invention (i.e., the dose of the ULD celecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lumiracoxib adult dose of the invention for the treatment of pain, inflammation and/or fever is less than about 50 mg, or less than about 45 mg, or less than about 40 mg, or less than about 35 mg or less than about 30 mg, or less than about 28 mg, or less than about 25 mg, or less than about 22 mg, or less than about 20 mg, or less than about 18 mg, or less than about 16 mg, or less than about 15 mg, or less than about 14 mg, or less than about 12 mg, or less than about 10 mg, or less than about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural lumiracoxib dose of the invention (i.e., the dose of the ULD lumiracoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.71 mg/kg, or less than about 0.7 mg/kg, or less than about 0.68 mg/kg, or less than about 0.66 mg/kg, or less than about 0.64 mg/kg, or less than about 0.62 mg/kg, or less than about 0.61 mg/kg, or less than about 0.60 mg/kg, or less than about 0.59 mg/kg, or less than about 0.058 mg/kg, or less than about 0.057 mg/kg, or less than about 0.056 mg/kg, or less than about 0.055 mg/kg, or less than about 0.054 mg/kg, or less than about 0.053 mg/
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural parecoxib adult dose of the invention (i.e., the adult dose of the ULD parecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about 3.5 mg,
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural parecoxib dose of the invention (i.e., the dose of the ULD parecoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.11 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or less than about 0.2 mg/kg, or less than about 0.19 mg/
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural etoricoxib adult dose of the invention (i.e., the adult dose of the ULD etoricoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 12.5 mg, or less than about 12 mg, or less than about 11.5 mg, or less than about 11 mg, or less than about 10.5 mg, or less than about 10 mg, or less than about 9.9 mg, or less than about 9.5 mg, or less than about 9 mg, or less than about 8.5 mg, or less than about 8 mg, or less than about 7.5 mg, or less than about 7 mg, or less than about 6.5 mg, or less than about 6 mg, or less than about 5.5 mg, or less than about 5 mg, or less than about 4.5 mg, or less than about 4 mg, or less than about
  • the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration and epidural etoricoxib dose of the invention (i.e., the dose of the ULD etoricoxib by the intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration or epidural route) for the treatment of pain, inflammation and/or fever is less than about 0.2 mg/kg, or less than about 0.19 mg/kg, or less than about 0.18 mg/kg, or less than about 0.17 mg/kg, or less than about 0.16 mg/kg, or less than about 0.15 mg/kg, or less than about 0.14 mg/kg or less than about 0.13 mg/kg, or less than about 0.12 mg/kg, or less than about 0.1 1 mg/kg, or less than about 0.1 mg/kg, or less than about 0.09 mg/kg, or less than about 0.08 mg/kg or less than about 0.07 mg/kg, or less than about 0.06 mg/kg, or
  • ULD NSAID invention i.e., the intrathecal dose of the selected NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib by the intrathecal route) for the treatment of pain is less than about 0.01 mg, or less than about 0.009 mg, or less than about 0.008 mg, or less than about 0.007 mg, or less than about 0.006 mg, or less than about 0.005 mg, or less than about 0.004 mg, or less than about 0.003 mg, or less than about 0.002 mg, or less than about 0.001 mg, or less than about 0.0009 mg,
  • the intrathecal dose of the ULD is administered
  • NSAID invention i.e., the intrathecal dose of the selected NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib by the intrathecal route) for the treatment of pain is less than about 0.00015 mg/kg, or less than about 0.00013 mg/kg, or less than about 0.00012 mg/kg, or less than about 0.0001 mg/kg, or less than about 0.00009 mg/kg, or less than about 0.00008 mg/kg, or less than about 0.00007 mg/kg, or less than about 0.00006 mg/kg, or less than about 0.00005 mg/kg, or less
  • the pharmaceutical composition can be administered in varying amounts, volumes and doses, depending on the method of administration, route of administration and patient characteristics (for example, IV bolus; IV slow injection; IV brief infusion; IV prolonged infusion; IV continuous infusion; subcutaneous [SC]) injection; SC infusion; continuous SC infusion; patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration); intrathecal and epidural injections; intrathecal and epidural infusions; IM injection; cerebrospinal fluid [CSF] volume; age, weight, and fluid status of patient; body mass; general health and nutrition; cachexia; pharmacokinetics; pharmacodynamics; nature and severity of pain, fever and/or inflammation; nature of surgical procedure; use of concomitant medications, including other analgesics; co-morbidities; availability of ve
  • the bolus IV injection volume of a single therapeutic injection dose does not exceed about 100 mL, or about 75 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the slow IV injection, brief or continuous IV infusions hourly volume does not exceed about 1000 mL, or about 500 mL, or about 250 mL, or about 200 mL, or about 150 mL, or about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL.
  • the SC injection volume of a single therapeutic injection dose does not exceed about 5 mL or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the brief or continuous SC infusion hourly volume does not exceed about 100 mL, or about 50 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the IM injection volume of a single therapeutic dose does not exceed about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.01 mL, or about 0.001 mL, or about 0.0001 mL, or about 0.00001 mL.
  • the intrathecal volume (excluding intrathecal infusions) of a single therapeutic dose does not exceed about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
  • the hourly intrathecal infusion volume does not exceed about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.4 mL, or about 0.3 mL, or about 0.2 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL, or about 0.00001 mL, or about 0.000001 mL.
  • the epidural volume (excluding epidural infusions) of a single therapeutic dose does not exceed about 100 mL, or about 80 mL, or about 60 mL, or about 30 mL, or about 20 mL, or about 10 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
  • the hourly epidural infusion volume does not exceed about 30 mL, or about 20 mL, or about 15 mL, or about 12 mL, or about 10 mL, or about 8 mL, or about 6 mL, or about 5 mL, or about 4 mL, or about 3 mL, or about 2 mL, or about 1 mL, or about 0.5 mL, or about 0.1 mL, or about 0.01 mL, or about 0.001 ml, or about 0.0001 mL.
  • the invention when the NSAID of the invention includes ethylenediamine and/or piperazine, the invention specifically excludes one of more NSAIDS selected from the group of compounds comprising ketoprofen, dexketoprofen, piroxicam and tenoxicam.
  • the invention specifically excludes one of more
  • NSAIDS selected from the group of compounds comprising dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with hydroxypropyl-beta-cylcodextrin.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with beta-cylcodextrin.
  • the invention specifically excludes diclofenac or its pharmaceutically acceptable salts, or mixtures thereof when used in conjunction with cylcodextrins.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with hydroxypropyl- beta-cylcodextrin.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with beta- cylcodextrin.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when used in conjunction with cylcodextrins.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said ULD of NSAID is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration).
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said ULD of NSAID is not administered by patient controlled analgesia (e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration) and preceded by a loading dose of the same NSAID by the same route of administration, said loading dose administered using at least the minimum approved or recommended dose of said NSAID by said route.
  • patient controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • a loading dose of the same NSAID by the same route of administration said loading dose administered using at least the minimum approved or recommended dose of
  • the invention specifically excludes NSAlDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when said NSAID is not given by bolus injection.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAID dosage form is devoid of ethylenediamine.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAID dosage form is devoid of piperazine.
  • the invention specifically excludes NSAIDS or or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof when the NSAID dosage form is devoid of glycine.
  • the invention includes a method and pharmaceutical compositions of treating pain, inflammation, and/or fever in a subject in need of such treatment, comprising administering a pharmaceutical composition comprising: (i) a ULD of an NSAID selected from the group of compounds comprising dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof; (ii) an adult dose of each said compound which is less than about 20 mg if said compound is dexibuprofen, less than about 20 mg if said compound is dexflurbiprofen, less than about 10 mg if said compound is dexket
  • the invention includes a method and pharmaceutical compositions of treating pain, inflammation, and/or fever in a subject in need of such treatment, said method comprising administering a pharmaceutical composition comprising: (i) a ULD of an NSAID selected from the group of compounds comprising dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, naproxen, piroxicam, tenoxicam and lornoxicam, or their pharmaceutically acceptable salts, in racemic form, enantiomeric form, enantiomeric excess, and mixtures thereof; (ii) an adult dose of each said compound which is less than about 0.01 mg or a dose for each said compound on a patient weight basis is less than 0.00014 mg/kg; (iii) an analgesic dose of an analgesic selected from the group of an NSAID selected from the
  • some or all of the specifications and claims of the invention are achieved after multiple dose and repeated dose administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved after intravenous, intramuscular, subcutaneous, intrathecal or epidural administration. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of moderate intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of moderately severe intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with pain of severe intensity. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with acute pain.
  • some or all of the specifications and claims of the invention are achieved in patients with breakthrough pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with acute exacerbations of chronic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with cancer pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with chronic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with neuropathic pain. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with fever. In certain preferred embodiments, some or all of the specifications and claims of the invention are achieved in patients with inflammation.
  • the selected NSAID given as a
  • ULD NSAID is administered only by patient controlled (intravenous) analgesia (PCA) or patient controlled epidural analgesia (PCEA).
  • PCA patient controlled analgesia
  • PCEA patient controlled epidural analgesia
  • NSAIDS ie., COX-2 and/or COX-I inhibitors
  • the methods and compositions described herein are useful for treating a wide range of specific types of pain including acute pain, subacute pain, chronic pain, cancer pain, breakthrough pain, neuropathic pain, nociceptive pain, visceral pain, idiopathic pain, inflammatory pain, non-inflammatory pain.
  • Nonlimiting examples of acute pain include peri-operative pain, postsurgical pain, headache, acute low back pain, fractures, strains and sprains, ligament pain, cystitis, post-traumatic pain, burn pain, instrumentation pain, and renal colic.
  • Nonlimiting examples of chronic pain include cancer pain, osteoarthritis, fibromyalgia, low back pain, idiopathic pain, rheumatoid arthritis, bursitis, myofascial pain and the like.
  • Nonlimiting examples of neuropathic pain include postherpetic neuralgia, trigeminal neuralgia, painful diabetic neuropathy, pain HIV associated neuropathy, painful polyneuropathy, phantom limb pain, stump pain, spinal cord injury pain, post-stroke pain, central pain and the like.
  • the ULD NSAID chosen from selected NSAIDs is for the treatment of fever, acute pain (e.g., postsurgical pain, procedure related pain, renal colic, posttraumatic pain, headache), breakthrough pain and acute exacerbations of chronic pain.
  • acute pain e.g., postsurgical pain, procedure related pain, renal colic, posttraumatic pain, headache
  • breakthrough pain e.g., breakthrough pain and acute exacerbations of chronic pain.
  • analgesic effectiveness is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.
  • therapeutic effectiveness is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, fever and/or inflammation, along with a tolerable level of side effects, as determined by the human patient.
  • the term "effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, fever and/or inflammation, along with a tolerable level of side effects, as determined by the human patient.
  • the pharmaceutical composition can be administered in varying amounts and volumes.
  • the method of the invention may comprise administering, to a subject in need of an analgesic, anti-inflammatory or anti-pyretic treatment, a pharmaceutical composition comprising a selected NSAID preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib plus as required, water for injection, saline, glucose solutions, pH adjustment agents, additional excipients, buffers, surfactants, and the like.
  • NSAID preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, de
  • Administration of the present invention can be via any parenteral route of administration.
  • suitable parenteral routes of administration are described in general terms as follows. Each of the following routes of administration can be used in the present invention, in particular in each of the specific embodiments described.
  • IM Administration Once a popular method of drug administration, the intramuscular (IM) route is used considerably less frequently today due to improved availability of oral drugs and due to the ease of intravenous administration. This method of drug administration involves injecting drug directly into muscle mass, from where drug will gradually be absorbed systemically. For drugs that are not irritating when given by the IM route which require only a single injection, the IM route is still a viable route of administration, particularly in the outpatient setting or when strict aseptic conditions cannot be assured. When repeated administration is required or a rapid and reliable onset is desired, the intravenous route is preferred as repeated IM administration can be painful and inconvenient. Commonly the deltoid, gluteus maximus and vastus lateralis are sites for IM injection.
  • IM administration is partly a function of the dose and the injection volume, both of which are reduced by ULD NSAIDS of the invention. Additionally, IM administration is particularly attractive in the ambulatory care/outpatient setting, where venous access is lacking or impractical, and in settings where sterility cannot be absolutely assured.
  • the reduced dose and volume of the ULD NSAIDS of the invention particularly facilitate deltoid injections which are more convenient, more socially acceptable and provide more reliable pharmacokinetics and clinical effects that injection into the gluteus maximus.
  • Subcutaneous Administration involves injection into the subcutaneous fatty tissue under the skin. It can be used for the intermittent administration and self-administration of insulin and other medicines. In a small number of patients, particularly outpatients, this route is also used for the continuous or intermittent administration of drugs, usually with a programmable subcutaneous infusion device.
  • Epidural and intrathecal infusions can provide effective analgesia, but require skilled personnel (usually an anesthetist) to put the systems in place.
  • Catheters can be placed at any level of the spinal cord, although most commonly these techniques are used for pain in the lower part of the body.
  • Epidural and intrathecal routes of administration are advantageous for difficult abdominal or pelvic pain.
  • epidural catheters can be placed percutaneously, and fixed either by secure taping or subcutaneous tunnelling. The drugs can then be delivered through a small pump or a syringe driver. Subjects can be ambulant and managed at home with these systems. However the treatment team must have the necessary training, knowledge and support.
  • intrathecal systems which can be fully implantable, have many advantages. These offer great freedom to the patient, as there is no external equipment and the pump only needs to be refilled every few weeks. Some of the pumps are programmable and offer great flexibility.
  • epidural and especially intrathecal doses of NSAIDs can be lower than intravenous doses.
  • Epidural and intrathecal administration of NSAIDs can be also be used in conjunction with intravenous NSAIDs to provide additive or synergistic analgesia.
  • Intraarticular Administration This method of administration can be used to provide analgesic and anti-inflammatory drugs directly into affected joints to relieve pain and inflammation, usually due to surgery, osteoarthritis or joint trauma.
  • Surgical site or open wound This method of administration can be used when localized attenuation of pain or inflammation is deemed desirable and is achieved by topical, dermal administration or infiltration of a dose to a surgical site or open wound.
  • the term "infiltration”, “local infiltration”, “tissue infiltration” and “local tissue infiltration” shall mean administration into a discrete surgical site, open wound or at the location of pain in a human or animal.
  • IV Drug Administration The mode of IV drug administration depends on the particular NSAID used, the patient's condition, and the desired clinical effects of the NSAID.
  • the four primary modes of IV drug administration are continuous infusion, intermittent infusion, direct injection, and patient-controlled analgesia.
  • Continuous infusion typically refers to the admixture of a drug in a large volume of solution that is infused continuously over several hours to several days.
  • the solution container is connected to an administration set, and the solubilized drug is infused through the venous access.
  • the infusion may be administered by gravity feed or by use of electronic infusion control pump to deliver the drug accurately.
  • continuous infusions can be used when the drug is highly diluted and constant plasma drug concentration should be maintained.
  • continuous infusion can be used where large volumes of fluids and electrolytes need to be replenished along with the administration of the NSAID.
  • Intermittent infusion refers to the administration of the drug as a small volume of fluid, typically 25 to 250 mL in adults, and infused over, for example, 15 to 120 minutes at periodic intervals.
  • advantages of the intermittent method are the ability of the drug to produce higher peak blood concentrations at periodic intervals (compared with a continuous infusion), decreased risk of fluid overload, and greater convenience for the patient.
  • Intermittent infusions may be given in a number of ways, including "piggyback" infusions through the established pathway of a primary infusion solution. Although the primary infusion is interrupted during the piggyback infusion, the drug from the intermittent infusion container mixes with the primary solution below the piggyback injection level. Thus, if this method is used, the drug and the primary solution must be compatible.
  • a second method to administer intermittent infusions is as a simultaneous infusion, where the drug is administered as a secondary infusion concurrently with the primary infusion. Instead of connecting the intermittent infusion at the piggyback port, it is attached to a lower secondary port.
  • One potential disadvantage of this method is the tendency for blood to back up into the tubing once the secondary infusion has been completed, potentially occluding the venous access device. This generally does not occur with the piggyback method because the hydrostatic pressure closes the back check valve once the intermittent infusion is completed.
  • a third method is the use of a volume control set. Although it was originally designed to control the fluid volume delivered to the patient, a drug may be added to a small amount of solution in the volume control set and infused at the desired rate. It is still used in some pediatric settings because it limits the amount of fluid the child receives.
  • a fourth method for administering intermittent infusions is directly into the venous access device.
  • the device is generally intended for intermittent administration, such as a peripheral heparin lock.
  • the drug is added to a minibag or minibottle and infused intermittently. Between doses, the drug container and tubing are discarded.
  • Direct injection also known as IV push, IV bolus, or slow IV injection
  • IV push is the administration of a drug directly into the venous access device or through the proximal port of a continuous infusion set.
  • a purpose is to achieve rapid plasma concentrations while avoiding costly and time consuming use of infusion devices.
  • a direct injection requires only the time it takes to push the syringe plunger. Since the drug may be incompatible with the infusing solution or heparin may be present in the intermittent device, the vascular access device can be flushed with normal saline before and after injecting the drug.
  • Direct injections may require that the drug be drawn into a syringe before administration or that the drug be available in a prefilled syringe.
  • a needle 1 inch or shorter should be used to administer the medication because longer needles may puncture the IV tubing or the vascular access device.
  • Another alternative is a needleless system, which also prevents inadvertent puncture of the tubing or device.
  • Patient-controlled analgesia e.g., patient controlled intravenous analgesia [PCA] or patient controlled epidural analgesia [PCEA], or patient controlled analgesia using the intrathecal or subcutaneous route of administration
  • PCA patient controlled intravenous analgesia
  • PCEA patient controlled epidural analgesia
  • patient controlled analgesia using the intrathecal or subcutaneous route of administration is the fourth method of administration of drug administration which promotes patient comfort through the self- administration of analgesic agents.
  • an automated pump is programmed to administer a small bolus of the drug when activated by the patient.
  • the bolus amount (demand dose) and the time between doses (lock-out interval) are predetermined and programmed into the pump.
  • a demand dose or bolus amount of drug administered whenever the patient presses a button includes (1) a demand dose or bolus amount of drug administered whenever the patient presses a button; (2) a lockout interval which determines how soon after a bolus is administered a second bolus will be delivered if the patient pushes the button again; and optionally (3) a daily or 24 hour maximum dose or a daily or 24 hour maximum number of demand doses; and (4) override doses, said override doses administered by or under the supervision of a qualified care giver or health care worker . If a patient presses the button before the lockout interval has elapsed, the pump simply ignores the request.
  • the dose and lockout are generally programmed into the pump for an individual patient and drug combination.
  • the dose is prescribed based on the clinician's assessment of the patient's opioid requirement (depending on weight, habituation, or other factors).
  • the lockout interval is generally set depending on the time to onset of clinical effect of a given drug.
  • the lockout interval is used to prevent a patient from giving himself or herself another bolus before the previous bolus has had a chance to take effect.
  • PCA refers to patient controlled analgesia by the intravenous route
  • PCEA refers patient controlled analgesia by the epidural route.
  • a co-administered drug may include other NSAIDs, NO-NSAIDs, COX-2 selective inhibitors, acetaminophen, nitroparacentamol, tramadol, local anesthetics, antidepressants, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, cannabinoid agonists, opioid receptor agonists, NO-opioids, NMDA receptor antagonists, gabapentin, pregabalin, gabapentinoids, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers, serotonin 5-HT(lB/lD) receptor agonists superoxide dismutase mimetics, p38 MAP kinase inhibitors, triptans, TRPVl agonists, dextromethorphan, dextrorphan, ketamine, glycine receptor antagonists,
  • Other therapeutically active agents from various therapeutic classes may also be used in combination with the present invention. They include, but are not limited to decongestants, analgesics, analgesic adjuvants, antidepressants, antipsychotics, anxiolytics, hypnotics, sedatives, drugs to treat urinary incontinence, antihistamines, expectorants, antitussives, diuretics, anti-inflammatory agents, antipyretics, antirheumatics, antioxidants, laxatives, local anesthetics, proton pump inhibitors, motility modifying agents, vasodilators, inotropes, beta blockers, beta adrenergic agonists, drugs to treat asthma and COPD, antiinfectives, anti-migraine agents, antihypertensives, antianginal agents, gastric acid reducing agents, anti-ulcer agents, anticoagulants, lipid and cholesterol lowering drugs, anti-diabetic drugs, anti-epileptic
  • the drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, sublingually, and the like.
  • Some preferred combination therapies comprise the use of a composition of the present invention in combination with a therapeutic and effective dose of one or more compounds selected from the group consisting of acemetacin, ⁇ -acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, S-adenosyhnethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), alvimopan, amfenac, amino chlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4- picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, anileridine, antrafenine, apazone,
  • Particularly preferred combination therapies comprise the use of a composition of the present invention in combination with an analgesic dose of acetaminophen, nitroparacetamol, propacetamol, alvimopan, morphine, morphine-6- glucuronide, meperidine, methylnaltrexone, hydrocodone, dihydrocodeine, hydromorphone, levorphanol, racemorphan, gabapentin, pregabalin, oxycodone, oxymorphone, tramadol, clonidine, ziconotide, methadone, nalorphine, nalbuphine, fentanyl, sufentanil, alfentanil, lofentanil, carfentanil, brifentanil, remifentanil, trefentanil, mirfentanil, lidocaine, mepivacaine, bupivacaine, levobupivacaine, dipyrone, pen
  • the drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, inhalationally, and the like.
  • Another aspect of the present invention is directed to a composition
  • a composition comprising one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof.
  • NSAID given as a ULD NSAID
  • composition comprising:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; and (b) a compound selected from ethylenediamine, piperazine, and mixtures thereof.
  • the composition comprising the selected NSAID and piperazine or ethylenediamine may be in the form of a solid.
  • the solid composition will be a crystalline form, e.g., a crystalline form of the selected NSAID and piperazine or a crystalline form of ketoprofen and ethylenediamine.
  • the solid for may be amorphous, e.g., an amorphous form of ketoprofen and piperazine or an amorphous form of ketoprofen and ethylenediamine.
  • Other embodiments may be a mixture of amorphous and crystalline forms, while still other compositions may be a glassy solid or a semi-solid.
  • the solid composition may be in the form of a salt, e.g., a salt between ketoprofen and piperazine or a salt between ketoprofen and ethylenediamine.
  • the solid composition may be a non-salt complex between the NSAID and the piperazine, ethylenediamine, or mixtures thereof, having various ratios as described above.
  • the ULD dose of the selected NSAID and the ethylenediamine and/or piperazine is a complex, preferably a salt.
  • exemplary complexes include a dexibuprofen-piperazine complex, dexibuprofen-piperazine salt, dexibuprofen- ethylenediamine complex, dexibuprofen-ethylenediamine salt, dexflurbiprofen-piperazine complex, dexflurbiprofen-piperazine salt, dexfiurbiprofen-ethylenediamine complex, dexfiurbiprofen-ethylenediamine salt, dexketoprofen-piperazine complex, dexketoprofen-piperazine salt, dexketoprofen- ethylenediamine complex, dexketoprofen- ethylenediamine salt, diclofenac-piperazine complex, diclofenac-piperazine salt, diclofenac-piperazine salt, diclo
  • the composition comprises (a) a ULD dose of the selected
  • NSAID chosen from a group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib; (b) piperazine; and (c) a pharmaceutically acceptable carrier.
  • the composition comprises (a) a ULD dose of the selected
  • NSAID chosen from a group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib; (b) ethylenediamine; and (c) a pharmaceutically acceptable carrier.
  • the composition comprises (a) a ULD dose of the selected NSAID chosen from a group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib;
  • the selected NSAID chosen from a group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam
  • composition comprising the selected
  • NSAID and piperazine contains the ULD dose of the selected NSAID chosen from a group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib and the piperazine in a ratio of about 10:1 to about 1 : 10; about 5:1 to about 1 :5; about 3:1 to about 1 :3; about 2: 1 to about 1 :2; in a ratio of about 1.1 : 1 to about 1 :1.1 ; or in a ratio of about 1: 1.
  • compositions wherein the ratio is about 5:1 , 4: 1, 3:1, 2:1, 1 :2, 1 :3, 1 :4, 1 :5, 0.99:1, 1 :0.99, 1:0.9, 0.9:1, 1 :0.8, or 0.8:1.
  • composition comprising the selected
  • NSAID and ethylenediamine contains the ULD dose of the selected NSAID chosen from a group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib and the ethylenediamine in a ratio of about 10: 1 to about 1 :10; about 5:1 to about 1:5; about 3:1 to about 1 :3; about 2: 1 to about 1 :2; in a ratio of about 1.1 :1 to about 1 : 1.1 ; or in a ratio of about 1 : 1.
  • compositions wherein the ratio is about 5: 1, 4: 1, 3:1, 2: 1, 1 :2, 1:3, 1 :4, 1 :5, 0.99:1, 1 :0.99, 1 :0.9, 0.9: 1, 1 :0.8, or 0.8:1.
  • Suitable values include about 0.001, 0.01, 0.1 , 1, 5, 10, 20, 25, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 500, 550, 600, 650, 700, 800, 900 or 1000 mg/mL.
  • the selected NSAID can be a parenteral drug formulation prepared, e.g., as a solid, liquid, semi-solid, or emulsion.
  • the most common forms include solid, e.g., dry powder, crystalline, amorphous, lyophilized, and liquid formulations.
  • Solid compositions can be reconstituted with a liquid vehicle just prior to administration. However, in many situations, it is particularly advantageous to provide a liquid formulation, more especially a ready-to-use or dilutable formulation.
  • the formulation may optionally contain one or more additives, adjuvants, excipients, auxiliary agents or enabling agents, such as buffers, stabilizing agents, tonicity agents, antioxidant, anesthetics or bulking agent.
  • the invention contemplates all possible pharmaceutically acceptable salts and complexes of the ULD of the selected NSAID.
  • the pharmaceutical composition contains the
  • ULD of the selected NSAID as a salt or complex of inorganic cation salts organic salts such primary, secondary, tertiary and quaternary amines include substituted amines
  • suitable pharmaceutically acceptable salts of selected NSAIDs include any of the inorganic cation salts such as sodium, potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic; organic salts with primary, secondary, tertiary and quaternary amines, or mixtures thereof.
  • Examples of such primary, secondary, tertiary and quaternary amines include substituted amines including but not limited to naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and mixtures thereof. More specifically, suitable amines include but are not limited to tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, /m-(hydroxymethyl)aminomethane, ⁇ - methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins and the like, and mixtures thereof.
  • suitable amines include but are not limited to tromethamine, triethyl
  • the pharmaceutical composition contains the
  • aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l-propanol, (./?)- l-amino-2-propanol, (S)-I- amino-2-propanol, 2-amino-l ,3-propandiol, N-(2-hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and N-methylgluco
  • the pharmaceutical composition contains the
  • ULD of the selected ⁇ SAID as a salt or complex of alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.
  • the pharmaceutical composition contains, in addition to the ULD of the selected ⁇ SAID, one or more cyclodextrins (e.g., beta- hydroxypropyl- cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether cyclodextrin, gamma-cyclodextrin).
  • cyclodextrins e.g., beta- hydroxypropyl- cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether cyclodextrin, gamma-cyclodextrin.
  • the pharmaceutical composition contains, in addition to the ULD of the selected ⁇ SAID, ethanol, benzyl alcohol, propylene glycol, polyethylene glycol (PEG)-600, PEG-400, PEG-200, propylene glycol, glycerol, hydrotropes, sodium benzoate, sodium hydroxybenzoate and methyl-p-hydroxybenzoate sodium, sodium metabisulfite, EDTA.
  • the pharmaceutical composition contains, in addition to the ULD of the selected ⁇ SAID is micronized or prepared as a nanoparticulate composition.
  • the pharmaceutical composition contains the
  • the pharmaceutical composition contains the
  • the selected NSAID as the unsalified celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, in racemic form enantiomeric form or enatiomeric excess and mixtures thereof, said pharmaceutical composition devoid of salts or complexes such as any of the inorganic cation salts (e.g., sodium, potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic), organic salts (e.g., tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2-
  • the pharmaceutical composition contains the
  • the pharmaceutical composition contains the
  • the pharmaceutical composition contains the
  • the pharmaceutical composition contains the
  • cyclodextrins e.g., beta-hydroxypropyl- cyclodext
  • the dosage form of the invention is devoid of one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds know in the art.
  • a surfactant benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol
  • the dosage form of the invention contains one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds known in the art.
  • a surfactant benzyl alcohol
  • a polyethylene glycol a N-methylglucamine or derivative thereof
  • arginine or a derivative thereof lysine or a derivative thereof
  • an adjuvant citric acid or derivative thereof
  • glycine or a derivative thereof glycerol or a
  • the pharmaceutical composition contains the
  • said pharmaceutical composition devoid of one or more salts or complexes such as any of the inorganic cation salts (e.g., sodium, potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic), organic salts (e.g., tromethamine, triethylamine, tripropylamine, dropopizine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, tris-(hydroxymethyl)aminomethane, N- methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins).
  • the inorganic cation salts e.g., sodium, potassium, lithium, magnesium, calcium, ces
  • the pharmaceutical composition contains the
  • said pharmaceutical composition devoid of one or more salts or complexes such as inorganic cation salts, organic salts such primary, secondary, tertiary and quaternary amines include substituted amines.
  • the pharmaceutical composition contains the
  • said pharmaceutical composition devoid of one or more salts or complexes of aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l -propanol, (R)-l-amino-2-propanol, (S)-I -amino-2-propanol, 2-amino- 1 ,3-propandiol, N-(2-hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D- glucosamine, and N-methylglucosamine
  • the pharmaceutical composition contains the
  • said pharmaceutical composition devoid of one or more salts or complexes of alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.
  • the pharmaceutical composition contains the
  • said pharmaceutical composition devoid of one or more compounds selected from the group comprising a surfactant, benzyl alcohol, a polyethylene glycol, a N-methylglucamine or derivative thereof, arginine or a derivative thereof, lysine or a derivative thereof, an adjuvant, citric acid or derivative thereof, glycine or a derivative thereof, glycerol or a derivative thereof, an alkylammonium compound, tonicity agents, cosolvents, antioxidants, chelating agents, pharmaceutically acceptable buffers, preservatives, nitrogen, antimicrobial agents, pharmaceutically acceptable buffers, cosolvents, antioxidants and chelating agents, said compounds know in the art.
  • the invention is directed to a stable parenteral formulation comprising a selected NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, pharmaceutically acceptable salts thereof and mixtures thereof; a compound selected from ethylenediamine and piperazine; and a pharmaceutically acceptable carrier.
  • NSAID preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, keto
  • Liquid carriers and excipients are known in the art. See, e.g., Remington's.
  • Suitable liquid carriers and excipients include, but are not limited to, water, saline, ethanol, benzyl alcohol, etc., and mixtures thereof.
  • a preferred carrier is water, in particular water for injection
  • the pharmaceutical composition may contain a buffer.
  • buffer refers to a pharmaceutically acceptable excipient that helps to maintain the pH of the solution within a particular range specific to the buffering system.
  • the buffer is present for example at a concentration in the range from about 0.03% to about 5.0% w/v, or about 0.1% to about 2.0% w/v.
  • Non-limiting illustrative examples of pharmaceutically acceptable buffering agents include phosphates, 2-amino-2-(hydroxymethyl)-l,3- propanediol ("tris"), ascorbate, acetates, citrates, tartrates, lactates, succinates, amino acids and maleates and the like. Buffers are known in the art. See, e.g., Remington's.
  • the pH of a liquid formulation of the present invention in preferred embodiments is generally from about 5 to about 9, preferably from about 6 to about 8. In other embodiments, the pH of the liquid formulation is about 5, 6, 7, 8, or 9. Alternatively, the pH of the liquid formulation is about 7.5. Alternatively, the pH of the liquid formulation may be selected from the following ranges: 6.0 to 6.9; 6.5 to 6.9; 7 to 7.5; 7.6 to 8.0; 7.6 to 8.5; and 7.6 to 9.0.
  • the concentration and dosage of the NSAID in the liquid parenteral formulation can vary as needed.
  • the ULD of the selected NSAID can be in an amount of about from about 0.000001 to about 1000 mg/mL, alternatively from aboutO.001 mg/mL to about 200 mg/mL, based for example on the mass of the NSAID, its solubility, the route of administration, the choice of dose, patient characteristics and the purpose of drug administration.
  • the liquid formulation may be packaged in any suitable container, for example, a vial, ampoule, bag, bottle, prefilled syringe, and the like.
  • the liquid formulation comprises a physiologically compatible fluid, such as sterile, buffered saline.
  • the liquid carrier used in preferred embodiments is preferably injection-quality water, by itself or preferably with the addition of conventional, physiologically tolerated solvents and/or solubilizing agents, e.g., propylene glycol, polyols such as glycerol, polyoxyalkylenes, e.g., poly(oxyethylene)-poly(oxypropylene) polymers, glycerol-formal, benzyl alcohol, or butanediol.
  • solubilizing agents produces a composition which is stable at low temperatures and minimizes or prevents partial crystallization of the selected NSAID, in spite of the high concentration NSAID that may be present.
  • the liquid pharmaceutical formulation may be characterized in terms of its osmolality.
  • the osmolality of the pharmaceutical formulation is from about 50 to about 1000 mOsm/L, preferably about 100 to about 500 mOsm/L.
  • the pharmaceutical compositions of the present invention are prepared such that the osmolarity is about 200 to about 300 mOsm/L, about 250 to about 350 mOsm/L, about 270 to about 330 mOsm/L, about 270 to about 290 mOsm/L, or about 280 to about 300 mOsm/L, or is 270, 280, 290, 300, or 310 mOsm/L.
  • Alternative preferred embodiments include compositions which have a lower osmolarity than physiological osmolarity.
  • the injection preparations according to the invention can be sterilized by conventional methods or filled under sterile conditions.
  • the concentration of the selected NSAID in the liquid pharmaceutical composition can vary and may depend on the intended use.
  • the injection solutions according to the invention contain from about 0.0001 to about 90% of the selected NSAID.
  • liquid formulations of invention may employ one or more stabilizing agents.
  • a stabilizing agent may slow, delay, reduce, or prevent the precipitation of an NSAID in free acid form. It will be understood that the effectiveness of such means for stabilizing the NSAID salt, illustrative examples of which are individually described in further detail below, depend on, inter alia, composition of the particular solvent liquid, selection and amount of NSAID salt, and desired final presentation of the composition.
  • One class of suitable salt stabilizing means is a means for limiting effective exposure of the composition to oxygen.
  • limiting effective exposure of the composition to oxygen includes placing the composition in contact with an oxygen-limited microatmosphere and/or including in the composition one or more excipients or agents that mitigate potential deleterious effects of oxygen. Limiting the effective exposure of the composition to oxygen can be accomplished by one or more of the illustrative, nonlimiting means described more fully immediately below.
  • One means for limiting effective exposure of the composition to oxygen is to place the composition in contact with an oxygen-limited microatmosphere in a sealed container.
  • a container can have a substantial internal headspace occupied by a microatmosphere having low oxygen pressure.
  • the container can have very little or no headspace, in which case effective exposure of the composition to oxygen is limited largely by the barrier effect provided by the sealed container itself.
  • Any suitable pharmaceutical container can be used to prepare an article of manufacture according to this embodiment.
  • the container can be a multi-dose container, enclosing an amount of the composition preferably corresponding to 2 to about 30, for example about 4 to about 20, unit doses. Alternatively, the container encloses an amount of the composition corresponding to a single unit dose.
  • Such a single-dose article of manufacture has the further advantage of eliminating a measuring step before administration of the composition.
  • the container preferably is sufficient to maintain sterility of a composition contained therein.
  • the container can also be used to facilitate direct administration (without need for transfer to another vessel or container) of a composition of the invention, e.g., a syringe.
  • suitable containers for an article of manufacture of this invention include vials of any shape and/or size, ampoules, syringes, packets, pouches, auto-injectors, etc.
  • the container further comprises means to protect the composition from exposure to light, e.g., amber glass walls.
  • a composition of the invention can be sealed in a container in any suitable manner including but not limited to frictionally- and/or hermetically-induced seals.
  • a seal can illustratively be provided by a stopper made of rubber or other polymeric material.
  • a preferred seal comprises an inert coating, for example a coating of a fiuoropolymer such as polytetrafluoroethylene, e.g., Teflon ® , to prevent chemical interaction between the composition and the seal.
  • the seal can illustratively be secured by a metal over-cap and/or an external cover, e.g., plastic, until use.
  • the seal can comprise at least one septum or thinner area of sealing material through which a needle can be inserted to extract the composition without cracking or breaking any glass or plastic portion of container wall. Regardless of what form of seal is used, such a seal should substantially inhibit movement of gas into or out of the container until the seal is penetrated for use of the composition present in the container.
  • compositions are enclosed in a sealed container with an oxygen limited micro atmosphere
  • effective exposure of the composition to oxygen can be further limited by one or more of the following means: 1) a container size and/or shape that substantially maximizes fill volume and/or substantially minimizes headspace volume; 2) low oxygen pressure in the headspace; 3) use in the solvent liquid of water which has been purged of molecular oxygen; and 4) use of a grade of PEG having a low peroxide content, for example not greater than about 1.5 meq/kg and preferably not greater than about 1.0 meq/kg.
  • headspace or "headspace volume” with respect to an article of manufacture of the invention refers to any interior volume of the container that is not occupied by, but is in contact with, the composition. Generally, the headspace volume is occupied by a gaseous medium.
  • fill volume with respect to an article of manufacture of the invention refers to any interior volume of the container that is occupied by the composition.
  • total volume refers to the entire interior volume of the container and may also be referred to elsewhere as overflow volume; total volume generally equals the sum of the fill and headspace volumes.
  • Yet another suitable means for limiting effective exposure of a composition, particularly a PEG-containing composition, of the invention to oxygen, and thereby providing said NSAID salt stabilizing means comprises one or more pharmaceutically acceptable antioxidants, preferably free-radical scavenging antioxidants, as a component of the solvent liquid.
  • Non-limiting illustrative examples of suitable antioxidants include ⁇ -tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cystein, cysteinate HCl, dithionite sodium, ethylenediamine tetraacetic acid, fumaric acid, gentisic acid and salts thereof, hypophosphorous acid, malic acid, methionine, monothioglycerol, N-acetyl-cysteine, alkyl gallates, for example propyl gallate, octyl gallate and lauryl gallate, sodium sulfite, sodium bisulfite, sodium and potassium metabisulfite, thioglycolate sodium, ethanolamine, glutamate monosodium, formaldehyde, sulfoxylate sodium and monothioglycerol.
  • Preferred free radical-scavenging antioxidants are alkyl gallates, vitamin E, BHA, BHT, ascorbate and methionine, more especially BHA, ascorbate and methionine.
  • an antioxidant is selected that is substantially soluble in the particular solvent liquid employed and does not result in changes to the composition which are detectable by unaided sensory organs (e.g., color or odor changes).
  • BHA is an illustrative preferred antioxidant for use in a composition of the invention. If included, one or more antioxidants are preferably present in a composition of the invention in a total antioxidant amount of about 0.001% to about 5%, preferably about 0.001% to about 2.5%, and still more preferably about 0.001% to about 1%, by weight.
  • the formulations may optionally contain a bulking agent.
  • a bulking agent refers to a pharmaceutically acceptable excipient that adds bulk to a formulation which results in a well-formed cake upon freeze drying.
  • the bulking agent is for example present in a formulation at a concentration in the range from about 1% to about 60% w/v, or about 3% to about 50% w/v.
  • suitable bulking agents include mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin.
  • the solid composition also may include a tonicity agent.
  • Suitable tonicity agents include, but are not limited to, glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, and sorbitol.
  • Non-limiting examples of suitable nonaqueous solubilizers that can be present in the solvent liquid include polyethylene glycol (PEG), ethanol, dimethylacetamide (DMAC), propylene glycol, and mixtures thereof. It is preferred that the solvent liquid comprise at least one of PEG, DMAC, and ethanol.
  • Yet another means for stabilizing the formulation in a PEG-containing composition is a metal sequestering agent or chelating agent.
  • suitable sequestering agents include ethylenediamine tetraacetic acid (EDTA), potassium polyphosphate, sodium polyphosphate, potassium metaphosphate, sodium metaphosphate, dimethylglyoxirne, 8-hydroxyquinoline, nitrilotriacetic acid, dihydroxyethylglycine, gluconic acid, citric acid and tartaric acid.
  • composition of the present invention can optionally contain a surfactant.
  • Non-limiting examples of suitable surfactants include cetrimide, docusate sodium, glyceryl monooleate, sodium lauryl sulfate, or sorbitan esters.
  • the surfactant may optionally be a polyoxyethylenesorbitan fatty acid ester.
  • Polyoxyethylenesorbitan fatty acid esters are also referred to as polysorbates, e.g., polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80), polysorbate 40 and polysorbate 20.
  • composition of the present invention can optionally be manufactured in glass- lined or a "greater than or equal to 316 temper-grade" steel tank.
  • Oxygen pressure in a container headspace of an article of manufacture of the invention can be limited in any suitable manner, illustratively by placing nitrogen and/or a noble gas (collectively referred to herein as "inert gases") in the container headspace.
  • the headspace volume preferably comprises one or more inert gases selected from the group consisting of nitrogen, helium, neon and argon.
  • One way to ensure low oxygen pressure in the headspace is to prepare, fill and seal the container under an atmosphere of inert gas and/or to flush the container headspace with inert gas after filling, illustratively using parallel in-line flushing.
  • An inert gas atmosphere can illustratively be provided using a zero oxygen tunnel commercially available from Modified Atmosphere Packaging Systems of Des Plaines, 111., or by using a nitrogen or noble gas atmosphere glove bag.
  • polymorphs of this invention may be prepared by crystallization under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
  • solvates of the invention may be prepared by conventional methods such as dissolving the compounds in solvents such as water, methanol, ethanol etc., and recrystallizing by using different crystallization techniques.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; (b) sterile water; (c) optionally one or more pharmaceutically acceptable buffers; (d) optionally one or more pharmaceutically acceptable antioxidants; (e) optionally one or more pharmaceutically acceptable tonicity adjusters; (f) optionally one or more pharmaceutically acceptable solubility enhancers and (g) optionally one or more pharmaceutically acceptable
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; (b) sterile water; (c) optionally one or more pharmaceutically acceptable buffers; (d) optionally one or more pharmaceutically acceptable antioxidants; (e) optionally one or more pharmaceutically acceptable tonicity adjusters; (f) optionally one or more pharmaceutically acceptable solubility enhancers and (g) optionally one or more pharmaceutically acceptable
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein the composition is substantially free of a surfactant.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of a surfactant.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of a benzyl alcohol.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of a benzyl alcohol.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of a polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of a polyethylene glycol (PEG).
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of a N-methylglucamine.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of a N- methylglucamine.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically -I l l-
  • compositions are substantially free of arginine or derivatives thereof.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of arginine or derivatives thereof.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of lysine or derivatives thereof.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of lysine or derivatives thereof.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of one or more of, or all of, alkylammonium salts, i.e., tromethamine, dropopizine, 3-(4-phenyl-l-piperazinyl)-l,2- propanediols, and derivatives thereof.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of benzyl alcohol.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of adjuvant.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of an adjuvant.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of adjuvant.
  • compositions are substantially free of: (i) preservatives; and/or (ii) antioxidants; and/or (iii) buffers; and/or (iv) tonicity adjusters; and/or (v) organic solvents; and/or (vi) bulking agents.
  • composition of the present invention comprises:
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of glycine or derivatives thereof.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of glycine or derivatives thereof.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; wherein said composition is substantially free of glycerol or derivatives thereof.
  • Other aspects of this embodiment include any of the above described embodiments of the pharmaceutical composition wherein the composition is substantially free of glycerol or derivatives thereof.
  • composition of the present invention comprises:
  • NSAID one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof may be in the form of a solvate, polymorph, hydrate, conjugate, ester or prodrug in racemic, enatiomeric excess or enantiomeric form, or mixture thereof.
  • the present invention is directed to a composition
  • a composition comprising the ULD of a selected NSAID with ethylenediamine and/or piperazine having an aqueous solubility of greater than about 50 mg/mL, greater than about 100 mg/mL, greater than about 200 mg/niL, greater than about 350 mg/mL, greater than about 400 mg/mL, greater than about 450 mg/mL, or greater than about 500 mg/mL.
  • the present invention is directed to sealed syringe comprising a sterile solution comprising one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof.
  • NSAID preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbi
  • a solution comprising water, e.g., purified by reverse osmosis, piperazine, and one or more selected NSAID and optionally sorbitol, and adjusted to a pH from about 6.5 to about 8.5 is added to presterilized syringes under nitrogen atmosphere and aseptic conditions.
  • the solution is optionally first filtered through a filter, e.g., a 0.45 micron filter, and deoxygenated with nitrogen or deoxygenated and finally passed through 0.22 micron membrane filter into presterilized syringes under nitrogen atmosphere and aseptic conditions.
  • the syringes are sealed under an inert atmosphere, e.g., nitrogen.
  • the sealed syringe containing the selected NSAID can be used in accordance with the methods described herein.
  • the solutions in the sealed syringe show no visible signs of crystallization or significant deviation in pH and osmolarity and contain 100% ⁇ 15% original NSAID content when stored for 12 weeks at 5 0 C, 25°C/60% RH, 30°C/60% RH, 40°C/75% RH as determined by HPLC.
  • the osmolality of the solution in the sealed syringe may be from about 200 to about 400, preferably from about 280 to about 300 mOsm/L.
  • compositions of the present invention can be prepared by direct salification or complexation between the selected NSAID acid, preferably selected from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, and mixtures thereof, and a pharmaceutically acceptable salt, complexing agent or solubility enabling agent.
  • the selected NSAID acid preferably selected from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac,
  • the acid addition salts may be prepared by salifying the amino function of the pharmaceutically acceptable salt with the carboxylic acid function of the selected NSAID in a stoichiometric or nonstoichiometric amount.
  • the selcetd NSAID acid is reacted with the least amount of pharmaceutically acceptable salt, complexing agent or solubility enabling agent required to prepare a stable, pharmaceutically acceptable formulation.
  • the reaction medium may be an organic solvent in which the selected NSAID and pharmaceutically acceptable salt, complexing agent or solubility enabling agent are mutually soluble, such as ethyl alcohol, wherein the selected NSAID is first dissolved and then the ethylenediamine or piperazine, with mixing, to form a clear solution.
  • the clear solution can be concentrated, as by evaporation of the organic solvent, or the salt can be separated from the reaction medium such as by precipitation or crystallization, all as described in the aforementioned and known to those of skill in the art.
  • the direct salification is often carried out in a medium which is predominantly aqueous, at moderate temperatures around ambient temperature, and for periods in the order of 1 or 6 hours.
  • the acid which is insoluble in an aqueous medium, is added to a solution or partial suspension of pharmaceutically acceptable salt, complexing agent or solubility enabling agent in a stoichiometric or nonstoichiometric amount and gradually goes into solution as the salification proceeds.
  • the product can be isolated by, for example, lyophilization or precipitation with appropriate solvents.
  • the preparation is carried out in the presence of an excess of an organic solvent, for example of a C M alcohol or acetone, and, in this case, the salt precipitates or crystallizes directly from the aqueous-alcoholic or aqueous-acetone medium. In general, high yields are obtained.
  • an organic solvent for example of a C M alcohol or acetone
  • a composition comprising a selected NSAID and pharmaceutically acceptable salt, complexing agent or solubility enabling agent is prepared by adding the selected NSAID and the pharmaceutically acceptable salt, complexing agent or solubility enabling agent in appropriate amounts to a volume of water, optionally with sonication to facilitate dissolution; and then obtaining the NSAID salt composition after the water has evaporated.
  • concentration of the NSAID in the solution prepared as described can vary.
  • the NSAID concentration is from about 0.0001 M to about 20 M, from about 0.005 M to about 10 M, 0.05 to 5 M, or from about 0.01 M to about 3 M. In other embodiments, the NSAID concentration is about 0.5 M, 0.1 M, 0.3 M, 0.5 M, 0.7 M, or 0.9 M.
  • the solution comprising one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(- )-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof may optionally be filtered with a suitable filtering device to remove small particulate matter.
  • the solution may be filtered with a 0.22 micron syringe filter.
  • filtering devices and methods may be used, and may be more appropriate depending on the amount of the composition being prepared, the integrity of the filter, the interaction between the filter and the pharmaceutical composition .
  • the composition comprising one or more selected NSAID given as a ULD NSAID, preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof
  • a double decomposition method for example, the reaction of a salt, such as sodium salt of the selected NSAID acid and the hydrochloride of the amine salt, e.g., ethylenediamine or piperazine.
  • a double decomposition method is preferably chosen from the group consisting of celecoxib,
  • the liquid compositions in particular the liquid compositions used for injection, can be prepared by dissolving the solid NSAID-salt composition in an appropriate liquid carrier.
  • the process of the invention is directed to the in situ preparation of the complex of the invention, as described above.
  • in situ preparation of the complex comprises adding one or more selected NSAIDs, in racemic, enantiomeric excess, or enantiomeric form, preferably selected from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib in racemic, enantiomeric excess, or enantiomeric form; to an aqueous solution comprising pharmaceutically acceptable salt, complexing agent or solubility enabling agent.
  • an amount of the NSAID can be added to a vessel, for example a glass vessel, which contains a liquid solution comprising pharmaceutically acceptable salt, complexing agent or solubility enabling agent.
  • a vessel for example a glass vessel
  • a liquid solution comprising pharmaceutically acceptable salt, complexing agent or solubility enabling agent.
  • the resulting solution is mixed for a period of time until the NSAID and pharmaceutically acceptable salt, complexing agent or solubility enabling agent are in solution and/or complexed.
  • the liquid solution may further contain suitable pharmaceutical excipients, buffers, preservatives, tonicity adjusters, antioxidants, stabilizers and the like, such that the resulting solution after mixing is ready for use in the methods described herein.
  • this in situ process is advantageous for the production of an aqueous pharmaceutical composition of the present invention over a process which first requires the manufacture, characterization, and release of a solid complex according to the invention, and shipment to the site of manufacture of the finished dosage form, wherein said solid NSAID- pharmaceutically acceptable salt is then dissolved in an appropriate aqueous carrier.
  • NSAID and base can be used in the in situ process to make a composition as described throughout the present application.
  • suitable amounts can be used to prepare a pharmaceutical composition according to the present invention wherein the ratio, concentration, amount, pH, etc. are specified herein.
  • the in situ process may comprise the addition of pharmaceutically acceptable salt, complexing agent or solubility enabling agent (e.g., ethylenediamine or piperazine, or mixtures thereof), in solution or not, to an appropriate container, for example, a glass-lined or stainless steel mixing vessel, containing an aqueous carrier, e.g., WFI, and an NSAID selected from celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib.
  • an appropriate container for example, a glass-lined or stainless steel mixing vessel, containing an aqueous carrier, e.g., WFI, and an NSAID selected from celecoxi
  • an in situ process of preparing the composition of the claimed invention can be used to prepare a composition comprising: (a) one or more selected NSAIDs, in racemic, enantiomeric excess, or enantiomeric form, preferably selected from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib and mixtures thereof; (b) pharmaceutically acceptable salt, complexing agent or solubility enabling agent (e.g., ethylenediamine or piperazine, or mixtures thereof); (b) sterile water; (c) optionally one or more pharmaceutically acceptable buffers; (d) optionally one or
  • Kits for use in treating pain comprising: (i) a dosage form of the invention in an ampoule, vial, prefilled syringe or autoinjector; (ii) a container for the dosage form; and optionally, any of (iii) to (ix): (iii) syringe; (iv) alcohol swab; (v) sterile absorbent gauze; (vi) sterile occlusive dressing to cover the injection site which is optionally adhesive (e.g., bandage, adhesive bandage, clear bandage, Liquid BandageTM, Band AidTM, ElastoplastTM, TegadermTM, etc); (vii) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, including information on the proper use and disposal of the medication; (viii) containers or bags for the safe disposal of any used or remaining unused dosage form and needles, preferably child proof, needle stick safe and flushable; (ix) tamp
  • compositions of the present invention can be evaluated in one or more of the tests described below:
  • the tail-flick test is considered to be very robust in that weak analgesic agents are not detected by this test. In contrast, it is considered highly selective. There is a high degree of correlation between drugs that are identified as antinociceptive in the tail-flick test and clinically active analgesic agents. It is especially predictive of rank-order of potency of opioid-type analgesic agents, and the clinically effective dose of a novel opioid may be predicted by the relative potency of the drug to a known substance, such as morphine, based on this assay. Importantly, agents that are sedating and may produce a positive response in the writhing test or hot plate test do not show antinociceptive activity in the tail-flick test. It is even possible to perform the tail-flick test in lightly anesthetized animals.
  • the raw tail withdrawal latencies are converted to a %MPE (% maximal possible effect) by the formula:
  • % MPE 100 x (test latency - basal latency)/(cut-off- basal latency).
  • This formula constrains the data to fit between 0% MPE and 100 % MPE. This allows the generation of dose-response curves and the calculation of ED 50 values (50% effective doses) with attendant confidence intervals. These calculations then allow for the determination of relative potencies of different drugs and allow for the isobolographic determination of possible synergistic effects. Instances where the test latency is less than the basal latency produces a negative % MPE, which is meaningless unless one is measuring hyperalgesia. By convention, these values are set to 0% MPE when the expected drug effect is antinociception or no activity.
  • the standard protocol for the evaluation of tactile hyperesthesia is to determine the paw withdrawal threshold of the hindpaw of the rats in response to probing with von Frey filaments.
  • Thermal hyperalgesia is indicated by a significant reduction in paw withdrawal latency to noxious radiant heat projected onto the plantar aspect of the hindpaw of the rat.
  • Tests are conducted with systemic (SC) and intrathecal (IT) administration.
  • SC systemic
  • IT intrathecal
  • sham-operated animals are also required. Since sham-operated rats do not develop tactile hyperesthesia, only responses to thermal stimuli are tested. Testing of sham-operated rats requires an additional 48 animals. Approximately 26 rats are be used for initial dose-finding experiments. Animals are tested within 7 to 10 days of SNL. Surgery and testing may be staggered to optimize testing efficiency.
  • the intrathecal drug administration studies require implantation of catheters 7 days prior to the SNL surgery, and testing at 10 days after SNL surgery.
  • Models of inflammation that produce more persistent pain include the injection of carrageenan into the footpad of the limb; the potential analgesic and/or anti-inflammatory properties of putative analgesics substances can be evaluated in this model. See generally Bhalla T.N. & Tangri, K.K. "The time course of the carrageenan-induced oedema of the paw of the rat.” J. Pharm. Pharmacol. 22:721 (1970); Randall, L.O. & Selitto, J.J., "A method for measurement of analgesic activity on inflamed tissue," Arch. Int. Pharmacodyn. Ther. //7:409-419 (1957); Hargreaves, K., et al. "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.” Pain 32:77-88 (1988).
  • rats are handled and acclimatized to the behavioral testing equipment over a minimum of 2 days prior to testing. Behavioral tests are performed on all rats on the day prior to dosing to establish baseline values, and the animals are randomized into treatment groups based on these pre-dose responses.
  • An assessment of the inflammatory agent (carrageenan) is performed prior to the main study, using the chosen behavioral tests. On the day of dosing, an inflammatory response is induced in the left hind paw of each rat by an intraplantar injection (approx. 0.05 mL) of carrageenan (0.6% w/v), under brief anesthesia.
  • the test substance, reference substance, or vehicle is generally administered 30 minutes prior to carrageenan administration for oral dosing.
  • Paw Volume Each animal is gently restrained, their hind limb extended, and the paw placed in the pre-filled chamber of a Digital Plethysmometer. The paw volume is then calculated based on the volume of liquid displaced in the chamber, for both the ipsilateral and contralateral hind paws.
  • Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at the various time points: Baseline (0 hour - pain intensity only), 15, 30 and 45 minutes, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8 and 12 hours after administration of study medication, and immediately prior to the first rescue dose. Time to onset of perceptible and meaningful pain relief is evaluated using the two stopwatch method. Patients record their global evaluation of study medication at the completion of the 8-hour assessment or at the time of first rescue medication use.
  • Efficacy endpoints include Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and Sum of Pain Relief Intensity Difference (SPRID) at various time points, Time to First Rescue, Time Specific Pain Intensity Difference (PID), Time Specific Pain Relief (PR), Peak Pain Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Confirmed Perceptible Pain Relief (stopwatch) and Time to Meaningful Pain Relief (stopwatch) and Patient Global Evaluation.
  • TOTPAR Total Pain Relief
  • SPID Sum of Pain Intensity Difference
  • SPRID Sum of Pain Relief Intensity Difference
  • Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at representative time points, e.g., Baseline (pain intensity only), 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours after administration of study medication and immediately prior to the first remedication. Time to onset of perceptible and meaningful pain relief is evaluated using the double-stopwatch method. Patients complete a global evaluation of study medication at the completion of the 8-hour assessment or just prior to the first remedication. Following completion of the single- dose phase (8 hours or just prior to first remedication, if ⁇ 8 hours), patients begin the multiple dose phase of the study. During the multiple dose phase, patients record their overall pain intensity since the previous scheduled dose, their current pain intensity and a patient global, immediately prior to each scheduled dose of study medication and at early termination.
  • Measures of efficacy in the single-dose phase include Sum of Pain Intensity
  • Measures of efficacy in the multiple-dose phase include the time specific overall pain intensity, current pain intensity and patient global at the time of scheduled remedication, the average of overall pain intensity, current pain intensity and patient global over 0-24, 24-48 and 48-72 and number of doses of rescue analgesic over 0-24, 24-48 and 48-72 and 0-72 hours.
  • composition of the invention may, In some preferred embodiments, be demonstrated in repeated dose randomized, double-blind, controlled studies comparing subanalgesic and analgesic doses of the invention.
  • patients who meet the American College of Rheumatology criteria for knee and/or hip OA are washed off their analgesics for 2 to 7 days to allow for pain of moderate to severe intensity to return. Once a stable baseline pain score is established, patients are randomized to treatment, usually for a period of one to 12 weeks.
  • Pain, joint stiffness and physical function can be measured with a multidimensional instrument, such as the WOMAC, quality of life with the SF- 12 or SF-36 and adverse events with a non-directed questionnaire at baseline and at post- baseline return visits. Response to pain, stiffness, physical function, quality of life and adverse events are calculated as change from baseline and compared between treatments. Sample sizes in the studies are sufficient to demonstrate the increased therapeutic benefit of the invention.
  • the increased therapeutic benefits associated with the administration of a composition of the invention may, In some preferred embodiments, be demonstrated in patients with migraine headaches, typically in a prospective, randomized, double-blind, parallel group, single-dose, placebo-controlled, study. Crossover studies are also possible.
  • the study population consist of male and non-pregnant female subjects, 18 to 65 years of age with a primary headache diagnosis of either migraine attack without aura or migraine attack with aura, as diagnosed according to the International Classification of Headache Disorders-2 criteria. To qualify, the subject must typically have a history, on average, of at least one migraine attack per month, but an average of no more than 6 migraine attacks each month during the past year.
  • headache diary subjects are instructed to treat and evaluate the headache pain and symptoms associated with one eligible migraine attack, with or without aura, with at least moderate headache pain intensity.
  • Eligible subjects are randomly assigned to receive the test drug or placebo to treat one migraine attack, with or without aura, with headache pain of at least moderate pain intensity as determined by them migraine questionnaire they are asked to take a single dose of study drug, according to their randomized treatment assignment.
  • Headache pain intensity, nausea, photophobia, phonophobia, vomiting, and ability to function are assessed at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 16 and 24 hours post-dose.
  • the recurrence of pain and use of any rescue mediation is documented.
  • Primary efficacy variables typically consist of the percent of subjects who are without: (i) pain; (ii) nausea; (iii) photophobia and, (iv) phonophobia, each at 2 hours post-dosing.
  • Secondary efficacy variables typically consist of headache pain intensity and associated symptoms at each evaluation time point, incidence of vomiting, patient function, sum of pain intensity difference at each evaluation time (SPID), percent of subjects who experience headache recurrence up to 24 hours, and the median time to recurrence.
  • Recurrence is defined as the reduction in pain from moderate or severe pain to none at 2 hours after taking study drug, followed by: (i) an increase to mild, moderate or severe pain within 24 hours after taking the study drug, or (ii) consuming a rescue medication within 24 hours after taking the study drug. ]
  • the included examples are illustrative but not limiting of the methods and composition of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention. Deflnitions
  • agent are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial effect. In general, this includes therapeutic agents in all of the major therapeutic areas, also including proteins, peptides, oligonucleotides, and carbohydrates as well as inorganic ions, such as calcium ion, lanthanum ion, potassium ion, magnesium ion, phosphate ion, and chloride ion.
  • “Pharmaceutically or therapeutically acceptable excipient or carrier” refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the hosts, which may be either humans or animals, to which it is administered.
  • Pharmaceutically or therapeutically acceptable excipients or carriers are well known in the art.
  • “Pharmaceutically or therapeutically acceptable excipient or carrier” or “excipient” may include compounds found on the FDA EAFUS database (http://vm.cfsan.fda.gov/ ⁇ dms/eafus.html); FDA Food Additives Status List (http://www.cfsan.fda.gov/ ⁇ dms/opa-appa.html); FDAGRAS list and database; FDA Color Additive Status List (http://www.cfsan.fda.gov/ ⁇ dms/opa-appc.html); FDA Inactive Ingredients Database (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm); Rowe, Sheskey and Owen, Handbook of Pharmaceutical Excipients, APhA Publications; 5th edition (2006); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 11th ed., McGraw Hill (2005); Remington:
  • complex means any physical combination of two or more discrete chemical compounds.
  • a complex includes, but is not limited to, a salt, a physical mixture, a chelate, and the like.
  • a complex comprising a selected NSAID and piperazine and/or ethylenediamine includes, but is not limited to: a salt comprising a selected NSAID and piperazine and/or ethylenediamine; a physical mixture comprising a selected NSAID and piperazine and/or ethylenediamine; a solid containing a selected NSAID and piperazine and/or ethylenediamine wherein the a selected NSAID and piperazine and/or ethylenediamine are associated by hydrogen bonding; a solid containing a selected NSAID and piperazine and/or ethylenediamine wherein the a selected NSAID and piperazine and/or ethylenediamine are associated by hydrophobic bonding; a solid containing a selected NSAID and piperazine and/or ethylenediamine
  • “Therapeutically effective amount” refers to the amount of an active agent sufficient to induce a desired biological result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the term "effective amount” means the quantity of a compound according to the invention necessary to prevent, to cure, or at least partially arrest a symptom of local pain or discomfort in a subject.
  • a subject is any animal, preferably any mammal, more preferably a human. Amounts effective for creating a substantially local therapeutic effect will, of course, depend on the severity of the disease causing the painful condition, and the weight and general state of the subject. Typically, animal models, such as those described in the Background and Examples herein, may be used to determine suitable dosages to be used.
  • parenteral and “parenteral administration” herein encompasses administration of a composition by means other than through the gastrointestinal tract such as into or through the skin of a subject, and includes intradermal, subcutaneous, intramuscular, intravenous, intramedullary, intra-articular, intrasynovial, intraspinal, epidural, intrathecal and intracardiac administration.
  • parenteral and “parenteral administration” herein also encompasses infiltration or topical application to a surgical site, open wound and local site of pain or inflammation. Any known device or delivery system useful for parenteral injection or infusion of drugs can be used to effect such administration.
  • particularly preferred parenteral routes of administration include intravenous, intramuscular, subcutaneous, intra-articular, local tissue infiltration, epidural or intrathecal route.
  • particularly preferred method of administration include PCA and PCEA.
  • subject for purposes of treatment includes any animal subject who has any one of the known forms of pain.
  • the subject is preferably a mammal and more preferably is a human.
  • the subject can of course include other non-human animals, preferably horses, livestock, cattle, domesticated animals, cats, dogs, and the like.
  • the pain is acute pain or acute exacerbation of chronic pain.
  • peripheral neuropathic pain e.g., acute and chronic inflammatory demeyelinating polyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome (CRPS) Type I and Type II, entrapment neuropathies (e.g., carpal tunnel syndrome), HIV sensory neuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain, postmastectomy pain), idiopathic sensory neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral), sciatica, acute he ⁇ es zoster pain, temporomandibular joint disorder pain and postradiation plexopathy; and (ii) central neuropathic pain, e.g., acute and chronic inflammatory demeyelinating polyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy
  • acute pain refers to self-limiting pain that subsides over time and usually lasting less that about 30 days and more preferably lasting less than about 21 days. Acute pain does not include chronic conditions such as chronic neuropathy, chronic neuropathic pain and chronic cancer and non-cancer pain.
  • neuroopathic pain is pain initiated or caused by a primary lesion or dysfunction of the nervous system and includes (i) peripheral neuropathic pain and (ii) central neuropathic pain.
  • chronic pain includes all non-neuropathic pain lasting more than 30 days, including inflammatory pain, non-inflammatory pain, muscle pain, joint pain, fascia pain, visceral pain, bone pain and idiopathic pain.
  • antipyretic As used herein, the term “antipyretic”, “anti-fever” or “fever reducing” refers to pharmaceutical agents that prevent or reduce fever by lowering the body temperature from a raised state.
  • Perceptible Pain Relief is assessed and defined as follows: At the time of dosing with the study medication, a trained member of study staff starts two stopwatches for each patient. The patient is instructed to stop the first stopwatch at the time of perceptible pain relief and the second stopwatch at the time when they first experience meaningful pain relief.
  • the usual definitions of the perceptible and meaningful pain relief are as follows: Perceptible Pain Relief is when the patient begins to feel any pain relieving effect from the drug. The patient is typically instructed as follows: “I would like you to stop the first stopwatch when you first feel any pain relief whatsoever.
  • Meaningful Pain Relief is when the patient feels their pain relief is meaningful to them. The patient is typically instructed as follows: “I would like you to stop the second stopwatch when you have meaningful pain relief. That is, when the relief from the pain is meaningful to you”. Confirmed Perceptible Pain Relief is Perceptible Pain Relief in those patients who go on to also have Meaningful Pain Relief.
  • NNT or “the number needed to treat” is the number of patients who need to be treated in order for one patient to obtain > 50% pain relief or > 50% reduction in pain intensity at a specified timepoint.
  • Responded/ is the number of patients who have a 30% postbaseline reduction in pain at a specified timepoint.
  • Fever also known as "pyrexia", or a “febrile response” refers to an increase in internal body temperature to levels that are above normal (i.e., above 37°C or 98.6°F). Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, usually by about 1-2°C. When a patient has or is suspected of having a fever, that person's body temperature is measured using a thermometer.
  • Fever may be present if: (i) the rectal temperature is at, or higher than 38°C (100.4 0 F); (ii) the oral temperature is at, or higher than 37.5°C (99.5°F); or (iii) axillar temperature is at, or higher than 37.2 0 C (99°F).
  • Fever is usually classified as: (i) low- grade: 38 - 39°C (100.4 - 102.2 0 F); (iii) moderate: 39 - 40 0 C (102.2 - 104 0 F); (iii) high- grade: > 40 0 C (> 104 0 F) or (iv) hyperpyrexia: > 42 0 C (> 107.6 0 F).
  • Hyperpyrexia is a medical emergency because it approaches the upper limit compatible with human life. Fever is a common symptom of many medical conditions, including infectious diseases, immune response, tissue destruction, malignancies, metabolic disorders, thromboembolic processes, drug induced and idiopathic [00460]
  • equianalgesic doses also referred to as “analgesic equivalence” is a term used by practitioners of the art to refer to approximately comparable doses of analgesics required to provide a similar magnitude of analgesia. There are established standards to allow practitioners of the art to convert the dose of one analgesic, given by any route of administration, to an approximately equivalent dose of another analgesic, given by any route of administration.
  • analgesic conversion tables provide what in the art is called “analgesic equivalence” or “equianalgesic doses” (Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Fourth Edition, 5 th ed, American, Pain Society (2003); Gutstein HB & Akil H. Opioid Analgesics. In: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 10th Ed., Hardman JG & Limbird LE (Eds), p 569-619, McGraw-Hill, New York, NY); ; Roberts LJ & Morrow JD. Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout.
  • Examples 1 to 11 involve complexes of ketoprofen, dexketoprofen and piroxicam with ethylenediamine and/or piroxicam. These examples demonstrate, among other things, the feasibility of preparing complexes of selected NSAIDS with ethyelenediamine and/or piroxicam to enhance solubilization, to facilitate small volume delivery, to facilitate bolus injections of selected NSAIDS (compared to the generally administered slow IV infusions) and to administer the dosage forms rapidly with decreased injection site pain, injection site inflammation, injection site irritation, phlebitis and thrombophlebitis.
  • Example 12 is a randomized double-blind clinical trial of a selected NSAID, ketoprofen in patients following surgery.
  • the ketoprofen was administered as a bolus IV injection at two dose levels, the minimum approved intravenous dose (100 mg) and at 50% of the minimum approved dose (50 mg). Results are presented comparing the efficacy on standardized pain measures to the maximum recommended bolus IV mo ⁇ hine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg) and 150% of the maximum approved IV bolus dose of tramadol (150 mg).
  • Ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) provided almost identical efficacy on all tested parameters, when compared with the minimum approved IV dose (100 mg) of ketoprofen. Both ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) and ketoprofen at the minimum approved IV dose (100 mg) provided far superior efficacy when compared with the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg), and 150% of the maximum approved IV bolus dose of tramadol (150 mg), P O.001.
  • ULD NSAID preferably chosen from the group consisting of celecoxib, dexibuprofen, dexflurbiprofen, dexketoprofen, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketoprofen, ketorolac, S(-)-ketorolac, lornoxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib, or their pharmaceutically acceptable salts, in racemic, enantiomeric excess, or enantiomeric form, and mixtures thereof; said ULD NSAID given at a dose not to exceed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1,
  • a aqueous mixture of 0.5 M of ketoprofen and 1.0 M and piperazine was sonicated until a clear solution was obtained.
  • the solution was then filtered with a 0.45 ⁇ m syringe filter (pH about 10.00 for filtered aliquot). Small aliquots (about 0.250 mL) were placed in a 12-depression spot ceramic plate. The physical mixture precipitated out at ambient temperature over several days (2-3 days).
  • the ketoprofen-piperazine complex was formed as a semisolid (physical mixture) having an aqueous solubility of greater than 360 mg/mL and a pH of about 9.4 (for a saturated solution).
  • the ketoprofen-ethylenediamine complex was formed as a semisolid having an aqueous solubility of greater than 500 mg/mL and a pH of about 7.3 (for a saturated solution).
  • ketoprofen solution was serially diluted in normal saline (NS) and isotonic Sorensen phosphate buffer pH 7.4 (ISPB) separately. Dilutions were made by adding respective volumes of the solutions to NS or ISPB such that a range of 4-2560 fold dilution was covered. Thus, for the first dilution 1 part of solution was added to 3 parts of NS or ISPB resulting in a 4-fold dilution. Subsequent dilutions were made serially resulting in a final 8-, 16-, 32-, 64-, 128-, 256-, and 2560-fold dilution.
  • NS normal saline
  • ISPB isotonic Sorensen phosphate buffer pH 7.4
  • Ketoprofen-ethylenediamine passed the static dilution test. No precipitation or turbidity was observed visually upon passing laser beam for the entire range of dilution (4-2560 fold) both after 1 minute as well as 24 hours following dilution. Results of Static Dilution Studies
  • Example 4 Static Dilution Test of a Ketoprofen-Piperazine Composition 70 A 50 mg ketoprofen solution was serially diluted in normal saline (NS) and isotonic Sorensen phosphate buffer pH 7.45 (ISPB) separately. Dilutions were made by adding respective volumes of the solutions to NS or ISPB such that a range of 2-3200 fold dilution was covered. Thus, for the first dilution 1 part of solution was added to 1 parts of NS or ISPB resulting in a 2-fold dilution. Subsequent dilutions were made serially resulting in a final 4-, 8-, 16-, 32-, 320-, 3200-fold dilution.
  • NS normal saline
  • ISPB isotonic Sorensen phosphate buffer pH 7.45
  • Ketoprofen-piperazine passed the static dilution test, i.e., no precipitation or turbidity was observed visually upon passing laser beam for the entire range of dilution (4-3200 fold) both after 1 minute as well as 24 hours following dilution.
  • ketoprofen formulations Two 50 mg/mL ketoprofen formulations (ketoprofen-ethylenediamine and ketoprofen-piperazine) were tested and compared for the occurrence of precipitation upon dynamic dilution in ISPB using a validated standard dynamic injection apparatus with high predictive value for phlebitis.
  • a validated standard dynamic injection apparatus with high predictive value for phlebitis.
  • Each solution at a flow rate of 5 mL/min was introduced to ISPB flowing at a rate of 5 mL/min in a tube for 30 seconds and passed through a flowcell.
  • Absorbance was measured at 540 nm using a UV spectrophotometer. The wavelength 540 nm was chosen since all the formulations had no or very small absorbance at that wavelength. The results of the tests are shown in the Figures.
  • ketoprofen-ethylenediamine solutions 50 and 500 mg/mL
  • ketoprofen-piperazine solutions 12.7 mg/mL and 50 mg/mL
  • the time required for each solution to pass between two marks on the viscometer was used to determine the relative velocity. Density was measured separately for the solutions. Water was used as reference liquid (viscosity of water at 20° C is 1.002 cP).
  • C j is the concentration of the ionic species
  • Z j is the charge on the ionic species
  • Ketoprofen at a flow rate of 5 mL/min was introduced to ISPB flowing at a rate of 5 mL/min in a tube for 30 seconds and passed through a flowcell. Absorbance was measured at 540 nm using a UV spectrophotometer. The wavelength 540 nm was chosen since all the formulations had no or very small absorbance at that wavelength. The results were compared with ketoprofen- ethylenediamine and ketoprofen-piperazine (without any pH adjustment or additives). [00481] The absorbance from the unsalified pH adjusted ketoprofen was a 83-fold and
  • ketoprofen as the ethylenediamine salt (0.1 M) at an initial concentration of 50 mg/mL and ketoprofen as the piperazine crystalline salt at an intial concentration of 10 mg/mL were retested after 3 months storage at room temperature using an HPLC analytical method. There was no significant degradation of ketoprofen. The detected concentration of ketoprofen after three months was 49.4 mg/mL (98.8%) and 9.94 mg/mL (99.4%) for ketoprofen-ethylenediamine and ketoprofen-piperazine, respectively, which is within the range of experimental error.
  • Ketoprofen solution at a concentration of 50 mg/mL was prepared in 0.1 N NaOH. The pH was gradually increased over 4 hours in order to avoid the presence of excess sodium hydroxide. The pH was increased using solid sodium hydroxide. The final pH of the solution was 8.72 (constant over 12 hours). The solution was filtered with a 0.45 ⁇ m syringe filter into a sterile evacuated vial.
  • Two male, purpose-bred New Zealand White rabbits (age 22 weeks, weight 2.8 to
  • Treatment A Kertoprofen 5 mg/0.1 mL or Treatment B (Ketoprofen 15 mg/0.3 mL) intravenously into a marginal vein of each ear, over one minute (i.e., Ketoprofen 5 mg/0.1 mL over one minute or Ketoprofen 15 mg/0.3 mlL over one minute). All animals were treated on Day 1 of the study.
  • the test sites were identified with indelible marker. Intravenous sites were marked with an indelible marker at the area of entry of the needle, approximately at the end of its progress and approximately 1 cm from that point.
  • Treatment A The intravenous administration of Treatment A (Ketoprofen: 5mg/0.1 mL) resulted in well defined erythema and slight edema were observed at the 24 hour observation period.
  • Treatment B The intravenous administration of Treatment B (Ketoprofen: 15mg/0.3 mL) resulted in very slight to moderate to severe erythema and very slight edema at the 24 hour observation period.
  • Treatment B Keratin: 15 mg/0.3 mL
  • the irritation was progressive over time and displayed the potential for a dose related response.
  • NSAIDs versus their respective ethylenediamine and piperazine salts when administered intravenously to rabbits, using a validated model for assessment of venous irritation and thrombophlebitis and a randomized design.
  • Test articles consisted of unsalified ketoprofen, unsalif ⁇ ed dexketoprofen, unsalif ⁇ ed piroxicam, ketoprofen-ethylenediamine, dexketoprofen-ethylenediamine, piroxicam-ethylenediamine, ketoprofen-piperazine, and dexketoprofen-piperazine. Eight rabbits each were allocated to each group as follows:
  • Piroxicam vs. Piroxicam-Ethylenediamine At the 1-hour post-infusion time point, piroxicam-ethylenediamine was not statistically different from unsalified piroxicam on the erythema (p ⁇ 0.38) and edema (p ⁇ 0.38) scores. At the 24-hour post-infusion time point, piroxicam-ethylenediamine produced significantly lower erythema (p ⁇ 0.0001) and edema (p ⁇ 0.00006) scores than unsalified piroxicam.
  • Ketoprofen vs. Ketoprofen-Ethylenediamine At the 1-hour post- infusion time point, ketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0002) scores than unsalified ketoprofen. Similarly, at the 24-hour post- infusion time point, ketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0008) scores than unsalified ketoprofen.
  • Ketoprofen vs. Ketoprofen-Piperazine At the 1-hour post-infusion time point, ketoprofen-piperazine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0003) scores than unsalified ketoprofen. Similarly, at the 24-hour post-infusion time point, ketoprofen piperazine produced significantly lower erythema (p ⁇ 0.0003) and edema (p ⁇ 0.0001) scores than unsalified ketoprofen.
  • Dexketoprofen vs. Dexketoprofen-Ethylenediamine: At the 1-hour post- infusion time point, dexketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0001) and edema (p ⁇ 0.0003) scores than unsalified dexketoprofen. Similarly, at the 24-hour post-infusion time point, dexketoprofen-ethylenediamine produced significantly lower erythema (p ⁇ 0.0006) and edema (p ⁇ 0.021) scores than unsalified dexketoprofen.
  • Dexketoprofen vs. Dexketoprofen-Piperazine: At the 1-hour post-infusion time point, dexketoprofen-piperazine produced significantly lower erythema (p ⁇ 0.0019) and edema (p ⁇ 0.0019) scores than unsalified dexketoprofen. Similarly, at the 24-hour post- infusion time point, dexketoprofen-piperazine produced significantly lower erythema (p ⁇ 0.0002) and edema (p ⁇ 0.0024) scores than unsalified dexketoprofen.
  • Piroxicam vs. Piroxicam-Ethylenediamine Piroxicam-ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified piroxicam, which had an intermediate incidence. Similarly, piroxicam-ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified piroxicam which had an intermediate incidence.
  • Ketoprofen vs. Ketoprofen-Ethylenediamine Ketoprofen-ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified ketoprofen, which had a high incidence. Similarly, ketoprofen ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified ketoprofen which had a high incidence.
  • Ketoprofen vs. Ketoprofen-Piperazine Ketoprofen-piperazine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified ketoprofen, which had a high incidence. Similarly, ketoprofen-piperazine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified ketoprofen which had a high incidence.
  • Dexketoprofen vs. Dexketoprofen-Ethylenediamine Dexketoprofen- ethylenediamine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified dexketoprofen, which had an intermediate incidence. Similarly, dexketoprofen-ethylenediamine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified dexketoprofen which had an intermediate incidence.
  • Dexketoprofen vs. Dexketoprofen-Piperazine Dexketoprofen-piperazine had a low incidence of inflammatory cell infiltrates at the end of needle progression and 1 cm away from the end of progression than unsalified dexketoprofen, which had an intermediate incidence. Similarly, dexketoprofen piperazine had none to negligible mean intensity (severity) of edema and infiltrates, compared with unsalified dexketoprofen which had an intermediate incidence.
  • AEs Adverse events
  • Diagnosis and main criteria for inclusion Male and female patients, 18 to 40 years of age (inclusive), and with a body weight of 50 kg to 115 kg (inclusive) who had surgical extraction of 2 or more third molars were eligible provided that one was a bony impacted mandibular third molar, and if only 2 third molars were extracted, they were ipsilateral. Qualified patients had moderate or severe pain within 6 hours of completion of surgery as measured by the categorical PI scale and a VAS measurement for PI of > 50 mm at Baseline. Patients provided written informed consent prior to participation in the study, were in good health as determined by the Investigator, and demonstrated the ability to properly complete the pain assessments, to understand the English language, and to cooperate with study procedures. Female patients of childbearing potential were non- lactating, had a negative urine pregnancy test within 24 hours before surgery, and practiced abstinence or a medically acceptable form of contraception.
  • Efficacy was total pain relief (TOTPAR) over the
  • ITT insulin therapy population
  • ITT patient-derived neurodegenerative disease population
  • PI post baseline PI or PR measurement.
  • Patients who took rescue medication within 60 minutes after dosing were included in the ITT population.
  • Each efficacy variable had multiple comparisons performed using Fisher's protected least significance (PLSD) in order to control for the comparison-wise error rate. If a variable was measured over multiple intervals, this was done for each interval.
  • the overall 2- sided test i.e., F, or log-rank
  • TOTPAR, SPID, SPRID, and time-specific PID, PR, and PRID were analyzed using an analysis of variance (ANOVA) model with effects for treatment and baseline pain stratification.
  • ANOVA analysis of variance
  • the time to perceptible pain relief was the time recorded by the first stopwatch, and the time to meaningful pain relief was the time recorded by the second stopwatch.
  • Time to confirmed perceptible pain relief was defined as the time to perceptible pain relief only if both perceptible and meaningful pain relief were experienced.
  • Time to perceptible pain relief, confirmed perceptible, meaningful pain relief; time to re- medication; time to first change from the Baseline assessment in PID (categorical) of > 1 ; and time to pain half gone were estimated using Kaplan-Meier method. Summary information including the median time estimates and 95% confidence intervals on the median time for the above time variables was provided using Kaplan-Meier methodology and the method of Simon and Lee, and treatment groups were compared using the log- rank test.
  • Peak PID, peak PR, and the patient global evaluation were analyzed using the stratified rank-sum test, stratified by baseline pain. The proportions of patients with 50% pain gone, with meaningful pain relief, and re-medicated were analyzed using the Chi- square test. [00518] The safety analyses were conducted on the treated patient population, defined as all randomized patients who received study medication. Safety measures were summarized using descriptive statistics.
  • ketoprofen 100 mg (the minimum approved dose of IV ketoprofen); ketoprofen 50 mg (50% of the minimum approved dose of IV ketoprofen); tramadol 150 mg (150% of the maximum approved dose of bolus IV tramadol; tramadol 100 mg (the maximum approved dose of bolus IV tramadol); and morphine 4 mg (the maximum recommended bolus dose of IV morphine).
  • ketoprofen 50 mg or 100 mg demonstrated efficacy results that were statistically significantly superior to those of a single IV dose of placebo or morphine 4 mg for all efficacy measures, and significantly superior to a single IV dose of tramadol 100 mg or tramadol 150 mg for almost all efficacy measures.
  • ketoprofen 50 mg or 100 mg received a global evaluation of
  • the proportions of patients with at least one adverse event for ketoprofen 50 mg, and ketoprofen 100 mg groups was 60.6%, and 64.5%, respectively.
  • the proportions of patients with at least one adverse event for morphine 4 mg, tramadol 100 mg and tramadol 150 mg was 72.7%, 72.7% and 86.4%, respectively
  • ketoprofen groups were mild or moderate in intensity; only 1/33 patients treated with ketoprofen 50 mg had severe adverse events (dry mouth [dry socket] and postoperative infection), and 2/31 patients treated with ketoprofen 100 mg reported one severe adverse event each (application site swelling and abdominal pain).
  • the majority of adverse events in the tramadol 100 mg group were mild or moderate; whereas, all adverse events in the tramadol 150 mg group were moderate or severe.
  • Five of 33 patients in the 100 mg group and 13/22 patients in the 150 mg group had severe adverse events.
  • Three of 33 patients in the morphine 4 mg group had severe adverse events.
  • Ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) provided almost identical efficacy on all tested parameters, when compared with the minimum approved IV dose (100 mg) of ketoprofen. Both ketoprofen by IV bolus at 50% of the minimum approved dose (50 mg) and ketoprofen at the minimum approved IV dose (100 mg) provided far superior efficacy when compared with the maximum recommended bolus IV morphine dose (4 mg), the maximum approved IV bolus dose of tramadol (100 mg), and 150% of the maximum approved IV bolus dose of tramadol (150 mg), P ⁇ 0.05 to ⁇ 0.001.

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Abstract

La présente invention concerne des compositions pharmaceutiques parentérales de dose ultrafaible de AINS pour conférer des effets analgésiques, anti-inflammatoires et antipyrétiques efficaces et leur utilisation pour traiter et prévenir la douleur, une inflammation et la fièvre. La présente invention concerne également un procédé d'administration de compositions pharmaceutiques de dose ultrafaible de AINS pour conférer des effets analgésiques, anti-inflammatoires et antipyrétiques efficaces et leur utilisation pour traiter et prévenir la douleur, une inflammation et la fièvre.
PCT/US2008/003723 2007-03-21 2008-03-21 Procédés et compositions d'ains WO2008115572A1 (fr)

Applications Claiming Priority (2)

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GB2465610A (en) * 2008-11-25 2010-05-26 Ethicon Inc Medical adhesive composition comprising a alpha-cyanoacrylate monomer and a NSAID
EP2325172A1 (fr) * 2009-11-02 2011-05-25 Laboratorios Del. Dr. Esteve, S.A. Co-cristaux de célécoxib et de L-proline
CN102093394A (zh) * 2011-01-10 2011-06-15 中国药科大学 氯诺昔康氨丁三醇共晶
US20110288611A1 (en) * 2010-05-18 2011-11-24 Vision Quest Industries Incorporated Dba Vq Orthocare Bracing and electrostimulation for arthritis
EP2474309A1 (fr) * 2009-09-04 2012-07-11 Farmalider, S.A. Composition pharmaceutique à base d'ibuprofène, de tramadol et d'un aminoacide basique, procedé pour sa préparation et utilisation de cette dernière
FR2971712A1 (fr) * 2011-02-22 2012-08-24 Map France Solution stable de ketoprofene pour injection intraveineuse
US20130035362A1 (en) * 2011-08-04 2013-02-07 Omeros Corporation Stable Anti-inflammatory Solutions for Injection
US8404704B2 (en) 2003-11-07 2013-03-26 Alfa Wassermann S.P.A. Use of polymorphic forms of rifaximin for medical preparations
US8580954B2 (en) 2006-03-28 2013-11-12 Hospira, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
WO2016141065A1 (fr) 2015-03-03 2016-09-09 Kindred Biosciences, Inc. Compositions et méthodes de traitement et de prévention de maladies cardiovasculaires
WO2017141734A1 (fr) * 2016-02-16 2017-08-24 太陽ホールディングス株式会社 Composition de résine photosensible, film sec, produit durci, carte de circuits imprimés et générateur de photobase
US9795620B2 (en) 2015-05-28 2017-10-24 Dr. Reddy's Laboratories, Ltd. Oral composition of celecoxib for treatment of pain
CN109985040A (zh) * 2019-05-15 2019-07-09 南京正大天晴制药有限公司 一种用于超前镇痛的注射用帕瑞昔布钠药用组合物及其制备方法
US10369101B2 (en) 2013-03-15 2019-08-06 Latitude Pharmaceuticals Inc. Parenteral diclofenac composition
CN110386869A (zh) * 2018-04-20 2019-10-29 华东理工大学 布洛芬离子液体及其制备方法
CN111454271A (zh) * 2019-09-12 2020-07-28 南京海融医药科技股份有限公司 一种吡咯烷羧酸类化合物的钠盐、结晶形式及其制备方法
WO2021010812A1 (fr) 2019-07-16 2021-01-21 AMEZCUA AMEZCUA, Federico Combinaison synergique de s-kétorolac et prégabaline dans une composition pharmaceutique pour le traitement de la douleur neuropathique
CN112430323A (zh) * 2020-11-26 2021-03-02 深圳瑞华泰薄膜科技股份有限公司 一种性能优异的透明聚酰亚胺薄膜及其制备方法
CN115536525A (zh) * 2022-09-23 2022-12-30 南京知和医药科技有限公司 一种s-（+）-氟比洛芬盐及其制备方法、药物组合物和用途
CN115634291A (zh) * 2022-10-08 2023-01-24 南京诺令生物科技有限公司 一种具有缓解糖尿病足痛功效的制剂与制备方法和应用
CN115697316A (zh) * 2020-04-21 2023-02-03 东佩制药股份公司 加巴喷丁和酮洛芬的协同掺加物、药物组合物及其医疗用途
US20230233574A1 (en) * 2017-01-04 2023-07-27 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam

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US8404704B2 (en) 2003-11-07 2013-03-26 Alfa Wassermann S.P.A. Use of polymorphic forms of rifaximin for medical preparations
US8946292B2 (en) 2006-03-28 2015-02-03 Javelin Pharmaceuticals, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
US8580954B2 (en) 2006-03-28 2013-11-12 Hospira, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
GB2465610A (en) * 2008-11-25 2010-05-26 Ethicon Inc Medical adhesive composition comprising a alpha-cyanoacrylate monomer and a NSAID
EP2474309A1 (fr) * 2009-09-04 2012-07-11 Farmalider, S.A. Composition pharmaceutique à base d'ibuprofène, de tramadol et d'un aminoacide basique, procedé pour sa préparation et utilisation de cette dernière
EP2474309A4 (fr) * 2009-09-04 2013-11-27 Farmalider Sa Composition pharmaceutique à base d'ibuprofène, de tramadol et d'un aminoacide basique, procedé pour sa préparation et utilisation de cette dernière
EP2325172A1 (fr) * 2009-11-02 2011-05-25 Laboratorios Del. Dr. Esteve, S.A. Co-cristaux de célécoxib et de L-proline
US20110288611A1 (en) * 2010-05-18 2011-11-24 Vision Quest Industries Incorporated Dba Vq Orthocare Bracing and electrostimulation for arthritis
CN102093394A (zh) * 2011-01-10 2011-06-15 中国药科大学 氯诺昔康氨丁三醇共晶
FR2971712A1 (fr) * 2011-02-22 2012-08-24 Map France Solution stable de ketoprofene pour injection intraveineuse
US20130035362A1 (en) * 2011-08-04 2013-02-07 Omeros Corporation Stable Anti-inflammatory Solutions for Injection
US10369101B2 (en) 2013-03-15 2019-08-06 Latitude Pharmaceuticals Inc. Parenteral diclofenac composition
WO2016141065A1 (fr) 2015-03-03 2016-09-09 Kindred Biosciences, Inc. Compositions et méthodes de traitement et de prévention de maladies cardiovasculaires
US10682337B2 (en) 2015-03-03 2020-06-16 Kindred Biosciences, Inc. Compositions and methods for treatment and prevention of pyrexia in horses
US9795620B2 (en) 2015-05-28 2017-10-24 Dr. Reddy's Laboratories, Ltd. Oral composition of celecoxib for treatment of pain
WO2017141734A1 (fr) * 2016-02-16 2017-08-24 太陽ホールディングス株式会社 Composition de résine photosensible, film sec, produit durci, carte de circuits imprimés et générateur de photobase
US20230233574A1 (en) * 2017-01-04 2023-07-27 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US11826354B2 (en) * 2017-01-04 2023-11-28 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
CN110386869A (zh) * 2018-04-20 2019-10-29 华东理工大学 布洛芬离子液体及其制备方法
CN109985040A (zh) * 2019-05-15 2019-07-09 南京正大天晴制药有限公司 一种用于超前镇痛的注射用帕瑞昔布钠药用组合物及其制备方法
WO2021010812A1 (fr) 2019-07-16 2021-01-21 AMEZCUA AMEZCUA, Federico Combinaison synergique de s-kétorolac et prégabaline dans une composition pharmaceutique pour le traitement de la douleur neuropathique
CN111454271B (zh) * 2019-09-12 2022-04-01 南京海融医药科技股份有限公司 一种吡咯烷羧酸类化合物的钠盐、结晶形式及其制备方法
CN111454271A (zh) * 2019-09-12 2020-07-28 南京海融医药科技股份有限公司 一种吡咯烷羧酸类化合物的钠盐、结晶形式及其制备方法
CN115697316A (zh) * 2020-04-21 2023-02-03 东佩制药股份公司 加巴喷丁和酮洛芬的协同掺加物、药物组合物及其医疗用途
CN112430323A (zh) * 2020-11-26 2021-03-02 深圳瑞华泰薄膜科技股份有限公司 一种性能优异的透明聚酰亚胺薄膜及其制备方法
CN112430323B (zh) * 2020-11-26 2021-05-11 深圳瑞华泰薄膜科技股份有限公司 一种性能优异的透明聚酰亚胺薄膜及其制备方法
CN115536525A (zh) * 2022-09-23 2022-12-30 南京知和医药科技有限公司 一种s-（+）-氟比洛芬盐及其制备方法、药物组合物和用途
CN115536525B (zh) * 2022-09-23 2024-02-23 南京知和医药科技有限公司 一种s-（+）-氟比洛芬盐及其制备方法、药物组合物和用途
CN115634291A (zh) * 2022-10-08 2023-01-24 南京诺令生物科技有限公司 一种具有缓解糖尿病足痛功效的制剂与制备方法和应用

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